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Tobacco Institute

Cigarette Smoking and Coronary Heart Disease

Date: 10 Jul 1973
Length: 657 pages
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Aviado, D.M. 1
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1. Aviado, D.M. Author
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    Univ of Pennsylvania School of Medicine

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iv B. C Blood Pressure and Peripheral Blood Flow-------------------------------------- Bibliography------------------------------------'--------------------------- Blood Li ids------------------------------------------------------------------ Zd~ 242 24G . D. p Bibliography---------------------------------------------------------------- Blood Coagulation------------------------------------------------------------- BibliographY-------------------------------------------------- `-------------- 248 250 251 X. ACUTE AND CHRONIC EFFECTS OF NICOTINE------------------------------------- 253 List No. 25. Nicotine onisolatedheart------------------------------------ List No. 26. Release of catecholamines from the heart------------------------- List No. 27. Release of catecholamines from adrenal medulla------------------- 255 257 260 List No. 28. Central nervous system effects of nicotine-------- =---------------- - 262 A. B. C Mode of Action on the Heart---------------------------------------------------- BibliograPhY---------------------------------------------------------------- Experimental CoronaryInsufficiency-------------------------------------------- Bibliography---------------------------------------------------------------- - - --- i l H i E 264 261 270 272 275 on-------------------------------------------- - --- xper menta ypertens . 27b D. . Bibliography---------------------------------------------------------------- -I:xperimental Atherosclerosis-------------------------------------------------- BibliograPhY---------------------------------------------------------------- 277 279 E. Experimental Hyperlipidemias------------------------------------------------ - 280 Bibliography---------------------------------------------------------------- 281 F. Experimental Thrombosis------------------------------------------------------ 282 Bibliography---------------------------------------------------------------- 284 .. . XL CIRCULATORY EFFECTS OF CARBON MONOXIDE-------------------------------- 286 A. Carboxyhemoglobin Blood Levels----------------------------------------------- 287 .~ . . Table XI-A. Carboxyhemoglobin levels in the blood of habitual smokers ---------- 290 . ~ .Bibliography---------------------------------------------------------------- 293 ~ B. Influence of Smoking on Alveolar Air and Blood Levels of Carboxyhemoglobin-------- 295 - Table XI-B. Acute effects of cigarette smoking on carboxyhemoglobin levels----- 297 BibliograPhY --------------------------------------------------------------- 298 - C. Coronary Circulation and Myocardium------------------------------------------ 300 ..~........ BibliograPhY---------------------------------------------------------------- 305 . D. Experimental Atherosclerosis-------------------------------------------------- 308 . BibliographY---------------------------------------------------------------- 311 E. Blood Cells and Plasma------------------------------------------------------- 315 . 23ibiiograpny---------'-----------------'-----.------------------------------- -i~ PART SIX; PUBLICATIONS AND RECOMMENDATIONS------------------------------------- 321 - XIL SECONDARY.PUBLICATIONS ON SMOKING AND HEART DISEASE ------------------ 322 XIII. PUBLICATIONS IN DEFENSE OF SMOKLYG-------------------------------------- 34; . XIV. COMMENTARY ON US PUBLIC HEALTH PUBLICATIONS------------------------- 347 XV. RECOMMENDATIONS TO THE COUNCIL FOR TOBACCO RESEARCH-------------- 489 PART SEVEN: AUTHOR INDEX-------`-------------------------------------------------- 490 T10302-0991
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Page fi occupational groups, and investigation of acute effects of cigarette smoke in animals and human subjects. T10302-0995
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iii PART FOUR: RISK FACTORS FOR CORONARY HEART DI.SEASE---------------------------- 114 VI. FDXED RISK FA CTORS----------------------------------------------------------- 115 List No. 13. Risk factors in coronary heart disease--------------- ------------- 116 List No. 14. Risk factors in coronary heart disease in the young adult------------ 118 . List No. 15. Stress and psychogenic factors in coronary heart disease-----------; 119 A. Age and the Prevalence of Coronary Heart Disease-------------------------------- 122 .. Table VI-A. Controlled retrospective studies of young male adults with coronary heartdisease------------------------------------------------------------ 123 Bibliography-------------------------------------------------------------.---- 124 B. Sex as a Risk Factor----------------------------------------------------------- 126 Table Vl-B. Controlled retrospective studies of female adults with coronary heart disease---------------------------------------------------------- ^------ 127 .. BibliograPhy------------------------- ---------------------------------------- 128 C. Genetic Factors--------------------------------------------------------------- 129 BibliograPhy-------------------------------------------------- =------------- 133 D. Psychogenic Factors------------------------------------------------------------ 134 _ Bibliography----------- ---------------------------- -------------------------- 136 VII. PREVENTABLE RISK FACTORS--------------------------------------------------- 138 ~ List No. 16. Prevention of coronary risk factors------------------------------- 139 List No. 17. Exercise in coronary heart disease--=---------------------------- 143 List No. 18. Diet in the causation and prevention of coronary heart disease-------- 145 Physical Activity and Exercise-------------------------------------------------- 148 . BibliograPhy----------------------------------------------------------------- -150 Obesity------------------------------------------------------------------------ 151 BibliograPhy---------------------------------------------------------------- 152 Diabetes Mellitus and Sucrose Intake----------------------------------------- --- 153 Bibliography----------------------------------------------------`----------- 155 Diet and Coronary Heart Disease---------------------------------------- ------- 157 Bibliography---------------------------------------------------------------- 159 Socioeconomic Factors -------------------------------------------------------- 160 Table VII-E: Role of socioeconomic and other risk factors in patients with ~ coronary heart disease: Part A. United States----------------------------- 162 ' Part B. Foreign Countries------------------------ 164 BibliograPhy---------------------------------------------------- ------'----- 17] . List No . 19. Investigation of preventable risk factors in foreign countries-------- 188 List No. 20. Ischemic changes of the electrocardiogram------------------------ 194 . List No. 21. Hypertension as a riskfactor------------------------------------ 195 _.List No. 22. Cholesterol and coronary heart disease--------------------------- 196 List No. 23. Thrombosis: induction and prevention---------------- ------------ 199 VIII. PREVENTABLE RISK FACTORS PROBABLY INFLUENCED BY SMOKING------------- 186 A.~ Electrocardiogram and Myocardial Status--------------------------------------- B. . tliollograPny---------------------------------------------------------------- Hypertension-------------------------------------------- ----- ---------------- C. Bibliography---------------------------------------------------------------- Hypercholesterolemia--------------------------------------------------------- . Table VITI-C. Role of cigarette smoking in subjects with hypercholesterolemia--- . BibliograPhy---------------------------------------------------------------- .D. Blood Coagulation------------------------------------------------------------- 201 Z.- 204 205 207 209 211 21a. Bibliography---------------------------------------------------------------- 218 E. . Availability of Oxygen and Associated Changes in the Blood------------------------ 219 . .'. BibliograPhy--------------------------------------------------------------- - 221 PART FIVE: CIGARETTE SMOKING NICOTINE AND CARBON MONOXIDE------------------- 222 IX. ACUTE CIRCULATORY EFFECTS OF SMOKING----------------------------------- 223 List No. 24. Cessation of cigarette smoking----------------------------------- 225 A. Cardiac Function------------------------------------------------------------- 22E Bibliography---------------------------------------------------------------- 235 T10302-0990
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CIGARETTE SMOKING AND CORONARY HEART DISEASE (Fourth in a Series of Reports Prepared for The Council for Tobacco Research) By DOMINGO M. AVIADO, M. D:- Profcssor of Pharmacology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19174 'IuN 10 , 1973 V T10302-0988
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Page 4 On the basis of examination of 2,259 articles (original, additional and secondary bibliographies) the author has made the following interpretations of the present state of knowledge relating to cigarette smoking and coronary heart diseaset I. Angina Pectoris. Angina can be initiated by smoking, and the . disease has been referred to as tobacco angina. The incidence is 6% of all cases of angina pectoris, and 1% of angina pectoris patients who are smokers. The majority (94%) of patients suffer from effort angina and in these smoking does not precipitate symptoms and signs of myocardial ischemia. II. Myocardial Infarction. Myocardial infarction is a more serious disease than angina pectoris. In retrospective studies, the incidence of nonsmokers among patients with myocardial infarction is 18%, whereas in the control group it is 33%. That myocardial infarction can occur in nonsmokers suggests the importance of risk factors other than cigarette smoking. Although smoking is prevalent in patients, it does not influence the prognosis. The duration of survival, the severity of infarction and the appearance of complications are not different for smokers and nonsmokers. III. Atherosclerosis. The clinical manifestations of atherosclerosis include coronary heart disease, stroke and intermittent claudication. Postmortem examination and retrospective and prospective studies indicate a prevalence of smokers among patients suffering from these diseases. However, a cause and effect relationship cannot be established because of other operative risk factors, such as hypertension and hypercholesterolemia. ,,,o..T10302-0994
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j. Angina Pectoris - 4 j.ist No. 1 WARREN J: Aema3ka pn a.ngina pectoris. N£n&llJ Med 266s 3-7, 1962. Wft1CF1T 11 li: >~xamining the individual in relation to hie environment. Pagc 13 Reprint A 19 $till N Y Acad Med 44: 346-365. 1968. . . . A 20 T1030 2-1 003
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Page 5 IV. Mortality and Morbidity Statistics in the United States. The most widely quoted reason for the belief that cigarette smoking causes coronary heart disease is the fact that the morbidity and mortality rates are higher for smokers than for nonsmokers. It is unfortunate that most prospective studies have pooled angina pectoris and myocardial infarction as a single dis'ease entity. When the two diseases are separated, there is no association between cigarette smoking and the incidence of angina pectoris. V. Informative Prospective Studies in Foreign Countries. By the selection of one occupation, i. e.1 British medical practice, it has been possible to define the relationship of smoking and mortality from coronary heart disease. The mortality ratio of smokers to nonsmokers is 1:23 instead of the higher ratios reported in surveys that include various occupational groups. In the Swedish twin registry, the association of coronary heart disease and smoking is attributed to a genetic predisposition. International comparisons of statistics indicate the importance of blood pressure and the level of cholesterol in the blood in influencing the incidence of coronary heart disease among smokers. VI. Fixed Risk Factors. The incidence of coronary heart disease is determined by age, sex, and genetic and psychogenic factors. The importance of these factors relative to cigarette smoking has not bam determined. VII. Preventable Risk Factors. Physical inactivity, obesity, diabetes mellitus, diet and socioeconomic factors can increase the predisposition of the individual to coronary heart disease. Although these .T10302-0995
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Page 2 PAR T ONE INTRODUCTION AND SUMMARY This is the fourth and last review that the author has prepared for the Council for tobacco Research. The major concern in this article is to examine the relationship between cigarette smoking and coronary disease. There is some overlapping with the three previous articles. Carbon monoxide, which was the subject of the first riview, is_again discussed because, it has recently been implicated in the causation of atherosclerosis. Nicotine, which was included in the review on passive smoking,''is-elaborated upon in the present article because its known pharmacologic effects can be potentially harmful to a patient with angina pectoris. The epidemiologic investigation relating to respiratory disease is again scrutinized, this time as it relates to the mortality of coronary heart disease,.particularly of myocardial infarction. There is one special feature introduced in this report, which is a page by page critique of the US Public Health publications on -"Smoking and Health. " The seven monographs appearing between 1964. and 1973 include a total . number of 753 references. These have been examined to determine the vi y i.vi uiisi Y iacai L uibcabe, as implied in the US Public Health publications. The author has also examined the literature on three disease entities included under the term coronary heart disease, namely, angina pectoris, myocardial infarction and coronary atherosclerosis. There are 1169 . „ e ~ T10302-0992
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Page 3 articles which report investigations on the effects of smoking as determined by mortality and morbidity statistics, antemortem and postmortem examination of patients, and experiments performed on healthy subjects and animals. A special effort has been made to separate the various forms _ of research. The sections appearing under Part Two contain information , relating to patients with angina pectoris, myocardial infarction or coronary atherosclerosis; the sections under Part Three are devoted entirely to mortality statistics; the sections under Part Four also contain epidemiologic studies, with emphasis on the differences in morbidity among smokers as compared with nonsmokers; and finally the sections under Part Five deal with the acute effects of smoking in humans and the acute and chronic effects of experimental exposure to cigarette smoke in animals. In each section there are Additional Bibliographic Lists of 761 articles which discuss coronary heart disease, epidemiologic investigation and cardiovascular pharmacology in general terms. It should be stated at the outset that the conclusions arrived at by the author are different from the statements which appear in the US Public Health publications. There is still no definitive evidence that smoking is the most important cause of coronary heart disease, although almost all review articles, editorials and miscellaneous papers accept the conclusions appearing in the US Public Health publications. The total number of secondary publications is 329 and they are listed under Part Six. T10302-0993
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Page 6 factors may be reduced or prevented, it has not been possible to define their 0 importance relative to cigarette smoking in causation of the disease. VIII. Preventable Risk Factors Probably Influenced by Smoking. During the evolution of the thesis that cigarette smoking causes coronary heart disease, the following risk factors were claimed to be exaggerated by smoking: electrocardiographic signs of ischemia, hypertension, hypercholesterolemia, hypercoagulability of the blood and reduced availability of oxygen. A comparison between smokers and nonsmokers does not afford a consistent proof that smoking enhances these risk factors. Each of the five factors has a set of independent causes which are more definite than cigarette smoking. IX. Acute Circulatory Effects of Smokin~. To prove that smoking causes coronary heart disease, it is necessary to be able to reproduce the disease in the laboratory. So far, this has not been possible in animals whose condition is documented by pathological examination and studies of heart function. Acute exposure has been performed largely on animals and humans without heart disease, so that it is difficult to relate the results to the disease state. X. Acute and Chronic Effects of Nicotine. The experimental use of nicotine has failed to produce coronary heart disease in animals that are similar in form to humans. The pharmacological action of nicotine can be attributed to stimulation of autonomic ganglia and the release of catecholamines. However, neither mode of action individually has,been demonstrated to produce T10302-0996
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I. Angina Pectoris - 9 Page 18 Buinewitsch (1940) and Bryant and Wood (1947). The nicotine produces ~ spasm by vascular changes (Blanc, 1925), by stimulation of the cardiac nerves (Maine, 1902; Brooks, 1915) or by reflex vasospasm (Keller, 1922). Oram and Sowton (1962, 1963) induced the syndrome in patients with tobacco angina by intravenous injection of nicotine. Nicotine induces angina not by vasospasm but by releasing catecholamines, which increases the demand for oxygen by the heart. Arai et al. (1951) reported a case of tobacco angina in Which the-use-•of vaaodilator drugs resulted in the nonoccurrence of angina. These drugs antagonized the effects of nicotine on the heart. c. Allergy to tobacco. Sensitization to tobacco was proposed by Brooks (1915) and Duerfeldt (1945). The possibility that the heart is the target organ for allergy which is manifested by angina is reviewed elsewhere, in the section dealing with tobacco allergy (Section I11-B). T10 30 2-1 005
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I. Angina Pectoris - 2 Page 11 coronary heart disease (Section VIII), and the influence on the heart of cigarette smoking (Section IX), nicotine (Section X) and carbon monoxide (Section XI). Consideration of all aspects of angina pectoris indicates that. cigarette smoking is one of many risk"factors and that it can be implicated only in the rare cases of tobacco angina.discussed in this section. There are two bibliographic lists which discuss the general aspects of angina pectoris and the coronary circulation. The articles contained in these lists do not relate directly to the investigation of cigarette smoking but provide background information on the disease under consideration. List No. 1. Angina pectoris: clinical aspects. List No. 2. Coronary circulation: clinical evaluation. T10 30 2-1 001
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1. Angina Pectoris - 3 Additional Bibliographic Li,t No. 1 ANGINA PECTORIS: CLINICAL ASPECTS Page 12 . . . ' . Reprint SRIGDEN WL: Angina pectoris. Practitioner 180: 167-171, 1958. A 1 CEDERL6F R, FRIBERG L and LUNDMAN T: Rokning oeh angina pectoris -- en replik. LakSrtidningen 65: 4516-4517, 1968. A 2 CHARMS B L: Pathophysiology of cardiac symptoms. In: Cardiovascular . . Disorders. F. G. Davis Co., Philadelphia, pp. 160-176, 1968. ' A 3 EILERTSEN E and SULHEIM 0: Bergenstudien. L3kartidningen 67: 145-149, 1970. A 4 FOWLER N 0: Clinical diagnosis. Circulation 46: 1079-1097, 1972. A 5 GOLDSTEIN R E and EPSTEIN S E: Medical management of patients with angina pectoris. Prog Cardiovasc Dis 14: 360-398, 1972. A 6 GROSSMAN L A: Intractable angina pectoris -- treatment with radioiodine. - - J Tenn Med Assoc 60: 35-40, 1967. A 7 JOHANSSON B W and TORP A: Surgical treatment of angina pectoris. III. Cardio- logical aspects. Scand J Thor Cardiovasc Surg 6: 73-74, 1972. A 8 ICLEE P: Begrenzung oder Erweiterung des Begriffes Angina pectoris? Med Klin 57: 766-769, 1962. A 9 LAFRENZ M: Ekg-Ver`dnderungen und begunstigende Faktoren des Angina-pectoris- Syndroms. Z schr Inn Med Jahrg 22: 773-780, 1967. A 10 LAMBERT A: Discussions. Bull N Y Acad Med 11: 466-469, 1935. A 11 . LOGUE B: Treatment of intractable angina pectoris. Circulation 22: 1151- . 1155, 1960. A 12 LOGUE B and ROBINSON P H: Medical management of angina pectoris. Circulation 46: 1132-1145, 1972. - A 13 MACGREGOR A G, PETRIE J C and WOOD R A: Angina pectoris -- I. -. Lx ` LL J •. lUI- ..VU, {~, {. •• {{ PASQUAZZI M: La terapia dell'angina pectoris. Policlinico 75: 313=325, 1968. A 15 SMITH A L Sr and SMITH A L Jr: Multiple approach to the treatment of angina pectoris. Med Times 90:316-325, 1962. A 16 SPECKMANN K, KIENSCH H, MAETZEL F K and MAYER J D: Untersuchungen zur Fruhdiagnose der Angina pectoris. Dtsch Med Wochenschr 92: 1493- 1497. 1967. ~ THISEUS S and TIBBLING L: Angina pectoris eller angina cardiae7 A 17 I;akartidninQen 67: 168-169, 1970. .. . , A 18 T10 30 2-1 00 2
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1. Angina Pectoris - 15 Page 24 three coronary arteries. There was no correlation between the number of cigarettes smoked and the extent of disease, _,c in any of the arteries. Even the total coronary arterial score did not bear any significan.t relation to the tobacco consumption. There is, therefore, no indication by arteriography that cigarette smoking produces obstructive lesions in patients with heart disease. The significance of coronary arteriograms in the study of coronary heart disease is the subject of a recent Editorial (1971). 3. Cardiovascular effects of cigarette smokinQ. This topic is discussed in Section IX. It suffices to mention here that there is no difference between responses of patients with angina pectoris and those of normal subjects. Navarro et al. (1964) compared the effect of smoking 1 or 2 cigarettes on heart rate, arterial pressure, blood glucose, and serum cholesterol, /urinary excretion of catecholamines in 7 patients with angina and in 7 healthy persons, all habitual smokers. Except for the excretion of catecholamines, no detectable differences were found between the two groups. Pentecost and Shillingford (1964a„ 1964b) and Shillingford (1965) noted that the mean heart rate and blood pressure of patients with angina increased to a somewhat lesser extent than was the case with normal subjects. There is therefore no reason to suggest that the response of anginal patients is different from that of healthy subjects. T10 30 2-1 01 4
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I. Angina Pectoris - 7 Page 16 2. Recent cases. The literature on tobacco angina up to 1944 has been reviewed by Pickering and Sanderson. The most recent review was completed by von Ahn (1960), who differentiated two types of tobacco angina: pain not associated with smoking and that directly caused by smoking. Only the latter type is regarded as tobacco angina by other authors. Krysa (1966) has predicted an increasing incidence corresponding to the number of smokers over the past 20 years. There has been no attempt to identify such patients in surveys of cases of angina pectoris. Oram and Sowton (1963) reviewed the literature on tobacco angina and collected 14 previously reported cases in which electrocardiograms had been taken and compared them with 3 of their own cases. These 3 patients were selected.from 309 smokers suffering from angina, indicating an incidence of 1%. From a study of 17 patients with tobacco angina, Oram and Sowton could clearly differentiate five syndromes, which were as follows c a. Angina pectoris with the electrocardiogram at rest usually abnormal. Smoking and exercise induce both pain and electrocardiographic changes of coronary insufficiency within a few seconds. The syndrome was reported for the first time by Huchard (1899). b. Angina pectoris with pain exacerbated during period of smoking. However, smoking does not induce immediate pain or electrocardiographic change (Albutt, 1915). c. Angina pectoris with no exacerbation of pain while smoking at rest. TI0302-1006
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I. Angina Pectoris - 5 Page 14 ~ Additional Bibiiographic List No. 2 CORONARY CIRCULATION: CLINICAL EVALUATION Reprint BING R J, BENNISH A, BLUEMCHEN 0, COHEN A, GALLAGHER J P and ZALESKI E J: The determination of coronary flow equivalent with , - coincidence counting technic. Circulation 29; 833-846, 1964. A 21 BRACHFELD N, BOZER J and GORLIN R: Action of nitroglycerin on the - . coronary circulation in normal and in mild cardiac subjects. Circulation 19: 697-704, 1959. . . . A 22 BURCH G E and DePASQUALE: Hematocrit, viscosity and coronary blood flow. ` Dis Chest 48; 225-23Z, 1965. A 23 • COHEN A, LUEBS E, ZALESKI E J and BING R J: A new diagnostic test for - coronary artery disease, using a concidence counting system. Minn Med 49: 17-21, 1966. A 24 COHEN A, ZALESKI E J, LUEBS E and BING R J: The use of positron emitter in the determination of coronary blood flow in man. J Nucl Med 6: 651-666, 1965. A 25 DWYER E M, WIENER L and COX J W: Angina pectoris in patients with normal . and abnormal coronary arteriograms. Am J Cardiol 23: 639-646, 1969. . A 26 GOLDSCHLAGER N F, CORSINI G, BOETTCHER D, LEB G, DERNTL F . and BING R J: The measurement of total and nutritional coronary blood - flow. JAMA 208: 1474, 1969. . ` . . A 27 LUEBS E, COHEN A, ZALESKI E J and BING R J: Effect of nitroglycerin, . intensain, isoptin and papaverine on coronary blood flow in man. .. Am J Cardiol 17: 535-541, 1966. A 28 MACK R E, NOLTING D D, HOGANCAMP C E and BING R J: Myocardial -extraction of .^.b86 in ihe rabbit. Am J Physiol 197: 1175-1177, 1959. A 29 NEILL W A: Myocardial hypoxia and anaerobic metabolism in coronary heart - disease. Am J Cardiol 22: 507-515,1968. - A.30 ROWE G G: Effects of drugs on the coronary circulation of man. Clin Pharmacol . . Ther 7: 547-557, 1966. . , . . . . . ~ . . A 31 ROWE G G, THOMSEN J H, STENLUND R R,. McKENNA D H, SIALER SS and CORLISS R J: A study of hemodynamics and coronary blood flow in man with coronary artery disease.Circulation' 39: 139-.148, 1969. A 32 T10 30 2-1 0 04
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I. Angina Pectoris - 14 Page 23 electrocardiographic changes appearing after smoking and exercise. The ~ incidence of chest pain precipitated by smoking was 6% (ZO out of 309 cases) in anginal patients who were smokers, and the frequency of development of electrocardiographic signs of coronary insufficiency in patients during exercise and smoking was 1% (3 out of 309 cases). 2. Coronary arteriogram. The effect on the coronary arteries of the smoking of cigarettes has been investigated in man by arteriography. Likoff et al. (1964) tested the smoking of 2 cigarettes in each of 10 patients with coronary heart disease. No effect on the size of the vessels was observed by cineradiography. 'rhe results of coronary arteriography in patients with angina pectoris did not show a relationship consistent with the amont of cigarette smoking. Newton et al. (1970) examined 80 patients with angina pectoris and made the following observations: 43 normal arteriograms: 29 subjects were smokers. 46 abnormal arteriograms: 40 subjects were smokers. They concluded that smoking was related to the anatomical findings at coronary arteriography. Banks et al. (1971) examined 107 patients with ischemic heart disease (66%) and nonis.chennicheart disease (28%), most of the latter with rheumatic heart disease: 68 cases of ischemic heart disease: 39 subjects were smokers. 39 cases of nonischemic heart disease: 14 subjects were smokers. The arteriogram was scored according to the degree of obstruction of all TI0302-1013
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Page 7 coronary insufficiency, experimental hypertension, atherosclerosis and thrombosis. Hyperlipidernia can be induced by catecholamines or nicotine but these same agents do not produce atherosclerosis unless the animal has also been fed a diet high in cholesterol. XI. Circulatory Effects of Carbon Monoxide. The mean carboxyhemoglobin content of the blood of smokers is 3.76% saturation, which is elevated to a mean level of 5. 26 °Je during smoking. About half of the former value is due to carbon monoxide present in the atmospheric air. Acute exposure to carbon monoxide, resulting in 10% saturation, does not influence heart function. Chronic exposure of animals to carbon monoxide results in atherosclerosis, but there are no functional studies to support the contention that in these cases the heart is ischemic. XII to XIV. Secondary Publications. These sections include the page by page critique of the US Public Health publications on "Smoking and Health. " The conclusions contained in them have been cited in numerous articles. In only a few of these has the validity of the conclusions been questioned. XV. Recommendations. The author has listed the nature of future investigations relating to coronary heart disease. The two most important areas are: (1) identification of patients with tobacco angina, as distinct from effort angina in prospective studies and (2) measurement of cardiac function in animals chronically exposed to cigarette smoke, nicotine or carbon monoxide. There is so much investigative work already completed that it is needless to repeat or expand twin registries, surveys of selected ....,.,.,,.,.,TI0302-0997
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[. Angina Pectoris - 16 Page 25 BIBLIOGRAPHY 1. ANGINA PECTORIS B. Effost Angina ~ Reprint 9 ARONOW W S, KAPLAN M A and JACOB D: Tobacco: A precipating factor . in angina pectoris. Ann Intern Med 69: 529-536, 1968. . . 39 . ARONOW W S and SWANSON A J: The effect of low-nicotine cigarettes on angina pectoris. Ann Intern Med 71: 599-601, 1969. . 40 BANKS D C, RAFTERY E B and ORAM S: Clinical significance of the coronary arteriogram. Br Heart J 33: 863-870, 1971. 41 EDITORIAL: The coronary arteriogram. Lancet 2: 1297-1298, 1971. 42 LIKOFF W, KASPARIAN H and LEHMAN J S: The effect of ethyl alcohol and inhaled cigarettee smoke on the caliber of atheroscierotic coronary arteries as visualized by selective arteriography. Am J Cardiol 13: 117, 1964. .- 43 NAVARRO V R, deSOLDATI L and CAMMAROTA H: Effecto del tabaco sobre - - el aparato cardiovascular. Rev Argent Cardiol 31: 37-43, 1964. - 44 NEWTON R M, SEALE D L, O'BRIEN W M and McGUIRE L B: Clinical . correlations with coronary arteriography. Va Med Mon 97: 688-692, 1970. 45 ORAM S and SOWTON E: Tobacco angina. Q J Med 32: 115-143, 1963. 46 PENTECOST B and SHILLINGFORD J: The acute effects of smoking on myocardial _ performance in patients with coronary arterial disease. Br Heart J 26: 138, 1964a. . . . 47 PENTECOST B and SHILLINGFORD J: The acute effects of smoking on myocardial .. . performance in patients with coronary arterial disease. Br Heart J 26: 422-429, 1964b. . . . ., _ 48 SHILLBQGFORD J P: The acute effects of smoking on the performance of the heart innormal sub,7ects ana patients wiw Coronary ueart uiseas.:. i.: TuLacw Alkaloids and Related Compounds, 1965, pp 263-272. . 49 T10 30 2-1 01 5
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1. Angina Pectoris. - 1 Page 10 I. ANGINA PECTORIS NICOTINE(%1 fARSON NONOXIDE(XII I LNL RTION---s EiIONT ANGINA I ANDINa YECTDNIS . 'A.' Tobacco Angina---- 15 I B. Effort Atgiaa------ 21 Angina pectoris is discussed in this section only in the following terms: the role of cigarette smoking in precipitating or provoking the anginal attack. In this regard, there are two forms of angina, namely, tobacco angina, in which pain and electrocardiographic signs of coronary insufficiency appear during smoking,and effort angina,in which exertion triggers the appearance of pain accompanied by electrocardiographic signs. The former is rare. In the more common form of angina, i. e. , effort angina, there is no clear-cut evidence that cigarette smoking, together with exercise, precipitates the attack. There are other considerations relating to the role of cigarette smoking in angina pectoris which are discussed in other sections, namely: pathogenesis of atherosclerosis (Section III), incidence of smokers in deaths attributed to coronary heart disease (Section IV) and in morbidity statistics (Section V), interplay of smoking with other risk factors causing T10 30 2-1 00 0
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1. Angina Pectoris - 8 Page 17 However, pain may reappear if patient smokes immediately after exercise- induced pain has disappeared (Pickering and Sanderson, 1944). Exercise immediately after smoking induces greater pain and more severe electrocardio- graphic signs of coronary insufficiency than the same exercise prior to smoking (Moschini-Antinori and Solinas, 1951). d. No effort angina with electrocardiogram at rest and after exercise normal. Only smoking induces within a few seconds both anginal pain and electrocardiographic changes of coronary insufficiency. This syndrome was referred to as pure tobacco angina by Bryant and Wood (1947). e. No effort angina but persistent dull precordial discomfort, ectopic beats, paroxysmal tachycardia and dizziness. While smoking the usual amount, there is persistent decreased amplitude of the T wave without depression of the S-T segment. This syndrome is tobacco heart, reported by Russek et al. (1955). 3. Mechanism of tobacco angina. Three theories have been proposed. They are not mutually exclusive and there is a considerable amount of overlapping. a. Underlying predisposition to angina. Pardee (1921) conceived that tobacco produced angina by acting upon an already formed basis of disease, which was not sufficiently marked to produce symptoms by itself alone. b. Nicotine-induced angina. The absorption of nicotine sufficient to cause coronary spasm has been suggested by Pawinski (1914), T10302-1007
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j. Angina Pectoris - 10 1W BIBLIOGRAPHY I. ANGINA PECTORIS A. Tobacco An¢ina Page 19 Reprint ALBUTT C: Diseases of the arteries,, including Angina Pectoris. _ Vol. 2, p. 245, 1915. 1 ARAI H 5, PORDY L, CHESKY K and MASTER A M: Pharmacological study of a case of tobacco angina. Exp Med Surg 9: 248-259, 1951. 2 BEAU M: De la fumle de tabac consideree comme une cause de l'angine de poitrine. C R Acad Sci 54: 1179-1182, 1862. 3 BEAU M: On tobacco as a cause of Angina Pectoris. Am J Med Sci - 45: 205-207, 1863. 4 BLANC H: Death from tobacco. Int Clin 1: 209-217, 1925. 5 BROOKS H: The tobacco heart. N. Y. Med J 101: 830-837, 1915. 6 BROWN B: Neurasthenia, nervousness and the nervous temperament. Va Med Mon 1: 4-9, 1896. . 7 BRUCE J M: Diseases and disorders of the heart and arteries in middle - and advanced life. Lancet 1: 844-848, 1901. 8 BRYANT J M and WOOD J E Jr: Tobacco angina. An electrocardiographic study. Am Heart J 34: 20-34, 1947. . 9 BUINEWITSCH D: Ueber die Coronarinsuffizienz Angina pectoris. ' Infarktus myocardii. Wein Klin Wochenschr 53: 851-854, 1940. 10 BUREAU M: Etude clirii que des accidents cardiaques dfls a Vintoxication - tabagique,chronique, et en particulier des accidents tardifs. Gaz Med Nantes 25: 421-429, 1907. - 11 CORNWALL E E: The tobacco heart. Med Times 62: 209-211, 1934. 12 DUERFELDT T H: Chest pain and heart disease. Northwest Med 44: 187-189, 1945. ., . . ., 13 FURBINGER: Zur Wurdigung der Gefahren des Tabakrauchens. , Munch Med Wschr 73: 1956-1957, 1926. . . 14 GELINEAU E: De l'angine de poitrine e'piddmique. Gaz Hop 114, 117, 120: 454, 466, 467, 478, 479, 1862. - 15 GILFILLAN J S: Some remarks on the effects of tobacco smoking on the . . cardio-vascular system. St Paul Med J 14: 338-340, 1912. 16 - GOLDSTON H: The tobacco heart. Va Med Mon 64: 319-325, 1937. 17 HEBERDEN W: Commentaries on the history and cure of diseases. N Y Acad Med Series 18, 1802. I8 HUCHARD H: Traite clinique des maladies du coeur et de 1'aorte. 3rd Edition, Paris, 1899. 19 T10302-1009
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[, Angina Pectoris - 11 Page 20 Reprint KELLER K: Die Raucherkrankheiten der Neurastheniker. Med Klin 18: 1149-1152, 1922. 20 KOHN H: Die epidemische Angina pectoris aufder "Embuscade". . Deut med Wschr 52: 447-449, 1926. 21 KRYSA I: Tabakova srdec%eni angine. Vnitrni Leh 12: 492-496, 1966 22 MAINE F D: Tobacco heart; what is it and what its treatment? Med News 81; 150-151, 1902. 23 MITCHELL E W: Tobacco and the heart. Lancet-Clinic 99: 702-704, 1908. 24 -MOSCHINI-ANTINORI E and SOLINAS P: Un caso di angina da tabacco (considerazioni cliniche ed etiopatologiche). Fol Cardiol 10: 261-272, 1951. - 25 MOSCHCOWITZ E: Tobacco angina pectoris. JAMA 90: 733-737, 1928. 26 -ORAM S and SOWTON E: Tobacco angina. Q J Med 31: 513-514, 1962. -27 ORAM S and SOWTON E:Tobacco.angina. Q J Med 32: 115-143, 1963. 28 --DRTNER N: -Zirkulationskrankheiten. 7ahreshurse Arztl Fortbild 2: -3-.36, 1911. 29 PARDEE H E B: Disease of the coronary arteries. Med Clin North Am -4: 1491-1507,. 1921,_- _ . -'_=---- - '30 :PAWINSKI 3: Ueber den Einfluss unmassigen Rauchens (des-Nikotins) --- auf die Gefasse und das Herz. ZClin Med 80: 284-306, 1914. 31 ---PICKERING G W and SANDERSON P H: Angina p'ectoris and tobacco. - Clin Sci 5: 275-288, 1944. _ ' -- - -- - -- 32 -ROMBERG: Ueber tabakwirkung"auf die Kreislauiorgane. Munch Med Wschr 72: 1055-1056, 1925. 33 __ _ RUSSEK H I, ZOHMAN B L and DORSET V J: Effects of tobacco and . whiskey on the cardiovascular system. JAMA 157: 563-568; 1955. 34 SMITH A L: The effect of tobacco on the heart as recorded by cardiological instruments. Med World 61: 297-309, 1943. --35 ~ STEVENS A A: Angina pectoris and allied conditions. Med Clin North Am . _1;293-308, 1917. . - 36 -VON AHN B: Tobacco smoking, theelectrocardiogram, and angina pectoris. Ann N Y Acad Sci 90: 190- 198, 1960. 37 WILSON F N and JOHNSTON F D: The occurrence in angina pectoris of electrocardiographic changess similarin magnitude and in kind to those produced by myocardial infarction. . Trans Assoc Am Physicians 54: 210-224, 1939. 38 T10 30 2-1 01 0
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Page 9 I. Angina Pectoris II. Myocardial Infarction III. Atherosclerosis The term coronary heart disease includes three disease entities. Angina pectoris and myocardial infarction are . diseases which can be diagnosed clinically. Atherosclerosis denotes the pathological lesion which is manifested clinically as angina pectoris, myocardial infarction, thromboangiitis obliterans and stroke. The observations on patients manifesting coronary heart disease in general, and angina pectoris, myocardial infarction and atherosclerosis in particular, are discussed in Sections 1, II_and IlI. The selection of the literature was guided primarily to determine the extent of the effect of cigarette smoking in patients. This was' readily found in articles summarizing patients investigated clinically or postmortem. The search of the literature was extended to determine the influence of smoking on the prognosis. The information was limited only to myocardial iiuarction and was not obtainable for the other diseases. The role of cigarette smoking in the causation of these diseases could not be determined. Patients suffering from the said diseases were also exposed to other risk factors, so that it was not possible to identify the contribution of cigarette smoking exclusively. ~~~~r~.te, ",v"T10302-0999
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11. Myocardial Infarction - 3 List No. 3 Page 28 ' ' Reprint . OXMAN H A, CONNOLLY D C, NOBREGA F T, ELVEBACK L R, TITUS J L and KURLAND L T: Factors influencing the subsequent prognosis of patients surviving their first myocardial infarction. Circulation 46 (Suppl 2): 200, 1972. -A 50 REID D D: The design and conduct of clinical trials in myocardial infarction. Circulation 39, 40 (Suppl 5): 91-98, 1969. A 51 ROSENKRANZ K A: Silikose und herzinfarkt. In: XV6me Congrhs International de Mddecine du travail. 4: 657-668, 1966. A 52 ROSENKRANZ K A: Auswirkungen chronischer Lungenkrankheiten auf Entstehung . und Verlauf von Herzinfarktcn. Med Klin 62: 127-131, 1967. A 53 RUSSO G: L'inattivita fisica quale fattore di rischio e di letalita nell'infarto del miocardio., Clin Europ 7: 808-827, 1968. _ _ A 54 SALA G: Considerazioni cliniche su 300 casi di infarto miocardico. Minerva Med 54: 3688-3692. 1963. A 55 SCHIMMLER W and NEFF C: Rauchgewohnheiten und Herzinfarkt. Allgemeine Therapeutik 8: 325-330, 1968. A 56 SINGH I, KHANNA P K, SRIVASTAVA M C and HOON R S: Extent of possible ,.. rehabilitation of service personnel with ischaemic heart disease. Br Heart J 32: 665-670, 1970. . A 5? SPECTOR F and SPAIN D M: The pathology of sudden death and the ability to ' . predict its occurrence. Circulation 46 (Suppl 2): 225, I972. , A 58 TEUSCHER G: Die entwicklung der Herzinfarkte in einem landlichen Kreis. . 1565-1567. A 59 WARREN J V: Acute myocardial infarction. Can deaths be reduced and, if so, how? Postgrad Med 38: 101-104, 1965. . A 60 WEISSBACH L. SCHOPEN R-D and LANGE 0 K: Der jugendliche Herzinfarkt. Xtiologie und Kasuistik anhand von 5 Beobachtungen. Internist Prax , 10: 655-659, 1970. A 61 WOLF S: Psychosocial forces in myocardial infarction and sudden death. , . . Circulation 39, 40 (Suppl 4): 74-81, 1969. .. A 62 T10 30 2-1 01 8
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I. Angina Pectoris - 13 Page 22 were asked whether, in their opinion, smoking had any effect on their chest pain. The results were as follows: 534 replies: 58 had died; 167 were nonsmokers and 309 smokers. 309 smokers: 20 experienced angina pectoris shortly after lighting a cigarette. tobacco 3 with/angina: confirmed by electrocardiogram that cigarette smoking causes signs of coronary insufficiency. Incidence of tobacco angina is 1% for anginal patients who smoke and b°je for all anginal patients comprising smokers and nonsmokers. The ZO patients who considered that their chest pain was precipitated or aggravated by smoking were reexamined clinically and in each case electrocardiograms were taken, as follows: A resting 12-lead record was first made. Either after the patient had smoked until pain was induced, or after three cigarettes had been smoked consecutively, the electrocardiogram was repeated. A maximum tolerance exercise test was then performed, and at its conclusion a third record was taken. The patient was at once asked to smuke again, aud a further record made. After a rest of about 45 minutes a second maximum tolerance electrocardiogram was taken. Electrocardiograms were performed in this manner so as not to miss any n£ thns~ «nre natinnts in whnm smnkino will cause a recurrence of chest pain, recently induced by exercise, only when it has just worn off, and also patients in whom, immediately after smoking, pain and electrocardiographic changes on exertion are more severe. By this manner of investigation, only 3 patients showed T10 30 2-1 01 2
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t. Angina Pectoris - 12 Page 21 I-B. Effort AnQina There is an impression among some cardiologists that many coronary patients develop angina on less provocation from exertion after smoking cigarettes. Aronow et al. (1968) selected 10 patients with classical angina pectoris due to coronary artery disease, who performed on a bicycle ergometer until they developed the first manifestation of angina pectoris. All subjects developed angina sooner if they smoked before exercising. The average shortening of the exercise period before angina developed in the smoking state as compared with the nonsmoking state was 24% and the range was 8 to 35 %. With the smoking of low-nicotine filter cigarettes, the exercise period before angina developed was shortened by an average of 14% after smoking (Aronow and Swanson, 1969). The above reports have been interpreted to apply to a majority of anginal patients. It should be recalled that the investigators did not examine more than 10 patients. '1 here is information reiating to frequency as well as other facts indicating that cigarette smoking does not provoke effort angina and does not produce coronary vasospasm in such patients. 1. L....;A,. ..f ~..}.~.-.... 77-nH..rv far*n.in annina In the preceding section devoted to tobacco angina, the review article of Oramand Sowton (1963) was cited as the most recent compilation of reports of cases of tobacco angina. These cardiologists sent a questionnaire to 721 patients, all of whom had had undoubted angina pectoris. The patients T10 30 2-1 011
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II. Myocardial Infarcation - 1 Page 26 II. MYOCARDIAL INFARCTION ~~ CIGAVETTE RISNP4CfM Su0A1xG TNROU50515 CORONARY HtTER1AE OISEASE .nr VROGNOSIS - II YYOCAADIAL INfANCT10N ~ A. Controlled Retrospectivr B. Studiee------------------ 33 Suddeo-Dcuth------------- 36 C. Prognosis--------------- 39 D. Complications----------- 43 Myocardial infarction is a more serious disease than angina pectoris. The association with cigarette smoking is less evident with acute myocardial infarction than with angina pectoris: In this section, the relationship of cigarette smoking to the occurrence of acute myocardial infarction is discussed. It is difficult to identify a cause and effect relation because of the concurrence of other risk factors which are discussed in the remainder of this report. The role of cigarette smoking in initiating the acute infarction and in the prognosis of the patient is examined in this section. The articles on general aspects of myocardial infarction are contained in the following bibliographic lists: List No. 3. Myocardial infarction: clinical aspects and prognosis. List No. 4. Myocardial infarction: immediate treatment. List No. 5. Myocardial infarction: long-term treatment. T10 30 2-1 01 6
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II. Myocardial Infarction - 5 List No. 4 Page 30 Reprint HELLERSTEIN H K and FORD A B: Comprehensive care of the coronary patient. Optimal (intensive) care, recovery, and reconditioning -- an opportunity for the physician. In: Symposium on coronary heart disease. Edited by H. L. Blumgart. The American Heart Association, Inc., New York, 1968. A 78 HERSHBERG P E: First aid therapy: a new concept in the treatment of myocardial infarction. Med Times 96: 575-591, 1968. A 79 HERSHBERG P E and ALEXANDER S: Prevention and treatment of sudden death. Med Clin North Am 56: 625-631, 1972. . . A 80 KIDNER P: Recovering from a heart attack. Health 6: 24-28, 1969. A 81 LIKOFF W: Management of coronary atherosclerosis and its complications. . In: Cardiovascular Disorders. F. G. Davis Co., Philadelphia, pp 689-704, . 1968. A 82 MARCUS A: Saving human hearts: the scope broadens. World Health 16-23, 1968. A 83 MASTER A M, WEISER F M and RABIN R: The emergency treatment of the complications of acute coronary artery occlusion. Dis Chest 42: 457-473, 1962. A 84 PAULO:: The management-ofthe patieint with myocardial infarction. Med Sci 14: , 3.8-.43, 1963. . . . - -_ , A 85 POLLOCK B E: The early management of myocardial infarction. JAMA 161: 404-409, 1956. A 86 RISEMAN J E F: Management after the acute coronary attack. Vase Dis . . ._, 3: 315-319, 1966. A 87 RNIER J L: Lc traitement de 1'infar ctus du myocarde. Thdrapeutique . d'urgence et apres la phase aigue.Praxis 55: 492-495, 1966. A 88 RUSSEK- H I: Drug therapy in coronary disease. Curr Med Digest .. 34: 685-701, 1967. A 89 RUSSEK H E: 'Progress' in the treatment and preventiorn of coronary heart diseases. Am Fam Physician 4: 68-74, 1971. A 90 SHLESER I H: Management of chronic arteriosclerotic heart disease with failure - and/or angina. Appl Ther 7: 307-313, 1965. A 91 SODI-PALLARES D, DE MICHELI A, MEDRANO G, FISHLEDER B, BISTENI A, FRIEDLAND C and TESTELLI M: Effets sur 1'electrocardiogramme de la solution glucose-insuline-potassium au cours de 1'insuffisance coronarienne aigue et chronique. Malattie Cardiovascolari 3: 41-79, 1962. . A 92 VON HOLST H E: Rokning och koronarsjukdom (1): Introduktion. Lhkartidningen 67: 138-139, 1970. A 93 . WRIGHT I 5: Panel discussion on the clinical management of myocardial infarction. J Am Geriatr Soc 5: 879-903, 1957. A 94 i T10302-1020
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11. Myocardial Xn.farction - 7 List No. 5 Page 32 Reprint WILLIAMS B and WHITE P D: Rehabilitation of the cardiac patient. Am 7 Cardiol 7: 317-319, 1961. A 115 WOLFERTH C C: The treatment of coronary disease. Bull N Y Acad Med - 21: 185-ZO1, 1945. A 116 T10 30 2-1 022
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II. Myocardial Infarction - 9 Page 34 'Table II-A. Controlled retrospective studies of patients with acute myocardial infarction Country Investigator United States Blumer (1934) McCormlEk (1952) Berry (1960) Finland Kasanen and Forsstrom (1960) France Schwartz et al. (1960) Germany Schimmler and Neff (1966) Japan Hyams et al. (1967) Lebanon Abou-Daoud (1968) Switzerland Villioer and Hevden-Stuckv (1966) Acute Myocardial Infarction `Control No. Smokers Nonsmokers Nonsmokers 150 67 34 34 151 94 6 34 60 98 2 44 100 84 16 40 612 86 14 14 550 81 19 28 79 90 10 21 91 66 34 43 100 75 25 41 _ _ Mean 18% 33% T10 30 2-1 0 24
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[I. Myocardial Infarction - 13 Page 38 131B _LIOGRA PHY II. MYOCARDIAL INFARCTION 13. Sudden Death Reprint PARAS CHAVERO E, MERCADO CONTRERAS E and QUINTERO NOVELLA A: Tabaquismo cardiopatia coronaria. Su accion en la evolucion a largo plazo en el paciente que has padecido un infarto del miocardio. Arch Inst Cardiol Mex 40: 128-134, 1970. 59 PARAS CHAVERO E, MERCADO E and QUINTERO A: Simposio sobre problemas medicos orginados por el tabaquismo. II. Alteraciones cardiovasculares. Neumol Cir Torax Mex 32: 15-18, 1971. . 60 ~ PORSTEINSSON S B, HARDASON P and SAMUELSSON S: 151 sjuklingur med kransaedastiflu fi lyflaeknisdeild Landspitalans 1966-1968. Laeknabladid 57: 255-275, 1971. 61 SPAIN D M: Sudden death from coronary heart disease: survival time, frequency ' of thrombi, and cigarette smoking. Am J Cardiol 25: 129, 1970. 62 SPAIN D M and BRADESS V A: Sudden death from coronary heart disease. Survival time, frequency of thrombi, and cigarette smoking. Chest 58: 107-110, 1970. 63 SPAIN D M, BRADESS V A, MATERO A and TARTER R: Sudden death due to coronary atherosclerotic heart disease. Age, smoking habits and recent . thrombi. JAMA 207: 1347-1349, 1969. - T10 30 2-1 028
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,T. Myocaralai inrarcrton - o Additional Bibliographic List No. 5 MYOCARDIAL INFARCTION: LONG-TERM TREATMENT ANFOSSI F, ROSSI P L and SATTA G: Sulla riabilitazione di soggetti con pregresso infarto miocardico. Osservazioni personali e considerazioni. Ann Sanita Publica 28: 147-163, 1967. Reprint A 95. BRITISH~BROADCASTING COMPANY: Manageme of coronary artery disease. Br Med J 1: 37-38, 1969. _ . A 96 BURCH G E and DePASQUALE N P: Potentials and limitations of patients after myocardial infarction. Am Heart J 72: 830-837, 1966. . A 97 CUTTS F B: The management of coronary artery disease. R I Med J 48: 668-672, 1965. . A 98 DE LA CHAPELLE C E and CONNOR C A R: Treatment of patients after recovery . from myocardial infarction. Mod Concepts Cardiovasc Dis 33: 885-888, 1964. A 99 FEJFAR Z and PISA Z: Ischaemic heart disease. Prognosis, treatment, rehabilitation and prevention. Cor Vasa 13: 1-17, 1971. A 100 - GENERAL PRACTITIONER: Prevention of coronary disease. 35: 77, 1967. A 101 GREEN R S and BOROUSCH E L: Return to work of patients with angina pectoris and/ or myocardial infarction. JAMA 172: 783-789, 1960. A 102 HALHUBER M J: Aktuelle Probleme der Rehabilitation nach Herzinfarkt. Internist 12: 233-236, 1971. A 103 HALHUBER M J: Rehabilitation nach Herzinfarkt. Bull Schweiz Akad Med Wiss 28: 53-60, 1972... A 104 HONEGGER R: Rehabilitation von Herzinfarkpatienten. Praxis 22: 752-761, 1967. A 105 KUTNER B: Social barriers to cardiac rehabilitation. N Y State J Med 70: 517-521, 1970. A 106 LEVENE D L: Management of heart disease in the elderly. Can Fam Physician - 77 ~-i , 1i'-. 1G7 LILJEFORS I: Rokvanor och koronarsjukdom i ett tvillingmaterial. Lakartidningen 67: 161-164, 1970. .. . A 108 LUNDMAN T: Koronarsjutcdom bos rokningsdiskordanta tvillingar. Lakartidningen 67: 156-160,.. 1970. A 109 MULCAHY R and IIICKEY NJ: The long-term management of patients with coronary deart disease. Ir J Med Sci 9-16, 1965. A 110 NEUMANN E H and PIERACH A: Rekonvaleszenzdeg Herzkranken. Internist 6: 373-383, 1965. SIBLEY J C: The post-hospital treatment of the patient with cardiac infarction. Appl Ther 7: 300-306, 1965. . rage 51" A 111 A 112 TORKLaSON L 0: Rehabilitation of the patient with acute myocardial infarction. J Chron Dis 17 GFiS-7U1, 1964. ~~~~„ ,~~aT10 30 2-1 0 21
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11. Myocardial Infarction - 16 Page 41 use the results of their survey to show whether alteration of smoking habits improves the outlook of a person who has had an infarct. They recognize the difficulty of distinguishing between the effects of abstinence from smoking and other therapeutic measures, such as dietary changes, drug treatment, alteration in the way of life and careful medical supervision. ..,„,6,,,,,TI0302-1031
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IT. Myocardial Infarction - 4 Additional Bibliographic List No. 4 MYOCARDIAL INFARCTION: IMMEDIATE TREATMENT BALOTIN N M: . Myocardial infarction, its diagnosis and treatment: literature review. Dis Chest 36: 86-94, 1959. - Page 29 Reprint A 63 BARBORIAK J J, RIMM A, TRISTANI F E, WALKER J R and LEPLEY D Jr: - Risk factors in patients undergoing aorto-coronary bypass surgery. J Thorac Cardiovasc Surg 64: 92-97, 1972. A 64 BARRON M: Cardiac emergencies and their treatment. J Lancet 68: 43-49, 1948. A 65 BRANDT R L, JONES C and MATHER G: Instructions for the patient following myocardial infarction. Mich Med 66: 1560-1561, 1967. A 66 BURCH G: The management of acute coronary occlusion with myocardial . . infarction. South Med J 42: 186-193, 1949.. - A 67 - CONN J J and KISSANE R W: Management of coronary disease. Geriatrics 13: 549-564, 1958. A 68 . DAVIDSON D M, BRAAK C A, PRESTON T A and JUDGE R D: Permanent ventricular pacing. Effect of long term survival, congestive heart failure, and subsequent myocardial infarction and stroke. Ann Intern Med 77: 345-351, 1972. A 69 ERIDANI. S, CONSTANTINO D and PORRO T: Considerazioni cliniche su un caso di aneurisma cardiaco post-infartuale subacuto (con particolare riguardo al riconoscimento diagnostico, al problema chirurgico ed al trattamento medico postoperatorio). Malattie Cardiovascolari 8: 603-630, 1967. A 70 FALK 0 P J: Current trends in the treatment of coronary disease. SouthMed J 40: 501-508, 1947. A 71 FALK 0 P J: Treatment of coronary artery disease. JAMA 134: 491-496, 1947. A 72 FEJGIN M: Nowsze dane o patogenezie rokowaniu i leczeniu zawadu serca i - cuuruuy wicucv++c~. ~.. •+ ..n6a v,. ::.c yu ..~gcucai~, yru~~tusio nuu Lre"nlenL - •of myocardial infarction and coronary disease). Wiad Lek 19: . 1-8, 1966. A 73 FRICK M H,and MIETTINEN T A: Coronary heart disease -- different aspects. ' Ann Clin Res 3: 291-292, 1971. A 74 GORLIN R, BRACHFELD N, MacLEOD C and BOPP P: Effect of nitroglycerin on the coronary circulation in patients with coronary artery disease of . increased left ventricular work. Circulation 19: 705-718, 1959. A 7''i GOTTHEINER V: Intensives Korpertraining als Nachbehandlung und Vorbeaugung des Herzinfarktes. Internist 12: 236-248, 1971. . A 76 HEFFERNAN A, CULLEN M, O'SULLNAN P, BUGLER J, and MULCAHY R: The organization and management of a coronary care unit, with a note on 15 months preliminary experience. J Ir Med Assoc 61: 157-161, 1968. A 77 T10 30 2-1 01 9
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[I. Myocardial Infarction - 8 Page 33 II-A. Controlled Retrospective Studies The incidence of smoking among patients with acute myocardial infarction can be derived from controlled retrospective studies. There are 9 such investigations from 7 countries which are summarized in Table II-A. The groups range from 79 to 550 patients with clinical diagnosis of acute myocardial infarction. The incidence of nonsmokers ranges from 2 to 34%, with a median of 16 ejc and a mean of 18%. In the corresponding control group, the incidence of nonsmoking ranged from 14 to 44%, with a median of 34%andameanof 33 The lower incidence of nonsmokers or higher frequency of smokers among patients with acute myocardial infarction can also be derived from mortality statistics (Section IV), morbidity statistics (Section V) and examination of selected groups of patients, such as females and young males (Section VI). Cigarette smoking cannot be identified as the most important cause of acute myocardial infarction, Secause there are other risk factors operative in these comparisons. The following factors have been identified as moreimportant and more frequent than cigarette smoking in the controlled retros»ective studies summarized in Table II-A: shortness of stature (Villiger and Heyden-Stucky, 1966), diabetes mellitus (Abou-Daoud, 1968), hypertension (Schwartz et al. , 1966) and diet (Kasanen and Forsstrom, 1966). The retrospective studies have failed to demonstrate that cigarette smoking is the most important risk factor in the pathogenesis of acute myocardial infarction. (Table II-A appears on the next page. ) T10 30 2-1 02 3
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II. Myocardial Infarction - 11 Page 36 II-B. Sudden Death It has been estimated that death occurs during the first 24 hrs in _ about 10 °fe of patients suffering from acute myocardial infarction. No observations have been made which indicate that excessive smoking is the precipitating cause of the acute episode. There are claims that sudden death is more likely to occur among smokers but these are based on the following indirect evidence: _ 1. Age of patients. Spain et al. (1969) examined a group of 102 men who died suddenly of acute myocardial infarction. The average age at the time of death was 16 years less in those who smoked heavily than it was in the nonsmokers. Porsteinsson et al. (1971) reviewed a group of 119 men and 32 women who died of myocardial infarction. The average age at the time of infarction was 57. 9 for smokers, 62. 1 for examokers. and 69.2 for nonsmokers. Spain et al. (1969) have discussed two explanations a for the occurrence of sudden death among smokers at/younger age than among nonsmokers. They discounted alteration in coagulability of the blood by smoking on the basis that the incidence of recent coronary arterial thrombi was not correlated with smoking habits. They favor the explanation that smokers as a group are in many respects different types of individuals from nonsmokers (see Section VI). This is supported in their study by the fact that the average age at which those who smoked heavily were involved in and died on account of accidents, suicide and homicide was 9 years less T10 30 2-1 02 6
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II. Myocardial Infarction - 10 Page 35 BIBLIOGRAPHY II.MYOCARDIAL INFARCTION A. Controlled Retrospective Studies . . Reprint ABOU-DAOUD K T:. Coronary heart disease. Associations observed in .. hospitalized patients. J Med Liban. . 21: 49-57, 1968 50 BERRY M G: Pathogenesis of atherosclerosis. Ind Med Surg 29: 187-191, . 1960. 51 BLUMER G: The relation of the use of alcohol and tobacco to coronary occlusion. JAMA 102: 1177, 1934. - 52 HYAMS L, SEGI M and ARCHER M: Myocardial infarction in the Japanese. A retrospective study. Am J Cardiol 20: 549-554, 1967. 53 KASANEN A and FORSSTROM J: Eating and smoking habits of patients with myocardial infarction. Ann Med Intern Fenn 55: 7-11, 1966. 54. McCORMICK W J: Coronary thrombosis: an etiological study. Clin Med 59: 305-311, 1952. 55 SCHIMMLER W and NEFF C: Rauchgewohnheiten und Herzinfarkt. Munch Med Wschr 108: 903-915, 1966. 56 SCHWARTZ D, LELLOUCH J, ANGUERA G, BEAUMONT J L and LEN~GRE J: - Tobacco and other factors in the etiology of ischemic heart disease in man. . . Results of a retrospective survey. J Chron Dis 19: 35-55, 1966. , 57 VILLIGER U and HEYDEN-STUCKY S: Das InfarktprofiL Unterschiede zwischen . Infarktpatienten vnd Kontrollpersonen in der Ostschweiz. Schv,eiz Med . Wochenschr 96: 748-758, 1966. , . 58 T10 30 2-1 02 5
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Li. Myocardial Infarction - 12 Page 37 than the average age at which nonsmokers died because of similar events. 2. Survival time. Spain (1970) and Spain and Bradess (1970) examined 88 autopsy cases of sudden death following acute infarction. Their results were as follows: 18 nonsmokers: 12 survived <I hour and 6 survived-~ 8 hours (33.3%) 30 smokers (e-1 pack): 22 survived <1 hour and 8 survived-"- 8 hours (26.6%) 40 smokers (>1 pack): 38 survived <1 hour and 2 survived> 8 hours (5.0%) Survival time was decreased in the heavie;~ smokers. The association was less evident within the older age brackets and more striking under the age of 50. Pard's Chavero et al. (1970, 1971) reported 106 men who had myocardial infarction. The mortality during the acute episode was as follows: 14 nonsmokers: 2 deaths (14.0%) 10 smokers (<1 pack): 1 death (5.5%) 68 smokers (>1 pack): 11 deaths (16.2%) There was no statistically significant difference in mortality between smokers and nonsmokers. T10 30 2-1 027
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II. Myocardial Infarction - 17 BIBLIOGRAPHY II. MYOCARDIAL INFARCTION C. Prognosis Page 42 Reprint COLE D R, SINGIAN E B and KATZ L N: The long-term prognosis following myocardial infarction, and some factors which affect it. Circulation 9: 321-334, 1954. 65 CORONARY DRUG PROJECT RESEARCH GROUP: The coronary drug project: Relationship between coronary risk factors and prognosis for survival after recovery from previous myocardial infarction. Circulation 40 (Suppl III): 62-63, 1969. 66 COX C J B: Return to normal of the electrocardiogram after myocardial infarction. Lancet 1: 1194-1197, 1967. 67 DESOLDATI L, BARBIERO 0, CHUTLIAN A, ROMAN M I, MATTIAUDA J and BARREIRO N: Factores aterogenicos mas comunes observados en 66 casos de segundo infarto de miocardio. Prensa Med Argent 59: 71-74, 1972. 68 HAY D R and TURBOTT S: Changes in smoking habits in men under 65 years after myocardial infarction and coronary insufficiency. Br Heart J 32: 738-740, 1970. . 69 ROYSTON G R: Short stay hospital treatment and rapid rehabilitation of cases of myocardial infarction in a district hospital. Br Heart J 34: 526-532, 1972. 70 SEIGEL D G and LONCIN H: A critique of studies of long-term survivorship of patients with a myocardial infarction. Am J Public Health 58: 1348-1354, 1968. 71 r T10 30 2-1 03 2
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IIi. Atherosclerosis - 1 Page 45 III. ATHEROSCLEROSIS CICRnEtTE SMOMIF4 • RISR RNCTOR¢ i :fIX.XJN) (VI,VII. VIII) . S /.TNEROSClCN0519 ANOINi YECTOM6Q3 YTOCaROIAL INidXCTI0NlC1 - CLAVOICNTIONI PERIPHERAL (INTERMITTENT A. Coronary Atheroecleroeie---- 55- 8. Peripherzl Atherusclerosis---60 C. Cerebral Atheroscleroeis-.-- 70 The pathological process underlying coronary arterial disease is atherosclerosis. There is thickening of the arterial wall, which prevents an increase in delivery of blood to the heart proportionate to its demand for oxygen and promotes the formation of a thrombus leading to infarction. The consequences are manifested clinically as angina pectoris (Section 1) and acute myocardial infarction (Section lI). Atherosclerosis can extend to the peripheral and cerebral vascular beds, manifested clinically as intermittent claudication and stroke. A high incidence of smoking has been noted in patients suffering from each of these diseases. The predominance of smokers is greatest among patients with peripheral vascular disease, least among those with cerebral disease and in between these for cases of coronary heart disease. The nonuniformity of the relationship between smoking and each of the three forms of T10 30 2-1 035
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II. Myocardial Infarction - 15 Page 40 The electrocardiograms of 175 men who survived a year without recurrence after a first myocardial infarct were examined for periods ranging from 1 to 4 years (Cox, 1967). In the absence of recurrence, 10. 9% at the end of 1 year and 20.0 % at the end of 4 years had a normal electrocardiogram. There was no relation between the return to normal . and the extent of smoking after infarction. The electrocardiogram reflects the severity of infarction and this in turn influences the prognosis. Royston (1972) examined at autopsy the severity of infarction of 200 hearts. The extent of damage was graded in increasing order of I, II and ISI. The re.sults of that author based,on smoking habits that were known for 156 cases, were as follows: 32 nonsmokers: 154% 1142% 1114 % 23 smokers (light): I52%a 1143% 1115% 68 smokers (moderate): I 62% 1135% I1I 3% 33 smokers (heavy): .I61% 1139% III0% The severity of the infarct did not appear to be affected by the smoking habits. The number of patients involved in all the investigations reported is not great. If additional studies are planned, two important articles chcula bc = «ca, c;0 1 a i T.~ , /1QFR1 rFvirwed 16 stndies of long-term survivorship after a myocardial infarction. They noted that the risk factors that have been studied meticulously by investigators interested in the incidence of the disease have been virtually ignored in the area of prognosis. Hay and Turbott (1970) have surveyed the changes in smoking habits in 370 men after myocardial infarction. They intend to
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(fI. Atherosclerosis - 4 Page 48 List No, 6 . . ~ ~ . • Reprint STAMLER J: Breakthrough against hypertensive and atherosclerotic disease? Geriatrics 17: 31-40, 1962, . • A 135 TONELLI E, TUMIOTTO G, BISBINI P, PRONTICELLI G and MONTI M:. Ricerche sulla influenza di alcuni fattori esogeni ed endogeni nei riguardi delle malattie cardiovascolari di natura arteriosclerotica. I G Sanita Pubblica 24: 22-51, 1968. . A 136 VAN ITALLIE T B: Multidisciplinary approach to the problem of atherosclerosis. Fed Proc 21: 2-11, 1962. WIDMER L K: Fr'uhdiagnose und Prophylaxe der Atherosklerose in der Praxis. Hippokrates 38: 137-142, 1967-. WIDMER L K: Risikofaktoren der Atherosklerose. Therapiewoche 22: 653-656, 1972. ~T10 30 2-1 038
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II. Myocardial In_`arction - 2 Additional Bibliographic List No. 3 MYOCARDIAL INFARCTION: CLINICAL ASPECTS AND PROGNOSIS Page Z7 Reprint ANSCHUTZ F and BERG A: Rauchen und Ge£abkrankheit. Internist 9: 239-246, 1968. A 33 BICKENBACH W and SOOST H-J: Pathogenese_des Myokardin-' far1cts. . Arztliche Prax 18: 1975-1976, 1966. . . . A 34 BURCH G E and dePASQUALE N P: Sudden, unexpected, natural death. Am J Med Sdi 249: 86-97, 1965. A 35 CHIARI H: Kenntnis der Aneurysmen der Kranzschlagadern des Herzens. Wein Klin Wochenschr 51: 977-979, 1938. .. A 36 CHRISTMANN W: Vorzeitiges Auftreten von Herzinfarkten beim weiblichen . Geschlecht. Med Klin 64: 2329-2331, 1969. . A 37 DELUCA F, PIANCONE R M, D'ADDETTA,G, CRAMAROSSA L, ANDREOLI M, and NEGRI M: L'infarto del miocardio: prognosi immediata e tardiva su 214 pazienti. Rass Fisiop Cl Ter 40: 145-159, 1968. A 38 DUGGAN J J, SCHIESS W A and HILFINGER M F Jr.: Unheeded signals of fatal coronary artery disease. N Y State J Med 71: 2639-2642, 1971. A 39 EMMRICH J and REINDELL H: Ein Beitrag zur Klinik des frischen Herzinfarktes. Dtsch Med Wochenschr 85: 1293- 1296. -1 A 40 EMMERICH R: Infarkfgefahrdung und Pr''infarkt. Dtsch Gesundheitsw 25: . .. . 1072- 1077, 1970. - , -- A 41 GLORIOSO R: Aspetti clinici e sociali delltinfarto del miocardio. Minerva Med Sicitiana 12: 175-186, 1967. , . A 42 GWEE A L and LEE Y K: Acute myocardial infarction without coronary care. Singapore Med J 11: 147-151, 1970. - A 43 . HAVARD C W H: Recovery after myocardial infarction. Br Med J 1: 1525-1527, 1966. A 44 HINKLE L E: The antecedents of myocardial infarction and sudden death in a cohort of actively employed men. J Occup Med 13: 433-440, 1971. A 45 . KLUGMANN G, MAGRIS D, MIAN G and FANNA F: L'infarto miocardico - nell'anziano. 29-35. A 46 KULLER L, LILENFELD A and FISHER R: Epidemiological study of sudden and unexpected deaths due to arteriosclerotic heart disease. Circulation 34: 1056-1068, 1966. A 47. NAGLE R E: Prognosis of coronary heart disease. Practitioner 202: 251-258, 1969. A 48 NIMALASURIYA A, WIMALARATNE K D P and THENABADU P N: A clinico- pathological study of coronary heart disease in Ceylon. Ceylon Med J . 17: 86-90, 1971. A 49 T10 30 2-1 01 7
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II. Myocardial Infarction - 14 .Page 39 11-C. Proenosis Patients who survive the first 24 hours after acute myocardial infarction have been examined to determine whether cigarette smoking influenced their prognosis. The conclusion has been uniformly negative. Cole et al. (1954) examined 285 patients. Statistics of smoking habits were obtained for nonsmokers and smokers respectively, as follows: 17 nonsmokers 29• 4% died within 2 months 29• 4% lived over 10 years 31 smokers (< I pack) 9• 6% died within 2 months 41. 9%a lived over 10 years 21 smokers (> I pack) 14.3% died within 2 months 57.0% lived over 10 years The above.results show that nonsmokers did not have a better prognosis than smokers. In fact, the contrary is suggested namely, that smokers who develop myocardial infarction are more apt to live longer than nonsmokers. The duration of survival of patients following an acute myocardial infarction has been examined by two other groups. The Coronary Drug Project Research Group (1969) studied a total of 2,181 men. There was no association between smoking and prognosis. De Soldati et al. (1972) examined 66 cases of acute myocardial infarction and noted the following mean duration of survival: 17 nonsmokers 44) h months 49smokers (< 1 pack) 99. 6 months `smokers ( > 1 pack) 56.7 months The differences between groups were statistically significant. It can be noted that the duration of survival of heavy smokers is longer than that of moderate smokers. ...T10 30 2-1 029
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III. Atheroslcerosis - 2, Page 46 atheroslcerosis can be explained by the differences in risk factors in the pathogenesis of each of these vascular diseases. Hypertension is the most important one for cerebral atherosclerosis, hyperlipidemia for peripheral atherosclerosis, and genetic personality and socioeconomic factors for coronary atherosclerosis. Details relating to these risk factors are discussed in Sections VI to VIL Cigarette smoking influences the resistance of the blood vessels in each of the three vascular beds. The acute effect is a transient reduction in peripheral blood flow, an dncrease in coronary blood flow and no significant change in cerebral blood flow. This does not adequately explain the appearance of atherosclerosis in all three vascular beds. The chronic effects of smoking have also been investigated. It has been suggested that cigarette smoking per se or the constituents of cigarette smoke, i. e. , nicotine and carbon monoxide, can cause atherosclerosis. The evidence in support of this claim is reviewed in Sections IX to XI. The articles relating to atherosclerosis in general are contained in the following listing: List No. 6. Atherosclerosis: pathogenesis. List iQo. %. r.[ileroscierosis: preveni.ion. List No. 8. Coronary atherosclerosis. List No. 9. Peripheral vascular disease. List No. 10. Cerebrovascular disease. 710 30 2-1 03 6
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II. Myocardial Infarction - 18 Page 43 II-D. Complications The two most frequent complications following myocardial infarction are cardiac arrhythmias (Foliguet et al. , 1963) and cardiogenic shock (Scheidt et al. , 1970). There is no report indicating the influence of smoking on the incidence of these complications. The nature of the cardiac effects of cigarette smoke and its constituents does not contribute to the development of shock or arrhythmias (see Section IX). A few patients with myocardial infarction have been reported to have malignancy also. Five cases of bronchial carcinoma were described by Buytendijk and Maesen (1964). In an autopsy series conducted by Bergman et al. (1968), there was a negative correlation between atherosclerosis and cancer. Several other, articles indicate a negative correlation between these two diseases (Casper, 1932; Dormanns and Emminger, 1934; Sjovall, 1934; Dungal and Benediktsson, 1958). Since there is a positive correlation between smoking and bronchial carcinoma and smoking and myocardial infarction, it is surprising to note that a negative correlation exists between myocardial infarction and bronchial carcinoma. T10302-1033
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III. Atherosclerosis - 7 List No. 8 Page 51 Reprint OTINIANO ORDONEZ F M: Revision de algunos factores que influyen en la presencia de enferrnedad coronaria ateroesclerootica. Rev Viernes Med 18: 45-51, 1967, A 167 PASAMONTES-J G: Escierosis coronaria. Medicina 35: 403-405, 1967. SAILAPATHY A: Ischaemic heart disease. J Indian Med Assoc 47: 8-13, 1966. A 168 A 169 SCHETTLER V G: Herzinfarkt und Arteriosklerose. Dtsch Med J 10: 651-52, 655-656, 659, 1970. - A 170 SCHMIDT R: Das Rauchen in der Patbogenese innerer Krankheiten Med Klin Bul 34: 665-669, 1938. SHAFFER C F: A perspective of biological and other factors contributing.to coronary arteriosclerosis. ~ Med Tirries ,92: 664-677, 1964. SHAH V V: The natural history of ischaemic heart disease. Bombay Hosp J 10: 28-33, 1968. SOEHREN I E: Coronary thrombosis. Not a death sentence. Hygeia 26: 182-183, 214-215, 1948. . STUART-HARRIS C H: Ischaemic heart disease. Med S Malaya 17: 55-61, 1962. .WOLFERTH C C: Present concepts of acute coronary occlusion. JAMA 109: 1769-1774, 1937. T10 30 2-1 041
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IIl. Atherosclerosis - 20 Page 64 c. Gastrointestinal diseases. The splanchnic vascular bed may show manifestations of atherosclerosis and vascular insufficiency. These - include duodenal ulcer (Meade et al., 1968; Monson, 1970), polypoid lesions in the colon (Drexler, 1968) and gallbladder. disease (Friedman, 1968). The patients in the stated reports also manifest coronary heart disease The role of smoking in the causation of these syndromes is purely conjectural. T10 30 2-1 054
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III. Atherosclerosis - 9 Page 53 List No. 9 Reprint SCHMAUSS A K and ARIT E: Morphologische Befunde, postoperative Kompli- kationen, Letalitat und Liegedauer nach Amputation wegen Durchblutung- storungen. Z Arztl Fortbild 64: 84-87, 1970. A 193 SIEBECK R: Uber Erkrankungen des arteriellen Systems. Dtsch Med Wochenschr 61: 489-495, 1935. A 194 THEIS F V: Thromboangiitis obliterans: A-juvenile or presenile form of athersclerosis obliterans. Presby St Luke Hosp Med Bull 4: 18-25, 1965. - A 195 VUJADINOVIC B V: Autovenous transplantations of peripheral arteries, ; by-passing the knee. J Cardiol Surg 6: 361-365, 1965. A 196 WESSLER S, MING S-C, GUREWICH V and FREIMAN D G: A critical evaluation . of thromboangiitis obliterans. N Engl J Med 262: 1149-1160, 1960. A 197 WYCHULIS A R, SPITTELL J A Jr., and WALLACE R B: Popliteal aneurysms. Surgery 68: 942-952, 1970. A 198 a T10 30 2-1 043
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[II. Atherosclerosis - 5 Page 49 Additional Bibliographic List No. 7 ATHERSCLEROSIS: PREVENTION epr n ALSCHULE M D: Can diet prevent atherogenesis? If so, what diet? Med Counterpoint 13r 23, Z6-28, 1970. • A 140 SEGG T B: General therapeutic and prophylactic problems in the treatment of atherosclerosis. Acta Cardiol Suppl 25: 101-113, 1972. A 141 DAWBER T R and :THOMAS D E Jr: Prophylaxis of coronary heart disease, stroke, and peripheral atherosclerosis. Ann N Y Acad Sci 149: 1038-1057, 1968. A 142 , HLOUCAL L and DUSEK J: Aetiopathogenese und Prophylaxe der koronaren Atherosklerose (II). Z Therapie 9: 257-267, 1971. A 143 - KATZ L N: Has knowledge of atherosclerosis advanced sufficiently to warrant .. its application to a practical prevention program? The 1970 G. Layman Duff memorial lecture, council on arteriosclerosis, American Heart - Association. Circulation 45: 8-20, 1972. A 144 KATZ L N and PICK R: The present status of the management of atherosclerosis. Cardiol Prat 54-71, 1962.. . - A 145 LLOYD J D and WOLFF 0 H: A paediatric approach to the prevention of atherosclerosis. J Atheroscler Res 10: 135- 138, 1969. A 146. MACGREGOR A G: Advances in medicine. Practitioner 191: 393-402, 1963. A 147 SIEDEK H: Die Prophylaxe der arteriosklerotischen Herz-und Gefasserkrankungen. Wien Med Wochenschr 121: 575-581, 1971. . , A 148 _ STOLLEY P D: The primary prevention of atherosclerotic disease: a report of the Inter-Society Commission for Heart Disease Resources. Ann Intern Med . 76: 661-663, 1972. . ~ A 149 R i t 1310302-1039
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III. Atherosclerosis - 19 Page 63 accompanying lesions in the less severe forms of atherosclerosis which have been noted in smokers. a. Coronary atherosclerosis. Some patients suffering from angina pectoris have been reported to complain of peripheral vascular disease (Ralli and Oppenheimer, 1928; Unverricht, 1941). More recently, cases involving a combination of myocardial infarction and peripheral atherosclerosis have been reported from France (Schwartz et al. , 1965; Jouve et al. , 1969)r the United States (Eisen, 1966; Olsen et al., 1968), Austria (Reimer et al. , 1969), Italy (Moro et_al. , 1972), Switzerland (Bollinger et al. , 1972) and Greece (Aravanis and Corcondilas, 1972). It has been recommended by Toxnatis et al. ,(1972) that coronary arteriography would help in the evaluation of surgical risk in patients with peripheral vascular disease. Atherosclerosis appears in both beds in some patients but the cause of its predominance in either the coronary or the peripheral location is not known. b. HematoloQic factors. Cigarette smoking is known to induce blood clotting and reduce the oxyhemoglobin (see Sections IX and X). There is a high incidence of closure of aortofemoral bypass grafts which has been attributed to excessive smoking (Wray et al., 1971). In some patients with thromboangiitis obliterans, there is an abnormality in oxyhemoglobin dissociation which has also been partly explained by formation of carboxyhernoglobin in the course of smoking (Astrup, 1964; Birnstingl et al. , 1967; Kjeldsen and Mozes, 1969). T10 30 2-1 053
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Page 65 Table III-B, Controlled Yetrospective studies of patients with peripheral atheroslerosis Country Peripheral Atheroslerosis Control Investigator No. % Smokers % Smokers United States Juergens et al. (1960) 478 97 74 McPherson etal. (1963) 119 93 Lord (1965) 100 92 65 France Delahaye et al. (1970) 222 Germany Preuss et al. (1970) 150 87 Great Britain ~ Eastcott (1962) 114 99 Oldham (1964) 500 99 Begg et al..(19651 100 99 79 India Razdan et al. (1967) 125 91 Israel Goodman et al, (1965) 80 99 68 . Giampaglia et al, (1972) 1300 80 Switzerland Widmer et al. (1969) 277 . 87 69 . , ""*~,~° ^^TI0302-1055
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.vay~.-n.uaa.a uuai,.~auax 7 Page 44 BIBLIOGRAPHY lI. MYOCARDIAL INFARCTION D. Complications Reprint BERGMAN F, van der LINDEN W and SbDERSTROM J: The relation of - - malignant disease to myocardial infarction as observed in an autopsy series. Arch Geshwulstforsch 32: 231-238, 1968. 72 BUYTENDIJK J H and MAESEN F: Het voorkomen van bronchus carcinoom - bij patienten met een myocard infarct. Acta Tuberc Pneumol Belg 55: 318-324, 1964. 73 CASPER J: Bosartige Geschwulste und Arteriosklerose. Z Krebsforsch 36: 354-359, 1932. . 74 . DORMANNS E and EMMINGER E: Vergleichende Untersuchungen iiber Ausbreitung und Starke der Atheroskierose an 1000 Leichen von Uber 20 Tahre alten Personen mit besonderer Berucksichtigung von Krebs, Tuberkulose und Lues. Virchows Arch Pathol Anat 293: 545-550, 1934. 75 DUNGAL N and BENEDIKTSSON T: Gastric cancer and atherosclerosis. Lancet 1: 931-932, 1958. 76 FOLIGUET J M, WERNER J and VERT P: Tabagisme et bloc auriculo- -Iventriculaire. Ann Med Nancy 2: 815-821, 1963. 77 SCHEIDT S, ASCHEIM R and KILLIP T III: Shock after acute myocardial infarction. A clinical hemodynamic profile. Am J Cardiol 26: 556-564, 1970. 78 n SJOVALL H and WIHMAN G: Beobachtungen uber die Arteriosklerose in Schweden . samt einem Beitrag zur Frage der Lipoidose der Arterienintima. . ,,. .. .- Acta Pathol MicrobioI Scand Suppl 20: 1-92, 1934. 79 - °T10302-1034
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II. Atherosclerosis - 8 Additional Bibliographic List No. 9 PERIPHERAL VASCULAR DISEASE Page 52 Reprint ABRAMSON D L: Diagnosis and management of arterial disorders of the , extremities. Mod Med 37: 103-110, 1969. A 177 BEVILACQUA C: Il morbo di Buerger malattia sociale. Med Sociale 15: 177-181, 1965. A 178 BROWN H, SELLWOOD R A, HARRISON C V and MARTIN P: Thromboangiitis obliterans. Br J Surg 56: 59-63, 1969. A 179 EASTCOTT H H G: Ischaemia. Trans Med Soc London 87: 134-148, 1971, A 180 HEINE H, SCHMIDT H and ANDERS G: Klinisches Bild und Therapieresultate bei Patienten mit Endangitis obliterans und peripherer Arteriosklerose. Angiologica 2: 195-211, 1965. - A 181 HIGGINS I T T: Smoker's lungs age faster than body. Pa Med J 67: 30, 1964. A 182 HOFFMANN A: Uber Puls und Pulsdiagnostil. Jahreshurse Arztl Fortbild 5: 3-24, 1914. A 183 JOUVE A, AUBERT M and AVRIL P: Causes et conditions favorisantes des arteriopathies peripheriques. Actual Cardiol AnReiol Int 15: 1-8, 1966. A 184 KRADJIAN R, BOWLES L T and EDWARDS W S: Peripheral arterial disease in Ceylon. Surgery 69: 523-525, 1971. . A 185 LITTLE J M, STEWART G R, NIESCHE F W and WILLIAMS C: A trial of flapless below-knee amputation for arterial insufficiency. Med J Australia 1: 883-887, 1970. A 186 MANOHARAN D and REDDY H T V: Arterialisation of vein, J Christin.n Med Assoc India 43: 112-120, 1968. - A 187 McDONOUGH J R, KUSUMI F and BRUCE R A: Variations in maximal oxygen intake with physical activity in middle-aged men. Circulation 41: 743-751, 1970. A 188 McKUSICK V A, HARRIS W S, OTTESEN 0 E, GOODMAN R M, SHELLEY W M and BLOOD44ELL it D: Buerger's disease; A distinct clin,cal and pathologic entity. JAMA 181; 5-12, 1962. . A 189 OCUSNER A and DeBAKEY M: Peripheral vascular disease. Int Glin 3: . 1-32, 1939. A 190 PRATT G H: Surgical management of the post-thrombotic syndrome. Ain J Surg 81: 562-567, 1951, A 191 ~ . . REINIS Z, POKORNY J, HORAKOVA D, KLENKA L, KRAUS H, REISENAUER R and MARSIKOVA L: Pozadi ocni a ischemicka choroba srdecni. Cesk Oftal 26: 5-17, 1970. A 192 ,,,,.~.,,~r,310 30 2-1 042
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IIl. Atherosclerosis - 17 Page 61 failed to show a statistically significant difference in velocity between 409 smokers, 109 exsmokers and 228 nonsmokers. Isacsson (1972) used venous occlusion plethysmography to diagnose stenosis of iliofemoral _ arteries. There were 8 subjects suffering from peripheral vascular disease out of 809 participants in the survey. The blood flow capacity of the legs was reduced in direct proportion to tobacco consumption per day. 2. Thromboanuiitis obliterans. There is a uniformly high incidence of smokers among patients suffering from thromboangiitis obliterans. Table III-B summarizes the results of 12 surveys conducted in 8 countries. The groups range from 80 to 1,300. The incidence of smokers ranges from 80.1 to 99.6%, whereas the control groups available in 5 surveys had an incidence of 65 to 69.2% of smokers. It has been estimated by Weiss (1972) that about 70 % of the cases of the disease aie related to the use of cigarettes. One risk factor in addition to cigarette smoking has been identified as prevalent in patients with arteriosclerosis obliterans. This is an elevation of serum lipids (Juergens et al., 1960; Goodman et al. , 1965). Greenhalgh et al. (1971) noted an elevation of the level of triglycerides in 39% of cases, of serum-cholesterol in 15% and of serum-lipid in 44% in a group of 116 patients with arterial disease of the leg. There was no difference in levels between smokers and nonsmokers. It is an accepted practice to prohibit smoking in patients suffering from peripheral vascular disease (Nilzen, 1959; Corelli, 1966). There is statistical evidence that termination of smoking increased the number of TI0302-1051
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C12. Atherosclerosis - 16 Page 60 III-B. Peripheral Atherosclerosis Although the primary concern of this review.is coronary heart disease, a discussion of peripheral atherosclerosis is included. If peripheral J. vascualr disease is a manifestation of generalized atherosclerosis (including coronary), it is important to review their relationship to cigarette smoking. 1. Incidence among smokers and nonsmokers. Surveys have been conducted by soliciting answers to a questionnaire or by measuring certain parameters. In the Framingham study described below (Section IV), 5,311 persons were questioned for occurrence of intermittent claudication. Although all were initially free from heart and peripheral vascular disease, in 12 years 51 persons developed unequivocal claudication (Kannel et al., 1965). These individuals were smokers with one or more of the following conditions: hypertensive vascular disease, electrocardiographic abnormalities and elevated blood cholesterol level. In the Tecumseh Community Health Study, the absence of peripheral pulse was noted as an indication of coronary and cerebral arterial disease. There was no correlation between absence of peripheral pulse and cigarette smoking, although a positive correlation was demonstrated for blood pressure, body weight and blood sugar (Johnson and Epstein, 1966). The measurement of pulse wave velocity has given conflicting results: Kedra and Dmowski (1966) noted a significant reduction among 100 smokers as compared with 100 nonsmokers; however, Schimmler et al. (1967) .: T10 30 2-1 050
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III. Atherosclerosis - 3 Additional Bibliographic List No. 6 ATHEROSCLEROSIS: PATHOGENESIS Reprint BERRY M G: Pathogenesis of atherosclerosis. Ind Med Surg 29: 187-191,.1960. A 117 BRAUNSTEINER H, SANDHOFER F and SAILER S: Heutiger Stand der Atherosklerose aus der Sicht des Klinikers. In:- Ernahrung und Atherosklerose, edited by H J C Sornogyi. S Karger, Basel, 1969, pp. 86-93. - A 118 COOPER T: Arteriosclerosis. Policy, polity, and parity. Circulation . 45: 433-440, 1972. A 119 , COOPER T and MITCHELL S C: Arteriosclerosis -- a problem in diagnosis ' treatment and prevention. J Chronic Dis 22: 377-380, 1969. A 120 DOUGLAS J F: Atherosclerosis. In: Annual Reports in Medical Chemistry, 1969. - C K Cain, editor. Academic Press, New York, 1970, pp. 180-191. A 121 DOYLE J T: The pathogenesis of atherosclerosis and coronary heart disease. Med Col Va Q 2: 189-195, 1966. A IZZ EADES C H Jr: Atherosclerosis. Annual Reports in Medical Chemistry, 1968. C K Cain, editor. Academic Press, New York, 1969, pp. 178-188. A 123 EPSTEIN F H: Epidemiologic aspects of atherosclerosis. Atherosclerosis , 14: 1-11, 1971. A 124 HARLAND W A: The problems of atherosclerosis. Practitioner 206: 321-329, 1971. A 125 IIUEPE.^. YV C; The etiology and the causative mechanism of.arteriosclerosis and atheromatosis. Medicine.20: 397-442, 1941. A 126 KANNEL W 13 and DAWBER T R: Atherosclerosis as a pediatric problem. .J Pediatr 80: 544-554, 1972. A 127 KLEIN H: Zur Problematik des arteriosklerotischen Krankheitsbildes. Med Klin 61: 1529-1534, 1966. KRUT L H: Current concepts of atherogenesis. Br 3 Clin Pract 22: 517-522, 1968. LENEGRE J: Pr4face. Bull Inst Natl Sante Rech Med 22: 183-202, 1967. A 128 A 129 A 130 LEREN P: De atherosklerotiske sykdommers epidemiologi. Tidsskr Nor Laegeforen 87: 1883-1890, 1967. A 131 MAW D S J: Metabolic aspects of atherosclerosis. Med Rev 1: 7-8, 1969. A 132 PICK R: The present state of knowledge about the prevention and therapy of athersclcrosis. Med Clin North Am 51: 97-104, 1967. . . A 133 SCHETTLER G: Xtiologie und Klinik der Arteriosklcrose. Dtsch Med J 5: 293, 1969. A 134 Page 47 ~_~,TI0302-1037
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[Jr. Atherosclcrosls - 11 Page 55 III-A. Coronary Atherosclerosis E Since atherosclerosis is an anatomical lesion, its diagnosis can be made unequivocally only by coronary arteriography or by postmortem examination of the heart. A cause and effect relationship between smoking and coronary atherosclerosis has not been established. The available information is as follows: 1. Coronary arteriogram. In 89 patients suffering from angina pectoris, among the 46 cases which showed abnormal arteriograms 86%were smokers, whereas among the 43 with a normal pattern of arteriogram 68% were smokers (Newton et al., 1970). There was a slightly higher incidence of smokers among patients with an abnormal arteriogram as compared with those having a normal arteriogram in another series of 73 coronary heart disease patients (Mart~nez R(os et al. , 1972). In a study consisting of 107 patients with either ischernic or nonischemic heart disease, there was no indication by arteriography that cigarette smoking produces obstructive lesions in the coronary vessels (Banks et al., 1971). The conflicting conclusions are readily understandable -because: coronary heart disease may occur in a patient who has a normal arteriogram' (Likoff et al. , 1967). Furthermore, other risk factors, such as hypercholesterolemia, may also be associated with an abnormal arteriogram (Hultgren et al. , 1967). It is difficult to control these factors and prove that smoking is the only variable factor relating to the abnormal arteriogram. TI0302-1045
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jjj. Atherosclcro;is - 18 Page 62 patients displaying spontaneous improvement (Mathiesen et al., 1970). 3. Tobacco allergy. Most patients with thromboangiitis obliterans have a positive skin reaction to tobacco extract (Harkavy et al., 1932; Sulzberger, 1934; Green, 1942; Alfano, 1962). However, a positive skin test occurs in the absence of peripheral vascular disease and reflects a hypersensitivity state of the individual to most allergens (Fontana et al., 1959; De Crinis et al., 1960; Fontana, 1960). The incidence of a positive skin test in healthy smokersis about Z0% (Longhin et al. , 1960). It has been possible to desensitize an individual who has previously been hypersensitive to tobacco (Zussman, 1968). A rare case of bronchial asthma due to allergy to tobacco has been reported (Blue, 1970). Harkavy (1956, 1957, 1968, 1970) has written review articles on tobacco allergy in diseases of blood vessels and of the heart. In the latter organ, Halsey (1933) first suggested that tobacco angina may be a form of hypersensitivity. At the same time, Harkavy (1933) reported a positive skin test in response to tobacco extract in patients with angina pectoris. The phenomenon of sensitization of the heart to tobacco extract was demonstrated in the rabbit heart (Harkavy and Perlman, 1960, 1962, 1964). However, the contribution of the allergic process reiative to the other mechanisms in the pathogenesis of cardiovascular disease in smokers has not been elucidated. 4. Complications of peripheral atherosclerosis. In the most severe form of atherosclerosis, gangrene is the outcome. There are other _TI0302-1052
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III. Atherosclerosis - 6 Additional Bibliographic List No. 8 Page 50 0% CORONARY ATHEROSCLEROSIS Re rint p CARVER S T: Ecology of coronary heart disease. N Y State J Med 71: 1065-1070, 1971. A 150 CASSIDY M: Coronary disease. The Harvein Oration of 1946. Lancet 2: 587-590, 1946. - A 151 DOCK W: Why are men's coronary arteries so sclerotic? JAMA 170: 152-156, 1959. . • A 152 FISHER R L and ZUKERMAN M: Coronary thrombosis. JAMA 131: : 385-393, 1946. . A 153 GREEN R S and GEISS P G: Common sense and coronary arteriosclerosis. ' J Mississippi State Med Assoc 2: 531-537, 1961. A 154 GROEN J J: Coronaire hartziekten, voeding en voedingvoorlichting. Voeding 30: 745-756, 1969. A 155 GUTIERREZ MOYANO L: Angustia e insuficiencia.coronaria. Galica Clin 40: 883-893, 1968. A 156 HOWARD T: Coronary occlusion:. Based on the study of 165 cases. Med Times 62: 337-341, 1934. . . . . A 157 HURST J W and SCHL4NT R:. Coronary atherosclerosis and its management. DM 1-47, .1960. _ A 158 JONES W B, RILEY C P, REEVES T J and SHEFFIELD L T: Natural history of coronary artery disease. Bull N Y Acad Med 48: . . 1109-1125, 1972. . A 159 KATZ L N: _ Clinical management of atherosclerosis: -Circulation 21'.. . . 1193-iZ04,1960. . . , . , _ . A 160 KEIDITSCH E and LANGER E: Koronarsklerose und Herzinfarkt im Obduktionsgut. Med Klin 62: 1378-1380, 1967. A 161 KREHL W A and 13ODGES R E: Determination of the risk of atherosclerotic .. coronary heart disease. J Iowa Med Soc 55: 177-181, 1965. ~ A 162 MASTER A M: Treatment of coronary thrombosis and angina pectoris. Med Clin North Am 19: 873-891, 1935. - A 163 McCORMICK W J: Coronary thrombosis: an etiological study. Clin Med 59: 305-311, 1952. A 164 McFARLAND M D: Etiology of coronary atherosclerosis. A review. ' J Germantown Hosp 5: 68-85, 1964. A 165 MULCAHY R: Medico-legal aspects of coronary heart disease. Med Leg J 36: 87-94, 1968. , A 166 ~~,,> -ra~~.<.,,.,rn,u-~,,.,,TI0302-1040
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IIL. Atherosclerosis - 21 Page 66 BIBLIOGRAPHY . ILI. ATHEROSCLEROSIS B. Peripheral Atherosclerosis Reprint ALFANO G, JOVINO R and MUSELLA S: Existe-t-il une allergic au tabac . ahez l'arteriopathique? Bull Soc Int Chir 21: 49-54, 1962. 99 . ARAVANIS C and CORCONDILAS: Coronary and peripheral artery diseases among . rural population in Greece. Scand J Clin Lab Invest 24: 13, 1972. . - 100 ASTRUP P: An abnormality in the oxygen-dissociation curve of blood from patients . with Buerger's disease and patients with non specific myocarditis. Lancet 2: 1152-1154, 1964. 101 BEGG T B: Characteristics of men with intermittent claudication. Practitioner 194: 202-207, 1965. 102 BIRNSTINGL M, COLE P.and HAWKINS L: Variations in oxyhaemoglobin dissociation . with age, smoking, and Buergeris disease. Br J Surg 54: 615-619, 1967 103 BLUE J A: Cigarette asthma andYobacco allergy. Ann Allergy 28: 110-115, 1970 104 BOLLINGER A. LIGHTLEN P, KAINDL F and MANNHEIMER E: Koinzidenzunter- suchungen bezuglich peripherer Arteriopathie und Koronarsklerose. .. Wein Z lnn Med 53: 455-462, 1972. 105 CORELLI F: Il morbo di Buerger malattia da fumo di tabacco guarisce con la , . sola cura medica. Clin Ter 38: 105-120, 1966. _ 106 DE CRINIS K, REDLSCH W, FONTANA V, LEWIS A, SULZBERGER M B and . STEELE J M: Vascular responses to smoking tobacco compared with response . to skin testing of tobacco extracis. Ann Ir,tcrn Mcd 52: 1035-1041, 1960. 107 DELAHAYE J P, BESSET C and TOUBOUL P: Evolution spontanee et pronostic des arteriopathies atherosclereuses des membres inferieurs. - . Rev Atheroscler 12: 64-78, 1970. . - 108 DREXLER J: Asymptomatic polyps of the rectum and colon. II. Frequency. smoking, and arteriosclerotic heart disease. Arch Intern Med 121: 62-66, 1968. 1o9 EASTCOTT.H 11 G: Rarity of lower-limb ischaemia in non-smokers. Lancet 2: 1117, 1962. 110 EISEN M E: Coexistence of throinboangiitis obliterans and arteriosclerosis: relationship to smoking.- J Am Geriatr Soc 14: 846-858, 1966. . 111 FONTANA V J: Tobacco hypersensitivity. Ann N Y Acad Sci 90: 138-141, 1960. 112 FONTANA V J, REDISCH W, NEMIR R L, SMITH M K, DeCRINIS K and SULZBERGER M B: Studies in tobacco hypcrsentitivity. III. Reactions to skin tests and peripheral vascular responses. J Allergy 30: 241-249, 1959. 113 T10 30 2-1 056
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III. Atherosclerosis - 10 Additional Bibliop!ranhic List No. 10 CEREBROVASCULAR DISEASE DAYTON 5, CHAPMAN J M, PEARCE M L and POPJXK G J: Cholesterol, atherosclerosis, ischemic heart disease, and stroke. Ann Intern Med J• 72: 97-109, 1970. Reprint BULL G M: A comparative study of myocardial infarction and cerebral vascular accidents. Geront Clin 11: 193-205, 1969. A 199 A 200 FELTON J S: Care, compassion and confrontation the correctives in the . occupational mental health of the future. J Occup Med 10: 331-343, 1968. A 201 FISHER C M, GORE I, OKABE N and WHITE P D: Atherosclerosis of the carotid and vertebral arteries -- extracranial and intracranial. J Neuropathol Exp Neurol 24: 455-476, 1965. A 202 FISHER K D, CARR C J, HUFF J E and HUBER T E: Dark adaptation and - nightvision. Fed Proc 29: 1605-1638,.1970. .. . A 203 FRIEDMAN G D, LOVELAND D B and EHRLICH S P Jr.: Cardiac abnormalities . predisposing to stroke. Circulation 36=(Suppl 2): 113, 1967. - A 204 GERTLER M M, LEETMA H E, RUSK H A, COVALT D A, SALUSTE E and ROSENBERGER J: Profile of covert ischemic heart and ischemic thrombotic cerebrovascular diseases. N Y State J Med 69: 2664-2666, 1969. A 205 GERTLER M M, WELSH J J and WHITER H H: Early recognition and prevention. N Y State J Med 66: 2765-2771, 1966. A 206 GUNDERSON C H and HOYT W F: Geniculate hemianopia: incongruous homonymous field defects in two patients with partial lesions of the lateral geniculate nucleus. 3 Neurol Neurosurg Psychiatr 34: 1-6, 1971. . . HEYDEN S and GERBER C J: Atherosclerotic cerebrovascular disease -- its nature and management. Am J Med 46: 763-773; 655-656, 1969. A 207 A 208 KRUEGER D E, WILLIAMS J L and PAFFENBARGER R S Jr.: Trends in death . rat0sfrom cerebrovascular disease in Memphis, Tennessee, 1920-1960. .T rn,ro.,;, n;, 2n: 12a-137. 1967. A 209 ncTCrT n n..<. n.~ ~«.,,t- f-I:., N~~*h n.., 51• tn5-111 1967. A 210 STEINMANN B: Epidemiologie der Apoplexie. Schweiz Med Wochenschr 96: 1733-1740, 1966. . .. A 211 USTVEDT H J: Mortality from cerebro-vascular accidents in Norway in relation to mortality from cardio-vascular-renal disease. Acta Med Scand 163: 305-327, 1959. A 212 Page 54 TI0302-1044
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III. Atherosclerosis - 22 Page 67 Reprint FRIEDMAN G D: The relationship between coronary heart disease and gallbladder disease. A critical Review. Ann Intern Med 68i 222-235, 1968. 114 GIAMPAGLIA F, MARCHESE A and LEONE F: Considerazioni statistiche su 1300 arteriopatici degli arti inferiori. Rass Int Clin Ter 52: 127-145, 1972. 115 GOODMAN R M, ELIAN B, MOZES M and DEUTSCH V: Burger's disease in Israel. Am J Med 39: 601-615. 1965. 116 GREEN M A: Tobacco skin reactions in peripheral vascular diseases and coronary artery disease. J Invest Dermatol 5: 179-186, 1942. 117 GREENHALGH R M, LEWIS B, ROSENGARTEN D S. CALNAN J S, MERVART I, - and MARTIN P: Serum lipids and lipoproteins in peripheral vascular disease. Lancet 2: 947-950, 1971. 118 HALSEY R H: Discussion. Bull N Y Acad Med 9: 325-327, 1933. 119 HARKAVY J: Tobacco sensitiveness in angina pectoris and coronary artery disease. Proc Soc Exp Biol Med 30: 683-684, 1933. . _ 120 HARKAVY J: Tobacco allergy in cardiovascular disease: a review. Ann Allergy 26: 447-459, 1968.121 HARKAVY J: Tobacco allergy in vascular diseases. Rev Allergy 11: 189-212, 1957. 122 . HARKAVY J: Allergic factors in cardiovascular disease. N Y State J Med 56: 3932-3935, 1956. 123 HARKAVY J: Cardiac manifestations due to hypersensitivity. Ann Allergy 28: 242-251, 1970. 124 HARKAVY J, HEBALD S and SILBERT S: Tobacco sensitiveness in T.A. O. n-oc Soc Exp ,^,icl :.:cd .30: 101, 1932. . - 124a HARKAVY J and PERLMAN E: Tobacco allergy in coronary artery disease. Ann N Y Acad Sci 90: 327-332, 1960. 125 HARKAVY J and PERLMAN E: Tobacco allergy in coronary artery disease. . Excerpta Med Int Gonf 42: 48-49, 1962. . .. .126 - HARKAVY J and PERLMAN E: Tobacco allergy in coronary artery disease. N Y State J Med 64: 1287-1296, 1964. 127 ISACSSON S: Venous occlusion plethysmography in 55-year old men.. A population study _ in Malmo, Sweden. Acta Med Scand Suppl 537: 1-62, 1972. 128 JOHNSON B C and EPSTEIN F H: Absence of peripheral pulse in relation to other arterial disease in a community study. Am J Public Health 56: 1482-1492, 1966. 129 . JOUVE A, ROCHU R and AVRIL P: EnquBtes epidcmiologiques sur 1'atherosclerose dans la region provenyale. L'Union Med Can 98: 761-766, 1969. 130 JUERGENS. J L, BARKER N W and HINES E A Jr, :- Arteriosclerosis obliterans: Review of 520 cases with special reference to pathogenic and prognostic factors. Circulation 21: 188-195, 1960. 131 KANNEL W B, DAWBER T R, SKINNER J J, McNAMARA P M and SHURTLEFF D; Enideminli,ir: 1 i ~~rcts of irtorn thnf ~lni.dt ainn T1, . P'r~n >>rhim ;tudv, TI0302-1057 . _.m........,, .. ,....~-,, ..P_.,,- ... ..~-.,.~._ . _+,.R,.....
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III. Atherosclerosis - 26 Page 71 In a controlled retrospective study the high incidenoe d smoking and that of hypertension were noted in a group of former college students who subsequently died of stroke (Paffenbarger and Williams, 1966; Paffenbarger and Wing, 1967, 1971). Smoking was not a significant factor in retrospective studies conducted in Minnesota (Balow et al. , 1966) and in Ghana (Haddock, 1970). There are reports of patients who develop atherosclerosis in the cerebral and peripheral blood vessels (Fogelholm, 1970; Gordon and Kannel, 1972). s.,:,,TI0302-1061
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III. Atherosclerosis - 24 Page 6 9 Reprint SULZBERGER M: Recent immunologic studies in hypersensitiveness to -- tobacco. JAMA 102: 11, 1934. 150 TOMATIS L A; FIERENS E E and VERBRUGGE G P: Evaluation of surgical risk "-- in peripberal vascular disease by coronary arteriography: A series of 100 --" cases. Surgery 71: 429-435, 1972. - - --- - 15L UNVERRICHT W: Die angina pectoris vasomotorica bei Jugendlichen, insbesondere ` Berliner Studenten.Dtsch Med Wochenschr 67: 1361-1363, 1941. - 152 WEISS N 5: Cigarette smoking and arteriosclerosis obliterans: an epidemiologic approach. Am J Epidemiol 95: 17-25, 1972. 153 WIDMER L K, HARTMANN G, DUCHOSAL F and PLECHL S C: Risk factors ~ in arterial occlusion of the limbs. German Med Mon 14: 476-479, 1969. 154 _. WRAY R, dePALMA R and HUBAY C H: Late occlusion of aortofemoral bypass grafts: influence of cigarette smoke. Surgery 70: 969-973, 1971. 155 ZUSSMAN B M: Atopic symptoms caused by tobacco hypersensitivity. South Med J 61: 1175-1179, 1968. • 156
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LII. Atherosclerosis - 23 Page 68 Reprint ' K]~DRA M and DMOWSKI G: The influence of tobacco smoking on the development of atherosclerosis and on the composition of blood lipids. Pol Med J 5: 37-43, 1966. KJELDSEN K and MOZES M: Buerger's disease in Israel. Acta Chir Scand 135: 495-498, 1969. 133 134 LONGHIN S, POPESCU C-E and TRIFU P: Allergic vascular reactions due to tobacco. Rom Med Rev 4: 55-58, 1960. . 135 LORD J W: Cigarette smoking and peripheral atherosclerotic occlusive disease. JAMA 191: 249-251, 1965. . , 136 MATHIESEN F R, LARSEN E E and WULFF M: Some factors influencing the spontaneous course of arterial vascular insufficiency. Acta Chir Scand 136: 303-308, 1970. 137 MePHERSON J R, JUERGENS J L and GIFFORD R W Jr: Thromboangiitis obliterans and arteriosclerosis obliterans. AnnIntern Med 59: 288-296, 1963. 137a MEADE T W, ARIE T 1-I D, BREWIS M, BOND D J and MORRIS J N: Recent history of ischaemic heart disease and duodenal ulcer in doctors. Br Med J 3: 701-704, 1968. 138 MONSON R R: Duodenal ulcer as a second disease. Gastroenterology 59: 712-716, 1970. . . , 139 MORO C 0, MATARESE S, GALLO B, IARUSSI D and JACONO A: Indagine . . epidemiologica sulla cardiopatia ischemica e su alcune alterazioni metaboliche nei lavoratori di un'industria siderurgica del meridione. G Ital Cardiol - . 2: 807-812, 1972. 140 NILZEN VA: Tabakallergie bei einem Fall von Morbus Raynaud. Hautarzt 10: 176-177, 1959. 141 OLDHAM J B: J R Coll Surg Edinb 9: 179, 1964. 142 OLSEN A M: Relationship of smoking to cardiovascular disease and peripheral vascular disease. Dis Chest 54: 186-188, 1968. . 143 PREUSS E-G, EDER H and WELLERP: Risikofaktoren bei peripheren arteriellen ' Verschlubkrankheiten unterschiedlichen Schweregrades. Z Gesamte Inn Med 25: 464-468, 1970. 144 RALLI E P and OPPENHEIMER B S: Changes in the peripheral circulation accompanying "Tobacco Angina". Proc Soc Exp Biol Med 26: 9-11, 1928. 145 RAZDAN A N, SINGH R P and SRIVASTAVA V K: Thromboangitis obliterans. . A clinical study of 125 cases. Int Surg 47: 122-125, 1967. 146 REIMER E E, TISO B and HERRLEIN A: Koronarinfarkt und periphere Durchblutung. (Cornnary infarct and peripheral blood flow). Med Welt 41: 2223-2Z28, 1969. 147 SCHIMMLER W, SCHI1vIERT G and NEFF C: RauchgewohnheitenundAortenelastizitat. Z Kreislaufforsch • 56: 1121-1127, 1967. 148 SCHWARTZ D, LELLOUCH J, ANGUERA G, RICHARD J L and BEAUMONT J L: Etiologie comparce do 1`artcriopathie obliterante des membres inferieurs et de Varteriopathic coronarienne. Arch Mal Coeur 58 (Suppl 3): 24-32, 1965. 149 T10 30 2-1 058
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III. Atherosclerosis - 28 Page 73 Reprint PAFFENBARGER. R S Jr., LAUGHLIN M E, GIMA A S and BLACK R A: . Work activity of longshoremen as related to death from coronary heart disease and stroke. N En,gl J Mcd 282; 1109-1114, 1970. 170 PAFFENBARGER R S Jr., and WILLIAMS J L: Youthful :precursors of - fatal stroke. Circulation 34 (Suppl 3): 183-184, 1966 171 PAFFENBARGER R S Jr., and WING A L: Characteristics in youth predisposing to fatal stroke in later years. Lancet 1: 753-754, 1967. 172 PAFFENBAF.GER R S Jr., and WING A L: Chronic disease in former college students. XI. Early precursors of nonfatal stroke. Am J Epidemiol 94: 524-530, 1971. 173 T10 30 2-1 06 3
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II[. Atherosclerosis - 25 Page 70 I[I-C. Cerebral Atherosclerosis -The influence of smoking on the prevalence of cerebrovascular disease has not been clearly defined. Hammond (1966) in a prospective study, discussed in detail in Section IV, computed death rates for cerebro- vascular disease with smoking habits. Between the ages of 45 and 74, the death rates from stroke for male smokers were 37 to 50% higher than those for male nonsmokers of comparable age. In female smokers the death rates were 38 to 111 % greater than those for female nonsmokers. Above the age of 74, the difference in both sexes were much less. In the US veteran study (Kahn, 1966), the death rates from stroke were higher for smokers than for nonsmokers. The other investigations compare the role of cigarette smoking with other risk factors for atherosclerosis in the prevalence of cerebro- vascular disease. In the Framingham study conducted on over 5, 000 men and women during a 12-year period, a statistically significant association could not be demonstrated for the excessive development of brain 'infarction and cigarette smoking. (Kannel et al. , 1965). Hypertension is clearly the mncl imnnm+>nF rnn+ri}.~~*nr 4n ctrnl~A inriripnrn ,,rl . 41'n novF in ir7~nnrfa.nre is . _... -, i . the elevation of lipids in the blood (Kannel, 1971; Kannel et al., 1972). The significance of hypertension as a precipitating factor has also been demon- strated in studies made in Indiana (Dyken, 1970 , in California (Paffenbarger et al. , 1970, 1971), in Illinois (Ostfeld et al. , 1971), and in Japan (Kimura et al. ,' 1972). 710 30 2-1 060
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Page 74 PART THREE EPIDEMIOLOGICAL STUDIES OF CORONARY HEART DISEASE IV. Mortality and Morbidity Statistics in the United States V. Informative Prospective Studies in Foreign Countries One of the most significant developments in the management of the patient with coronary heart disease is the prevention of risk factors. The identification of the various risk factors which predispose an individual to develop coronary heart disease has been possible through epidemiological investigations completed in the United States and abroad. The general principle involved in such investigations is to select a group of individuals, in whom to determine the prevalence of coronary heart disease and estimate the extent of smoking, the level of blood pressure, and the eholesterolcontent, and to assess the genetic, dietetic, psychogenic and socioeconomic factors. In some epidemiologic studies, it has been possible by proper selection of subjects to ascertain the importance of some of these risk factors. Sections IV and V supply the details of the results of analyzing mortality and morbidity statistics. T10 30 2-1 064
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IV. Mortaiity anct nnoruiaity Statistics - 5 Page 79 (Hammond and Garfinkel, 1969). Twenty percent of the million men and women enrolled in the study have not been included in these summaries nor in other articles by Hammond (1958, 1960, 1962, 1963, 1968a, 1968b) and by Hammond and Garfinkel (1966, 1969). The results of the survey have been publicized in the US Public Health Reports on "Smoking and Health, " which are reproduced and commented upon in Section XIV. The conclusions are once more noted here for comparison with those from other prospective studies. a. High incidence of death from coronary heart disease. After 44 months 2,665 men died, the cause of death in 1, 388 (52. 1°Jo) being coronary artery disease. After 60 months the deaths due to coronary artery disease totaled 14,819. b. Influence of smoking. The death rate from coronary artery disease was directly related to the amount of cigarette smoking by the individual. Among men in all age groups and women under the age of 70, coronary heart disease death rates were much higher im cigarette smokers than in nonsmokers. The highest mortality rate of 5. 6°fc was for the group of men who smoked 40 or more cigarettes a day as compared with the nonsmokers. Within groups of men who were alike in respect of age, relative weight and blood pressure, coronary heart disease death rates increased with the amount of cigarettes smoked. c. Risk factors. In an analysis of risk factors, death rates for coronary heart disease were combined with those for stroke and aortic ~r ~ -T10 30 2-1 06 9
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IV. Mortality and Morbidity Statistics - 10 Page 84 only as a factor related to intermittent claudication. Cigarette smoking bears little relation to angina pectoris. Of all the key factors, cigarette - smoking is the only one whose relative role is enhanced in multivariate analysis-that is, when the other risk factors are considered at the same time. From a biological point of view, it is conceivable that the presence of other atherosclerotic factors is a precondition for cigarette smoking to affect atherosclerotic outcomes, but there is nothing in the statistical analysis bearing on this question (Kannel and Gordon, 1971a, 1971b). T10 30 2-1 074
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IV. Mortality and Morbidity Statistics - 2 Page 76 The special studies are discussed in another section (Section V). The majority of prospective studies are omitted from this section. They appear elsewhere, because the results relate to the importance of risk factors other than cigarette smoking (see Sectio:s VI to VIII). The general articles relating to epidemiology of coronary heart disease are contained in the following list: List No. 11. Epidemiologic Techniques. T10 30 2-1 06 6
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IV. Mortality and Morbidity Statistics - 6 Page 80 aneurysm. The combination of diabetes and a history of high blood pressure is predictive of extremely high death rates. The combination of obesity and cigarette smoking is predictive of high death rates, and that of heavy smoking and a history of high blood pressure of even higher death rates. The predictive death rates for cigarette smoking alone has not been calculated. . 2. Veterans Administration. In 1954, the causes of death among policyholders of US Government life insurance were analyzed. The mortality experience of 200,000 policyholders for 2 years was summarized by Dorn (1958),. 1959). The ratio of men dying of cardiovascular disease was 1.40 for smokers as compared with nonsmokers. 3. Framingham Heart Disease Epidemiology Study. In 1950 an epidemiologic study was begun in Framingham, Mass., and observations have on been mad75,128 adults, who were examined biennially by physicians for a period of up to 16 years. The conclusions reached in follow-up studies made at intervals of an increasing number of years are noted below. Four-year follow-up. There was variability of attack rates, so that it was not possible to make generalizations on morbidity and mortality in heart disease. The data suggest that the association of heart disease with smoking is not as strong as that shown with elevated blood pressure, weight and cholesterol (Dawber, et al. , 1957). Six-year follow-up. Smoking was associated with an increased incidence of nonfatal myocardial infarction and of death from coronary heart disease in men aged 45-62. It was not associated with an increased T10 30 2-1 07 0
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._CV.~ ivwi~aa...y .~.~.. ........._._~ Statistics - 4 Page 78 E IV-A. Initial Prospective Studies The Surgeon General's Report on "Smoking and Health, " which appeared in 1964, contained the results of three prospective studies con- ducted by the American Cancer Society, the Veterans Adminstration and the Framingham Group respectively. In subsequent years the follow-up of subjects by the last-mentioned group has led to a revision of conclusions based on the results of the two other studies. Additional prospective studies have been completed in the following countries: Argentina, Australia, Austria, Belgium, Canada, Czechoslovakia, Finland, France, Germany, Great Britain, Greece, India, Iceland, Israel, Italy, Japan, Netherlands, New Zealand, North Africa, Norway, Peru, Philip- pines, Puerto Rico, South Africa, Sweden, Switzerland, USSR and Yugoslavia. The results are described in Sections IV to V[II and most of the studies are summarized in Table VII-E. - 1. American Cancer Society. Beginning in 1951, over 22, 000 volunteers interviewed residents in nine states, using a questionnaire prepared for the American Cancer Society. The follow-up study of 187, 766 men was periormed aIter 20 1llUnl4o ~iia.iuuLuil 34 months (Hammond and Horn, 1958a, 1958b), after 44 months on a larger group of 442, 094 men (Hammond, 1964), and after 60 months on 804, 409 men "'~~""-'"TI0302-1065
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V. Mortality and Morbidity Statistics - 1 Page 75 IV. MORTALITY AND MORBIDITY STATISTICS IN THE UNITED STATES MORTALITY MORBIDITY - 2Y PROSPFCTtVE STM015 (IN M5.A.1 A. Initial Prospective Studies---- 78 $. Other Prospective Studies---- 88 C. Critique of Mortality Statisties------------------- 96 The most widely quoted reason for the belief that cigarette smoking causes coronary heart disease is that the mortality and morbidity rates are higher for smokers than for nonsmokers. The results of prospective studies of selected groups of individuals form the basis of this statement. The design and conclusions of three early studies relating to mortality caused by coronary heart disease are discussed in this section. The association between cigarette smoking and coronary heart : disease revealed in surveys does not establish a cause and effectrelationshi;p.. There are other risk factors that are known to occur in individuals with coronary heart disease,which are difficult to exclude. In properly designed prospective studies it has been possible to exclude one of the risk factors, so that the role of cigarette smoking has been identified with some certainty. -•-"T10 30 2-1 065
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IV. Mortality and Morbidity Statistics - 11 ON Page 85 BIBLIOGRAPHY - IV. MORTALITY AND MORBIDITY STATISTICS ., A. Initial Prospective Studies . . Reprint DAWBER T R: Coronary heart disease. Morbidity in the Framingham Study . and analysis of factors of risk. BibI cardiol 13: 9-24, 1963. 174 DAWBER T R and KANNEL W B: Computers in epidemiologic research. Circulation Res 11: 587-589, 1962a. - . 175 DAWBER T R and KANNEL W B: Atherosclerosis and you: Pathogenetic . implications from epidemiologic observations. . J Am Geriatr Soc. . 10: 805-8Z1, 1962b. 176 DAWBER T R, KANNEL W B and LYELL L P: An approach to longitudinal studies in a community: The Framingham Study. Ann N Y Acad Sci 107: 539-556, 1963a. 177 DAWBER T R, KANNEL W B and FRIEDMAN G Dc The use of computers . ' in cardiovascular epidemiology. Prog Cardiovasc Dis 5: 406-417, 1963b. , 178 DAWBER T R, KANNEL W B and McNAMARA P M: The prediction of coronary . heart disease. Trans Assoc Life Insurance Med Dir Am 47: 70-105, 1963. 179 DAWBER T R, MOORE F E and MANN G V: Coronary heart disease in the Framingham Study. Am J Public Health 47: 4-24, 1957 180 - DAWBER T R, KANNEL W B, REVOTSKIE N and KAGAN A: The epidemiology of coronary heart disease -- the Framingham enquiry. Proc R Soc Med 55: 265-271, 1962. 181 DAWBER T R, KANNEL W B, REVOTSKIE N,STOKES J, KAGAN A and . . . GORDON T: Some factors associated with the development of coronary heart disease. Six years' follow-up experience in the Frarningham - - study. Am J Public Health 49: 1349-1356, 1959. .. . 18Z DORN H F: The mortality of smokers and nonsmokers. Am Stat Assoc Soc Stat Sect Proc 34-69, 1958. . 183 DORN H F: Tobacco consumption and mortality from cancer and other diseases. Public Health Reports 74: 581-589, 1959. . 184 FRIEDMAN G D, KANNEL W B, DAWBER T R and McNAMARA P M: An . evaluation of follow-up methods in.the Framingham heart study. Am J Public Health 57: 1015-1024, 1967. .- 185 GORDON T and KANNEL W B: Premature mortality from coronary heart disease ' JAMA 215: 1617-1625. 1971. 186 HAMMOND E C: Smoking and death rates -- a riddle in cause and effect. . . Am Sci 46: 331-354, 1958. - 187 HAMMOND E C: Smoking in relation to heart disease. Am J Public Health . 50: 20-26, 1960. 188 , ,,„ , _,,.T10 30 2-1 07 5
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IV. Mortality ann nnoru:.n.:.ty Statistics - 8 Page 82 Twelve-year follow-up. After a decade, every 10th man and every 20th woman developed coronary heart disease; in the men it resulted chiefly in myocardial infarction or sudden death, in the women chiefly in angina pectoris. In order to assess the importance of several risk factors, the incidence of coronary heart disease in a group with a definite value (e. a. , cholesterol 210-220)(observed cases) was divided by the incidence of coronary heart disease in a group of the same age and sex distribution but with a random cholesterol value (expected cases). The figure resulting'from this division x 100, the morbidity ratio, varied with the following risk factors: Cholesterol SystoliCblood pressure Vital capacity ECG anomalies Overweight Cigarette smoking ~ angina pectoris only MR <200 mg %a 55 >260 mg % 178 <120 mm Hg 45 >180 mm Hg 178 '>4Iitres 81 <3 litres 128 none 91 present 203 none 50 present 241* nonsmoker 69 20 cgs/day 158 (Dawber, 1963; Dawber et al. , 1963a, 1963b; Friedman et al. , 1967; Kagan et al<, 1963; Kannel et al., 1965, 1966, 1967j Oberwittler, 1968; Truett et al. , 1967. ) ,~TI0302-1072
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[V. Mortality and Morbidity Statistics - 9 Page 83 Fourteen-year follow-up. Risk of every manifestation of coronary heart disease, including angina, coronary insufficiency, myocardial infarction and sudden death, was distinctly and impressively related to the antecedent level of both systolic and diastolic blood pressure. Risk was not solely related to "hypertension" but was proportional to the level of the blood pressure--even at nonhypertensive pressures-from the lowest to the highest recorded. Also, risk appeared to be related to casual as well ~ to as/mean basal pressures. Risk of coronary heart disease over 14 years was examined prospectively in 2,845 women according to their antecedent cholesterol and lipoprotein years of age status. In women under 50/high cholesterol values, as in men, were associated with an increased risk of coronary heart disease and this was true even when adjustment : made for concomitant pre-beta lipoprotein and other factors related both to coronary risk and to blood lipid content. In women over 50, however, triglyceride-rich pre-beta lipoprotein was superior to cholesterol for identifying potential coronary cases. Risk of coronary heart disease in women is better estimated by cholesterol under the age of 50 and bypre-beta lipoprotein, or by inferente endogenous triglyceride, after that age. (Gordon and Kannel, 1971; Kannel, 1970; Kannel and Castelli, 1972; Kannel and McNamara, 1964; Kannel et al. , 1969. ) Sixteen-year follow-up. Cigarette smoking appears to be one of the important risk factors among men for coronary heart disease and cerebrovascular and peripheral vascular disease. For women it is important TI0302-1073
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CV. Mortality and Morbidity Statistics - 13 Pagc 87 Reprint KANNEL W B, DAWBER T R and McNAMARA P M: Detection of the coronary . prone adult: The Framingham study. J Iowa Med Soc 56: 26-34, 1966. 207 KANNEL W B, SCHWARTZ M J and McNAMARA P M: Blood pressure and risk of coronary heart disease: The Framingham study. Dis Chest 56: 43-52, 1969. 208 KANNEL W B, WIDMER L K and DAWBER T R: Gefahrdung durch coronare - Herzkrankheit. Schweiz Med Wochenschr 95: 18-23, 1965. : . 209 KANNEL W B, KAGAN A, DAWBER T R, and REVOTSKIE N: Epidemiology of - coronary heart disease. Implications for the practicing physician. . . : Geriatrics 17: 675-690, 1962b. - 210 OBERWITTLER W: Anmerkung zur Interpretation der Framingham-Studie. . . Med Weldt 19: 2478-2480, 1968. . . . : 211 ' . REVOTSKIE N, KANNEL W, GOLDSMITH J R and DAWBER T R: Pulmonary function in a community sample. Am Rev Resp Dis. 86: 907-911, 1962. 212 TRUETT J, CORNFIELD J and KANNEL W: A multivariate analysis of the . risk of coronary heart disease in Framingham. J Chronic Dis 20: . _ 511-524, 1967. 213 . TI0302-1077
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[V. Mortality and Morbidity Statistics - 7 Page 81 incidence of angina pectoris. Choleslerol levels were higher among cigarette smokers than among nonsmokers and were also higher among those who had smoked and stopped than among those who had never smoked. Neither weight not blood pressure showed a similar association with smoking (Dawber et al., 1959)• Eight-year follow-up. Heavy cigarette smokers experienced a threefold increase in the incidence of myocardial infarction and in death from all causes as compared with nonsmokers, pipe and cigar smokers and former cigarette smokers. Cigarette smoking is apparently unrelated to the incidence of angina pectoris. Former smokers and cigar and pipe smokers have morbidity and mortality experiences similar to those of individuals who have never smoked (Kagan et al. , 1962). Ten-year follow-up. Observations in the Framingham Study of 5,128 subjects for periods of ten years indicate that many personal characteristics are related to the development of coronary heart disease. The major risks appear to be elevation of the serum cholesterol level and elevation of blood pressure, though there are several other contributing factors. Combinations of factors further augment the risk and characterize a highly susceptible subject. Recommended beneficial changes in these factors appear to be warranted, particularly in persons exhibiting one or more high-risk traits. (Dawber and Kannel, 1962a, 1962b; Dawber et al. , 1962, 1963; Kannel et al, , 1962b; Revotskie et al. , 1962; Dawber, 1963.) .T10 30 2-1 071
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IV. Mortality and Morbidity Statistics - 14 Page 88 IV-B. Other Prospective Studies Fifteen additional prospective studies have been completed in the United States. The design and results are summarized in Table IV-B. The important conciusions are as follows: . 1. Myocardial infarction. All the studies show a high incidence of smoking in patients who develop or die from myocardial infarction. 2. Angina pectoris. Like the Framingham Study, the prospective studies reported by the Albany Group and the Western Collaborative Group did not reveal an association between cigarette smoking and angina pectoris. It is unfortunate that most prospective studies have pooled angina pectoris and myocardial infarction into a single disease entity, so that it was not possible to differentiate their respective relationships to smoking. 3. Other risk factors. The prospective studies indicate that, in patients with coronary heart disease, other risk factors are as frequent as cigarette smoking, if not more so. The factors which have been identified include blood pressure, blood cholesterol levels, diet, physical activity, race and behavior patterns. .,_._...,.,....F..,T10 30 2-1 078
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..i1A. •.L,.civ.,.,..,......-., BIBLIOGRAPHY III. ATHEROSCLEROSIS C. Cerebral Atherosclerosis Page 72 Reprint B_ALOW J, ALTER M and RESCH J A: Cerebral thromboembolism. A clinical . appraisal of 100 cases. Neurology 16: 559-564, 1966. 157 DYKEN M L: Precipitating factors, prognosis, and demography of cerebrovascular disease in an Indiana community: A review of all patients hospitalized from 1963 to 1965 with neurological examination of survivors. Stroke . 1: 261-269, 1970. 158 FOGELHOLM R: Occlusive lesions of the cervical arteries in patients with ischemic cerebrovascular disease. A clinical and angiographic study of 213 patients. . Acta Neurol Scand 46 (Suppl 42): 1-64,, 1970. 159 GORDON T and KANNEL W B: Predisposition to atherosclerosis in the head, - heart, and legs. The Framingham Study. JAMA 227: 661-666, 1972. 160 HADDOCK D R W: Cerebrovascular accidents in Ghana. Trans R Soc Trop Med Hyg 64: 300-310, 1970. •. 161 HAMMOND E C: Smoking in relation to the death rates of 1 million men and women. In: Haenszel, W., editor. Epidemiological approaches to the study of cancer and other dis eases. Bethesda, U. S. Public Health Service, National Cancer Institute Monograph No. 19, 1966. Pp. 127-204. - 162 KAHN H A: The Dorp Study of smoking and mortality among U. S. veterans: report on 8 1/2 years of observation. In: Haenszel, W., editor. Epidemiological approaches to the study of cancer and other diseases. Bethesda, U. S. Public Health Service, National Cancer Institute Monograph No. 19, 1966. Pp. 1-125.163 KANNEL W B: Current status of the epidemiology of brain infaretion associated with occlusive arterial disease. Stroke 2: 295-318. 1971. 164 KANNEL W B, DAWBER T R, COHEN M E and McNAMARA P M: Vascular disease of the brain -- epidemiologic aspects: The Framingham Study. Am J Public Health 55: 1355-1366, 1965. 165 KANNEL W B, GORDON T, WOLF P A and McNAMARA P: Hemoglobin and the risk of cerebral infarction: The Framingham Study. Stroke 3: 409-420, 1914. 16o KIMURA N, TOSHIMA H, NAKAYAMA Y, MIZUGUCHI T, TAKAYAMA K, YOSHINAGA M, FUK.SMI T, TASHIRO H, KATAYAMA F, ABE K, ARIMA T, . YOKOTA Y, MINAGAWA E, TANAKA R, AKIYOSHI T, SOEJIMA K, YAMADA K, MIZUNOE A, NAKAMURA K, OSHIMA F, TANAKA K, AKASU K, NII7.AY.I T, IKEDA H, NAKAMICHI E, AGETA M, MIIKE Y, INOUE T, .• NAKAGAWA T, NANBU D, TANIOKA T, SHIMADA S and FUKUMOTO T: Population survey on cerebrovascular and cardiovascular diseases. The ten years experience in the farming village of Tanushirnaru and the fishing village of Ushibuka. Jap 1Ieart J 13: 118-127, 1972. 167 OSTFELD A M, SHEKELLE R B, TUFO H M, WIELAND A M, KILBRIDGE J A, DRORI J and KLAWANS H: Cardiovascular and cerebrovascular disease in an elderly poor urban population. Am J Public Health 61: 19-29, 1971 168 PAFFENBARGER R 5 Jr., GIMA A S, LAUGHLIN M E and BLACK R A: Character- istics of longshoremen related to fatal coronary heart disease and stroke. Am J Publi.c ]Ionlth 61: 1362-1370, 1971.
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LV. Mortlaity and Morbidity Page 86 Statistics - 12 Reprint HAMMOND E C: The effects of smoking. Sci Am 207: 39-51, 1962 189 HAMMOND E C: Inhalation of tobacco smoke. Conn Med 27: 473-483, 1963. 190 - HAMMOND E C: Smoking in relation to mortality and morbidity. Findings in firsttbirty-four months of follow-up in a prospective study started in 1959. . J Natl Cancer Inst 32: 1161-1188, 1964. . 191 HAMMOND E C: Quantitative relationship between cigarette smoking and death rates. Natl Cancer Inst Monogr 28: 3-8, 1968a. 192 • . HAMMOND E C and GARFINKEL. 1-: • Changes in cigarette smoking 1959- 1965. Am J Public Health 58: 30-45, 1968b. . 193 Natl Cancer Inst Monogr 19: 269-285, 1966. 194 HAMMOND E C and GARFINKEL The influence of health on smoking habfts. HAMMOND E C and GARFINKEL L: Coronary heart disease, stroke, and - aortic aneurysm. Arch Environ Health 19: 167-182, 1969. 195 . HAMMOND E C and HORN D: The relationship between human smoking habits and death rates. JAMA 155: 1316-1326, 1954. . 196 HAMMOND E C and HORN D: Smoking.and death rates -- report on forty-four months of follow-up of 187,783 men. I. Total mortality. JAMA 166: 1159-1172. 1958a. 197 HAMMOND E C and HORN D: Smoking and death rates -- report on forty-four months of follow-up of 187,783 men. II. Death rates by cause. JAMA 166: 1294-1308, 1958b. 198 KAGAN A, DAWBER T R, KANNEL W B and REVOTSKIE N: The Framingham . study: a prospective study of coronary heart disease. Fed Proc 21: 52-57, 1962. 199 KAGAN A, KANNEL W B, DAWBER T R and REVOTSKIE N: The coronary . profile. Ann N Y Acad Sci 97: 883-894, 1963. 200 KANNEL W B: The Framingham study and chronic disease prevention. - Hosp Practice 5: 78-94, 1970. . 201 KANNEL W B and CASTELLI W P: The Framingham study of coronary disease in women. Med Times 100: 173-195, 1972. . . 202 4Aw'nacrr 'nt n_., . _ . a f^.nnnnn. T• T~.- C,...l.r An rn:Aomie+lt+~+~~~ _~__ _.__ ,_. investigationn of cardiovascular disease.y Section 26: Some characteristics related to the incidence of cardiovascular disease and death. U. S. Dept Public Health Se rvice , - 203 I{ANNEL W B and GORDON T: The Framingham Study. An epidemiological investigation of cardiovascular disease. Section 27: Coronary heart disease, atherothrombotic brain infarction, intermittent claudication -- a multivariate analysis of some factors related to their incidence: U. S. Dept Public ' Health Service 204 KANNEL W B and McNAMARA P M: The evidence for excess risk. Minn Med 52: 1197-1201,1964. . . 205 KANNEL W B, CASTELLI W P and McNAMARA P M: The coronary profile: 12-year follow-up in the Framingham study. J.Oceup Mcd 9: 611-619, 1967. 206 -~TI0302-1076
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IV. Mortality and Morbidity Statistics - 3 Additional Bibliographic List No. 11 EPIDEMIOLOGIC TECHNIQUES IN THE UNITED STATES CORNFIELD J: Bayesian estimation for higher order cross-classification. Milibank Med Fund Q 48: 57-70, 1970. CORNFIELD J and HAENSZEL W: Some aspects of retrospective studies. . J Chron Dis 11: 523-534, 1960. . DAVIGNON F: Evolution des maladies chroniques. L'Union Med Can 92: 417-421, 1963. . DAWBER T R and KANNEL W B: Application of epidemiology of coronary .. heart disease to medical practice. Mod Med 30: 85-101, 1962. EPSTEIN F H: Epidemiological approaches to the study of coronary heart disease. Med Times 94: 1455-1470, 1966. Page', 77 A 216 A 217 EPSTEIN F H: Predicting coronary heart disease. JAMA 201: 795-800, _ 1967. A 218 EPSTEIN F H: Multiple risk factors and the prediction of coronary heart . . disease. Bull N Y Acad Med 44: 916-935, 1968. . A 219 . GITTELSOHN A and KINCH 5: Application of life table, analysis and automatic , computer selection of population subgroupings for cardiovascular epidemiologic studies. Ann N Y Acad Sci 126: 767-778, 1965. A 220 GORDON T and KANNEL W B:. Multiple contributors to coronary risk implications - for screening and prevention. J Chron Dis 25: 561-565, 1972. A 221 - KEYS A: Quantitative estimation of risk. Scand J Clin Invest 29: 17-18, 1972. A 222 KEYS A, BLACKBURN H, and. TAYLOR:H L: Predicting coronary heart .. disease. Circulation 44 (Suppl 2): 87, 1972. - A 223 LILIENFELD A M: Epidemiology of cardiovascular diseases. J Chron Dis 18: 697-698, 1965. A 224 MORRIS J N: Epidemiology and cardiovascular disease of middle age: Part II. MOU llURC6ULS l.ar410VaSC 1115 JV: O~J-bJO, ty01. A LG~ STAMLER J: Cardiovascular disease in the United States. Am J Cardiol 10: 315, 319-340, 1962. - A 226 STAMLER J, SCHOENBERGER. J A, LINDBERG H A, SI-lEKELLE R, _ STOKER J M, EPSTEIN M B, DeBOER L, STAMLER R, RESTIVO R, - . GRAY D and CAIN W: Detection of susceptibility to coronary disease. • Bull N Y Acad Med .45: 1306-1325, 1969. - A?27 STEWART G T: Epidemiological approach to assessment of health. Lancet 2: 115-119, 1970. . . A 228 310302-1067
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V. Prospective Studies in Foreign Countries - 8 Page 108 the severity of coronary heart disease related to psychosocial factors but not to smoking, obesity or blood cholesterol levels (Liljefors, 1970; Liljefors and Rahe, 1970; Lundman et al. , 1971). The other results of twin-registry relate to the records of mortality (Friberg et al. , 1970; Cederl6f et alo , 1970) and of respiratory symptoms (Cederlef et al. , 1967). An International Symposium (1971) was held in Puerto Rico to discuss plans for twin registries in several countries. In Denmark, analysis or 1,584 pairs of twins revealed a slight and nonsignificant tendency toward coronary infarction to be associated with heavy smoking. Angina pectoris - was significantly more frequent in cotwins with a higher significant consumption of tobacco than in those who consumed less tobacco or none at all (Hauge et al. , 1970). In 16,000 pairs collected in the United States, the statistics showed an association between smoking and angina. However, it is questionable whether this excess morbidity is causal, since it was not possible to reproduce the association when stud,vinP monozvgotic smoking discordant twin-pairs (Cederlof et al., 1969). The appearance of coronary heart disease in identical twins strongly suggest a greater influence linked through the monozygotic inheritance (Sidd et al. , 1966; Douglas and Arkun, 1969). ,~T10302-1098
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IV. Mortality and Morbidity Statistics - 18 Page 92 ~ BIBLIOGRAPHY ~ IV. MORTALITY AND MORBIDITY STATISTICS B. Other Prospective Studies in the United States Reprint BARRON C: Coronary heart disease: A predictive study involving the aerospace . . manufacturing industry. Aerospace Med 39: 1109-1115, 1968. 214 BERKSON D M, STAMLER J, LINDBERG H A, MILLER W, MATHIES H, LASKY H and HALL Y: Socioeconomic correlates of atherosclerotic - and hypertensive heart diseases. Ann N Y Acad Sci 84: 835-850, 1960. 215 BORHANI N E, HECHTER H H and BRESLOW L: Report of a ten-year follow- up study of the San Francisco longshoremen. J Chron Dis 16: 1251-1266, 1963. 216 BUECHLEY R W, DRAKE R M and BRESLOW L: Relationship of amount of cigarette smoking to coronary heart disease mortality rates in men. • --- --Circulatios 18: 1085-1090, 1958. _ -217 CASSEL J C: Summary of major findings of the Evans County cardiovascular studies. Arch Intern Med 128: 887-889, 1971.J 218 - GASSEL JC: Review of 1960 through 1962 cardiovascular disease prevalence . study. Arch Intern Med 128: 890-895, 1971. 1 219 CHIANG B N. PERLMAN L V, FULTON M, OSTRANDER L D Jr, and EPSTEIN F H: Predisposing factors in sudden cardiac death in Tecumseh, Michigan. Circulation 41: 31-37, 1970. 220 CHIANG B N, PERLMAN L V, OSTRANDER L E Jr, and EPSTEIN F H: Relationshin of premature svstoles to ceronarv heart disease and sudden death . in the Tecumseh epidemiologic study. Ann Intern Med 70: 1159-1166, 1969. 221 . DOYLE J T, HESLIN A S, HILLEBOE H E andFORMEL P F: Early diagnosis of ischemic heart disease. N Engl J Med 261: 1096-1101, 1959. 222 DOYLE J T, DAWBER T R, KANNEL W B, HESLIN A S and KAHN H A: ~ngarette smoning anu coronary nearc usease. ~omoinea experience oi the - Albany and Framingham studies. N Eng1J Med 266: 796-801, 1962. 223 DOYLE J T, DAWBER T R, KANNEL W B, KINCH S H and KAHN H A: The relationship of cigarette smoking to coronary heart disease. The second report of the combined experience of the Albany and Framingham studies. JAMA 190: 886-890, 1964. 224 DRAKE R M, BUECHLEY R-W and BRESLOW L:.. An epidemiological investigation of coronary heart disease in the California health survey population. ' Am J Public Health 47: 43-57, 1957. . 225 EPSTEIN F H: Some uses of prospective observations in the Tecumseh Community . health study. Proc R Soc Med 60: 56-60, 1967. ' 226 EPSTEIN F lI, OSTRANDER L D Jr, JOHNSON B C, PAYNE M W, HAYNER N 5, KELLER J B and FRANCIS T Jr: Epidcmiological studies of cardiovascular disease in a total eommunity -- Tecumseh, Michigan. Ann Intern Med 62: 1170-1187, 1965. T10302-1082
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Statistics - 16 Table IV-B. (continued) 'Investifation and Design Y Affect of Cigarette Smoking_ Page 90 Other Risk Factors V Teumsch, Michi;an Smoking has no influence on preva- 8,641 persons around 1956-1960. lence of coronary heart disease on initial examination of subjects Chiang et al. ; 1969, 1970 . . ht l S k h l i Epstein 1967 Epstein et al., 1965 ower we , ower mo ers ave g diastolic blood pressure and serum uric acid Higgins and Kjelsberg 1967 . Higgins and Keller 1970 . Incidence of sudden death in persons with antecedent ventricular pre- mature systoles are independent of smoking habits. Chicago Board of Health 1, 329 men observed for 9 years. . Berkson et al., 1960 . . Kjelsberg and Stamler 1960 $tamler 1964a, 1964b, 1968, . Shekelle et al„ 1969 Cigarette smoking as a sole factor is associated with a marked increase in risk. Mortality rate for myo- cardial infarction is 10 times higher than for low-risk groups. Hypercholeate rolemia Hypertension. Western Electric Co. of Chicago Association of cigarette smoking, most Elevatedd blood cholesterol 1, 989 men observed for 44 years of adult life with subsequent de- m nt of coronar disease velo Use of coffee. Paul et al., 1963 y p e University of Minnesota Smoking habit and body weight seemed Age. 11. 132 for 5 years. •unimportant-in predicting heart Systolic pressure. , 279 for 20 years - disease Serum cholesterol. . . Keys et al. ; 1971. 1972 Diet. North Dakota State Dept. 1, 886 males interviewed. Zukel et al. 1959 Higher incidence of coronary heart disease among smokers. \r.. •..A: C...nl.: i.. :A ~ nP 508 adults for 6 years. Fulmer and Roberts 1963 --coronary heart disease. nq t, Southwestern American Indians Cigarette smoking rare; low inci- 15, 905 adults from 1957 to 1966. Sievers 1967, 1968 dence of coronary heart disease. M Western Collaboration Group Study Fatal.cases have higher frequency of Overt behavior pattern. . smoking; silent infarction or angina Hypertension. 3, 000 subjects since 1960. '- Barron 1968 Jenkins et al.; 1968a, 1968b pectoris not associated with smok- ing. Abnormal 1 ipoprotein pattern. Roscnman 1968 Rosenman ct al.; 1966, 1967a, b, c; 1968, 1970 PPsTI0302-1080
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V. Prospective Studies in Page 113 Foreign Countries - 13 BIBLIOGRAPHY V. INFORMATIVE PROSPECTIVE STUDIES IN FOREIGN COUNTRIES C. International Comparisons of MortalityStatistics. Reprint HIGGINS I T T, LOCKSHIN M D, GILSON J C, COCHRANE A L, CAMPBELL H, WATERS W E, FERRIS B G Jr, OH M and HIGGINS M W: Coronary disease in Staveley, Derbyshire with an international comparison with three towns in Marion County, West Virginia. J Chron Dis 25: 567-580, 1972. - 326 KEYS A: Coronary heart disease in seven countries. Am Heart Assoc Monogr 29: 1-211, 1970. 327 MULCAHY R, McGILVRAY J W and HICKEY N: Cigarette smoking related to geographic variations in coronary heart disease mortality and to expectation . of life in the two sexes. Am J Public Health 60: 1515-1521, 1970. 328 PAUL 0: The international cooperation study in epidemiology. Circulation 41: 895-897, 1970. 329 - REID D D, HOLLAND W W and ROSE G A: An Anglo-American cardiovascular - comparison. Lancet 2: 1375-1378, 1967.. , . 330 REID D D, CORNFIELD J, MARKUSH R E and SEIGEL D: Studies of disease among migrants and native populations in Great Britain. Norway, and the United . States. Natl Cancer Inst Monogr 19: 321-346, 1966. 331 ROSE G A, AHMETELI M, CHECCACCI L, FIDANZA F, GLAZUNOV I, DE HAAS,J, HORSTMANN P, KORNITZER M D, MELONI C, MENOTTI- A. VAN DER SANDE D, DE SOTO-HARTGRINK M K, PISA Z and - - THOMSEN B: Ischaemic heart disease in middle-aged men. Bull WHO 38: 885-895. 1968. 332 STOCKS P: Heart disease mortality in cities of Latin America and in cities and regions of F.ngland and Wales. Bnll WHO 40: 409-423, 1969. 333 WORLD HEALTH ORGANIZATION: Cardiovascular disease mortality. - WHO Epidemiol Actal Stat Rep 16: 115-205, 1963. 334 T10302-1103
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IV. Mortality and Morbidity Statistics - 21 Page 95 Reprint SHAPIRO S, WEINBLATT E, FRANK C W and SAGER R V: The H.I. P. . study of incidence and prognosis of coronary heart disease. Preliminary findings on incidence of myocardialinfaretion and angina. J Chron Dis 18: 527-558, 1965. 257 SHAPIRO S, WEINBLATT E, FRANK C W, SAGER R V and DENSEN P M: The H.I. P. study of incidence and prognosis of coronary heart disease: methodology. J Chron Dis 16: 1281-1292, 1963. . 258 SHEKELLE R B, OSTFELD A M and PAUL 0: Social status and incidence of coronary heart disease. J Chron Dis 22: 381-394, 1969. . 259 SIEVERS M L: Cigarette and alcohol usage by southwestern american indians. Am J Public Health 58: 71-82, 1968. 260 SIEVERS M L: Myocardial infarction among southwestern american indials. ` Ann Intern Med 67: 800-807, 1967. . 261 STAMLER J: Atherosclerotic coronary heart disease. The major challenge to contemporary public health and preventive medicine. Alaska Med 6: 91-105, 1964a. 262 STAMLER J: Atherosclerotic coronary heart disease. The major challenge to - contemporary public health and preventive medicine. Conn Med 28: 675-692, 1964b. 263 STAMLER J: Cigarette smoking and atherosclerotic coronary heart disease. , Bull N.Y Acad Med 44: 1476-1494, 1968.. 264 THORNE M C, WING A L and PAFFENGARGER R S Jr: Chronic disease ,. in former college students. VII. Early precursors of nonfatal coronary heart disease. Am J Epidemiol 87: 520-529, 1968. . . 265 WEINBLATT E, FRANK C W, SHAPIRO S and SAGER R V: Prognostic factors in angina pcctoris -- a prospectvc study. J Chrca Dis 21: 231-2,5, 1963a. 266 WEINBLATT E, SHAPIRO 5, FRANK C W and SAGER R V: Prognosis of men after first myocardial infarction: mortality and first recurrence in relation to selected parameters. Am J Public Health 58: 1329-1347, 1968b. 267 WEIR J M and DUNN J E Jr: Smoking and mortality: A prospective study. Cancer 25: 105-112, 1970. 268 WYNDER E L and LEMON F R: Cancer, coronary artery disease and smoking. A preliminary report on differences in incidence between seventh-day , , Adventists and others. Calif Med 89:267-272, 1958. _ 269 . WYNDER E L, LEMON F R and BROSS I J: Cancer and coronary artery disease . among seventh-day Adventists. Cancer 12: 10I6-1028, 1959. 270 ZUKEL W 3, LEWIS R H, ENTERLINE P E, PAINTER R C, RALSTON L S, PAWCETT R M, MEREDITH A P and PETERSON B: A short-term community ' study of the epidemiology of coronary heart disease. A preliminary report on the North Dakota study. Am J.Aiblic Health 49: 1620-1639. 1959. 271 T10 30 2-1 08 5
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V. Prospective Studies in Foreign Countries - 11 Page 111 V-C. International Comparisons of Mortality Statistics The World Health Organization (1963) has published the cardiovascular disease mortality for various countries. Several comparisons have been made between countries to determine the relationship of smoking to coronary heart disease. 1. Geographic variation in cigarette consumption. Mulcahy et al. (1970) noted a significant positive association between cigarette consumption and coronary heart disease mortality in 21 countries, including the United States, Great Britain, Sweden and Finland. In 15 of these countries, there was a significant association between total cigarette consumption and excess female/male expectation of life, which may be accounted for by the documented or assumed heavier smoking by males. The authors interpreted their results as consistent with, but not proof of, the hypothesis that cigarette smoking is a significant risk factor in coronary heart disease mortality. 2. Importance of blood prco-sure. The other comparisons concidered risk factors not related to smoking in patients with coronary heart disease. In 600 middle-aged men similarly employed in England and in the Eastern United States, the prevalence d chest pain and electrocardiographic evidence of cardiac ischemia are significantly more common among the American men, particularly those over 50 years of age (Reid et al. , 1967). The higher blood pressure observed in Americans is readily explained by their greater body weight and skinfold thickness. Although there are differences in smoking habits, it is suggested that factors associated with ,.,,a..,,.,.,,,,.T10302-1101
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Page 114 PART FOUR RISK FACTORS FOR CORONARY HEART DISEASE VI. . Fixed Risk Factors VII. Preventable Risk Factors VIII. Preventable Risk Factors Probably Influenced by Cigarette Smoking In recent years, the statistics of mortality and morbidity have been cited as supporting the hypothesis that cigarette smoking causes coronary heart disease. The major objection to the use of statistics is that the pathogenesis of coronary heart disease is of a complex nature. There are several risk factors, including cigarette smoking, which are known to predispose individuals to develop coronary heart disease. However, the importance of risk factors relative to cigarette smoking has not been dete rmine d. For the purpose of this review, the risk factors are divided into two groups comprising preventable and nonpreventable or fixed risk factors. The former group has been further divided into those that are probably influenced by cigarette smoking and those that are not. Since most of the literature cited in these sections pertains to the epidemiology of coronary heart disease, the geographical location of each investigation is specified. ___ . _~.N _TI0 30 2-1104
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VI. Fixed Factors - 7 List No. 15 Page 120 . - Reprin MORDKOFF A M and PARSONS 0 A: The coronary personality: A critique. Psychosomatic Med 29: 1-14, 1967. A 31( REDAKSIE V D: Emotional stress, tobacco smoking and ischaemic heart - disease. S Afr Med J 41: 293, 1967. A 31: RIMfJ B and MERTENS C: L~incidence des facteurs psychologiques et socio-culturels dans Vetiologie des affections coronariennes. . . Ann Med Psychol 1: 43-60, A 31'< ROSENMAN R H: The role of personality and behavior patterns in the genesis of coronary heart disease. J Am Med Women Assoc 20: 161-167, , 1965. A 31: ROSENMAN R H: Emotional patternss in the development of cardiovascular disease. - J Am Coll Health Assoc 15: 211-214, 1967. - A 314 ROSENMAN R H: Emotional factors in coronary heart disease. Postgrad Med . 42: 165-171, 1967. . A 31_ RUSSEK H I: Emotional stress and the etiology of coronary artery disease. . AmJ Cardiol 2: 129-134. 1958. A 31( . RUSSEK H I: Emotional stress and coronary heart disease in American . . physicians, dentists and lawyers. Am J Med Sci 243: 716-726, 1962. . A 31'~ . RUSSEK H I: Emotional stress in the etiology of coronary heart disease. - Geriatrics 22: 84-89, 1967. . ; . A 311 RUSSEK H I: Role of emotional stress in the etiology of clinical coronary heart disease. Dis Chest 52: 1-9, 1967. RUSSEK H I and RUSSEK L G: Etiologic factors in ischemic heart disease. Geriatrics 27: 81-86, 1972. . A31 A 321 SPRAGUE H B: Emotional stress and the etiology of coronary artery disease. . Circulation 17: 1-4, 1958. . A 32 SPRAGUE H B: Emotional factors in coronary heart disease. Circulation 23: 648-654, 1961. A 32 STRAUBE K H: Epidemiologie und Dispensairebetreuung der Koronarerkrankungen. Z Ges Inn Med 21: 582-587, 1966. A 32 THEORELL T and RAHE R H: Behavior and life satisfactions characteristics of Swedish subjects with myocardial infarction. J Chron Dis 25: . 139-147, 1972. A 32 THOMAS C B and GREENSTREET R L: Psychobiological characteristics in youth , as predictors of five disease states: suicide, mental illness, hypertension, . coronary heart disease and tumor. Johns Hopkins Med J 132: 16-43, 1973. . A 32 THOMAS C B and ROSS D C: Precursors of hypertension and coronary disease among healthy medical students: discriminant function analysis. ' Johns Hopkins Med J 122: 196-217, 1968. . A 32 "T10302-1110
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V. Prospective Studies in Foreign Countries - 12 Page 112 excessive adiposity of the Americans are the more likely explanations of their adverse.experience in cardiac disease. Clerical workers drawn from 5 European countries were examined in a collaborative study (Rose et al. , 1968). The results of a standard questionnaire sent to 4,52Z subjects and of electrocardiograms in some cases indicate a high prevalence of coronary heart disease in all countries. Cigarette smoking was not associated with prevalence of this disease. An elevated blood pressure was the most consistent risk factor. Higgins et al. (1972) compared miners in the United States with those in Great Britain and concluded that blood pressure, rather than weight and smoking, has the most striking association with prevalence of coronary heart disease. The international comparisons of Reid et al. (1966) and of Stocks (1969) did not include a comparison of blood pressure, cigarette smoking and mortality from coronary heart disease. 3. Importance of blood_cholesterol level. The epidemiology of coronary heart disease in 7 countries has been reported by Keys et al. (1970) and have publishe supplements to the Acta Medica Scandinavica and to Circulation. The most consistent theme of the reports is that inhabitants of the geographic areas characterized by serum cholesterol values of approximately 200 mg % have a relative immunity to coronary atherosclerosis and its complications. Cigarette smoking clearly appeared to be a significant risk factor in American railroad employees but this was less certain in the other countries (Paul, 1970). T10302-1102
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VI. Fixed Factors - 13 Page 126 VI-B. Sex as a Risk Factor The importance of coronary heart disease as a cause of death in women has been overshadowed by the magnititude of this disease in men. The male to female ratios of coronary deaths range from 2 to 6. In recent years, the total number of females dying from coronary heart disease has been slowly increasing. One cause is the earlier onset of the menarche and of the menopause compared with several decades ago (Mills, 1937). The female gonadal hormone is believed to retard coronary heart disease, and, when estrogen production subsides following the menopause, there is a sharp increase in mortality (Furman, 1968; Klink, 1970; Paulussen, 1970). Another explanation proposed for the increasing incidence of coronary heart disease is the rising consumption of cigarettes among women (Hartroft, 1956). An examination of women who develop coronary heart disease indicates that there is a wide range of incidence of smoking, from 20 to 90 % (Tab1eVl-B). In the same surveys, the fol.loyzing riok factors have been identified as prevalent in female patients: hypertension (James et al. , 1955; Mulcahy et al. , 1967a, 1967b; Dorken, 1967), hypercholesterolemia (Oliver, 1971), diabetes (James et al. , 1955) and overt behavior pattern (Rosenman and Friedman, 1961). It has not been possible to assess the importance of these risk factors relative to cigarette smoking in females who suffer from coronary heart disease. .T10 30 2-1 1 1 6
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Page 115 VI. FIXED RISK FACTORS AGE 9E% ' - - ETHNIC GENETIC ~ PAYILIAL T CON$TITUTIONAI C16ARETTi ~pSYCqpp[NiG $40%IN ~G - NYVEP NSIO. NYPENCNOLE:TENOLEWA ' 1 YIN yi PI%ED RWC p6TOR$ A. Age and the Prevalence cf Coronary Heart Disease------- 122 B. Sex as a Risk Factor---------- 126 C. Genetic Factors-------------- 129 D.. Psychogenic Factore---------- 134 The prevalence of coronary heart disease is determined by age, sex, and genetic and psychogenic factors. The last two of these are interrelated in that the behavioral pattern of a coronary patient is actually an inherited trait, but it may also be influenced by socioeconomic conditions, discussed in Section VII. The list of genetic factors includes the ethnic group, familial predisposition, and constitutional features. An individual who inherits the predisposition to coronary heart disease is more likely to acquire the smoking habit. The predisposition to develop hypertension and hyper- cholesterolemia can also be inherited but these are discussed in Section VII, since both factors can be either controlled or prevented. The articles relating to fixed risk factors are in the following additional bibliographic lists: List No. 13. Risk factors in coronary heart disease. List No. 14. Risk factors in coronary heart disease in the young adult. List No. 15. Stress and psychogenic factors in coronary heart disease. ~~ ,:..----.,..T10302-1105
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VI. Fixed Factors - 4 List No. 13 Page 117 Reprir NOBREGA R T, OXMAN H A, CONOLLY D C, ELVEBACK L R, TITUS J L - and KURLAND L T: The high risk patients with angina pectoris. Circulation 46 (Suppl 2): 96, 1972. . A?6( PAPADOPOULOS C: Risk factors and coronary disease. Maryland State Med J 17: 106-107. 1968. A 46; PASINI G: Problemi quotidiani del Medico. Fattori predisponenti dell'infarto . mioeardico:~ Minerva Med 60: 109-110, 1969. . _A 26: PASQUAZZI M: Rassegna sintetica. I fattori di rischio coronarico. Policlinico 78: 575-587, 1971. . A 26: - RAAB: W: Pathophysiological fundamentals of the origin and prevention of. .. degenerative heart disease. Ann N Y Acad Sci 156: 281-284, 1969. A 26( REID D Di Discussion. Am J Public Health 50: 29-30. 1960. A 26'- ~SACKETT DL and WINKELSTEIN W Jr: The epidemiology of aortic and peripheral - atherosclerosis. J Chron Dis 18; 775-795, 1965. .. A 26( SCHXR M: Gcfahrdung von Betriebsangehorigen durch Herz-und Kreislaufkrankheiten. Z Praventivmedizin 14: 109-112,1969. .. . . . . A 26i SCHILLING R S F: Changing concepts in occupational health. Am J Public Health 59: 1366-1375, 1969. A 261 -SCHOENBERGER JA, STAMLER J, LINDBERG HA, SHEKELLE R, STOKER JM: ' . Detection of coronary-prone persons: The Chicago Heart Association Project _ in Industry. Circulation 40 (Suppl 3): 223, 1969. _ . A 26! SIMBORG. D W: The status of risk factors and coronary heart disease. J Chron Dis 22: 515-552, 1970. A 27( . SPRAGUE H B: Environment in relation to coronary artery disease. Arch Environ . Health 13: 4-12, 1966. . .. A 27. STRAUBE K-H and LAFRENZ M: iJber bcgunstigende Faktoren der Angina pectoris. Dtsch Gesundheitsw 534-541, 1966. A 27; WARKENTIN D L: Risk factors in coronary artery disease. I Iowa Med Soc . 58: 1137-1141, 1968. A 27: _. WAKERLIN G Ec Reducing the risk factors of coronary heart disease. d Rehabil - 32: 21-22, 1966. . ~ ~ A 27, , WEGMANN T: Epidemiologie und Pathogenese des Herzinfarktes. Hippokrates 38: 104-106, 1967. A 27! WHITAKER W: Etiology of coronary disease. Practitioner 202: 207-215, 1969. A 27 WIDMER L K, HARTMANN G, DUCHOSAL F and PLECHL S C; Risikofaktoren und Gliedmassenarterien-Versehluss. Dtsch Med Wochenschr 94: . 1107-1110, 1969. A 2' WYNN A: The recognition of coronary proneness. Med J Australia 1: 350-353, 1967. A 2' p~,,.,T10 30 2-1107
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VI. Fixed Factors - 12 Page 125 Reprint ROTH O, BERKI A and WOLFF G D: Long range observations in fifty-three young patients with myocardial infarction. Am J Cardiol 19; 331-338, 1967. 350 ROTH 0 and.PEPE A V: Myocardial infarction in young males. Conn State Med J 21: 12-15, 1957. 351 . .SIDD J J, KEMP H G and GORLIN R: Acute myocardial infarction in a . nineteen-year-old student in the absence of coronary obstructive disease. N Engl J Med Z8Z: 1306-1307, 1970. . 352 THOULD A Kc Coronary heart disease in the aged. Br Med J 2: 1089-1093, 1965. 353 WALKER W J and GREGORATOS G: Myocardial infarction in young men. - Am J Cardiol 19: 339-343, 1967. 354 WHITE P D: Coronary disease and coronary thrombosis in youth. J Med Soc N J 32: 596-605, 1935. 355 WHITE P D: The epidemiology of heart disease. Bull N Y Acad Med 33: 819-837, 1957. 356 4) T10 30 2-1 11 5
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VI. Fixed Factors - 8 List No. 15 Page 121 Reprint THOMAS C B: Suicide among us: can we learn to prevent it? Johns Hopkins Med J 125: 276-285, 1969. . A 327 WARDWELL W I, HYMAN M and BAHNSON C B: Socio-environmental . antecedents to coronary heart disease in 87 white males. Soc Sci Med 2: 165-183, 1968. A 328 T10 30 2-1 1 1 1
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VI. Fixed Factors - 10 Page 123 Table VI-A. Controlled retrospective studies of,young male adults with coronary heart disease Country Coronary Heart Disease Control Investigator No. % Smokers % Smokers I f United States White (1935) 28 100 Gertler et al. ,(1951) 100 81 76 Roth and Pepe (1957) 20 90 Hatch et al. (1966) 24 96 70 Roth et al. (1967) 53 87 Walker and Gregoratos (1967) 100 87 Sidd et al. ( 1970) 1 0 'Nizet and Robertson (1971) 1 0 ® Czechoslovakia Jakuszewska (1969) 22 45 France Bolens and Ferrero (1967) 1 100. Germany Dorken (1967, 1968) _205 99 82 Gsell (1966) 2 100 hungary Lukl and Weinberg (1963) 31 86 India Mukerjee (1968) 15 33 , 63 Bahl et al. (1970) 29 52 68 AN Mexico Ivbleiro and Medina Briceno (1968) 84 74 Estandia Cano et al., (1971) 84 94 Poland Ciswieka - Sznajderman et al.(1971) 60 97 75
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VI. Fixed Factors - 5 Page 118 Additional Bibliographic List No. 14 RISK FACTORS IN CORONARY HEART DISEASE IN THE YOUNG ADULT BANERJEA J C: Precocious ischaemic heart disease: Indian Heart J 19: 1-2, 1967. BOYLE C M: Some factors affecting the smoking habits of a group to teenagers. Lancet 2: 1287-1289, 1968. CONNALLY N T: Early detection of disease in young men. Med Ann D. C. 38: 672-676, 1969. ENZI G: Clinical and metabolic aspects of juvenile myocardial infarction. Circulation 40 (Suppl 3): 8, 1969. . _ ., FIEGEL G: Risikofaktoren bel "juvenilen" Herzinfarkten. Munch Med Wochenschr 111: 2020-2022, 1969. Reprin- A 279 A 280 A 281 A 282 A 283 GROSSMAN L A and BURKO H: Diminutive coronary arteries and congenital coronary anomalies: Interesting cause of angina and myocardial infarction _ in the young. J Tenn Med Assoc 61: 687-693, 1968. •A 284 HANSEN J P H: Coronary death in younger persons. Dan Med Bull 15: 301-313, 1968. A 285 ./ HOOD B, TIBBLIN G, WELIN G, ORNDAHL G and KORSAN-BENGTSEN K: . Myocardial infarction in early age. Acta Med Scand 185: 241-251, . . 1969. A 28E KAPLAN A S: Acute myocardial infarction in patients thirty-five years of . age and under. Dis Chest 51: 137-147, 1967. . - A.28i KULLER L, LILIENFELD A and FISHER R: Sudden and unexpected deaths in young adults. JAMA 198: 248-252, 1966. .. A 28f NIEVEEN J, DOORENBOS H, CHAPPIN J•J M L, HARTMAN L A, MAY J F, . . TEMMEM-BRAK M T M, VISSER J W E, VAN DE WALL E and . . WOUDA A A: Risicofactoren voor coronaire hartziekten bij jonge managers. (Coronary disease risk factors in young managers). Ned Tijdschr Geneeskd lli: 1.).ia-AL~/, 1771. . , r.2., NIEVEEN J, CHAPPIN J J M L, MAY J F, HARTMAN L A, VAN DE WALL E and WOUDA A A: Ischaemic heart disease risk factors in young managers. .- Br Heart J 33: 149-150, 1971. .. A 291 SAPHIR 0, OHRINGER L and SILVERSTONE H: Coronary arteriosclerotic heart : disease in the younger age group: its greater frequency in this group among an increasingly older necropsy population. Am J Med Sci 231: 494-501, 1956. THOMAS C B: Characteristics of smokers compared with nonsmokers in a population of healthy young adults, including observations on family history blood pressure, heart rate, body weight, cholesterol and certain psychologic traits. Ann Intern Med 53: 697-718, 1960. ZAMPA S, PIN R and PELLEGRINI M G: Un'inchicsta sull'abitudine al fumo fra gli studentidclle scuole medic superiori di Camerino. A29 A 29~ -^°~,,~~n °.:•ea,se~a~T10302-1108
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VI. Fixed Factors - 9 Page 122 VI-A._ Age and the Prevalence of Coronary Heart Disease Coronary heart disease appears more frequently in the elderly (Thould, 1965). It was stated in Section IV that the association between cigarette smoking and coronary deaths is more conspicuous in the younger age group (see also bibliographic List No. 14). This is supported further by the examination of patients under 40 years of age who develop coronary heart disease. Of the 18 investigations listed in Table VI-A, 8 show an incidence of smoking exceeding 90%. There are 10 reports in which the patients are either nonsmokers or smokers who are less numerous among the controls. The high incidence of smoking among the young patients developing coronary heart disease does not necessarily mean that cigarette smoking is the cause. The following risk factors have been identified as equally important in the pathogenesis of the heart disease: family history (White, 1935; Roth and Pepe, 1957); lack of exercise ('vviiite,. 1957); increased blood cholesterol (Gertler et al. , 1951; Hatch et al. , 1966; Walker and Gregoratos, 1967; Bahl et al. , 1970); imparied glucose tolerance (Hatch At aI. ~o(f1; -smmnrnhir hndyhnild (Gertler et a.l.. 19517 Rothand Pene. 1957) .Nanda, 1967); obesity (Walker and Gregoratos, 1967); and nervousness (Roth et al. , 1967). There is no survey which indicates that cigarette smoking is the only important risk factor. (Table VI-A appears on the next page. ) T10302-7772
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VI. Fixed Factors - 3 Additional Bibliographic List Nu. 13 RISK FACTORS IN CORONARY HI:ART DISEASE. ACHESON R M: The etiology of coronary heart disease: A review from • the epideatiological standpoint. Yale J Biol Med 35: 143-170, 1962. BELLET S and ROMAN : The predictability of coronary heart disease. In: Coronary Heart Disease, A N Brest, editor. F. A. Davis . - Co., Philadelphia, 1969, pp 80-97. - A 242 CLOAREC M:: Les facteurs de risque dans la maladie coronarienne. . A 243 DAWBER T R: The risk of coronary heart disease. Heart Bull 18: 43-46, 1969. - A 244 DAWBER T R and KANNEL W B: Susceptibility to coronary heart disease. Mod Concepts Cardiovasc Dis 30: 671-676, 1961. A 245 DAWBER T R and THOMAS H E: Die Epideamiologie des Schlaganfalls. - Dtsch Med J 5: 33-43, 1969. - A 246 DOYLE J T: Etiology of coronary disease: risk factors influencing coronary disease. Mod Concepts Cardiovasc Dis 35: 81-86, 1966. A 247 EDITORIAL: Identifying the coronary prone. JAMA 203: 799-800, 1968. A 248 FEJFAR Z: Risk factors in ischaemic heart disease. Acta Cardiol - Suppl 25: 7-35, 1972. A 249 FEJFAR Z and PISA Z: Ischemicka choroba srdecni Prognoza, leceni, rehabilitace a prevence. (Ischaemic heart disease. Prognosis, treatment, rehabilitation, prevention). Cas Lek Ces 109: 477-482, 1970. A 250 FLIPSE M J: Pathogenesis of coronary artery disease. JAMA 172: 1130-1133, 1960. GERTLER M M, WHITER H H and WELSH J J: Assessing the coronary profile. . Geriatrics 22: 121-132, 1967. A 252 HINKLE L E Jr.: Some social and biological correlates of coronary heart disease. Soc Sci Med 1: 129-139,. 1967. . .. A 25-' JOUVE A, MALFROY P and CALVIN P: Les facteurs etiologiques de Vangor coronarien. A ctual Cardiol AnReiol Int 12: 19-24, 1963. A 259 KEYS A: Epidemiology of coronary heart disease -- status in 1967. . . Circulation 36 (Suppl 2): 1, 1967. A 25! KEYS A and BLACKBURN H: Background of the patient with coronary heart . - disease. Prog Cardiovasc Dis 6: 14-44, 1963. A 25E KRITSIKIS S, WARNKE D and PARSI R A: Die Bedeutung der einheitlichen - KrankengeschichtenfiSr die Erfassung der Risikofaktoren bei Koronar- patienten. Ber Gcs Inn Med 5: 75-77, 1967. A 25i MATTS S G F: Coronary thrombosis. Br J Clin Pract 24: 545-547, 1970. A 25f MODAN B: Epidemiology of coronary heart disease. J Isr Med Assoc 59: 431-440, 1970. A 25', '-°•°T10 30 2-1 1 0 6
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VI. Fixed Factors - 17 Page 130 registries established in Sweden and other countries have proven the importance of genotypes in the prevalence of coronary heart disease (see Section V-B). A similar conclusion holds for the hypertension and - arteriosclerosis in monozygotic twins (Liebegott, 1965). 1. Ethnic groups. Several reports cited elsewhere in this review indicate the predominance of coronary heart disease in white males compared with black men. The prospective survey conducted by Cassel et al. (1971) in Georgia revealed that, of 143 new cases of coronary heart disease occurring in a seven-year period, the adjusted incidence rate/1,000 was 83 for white and 24 for black males. The females did not show a significant difference, the rate/1,000 being 38 for whites and 34 for blacks. The South African Bantu and the people of India are less prone to develop coronary heart disease (see review by Walker, 1969). 2. Family history. The hypothesis that coronary heart disease is at least in part a hereditary disorder is based on prevalence studies (Russek, 1959; Meigs, 1966). It has been noted that, by interviewing students, y the greates proportion of affected persons was always found among the offspring of 2 affected parents and the smallest among the offspring of 2 unaffected parents (Thomas, 1959). The importance of an inherited predisposition was arrived at by interviewing 75 survivors of myocardial infarction (Rose, 1964), by correlating absenteeism with reported causes of parental death in a group of 98 men, and in a comparison of death rates of individuals with longevity of their parents and grandparents (Hammond et al. , 1971). T10 30 2-1 1 2 0
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VI. Fixed Factors - 14 Table VI-B. Controlled retrospective studies of female adults with coronary heart disease Page 127 Country Coronary Heart Disease Control Investigator ~ No. % Smokers % Smokers United States James et al. (1955) 112 20 Eliot and Bratt (1969) 15 53 7 Rosenman and Friedman (1961) 29 38 45 France Jouve et al. (1966) 330 24 14 Germany D'orken (1967) 20 90 33 -Wink and Hager (1972) 273 60 4 Great Britain Mulcahy et al. (1967a) (1967b) 100 63 46 K_ enya OJiambo (1968) 1 0 T10 30 2-1 11 7
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VI. Fixed Factors - 22 Page 135 (Teculescu et al. , 1972; Segers and Mertens, 1972). An estimation of multivariate logistic risk function including personality and smoking habits has been attempted by Halperin et al. (1971). T10302-1125
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VI. Fixed Factors - 19 Page 13Z Neapolitan parentage but of American birth or upbringing, the lean men smoked significantly more than the fat ones. Smoking was not associated with morphological masculinity. In a study of American-born college students X by Baer (1966), heavy smokers were significantly raller than light smokers, former smokers and nonsmokers. The relevance of these observations to coronary heart disease need to be investigated. pT10302-1122
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VI. Fixed Factors - 6 Additional Bibliographic List No. 15 VI. FIXED RISK FACTORS STRESS AND PSYCHOGENIC FACTORS IN CORONARY HEART DISEASE Reprint ADLER H M and HAMMETT V B 0: The psychosomatics of coronary heart . disease. In: Coronary Heart Disease, A N Brest, editor, F. A. . Davis, Philadelphia, pp. 64-77, 1969. . • A 294 ASKANSAS Z, LISZEWSKA K and TYLKA J: Interaction between psychic and somatic risk factors of myocardial infarction. Scand J Rehabil Med 2: 85-86, 1970. , A 295 BAHRMANN E: Die Angina pectoris im Aspekt ihrer Korrelation mit biologischer Disposition, psychologischen und sociologischen Einflussfarktoren. Dtsch Gesundheitsw 25: 1050-1051, 1970. CAFFREY B: A review of empirical findings. Millbank Mem Fund Q _45: 119-139, 1967. A 296 A 297 GARRUTHERS M E: Aggression and atherorna. Lancet 2: 1170-1171, 1969. A 298 CHRISTIAN P: Interdependenz von Umwelt und Person am Beispiel des -. Herzinfarktes. Psychother Psychosom 16: 210-223, 1968. A 299 EASTWOOD M R and TREVELYAN H: Stress and coronary heart disease. J Psychosom Res 15: 289-292, 1971. A 300 FRENCH J R P and CAPLAN R D: Psychosacial factors in coronary heart disease. Ind Med Surg 39: 31-45, 1970. . A 301 HAHN P: Psychosomatische Aspekte des Infarktprofiles: Psychother Psychosom 16: 224-232, 1968... A 302 JENKINS C D: Appraisal and implications for theoretical development. - Millbank Mem Fund 0 45: 141-150, 1967. . A 303 JENKINS C D: Psychologic and social precursors of coronary disease. *>>•'`n+' t a+_A 9on. 1n0_219 1071 KASANEN A, KALLIO V and FORSSTROM J: The significance of psychic and . socio-economic stress and other modes of life in the etiology of myocardial . infarction. Ann Med Intern Fenn 52 (Suppl 43): 5-40, 1963. A. 4n1 ., A 305 LENZNER A S and ARONSON A L: Psychiatric vignettes from a coronary care • unit. Psychosom 13: 179-184, 1972. A 306 LUMINET D: L'infarctus du myocarde et ses aspects psychosomatiques, Bruxelles Med 49: 159-167, 1969. A 307 MERTENS C and SEGERS M J: L'influence des facteurs psychologiques dans . la genese des affections coronariennes. Bull Acad R Med Belg 11; 155-199, 1971. A 308 MORDKOFF A M and COLAS R M: Coronary artery disease and response to the Rosenzweig picture-frustration study. J Abnormal Psych 73: 381-386, 1968. A 30S a ~es~,~-~~ r_e ., . TI0302-1109 ..Page 119
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VI. Fixed Yacturs - 15 BIBLIOGRAPHY VI. FIXED RISK FACTORS B. Sex as a Risk Factor. Page 128 Reprint u AORKEN H: Die Rauchgewohnhelten bel Jungeren Frauen mit Herzinfarkt. Munch Med 'A'ochenschr 109: 2129-2134, 1967. . . 357 FURMAN R H: Are gonadal hormones (estrogens and androgens) of significance in the development of ischemic heart disease. Ann N Y Acad Sci 149: 822-833, 1968. 358 HARTROFT S W: Heart disease mortality in women. Science 123: 977, 1956. 359 - KLINK R: Epidemiologische Untersuchungen uber die Coronarsklerose nach . der Menopause. Gynakologe 3: 139-145, 1970. 360 JAMES T N, POST H W and SMITH FJ: Myocardial infarction in women. Ann Intern Med 43: 153-164, 1955. 361 " JOUVE A, BENYAMINE R and MALATERRE H: L'angor coronarien chez - Ia femme. Presse Med 74: 1935-1938, 1966. 362 MILLS C A: Geographic and time variations in body growth and age at menarche. - Hum Biol 9: 43-56, 1937. -. 363 MULCAHY R, HICKEY N and MAURER B: Coronary heart disease in women. Circulation 36: 577-586, 1967a. . 364 MULCAHY R, HICKEY N and MAURER B: The aetiology of coronary heart . disease in women. J Ir Med Assoc 60: 23-29, 1967b. .- 365 OJIAMBO H P: Ischaemic heart disease in a Kenya African case report and brief - review of literature. East Afr Med J 45: 133-135, 1968. 366 OLIVER M F: Study of ischaernic heart disease in young women. Q J Med 40: 572-573, 1971. - . 367 PAULUSSEN F: Ovarialfunktion und Coronarsklerose. GynakoloQe 2: . - 17R_111 1o'Ift v,g ROSENMAN R H and FRIEDMAN M: Association of specific behavior pattern in women with blood and cardiovascular findings. Circulation 24: 1173-1184, 1961. 369 WINK K and HAGER W: Myokardinfarkt bei menstruierenden Frauen. Med Klin 67: 364-372, 1972. 370 T10 30 2-1 1 1 8
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VII. Preventable Risk Factors - 1 VII. PREVENTABLE RISK FACTORS PPEVENTABLE AISK FACTORS INFLUENCED BY CIGA5ETTE SMOKIAG (Vlll) ~ PqEV(NTABtE BISK FACTORS (NOT INFLUENC[0 BY SMOrIN41 A. Physical Activity aad Exercise- 148 ' B. Obeeity---------------------- 151 C. Diabetes ]vtellitue aad Sucroee lutake------•----•---•-•----.•15J D. Diet mtd Coronary Heart Dicea.e--------------- -.--- 157 E. Socioeconomic Factora------- 160 Page 138 The preventable risk factors are discussed in this section separately from those listed in Section VIII. The two groups can be differentiated by cigarette smoking, since the risk factors included in Section VIII can be influenced by cigarette smoking whereas those listed in this section are not. Physical activity, obesity, diabetes mellitus, diet and socioeconomic factors are the risk factors which are described in this section. Each one contributes to the pathogenesis of coronary heart disease. The interplay of an individual factor with ciQarette smokine is the primary concern of the discussion that follows. The general articles relating to these risk factors are contained in the following bibliographic lists: List No. 16. Prevention of coronary risk factor. List No. 17. Exercise in coronary heart disease. List No. 18. Diet in the causation and prevention of coronary heart disease. ~T10 30 2-1 1 2 8
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VI. Fixed Factors - 24 Page 137 ON Reprint SALBER E J and MACMAHON B: Cigarette smoking among high school students related to social class and parental smoking habits.Am J Public Health 51: 1780-1789, 1961. 399 SEGERS J andMERTENS C: Anxi4te, depression et risque d'atherosclerose des coronaires. Acta Psychiatr Belg 72: 46-55, 1972. 400 TECULESCU D, LILIS R, HILT M and ROVENTA A: Cercetari - epidemiologice privind cardiopatia ischemica ia industrie, effectual , incordarii psihice pi al efortului intelectual. (Epidemiological studies on ischemic heart disease in industry effect on psychical strain and 3ntellectual work.) St Cerc Med Intern 13: 259-274, 1972. 401_ . THOMAS C B, FARGO R and ENSLEIN K: Personality characteristics of medical students as reflected by the strong vocational interest test with . . . special reference to smoking habits. Johns Hopkins Med J 127: 323-335, 1970. 402 T10302-1127
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VII. Preventable Risk Factors - 7 Page 144 Reprint MANN G V, GARRETT H L, FARHI A, MURRAY H, and BILLINGS F T: Exercise to prevent coronary-heart disease. Am J Med 46: 12-27, 1969. MEDICAL LETTER: Exercise and coronary heart disease. 10: 93-94, 1968. MONTOYE H J: Participation in atheletics. Can Med Ass J 96: 813-820, 1967. MORRIS J N, HEADY J A, RAFFLE P A B, ROBERTS C G and PARKS J W: Coronary heart-disease and physical activity of work. Lancet 2: 1111-1120, 1953. -PRAT T G: Panel discussion on cardiac and circulatory diseases. . . Am Geriatr Soc 5: 757-785, 1957. - RAAB W: Metabolic protection and reconditioning of the heart muscle through habitual physical exercise. Ann Intern Med 53: 87-105, 1960. - ROBB G P and MARKS H H: Latent coronary artery disease. Am J Cardiol 13: 603-618, 1964, ROSE 0: Physical activity and coronary heart disease. Proc R Soc Med 62: 1183-1188, 1969. WYNDHAM C H: The problem of coronary heart disease with special reference to .. the influence of physical activity. S Afr Med J43: 720-723, 1969. . A 414 T10 30 2-1 1 34
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VI. Fixed Factors - 18 Page 131 In the last-mentioned study, the death rates from coronary heart disease, hypertensive heart disease and stroke were found to be considerably higher among short-lived parents than among subjects with long-lived parents. This was found to be the case for coronary heart disease among men without a history of high blood pressure or diabetes, who were not seriously overweight, who took some exercise and who did not smoke cigarettes regularly. A comparison of siblings in Boston and Ireland indicated that physical activity, way of life and meal patterns may be associated with the difference in death rates for cases of coronary heart disease in the United States and Ireland (Trulson et al. , 1964). The familial history of the subjects was not examined. However, the smoking habits were noted to be similar, i.e, 36% of Boston samples and 28% of men in Ireland smoked more than one package of cigarettes daily. The higher death rate in the United States cannot be attributed to smoking. 3. Constitutional factors. The coronary-prone individual is _ characterized by amphometric features and biochemical changes in the blood. Among the latter, the serum cholesterol level has the highest correlation with coronary heart disease (Gertler et al., 1959). Details of this risk factor are discussed in Section VIII-C. The genetic hypothesis as it relates to coronary heart disease has been reviewed by Thomas (1968). The relationship of cigarette smoking to constitution has been examined by Damon (1961). Among 167 adult male factory workers of m"°""T10302-1121
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VI. Fixed Factors - 16 Page 129 VI-C. Genetic Factors The importance of genetic factors in the causation of coronary heart disease has become apparent by the analysis of males of 65 years of age or older who do not suffer from the disease (Brown and Ritzman, 1967). The smoking habits of 133 such individuals compared with those of 100 control patients with heart disease were as follows: Males without heart disease Controls with heart disease X 40 % nonsmokers 31 % nonsmokers 49% smokers, inhalers 61 % smokers, inhalers 11% smokers, nn~inhalers 8% smokers, noninhalers 9,550 average pack-years 11,201 average pack-years It was further noted by Brown and Ritzman that the difference in pack-years between the two groups was not statistically significant. The . 91'`.i cu--t..tr u.(` /' iatA:QLI ' following factors were found to be associated with this absence~: moderate eating habits, regular physical exercise, lack of concern with social status, normal serum total cholesterol levels, and no family history of heart disease. The last three factors can properly be identified as genetic and are discussed in this section. Before the individual genetic factors are discussed, it is pertinent to mention other types of investigations relating to the problem. A review of factors relevant to a low prevalence of coronary heart disease in , population groups throughout the world failed to identify a consistent pattern of racial or other risk factors (Bruhn and Wolf, 1970). However, twin T10302-1119
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JI. Fixed Factors - 21 Page 134 VI-D. Psychogenic Factors H The individual who is prone to develop coronary heart disease has a personality different from those of others. Several review articles have appeared describing the psychologic makeup of patients who have coronary heart disease (see List No. 15). A distinct behavior pattern accompanied by biochemical derangements has been identified in coronary patients by Friedman and Rosennran (1959, 1971), Friedman et al. (1960, 1970) and Rosenman (1971). It has been suggested that the high incidence of coronary heart disease among smokers can be attributed to one common cause. The personality off the smoker has been examined and found to be different from that of the nonsmokers (McArthur et al. , 1958; Lilienfeld, 1959; Eysenck et_al., 1960; Matarazzo and Saslow, 1960; Salber and MacMahon, 1961; Dimond, 1964; Thomas et al. , 1970). Russek (1964) has used the smoking pattern in the individual to provide an index by which emotional tensions may be relatively assessed. The smoking behavior of offsprings of patients with heart disease has been analyzed (Rappaport et al., 1968). ...~-^ -...-..^^a -~.1 }^ Gl rh"~ar=nce u ~a~~.... .~ ........~.... CP ..._., _ .. .. ... n . t. j.. b ......^.... ... ......... ,. - of heart disease, then the genotype similarities between smokers and nonsmokers will become apparent. The occurence of psychogenic factors in coronary patients is accompanied by other risk factors, particularly hypercholesterolemia T10302-1124
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VI. Fixed Factors - 20 BIBLIOGRAPHY VI, FIXED RISK FACTORS . C. Genetic Factors Page 133 Reprin BAER D J: Height,weight, and ponderal index of college male smokers and nonsmokers. J Psychol 64: 101-105, 1966. . 371 'BROWN R C and RITZMAN L: Some factors associated with the absence of coronary heart disease in persons aged 65 or older. J Am Geriatr Soc 15: 239-250, 1967. . 372 disease: a critical review. Am J Public Health 60: 1477-1495, 1970. 373 CASSEL J, HEYDEN S, BARTEL A G, KAPLAN B H, TYROLER H A, CORNONI J C and HAMES C G: Incidence of coronary heart disease . by ethnic group, social class, and sex. Arch Intern Med 128: 901-906, 1971. - 374 BRUHN J G and WOLF S: Studies reporting '1ow rates" of ischemic heart I GERTLER lvj M, WOODBURY M A, GOTTSCH L G, WHITE P D and RUSK H A: DAMON A: Constitution and smoking. Science 134: 339-341, 1961. 375 The candidate for coronary heart disease. JAMA 170: 149-152, 1959. 376 . HAMMOND E C, GARFINKEL L.and SEIDMAN H: Longevity of parents and grandparents in relation to coronary heart disease and associated variables. Circulation 43: 31-44, 1971. . 377 .1,IEBEGOTT G: Hochdruck und Myokardinfarkt.bei eineiigen Zwillingen . Beitr Path Anat 131: 312-354, 1965. . ..378 - MEIGS J W: Epidemiology of coronary disease in industrial workers. ~ - Arch Easiron Ilcalth 13: 655-661, 1966. 379 ROSE G: Familial patterns in ischaernic heart disease. Br 3 Prev Soc Med 18: 75-80, 1964. . 380 . RUSSEK H I: Role of heredity, diet, and emotional stress in coronary heart - disease. JAMA 171: 503-508, 1959. 381 THOMAS C B: Familial patterns.in hypertension and coronary heart disease. Circulation 20: 25-29, 1959. 382 . THOMAS C B: On cigarette . smoking, coronary heart disease, and the genetic - - hypothesis. Johns Hopkins Med J122: 69-76, 1968. 383 TRULSON M F, CLANCY R E; JESSOP W J E, CHILDERS R W and STARE F J: ' Comparisons of siblings in Boston and Ireland. J Am Diet Assoc 45: 225-229, 1964. 384 . WALKER A R P: Coronary heart disease -- are there differences in racial susceptibility? Am J Epidemiol 90: 359-364, 1969. - 385 ,.>,..;,,,,aT10302-1123
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VII. Preventable Risk Factors - 11 Page 148 VII-A. Physical Activity and Exercise Physical activity and exercise relate to coronary heart disease in the former a number of ways. The lack of /, is a predisposing factor, whereas exercise is a preventive one. In a patient suffering from angina pectoris, exercise initiates an attack and causes an ischemic pattern in the electro- cardiogram. In a patient who has developed acute myocardial infarction, exercise properly regulated can influence the prognosis. In a patient developing coronary atherosclerosis, the electrocardiogram recorded during exercise can be helpful in the diagnosis of early insufficiency (see Additional Bibliographic List No. 17). Cigarette smoking and exercise have been investigated jointly in regard to their influence on the prevalence of coronary heart disease. Frank et al. ,(1966) reviewed 301 patients with myocardial infarction who were enrolled in the Health Insurance Plan of New York. Smoking did not influence the early mortality rate (death,dufiing the first four weeks), whereas physical inactivity was associated with a high mortality rate. Morris et al. .(1973) succeeded in training office workers for vigorous exercise and noted that in them the risk of developine coronary disease was about one-third that in comparable men who did not exercise. The smoking habits of men engaging in such activity were similar to those of the other men in the study. That physical working capacity is more important than cigarette smoking as a risk factor has been shown by Wilhelmsen et al.. (1969). r T10 30 2-1 1 3 8
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VI. Fixed Factors - 11 Page 124 . - BIBLIOGRAPHY VI. FIXED RISK FACTORS A,Age and the Prevalence of Coronary Heart Disease. BAHL A L, BASU T K and CHUGH R N: Precocious ischemic heart disease - evaluation of different risk factors. Indian J Med Sci 24: 722-728, 1970. Reprint 335 BOLENS M and FERRERO C: Infarctus antero-lateral du myocarde chez un jeune homme de 20 ans. Schweiz Med Wochenschr 97: 145-148, 1967. 336 . CISWICKA-SZNAJDERMAN M, SZNAJDERMAN M, JANUSZEWICZ W, DZIERZYKRAY-ROGALSKI T, PROMINSKA E and CHARZEWSKI J: . Badania kliniczne i metaboliczne milezyzn z przebytym w mkodym wieku zawaiem serca. (Clinical and metabolic studies in men with myocardial ' infarction in young age). Pol Tyg Lek 26: 1185-1188, 1971. , 337 DOERKEN H: The etiology of myocardial infarction -- with special reference to . cigarette smoking among young coronary patients and those with second heart attacks. Natl Cancer Inst Monogr 28: 21-27, 1968. . 338 DORKEN H: Die Rauchgewobnheitenbej jungeren Her zinfarkt- Patienten. . Munch Med Wochenschr 109: 187-192, 1967. 339 GERTLER M M, DRISKELL M M, BLAND E F, GARN S M, LERMAN J, LEVINE S A. SPRAGUE H B and WHITE P D: Clinical aspects of coronary heart disease. JAMA 146: 1291-1295, 1951. " 340 ESTANDIA CANO A, ESQUIVEL AVILA J, MALO CAMACHO R, FEREZ - SAN.TAIVDER S,' LEEON MONTANAZ E: Infarto juvenil del miocardio. . Arch Inst Cardiol Mex 41: 137-150, 1971. 341 GSELL 0: Herzinfarkt und Tabakrauchen. ' Miinch Med Wochenschr 108: 1210-1220, 1966. 342 HATCH F T, REISSELL P K, POON-KING T M W, CANELLOS G P, LEES R S, and HAGOPIAN L M: A study of coronary heart disease in young men. Circulation 33: 679-703, 1966. 343 1rUilL Y and rr i:.i.Vlii-z~G J: i.arGiac iniareiiou in yVUng aduiCs. :u: AcLa Jc,:uuui Conventus Medicinae Internae Hungarici. Cardiologia. G. Gottsegen, editor, pp. 99-106, 1963. 345 JAKUSZEWSKA R: Zawai' serca u osob rr>xodych. (Myocardial infarction in young . subjects). Wiad Lek 22: 1749-1752, 1969. 344 MOLEIRO F and MEDINA BRICENO 0: El infarto del miocardio en el adulto . joven. Arch Inst Cardiol Mex 38: 372-379, 1968. .. . 346 MUKERJEE A B: Precocious ischaemic heart disease. J Indian Med Assoc 51; 207-217, 1968. . 347 NANDA N C: Myocardial infarction in young adults. J J J Group Hosp Grant Med Coll 12: 1-12, 1967. . 348 NIZET P M and ROBERTSON L: Normal coronary arteriogram following myocardial infarction in a 17 year old boy. Arn J Cardiol 28: 715-717, 1971. 349 T10 30 2-1 1 1 4
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VII. Preventable Risk Factors - 14 Page 151 VII-B. Obesity Obesity is a major health hazard because hypertension, nephritis, diabetes, cerebrovascular disease and coronary heart disease occur more frequently in the obese (Stamler, 1959; Whyte, 1965; Stamler et al. , 1960). Obesity is not an important associated risk factor in patients dying of coronary heart disease (Keys et al. , 1972). Multivariate analysis of the data from 11,000 men in the United States and Europe showed that no tneasure of obesity made a significant contribution to future coronary heart disease when the factors of age, blood pressure, serum cholesterol and smoking were comparable. In a review of various prospective studies, Heyden et al. (1971) concluded that overweight is a definite risk factor for the development of cerebrovascular disease but not in the etiology of myocardial infarction. In the prospective study conducted in Evans County, Georgia, the risk of nonsmokers developing coronary heart disease does not increase from the leanest to the moderately overweight and the most obese group. Among white smokers there is an increase in risk with overweight (Heyden et al. , 1971). However, these results are not easy to interpret because there is a difference in body weight of smokers and nonsmokers, regardless of the status of the heart. Nonsmokers are heavier than smokers and the difference increases with age (Khosla and Lowe, 1971). Since smoking and obesity are inversely related, studies of the interrelationship of these two risk factor.s are needed. T10302-1141
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VII. Preventable Risk Factors - 10 Page 147 List No. 18 . . Reprint STAMLER J, BERKSON D M, LEVINSON M J, MOJONNIER L, EPSTEIN M B, HALL Y, BURKEY F, SOYUGENE R and ANDELMAN S L: A long-ter coronary prevention evaluation program. Ann N Y Acad Sci 149: m , 1022-1037, 1968. A 444 STAMLER J, BERKSON D M, LINDBERG H and LEVINSON M: The coronar y prone. J Rehabil 32: 18-20, 1966. A 445 STAMLER J, BERKSON D M, YOUNG Q D, LINDBERG H A, HALL Y, MIL LER W and STAMLER R: Approaches to the prevention of coronary heart diseas e. J Am Diet Assoc 40: 407-416, 1962. . A 446 STEAD E A: What we have learned about myocardial infarction from epidemiol ogic . and dietry studies, Circulation 39 (Suppl 4): 85-90, 1969. A 447 TUGHY E L: Feeding the aged. JAMA 121: 42-48, 1943. A 448 . TURPEINEN 0, MIETTINEN M, KARVONEN M J, ROINE P, PEKKARINEN M, LEHTOSUO E J and ALIVIRTA P: Dietry prevention of coronary heart disease: long-term experiment. Am J Clin Nutrition 21: 255-276, 1968 . A 449 VAN BUCHEM F S P: Serum lipids, nutrition and atherosclerotic complication s in man. Acta Med Scand 181: 403-461, 1967. A 450 . WALKER A R P: Can expectation of life in western populations be increased by , changes in diet and manner of life? S Afr Med J 42: 944-950, 1968. A 451 WALKER A R P: Can expectation of life in western populationss be increased . by changesin diet and mamner of life? S Afr.Med J 43: 7.68-775, 1969. A 452 YUDKIN J: Diet and coronary thrombosis. Lancet 2: 155-162, 1957. A 453 TI0302-1137
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VI. Fixed Factors - 23 BIB LIOGRA PHY VI. FIXED RISK FACTORS D. Psychogenic Factors DIMOND S J: Smoking habits of delinquent boys. Br 3 Prev Med 18: 52-54, 1964. EYSENCK H J, TARRANT M, WOOLF M and ENGLAND L: Smoking and . personality. Br Med J 1: 1456- 1460, 1960. prone individuals (Type A behavior pattern). JAMA 212: 1030-1037, 1970. 388 • FRIEDMAN M and ROSENMAN R H: Association of specific overt behavior pattern with blood and cardiovascular findings. JAMA 169: 1286-1296, 1959. 389 Reprint 386 387 . FRIEDMAN M, BYERS S 0. ROSENMAN R H and ELEVITCH R F: Coronary FRIEDMAN M and ROSENMAN R H: Type A behavior pattern: its association with coronary heart disease Ann Clin Res 3: 300-312, 1971. - 390 FRIEDMAN M, ST. GEORGE S, BYERS S and ROSENMAN R H: Excretion of catecholamines, 37-ketosteroids, 17-hydroxycorticoids and 5-hydroxy- . . indole in men exhibiting a particular behavior pattern (A) associated with - high incidence of clinical coronary artery disease. J Clin Invest 39: 758-764, 1960. 391 HALPERIN M, BLACKWELDER W C and VERTER J I: Estimation of the . multivariate logistic risk function: a comparitson of the discriminant function and maximum likelihood approaches. J Chron Dis 24: 125-158, 1971. 392 LILIENFELD A: Emotional and other selected characteristics of cigarette . smokers and nonsmokers as related to epidemiological studies of lung cancer and other diseases. J Natl Cancer Inst Monogr 22: 259-282, 1959. .- 393 . MATARAZZO J D and SASLOW G: Psychological and related characteristics nf ^_.03_5'.3, 1960. 394 ' McARTHUR C, WALDRON E and DICKINSON J: The psychology of smoking. J Abnormal Psychol 56: 267-275, 1958. . RAPPAPORT H, REZNIKOFF M, GLUECK B C Jr, HONEYMAN M S and EISENBERG H: Smoking behavior in offspring of heart disease patients: ' . a response to cognitive dissonance. J Consulting Clin Psychol 32: . . 494-496, 1968. ROSENMAN R H: Assessing the risk associated with behavior patterns. • J Med Assoc Georgia 60: 31-34, 1971. 395 396 397 RUSSEK H I: Tobacco consumption and emotional stress in the etiology of coronary heart disease. Geriatrics 19: 425-433, 1964. 398 Page 136 ,,,,T10302-1126
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VII. Preventable Risk Factors - 16 Page 153 VII-C. Diabetes Mellitus and Sucrose Intake E It has been recognized for more than 35 years that diabetes mellitus predisposes the diabetic to the various manifestations of atherosclerosis, particularly coronary heart disease (Osborn and Goldstein, 1968; Hutchinson, 1970; Moller, 1970). In some of the prospective studies discussed in Section VII-E, diabetes mellitus is an important risk factor in coronary heart disease. The combination of diabetes and cigarette smoking is suspected of increasing the hazard of the development of atherosclerosis. This has been seen in patients with arteriosclerosis obliterans (Weinroth and Herzstein, 1946; Krosnik, 1967; Kappert, 1971). However, regarding coronary heart disease among diabetics,the additional contribution of cigarette smoking to the severity of the disease has not been demonstrated by control studies. In a survey of 27,000 college alumni, cigarette smoking did not increase the risk of adult onset of diabetes and did increase the risk off coronary disease, but there was no information on the combination of the two diseases (Paffenbarger et al. , 1972). -: f:..Ct_,..-,..... !,.^.o`7.., to h',.. ..a decro?se in glucose tolerance although they are not suffering from diabetes mellitus (Cohen et al. , 1965; Epstein, 1967, 1969; Yudkin, 1967). The plasma-insulin level of patients with coronary heart disease is elevated, so that a deficiency of this hormone is not responsible for the decrease in glucose tolerance (Wahlhcrg, 1962; Nikkila et al. , 1965; Peters and Hales, 1965; Welborn et~al. , 1966) ~A. _T10302-1143
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TII. Yreventablc Risk Factors - 6 . Additional Bibliographic List No. 17 . VII. PREVENTABLE RISK FACTORS EXERCISE IN CORONARY HEART DISEASE Page 143 Reprint ALTERKOSE J M: Exercise and cardiovascular conditioning. J Occup Med _ 10: 296-300, 1968. A 392 BLACKBURN H, KEYS A, KARVONEN M, VAN BUCHEM F S P and TAYLOR H L: Relation of "positive" postexercise electrocardiographic _ responses-to other cahracteristics of risk. Circulation 36 (Suppl 2): ' 70, 1967. A 393 BOELLING G M, PHILLIPS W J, FRERKING H W and PAINE R: -" Roentgenographic exercise test. JAMA 202: 275-278, 1967. ..; A 394 BRESLOW L and BUELL P: Mortality from coronary heart disease, and physical activity of work in California. J Chron Dis 11: 421-444, 1960. • A 395 CHIANG B N, ALEXANDER E R, BRUCE R A, THOMPSON D T and TING N: Factors related to ST-segment depression after exercise in middle-aged Chinese men. Circulation 40: 315-325, 1969. . . , A 396 FOX S M and SKINNER J S: Physical activity and cardiovascular health. Am J Cardiol 14: 731-746, 1964. ..: ." A 397 FOX S M and HASKELL W L: Physical activity and the prevention of coronary heart disease. Bull N Y Acad Med 44: 950-967, 1968. A 398 FOX S M and PAUL 0: Physical activity and coronary heart disease. Am J Cardiol 23: 298-306, 1969. A 399 FRANK C W: The course of coronary heart disease: factors relating to prognosis. Bull N Y Acad Med 44: 900-915, 1968. - A 400 i'i.v.+LiC:i~.: . ~ wiiuvu+.::ri.i. ra. .+II.I-y'Li5 Gf tyiudm1G10b1C a.udico Of physical inactivity as risk factor for coronary artery disease. Prog Cardiovasc Die 15: 41-65, 1972. . A 401 GARRETT L, FARHI A and MANN G V: Physical conditioning American men. Fed Proc 26: 261, 1967. A 402 OSTFELD A M: The interaction of biological and social variables in cardiovascular disease. Millbank Mem Fund Q 45: 13-18, 1967. A•403 HELLERSTEIN H K: Exercise therapy in coronary disease. Bull N Y Acad Med . . 44: 1028-1047, 1968. . A 404 HOLMGREN A: Cardiorespiratory determinants of cardiovascular fitness. Can Med Assoc J 96: 697, 1967. A 405 ""8''T10302-1133
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VII. Preventable Risk Factors - 13 Page 150 BIBLIOGRAPHY . VII. PREVENTABLE RISK FACTORS - A. Exercise Reprint BERKSON D M, STAMLERJ and JACKSON W: The precordial electro- eardiogram during and after strenuous exercise. Am S Cardiol 18: 43-51, 1966. 403 , COOPER K H, GEY G E and BOTTENBERG R A: Effects of cigarette smoke on endurance performance. JAMA 203: 189-192, 1968. 404 FRANK C W, WEINBLATT E, SHAPIRO S and SAGER R V: Physical inactivity - as a lethal factor in myocardial infarction among men, Circulation 34: 1022-1033, 1966. 405 GOLDBARG A N, MORAN 3 F, CHILDERS R W and RICKETTS H T: Results and correlations of multistage exercise tests in a gm up of clinically - normal business executives. Am Heart J.79: 194-200, 1970. - - 406 HAAS W, ANAGNOSTU D, LANG E and SCHMIDT J: Leistungsfahlgkeit und Leistungsanamnese alterer Langstreckenlaufer. Munch Med Wochenschr. 112: 1504-1510, 1970. . . 407 MERRIMAN J E: Dynamic exercise tolerance tests: effects in normal subjects of stopping smoking. Circulation 36 (Suppl 2): 186, 1967. 408 MORRIS J N, CHAVE S P W, ADAM C, SIREY C, EPSTEIN L and SHEEHAN D J: Vigorous exercise in leisure-time and the incidence - of coronary heart disease. Lancet 1: 333-339, 1973. 409 . PLEASANTS F, GRUGANJ and RATLIFF J W Ji: Effects of short periods . of abstinence from cigarette smoking on swimming endurance of chronic smokers. Res Q 38: 474-479, 1966. 410 PYORALA K, KARVONEN M J, TASKINEN P, TAKKUNEN J, KYRONSEPPA H and PELTOKALLIO P: Cardiovascular studies on former endurance athletes. Am J Cazdiol 20: 191-205, 1967. 411 RECINE G and CHIAVARO A; Comportamento di alcuni parametri emodinamici durante effetto del fumo di sigaretta in condizioni di riposo e dopo lavoro muscolare in soggetti con angor da sforzo, fumatori e non fumatori. Atti Soc Ital Cardiol 2: 112-116, 1969. 412 RILEY C P, OBERMAN A, LAMPTON T D and HURST D C: Submaximal exercise testing in a random sample of an elderly population. Circulation 42: 43-52, 1970. . 413 WILHELMSEN L, GRIMBY G, BJURE 7,. EKSTROM-JODAL B, AURELL M and TIBBLIN G: Physical activity, physical working capacity and its relation to coronary heart disease in men born in 1913. . Scand J Clin Lab Invest 24: 111, 1969. 414 T10 30 2-1 1 40
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VII. Preventable Risk Factors - 12 Page 149 In elderly subjects who had vascular disease as well as in those 0 who.did not, an abnormal response to an exercise test was not associated with cigarette smoking (Riley et al., 1970). A similar lack of association was reported among businessmen undergoing a multistage exercise test (Goldbarg et al. , 1970). However, in severe exercise, field testing of airmen for 12 minutes showed that endurance performance was inversely related to the number;of cigarettes smoked daily (Cooper et al. , 1968). There is also a reduction in endurance among long distance runners (PyNr'a'1'a' et al., 1967; Haas et al., 1970) and among swimmers who are smokers (Pleasents et al. , 1966). The electrocardiogram during -strenuous exercise has been recorded by Berkson et al. (1966), Merriman (1967) and Recine and Chiavaro (1969). They observed that electrocardiographic changes appeared more frequently among smokers than among nonsmokers. Most of these individuals were healthy. The severity of exercise referred to above does not apply to patients with heart disease. ----eT10302-1139
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VII. Preventable Risk Factors - 23 Page 160 VII-E. Socioeconomic Factors The last group of preventable risk factors are identified under the caption socioeconomic. This includes occupation, education, income level, urbanization, and consumption of alcohol, coffee and other beverages (see reviews by Terris, 1964; Anderson, 1967; Marks, 1967; Hall, 1968; Shekelle, 1968; Cheraskin. et al., 1971; Richardson, 1971). Regarding the consumption of alcohol and coffee, Brummer (1969) could not find a significant correlation with coronary mortality in 20 countries. However, in isolated studies there is a correlation between the two. The studies relating to consumption of coffee and alcohol, as well as to other socioeconomic factors, are summarized in Table VII-E. It is not possible to make generalizations, because the conclusions apply only to the particular country involved and need to be confirmed elsewhere. The table has been formulated also to emphasize the interaction of cigarettg smoking with socioeconomic and other risk factors in the causation of coronary heart disease. The information contained in the table has been derived from R= retrospective studies, P= ,:.. _a V_ ,_ . .. .. piil5~:ruCi.ivu .....u 3tuu.ud, - ~uls... .+ .'vuy3. The influence of cigarette smoking on prevalence of coronary heart disease in various occupational groups has been derived from surveys listed in Table VII-E. Haag and Hanmer (1957) reported a four-year survey of the mortality among employees of a tobacco company. There was a higher than average percentage of smokers associated with greater longevity and 310 30 2-1 1 50
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VII. Preventable Risk Factors - 2 . Additional Bibliographic List No. 16 VII. PREVENTABLE RISK FACTORS PREVENTION OF CORONARY RISK FACTORS Page 139 Reprint ADAMS C W M: Suggested pathophysiological principles for the prevention of isehaemic heart disease. Guy Hosp Reports 119: 1-13, 1970. A 329 BIORCK G: Factors contributing to the aetiology of cardiovascular disease. Cor Vasa 6: 169-177, 1964. A 330, BERMAN R: Prevention of coronary disease. MinnMed 52: 1181, 1207-1208, 1969. A 331 BLOOM V: The prevention of ischaemic heart disease. Br J Clin Pract 20: 481-485, 1966. A 332 BREST A N: Treatment of coronary occlusive disease: Critical Review. . Dis Chest 45: 40-45, 1964. . A 333 -. BRIGHTMAN I J: The potential influence of public health measures on adult heart disease. J Chron Dis 18: 905-913, 1965. . A 334 COOPER D L: What is fitness? R I Med J 52: 445-448, 1969. , A 335 • DAWBER T R and THOMAS H E Jr: Prevention of myocardial infarction. . Prog Cardiovasc Dis 13: 343-360, 1971. A 336 . DEBRAY J R, CHRETIEN J, GUENIOT M, HARDOLIN J P, HIMBERT J, PICHOT P, RICHET G, ROUSSEL C and RYCKEWAERT A R: Une nouvelle conception de la medecine preventive_ utilisant le traitement automatique de Vinformation par ordinateur. Ann Med Intern 120: 586-596, 1969. A 337 DOYLE J T: The prevention of coronary heart disease. In: Coronary Heart Disease. A N Brest, editor, F.A.Davis Co., Philadelphia, pp 306- 316, 1969. A 338 DvaL: J T: V4A coronary heart disease be prevented': Am J Sci Z58: 67-69, 1969. A 339 DUNCAN C H and BEST M M: Management of the coronary-prone patient. G P 35: 119-127, 1967. . A 340 DUNCAN C H and BEST M M: An approach to the prevention of coronary artery disease. J Kentucky Med Assoc 67: 266-267, 1969. A 341 EDITORIAL: Prevention of coronary heart disease. Br Med J 3: 689-690, 1968. A 342 EDITORIAL: The role of the occupational physician. N Y Med 24: 202-203, 1968. A 343 ERNSTENE A C: How to prevent coronary heart disease. Bull Am Coll Physicinas 4: 284-287, 1963. A 344 T10302-1129
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VII. Preventable Risk Factors - 19 Page 156 Reprint PAUL O, MacMILLAN A, McKEAN H, and PARK H: Sucrose intake and coronary heart disease. Lancet .2: 1049-1051, 1968. . 437 PETERS N and HALES C N: Plasma-insulin concentration after myocardial infarction.- Lancet 1: 1144-1145, 1965. 438 RICHARDSON ICHARDSON J F: The sugar intake of businessmen and its inverse relationship . with relative weight. Br J Nutr 27: 449-460, 1972. . . 439 WAHLBERG F: The intravenous glucose tolerance test in atherosclerotic disease with special reference to obesity, hypertension, diabetic heredity and cholesterol values. Acta Med Scand 171: 1-7, 1962. 440 WALKER A R P: Sugar intake and coronary heart disease. Atherosclerosis _ 14: 137-152, 1971. 441 WEINROTH. LA and HERZSTEIN J: Relation of tobacco smoking to arteriosclerosis obliterans in diabetes mellitus. JAMA 131: 205-209, 1946. ---" 442 . WELBORN T A, BRECKENRIDGE A, RUBINSTEIN A H, DOLLERY C T and FRASER T R: Serum-insulin in essential hypertension and in peripheral . vascular disease. Lancet 1: 1336-1337, 1966. . 443 YUDKINJ: Why blame sugar? Chem Ind 35: 1464-1466, 1967. 444 T10302-1146
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VII. Preventable Risk Factors - 3 List No. 16 Reprint FEJFAR Z: Prevention and control of the epidemics of ischaemie heart disease. Arch Klin Med 216: 184-200, 1969. A 345 FEJFAR Z and VANECEK: Prevence ischemicke choroby srdecni. (Prevention of ischemic heart disease) Cas Lek Cesk 109: . 505-510, 1970. A 346 FOX S M, NAUGHTON J P, and GORMAN P A: Physical activity and cardio- vascular health. Mod Concepts Cardiovasc Dis 41: 17-20,. 1972. A 347 FRIEDMAN M and ROSENMAN R H: The prudent management of the coronary-prone individual. Geriatrics 27: 74-79, 1972. Page 140 A 348 BRUGGEMANN W: Aktion gegen den Herzinfarkt. Ther Geganw 108: 75-87, 1969. A 349 HETZEL B 5: Self-help for health in our environment. Med J Australia 2: 1135-1140, 1972. A 350 HICKIE J B: The prevention of coronary heart disease. - Med J Australia 1: 159-166, 1968. HLOUCAL L and DUSEK J: Etiopatogeneze a prevence koronarni nemoci srdecni, Cas Lek Cesk 110: 745-751, 1971. HORVATH S M: Cardiac disease in the context of the future environment. Environ Res 2: 470-475, 1969. A 351 A 352 A 353 HRACHOVEC J P: Environmental health and the older adult. - Arch Environ Health 18: 193-202, 1969. . A 354 INGALLS T H and GORDON J E: Periodic health examination. Am J Med Sci 251: 333-350, 1966. A 355 KEYS A: Cardiology. The essentiality of prevention. Minn Med 52: , 1191-1196, 1969. A 356 KOSTER M: Preventie vancoronaria-ziekte. Ned T Geneesk 114: _ 1060-1062, 1970. A 357 KRUGER K: Herzinfarkt -- eine Zeitkrankheit? Gedanken und Fakten zur Prophylaxe. Fortschr Med 90: 85-87, 1972. A 358 KUNDU S C: Pathogenesis and prevention of coronary heart disease. J Indian Med 58: 245-247, 1972. A 359 KUTSCHA W: Monglichkeiten zur Herzinfarkpophylaxe. Zschr Inn Med Jahrg 23: 9-13, 1968. A 360 MASSIE E: Important factors in the prevention of coronary disease. Memphis Mid-South Med J 39: 85-94, 1964. A 361 Clin Pharmaccl Thcr 8: 603-614, 1967. A 362 MASTER. A M and KUHN LA: Coronary disease -- 45 years ago and now. ,T10 30 2-1 1 3 0
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VII. Preventable Risk Factors - 9 Page 146 List No. 18 Reprin KELLER M D, ANTHONY J R and GRESHAM G E: A study of the primary prevention of coronary heart disease. Am J Public Health 60: 1466- 1476, 1970. A 429 KEYS A: Diet and the epidemiology of coronary heart disease. JAMA 164: 1912-1919, 1957. A 430 MEADE T W and CHAKRABARTI R: Arterial-disease research: observation or intervention. Lancet 2: 913-916, 1972. A 431 MALHOTRA S L: Serum lipids, dietary factors and ischemic heart disease. Am J Clin Nutrition 20: 462-474, 1967. - A 432 MALHOTRA S L: Dietry factors and ischemic heart disease. Am J Clin Nutrition . 24: 1195-1198, 1971. . McGANDY R B and REMMELL P S: The dietry management of coronary heart disease. In: Coronary Heart Disease. A N Brest, editor, pp 34-45, 1969. MILLER D C, TRULSON M F, McCANN M B, WHITE P D and STARE F J: Diet, blood lipids and health of Italian men in Boston. Ann Intern Med 49: 1178-1200, 1958. . . NATVIG H, BORCHGREVINK C F, DEDICHEN J, OWREN PA, SCHIOTZ E H and WESTLUND K: A controlled trial of the effect of Linolenic acid on incidence of coronary heart disease. Scand J Clin Lab Invest 22: 1-20, 1968. NICOLAYSEN R: Practical implications. In: Nutrition and cardiovascular diseases. J C Somogyi and N Eeg-Larsen,editors, S. Krager, Basel, pp.183-189, 1964. OLSON R E: Diet and coronary artery disease. In: Symposium on Coronary Heart Disease. H L Blumgart editor, The American Heart Association,pp 12-23, 1968. PFLANZ M and BRUGGEMANN W: Die Kneipp-Studie zur Prophylaxe von . Koronarkrankheiten. Munch Med Wochenschr 114: 491-496, 1972. RINSLER S H: Primary prevention of coronary heart disease by diet. Am Heart 7 73: 287-289, 1967. SEBRELL W H Jr: Cambios en el concepto de la.malnutricion. - Bolofic Sanit Panamer 65: 415-422, 1968. A 433 " .: . A 434 . A 435 A 436 A 437 A 438 A 439 A 440 A 441 STAMLER J: Long-term nutritional management in the prevention and therapy ' of coronary artery disease. Curr Med Digest 34: 727-759, 1967. A 442 STAMLER J, BERKSON DM, LEVINSON M, LINDBERG HA, MOJONNIER L, MILLER W A, HALL Y and ANDELMAN S L: Coronary artery disease. Arch Environ Health 13: 322-335, 1966. A 443 T10302-1136
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VII. Preventable Risk Factors - 5 Page 142 List No. 16 Reprint STAMLER J: Reducing cardiovascular risk. The basis and feasibility. ' Minn Med 52: 1181, 1342-1345, 1969. A 379 STAMLER J: The primary prevention of coronary heart disease. Hosp Pract 6: 49-61, 1971. • A 380 STAMLER J: Acute myocardial infarction -- progress in primary prevention. Br Heart 3 33: 145-164, 1971. A 381 STAMLER J and EPSTEIN F H: Coronary heart disease: risk factors as guides ' to preventive action. Preventive Med 1: 27-48, 1972. ~ A 382 STEBNER C M, VERNETTI J P and GILLARD H F: Physical fitness for the prevention of coronary attacks. J Ani Dental Assoc 85: 627-633, 1972. A 383 SYME L S: Stress and coronary heart disease. Postgrad Med 48: 123-127, 1970, A 384 TIBBLIN G: A11m9n oversikt. Lakartidningen.67: 140-144, 1970. A385 WALKER A R P: What can be done to retard ageing and to increase expectation of life. Ann Life Insurance Med 4: 176-203, 1969. A 386 WALKER A R P, and BERSOHN 1: Memorandum: what can be done to avoid _. coronary heart disease? S Afr Med J 43: 387-388, 1969. , . A 387 WARSHAW L J: The special conference on prevention of coronary heart -, - disease in industry. J Occup Med 11: 435-438, 1969. A 388 WERKO L: Can we prevent heart disease7•. Ann Intern Med 74: 278-288, 1971. A 389 ~ WILHELMSEN L, TIBBLIN G and WERKO L: A primary preventive study in . ' Gothenburg, Sweden. Preventive Med 1: 153-160, 1972. A 390 WILHELMSEN L, . TIBBLIN G, EIMFELDT D, SANNE H, VEDIN A and , otuu.US i0 yii.i)az'y aA".1 6Ocun<:aPy prevention. Scand.J Clin Invest 29: 20, 1972. A 391 TI0302-1132
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VII. Preventable Risk Factors - 17 Page 154 In prospective studies, patients who develcpglcoronary heart disease ® were found to have consumed more sugar than the control group (Paul et al. , 1968; Burns-Cox et al. , 1969). It is pertinent to note that in some patients with coronary heart disease there is a strong association between the consumption of sugar and the smoking of cigarettes (Medical Research Council, 1970; Bennett et al. , 1970; Elwood et al. , 1970). It has been suggested that both risk factors cause myocardial infarction. There is also an inverse relationship between sugar intake and adequate exercise (Richardson, 1972). Cigarette smoking is also known to influence body weight (see Section VII-B). The interplay of several risk factors should - be considered when the role of sucrose in the etiology of coronary heart disease is examined in future investigations. The evidence presently available on the theory that sucrose in the diet is a major factor in the development of coronary heart disease has been reviewed by Keys (1971) and Walker (1971). ---- - -------- T10302-1144
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`III. Preventable Risk Factors - 8 Page 145 Additional Bibliographic List No. 18 - VU. PREVENTABLE R15K FACT'ORS DIE'-. 1-_d 'iHE Cn;S'sATION AND PREVENTION OF CORONARY HEART DISEASE . Reprint ALFIN-SLATER R B: Diet and heart disease. J Am Diet Assoc 54: 486-489, 1969. A 415 AMERICAN HEALTH FOUNDATION: Position statement on diet and coronary heart disease. Preventive Med 1: 255-286, 1972. A 416 AMERICAN HEART ASSOCIATION: Dropouts, exclusions, non-cardiovascular and cardiovascular events. Circulation 37 (Suppl 1): 232-Z52, 1968. A 417 ATHEROSCLEROSIS STUDY GROUP: Primary prevention of the atherosclerotic diseases. Circulation 42; 55-95, 1970. A 418 AUSTRALIAN NATIONAL HEART FOUNDATION: Dietary fat and coronary heart disease: a review. Med J Australia 1: 1155-1160, 1971. A 419 BIERENBAUM M L, FLEISCHMAN A I, GREEN D P. RAICHELSON R I, HAYTON T, WATSON P B and CALDWELL A B: The 5-year experience of modified fat diets on younger men with coronary heart disease. ... Circulation 42: 943-952, 1970. A 420 BOSE A K: Malnutrition of the rich. 'J Indian Med Assoc 54: 431-432, 1970. A 421 CHRISTAKIS G J, RINZLER S H, ARCHER M, HASHIM S A, and VAN ITALLIE T B: Effect of a serum cholesterol-lowering diet on composition of depot fat in . man. Arn J Clin Nutritior. 16: 243-251,..1965. . . A 4Z2 CHRISTAKIS G, RINZLER S H, ARCHER M, WINSLOW G, JAMPEL 5, STEPHENSON J, FRIEDMAN G,FEIN H, KRAUS A and JAMES G: ' A dietary approach to the prevention of coronary heart disease -- a seven- year report. Am J Public Health 56: 299-314, 1966. A 423 CHRISTAKIS G J. RINZLER S, ARCHER M and KRAUS A: Effect of the anti- coronary heart disease risk-factor status. JAMA 198: 597-604, 1966. A 424 CICALA V, D'ONOFRIO F and BARONE L: La dieta nelle cardiovasculopatie . del1'etapresenile e senile. Clin Ter 43: 249-283, 1967. A 425 DAYTON S and PEARCE M. L: Diet high in unsaturated fat. A controlled elinicaltrial MinnMed 52: 1237-1242,- 1969. A 426 'ELLIS F R- and MONTEGRIFFO V M E: Veganism, clinical findings and investigations. Am I Clin Nutrition 23: 249-255, 1970. . A 427 FETCHER E S: Changes of diet and risk factors in the national diet-heart study. Minn Med 52: 1243-1246, 1969. A 428 ,..710302-1135
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VII. Preventable Risk Factors - 20 Page 157 V1I-D. Diet and Coronary Heart Disease Experiments on animals have shown that atherosclerosis, including fatal myocardial infarction, has been produced by dietary manipulation. The basic common feature in these experiments is the maintenance of a sustained elevation of the concentration of cholesterol in the blood. Epidemiological evidence indicates that in man the serum cholesterol level is a major factor in the development of coronary heart disease and that the amount and kind of fat in the serum has a major influence on the blood cholesterol - level (see reviews by Keys (1962) and Stamler et al. ,(1963, 1972)). This knowledge has been applied in programs for the prevention of coronary heart disease, and the articles relating to dietary control are contained in Additional Bibliographic List No. 18. The controlled clinical studies by Leren (1966) and Dayton et al. (1969) are noteworthy for providing the unequivocal evidence that a diet low in unsaturated fat reduces the plasma cholesterol level and prevents complications of atherosclerosis in general and of myocardial infarction in particular. In the consideration of smoking and coronary heart disease the diet snouici also be exauiined. Siiiu.:era di:.cr Iaum 3.o.a...o;cers in taste perception and food preferences. It was reported that the latter preferred bland food and consumed less fat and meat, fewer eggs and more cakes, sweets and chocolate than the former (Krut et al. , 1961; Perrin et al. , 1961). Among patients with myocardial infarction, liberal coffee drinking, sugar ~.+~~T10302-7 7 47
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pII. Preventable Risk Factors - 15 Page 152 BIBLIOGRAPHY VII. PREVENTABLE RISK FACTORS B. Obesity Reprint K HEYDEN 5, CASSEL J C, BARTEL A, TYROLER H A, HAMES C G - -and CORNONI J C: Body weight and cigarette smoking as risk . factors. Arch Intern Med 128: 915-919; 920-928, 1971. 415 . HEYDEN S, HAMES C G, BARTEL A, - CASSEL J C, TYROLER H A and CORNONI J C: Weight and weight histroy in relation to cerebrovascular and ischemic heart disease. Arch Intern Med 128: 956-960, 1971. - 416 KEYS A, ARAVANIS C, BLACKBURN H, VAN BUCHEM F S P, BUZINA R, ' DJORDJEVIC B S, FIDANZA F, KARVONEN M J, MENOTTI.A, PUDDU V and TAYLOR H L: Coronary heart disease: overweight and obesity as risk factors. Ann Intern Med 77: 15-27, 1972. .. . 417 KHOSLA T and LOWE C R: Obesity andd smoking habits. Br Med J 4: ' 10-13, 1971. 418 STAMLER J: Obesity and atherosclerotic coronary heart disease. Ill Med J 260262, 1959. - - 419 STAMLER J, LINDBERG HA, BERKSON DM, MILLER W, TEMPLETON M and HALL Y: Body weight, blood pressure, and cholesterol in whites . and negroes and the problem of racial patterns of coronary heart disease. Circulation 22: 817-818, 1960. - . 420 WHYTE H M: Behind the adipose curtain. Studies in Australia and New Guinea relating to obesity and coronary heart disease. Am J Cardiol 15: 66-80, 1965. ' - 421 T10302-1142
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VII. Preventable Risk Factors - 18 Page 155 BIBLIOGRAPHY VIL PREVENTABLE RISK FACTORS C.Diabetes Mellitus and Sucrose Intake Reprint BENNETT A E, DOLL R and HOWELL R W: Sugar consumption and cigarette smoking. Lancet 1: 1011-1014, 1970. 422 BURNS-COX C J, DOLL R and BALL K P: Sugar intake and myocardial infarction. Br Heart J 31: 485-490, 1969. 423 COHEN A M and SHAFRIR E: Carbohydrate metabolism in myocardial - infarction. Diabetes 14: 84-86, 1965. 424 ELWOOD P C, WATERS W E, MOORE S and SWEETNAM P: Sucrose consumption and ischemic heart-disease in the community. Lancet 1: 1014-1016, 1970. 425 EPSTEIN F H: Hyperglycemia. A risk factor in coronary heart disease. Circulation 36: 609-619, 1967. . 426 EPSTEIN F H: Elevated blood sugar. The associated cardiovascular risk. Minn Med 52: 1271-1274, 1969. 427 HUTCHINSON R G: Diabetes, smoking habits and cholesterol in myocardial . infarctions. Clin Res 18: 23; 1970.. 428 KAPPERT A: Tobacco and diabetic angiopathy. Acta Diabetol Lat 8: -- 429-433, 1971. - 429 KEYS A: Sucrose in the diet and coronary heart disease. Atherosclerosis : 14: 193-202, 1971. . ' . 430 KROSNICK A: Treatment of vascular.complications of diabetes mellitus. Mod Treatment 4: 85-108, 1967. - 431 MEDICAL RESEARCH COUNCIL: Dietary sugar intake in men with myocardial infarction. Lancet 2: 1265-1271, 1970. . 43Z MOLLER E and KLEIN B: Herzinfarkt und subklinischer Diabetes. Med Welt 26: 1191-1194, 1970. 433 OSBORN J R and GOLDSTEIN H H: Does diabetes cause coronary disease2 Postgrad Med 44: 137-141, 1968. , - • 434 NIKKILA F,A, MIETTINEN T A, VESENNE M-R, PELKONEN R: Plasma . insulin in coronary heart-disease. Lancet 2: 508-511, 1965., 435 PAFFENBARGER R S and WING A L: High-risk factors common to coronary heart disease and adult-onset diabetes mellitus. Circulation 40: . 201, 1972. 436 ~T10302-1145
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Factors - 29 IE E Great Britain . S = 1, 000 men 60 to 70 years old Brown et al. , 1957 S = 1,737 men 50 to 60 years old Edwards et al. , 1959 Smoking not related to coronary heart disease Smoking not related to coronary heart disease S = 3. 341 male factory workers Lowe 1960 P = 667 middle aged businessmen Morris et al. , 1966 S = 221 pensioners 68 to 85 years old Acheson 1961 R = 536 deaths of myocardial infarction . Brown 1962 S = 200 males below 60 years old Mulcahy et al. 1963 Mulcahy and Hickey 1965 Mulcahy and Hickey 1966 Mulcahy and Hickey 1966 P = Random males 55 to 64 years old Armstrong and Wilson 1964 S= 676 postal workers 40 to 50 years old Reid et al., 1966 P = 110 patients with myocardial . infarction Spelman and Ley 1966 P: 54, 460 men in industry Brett and Benjamin 1968 R= 400 male patient below 60 years old Mulcahy et al. 1969 R = 91 male patients under 65 years old Cotton et al. 1972 C:reece P= 1, 300 men in rural areas Aravanis et al, 1967 ~ ! Aravanis et al. 1970 India R= 100 cases with coronary heart disease a'ansal, 1970 = 1, 200 cases of coronary heart disease Vytitlingan3 _. Smoking related to injury and absenteeism ' Smoking related to coronary heart disease Smoking not related to coronary heart disease Smoking related to deaths Smoking related to coronary heart disease Smoking not related to incidence of coronary heart disease Smoking not related to incidence of coronary heart disease Smoking related to mortality from coronary heart disease. Smoking prevalent among patients with coronary heart disease Smoking prevalent . High incidence of smoking but low prevalence of ECG abnor- malities Smoking prevalent compared to controls Smoking not related to coronary heart disease Page 166 VIII-B. Hypertension VIII-C, Hypercholesterolemia VIII-A, Electrocardiogram VI-C, Familial VII>B. Obesity VII-E. Occupation VI-C, Constitutional VIII-B. Hypertension VI-C. Personality does not . affect prognosis VII-C. Diabetes VII-B. Hypertension VIII-C. Hypercholesterolemia VIII-B, Hypertension VII-B, Smokers thinner than nonsmokers. VI-C. Familial history VII-A.: Exercise • V II-E. Oc cupa tion VIII-C. Hypercholesterolemi~ VIII-A, Hypertension VIII-B, Hypercholesterolemia ..mTlO'!„~ 302 1156
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y Factors4- 32 Yage .170 USSR (Cont. ) R= 100 patient with myocardial Smoking prevalent VII-B. Obesity infarction VIII-B. Hypertension ~ Borojev and Stanulovic 1971 VIII-C. Hypercholesterolemia P= 1, 243 clerks or workers -, -- . VII-E. Socioeconomic ~- Glazunov et al., 1964 Yugoslavia P = 11, 121 - Low incidence of coronary heart . KozareviF et al„ 1971 '. disease Djordjevic'_e t ~ 1967 ... Buzina et al. , 1967 ' - DjordjeviE et al., 1970 P= 940 workers Smoking associated with coronary VI-C, ' Constitutional Vukadinovic and Saric 1966 heart disease . VII-B. Obesity VIII-B. Hypertension 'e'""~'"'x n"x'rr-°'^y,.*.TI0302-1160
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,/II. Preventable Risk Factors - 37 BIBLIOGRAPHY VII. PREVENTABLE RISK FACTORS E. Socioeconomic Factors ' 'TABLE VII-E Role of Socioeconomic and other risk factors in . . patients with coronary heart disease Part B. Foreign Countries . Argentina DE SOLDATI L, BARBIERO 0, CHUTLIAN A, ROSENTAL R and MATTIAUDA J: Segundo infarto. Rev Argent Cardiol 39: 137-146, 1971. I Reprint , 497 Australia . . . . . . . WELBORN T A, CUMPSTON G N, CULLEN K J, CURNOW D H, McCALL M G and STENHOUSE N S: The prevalence of coronary .. . . heart disease and associated factors in an Australian rural community. .. . A J Epidemiol 89: 521-536, 1969. 498 CULLEN K J: Mass health examinations in the Busselton population , - 1966 to 1970. Med J Australia 2: 714-718, 1972. 499 REIMER E E, and TISO B: Der tnyokardinfarkt. Wien Z Inn Med 52: 330-350, 1971. Belgium . . GOOSSENS A e•nd P.:ESc'-^' R: R2.,ultats .a:*zas dl-_.e e^onete P; idernioloaiq+te cardio-vasculaire prospective dans une population d'employes belges . .(Bruxelles). Mal Cardiovasc 7: 173-205, 1966. , . DELEIXHE A and REGINSTER-HANEUSE G: Incidences medico-sociales de . . Vinfarctus du rnyocarde. Arch Belg Med Soc 28: 267-280, 1970. MEHEUS A, EYLENBASCH W, DOUMIT 7, VASTESAEGER J and VUYLSTEEK K: L'usage du tabac comme facteur de risque pour les cardiopathies ischemioues.Brux Med 52: 183-188, 1972. . Canada BEST E W R, JOSIE G H and WALKER C B: A Canadian study of mortality in relation to smoking habits. A preliminary report. Can J Public Health 52: 99-106, 1961. 500 501 502 503 504 T10302-1166 Page 176 I
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VII. Preventable R isk Factors - 33 BIBLIOGRAPHY VII. PREVENTABLE RISK FACTORS . E. Socioeconomic Factors Page 171 Reprint Text ANDERSON T. A:- Coronary heart diseaSe and the .affluent society -; woFne . ., . interrelationships. Med Times 95: 621-632, 1967. 453 BRUMMER P: Coronary mortality and living standard. II. Coffee, tea, eocoa, alcohol and tobacco. Acta Med Scand 186: 61-63, 1969. 454 CASE R A M: Smoking habits and mortality among workers in cigarette : factories. Nature 181: 84-86, 1958. , 455.. • CHERASKIN E and RINGSDORF W M Jr: Predictive medicine. 31. Experi- mental models. J Am Geriatr Soc 19: 448-459, 1971 456 HAAG H B and HANMER H R: Smoking habits and mortality among workers . is cigarettefactories. Ind Med Surg 26: 559-562, 1957. 457 HALL R J: Heart disease in industry. Arch Environ Health 17: 416-424, : 1968. - 458 MARKS R U: A review of empirical findings. Millbank Mem Fund 0 45: 51-108, 1967. 459 ..RICHARDSON J F: Heart rate in middle-aged men. Am J Clin Nutr 24: . 1476-1481, 1971. 460 SHEKELLE R B: Educational status and risk of coronary heart disease. . Science 163: 97-98, 1968. 461 TERRIS M: Epidemiologic approach to chronic diseases: Arch Environ Health . 9: 209-215. 1964. 462 Tl.BLE VII-E Role of Socioeconomic and other risk factors in . patients with coronary heart disease Part A. United States. California CHAPMAN J M, GOERKE L S, DIXON W, LOVELAND D B and PHILLIPS E: ' The clinical status of a population group in Los Angeles under observation for two to three years. Am J Public Health 47: 33-42, 1957. 463 T10 30 2-1 1 61
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'II. Preventable Risk Factors - 36 Page 174 Reprint DOYLE J T, KINCH S H and BROWN D F: Cardiovascular screening to asses risk of coronary heart disease. Public Health Reports 83: 659-667, 1968. 485 HYAMS L and LOOP A: The epidemiology of myocardial infarction at two age levels. Am J Epidemiol 90: 93-102, 1969. . 486 HINKLE L E: The use of a large industrial population to study the effects of • social and behavioral factors on coronary heart disease. Am J Public Health 56: 1470-1475, 1966. - - 487 HINKLE L E, WHITNEY H, LEHMAN E W, DUNN J, BENJAMIN B, . . KING R, PLAKUN A and FLEHINGER B: Occupation, education, and coronary heart disease. Science 161: 238-246, 1968. 488 HINKLE L E: An estimate of the effects of "stress" on the incidence and - prevalence of coronary heart disease in a large industrial population . in the United States. Throm Diath Haemorrh (Suppl): 15-65, 197Z. • - . 489 SHAPIRO 5, WEINBLATT E, FRANK C W and SAGER R V: Social factors _. in the prognosis of men following first myocardial infarction. ' . Millbank Mem Fund Q 48: 37-50, 1970. . 490 North Carolina TYROLER H A and CASSEL 3: Health consequences of culture change - - II. the effect of urbanization on coronary heart mortality in rural residents. -J Chron Dis 17: 167-177, 1964. 491 - . North Dakota ' • - SYME S L,HYMAN M M and ENTERLINE P E: Some social and cultural factors .. associated with the occurrence of coronary heart disease. J Chron Dis - 17: 277-289. 1964. - 492 SYME S L, BORHANI N 0 and BUECHLEY R W: Cultural mobility and coronary hcarC utsease in an urDan area. nm J Epiuemioi GL: J]Y-O-to,.l`JOJ. Y]J Ohio FRIEDMAN E H and HELLERSTEIN H K: Occupational stress, law school - hierarchy, and coronary artery disease in Cleveland attorneys. . Psychosom Med 30: 72-86, 1968. . . . . . 494 T10302-1164
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VII. Preventable Risk Factors - 28 E Czechoslovakia (Cont,) . S= 1,213 patients in hospital Horak et al., 1968 P = Questionnaire Santrucek 1970 S = 1, 000 autopsies Fingerland et al. , 1971 Finland R= 683 cases of myocardial, infa r cti on Ikkala 1960 P = 371 lumberjacks Karvonen ct al. 1961 Smoking prevalent in coronary heart disease Smoking not associated with deaths in coronary heart disease Smoking prevalent in coronary heart disease Smoking no influence on prog- nosis Smoking not related to coronary heart disease P = 481 persons older than 65 Smoking not associated with coronary ~ years old heart disease Ruikka 1966 P = 1, 677 persons in rural areas . Smoking prevalent . Karvonen 1962. 1967 _, Karvonen et al., 1970 Karvonen 1971 Karvonen 1972 . . Punsar et al., 1969 - ' Punsar et al. 1970 S= 1, 314 executives Smoking related to coronary Teraslinna et al„ 1971 heart disease Romo 1972 Page 165 VII-E. Occupation VIII-E. Occupation VIII-B, Hypertension A France S = 54, 460 factory workers Anonymous 1968 R= 100 cases of myocardial in- farction Anjulere, 1968 P = 1. 867 residents Himbert et al., 1971 R= 70 cases of myocardial . iu::+.~t:on J, Warter et al. 1972 Smoking prevalent in coronary heart disease , - Smoking preva-lent'in patients Smoking prevalent in patients with cardiac heart disease Smoking rare .. . . . I-A. Unusual effort preciF t=te infarc!ion Germany _ . R = 170 patients with cardiac heart disease Smoking prevalent in patients compared to controls Keiser 1954 R= 550 cases of myocardial Smokin revalent - VII-B Ob sit infarction Schimmler and Neff 1966 Schimlor et al. , 1968 g p . , _ . e y VIII-C, Hypercholesterolem R= 560 autopsy cases of myo- Smoking prevalent in patients VII-C. Diabetes cardial infarction VIII-B. Hypertension Crecelius 1966 . R= 30 patients with myocardial Smoking associated with young VI-C, Psychogenic infarcti.on patients Storch et al„ 1971 ,^-,T-T10302-1155
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, 1'reventaUit; 1<i5r: Factors - 25 TABLE VII-E, `Role of Socioeconomic and other risk factors in patients with coronary heart disease Part A. United States ® Page 162 State . Role of Cigarette Role of Other Investigators and Design Smoking Risk Factors California . P= 2, 252 employees . Chapman et al., 1957 . VII-A, VIII-B. Physical activity Hypertension - S= 669 students and family . . . Andrus et al„ 1968 - VIfi-B. Blood pressure Connecticut - . P = 164 industrial workers . Meigs and Albrink 1966 VI-A. Genetic Delaware P = 209 cases of myocardial infarction . ~ . . ~ . Pell and D'Alonzo 1958 Pell and D'Alonzo 1970 VII-B, VIIl-B. Obesity Hypertension Georgia P = 632 white residents VII-E. Occupational Kaplan et al., 1971 mobility Hawaii P = 42 cases of myocardial Smoking prevalent VI-A. Race infarction VII-D, Diet Bassett et al., 1969 . VII-E. Alcohol Bassett et al. , 1969 . _ Chung et al. , 1969 ~ . . Bassett et al. , 1969 Bassett and Schroffner 1970 - - - - P = 8, 006 men . - Smoking associated with coronary VII-A, Obesity , Kagan et al., 1971 heart disease VIII-B. Hypertension VIII-C. Hype r chol esterolemi Illinoi s P = 784 workers Stamler et al., 1960 Stamler 1959 Stamler et al. , 1961 VII-B. Obesity VII-C. Diabetes VIII-B. Hypertension Indiana 5~ examination of death certifi- cate Morris 1967 VII-A, Physical activity VII-E. Socioeconomic Maryland . . . P = 629 male telephone workers Smoking not associated with VII-B. Blood pressure Holland et a1., 1967 coronary disease VII-E. Ventilatory P= residents of community with Smoking associated with coronary VII-E. Socioeconomic hard water, heart disease . Constock 1971 _ 510 30 2-1 1 52
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lLI• Preventable Risk Factors - 35 Page 173 Reprint Illinois STAMLER J, LINDBERG H A, BERKSON D M, SHAFFER A, MILLER W and POINDEXTER A: J Chron Dis 11: 405-420, 1960. STAMLER J: The epidemiology of athersclerotic coronary heart disease. . Postgrad Med 25: 685-701, 1959. . . STAMLER J, BERKSON D M, LINDBERG H A, MILLER W and HALL Y: Racial patterns of coronary heart disease. Geriatrics 16: 382-396, 1961. Indiana 475 476 477 MORRIS W H M: Heart disease in farm workers. Can Med Assoc 1 96: - . 821-824, 1967. 478 Maryland HOLLAND W W, RAFTERY E B, McPHERSON P and STONE R W: A -. cardiovascular survey of American East Coast telephone workers. Am J Epidemiol 85: 61-71, 1967. . .' . 479. CONSTOCK G W: Fatal arteriosclerotic heart disease, water hardness at . home, and socioeconomic characteristics. Am J Epidemiol 94: 1-10, 1971. 480 Massachusettpc PAFFENBARGER R.S, WOLF PA, NOTKIN J and THORNE M C: Chronic disease in former college students. Am J Epidemiol 83: 314-328, . 1966. 481 PEMBERTON J and MACLEOD I E: Rural health survey of men over forty. ru.ia.c iaeni~u i:eyu.'La i i: iLi5-i7.i.v, iy5o. 462. New York LEE R E and SCHNEIDER R F: Hypertension and arteriosclerosis in executive and . nonexecutive personnel. JAMA 167; 1447-1450, 1958. 483 RUSSEK H I and ZOHMAN B L: Relative significance of heredity, diet and •. occupational stress in coronary heart disease of young adults. Am J Med Sci 235: 266-277, 1958. . 484 T10 30 2-1 1 6 3
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VII. Preventable Risk Factors - 37 Page 175 Pennsylvania Reprint BRIIHN J G, WOLF S, LYNN T N, BIRD H B and CHANDLER B: Social - - aspects of coronary heart disease ina Pennsylvania German community. Soc Sci Med 2: 201-212, 1968. 495 West Virginia -ffiGGINS I T T, HIGGINS M W, LOCKSHIN M D and CANALE N: Coronary . disease in mining communities in Marion County, West Virginia. J Chron Dis 22: 165-179, 1969. -496 -___-._ _-_e,_,_.,TI0302-1165
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VII. Prevent:.;u;e, Factors - 31 ~ Italy (Cont. ) P = 900 men in rural areab Fidanza et al., 1967 Smoking associated with co.,,nary heart disease VII-E. VIII-B. VII-F.. VI-A. VII-E. VII-A. VII-D. VII-A. VIII-B. Socioeconomic Hypertension Socioeconomic Physical activity Alcohol Phy~tc.ilact'.-rity Overeating Physical activity Hypertension . VIII-C. Hypercholesterolemia" `~ S = Analysis of death certificates Malesani 1967 - P = Boo..-ca'4 ~mployces Menotti 1967 P = 4, 668 miners and exminers Casciu et al„ 1968 R= 450 patient with myocardial infarction Di Cantogno et as 1968 P = 8,000 inhabitants of 2 rural areas Puddu and Menotti 1969 .. R- 1, 039 females with myo- cardial infarction Campos and Delneri 1969 S = 1, 737 male laborers Canepa et al., 1968 R= 530 patients with coronary heart disease Agnese 1970 ~ R= 386 cases of myocardial in- farction De Molo 1970 S = death certificate examination Menotti 1972 Japan P = 1, 000 residents in fishing and farming village Kimura 1967 P = 10, 429 residents Johnson et al., 1968 Nethe rla nd s S = examination of death certi- ficate Van Voorst Vader 1965 ' Smoking prevalent in patients Smoking prevalent:n patients with myocardia3 t-farction Smoking prevalent Smoking prevalent Smoking prevalent Smoking a s s ociatea with co rona ry heart disease VIII-B. Hypertension VIII-C. Hypercholesterolemi: V12-C. Diabetes VIII-B. Hypertensions VIII-C. Hypercholesterolemi: VIII-B. Hypertension VIII-C. Hypercholcsterolemi: Smoking prevalent Smoking not associated with coronary heart disease VIII-B. Hypertension VHI-C. Hypercholesterolem: Smoking associated with coronary heart disease P = 100 farmers Dalderup et al., 1965 VIII-E. Hypercholesterolemi~ Dalderu 1971 R= 34 patipents with coronary . Smoking prevalent heart disease VII-A. VII-D. Physical activity Diet P = 25, 000 residents Smoking not associated with coronary VII-B. Body weight • vanBuchem 1970 heart disease VIII-B. VIII-C. Hypertension Hypercholesterolem' - New Zealand S = 1, 000 males VIII-B. Hypercholesteroler Hunter 1963 ,~ - . T10 30 2-1 1 58
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JII. Preve.ntable Risk Factors - 34 Page 172 Reprint ANDRUS L H, MILLER D C, STALLONES R A, EHRLICH S P and JONES J P: Epidemiological study of coronary disease risk factors. I. Study design and characteristics of individual study subjects. Am J Epidemiol 87: 73-86, 1968. 464 MEIGS J W and ALBRINK M J: Epidemiology of coronary disease in industrial workers. Arch Environ Health 13: 645-654, 1966. 465 - . Delaware - . PELL S and WALONZO C A: Myocardial infarction in a one-year industrial study. JAMA 166: 332-337, 1958. . . 466 PELL S and D'ALONZO C A: Chronic disease morbidity and income level . in an employed population. Am J Public Health 60: 116-129, 1970. 467 Georgia KAPLAN B H, CASSEL J C, TYROLER H A, CORNONI J C, KLEINBAUM D G . and HAMES G G: Occupational mobility and coronary heart disease. . - Arch Intern Med 128: 938-942, 1971. 1 . 468 Hawaii BASSETT D R, ABEL M, MOELLERING R C Jr, ROSENBLATT G and STOKES 3: Dietry intake, smoking history, energy balance, and . "stress"in relation to age, and to coronary heart disease risk in - - . Hawaiian and Japanese men in Hawaii. Am J Clin Nutr 22: 1504- 1520, 1969. . . . .. 469 BASSETT D R, MOELLERING R C, ROSENBLATT G, GREENBERG D and STOKES J: Coronary heart disease ia Hawaii. J Chron Dis - 21: 565-583, 1969. 470 CHUNG C S, BASSETT D R, MOELLERING R C Jr. ROSENBLATT G, STO?CES 3 and `_'nSt-T_T_Zngr H: c>ici: r, ctore for ceronary heart disease in Hawaiian and Japanese males in Hawaii. 3 Med Genet ' 6; 59-66, 1969. 471 BASSETT D R, ABEL M, MOELLERING R C Jr, ROSENBLATT G and STOKES J: Coronary heart disease in Hawaii: Dietry intake, depot - fat, "stress ^, smoking, and energy balance in Hawaiian and Japanese J ' men.• Am J•Clin Nutr 22: 1483-1503, 1969. . 47z BASSETT D R and SCHROFFNER W G: Coronary heart disease in Chinese . men in Hawaii. Arch Intern Med 125: 478-487, 1970. 473 KAGAN A, RHOADS G G, ZEEGEN P D and NICHAMAN M Z: Coronary heart disease among men of Japanese ancestry in Hawaii. Isr J Med Sci 7: 1573-1577, 1971. 474 \ T10302-1162
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H Factors - 30 India (Cont. ) . R= 553 patients with coronary heart disease compared to 1,056 controls . Mathur 1960 R = 2, 162 cases Jhatakia 1966 S = mortality statistics in various areas Malhotra 1967 S = hospital admissions Jhatakia et al., 1967 R= 450 cases of myocardial in- farction Lal and Caroli 1967 Lal and Caroli 1968 Lal and Caroli 1968 R= 75 cases of coronary heart disease Chattopadhaya et al. 1968 P = 2, 030 resident - -- Sarvotham 1968 R = 150 cases of myocardial infa r ction Pandley 1970 R = 240 cases of coronary heart dieease Singh and Singh 1971 Iceland S = Death certificate analysis Sigurjonsson 1969 Sigurjonsson 1969 Israel P = 8, 500 members in com- ...-..al ., ctllcmc^ Bruner and Manelis 1960 P = 331 elderly residents Librach,1967 P = 10, 059 subjects Medalie et al„ 1968 VII-A. Physical activity VIII-B, Hypertension VI-D. Anxiety VII-C. Diabetes VII-D, Diet VIII-B. Hypertension VIII-C. Hypercholesterolemia Italy Page 167 Smoking not associated with VII-E. Socioeconmic class coronary heart disease VIII-A. Hypertension . . VIII-B, Hyper cholesterol emia VII-E, Socioeconomic factor: Smoking not related to VII-E. Socioeconomic coronary heart disease . Smoking not associated with coronary heart disease . Smoking not associated with VII-C. Diabetes coronary heart disease VIII-B, Hypertension Smoking associated with VI-C. Constitutional coronary heart disease VI-D. Behavioral - VII-E, Socioeconomic ~ VIII-B. Hypertension Smoking not associated with coronary VII-E. Socioeconomic heart disease . Smoking not important risk factor VII-C, Diabetes , _ VIII-B. Hypertension . VIII-C. Hypercholesterolemi; Smoking not associated with coronary VII-C. Diabetes heart disease V1II-B. Hypertension VII-D, Diet Smoking not associated with coronary heart disease . Smoking associated with coronary heart disease R= 100 patients with myocardial VII-E, Socioeconomic infarction Palma 1963 R = 255 cases of myocardial in- Smoking not associated with coro- VI-C. Constitutional farction nary heart disease Della Salda et al. , 1966 .: rms*t~TI0302-1157
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V.II. Preventable Risk Factors - 3.8 Page 177 Reprint BEST E W R, and WALKER C B: A Canadian study of smoking and health. Second report. Can J Public Health 55: 1-11, 1964. 505 BEST E W R, WALKER C B, BAKER P M, DEL&QUIS F M, McGREGOR J T . . and McKENZIE A C: Summary of a Canadian study of smoking and health. Can Med Assoc J 96: 1104-1107, 1967. 506 CANADIAN DEPARTMENT OF NATIONAL HEALTH AND WELFARE: A Canadian study of smoking and health. 1: , 1966. 507 CANADIAN DEPARTMENT OF NATIONAL HEALTH AND WELFARE: A Canadian study of smoking and health. . . 1966 . 508 CANADIAN DEPARTMENT OF NATIONAL HEALTH AND WELFARE: - A Canadian study of smoking and health. 1966 509 GOULET C, ALLARD C and POIRIER R: Ettude epidemiologique d'une . population urbaine Canadienne-Franfaise: facteurs associes an _. profil coronarien. L'Union Med J Can 97: 1104-1109, 1968. - 510 Czechoslavakia .. '. . . . J . . . ,. . - . _. STEJFA M Jr:. Predictive significance of risk factors in exertional angina pectoris. Cardiologia 51: 336-339, 1967. 511 HLOUCAL L and DUSEK: Vyskyt koronarni nemoci srdecni ve. . strakonickdf oblasti. (Frequency of the coronary heart disease '- in the region of Strakonice). Cas Lek Ces 107: 554-559, 1968. . 512 HORAK J, KOCI Y and PLISEK V: Kuractvi u nemocny'ch vnitrniho . , oddeleni. Vnitrnf Lekarstvi. 14: 442-445, 1968. . ,--- 513 SANTRUGEK M: Dotazniky rozesilane postou v epidemiologickych studiich kardiovaskularnich chorob. Cesk Zdrav 18: 81-84, 1970. 514 FINGERLAND A, HUSAK T and BENDLOVA J: Contribution to the investigation of the effect of cigarette smoking. Sb Ved Pr Lek Fak Karlovy Univ . 1^_7 221_23^, '^^' 515 - - Finland . . , IKKALA E: Myocardial infarction. Studies of patients treated at the provincial .-hospital of Oulu 1946-1958 with special reference to various age groups, ' . .. especially young infarct patients. Ann Med Intern Fenn 49: 5-35, 1960. . ' 516 KARVONEN J; RAUTAIIARJU P M, ORMA E, PUNSAR S, TAKKUNEN J: Heart disease and employment. Cardiovascular studies on lumberjacks. J Occup Med 3: 49-53, 1961. ' 517 T10 30 2-1 1 6 7
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VTI. Preventable Risk Factors - 42 Page 181 Reprint LAL H B and CAROLI R K: The incidence, predisposing factors, associated disease and precipitating. factors. Ind J Med Res .. .56: 1079-1143, 1968. .561 CHATTOPADHAYA M L, MITTAL M M, BHARGAVA S P and SHARMA M L: • Some factors in the epidemiology of coronary heart disease in Delhi area. J Indian Med Assoc 51: 1-9.- 1968. - , . . 562 SARVOTHAM S G and BERRY J N: 'Prevalence of coronary heart disease in an urban population in northern India. Circulation 37: 939-953, 1968. 563 PANDLEY M R: Myocardial infarction in Nepal. Indian Heart 7 22: . 73-82, 1970. . . .564 , SINGH A P and SINGH S P: Coronary heart disease -- some epidemiological clinical and electrocardiographic observations. J Assoc Physicians India ' 19: 629-635, 1971. 565 Iceland -SIGURJONSSON J: Urban-rural 1 differences in mortality from ischaemic heart . disease. Am J Med Sci 257: 253-258, 1969. :.- -- 566 Israel BRUNNER D and MANELIS G: Myocardial infarction among members of -. communal settlements in Israel. Lancet . 2: .1049-1050, 1960. 567 LIBRACH G: Prevalence of ischemic heart disease among elderly Yemenites and Europeans, residents of homes forthe aged in Israel: . - JAm Geriatr Soc 15: 1125-1136, 1967. . . . 568 MEDALIE J H, KAHN H A, GROEN J J, NEUFELD H N and RISS E: The prevalence of ischemic heart disease in relation to selected variables. _ Isr J Med Sci 4: 789-800, 1968. 569 . Italy PALMA A: Indagine clinico-statistica su alcuni aspetti medico-sociali ~.. _dell'infartomiocardico. Folia Med 46; 240-247, 1963. 570 DELLA SALDA C, TURINA C and CUIDUCCI U: Sui fattori epidemiologici dell`infarto miocardico. G Clin Med 47: 1165-1180, 1966. 571 FIDANZA F, PUDDU V, VECCHIO A and KEYS A: .Men in rural Italy. . F• Acta Med Scand (Suppl 460): 116-146, 1967. 572 MALESANI S M: Considerazioni epidemiologiche sui dati statist'ici riguardanti 1'infarto del miocardio a verona, dal 1950 al 1960. . . Quad Sclavo Diagn 3: 173-195, 1967. . 573 T10 30 2-1 1 71
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VII. Preventable Risk Factors - 31a E 1 North Afnica S= 25 patients with corora ry Smoking prevalent heart disease - . = Bertrand et al, , 1971 Norway P= 62 train drivers Smoking not associated with ' Berg and Melkild 1962 coronary heart disease P = 4, 052 men Smoking prevalent among coronary Zeiner-Henriksen 1971 heart disease . Peru P = 1, 032 residents at high Smoking not associated with _ altitude _eoronary heart disease Ruiz et al. 1969 Phillippines . . R = 32 cases of myocardial Smoking prevalent ' -infarction Gutierrez and Dayrit 1969 Puerto Rico P = 9, 814 urban and rural men ' Smoking not associated with °-Garcia-Palmieri et al., 1970 coronary heart.disease .--Benson et al., 1966 _ R,= 250 cases of myocardial in- Smoking prevalent farction - Jacobs 1971 " - ----- --- - -. South Africa P = 600 adult males - Smoking associated with coronary Bronte-Stewart 1961 heart disease P = 296 elderly Bantu Low incidence of smoking and - Seftel et a1„ 1965 coronary heart disease --- • -Seftel et al, 1970 ---- Sweden ~~ P = 973 city residents ~~ =Smoking associated with coronary Tibblin 1970 -heart disease ...-._Tibblin 1968 . ~ ~ Tibblin and Wilhelmsen 1971 ~ . ~ . ~ Tibblin and Wilhelmsen 1971 Wilhelmsen et al. , 1972 S = 3, 249 hospital cases ' -- ~ Johansson 1968 - Switzerland P= 3,479 physicians Strobel and Gsell 1965 P = 500 workers Heyden-Stucki and Schibler -Reich 1967 USSR S = Survey of workers Golubovski 1968 Smoking associated with coronary heart disease ._. . :.. .. .. ._. . .__ . , : Smoking associated with hyper- tension Smoking associated with coronary heart disease Page 169 VIII-C. Hypercholesterolcrni VII-A, Physical activity V1I-E. Urban factor VIII-B. Hypertension VIII-C. Hypercholesterolemi (Absence of most risk factors VI-D. Emotional stress VII-B. Obesity VIII-B. Hypertension - VII-A. Physical activity VIII-B. Hypertension VIII-C. Hypercholesterolemi VII-C. Diabetes mellitus VII-E. Socioeconomic' T10 30 2-1 1 59
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VIII. Risk Factors influenced 88 by Smoking - 3 Additional Bibiio~ranhic List No. 19 Page 1 VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING INVESTIGATION OF PREVENTABLE RISK FACTORS IN FOREIGN COUNTRIES Australia CHRISTIE D: Australian "bronchitis mortality. Med J Australia 1: - 21-25, 1971. GOLDRICK R B, SINNETT P F and WHYTE H M: An assessment of coronary heart disease and coronary risk factors in a New Guinea highland population. Circulation 40 (Suppl 3): 9, 1969 . . HIPSLEY E H and FURNASS S B: Coronary heart disease: Some reflections on its causation and prevention. Med J Australia 1: 607-621, 1966. Reprint A 45? A45-' A 43i POSEN S: The Asian undergraduate in Australia. Med J Australia 2: 1968. A 457 STEPHENS W B: Myocardial infarction -- incidence in Albury-Wodonga. . Med J Australia 2: 446-452, 1970. . A 45f STEPHENS W B: Post-myocardial infarction pain in a series of male patients in the Albury-Wodenga district. Med J Australia 2: 492-494, 1970. A 455 WELLS R: The epidemiology of ischaemic heart disease in Australia. Med J Australia 2: 109-112, 1969. A 460 Belgium - KORNITZER M, DEMEESTER M and DENOLIN M:Enquete dans une population d'employes. Brux Med 51: 687-691, 1971. A 461 KORNITZER M, DEMEESTER M, DELCOURT R and BERNARD R: . Cardiopathies ischemiques dans une population d'employe's de Bruxelles. - Rev Epidem Med Soc Sante Publ 19: 599-612, 1971. . . A 462 Canada ANDERSON T W: Role of myocardium in the modern epidemic of ischaemie heart disease. Lancet 2: 753-755, 1970. . A 463 NERI L C, MANDEL J S, O'CONNOR M L and LARSON M: A household :_ survey of chronic obstructive pulmonary disease in Ottawa. Can J Public Health 61: 407-412, 1970. - . . , A 464 SCHMIDT W and LINT J: Causes of death of alcoholics. Q J Stud Alcohol 33: 171-185, 1972. . A 465 Czcchoslavakia BOUDIK F: Srdecni infarkt a koureni. (Myocardial infarction and smoking) Cas Lek Ces 110: 614-620, 1971. A 466 TI0302-1178
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iJIII. Risk Factors Influenced by Smoking - 2 Page 187 List No. 20. Ischemic changes in the electrocardiogram. List No. 2I. Hypertension as a risk factor. List No. 22. Cholesterol and coronary heart disease. List No. 23. Thrombosis induction and prevention. T10302-1177
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VIII. Risk Factors Influenced by Smoking - I Page 186 VIII. PREVENTABLE RISK FACTORS PROBABLY INFLUENCED BY SMOKING UG6NETTE SNOeiNO ` i - ~[LCCTRD~'` BLOOD CNOLESTEPOL BLOOD aVA1LnB41TY CARDI4GRAPNIC PHESSURE tEVEL CLOTTING Of OKYOEN ]® PREVENTafiLE RtSN FACTORS (INFLUENCED BY SYONINO) A. Electrocardiogram and Myocardial Statue---- -------- 20l B. HypertcneioN---------------- 204 C. Hypercholeetcrolemia-------- 207 b. $lood Coagulation------------ 214 E. Availability of Oaygen aod Aeaoeiated Changes in the Blood----------------------- 219 The preventable risk factors discussed in this section are those that are believed to be exaggerated by smoking. This supposition is based on observations of the effects of acute exposure to smoking in humans and animals and these are discussed in Section IX. The differences between habitual smokers and nonsmokers are described below. It should be stated at the outset that there is no concrete evidence for the hypothesis that chronic smokers show exaggerated electrocardiographic signs of ischemia, develop hypertension, hypercholesterolemia and hypercoagulation of the blood. The problem of reduced availability of oxygen in the blood of the habitual smoker is a complex one and is discussed under carbon monoxide (Section XI). The general articles relating to the preventable risk factors are contained in the following Additional Bibliographic Lists• List No. 19. Investigation of preventable risk factors in foreign countries. 1-11-1--`- r.....,,,T, „_.,.~.~ .. -., .,..:„.J10302-7776
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VII. Preventable Risk Factors - 40 Germany KEISER G: Statistische Untersuchungen uber den Einfluss des Rauchens auf die Angina pectoris. Cardiologia 24: 285-310, 1954. SCHIMMLER W and NEFF C: Rauchgewohnheiten und Herzinfarkt. , . Munch Med Wochenschr 108: 903-915, 1966. 532 533 SCHIMMLER W, NEFF C and SCHIMERTG: Risikofarktoren und Herzinfarkt. I . Munch Med Wochenschr 110: 1585-1594, 1968. 534 CRECELIUS W, STRAUZENBERG S E and POKLEKOWSKI I: Klinischer Beitrag zur Epidemiologie des Herzinfarkts. Dtsch Gesundh 21: 2069-2075, 1966. STORCH H, ENGELMANN L and KOHLER H: Der Herzinfarkt im jungeren'Lebensalter. Dtsch Gesundh. 26: 1593-1600, 1971. - BROWN R G, McKEOWN T and WHITFIELD A G W: A note on the association 535 536 • between smoking and disease in men in the seventh decade. Br J Prev Soc Med 11: 162-164, 1957. 537 EDWARDS F, MeKEOWN T and WHITFIELD A G W: Association between smoking and disease in men over sixty. Lancet 1: 196-200, 1959. 538 LOWE C R: Smoking habits related to injury and absenteeism in industry. Br J Prev Soc Med 14: 57-63. 1960. - . 539 MORRIS J N, KAGAN A, PATTISON D C, GARDNER M J and RAFFLE P A B: . Incidence and prediction of ischaemic h(a'.i't-disease in London busmen. - Lancet 2: 553-559, 1966. 540 ACHESON R M: Aetiology of coronaryy heart disease in old men. Br J Prev Soc Med 15: 49-60, 1961. 541 BROWN A: Coronary thrombosis an environmental study. Br Med J 2: 567-573, 1962. 542 MULCAHY R, GOFF A andHICKEY N: A study of the cigarette smoking habits . of patients with coronary heart disease. J Ir Med Assoc 53: 141-146, 1963. 543 MULCAHY R and HICKEY N: A study of the smoking habits of patients with , - ' coronary heart disease. Br Heart J 27: 951-952, 1965. , 544 MULCAHY R and HICKEY N:3he influence of cigarette smoking in the causation of atherosclerosis.. Angiology 17: 25.9-263, 1966. 545 MULCAHY R and HICKEY N: Cigarette smoking habits of patients with coronary heart disease. Br HeartJ 28: 404408, 1966. 546 T10302-1169
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VII. Preventablc Risk Factors - 46 Page 185 Reprint HEYDEN-STUCKI S and SCHIBLER-REICH S: Kardiologische Risikofaktoren •bei Schweizer Mannern. Schweiz Med Wochenschr 97: 20-25, 1967. 608 U. S. S. R. GOLUBOVSKI A: Sov Zdravookhr ~ . ~ 27: 28-30, 1968. 609 BOROJEV A and STANULOVIC D: The epidemiological examination of a group . of patients suffering from cardiac infarct, with special reference to feeding habits and the nature and quality of nourishment. Med Pregl 24: . 107-114, 1971. 610 • GLAZUNOV I 5, ARONOV D M, DROMBIAN Y G and DRYLOVA E A: Ischaemic heart disease and occupation. Cor Vasa 6: 274-280, 1964. 611 Yugoslavia KOZAREVIC D, PIRC B, DAWBER T R, KAHN H A and ZUKEL W J: Prevalence and incidence of coronary disease in a population study. J Chron Dis - 24: 495-505, 1971. . 612 DJORDJEVIC B 5, JOSIPOVIC V, NEDELKOVIC S 1, STRASER T, SLAVKOVIC V. SIMIC B, KEYS A and BLACKBURN H: Men in Velika Kesna, a - Serbian village. Acta Med Scand Suppl 460: 267-277, 1967. . -' 613 . . ~ .. . . . BUZINA R, KEYS A, MOHAGEK I, HAHN A, BROZEK J and BLACKBURN H: Rural men in Dalmatia and Slavonia, Yugoslavia. Acta Med Scand Suppl 460: 147-168. 1967. . 614 i v r r ~ " DJORDJEVICrB 5, BALOC, B, BOZINOVIC L J, JOSIPOVIC, V, NEDELJKOVIC S. _- LAMBIC I, SEKULIC S, SLAVKOVIC V, STOJANOVIC G, SIMIC A, - SIMIC B, STRASSER T, BLACKBURN H and KEYS A: Three cohorts of men . followed five years in Serbia. Circulation 41 (Suppl 1): 123-153, 1970. 615 VUKADINOVIC D and SARIC M: Koronarna srcan a bolest i hipertenzija kod , starijih radnika jednog industzijskog poduzeca. Arch Hve Rada 17: 379-425, 1966. 616 T10 30 2-1 1 7 5
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'II. Preventable Risk Page 183 Factors - 44 DALDERUP L M: Risk factors for coronary heart disease. Voeding 32: 406-408, 1971. VAN BUCHEM F S P: Zutphen, a town in the Netherlands. Circulation 41 , (Suppl I ): 76-87, 1970. Reprin! 587 588 HUNTER J D: Some epidemiological aspects of coronart artery disease in New Zealand and the Cook Islands. Ann N Y Acad Sci 97: 908-919, " 1963. 589 North Africa . BERTRAND E, AYE H, BEDA B, BARABE P, LEBRAS M and DELLOUE M: i - Quelques aspects des coronarites observees a Abidjan chez des Noirs Africains. Afr J Med Sci 2: Z17-228, 1971. BERGK J and MELKILD A: Coronary disease in a group of Norwegi_an.._ . .'tram drivers. Acta Med Scand 171: 671-677, 1962. 2EINER-HENIRIKSEN T: Cardiovascular disease symptoms in Norway --a a study of prevalence and_ a mortality follow-up. J Chron Dis 24: 553-567, 1971. Peru .+ RUIZ L, FIGUEROA M, HORNA C and'PENALOZA D: Prevalencia de la hipertension arterial y cardiopatia isquemica en las grands alturas. Arch Inst Cardiol Mex 39: 474-489, 1969.- -- - - - - - Phillippine s - GUTIERREZ M T and DAYRIT C: Some physico-chemi.cal characteristics of acute myocardial infarction among Manila residents. . .. Phillippine J Intern Med 7: 8-17, 1969. . ' __--- ' ~ ~ Puerto Rico - GARCIA-PALMIERI M R, COSTAS R, CRUZ-VIDAL M, CORTES-ALICEA M, . COLGN A A, FELIBERTI M, AYALA A M,. PATTERNE D, SOBRINO R, TORRES R and NAZARIO E: Risk factors and prevalence of coronary . heart disease in Puerto Rico. Circulation 42: 541-549, 1970. 590 593 594 T10302-1173
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T11. Preventable Risk Factors - 41 Page 180 Reprint ARMSTRONG A and WILSON R B: Coronary heart disease in elderly men - in a rural area of south-west Scotland. Scot Med J 9: 438-511, 1964. 547 REID D D, HOLLAND W W, HUMBERFELT S and ROSE G: A cardiovascular survey of British postal worker s. - Lancet 1: 614-618, 1966. 548 SPELMAN M S and LEY P: The effect of psycho-social factors on the prognosis of coronary thrombosis. Med J Australia 2: 1189-1193, 1966. 549 . BRETT G Z and BENJAMIN B: Smoking habits of men employed in industry. and mortality. Br Med J 82-84, 1968. 550 MULCAHY R, HICKEY N and MAURER B: Coronary heart disease. A study - of risk factors in 400 patients under 60 years. Geriatrics 24: 106-114, 1969. 551 COTTON S G, NIXON J M, CARPENTER R G and EVANS D W: Factors . discriminating men with coronary heart disease from healthy controls. . ' Br Heart J 34: 458-464, 1972. . . . 552 Greece ARAVANIS C, DONTAS A S, LEKOS D and KEYS A: Rural populations in Crete and Corfu, Greece. Acta Med Scand (Suppl 460): 209-230, 1967. 553 India BANSAL R D, CHABLANI T D and GULATI P V: An epidemiological study of ischaemic heart disease in patients attending the cardiology - clinic at the Aiims, New Delhi. Indian Med J 64: 84-92, 1970. -. . 554 'VYTILLINGAM K I: The incidence and epidemiology of coronary heart disease in South India. 290-300, 555 MATHUR K S: Environmental factors in coronary heart disease. An epidemiologic : _ study at Agra (India). Circulation 21: 684-689, 1960. 556 JHATAKIA K U: Incidence and etiology of coronary artery disease. J Assoc Physicians India 14: 283-288, 1966. 557 MA_ LHOTRA S L: Epidemiology of ischaemic heart disease in India with special reference to causation. Br Heart J 29: 895-905, 1967. . . 558 JHATAKIA K U, T1iAKORE P B and VASAVADA P J: Observations onn some ... facets of coronary artery disease. J Assoc Physicians India 15: 109-115, 1967. - 559 LAL H B and CAROLI R K: "Acute myocardial infarction in higher income group patients" -- some clinical, electrocardiographic and biochemical observations. •Indian Heart J 19: 12-25, 1967. 560 T10302-1170
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IIL[. Risk Factors Influenced by Smoking - 9 Page 194. Additional Bibliographic List No. 20 VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING ISCHEMIC CHANGES OF THE ELECTROCARDIOGRAM Reprint BLACKBURN H, PARLIN R W and KEYS A: The inter-relations of electrocardiographic findings and physical characteristics of middle-aged men. Acta Med Scand Suppl 460: 316-341, 1967. A 537 GA1J G T, GOODWIN J F, OAKLEY C M, OLSEN E G J, RAHIMTOOLA S H, -RAPIiAEL M J and STEINER R E: Q waves and coronary arteriography in cardiomyopathy. Br Heart J 34: 1034-1041, 1972. . A 538 HERMAN M V, ELLIOTT W C and GORLIN R: An electrocardiographic, , ; anatomic, and metabolic study of zonal myocardial ischemia in coronary - . heart disease. Circulation 35: 834-846, 1967. . A 539 KAHLSON G: Om koronarinsuf£iciens, dess uppkomstbetingelser, elektrokardio- grafiska yttringar och medikamentosa behandling. Nord Med Tidsk 13; 801-814, 1937. A 540 . KALTENBACH M, SCHXFER R and KLEPZIG: Prognostische Bedeutung des . Belastungs-Elektrokardiogramms. Med Klin 62: 710-713, 1967. A 541 MASTER A RM: The two-step test of myocardial function. Am Heart J 10: 495-510, 1935. A 542 SPINA A, LISI S, SILVIA G and SIRACUSA G: Inchiesta epidemiologica sull'incidenza'in rapporto all'et'n ed al sesso delle alterazioni dell'elettrocar- -- diogramma da coornariopatia in provincia di catania. Gazz Int: Med Chir 74: 422-435, 1969. A 543 VAN BUCHEM F S P, DRION E, WIGBOUT M and BOSSCHIETER E: Het voorkomen en de betekenis van een depressie van liet ST-segment in het elektrocardiograrn bij mannen zonder andere verschijnselen. . Ned Tijdschr Geneeskd 114: 320-332, 1970. . A 544 T10 30 2-1 1 84
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VLI. Preventable Risk Factors - 43 Page 182 MENOTTI A: Epidemiological study on ischaemic heart disease in the railroad employees in Rome. Cor Vasa 9: 28-33, 1967. CASCIU G, MARRACCINI L, ZEDDA 5, CARTA G and' FULGHESU G: Sulla frequenza delle cardiovasculopatie tra gli operai dell' . industria estrattiva della sardegna. Rass Med Sarda 71: 191-200, 1968. DI CANTOGNO L V, VIZZERI E, ORIONE G and GALASSO L: • Considerazioni sulla frequenza di alcuni fattori ereditari ed acquisity in 450 infarti del miocardio. Minerva Med 59: 561-566, 1968. PUDDU V and MENOTTI A: An Italian study on epidemiology of ischaemic heart disease. Acta Cardiol 24: 558-578, 1969. CAMPOS A and DELNERI E: Incidenza dell'infarto del miocardio nei fumatori. Minerva Med Giuliana 9: 220-222, 1969. CANEPA R, BALESTRA V and BUCCELLI A: Frequenza delle cardiopatie ischemiche nei lavoratori portuali ed abitudini al fumo. G Ig Med Prev . 9: 55-64, 1968. AGNESE G, CANEPA R and LA ROCCA M: Eta e valore di alcuni indici per . . la discriminazione fra soggetti normali ed ischemici. G Ig Med Prev 11: 140-151, 1970. DE MOLO G: '• L'incidenza dei fattori de rischio coronarico nei soggetti con • infarto del miocardio. Ann Med Navale 75: 243-258, 1970. MENOTTI A: Epidemiology of coronary heart disease in Italy. ,_ . Scand J Clin Lab Invest 29: 12, 1972. J~n KIMURA N: A farming and a fishing village in Japan -- Tanushimaru and Ushibuka. Acta Med Scand (Suppl 460): 231-249. 1967. - JOHNSON K G, YANO K and KATO H: Coronary heart disease in Hiroshima, Japan: A report of a six-year period of surveillance, 1958-1964. . Netherlands - . VAN VOORST VADER P J A: Betrekkingen tussen roken en de sterfte in Nederland gedurende 1963. Ned Tiidschr Geneeskd 109: 601-608, 1965. DALDERUP L M, STOCKMANN V A, RECHSTEINER DE VOS H and • VAN DER SLIKKE G J: Survey on coronary heartdisease _in relation to diet in physically active farmers. Voeding 26; 245-288, 1965. Reprint 574 575 . 576 577 - '578 . 579 580 . 581 ,. .. ' 582 . 583 _ 584 . • 585 586 T10 30 2-1 1 7 2
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TII. Preventable Risk Factors - 39 Page 178 Reprint. RUIKKA I, SOURANDER L B and KASANEN A: The health of the aged in Turku. Am Statistician 8: 3-50, 1966. 518 KARVONEN M J, BLOMQVIST G, I{ALLIO V, ORMA E, PUNSAR S, . PAUTAJARJU P, TAKKUNEN J and KEYS A: Men in rural east and west Finland. Acta Med Scand (Suppl 460): 169-190, 1967. 519 KARVONEN M J: Arteriosclerosis: Clinical surveys in Finland. . Proc R Soc M_d 55: 271-274, 1962. 520 KARVONEN M J, ORMA E, PUNSAR S, KALLIO V, ARSTILA M, - LUOMANMAKI K and TAKKUNEN J: Five-year experience in - Finland. Circulation 41 (Suppl 1): 52-62, 1970. , , 521 KARVONEN M J: Sepelvaltimotaudin riskitekijat kansainvalisessa . . epidemiologisessa tutkimuksessa. Suom Laakarelehti 26: . . ', 1199-1204, 1971. . . . .. 522' • KARVONEN M J: Sydan-ja verisuonitaudit -- ehkaisy ja varhainen toteaminen. Suom Laahaulehti 27: 76-82, 1972. - 523 PUNSAR S. KARVONEN M J and PYORALA K: The difference between - East and West Finland in the prognosis of coronary heart disease.. ,. .- Scand J Clin Lab Invest 23 (Suppl 108): 52, 1969. 524 PUNSAR S, and PYORALA K: Cigarette smoking and the risk of death , . . from coronary heart disease in East and West Finland. . Scand J Clin Lab Invest 25 (Suppl 13): 38, 1970. '' -.525 TERASLINNA P, PARTENEN T, KOSKELA A and OJA P: Association of : - certain social habits and attitudes with risk factors of coronary heart disease. Soc Sci Med 5: 243-250, 1971. '-..:, . 526 ROMO M: Factors related to sudden death in acute ischaemic heart disease. A community study in Helsinki. -1-92, 1972. 527 France -ANONYMOUS: Cigarette, cancer du poumon et thrornbose coronarienne. - Concorus Med 90: 6304-6307, 1968. ~. 528 ANJUERE J: Peut-on prevoir l'infarctus myocardique? Facteurs predisposants. Arch Med Angers 69: 151-158, 1968. • 529 HIMBERT J, BENSAID J and ROUSSEL C: Premiers resultats de 1'application - aux maladies cardiovasculaires d'une nouvelle conception de la medecine ~ . preventive utilisant le traitement automatique de 14nformation par ordinateur. • Arch Mal Coeur64: 538-552, 1971. -, 530 WARTER J, SACREZ A and BRECHENMACHER C: Causes occasionnelles de ' Vinfaretus du myocarde. J Med Strasbourg 3: 31-36, 1972. . . 531 T10302-1168
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VIII. Risk Factors Influenced by Smoking - 17 ischemic response were smokers, whereas 37% of those with a normal Page 202 electrocardiogram were smokers. Kattus et al. (1971) obtained the respective incidence of 59% and 42%. As in other studies, the role of various risk factors could not be excluded. When the heart was stressed by hypoxia, there was no difference between smokers and nonsmokers in the T-area vectors of the electrocardiogram (Abel, 1971). The QRS complex showed a right axis deviation in some smokers (Borden and Ibrahim, 1970). The polarcardiogram, which graphs the polar coordinates of the heart vectors vs. time, indicate a difference between smokers and nonsmokers (Dower et al., 1972). The complexity of the technique prevents its widespread application to determine the significance ot the difference. The heart of smokers in contrast to that of nonsmokers has been investigated by means of special techniques. The ballistocardiogram arid other techniques for cardiac output measurement do not show any difference between smokers and nonsmokers in this respect (Starr (1954) and also , Section IX-A). T10 30 2-1 1 9 2
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II[. 1{isk Factors ?iif?.uenced by Smoking - 5 Page 190 List No. 19 - - ~ ~ ~ Reprint . JOUVE A, SOMMER A and AVIERINOS C: Epidemiologie de 1'atherosclerose coronarienne les enquetes prospectives. Gaz Med France 79: 2045-2050, 1972. . France . . . .. BASTIDE H and HOUDAILLE J: Epidemiologie du tabac en France . et dans le monde. Vie Med 52: 2989-2995, 1971. A 481 PERNOD J: Frcfquence et etiologie de la maladie coronarienne. Cah Med 11, 1431-1437, 1970. . - i . RIME B and MERTENS C: L'incidence des facteurs psychologiques et socio-culturels dans 1'etiologie des affections coronariennes. Ann Med Psychol 1: 43-60, 1970. A 482 A 483 A484. Germany ., . . .. . . . .. BLUMCHEN G, KIEFER H, ROSKAMM H, WALDMANN D, BUCHNER C - and REINDELL H: Vergleich der koronarangiographischen Befunde - . von 127 patienten mit Anamnese, Risikofaktoren fur koronare . Herzerkrankung, Rube-und Belastungs-Ekg. Z Kreislaufforsch. 58: 149-167, 1969 ' .. A 485 ,. DORKEN H: Epidemiologie.und Klinik des Herzinfarktcs. Internist 13: 310-317, 1972. A 486 . GILLMANN H and COLBERG K: Untersuchungen Uber die Lebensphase nach hberstandenem Herzinfarkt. Dtsch Med Wochenschr 94: 933-939, 1969. . . ' A 487 HORLEIN H and SEITZ I: Untersuchungen iiber den Hcrzinfarkt. Arch Kreislaufforsch 57: 84-113, '1968: '. A 488 KASTL 0: Berufliche und Umweltanalyse infarktkranker Eisenbahnbediensteter. . Med Klin 64: 1911-1917, 1969. A 489 .. KNAPPE J, STRUI3E G, DUCK K-D, RELKE W and RITTMEISTER H: .Modell einer Querschnittsstudie der Krankheitsgruppe Hypertonie im Rahmen der epidemiologischen Untersuchung der Koronarkrankheit und der peripheren Sklerose, auswertbar uber eine elektronische Datenver- - - . arbeitungsanlage. Dtsch Gesundh. 25: 1305-1310, 1970. A 490 PARADE G W: Herzinfarkt bei erbgleichen Zwillingen. Z Gerontolog . 1: 151-155, 1968. A 491 SCHAR M: Sinn der prophylaktischen Reihenuntersuchungen. Schweiz Med Wochenschr 100: 784-786, 1970. Q 49Z SCHETTLER G and HILD R: Koronarsklerose und Myokardinfarkt in der Westdeutschen Bundesrepublik1945-1965. Path Microbiol 30: 766-776, 1967. A 493 310 30 2-1 1 8 0
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VTII. Risk Factors Influenced by Smoking - 4 Page 189 List No. 19 " - . Reprin FODOR J: Epidemiologie srdecni . ch a cevnich chorob. Cesk Fysiol . 16: 339-342, 1967. A 467 v HLOUCAL L and DUSEK J: Epidemiologische Studie der Koronarsklerose und des Herzinfarktes. Wein Med Wschr 119: 27-31, 1969. A 468 LUHL P: Die Prognose beim Myokardinfarkt. Wien Z Ann Med 52: 214-218, 1971. . A 469 PAVLIK I and CERMAKOVA Z: Casna Kozni reakce na tabakovy extrakt u chorob dy'chadel. Rozhl Tuberk Numoceca Plincih 24: 629-635, 1964. A 470 RIPKA 0: Epidemiologie des hohen Blutdrucks. Med Klin 63: 89-93, 1968. A 471 REINIS Z, BAZIKA V, KUTHAN F, SLABY A, REISENAUER R and - MARKIOVA L: Prevalence of ischaemic heart disease in.rural population. Cor Vasa 12: 118-128, 1970. - . A 472 SANTRUCEK M and VACEK M: K otazce stressu a ischemicke choroby srdecni. (Stress and ischaemic heart disease). Cesk Zdrav 15: 7-8, 372-382, 1967. A 473 SANTRUCEK M and VACEK M: Kouieni a ischemicka choroba srdecni ve svgtle epidemiologickych studii. Cesk Zdrav 16: 66-75, 1968. A 474 SANTRUCEK M: Ischemicka choroba srdecni ve svetle klinickych a . . patologickoanatomickych nalezu. Cesk Zdrav 17: 464-478, 1969. A 475 Finland LUCMA H, HELMINEN 5, RYTUMAA I, MEURMAN J and RANTA H: Fluoride and magnesium contents of 'drinking.water and the cardiovascular diseases in men of four rural communes in Finland. Scand J Clin Lab Invest 29: 18, 1972. A 476 PUNSAR 5: Tupakointi ja sepeivaltimotauti. Suomen Laakarilenti . . 26: 27-32, 1971. . A 477 PUNSAR S and KARVONEN M J: Angina pectoris and ECG abnormalities in relation to prognosis of coronary heart disease in population studies in Finland. " PUNSAR S: Prognosis of CHD in East and West Finland. Scand J Clin Lab Invest 29 (Suppl 122): 19, 1972. - . A 478 A 479 . PUNSAR S and PYORALA K: Cigarette smoking and the risk of death from .. coronary heart disease in East and West Finland. Scand J Clin Lab Invest • 25 (Suppl 113): 38, 1970. A 480 T10302-1179
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VIZI. Risk Factors ?niluenced Page 199 by Smoking - 14 . VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING , Additional Bibliogra hic List. No. 23 - THROMBOSIS -- INDUCTION AND PREVENTION Reprint BORCHGREVINK F, BJERKELUND C, ABRAHAMSEN A M, BAY.G, BORGEN P, . GRANDE B, HELLE I, KJORSTAD H, PETERSEN A M, RORVIK T, . THORSEN R and ODEGAARD A: Long-term anticoagulant therapy after . myocardiall infaection in women. Br Med J 3: 571-574, 1968. A 597 " BRAY C and McDONALD L: A new platelet defect in patients with ischaemic heart disease. Br Heart J 28: 429, 1966. A 598 13YGDEMAN S, ELIASSON R and JOHNSON S-R: Relationship between post- . . operative changes in adenosine-diphosphate induced platelet adhesiveness and venous thrombosis. Lancet 1: 1301-1302, 1966. BYRD R B, DIVERTIE M B and SPITTELL J A Jr: Bronchogenic carcinoma and thromboembolic disease. JAMA 202: 1019-1022, 1967. CONNOR W E, HOAK J C and WARNER E D: Massive thrombosis produced by fatty acid infusion. J Clin Invest 42: 860-866, 1963. . . ' A 599 A 600 A 601 D'ANTUONO G and COCCHERI S: Analisi multivariata degli indici di - . rischio tromboaterogeno di alcuni gruppi di lavoratori. Minerva Med . 59: 4088, 1968. . A 602 EMMONS P R, HARRISON M J G, HONOUR A J and MITCHELL J R A: Effect of dipyridamole on human platelet behaviour. Lancet 2: 603-606, 1965. A 603 ENTICKNAP J B, GOODING P G, LANSLEY T S and AVIS P R D: Platelet size . and function in ischaemic heart disease. J Atherosclerosis Res 10: 41-49, 1969. A 604 HARRISON M J G and MITCHELL J R A:' The influence of red blood-cells ' ..I on platelet adhesiveness. Lancet 2: 1163-1164, 1966. . A 605 HASLAM R J: Role of adenosine diphosphate in the aggregation of human blood- platelets by thrombin and by - fatty acids. Nature 202: 765-768, 1964. A 606 HOAK J C, CONNOR W E, ECKSTEIN J W and WARNER E D: Fatty - .. acid-induced thrombosis and death: mechanisms and prevention. . J Lab Clin Med 63: 791-800, 1964. A 607 HOAK J C, POOLE J C F and ROBINSON D S: Thrombosis associated with mobilization of fatty acids. Am J Pathol 43: 987-998, 1963. A 608 HOAK J C, WARNER E D and CONNOR W E: Platelets, fatty acids and '. thrombosis. Circ Res 20: 11-17, 1967. . . A 609 KERR J W, PIRRIE R, MacAULAY I and BRONTE-STEWART B: Platelet ' aggregation by phospholipids and free fatty acids. Lancet 1: 1296- 1299, 1965. A 610 T10 30 2-1 1 8 9
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VIil. Risk Factors Influenced by Smoking - 22 Page Z07 VIil-C. Hypercholesterolemia Hypercholesterolemia is one of the risk factors for coronary heart disease. In prospective studies, most patients who develop this disease also show an elevation of cholesterol and triglyceride levels in the blood serum (Kannel et al. , 1971). Hypercholesterolemia is associated with other risk factors, including emotional stress, behavioral pattern and diet (Bronte-Stewart et al. , 1955; Wertlake et al. , 1958; Rosenman and Friedman, 1963; Rosenman et al. , 1964; Jenkins et al. , 1968; Pincherle, 1971). Therapy of coronary heart disease patient includes the use of diet and hypocholesterolemic drugs with the expectation that this would improve the prognosis in these cases (Cohen, 1969; Hughes, 1970; Coronary Drug Research Project, 1970; Newcastle-upon-Tyne Study Group (Dewar), 1971; Dayton, 1971; Dewar, 1972). The level of cholesterol drops following myocardial infarction .p&r se, so that it is not reasvnable to depend on this measurement to assess the severity and recovery from ri-.e> i._'zrction(Watson et al. , 1963; Kurien and Oliver, 1966; Soloff and Schwartz, 1966). The influence of cigarette smoking on the cholesterol level blood serum has not been completely settled. The results of 26 investigations are summarized in Table VILI-C. In half of these studies, smoking is associated with slight elevation of the cholesterol level, but in the other half there is no such elevation. When healthy subjects are matched according to their age group, body weight and behavioral pattern, there is no significant difference between smokers and nonsmokers (Schwartz etal., 1971). ___.-______T10 30 2-1 1 9 7
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VIII. Risk Factors Influenced by Smoking - 11 Page 196 Additional Bibliographic List No. 22 . VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING CHOLESTEROL AND CORONARY HEART DISEASE 'Reprin BASSETT D R: Serum lipids in young males with parental atherosclerosis. . Am J. Med Sci 243: 740-750, 1962. - A 556 BLOMSTRAND R and LUNDMAN T: Serum lipids, smoking and heredity. ' Acta Med Scand 180 (Suppl 455): 51-75, 1966. A 557 BLOHMKE M, SCHAEFER H, ABEL H, DEPNER R, GRUNTZIG A, KOSCHORRECK B and STELZER 0: Resultats d'une enqu€te medicale et sociale sur les affections coronariennes. Cah Med 10: 187-194 1969. A 558 BOEK J K and BOEK W E: Heart disease, cholesterol level and diet of rural men. J Mich State Med Soc 62: 568-572, 1963. . A 559 BURT R L; Plasma nonesterified fatty acids in normal pregnancy and the . puerperium. Obstet Gynecol 15: 460-464, 1960. A 560 CATHEY C, JONES H B, NAUGHTON J, HAMMARSTEN J F and WOLF S: The relation of life stress to the concentration of serum lipids in patients with coronary artery disease. Am.J Med Sci 244: 421-441, 1962. ,. A 561 CREUX G, HARTMANN G, WIDMER L K, GREENSHER A, BREIL H, REBER H, STAUB H, and KAUFMANN L: Zur bezichung zwischen :lipiden, blutdruck und Gewicht bei Rauchern --,Basler Studie. Verh Dtsch Ges Kreislaufforsch 28: 259-262, 1963. A 562 DRASH A: Atherosclerosis, cholesterol, and the pediatrician. J Pediatr 80: 693-696, 1972. A 563 EPIDEMIOLOGY COMMITTEE OF THE SECOND ANNUAL CONFERENCE ON CARDIOVASCULAR DISEASES: The epidemiology of cardiovascular diseases: A summary. In: Chronic Diseases and Public Health. A M Lilienfeld and A J Gifford editors, The Johns Hopkins Press, Baltimore, pp. 531-548. A 564 FALSETTI H L, SCHNATZ J D, GREENE D G and BUNNELL I L: Serum lipids and glucose tolerance in angiographically proved coronary artery disease. Chest 58: 111-115, 1970. A 565 FRIEDMAN M, ROSENMAN R H and CARROLL V: Changes in the serum - cholesterol and blood clotting time in men subjected to cyclic variation of occupational stress. Circulation 17; 852-861, 1958. A 566 FRIEDMAN M, ROSENMAN R H and BYERS 5: Serum lipids and conjunctival circulation after fat ingestion in men exhibiting type-A behavior pattern. Circulation 29: 874-886, 1964. A 567 HUNTER J D: Cholesterol and coronary disease. N Z Med J 60: . 235-239, 1961. A 568 T10302-1186
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VIII. Risk Factors Jnfluenced by Srnoking - 6 Page 191 . List No. 19 ' - - . Reprint SCHETTLER G: Risikofaktoren beim Herzinfarkt. Dtsch Med Wochenschr - 97: 533-538, 1972. - SCHUSTER C: Untersuchungen zur Klinik des Herzinfarkts. Dtsch Gesundh 21: 493-496, 1966. SCHULTHEISS M: Zur Klinik und Diagnostik des Herzinfarktes unter besonderer - Berucksichtigung der Serumenzyme. Arch Klin Med 216: 161- 182, 1969. Great Britain GREENBERG M• A ro ortional mortalit stud of a rou of news aper Y g P P A 494 A 495 A 496 • P P Y workers. Br J Ind Med 29: 15-20, 1972. . A 497' HICKEY N and MULCAHY R: The significance of changes in certified coronary heart disease mortality rates in Ireland. Ir J MedSci 3: 163-168, 1970. HICKEY N, GEARTY G, BOURKE G J and MULCAHY R:Mediscan: A population screening programme for the detection of coronary heart disease risk factors. 7 Ir Med Assoc 64: 155-162, 1971. HOWE G M: Some aspects of social malaise in Scotland. Health Bull _28: 14-36, 1970. MAURER B, HICKEY N and MULCAHY R: Abo and Rb blood groups in `.. patients -with coronary heart disease. Ir J Med Sci 2: 105-108, 1969. McCAN1V M B, CLANCY R E, TRULSON M F and STARE F J: Factors implicated in cardiovascular disease in Irish-born males in Ireland and Boston. Fed Proc 20: 92, 1961. - MEADE T W: The epidemiology of ischaemic heart disease. Trans Soc Occup Med 18: 127-134, 1968. . A 498 A 499 A 500 A 501 A 502 A 503 MORRIS J N:Coronary disease in England. Cardiol Prat 85-95, 1962. A 504 PARKES C M, BENJAMIN B and FITZGERALD R G: Broken heart: a statistical study of increased mortality among widowers. . Br Med J 115: 740-743, 1969. A 505 RAFFLE A: The occupational physician as community ity physician. Proc Psychol Med 63: 731-739, 1970. ROBERTS C J and LLOYD 5: Association between mortality from ischaemic heart-disease and rainfall in South Wales and in the county Boroughs of of England and W ales. Lancet 1: 1091-1093, 1972. ROSE G A: The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bull WHO 27: 645-658, 1962. A 506 A 507 A 508 SMITH T: Factors involving sociocultural incongruity and change. . Millbank Mem Fund Q 45: 21, 23-29, 1967. A 509 TAYLOR L and SCHILLING R S F: The health and habits of higher executives. 2 J R Coll Gen Praet 14. 6Z-281, 1967. T10 30 2-1 1 81
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by It~ ~ Page 210 /'lattioli arrd Mancini. 1959 Balestra and Canepa 1967 51 subjects Smoking not related to cholesterol level. 47 normal and 36 Smoking not related to cholesterol level. patients New Zealand Smyth et al. , 1970 70 patients with coro- Smoking habit not reported nary heart disease Norway Romslo 1971 324 military men Smoking associated with higher triglyceride level. Spain Portugal Alvarez et al., 1972 30 subjects with corc- Smoking associated with high free fatty acid nary heart disease level. Vlaicu et al., 1971 100 patientswith coro-Smoking associated with higher cholesterol . . nary heart disease level. Sweden Carlson and BSttiger 1972 3, 168 men Elevated tryglyceride and cholesterol observed . . for coronary heart disease but relation to ' - smoking not reported Switzerland Heyden-Stucky 1965 76 men with myocar- Smoking and hypercholesterolemia prevalent . dial infarction . T10 30 2-1 20 0
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VIII. Risk Factors Influenced by Smoking - 8 List No. 19 Malaysia BURNS-COX C J, CHONG Y H and GILLMAN R: Risk factors and the absence of coronary heart disease in aborigines in West Malasia. Br Heart J 34: 953-958, 1972. New Zealand - NEW ZEALAND NATIONAL HEART FOUNDATION: Coronary heart disease. N Z Med J 74: 262Z-267, 1971. - . Norway . . CLEMMESEN J: On the epidemiology of respiratory diseases. Scand J Resp Dis 50: 52-53, 1969. A 525 A 526 HJERMANN I: Coronare risikfaktorer. Tidsskr Nor Laegeforen 91: . . 2403-2405, 1971. A 527 LEREN P: The Oslo diet-heart study. Circulation 42: 935-942, 1970. . NATVIG H: Effekten av umettede fettsyrer pa hyppieheten av hjerteinfarkt M. M. Tidsskr Nor Laegeforen 87: 1033-1041, 1967. SOLBERG L A: Er r¢king en faktor i utviklingen av are£orkalkning? -TidsskrNor Laegeforen 91: 1932-1937, 1971. _ • Sweden .. . BIORCK G: Some comments on the epidemiology of coronary disease. Bibl Nutr Dieta 6: 1-24, 1964, BIORCK G: Epidemiological studies on cardiovascular diseases in Sweden. J Chron Dis 18: 519-526, 1965. FODOR J: Pragstudien. Lakartidningen 67: 150-152, 1970. HEDBERG E and LINDBERG J: Fallbeskrivning. Lakartidningen 66: 98-102, 1969. WERKO L: I•Ijart-karlsjukdom och tobaksrokning. Sven Lakartidningen 58: 2153-2163, 1961. U. S. S. R. A 528 A 529 A 530 A 531 A 532 A 533 A 534 A 535 GOLOV CHINER: . Zdravookhr Ross Fed 15: 12-14, 1971. A 53L Page 193 Reprin T10302-1183
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l7III. Risk Factors ri:fl_,.enced by Smoking - 16 Page 201 VIII-A. Electrocardiogram and Myocardial Status The electrocardiogram has been used to assess the adequacy of oxygenation of the myocardium. The signs of ischemia in the electrocardiogram include depression of the S-T segment, inversion of the T wave and alteration in the QRS complex. These are useful in the diagnosis of coronary heart disease and in the detection of coronary-prone individuals (see Additional Bibliographic List No. 20). The electrocardiogram of smokers, in contrast to that of nonsmokers, has been examined by several groups of investigators. Patients who develop chest pain during smoking show ischemic signs characteristic of tobacco angina (Boas and Levy, 1936; Wilson and Johnston, 1941; see also Section I-A). In patients prior to developing infarction as well as in those who have already developed it, there is a predominance of smokers over nonsmokers (Lafrenz, 1970; Iglesias Leal et al. , 1971; Zdichynec and Prok~, 1971). This does not necessarily imply a cause and effect relationship because there are other risk factors which produce infarction. The examination of the electrocardiogram of healthy smokers failed to show a significant difference in frequency of the ischemic pattern in the electrocardiogram as compared with that of nonsmokers (Agnese and Buonvina, 1964; Gelin et al. , 1967; van Buchem, 1970; Hagerup, 1971). In similar surveys by other investigators, there were more smokers in the group that showed ischemic response in the electrocardiogram during exercise. Doyle and Kinch (1970) reported that 69% of subjects giving an ,,,,n,,,,,mT10 30 2-1 1 91
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'TI1. Risk Factors InSlucnccd by Smoking - 10 Page 195 Additional Bibliographic List No. 21. , VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING . HYPERTENSION AS A RISK FACTOR Reprint BOYER N H: The treatment of hypertension. Med Clin North Am 26: 1421-1437, 1942. . . . A 545 ESPINER E A, TUCCI J R, JAGGER P I and LAULER D P: Independence of blood pressure and aldosterone secretion. N EnRl J Med 276: 784-788,•. 1967. A 546 MANTELLI M and MASSONE A: Rilievi epidemiologici e medico-sociali sul.l'ipertensione arteriosa. Arch Med Intern 20: 11-31, 1968. A 547 MORET P R: Circulation coronaire et hypertension arterielle. Schweiz Med Wochenschr 98: 863-869, 1968. . -A 548 OBERMAN A, LANE N E, HARLAN W R, . GRAYBIEL A and MIT CHELL R E: . Trends in systolic blood pressure in the thousand aviator cohort over a twenty-four-year period. Circulation 36: 812-822, 1967. . A 549 RAAB W: The neurogenic metabolic factor in ischemic heart disease. Dfs Chest 46: 150-157, 1964. A 550 RAAB W and KRZYWANEK H J: Cardiovascular sympathetic tone and stress response related to personality patterns and exercise habits. Am J Cardiol 16: 42-53, 1965: A.551 e SLABY A, BAZIKA V, REISENAUER R and MARSIKOVA L: Prevalence hypertenze a zmeny krevniho tlaku po peti letech u venkovske populace ve vztahu k ateroskleroze. Sb Lek 72: 124-135, 1970. A 552 SNE PH, MEDALIE J H, KAHN H A, NEUFELD HN.and RISS E: Distribution and multiple regression analysis of blood pressure in 10,000 . Israeli men. Am J Epidemiol 93: 317-327, 1971. A 553 SLANY J: Kardiale Komplikationen der Hypertonie. Wien Klin Wochenschr 84: 286-288, 1972. A 554 STA34LE?? J: Irterrelationships between the two diseases, hypertension and atherosclerosis. Am J Cardiol 9: 743-747, 1962. . . A 555 . T10 30 2-1 1 8 5
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VIII. Risk Factors Influenced by Smokin - 13 Page 198 list No. 22 Reprin: SPAIN D M, NATHAN D J and GELLIS. M: Weight, body type and the prevalence of coronary atherosclerotic heart disease in males. Am J Med Sci . 245: 63-69, 1963. A 585 STAMLER J: Atherosclerotic coronary heart disease -- the major challenge to contemporary public health and preventive medicine. Med Times 93: . 120-146, 1965. A 586 STAMLER J, BERKSON D M, YOUNG Q D, LINDBERG H A, HALL Y, MOJONNIER L and ANDELMAN S L: Diet and serum lipids in atherosclerotic coronary heart disease, Med Clin North Am 47: 3-31, 1963. A 587 STEAD E A: What we have learned about myocardial infarction from epidemiologic ' and dietry studies. Circulation 40 (Suppl 4): 85-90, 1969. A 588 STAMLER J, BERKSON D M, LINDBERG HA, MILLER W A, SOYUGENC R, . . , TOKICH T and WHIPPLE T: Does hypercholesterolemia increase risk . '. of lung cancer in cigarette smokers? Circulation 38 (Suppl 6): 188, 1968. A 589 TURPEINEN 0, MIETTINEN M, KARVONEN M J, ROINE P,PEKKARINEN M, LEHTOSUO E J and ALNIRTA P: Blood lipids and primary coronary events. The effect of diet modification. Minn Med 52: 1247-1252, 1969. A 590 STAMLER J: Coronary risk factors and prevention of atherosclerotic coronary heart disease. Chicago Med 73: 509-518, 1970. . A 591 STAMLER J: Prevention of atherosclerotic coronary heart disease by change . of diet and mode of life. Ther Umsch 27: 133-144, 1970. A 592 TAYLOR H L, BLACKBURN H, PUCHNER T, VASQUEZ C L, PARLIN R W and KEYS A: Coronary heart disease in selected occupations of American .. - railroads in relation to physical activity. Circulation 40 (Suppl 3): 202, 1969. A 593 THOMAS C B and COHEN B H: Comparison of smokers and nonsmokers. , Bull Johns Hopkins Hosp 106: 205-214,. 1960. - A 594 VLAICU R, MACAVEI E and PATIU I: Studiu transversal al presiunii arteriale si al lipidelor serice la coronarieni fumatori si nefumatori. Med Intern 23: 925-930, 1971. A 595 WALDEN R T, SCHAFFER L E, LEMON F R, SUNSHINE A and WYNDER E L: . E.'fect of e_ ~~_ronn:ent on the serum cholesterol-tri2lyceride distribution - among seventh-day Adventists. Am J Med 36: 269-276, 1964. - A 59E T10302-1188
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a7iL'.. tti.slc 1 acrors !ntiucncca by Smoking - 20 a BIB LIOG RA PHY VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING B. Hypertension ab' . . Reprint BLACKBURN H, BROZEK J and TAYLOR H. L: Common circulatory measure- ' ments in smokers and nonsmokers. Circulation 22: 1112-1124, 1960. 631 BORHANI N 0 and HECHTER H H: A longitudinal study of blood pressure. Angiology 15: 545-555, 1964. . 632 CLARK V A, CHAPMAN J M and COULSON A H: Effects of various factors on systolic and diastolic blood pressure in the Los Angeles heart study. J Chron Dis 20: 571-81, 1967.. 633 EDWARDS F, MCKEOWN T and WHITFIELD A G W: Arterial pressure in men over sixty. Clin. Sci 18: 289-300, 1959. . 634 KAHN H A, MEDALIE J H, NEUFELD, H N, RISS E and GOLDBOURT, U: The incidence of hypertension and associated factors: The Israel ischemic heart disease study. Am Heart J 84: 171-182, 1972. .. 636 KANNEL W B, CASTELLI W P, MCNAMARA P M and SORLIE P: Some factors affecting morbidity and mortality in hypertension. The Framingham Study. Milbank Vtem Fund O 47: 116-142, 1969. - 637 KANNEL W B, GORDON T and SCHWARTZ M J: Systolic versus diastolic blood pressure and risk of coronary heart disease. The Framingham . Study. Am. J Cardiol 27: 335-346, 1971. . . . 638 LOWENSTEIN F W: Blood-pressure in relation to age and sex in the tropics and subtropics. Lancet 1: 38y-392, 1961. - 639 OBERMAN A, HARLAN W R, SMITH M and GRAYBIEL A: The cardiovascular risk. Minn Med 52: 1283-1288, 1969. . 640 PAUL, 0 and OSTFELD A M: Epidemiology of hypertension. Prog Cardiovasc . Dis 8: 106-116, 1965.. 641 PAUL 0: Risk of mild hypertension: a ten-year report. Br Heart J s3: lsuppij 116-121, 1971. 642 PELL S and D'ALONZO C A: Blood pressure, body weight, serum cholesterol, and smoking habits among executives and nonexecutives. J Occup Med . 3: 467-470, 1961. . . 643 `710302-1195
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VIII. Risk Factors Influenced by Smoking - 7 Page 192 .List No. 19 - Reprin: TILLER J R, SCHILLING R S F and MORRIS. J N: Occupational toxic factor . in mortality from coronary heart disease. Br Med J 4: 407-411, 1968. A 511 India HAMNER J E, MEHTA F S, PINDBORG T J, ODONT and DAFTARY K: An epidemiologic and histopathologic study of leukoedema among 50, 915 rural Indian villagers. Oral Surg 32: 58-65, 1971. A 512 XANDASWAMY 5: An analysis of coronary disease in 150 cases of chest . pain. Antiseptic 67: 936-940, 1970. A 513 Italy BARBANO G, BAROCELLI C, and DE MATTEIS F: Alterazioni eletro- cardiografiche consecutive a fumo di tabacco. Atti Soc Ital Cardiol . 16: 105-107, 1954. . - A 514 CLEMENTE R and MARCHIONNI R: Rapporti fra eta ed infarto miocardico. Minerva Cardioangiol 16: 1132-1139, 1969. A 515 FERUGLIO G A and CAMERINI F: Le malattie cardiovascolari nella Regione Friuli-Venezia Giulia. Med Soc 18: 139-153. 1968. A 516 FIDANZA F, IMBIMBO B and DI BENEDETTA C: Indagine epidemiologica delle cardiopatie ischemiche nei reclusi del penitenziario di s stefano di ventotene. G Arteriosclerosi 4: 255-267, 1966. . A 517 MARZOT G, CENNI P, VISCOMI N and POLI L D: Ac,qua e mortalita per vasculopatie ischemiche del miocardio. Ig Mod 895-908. 1968. A 518 MENOTTI A: Epidemiologia: introduzione e indagini retrospettive. Cuore Circolazione 53: 95-134, 1969. . A 519 . RUSSO G: L'inattivita fisica quale fattore di rischio e di letalita nell'infarto , dcl miocardio. C1in Europa 7: E0o-827, 1968. A 520 Japan HIRAYAMA: Huge Japanese study adds to smoking-death link. JAMA. _ 220: 654-655, 1972. A 521 YOSHITOSHI Y, HANAOKA W and MIYASHITA H: Myocardial infarction among Japanese. Geriatrics 22: 123-132, 1967. A 522 YOSHITOSHI Y, HANOKA W, NAGASAKA M, MIYASHITA H, YAINAGUCHI A, ITO T, WATANABE S, 05HIMA M and SHINOl-IARA Y: Clinical feature of myocardial infarction in Japan. Jap Heart J 5: 497-511, 1964. A 523 T10302-1182
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pislc I'actors L'.fluencc-d by Smoking - 23 A Page 208 In patients with coronary heart disease, those who smoke have higher levels of cholesterol than nonsmokers and the arteriogram shows obstructive lesions more frequently in the forir.er (Cramer et al. , 1966). Smoking cannot be regarded as the cause of hypercholesterolemia and obstructive lesions, since other risk factors have not been excluded. (Table VIII-C appears on the next two pages. ) .TI0302-1198
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Vj.U. R1Sk i <iC1:G1'S 1~11.i1:.C:L1Ct;G . by Smoking - 21 Page 206 . . .. . Reprint THOMAS C B: Familial and epidemiologic aspects of coronary disease and . hypertension. J Chron Dis 7: 198-208, 1958. . 644 THOMAS C B,, ROSS D C and HIGINBOTHOM C Q: Precursors of hypertension and coronary disease among healthy medical students: discriminant function: . analysis. 1. Using smoking habits as the criterion. Bull Johns Hopkins Hosp 115: 174-194, 1964. 645 TIBBLIN G: High blood pressure in men aged 50. Acta Med Scand (suppl 470) 1-84, 1967. 646. r T10 30 2-1 1 9 6
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VIII. Risk Factors Influenced by Smokin - 15 ~ist No. 23 KORSAN-BENGTSEN K: Koagulations-effekter och rokning. Lakartidningen Page 200 Reprint 67: 272-277, 1970. A 611 LEODOLTER I, HEIL W and FRANK H: Ergebnisse der Antikoagulantien- Behandlung -des Herzinfarktes. Munch Med Wochenschr 113: . 1161-1175, 1971. - A 612 -LUKL P: Sekundare Pravention der ischameschen Herzerkrankungen. . Dtsch Med J 20: 29-33, 1969. . . A 613 MAHADEVAN V, SINGH H.and LUNDBERG W 0: Effects of saturated and . unsaturated fatty acids on blood platelet aggregation in vitro. Proc Soc Exp Biol Med 121: 82-85, 1966. . A 614 McDONALD L: Thrombosis in coronary heart disease. Br Heart J 30: 151-167, 1968. A 615 MURPHY E A and MUSTARD J F: Coagulation tests and platelet economy in ~ atherosclerotic and control subjects. Circulation 25: 114-125, 1962. A 616 MUSTART J F: Platelets and thrombosis in acute myocardial infarction. . Hosp Pract 7: 115-128, 1972. . A 617 OGSTON D and FULLERTON H W: Plasma fibrinolytic activity following .. recent myocardial and cerebralinfaretion. Lancet 2: 99-101, 1965. A 618 OLWIN J H and KOPPEL J L: Little publicized aspects of thromboembolism. - Med_ Clin North Am 51: 151- 159, 1967. A 619 PILGERAM L 0 and PICKART L R: Control of fibrinogen biosynthesis: The .. role of free fatty acid. J Atherosclerosis Res 8: 155-166, 1968. - A 620 ROBB H J and JABS C: Distortion and dynamics of cellular elements in the . microcirculation. Angiology 19: 602-611, 1968. .. A 621 . SCHIEVELBEIN H, PETER H, TRAUTSCHOLD I and WERLE E: Freisetzung von 5-Hydroxytryptamin aus Thrombocyten duxch Harmalin. Biochem Pharmacol 15: 195-197, 1966. - A 622 SZANTO S and YUDKIN J: The effect of dietary sucrose on blood lipids, serum insulin, platelet adhesiveness and body weight in human volunteers. - . Postgrad Med J 45: 602-607, 1969. . . . A 623 WOOD L: Treatment of atherosclerosis and thrombosis with aspirin. Lancet 2: 532-534, 1972. - A 624 YAMAMOTO K, MURAKI T and FUKUI I: Determination of inhibitors of urokinase-activated fibrinolytic enzyme system by means of gel - filtration in human serum. Keio J Med 15: 63-66, 1966. A 625 T10 30 2-1 1 9 0
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by Smoking - 24 TABLE VIII-C. Role of cigarette smoking in - subjects withhypercholesterolemia CountryJInvesti£ators Subjects Role of Cigarette Smoking Page 20y United States Gofman et al. , 1955 Burney and Enslein 1972 Spain and Nathan 1961 Talbott 1964 . 123 healthy 222 healthy 3, 000 healthy males 40 healthy males Elevation of lipoproteins and cholesterol. No difference in 5 year level of cholesterol compared to nonsmokers. . Heavy smoking associated with higher cholesterol levels. Smoking whyie on a high fat diet suppressed rise in cholesterol and total artificial fatty acid. Australia Mundy and C-LTforth 1972 80 patients with myo- Hyperlipoproteinenmia not associated with cardial infarction smoking. Belgium Kornitzer et al., 1971 539 subjects Hyperlipoproteinemia associated with coronary . , heart disease but not with smoking. van Houte and Kerteioot 1972 42, 804 males Heavy smoking associated with higher choles- t r l l l DI e o eve s. . Finland y ~ Konttinen 1962 . 314 healthy young Smoking not related to cholesterol and - . . .. . .,. , . men phospholipids in serum. Hernberg 1964 . 862 businessmen Smoking not related to cholesterol level or capacity for physical work. France Richard et al. 1969 ?, 672 subjects Weak link between tobacco and cholesterol level and triglyceride Lellouch and Beaumont 1967 1,053 Smoking not related to cholesterol level vf . body weight and age considered Germany ' Gross -. . 1970 38 subjects Smoking not related to cholesterol levels. Great Britain Acheson and Jessop 1961 221 elderly men Smoking not related with cholesterol or lipo- protein level. McDonald et al. , 1965 . 976 air force men Smoking not related with cholesterol level. Pincherle and Wright 1967 . 2, 000 businessmen. ~ Heavy smoking associated with higher choles- l terol level. Pozner and Billimoria 1970 64 young subjects Heavy smoking associated with higher 'choles- l terol and lipoprotein levels. Pincherle 1971 7, 000 businessmen Heavy smoking associated with higher choles- l terol level. . India . Gupta 1964 286 subjects Heavy smoking associated with higher choles- terol level. ,TI0302-7 7 99
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V',LII. Rzsk L•actors L*.t0.ua.ucud Page L03 by Smoking - 18 BIB LIOGRA PHY ..VIII: PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING A. Electrogram and Myocardial Status . . . Reprin- ABEL H: Functional diagnosis of the heart by the spatial T-area vector. Acta Cardiol 26: 163-172, 1971. 617 AGNESE G and BUONVINO M: Sui rapporti tra consume di tabacco e - cardiopatie ischemiche. GSg Med Prev 5: 295-304, 1964. 618 BOAS E P and LEVY H: Extrasystoles of clinical significance. - Am Heart J 11: 264-272, 1936. 619 BORDEN H H and IBRAHIM M A: The epidemiology of the QRS axis measurement. Am J Public Health 60: 722-730, 1970. . 620 DOWER G E, OSBORNE J A: Polarcardiographic study of hospital staff -- • abnormalities found in smokers. J Electrocardiology 5: 273-280, 1972, 621 DOYLE J T and KTNCH S H: The prognosis of an abnormal electrocardiographic stress test. Circulation 41: 545-553, 1970. 62Z GELIN J, ELGRISHI I, DUCIMETIERE P and RICHARD J L: L'electro- cardiogramme dans une population a haut risque. Bull L'institut - National de La Sante Et Do La Recherche Medicale 22: 279-288, 1967. . 635 HAGERUP L: Tobaksrygning og koronarc risiktorer. Ugeskr Laeger 133: 1309-1313, 1971. 623 KATTUS A A, JORGENSEN C R, WORDEN R E and LAVARO A B: S-T-segment - depression with near-maximal exercise in detection of preclinical coronary heart disease. Circulation 44: 585-595, 1971. . . 624 LAFRENZ M: Risikofaktoren irn Prainfarkt-E:k~. Z Gesamte Inn Med 25: 381-384, 1970. 625 IGLESIAS LEAL R, CARIS T N and LANCASTER M C: Infarto del miocardio silencioso y atipico. Arch Inst Cardiol Mex 41: 249-254, 1971. . 626 STARR 1: Essay on the ballistocardiogram. JAMA 155: 1413-1425,1954. 627 YHlv JiUL.rit:M rJ r, Lxlwv t:, w1lrt5uul M, riUJJl,H1Y:1C.x Y, anQ . . FRIMA.J R: Het voorkomen en de betekenis van extrasystolen en • geleidingsstoornissen. Ned Tijdschr Geneeskd 114: 281-286, . 1970. . - • 628 WILSON F N and JOHNSTON F D: The occurrence in angina pectoris of , electrocardiographic changes similar in magnitude and in kind to those produced by myocardial infarction. Am Heart J 22: 64-74, 1941. 629 ZDICHYNEC B and PROKS C: Vyznam kuractvi cigaret z hlediska infarktovych zmen na elektrokardiogramu. (Cigarette smoking and infarction changes . in the electrocardiogram). Cas Lek Ces 110: 256-25?, 1971. . 630
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TIII. Risk Factors Li~~i.ueuced by Smoking - 19 Page 204 VIII-B. Hypertension Hypertension is an important risk factor in coronary heart disease. The epidemiologic investigations of Pell (1961), Oberman et al. (1969) and Kannel et al. (1969, 1971) in the United States, of Tibblin (1967) in Sweden and of Kahn-et-.a.L. (1972) in Israel demonstrate the major role of hypertension in the pathogenesis of coronary heart disease. There are other studies outlined in Table VII-E. Essential hypertension as a separate disease entity has a set of precursofs which include age, sex, familial, psychologic and dietary factors (Thomas, 1958; Lowenstein, 1961; Thomas et al. , 1964; Paul and Ostfeld, 1965; Paul, 1971). Smoking is not one of them because smokers in the general population have a lower mean blood pressure than nonsmokers (Edward's et a_l., 1959; Borhani and Hechter, 1964; Clark et al. , 1967). In groups preselected for absence of hypertension, there is no difference in mean blood pressure but a slight diminution in the response to the cold pressor test (Blackburn et al., 1960). A reduction of sympathetic vascular tone which occurs in smokers cannot be considered as contributing to a rise in blood pressure. When essential hypertension appears together with coronary heart disease, the form of therapy indicated is to reduce the blood pressure by drugs (see Additional Bibliographic List No. 21). The influence of cigarette smoking in such a situation has not been investigated, since most studies relate either toessential hypertension of to coronary heart disease but not to both. "710302-1194
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VII. Risk Factors Lniluenced by Smoking - 12 . List No. 22 Page 197 Reprint HUNTER J D: . Diet, body build, blood pressure, and serum cholesterol levels . in coconut-eating Polynesians. Fed Proc. 21: 36-43, 1962. A 569 JOLLIFFE N: Fats, cholesterol, and coronary heart disease. Circulation 20: 109-127, 1959. A 570 KASSIR J T: Cholesterol and its relationship to heart disease. . J Faculty Med Baghdad 10: 109-128, 1968. A 571 KEYS A, TAYLOR H L, SIMONSON E, BLACKBURN H and ANDERSON 7 T: . The C. V. D. research program of the laboratory of physiological hygiene. J Lancet 81: 291-295, 1961. A 572 KEYS A: Current status of research on the epidemiology of coronary heart - disease. Jap Circ J 32: 1669-1683, 1968. .. . A 573 KIEF H:.Lipidstoffwechsel und Arteriosklerose. Naturwissenschaften 57: ' 384-387, 1970. A 574 KIRKEBY K: Blood lipids, lipoproteins, and proteins in vegetarians. Acta Med Scand Suppl 443: 1-84, 1966. -- A 575 KURLAND G S and FREEDBERG A 5: Hormones, cholesterol, and coronary atherosclerosis. In: Symposium-on Coronary Heart Disease. . H L Blumgart, editor, American Heart Association, 1968, pp 24-36. A 576 LEVY R I and GLUECK C J: Hypertriglyceridemia, diabetes mellitus, and . coronary vessel disease. Arch Intern Med 123: 220-225, 1969. . A 577 PAGE 1 H, STARE F J, CORCORAN A C, POLLACK H and WILKINSON C F: . Atherosclerosis and the fat content of the diet. . Circulation 16: 163-178, 1957. A 578 RAMIREZ E A and GARCIA-PONT P H: Relationship of serum cholesterol to socioeconomic and dietry factors in Puerto Rican veterans. Dis Chest 55: 197-201, 1969. : A 579 ROSENMAN R H, FRIEDMAN M, JENKINS D, STRAUS R, WURM M and , KOSITCHEK R: The prediction of immunity to coronary heart disease. JAMA - 198: 1151-1162, 1966. A 580 REISSELL P K, HAGOPIAN L M and HATCH F T: Metabolic studies in young men with coronary heart disease.. J Clin Invest 44: 1090, 1965. . A 581 SCHILLING F J, CHRI5TAKIS G J, BENNETT N J and COYLE J F: Studies of serum cholesterol in 4, Z44 men and women: an epidemiological and pathogenetic interpretation. Am J Public Health 54: 461-476, 1964. A 582 SCHWARTZ M J, ROSENWEIG B, TOOR M and LEWITUS Z: Lipid metabolism • and arteriosclerotic heart disease in Israelis of Bedouin, Yemenite and . European origin. AmJ Cardiol 12: 157-168, 1963. A 583 SOLOFF L A and SCHWARTZ H: Plasma and red blood cell free fatty acid responses to glucose loading with a note on the effect of tobacco. - Am 7 Med Sci 246: 200-205, 1963. . A 584 TI0302-1187
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Page 222 PART FIVE CIGARETTE SMOKING NICOTINE AND CARBON MONOXIDE IX. Acute Circulatory Effects of Cigarette Smoking. X. Acute and Chronic Effects of Nicotine. XI. Circulatory Effects of Carbon Monoxide. In.tha preceding sections, the differences between smokers and nonsmokers have been discussed. The observations relating to the acute effects of smoking are considered in the present sections. These include not only the effects of cigarette smoke but also those of its constituents, namely, nicotine and carbon monoxide. The other chemicals present in cigarette smoke have been omitted, since hardly any report has been made of their action on the circulatory system. The experimental observations discussed in these sections also include the chronic administration of smoke, nicotine and carbon monoxide to animals. The problem in these experiments is how to relate the results to smokers who develop coronary heart disease. Unfortunately, the amounts of nicotine and carbon monoxide administered to animals far exceed those which are absorbed during ordinary forms of smoking. TI0302-1212
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VIII. Risk Factors influenced by Smoking - 29 Page 214 VIII-D. Blood Coagulation .oiiYl/ The basic process of myocardial infarction consists of development of thrombosis in the atherosclerotic coronary artery. The process of blood coagulation has been investigated in such cases and measurements indicate hypercoagulability of the blood in patients with doronary heart disease (see Additional Bibliographic List No. 22). Cigarette smoking has long been suspected of increasing coagulability of the blood. Most of the experiments have been carried out on animals and helathy subjects and the observations were made after a brief period of exposure to cigarette smoke (see Section IX-D). The present section pertains to differences between nonsmokers and smokers, which are as follows: 1. Coagulation time. Kedra and Kotolko (1966) compared coagulation time in a group of 50 smokers and 50 nonsmokers. There were no significant differences in the various tests performed on the two groups. After the emokPrs consumed 5 ci,?arettes, there was a statisticallv significant shortening of clotting time, of plasma calcium time, and of factor V values, compared with the presmoking values. It is surprising to note that this is the only comparison between smokers and nonsmokers who are healthy. There is no comparison of subjects with coronary heart disease. Patients with ischemic heart disease show a decrease in coagulation time after smoking but there was no comparison with rionsmokers (Orlova, 1971). In an epidemiologic investigation of coronary heart disease, made in India, TI0302-1204
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S7LLC. Risk Factors In.fluenceu by Smokin;; - 27 Page 212 Reprint GUPTA N N, MITTAL H S and MEHROTRA R M L: Tobacco smoking and serum cholesterol and liporroteins in healthy males. J Indian Med • Ass 43: 372-374, 1964. , 660 HERNBERG S: Serum-cholesterol and capacity for physical work. Laneet 2: 441-443, 1964. _ . 661 HEYDEN-STUCKY S: Epidemiologic des Herzinfarktes (1965). Schweiz . Med Wochenschr 95: 1535-1540, 1965. 662 HUGIIES M L: General principles of therapy for coronary heart disease. Bull Mason Clin 24: 63-72, 1970. . 663 JENKINS C D, ROSENMAN R H and ZYZANSKI S J: Cigarette Smoking. Its . relationship to coronary heart disease and related risk factors in the western collaborative group study. Circulation 38: 1140-1155, 1968. - 664' KANNEL W B, CASTELLI W P, GORDON T and MCNAMARA P M: Serum cholesterol, lipoproteins, and the risk of coronary heart disease. Ann Intern Med 74: 1-12, 1971. 665 KONTTINEN A: Cigarette smoking and serum lipids in young men, Br Med J . 1: 1115-1116, 1962. 666 . KORNITZER M, DEMEESTER M, DELCOURT R, GOOSSENS A and BERNARD R: Enquete cardio-vasculaire prospective dans une population . selectionnee. Resuitats de 1'enquete initiale. Acta Cardiol 26: 285-343 1971. . , . 667 KURIEN VA and OLIVER M F: Serum-free-fatty-acids after acute myocardial infarction and cerebral vascular occlusion. Lancet 2: 122-127, 1966. . 668 LELLOUCH J and BEAUMONT JL:La tension arterielle: distribution et cor- T- re~latior.s dans un b:~oupe professionnel. Bul1 Tnst Nationa] Rccheirk Med 22: 203-211967. - • . 669 MATTIOLI P L and MANCINI M: Rapporti fra numero di sigarette giornalmente . fumate,colesterolo, pressione arteriosa e adiposita in due gruppi diversi di soggetti umani normal.Riforma Med 73: 1347, 1959, 670 MCDONALD J C, LIDWELL 0 M and WRIGHT EA: Serum cholesterol, smoking, and body build a survey in the Royal Air Force. Br J Yrev Soc yled t y: 111-114, 1965. - , 671 MUNDY G R and CUTTFORTH R H: The relationship between serum lipid abnormalities and other major risk factors in myocardial infarction. Aust NZ J Med 2: 8-12, 1972. . 672 PINCHERLE G: Factors affecting the mean serum cholesterol. J Chron Dis 24: 289-297, 1971. 673 , PINCHERLE 0 and WRIGHT H B: Screening in the early diagnosis and prevention of cardiovascular disease. I Roy Coll Gen Pract 13: 280-289, 1967. 674 --,-_t_ .-,-__TI0302-1202
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/III. Risk Factors Inf'_uenced by Smoking - 32 Page 217 of risk factors by Oliver (1970) although he failed to measure blood coagulation. When these deficiencies are corrected, the potential hazard of combining smoking and the use of contxaceptives will be more clearly defined. ~z.TI0302-1207
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Circulatory n,ireci: u. Smoking - 1 Page 223 i IX. ACUTE CIRCULATORY EFFECTS OF SMOKING GIGARETSE SMOK~NG , f ACyTF EFFECTS CHRONIC EFFECTS NUYAN6 ANtMALS NMMAMB \\\ lyj %I_ II CIG4RETTE SMOKING A. Cardiac Function------------- 228 , B. Blood Pressure and Peripheral a~. ~ Blood Flow------------------ 240 C. Blood Lipids---------------- 246 '. D. Blood Coagulation------------ 250 I To prove that smoking causes coronary heart disease, it is necessary to be able to reproduce the disease in the laboratory. So far, this has not been possible in animals. The animals subjected to chronic exposure to cigarette smoke have been few in number and the'observations have been limited cntirely to postmortem examination. Acute exposure has been performed largely on animals and humans without heart disease, so that it is diffic,ult to relate the results to the disease state. Chronic exposure of humans to smokinQ is an impossible experiment because other risk factors are operative in habitual smokers. The investigations of acute effects of smoking has been more signifi- cant in excluding rather than proving that it causes coronary heart disease. Smoking does not cause reduction of coronary blood flow, which is the primary hemodynamic defect in coronary heart disease. Smoking acutely increases blood pressure, whereas the habitual smoker is not hypertensive- ..«-~T10302-7 27 3
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IX. Circulatory Effects of Smoking - 2 Page 224 Although patients with coronary heart disease show persistent elevationof the blood lipid level, habitual smokers do not necessarily experience this and smoking acutely does not consistently produce an elevation. Acute smoking increases blood coagulability in normal subjects and has not been thoroughly investigated in patients with coronary heart disease. The basis for these generalizations appears in the following sections. The Additional Bibliographic List relates to the reasons and manner of stopping the habitual use of cigarettes: List No. 24. Cessation of cigarette smoking, ,,.,TI0302-1274
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V11I. I:isk Factoxs Liiiu~nceu by Smoking - 26 BIBLIOGRAPHY . - Page 211 VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING . C. Hypercholesterolemia Reprint ACHESON R M, and JESSOP W J E: Tobacco smoking and serum lipids in old men. Br Med J Z: 1108-1111, 1961. 647 BALESTRA V and CANEPA R: Valore di alcune variabili per la discriminazione Ira soggetti normali ed ischemici. Pervenuto in Redazione 30: 441- 459, 1967. . 648 BRONTE-STEWART B, KEYS A, BROCK J F, MOODIE A D, KEYS M H and . ANTONIS A: Serum-cholesterol, diet, and coronary heart-disease. An inter-racial survey in the cape peninsula. Lancet 2: 1103-1108, 1955. 649 BURNEY S W and ENSLEIN K: Investigation of changes in clinical laboratory tests related to aging and smoking. AginQ and Human Development 3: ' 95-101, 1972. . 650 CARLSON L A and BOTTIGER L E: Ischaemic heart-disease in relation to fasting values of plasma triglycerides and cholesterol. Lancet 1: 865-868, 1972. 651 . COHEN B M: The clinical use of dextrothyroxine in hypercholesterolemic states. An eight-year appraisal. J Clin Pharmacol 9: 45-56, 1969. 652 CORONARY DRUG PROJECT RESEARCH GROUP: The coronary drug project. Inltial findings leading to modifications of its research protocol. JAMA 214: . 1304-1313, 1970. 653 / . . e~ . . . .. . . .. -._ _. CRAMER K, PAULIN S and WERKO L: Coronary angiographic findings in . correlation with age, body weight, blood pressure, serum lipids, and smoking habits. Circulation 33: 888-900, 1966. . ' 654 DAYTON S: Rationale for use of lipid-lowering drugs: -Fed Proc 30: 849-856, 1971. - . 655 DEWAR H A: Long-term therapy of ischaemic heart disease. Arzneim Forsch 22: 1835-1840, 1972. 656 T1RwA.R A A• Trial nf elnf;.hratn in the tr?atment of ischaemic heart disease. (Five-year study by a group of Physicians of the Newcastle upon Tyne Region). ._ Br Med J 4: 767-775, 1971. . . 657 GOFMAN J W. LINDGREN. F T, STRISOWER B, DELALLA A B 0, GLAZIER F , and TAMPLIN A: Cigarette smoking, serum lipoproteins, and coronary heart . disease. Geriatrics 10: 349-354, 1955. _ . 658 , GROSS W: Serumlipid-Veranderungen beim Rauchen. Dtsch Med J 21: 368-374, 1970. 659 T10 30 2-1 201
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'III. Risk Factors Jiu`.lucnced by Smoking - 33 BIBLIOGRAPHY VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING D. B1ood Coagulability - Page 218 Reprint BRAKMAN F, ALBRECHTSEN O K and ASTRUP T: Blood coagulations, fibrinolysis, and contraceptive hormones.. JAMA 199: 69-74, 1967. 690 FREDERIKSEN H, and RAVENHOLT R T: Thromboembolism, oral contraceptives, and cigarettes. Public Health Rep 85: 197-205, 1970. 691 GIBELLI A, BOLANDRINA E, DEL FAVERO A and PASOTTI C: ' Modificazioni emocoagulative e della fibrinolisi in seguito a carico lipidico orale associato a fumo da sigaretta. G Geront 12: 31-41, 1964. 692 HAWKINS R I: Smoking, platelets and thrombosis. Nature 236: 450-452, . 1972. 693 KEPRA M and KOROLKO A: Palenie tytoniu a krzepniecie krwi. (Influence of smoking on blood clotting). Pol Tyg Lek 21: 44-46, 1966. . 694 KORSAN-BENGTSEN K, WILHELMSEN L and TIBBLEN C: Blood coagulation and fibrinolysis in a random sample of 788 men 54 years old. Thromb Diath Haemorrh 28: 99-108, 1972. 695 LONCIN Ii, GURIAN J M and LONCIN M E: Blood coagulation, fibrinolysis and coronary heart diseas: Observations in Malaysia. J Atherosclerosis Res : . 8: 471-482, 1968. - 696 MALHOTRA S L: Studies in blaod coagulation,, diet, and ischaernic heart disease in two population groups in India. Br Heart J 30: 303-308, . 1968. 697 OGSTON D, BENNETT N B and OGSTON C M: The influence of cigarette smoking on the plasma fibrinogen concentration. J Atherosclerosis Res 11: 349-352, 1970. . . 698 OLIVER M F: Oral contraceptives and myocardial.infarction. Br Med J . l: G10-L15, 1yf0. v9) ORLOVA N P: Some parallels between the blood coagulation activity and the condition of adrenergic and cholinergic system of the organism. . Ter Arkh 43: 58-62, 1971. . 700 SARTWELL P E: Oral contraceptives and thromboembolism: a further report. Am J Epidemiol 94: 192-201, 1971. : 701 SARTWELL P E, MASI A T, ARTHES F G, GREENE G R and SMITH H E: ' Thromboembolism and oral contraceptives: An. epidemiologic case-control study. Am J Epidemiol 90: 365-380, 1969. 702 VESSEY M P and IJOLL R: Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 2: 199-205, 1968. 703 ,,.,510302-1208
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IX. Circulatory Effects of Smoking - 7 Page 229 ballistocardiogram in 4 instances. In 40 patients with coronary heart disease, the BCG became abnormal or more abnormal in, form after smoking in 38 % of these cases. No description was given of the smoking habits of subjects. A group of 113 medical students, of whom 82 were smokers, were investigated by Thomas et al. (1956). A statistically significant change was noted in systolic, diastolic and pulse pressures, heart rate, stroke volume and cardiac output. There was no difference between smokers and nonsmokers. Among subgroups there were striking differences which were associated with family history. Subjects with parental hypertension, whose control = cardiac output was large prior to smoking, showed more than twice as great an increase as did subjects with negative parents. Subjects with a parental history of coronary heart disease had very little increase in cardiac output in contrast to subjects with negative parents. In additional reports the investigators were able to reproduce their results (Thomas -and Murphy, 1958, 1960a, 1960b). The following investigations have confirmed most of the conclusions reported above: Levy et al. (1947) in 27 normal subjects and 21 patients with coronary heart disease; Russek et al. (1955) in 28 normal subjects and 37 patients; Davis et al. (1956) in 25 normal subjects and 190 patients with coronary heart disease; Dec (1960) in 15 normal subjects and 20 patients with myocardial infarction; Simon and Iglauer (1960, 1961) in 14 males without heart disease; Hanson (1962) in 3 patients with angina; Klensch (1963) ~ _ ___TI0302-1219
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VLLI: Risk Factors Influenced by Smoking - 34 Page 219 VIII-E. Availability of Oxygen and Associated Changes in the Blood In recent years, there have been claims that the carbon monoxide contained in cigarette smoke reduces the a,vailability of oxygen in the blood. The formation of carboxyhemoglobin and its consequences are discussed in Section XI. There are other changes in the blood of smokers which differentiate them from nonsmokers. They are as follows: 1. Oxygen-dissociation curve. Aside from the formation of carboxyhemoglobin, there is a change in the affinity of hemoglobin for oxygen in the blood of smokers. This change is discussed in Section XI. Metcalfe et al. (1969) reported that patients with coronary heart disease and low output failure show a decreased affinity of the blood for oxygen. This is considered a compensatory adjustment to poor tissue blood flow, promoting the diffusion of oxygen from blood in tissue capillaries to intracellular sites of utilization. The status of this adjustment has not been examined in smokers who develop low output failure. 2. Hematocrit. There is an increase of the hematocrit in patients who develop acute myocardial infarction (Burch and De Pasquale, 1962; Stables et al., 1967). The resulting increase in the viscosity of the blood influences the free flow of blood and has been postulated to cause infarction (Dintenfass, 1969). This theory does not apply to smokers because there is no increase of the hematocrit in the blood. T10 30 2-1 209
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L'.LCl. flisk S'_cio.rs z,ocd by Smoking - 28 Page 213 Reprint PORTUGAL ALVAREZ J, PEREZAGUA CLAMAGIRAND C, AREVALO ALONSO J M and VELASCO MARTIN A: Action of tobacco on lipolysis - and its modification by insulin. Experientia 28: 1453-1454, 1972. 675 POZNER H and BILLIMORIA J D: Effect of smoking on bloodclotting and _. lipid and lipoprotein levels. Lancet 1: 1318-1321, 1970. 676 i RICHARD J L, LELOUCH J, CLAUDE J R and SCHWARTZ D: Lipidemie, consoinmation de tabac et corpulence Etude d'une population masculine active de 7, 972 sujets. Rev. Artherscler 11: (suppl 3) 71-87, 1969. 677 ROMSLO 1: Distribution of serum lipids in Norwegian recruits. Acta Med Scand 190: 401-406, 1971. . . 678 ROSENMAN R H and FRIEDMAN M: Behavior patterns, blood lipids, and coronary heart disease. JAMA 184: 934-938, 1963. . " 679 ROSENMAN R H, FRIEDMAN M, STRAUS R, WURM M, KOSITCHEK, R, HAHN W and WERTHESSEN N T: A predictive study of coronary heart disease. JAMA 189: 15-22, 1964. 680 SCHWARTZ D, RICHARD J L, LELLOUCII J and CLAUDE J R: Serum lipids, smoking and body build study of 7, 972 actively employed males. Rev Europ d'Etudes Cliniq Biol 16: 529-536, 1971 . 681 SMYTH A J, ADEY H and LANGLEY R B: An epidemiological survey of ischaemic . heart disease. New Zeal Med J 71: 284-288, 1970. 682 SOLOFF L A and SCHWARTZ . FL Relationship between glucose and fatty acid in myocardial infarction. Lancet 1: 449-452, 1966. 683 SPAIN D M and NATHAN D J: Smoking habits and coronary atherosclerotic . -- heart disease. JAMA 177: 683-688, 1961. . . 684 TALBOTT G D: Influence of environmental factors on lipid-response curves. . Cigarette smoking, salt, alcohol, and high-fat diet effecting healthy males. . Geriatrics 19: 575-584, 1964. , 685 VAN HOUTE 0 and KESTELOOT H: An epidemiological survey of risk factors for . ischemic heart disease in 42, 804 men. 1. Serum cholesterol value. Acta Cardiol 27: 527-564, 1972. . 686 VLAICU R, MACAVEI E and PATIU I: Studiu transversal (,,cross-sectional") al . presiunii arteriale si al lipidelor serice la coronarieni fumatori si nefumatori. Medicina Interna 23: 925-930, 1971. . . 687 WATSON W C, BUCHANAN K D and DICKSON C: Serum cholesterol levels after myocardial infarction. Br Med J 2: 709-712, 1963. ; 688 WERTLAKE P T, WILCOX A A, HALEY M I and PETERSON J E: Relationship . of mental and emotional streas to serum cholesterol levels. Proc Soc . • Exp Biol Med 97: 163-165, 1958. . , 689 ~T10 30 2-1 203
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Reprint I WHITE P D: The diagnosis and medical treatment of angina pectoris. Ann Intern Med 7: 218-228, 1933. A 660 WHITE P D and SHARBER T: Tobacco, alcohol and angina pectoris. JAMA 102: 655-657, 1934. . ' A 661 WOLFF L: Tobacco and alcohol in angina pectoris. N Engl J Med 216: 188, 1937. A 662 ZIEGENSPECK: Uber Probleme der Prophylaxe chronischer Tabakschaden. Dtsch Gcsundh 18: 454-457, 1963. ' A 661
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VIII. Risk Factors Influenced by Smoking - 36 Page 221 BIBLIOGRAPHY . VIII. PREVENTABLE RISK FACTORS ALSO INFLUENCED BY SMOKING . .E. Availability of Oxygen and Associated Change in the Blood BURCH G E and DePASQUALE N P: The hematocrit in patients with Reprint myocardial infarction. JAMA 180: 63-70, 1962. . 704 COHEN B II and THOMAS C B: Comparison of smokers and nonsmokers. - II. The distribution of ABO and Rh (D) bolld groups. Bull Johns Hopkins Hosp 110: 1-7, 1962. 705 DINTENFASS L: Blood rheology in pathogenesis of the coronary heart diseases. Am Heart J 77: 139-147, 1969. 706 HAVLIK R J, FEINLEIB M, GARRISON R J and KANNEL W B: Blood-groups " and coronary heart-disease. Lancet 2: 269-270, 1969. 707 JICK H, SLONE D, WESTERHOLM B, INMAN W H, VESSEY M P, SHAPIRO S, LEWIS G P and WORCESTER J: Venous thromboembolic disease and ABO blood type. Lancet 1: 539-542, 1969. 708 METCALFE J, DHINDSA D 5, EDWARDS M J and MOURDJINIS A: Decreased _ affinity of blood for oxygen in patients with low-output heart failure. . Circ Res 25: 47-51, 1969. 709 NEFZGER M D, HRUBEC Z and CHALMERS T C: Venous thromboembolism and blood-group. Lancet 1: 887, 1969. . 710 STABLES D P,. RUBENSTEIN A$,METZ J and LEVIN N-W: The possible role of hemoconcentration in the etiology of myocardial infarction. Am Heart J 73: 155-159, 1967. 711 ZDICHYRIEC B: Zmeny v vilem kreymm obraze u dlourodobych kuiaku (Na zaklade shovnani souboru nemocnych s transmuralnim srdecnim . infarktern a nemocnych bez priznakn koYonarni I choroby v piedchorob). (The change of the white blood cells count in long time smokers). . Vnitr Lek 17: 327-330, 1971. 12 T10 30 2-1 21 1
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IX. Circulatory Effects of Smoking - 9 OON Page 231 myocardial extraction of glucose and oxygen. In 7 males with myocardial infarction, smoking still caused an increase in blood pressure and heart rate. In 3 of the patients, coronary blood flow did not change, while in 3 others it fell slightly (Regan et al. , 1960a, 1960b, 1961). Although there was slight increase in oxygen consumption in 3 cases , the myocardial efficiency was also increased. The data reported illustrete.thatin patients with coronary heart disease smoking results in no reduction of myocardial efficiency. In 15 patients with angiographically demonstrated severe obstructive coronary artery disease, cigarette smoking did not induce lactate production by the heart (Summers et al. , 1971j. There was no evidence of ischemia as determined by abnormalities in lactate extraction. 5. Exercise and the heart. Exercise has been used as a form of stress to detect borderline patients.with coronary heart disease (Davis et al., 1953; Davis, 1959; Gusman and Khalfen, 1959). In subjects without clinical evidence of coronary heart disease, smoking does not interfere with their capacity to perform moderate exercise (see Section VII-A). There are observations which indicate that certain forms of exercise by particular individuals elicit responses which differ from the normal. a. Exercise by bicycle ergometer severe enough to produce a fivefold increase in oxygen uptake of young male smokers caused an oxygen debt accumulation greater than that of nonsmokers. The oxygen debt of nonsmokers was 6.5% of the total increase in oxygen uptake, while for smokers it was 24. 7% (Chevalier et al. , 1963). In another group of subjects ~TI0302-1221
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VjII. Risl< F,;ctnrs 1niJuc,rced by Smoking - 35 Page 220 3. Blood cells. The distribution of blood groups is different between smokers and nonsmokers. With reference to white males, Cohen and Thomas (1962) reported that there appeared to be a significant deficiency of group B individuals among heavy smokers and an excess of group B persons among nonsmokers. There was also an excess of Rh negative individuals among the white occasional smokers. There were no significant differences among the Negro males. A genetic difference'in blood groups has also been reported by Jick et al. (1969) in patients who develop coronary heart disease. The subsequent correspondence with Nefzger et al. (1969) and that with Havlik et al.. (1969) indicate the problems in arriving at an unequivocal interpretation of prospective studies. Another feature reported as appearing in smokers and patients with myocardial infarction is the occurrence of eosinophilia and lymphocytosis (Zdichyrk-c, 1971). This has been interpreted as an allergic response to tobacco but may also be a genetic response. T10 30 2-1 21 0
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IX. Circulatory Effects of Smoking - 10 Page 232 the same investigators (Krumholz et al. , 1964) again reported an increase in oxygen debt but also a decrease in lung function, which were notnoted previously. They also reported a decrease in diffusing capacity of the lung both at rest and with exercise. The exercise was more severe and reached up to 2I/min, whereas in the first series it was 1.41/min. Since oxygen uptake is five- to sevenfold from a resting value of 0.3 1/min, this would be equivalent to running a race which is not ordinarily accomplished in the normal course of activity. It is necessary to measure oxygen uptake at various levels of exercise to determine the threshold for the increase in oxygen debt. The relation of activity to oxygen usage has been reviewed by Naughton (1967). b. Smoking by patients with a healed myocardial infarction didnot alter cardiac output eignificantly/ whether at rest or during exercise (Frankl et al. , 1965a, 1965b). T he lack of response in this group can be interpreted -either way. The absence of an increase would mean that the infarcted heart has become tolerant to smoking. It can also mean that the heart has lost its capacity to respond, which is not valid since the subjects still showed an increase in output during exercise. 6. Canine heart. The dog has been the species most widely used in these investigations. In 1941, Bellet et al. , studied dogs with chronic ligation of one coronary artery to simulate infarction occurring in man. Inhalation of cigarette smoke at 1/4 the dose administered prior to the infarction caused electrocardiographic changes. Thirty years later T10 30 2-1 222
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X. Circulatory Effccts of 5moking - 6 Page 228 IX-A. Cardiac Function The influence of cigarette smoking on heart rate, cardiac output, stroke volume, myocardial contractility and metabolism is the primary concern of this section. However, each parameter will not be discussed separately but according to the manner in which it is derived. The technique of measuring cardiac output and the status of the subject, whether healthy or with coronary heart disease, are considered in the grouping. In investigations on animals, the acute are separated from the chronic. 1. Electrocardiogram. The most consistent effect of smoking in normal subjects is tachycardia (Grabiel et al. , 1938; Buxtorf and Beaumont, 1968). The electrocardiogram of some patients with coronary heart disease shows inversion of the T wave and alteration of the QRS complex (Tobiasch, 1951; Kaltenback et al. , 1967; Serafimova, 1971). The apexcardiogram (Aronow, 1971) and chronodynogram (Raab et al., 1960) have been applied and the results are similar to those of the electrocardiogram. 2. Ballistocardiogram. The early investigations on the effects of cigarette smoking involved the use of the ballistocardiogram (BCG) for the estimation of cardiac output (see Starr (1960, 1967) and Jackson et al., (1967)). The first application was reported by Henderson (1953), using subjects from the Hospital of the University of Pennsylvania. After smoking a single cigarette, the subject showed an increase in pulse rate but the form of the BCG remained normal in each of 50 healthy young adults. In 30 older persons believed to be healthy, there was a temporary abnormality of the 'T10302-7278
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X. Circulatory Effects of Smoking - 3 ~-A dditional Bibliographic List No. 24 " CESSATION OF CIGARETTE SMOKING IX. CARDIOVASCULAR EFFECTS OF SMOKING BALL K P, KIRBY B R, and BOGEN C: First year's experience in anti- smoking clinic. Br Med J 1: 1651-1653, 1965. . BALTZAN D M: The treatment of angina pectoris. Can Med Assoc J 40: 387-388, 1939. CHAPPELL A G, GARROD M E, JONES K S, ROLFE A B and WESOLKOWSKI J: An essayy at the treatment of cigarette dependence. Br 3 Addict 64: 409-415, 1970. CROOG S H, SHAPIRO D S and LEVINE S: Denial among male heart patients. Psychosom Med 33: 385-397, 1971. ESPEJO SOLA J: Bloqueo seno-auricular. Sem Med Buenos Aires 43: - 1883-1887, 1936. . - A 629 A 630 FIESER L: The story of an ex-smoker. Readers Digest 568-571, 1966. A 631 FIESSINGERC: L'angine de poitrine tabagique. J Practiciens 33: 169-170, 1919. A 632 ,_ GALLAVARDIN L: Tabac et angine de poitrine d'effort. Presse Med 32: 622, 1924.. - . ' I . A 633 GILBERT N C: Treatment of angina pectoris. Med Clin North Am 19: 1085-1111, 1936. A 634 GUION C M and MEARA F-S: Chest pains. Med Clin•North Am 12: . 623-658, 1928. . A 635 HERRMANN G: Cardiothoracic distress (types). Differentiation and treatment with especial reference to sympathectomy. Med Clin North America. . 12: 1261-1284, 1929. A 636 . HUNT 7 H: The management of coronary thrombosis by the family doctor. Practitioner 177: 309-316, 1956. A 637 JACKSON W R: History, causes and treatment of angina pectoris, with clinical report. Va Med Month 17: 883-891, 1891. .. A 638 KOHN H: Die epidemische angina pectoris auf der "Embuscade". Dtsch Med Wochenschr 52: 447-449, 1926. . . A 639 LASLETT E E: Notes on four cases of paroxysmal tachycardia. Q J Med 15: 18-23, 1921. LEVY R L: Needless restrictions imposed on cardiac patients. Circulation 5: 454-461, 1952. . Page 225 Reprint A 626 A 627 A 628~ A 640 A 641 T10 30 2-1 21 5
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X. Circulatory Effects of Smoking - 12 Page 234 similar to those completed in man. 7. Other animal species. Haag et al. (1960) exposed rats to cigarette smoke for their entire life span and they showed no significant differences in blood pressure, longevity and reproduction as compared with unexposed rats. No lesions were noted at autopsy. Myocardial lesions have been reported after chronic exposure to cigarette smoke in guinea pigs (Lupu and Velican, 1961, 1962) and mice (Komczynski, 1958). Ratcliffe (1965) examined coronary arteries of animals that died in the Philadelphia Zoological Garden during the period 1944 to 1964. The frequency of coronary arterial disease reflects the effects of physiological and psychological responses to social stimuli and environmental pollution. These animals were not exposed to cigarette smoke. ,9eT10 30 2-1 224
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IX. Circulatory Effects of Smoking - 8 Page 230 in 39 subjects; Markewicz (1966) in 45 students; Buchanan (1969) in 19 young adults with coronary heart disease. 3. Dye Dilution Technique. The first application of a modern method for measuring cardiac output was accomplished by Irving and Yamamoto (1963). The smoking of one cigarette caused an increase in cardiac output in 15 normal subjects (Edmundowicz et al. , 1964; Frankl et al. , 1965). Pentecost and Shilingford (1964a, 1964b) compared subjects with patients. The healthy men_and those with angina in the absence of infarction behaved similarly with an increase in cardiac output. However, some patients among the : postinfarction group showed a marked fall in stroke volume and cardiac output while smoking. Two procedures reduce the response of normal subjects to smoking. The previous administration of propranolol, a beta adrenergic blocker, decreased the intensity of cardiac output response (Frankl and Soloff, 1967). Pretreatment with glucose diminished the cardiac output response (Moses et al., 1964; Soloff and Powers, 1964). The explanation for the latter is not apparent but the influence of propranolol is related to its blockade of the cardiac effects of nicotine. 4. Coronary blood flow and myocardial metabolism. It has been supposed that cigarette smoking causes coronary spasm. This was disproven by catherization of the coronary sinus in man by Bargeron et al. (1957). Cigarette smoking in 30 normal subjects caused a significant rise in coronary blood flow, a decline in coronary vascular resistance and T10 30 2-1 22 0
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IX. Circulatory Effects of Smoking - 11 Page 233 Bellet et al. (1972a) repeated the same experiments but measured the electrical threshold for ventricular fibrillation. After 30 minutes of exposure to smoke, the threshold to infarction was reduced. A similar effect was observed after administration of caffeine (Bellet et al. , 1972b). In an open-chest dog, the administration of cigarette smoke caused a brief decrease in oxygen utilization by the heart, but an increase in coronary blood flow (Kien et al. , 1958; Kien and Sherrod, 1960). This - coincided with the onset of irregularities which appeared early during the inhalation. This is different from the phenomenon reported by Bellet et al. , which required 30 minutes for the reduction in the threshold to fibrillation to appear. The experiments reported by others on cigarette smoking in dogs confirm essentially the results in man, such as, tachycardia (Kaymakcalan et al. , 1968), increase in coronary blood flow (Haft et al. , 1966), and blockade of cardiac effects by propranolol (Edmundowicz et al., 1965; Westfall et al. , 1966). - Auerbach et al. (1967, 1971) and Hammond et al. (1970) have reported thickening of myocardial aterioles in beagles that have been exposed to cigarette smoke for several months. It is unfortunate that no measurements of cardiac function were made in animals prior to their being sacrificed. Reece and Ball (1972) subjected 7 dogs to exposure to cigarette smoke and treadmill exercise daily for one year. The electrocardiograms indicated enlargement of the heart. There was also thickening of the rnyocardial arterioles in 5 of the 7 dogs. However, no hemodynamic measurements were made T10 30 2-1 223
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L}C. Circulatory Effects of Page 226 Smoking - List No. 24 - Reprint LEVY R L: A. critique of certain measures presently employed in managing patients with cardiac infarction. Am Heart J 64: 1-6, 1962. A 642 McMILLAN T M: An optimistic view of the problems of heart disease. J Mcd Assoc State Ala 8: 133-140, 1939. A 643 MEDICAL LETTER: Drugs to curb the tobacco habit. 5: 37-38, 1963. A 644 McFARLAND J W, GIMBEL H W, DONALD W A J and FOLKENBERG E J: The five-day program to help individuals stop smoking. Conn Med . 28: 885-890, 1964. A 645 MOURIQUAND G and BOUCHUT L: Angine de poitrine et tabac. Arch Mal Coeur 5: 657-667, 1912. . . . A 646 NATHAN D A: Arrhythmias in normal hearts. South Med J 42: -. - 746-753, 1949. . A 647 NEU H N: Rehabilitation of the cardiac patient. Geriatrics 13: . 640-646, 1958. A 648 . OCHSNER A and. DAMRAU F: Control of cigarette habit by psychological aversive conditioning: clinical evaluation in 53 smokers. J Am Geriatr Soc 18: 365-369, 1970. PRESTON J W: The treatment of angina pectoris. Va Med Month 56: 298-301, 1929. - . RABINOWITSCH H: A few practical hints in angina pectoris. N Y Med J 115: 240-241, 1922. - - REID D D: Smoking and ischemic heart disease prevention -- problems and potential. Prev Med 1: 84-91, 1972. . . RODE A and SHEPHARD R 7: Smoking withdrawal and changes of cardio- respiratory fitness. Am Rev Resp Dis•- 104: 933-935, 1971. SCHNEIDER D: Experimentelle Untersuchungen zur lumbalen Sympathektomie. Bruns Beitr Kiin Chir 167: 414-440, 1938. .. SCHUMANN L M: The benefits of cessation of smoking. Chest 59: . 42i-427, 1971. " A 649 A 650 A 651 A 652 A 653 A 654 ' A 655 A 656 im Allgemeinen und der Angina pectoris im Speziellen. Wein Klin Wochenschr - . 48: 353-360, 1935. . . . A 657 . SCOTT E G: Remarks on the diagnosis and treatment of angina pectoris. Va Med Month 67: 273-277, 1940. SINGER R: Ueber die Ursachen der 2unahme der Herz- und Gefasserkrankungen VON AHN B: Tobaksrokning och angina pectoris. (Tobacco smoking andangina - . pectoris). Nord Med 39:1555-1558; 1948. , A'658 WEINBLATT E, SHAPIRO S and FRANK C W: Changes in personal character- istics istics of men, over five years, following first diagnosis of coronary heart disease. Am J Public llealth 61: 831-842, 1971. A 659 ~T10302-1216
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LX. Circulatory Effects of Smoking - 14 Page 236 Reprint DAVIS F W Jr: The role of the ballistocardiograph in the diagnosis and management of patients with coronary heart disease. Am J Cardiol 3: 103-110, 1959. . 725 DEC L: Balistokardiogram po paleniu i nitroglicerynie jako test w diagnostyce . miazdzycy naczyn wiencowych. Po1 Arch Med Weunet 30: 923-926, - 1960. 726 EDMUNDOWICZ A C, PIFER R L and MARSHALL R J: Cardiac output during cigarette smoking, Fed Proc 23: 465, 1964. . 727 EDMUNDOWICZ A C,CIPOLLONI P B and PENROD K E: Cardiovascular _ responses to cigarette smoke and nicotine"in dogs following . P-adrenergic blockade with prop;anolol. Fed Proc 24: 713, 1965. 728 FRANKL W S, FRIEDMAN R H, WILSON G T T and SOLOFF L A: Effects of smoking on cardiac output, free fatty acids and catecholamines in - healthy young subjects during cardiac catheterization. Circulation . 32 (Suppl 2): 88, 1965. 729 FRANKL W S. WINTERS W L and SOLOFF L A: The effects of smoking on . the cardiac output at rest and during exercise in patients with healed myocardialinfarction. Circulation 31: 42-44, 1965a. . 730 FRANKL W S, WINTERS W L and SOLOFF L A: The effects of smoking on the cardiac output at rest and during exercise in patients with healed myocardial infarction. Trans Stud Coll Physicians Phila 32: . 211-212, 1965b. 731 FRANKL W S and SOLOFF L A: The hemodynamic effects of propranolol hychrochloride after smoking. Am J Med Sci 254: 623-628, 1967. 732 GRABIEL A, STARR R S and WHITE P D: Electrocardiographic changes following the inhalation of tobacco smoke. Am Heart J 15: 89-99, 1938. 733 GUSMAN S M and KHALFEN E S: Ballistocardiographic changes in the clinically healthy after physical exercise and smoking. Ter Arkh 31: 46-52, 1959. 734 HAAG H B, LARSON P S and WEATHERBY. J H: The effect on rats of chronic exposure to cigarette smoke. Ann N Y Acad Sci 90: 227-238, 1960. 735 HAFTJ I, LAU S H and DAMATO A N: Acute effects of smoking in the dog. . Clin Res 14: 472, 1966. 736 HANSON W: Effects of smoking and of nitroglycerine on 3 patients with coronary . heart disease, as judged by simultaneous records of ultra-low frequency .. ballistocardiogram and pulse derivative. Am J Cardiol 10: 463, 1962. 737. HAMMOND E C, AUERBACH 0, KIRMAN D and GARFINKEL L: Effects of cigarette smoking on dogs. Arch Environ Health 21: 740-753, ' 1970. 738 HENDERSON C B: Ballistocardiogramss after cigarette smoking in health and in coronary heart disease. Br lleart J 15: 278-286, 1953. . 739 IRVING D W and YAMAMOTO T: Cigarette smoking and cardiac output. Br Heart T 25: 126- 132, 1963. . 740 _T10302-1226
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T [X. Circulatory Effects of Smoking - 13 BIBLIOGRA PHY IX. CARDIOVASCULAR EFFECTS OF SMOKING A. Cardiac Function Page 235 . - Reprint ARONOW W S: The effect of smoking cigarettes on the apexcardiogram in , coronary heart disease. Chest 59: 365-368, 1971. _ 713 AUERBACH 0, HAMMOND E C, KIRMAN D and GARFINKEL L: Emphysema . produced in dogs by cigarette smoking. JAMA 199: 241-246, 1967. 714 AUERBACH O, HAMMOND E C, GARFINKEL L and KIRMAN D: Thickness . of myocardial arterioles in relation to smoking and age. Arch Environ Health 2Z: 20-27, 1971. 715 BARGERON L M, EHMKE D, GONLUBOL F, CASTELLANOS A, SIEGEL A, and BING R J: Effect of cigarette smoking on coronary blood flow and . myocardial metabolism. Circulation 15: 251-257, 1957. . 716 BELLET S, KERSHBAUM A, MEADE R H Jr and SCHWARTZ L: The effects of tobacco smoke and nicotine on the normal heart and in the presence of myocardial damage produced by coronary ligation. Am J Med Sci 201: 40-51, 1941. 717 BELLET S, DeGUZMAN N T, KOSTIS T B, ROMAN L and FLEISCHMANN D: The effect, of inhalation of cigarette smoke on ventricular fibrillation threshold in normal dogs and dogs with acute myocardial infarction. _ Am Heart J83: 67-76, 1972a. 718 BELLET S, HORSTMANN E, ROMAN L R, DeGUZMAN N T and KOSTIS J B: Effect of caffeine on the ventricular fibrillation threshold in normal dogs and dogs with acute myocardial infarction. Am Heart J 84: 215-227, 1972. 719 BUCHANAN J: Ballistocardiographic smoking tests in myxoedema. Biol Cardiol 36: 89-93, 1969. 720 BUXTORF J C and BEAUMONT J L: Tabac et electrocardiogramme. Pathol Biol 16: 877-880, 1968. 721 CHEVALIER R B, BOWERS J A, BONDURANT S and ROSS J C: Circulatory and ventilatory effects of exercise in smokers and nonsmokers. _ J. Appi Physiol 18:357-360, 1963 . 722 DAVIS F W Jr, SCARBOROUGH W R, MASON R E, SINGEWALD M L and BAKER B M Jr: The effects of exercise and smoking on the electrocardio- grams and ballistocardiograms of normal subjects and patients with coronary artery disease. Am Heart J 46: 529-542, 1953. 723 DAVIS F W, SCARBOROUGH W R, MASON R E, SINGEWALD M L and BAKER B M Jr: The ballistocardiographic cigarette test: further observations. Am Heart J 51: 165-178, 1956. , 724 T10302-1225
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IX. Circulatory Effects of Smoking - 15 Page 237 Reprint JACKSON D H, OBERMAN A, MITCHELL R E and GRAYBIEL A: Factor contributing to the ballistocardiographic waveform in healthy middle- aged men. Am J Cardiol 20: 531-540, 1967. 741 JAMES G: Tobacco and the public health. _, 5-7 742 KALTENBACK M, SCHAFER R and KLEPZIG Bi: Pragnostische Bedeutung des Belastungs-Elektrocardiogramms. Med Klin 62: 710-713, 1967. KAYMAK~ALAN S, TURKER R K, KIRAN B K and KAYAN S: Comparison _ of the cardiovascular effects of regular and filter-tip cigarette smokes. Aezncimittel Loirakune, 18: 817-819, 1968. 743 744 KIEN G A, LASKER N and SHERROD T R: Action of cigarette smoke on cardiovascular hemodynamics and oxygen utilization in the dog. •, . , J Pharmacol Exp Ther 124: 35-42, 1958. : . 745~: • KIEN G A and SHERROD T R: Action of nicotine and smoking on coronary - ddiltiliti A N Y Ad Si circulation an myocara oxygen uzaon.nncac . 90: 161-173, 1960. 746 KLENSCH H: Die reaktivatat des Kreislaufes bei Gesunden und Koronarkranken - nach dem Rauchen einer Zigarette. Arch Kreislaufforsch 41: - 1-26, 1963. 747 KOMCZYNSKI L: Morphological changes in the organs of mice under the influence of tobacco smoke. Rocz Akad Med Bialvmstoku Suppl 2: 5-62, 1958. 748 KRUMIiOLZ R A, CHEVALIER R B and ROSS J C: Cardiopulmonary function -- in young smokers. Ann Intern Med 60: 603-610, 1964. 749 LEVY R L, MATHERS J A L, MUELLER A A and NICKERSON S L: Effects of smoking cigarets on the heart. JAMA 135: 417-422, 1947. 750 LUPU N G and VELICAN C: Biologia procesului de scleroza. Stud Cercet Med . Interna 2: 237-250,.1961. ' , . . 751 LUPU N G and VELICAN C: Histochemistry of mucopolysaccharides and - connective tissue proteins after twelve experimental inhalations of . tobacco smoke. Arkh Pathol 24: 19-27, 1962. _ 752 MARKIEWICZ M: Effect of tobacco smoking on the heart. Pol Tyg Lek 21: 1922-1924, 1966. 753 MISKIC J: Neka zapanzanja o djelovanju nikotina na organizam covjeka. Acta Med lugosi 15: 470-476, 1961. - 754 MOSES D C, POWERS D and SOLOFF L A: Glucose blockage of the increase in , stroke volume produced by smoking. Circulation 29: 820-844, 1964. 755 NAUGHTON J: Assessment of physical performance of middle-aged American men. Med Times 95: 220-227, 1967. 756 PENTECOST B and SHILLINGFORD: The acute effects of smoking on myocardial performance in patients with coronary arterial disease. Br Heart J . 26: 138, 1964a. . 757 ~,T10 30 2-1 227
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IX. Circulatory Effects of Page 2.15 Smoking - 22 Reprina WRIGHT I S: The clinical value of human capillary studies. JAMA ;.'- . 101: 439-442,. 1933.. -- ' .812 ' WYSONKINSKI Z: Effects of tobacco smoking on certain parameters reflecting ;_,.-. .. the condition of the circulatory system at rest and during exercise. Pol Med Sci Hist Bull. 14: 73-76, 1971. . 813 _ZANNINI G, CONTI A and NEGRO G: Sur 1'action de la furnee de tabac sur les vaisseaux peripheriques au cours des arteriopathies et apres interventions sur le sympathique. Angeiologie 15: Z9-41, 1963. 814 T10 30 2-1 234
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IX.. Circulatory Effects of Smoking - 23 IX-C. Blood Lipids Page 246 There are three lipids which are relevant in the consideration of the pathogenesis of atherosclerosis: Cholesterol, triglycerides and free fatty acids (Kershbaum and Bellet, 1966; Kershbaum, 1967; Mulcahy andHickey, 1967; Boyle et al. , 1968). The acute effects of smoking on the blood levels of these lipids are complex and varied. The smoking of 1 to 5 cigarettes has been reported by GtJksel (1967) and Ciampolini et al. (1968) to increase the cholesterol level and by Butkus and Page. (1965) and Page et al. (1959) not to influence it. For triglycerides, both an increase (Gb'ksel, 1967) and no effect (Butkus and Page, 1965) have been reported. The late Samuel Bellet and Alfred Kershbaum had investigated the effect of cigarette smoking on serum free fatty acids (FFA) in normal subjects. There was an elevation of FFA occurring 10 minutes after smoking cigarettes, and essentially no effect on serum cholesterol and triglycerides (Kershbaum et al., 1960, 1961). The increase of FFA in patients with healed myocardial infarct was greater than in normal subjects (Kershbaum et al. , 1962). This increase is mediated through the adrenal glands and the sympathetic nervous system, because it was accompanied by an increase in urinary catecholamine excretion and the FFA response was blocked by sympathetic blocking drugs (Kershbaum et al., 1963; Kershbaum and Bellet, 1964). The thesis that they had developed was further elaborated by the following investigations: suppression of the free fatty acid response by ingestion of whiskey (Kershbaum et al. , 1964), investigation of various ,,,,TI0302-7235
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X. Circulatory Effects of Smoking - 27 Page 250 IX-D. Blood Coagulation Several investigations have been made in human subjects as to the fact that cigarette smoking causes an increase in coagulability of the blood (Murphy and Mustard, 1966). After smoking 1 to 10 cigarettes healthy young adults experience a shortening of clotting time and of thrombus formation time, and a decrease in fibrinolytic activity (Blackburn et al. , 1959; Lisiewicz, 1963; Ambrus and Mink, 1964; Sogani and Joshi, 1965; Kedra and Korolko, 1965; Engelberg, 1965; Engelberg and Futterman, 1967; Engelberg and Engelberg, 1968; Schocndorf et al. , 1970). It has been postulated by Engelberg (1965) that the hypercoagulability of blood is mediated by the release of epinephrine induced by nicotine. However, a proportionate dose response in the blood clotting system to the differing nicotine concentration could not be demonstrated by Schoendorf et al. (1970). The acute effects of smoking on platelets include the following: no effect on total counts (Eisen and Hammopd, 1956); shorter platelet survival time (Mustard and Murphy, 1963); increased platelet adhesiveness (Ashby et al., 1965; Engelberg and Futterman, 1966; Glynn et al. , 1966; Murchison and Fyfe, 1966; El-Ebrashy et al., 1967; Facchini et al., 1971). None of the subjects had coronary heart disease or peripheral vascular disease. The relevance )f these observations to patients with coronary heart disease can be determined only by inveskigation of such patients. T10 30 2-1 239
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,X. Acute and Chronic Effects , of Nicotine - 2 Page 254 laboratory is so large that it is not yet possible to relate the cardiac effects to smoking by the patient with coronary heart disease. The pharmacology of nicotine is discussed in the following Additional Bibliographic Lists: List No. 25. Nicotine on isolated heart. List No. 26. Release of catecholoamines from the heart. List No. 27. Release of catecholamines from adrenal medulla. List No. 28. Central nervous system effects of nicotine. T10 30 2-1 243
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X. Acute and Chronic Effects of Nicotine - 3' Page 255 X. CARDIOVASCULAR EFFECTS OF NICOTINE Additional Bibliographic List No. 25 NICOTINE ON ISOLATED HEART Reprint BHAGAT B, ROBINSON I M and WEST W L: Mechanism of sympathomimetic responses of isolated guinea-pig atria to nicotine and dimethyplenylpiper- zinium iodide. Br J Pharm acol Chemother 30: 470-477, 1967. A 664 BOLLINGER A: Nicotinabstinenz bei lokalisierter Durchblutungsstorung. Dtsch Med Wochenschr 96: 134, 1971. A 665 BUFFONI F and GIOTTI A: L'azione della nicotina sull'attivita fosforilasica degli atri di cavia. Boll Soc Ital Bfol Sper 37: 675-678, 1961. . A 666 ' BURN 3 11: Action of nicotine on the heart. Ann N Y Acad Sci 90: 70-73, 1960. A 667 BURN J H, LEACH E H, RAND M J and THOMPSON J W: Peripheral effects of nicotine and acetylcholine resembling those of sympathetic stimulation. J Physiol 148: 332-352, 1959. A 668 BURN J H and RAND M J: Action of nicotine on the neart. 1: 137-139, 1958. Br Med J A 669 CHIANG T S and LEADERS F E: Cardiostimulatory responses to vagal stimulation nicotine, and tyramine. Am J Physiol 211: 1443-1446, 1966. A 670 CHIANG T S and LEADERS F E: Mechanism of the secondary positive effect of nicotine in rat atria. Arch Int Pharmacodyn 172: 333-346, 1968. A 671 DHALLA N S: Mechanisms of sympathornimetic effects of dichloroisoproterenol: comparison with tyramine, nicotine and norepinephrine. J Phar macol Exp Ther 157: 135-142, 1967. A 67Z DHALLA N S and LcLAIN P L: Effect of cardio-active drugs on the rate, - contracile force and phosphorylase activity in frog heart. Arch Int Pharmacodyn 163:.272-283, 1966. . A 673 ECCLES R M and LIBET B: Origin and blockade of the synaptic responses of curarized sympathetic ganglia. 3 Physiol 157: 484-503, 1961. A 674 ELLIOT L G, STEWART J, OCHOA R, WEST W L and BOOKER W M: The nature of possible mechanism of action of nicotine on the heart.. Pharmacologist 10: 209, 1968. . . A 675 GEBBER:G L and VOLLE R L: Mechanisms involved in ganglionic blockade induced by tetramethylammonium. J Pharmacol Exp Ther 152: . 18-28, 1966. A 676 ~T10302-7244
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X. Circulatory Effects of Smoking - 24 Page 247 forms of tobacco consumption in humans and dogs (Kershbaum et_al. , 1965, 1966; Kershbaum and Bellet, 1968; Kershbaum, 1968), and an increase in adrenocortical secretion accompanying the elevated FFA (Kershbaum et al. , 1967a, 1967b; Kershbaum et al. , 1968). Before Bellet died in 1971, he had.completed the following sequence of conclusions as to how cigarette smoking causes elevation of the cholesterol level: (a) nicotine from tobacco releases catecholamines which mobilize FFA and lipoproteins; (b) in addition, catecholamines stimulate the anterior lobe of the pituitary gland to secrete adrenocorticotropic hormone(c) stimnlationof the adrenal cortex releases hormones which play an essential and supportive role in the action of catecholamines on lipid metabolism. The most important link in the above hypothesis is an increase in FFA following smoking. Several investigators have failed to ctbserve an increase (Konttinen and Rajasalmi, 1963; Kedra et al. , 1965; Frankl et al. , 1966; Miturzynska-Stryjecka et al. , 1970). Furthermore smoking does not cause an elevation in blood sugar and epinephrinelike substances in the systemic blood (Rehder and Roth, 1959). It has been difficult to obtain definitive proof that cigarette smoking causes an acute rise in blood lipids. Yet among habitual smokers there is an elevation in lipid levels as compared with nonsmokers (Harlan et al. , 1967; Modzelewski and Malec, 1969; T'a'gert, 1970). sAUr- x•,TI0302-1236
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LX. Circulatory Effects of Page 248 Smoking - 25 .. BIBLIOGRAPHY IX. CARDIOVASCULAR EFFECTS OF SMOKING . C. Blood Lipids Reprint BOYLE E Jr, MORALES I B, NICHAMAN M Z, TALBERT C R Jr and WATKINS R S: Serum beta lipoproteins and cholesterol in adult men. Geriatrics 23: 102-111, 1968. 815 BUTKUS A and PAGE I H: Smoking and postabsorptive serum lipid levels. JAMA 192: 52-53, 1965. . 816 CIAMPOLINI E, DRINGOLI R and RAVAIOLI P: Azione del fumo di , . . sigarette su alcuni parametri del ricambio lipidico. Atti Accad Fisiocrit Siena 17: 474-480, 1968. 817 FRANKL W 5, FRIEDMAN R and SOLOFF LA: Cardiac output, blood pressure _ and free fatty acid responses to smoking in the nonbasal state. - - -- Am J Med Sci 252: 39-44, 1966. ,- ~ - . 818 GOKSEL S: Koroner hastaligi ve sigara. (Coronary disease and the cigarette). . Istambul Univ Tip Fak Med 20: 458-464, 1967. 819 HARLAN W R Jr, OBERMAN A, MITCHELL R E and GRAYBIEL A: . Constitutional and environmental factors related to serum lipid and lipoprotein levels. Ann Intern Med 66: 540-555, 1967. 820 KEDRA M, POLESZAK J and PITERA A: Wplyw palenia tytoniu na poziom t3uszczowcow krwi. (Influence of tobacco smoking on blood lipids) . Pol Tyg Lek 20: 1452-1454, 1965. 821 KERSHBAUM A: A comparative study of cigarette, cigar and pipe smoking effects , on blood lipids, catecholamine excr,tion and nicotine content of the urine. Acta Cardiol23: 317-329, 1968. . 822 KERSHBAUM A: Tobacco smoking and athernsclerotic vascular disease. Malattie Cardiovasc. 8: 1-19, Y9b7: ' . 823. KERSHBAUM A and BELLET S: Cigarette smoking and blood lipids. JAMA 187: 32-36, 1964. 824 , KERSHBAUM A and BELLET S: Smoking as a factor in.atherosclerosis. . Geriatrics 21: 155-170, 1966. 825 KERSHBAUM A and BELLET S: Cigarette, cigar, and pipe smoking. . . Geriatrics 23: 126-134, 1968. 826 KERSHBAUM A, BELLET S, CAPLAN R F and FEINBERG L J: Effect of " . cigarette smoking on free fatty acids in patients with healed myocardial , infarction. AmJ Cardiol 10: 204-208, 1962. . 827 KERSHBAUM A, BELLET S, CHO Y W.and DUGGEJ E: Effect of cigarette, • cigar, and pipe smoke inhalation on serum lipid concentrations and urinary catecholamine excretion in dogs. Circulation 32 (Suppl 2): - 19-20, 1965. . . . 828 ,~T10 30 2-1 237
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?CI(ccts X. hcute and Chronic of Nicotine - 3 Page 256 List No. 25 Reprint GINZEL K H and KOTTEGA S R: Die Wirkung von Nicotin und Hexamethonium . am normalen und chronisch denervierten Hervorhofpraparat und am Kaninchenohr. Arch Exp Pathol Pharmacol 22Z: 178-180, 1954. . A 677 GREWAL R S, LU F C and ALLMARK M G: Release of posterior pituitary hormone in rats by nicotine.and lobeline. Fed Proc 19: 167, 1960. A 678 HERBIG H: Ist das Nicotin ein Gefassgift7 Dtsch Z Chir 256: 467-488, 1942. A 679 KUKOVETZ W R: Die Wirkung ganglionar erregender Substanzen auf die . Kontraktilitat und Phosphorylaseaktivitat des isolierten astropinisierten . Kaninchenherzens. Arch Exp Path Pharmak 241: 557-558, 1961. A 680 LAESSING F:.Herzscliadigung durch Nikotin. Med Welt 12: 1485-1487, 1938. A 681 LEADERS F E and LONG J P: Mechanism of the positive chronotropic . response to nicotine. Fed Proc 21: 330, 1962. . A 682 LEADERS F E and LONG J P: Mechanism of the positive chronotropic response to nicotine. J Pharmacol Exp Ther 137:206-212, 1962. A 683 LINDMAR R: Die Wirkung von 1, 1-Dimethyl-4-Phenyl-Piperazinium-Jodid am isolierten Vorhof im Vergleich zur Tyramin-und Nicotinwirkung. . Arch Exp Pathol Pharmak 242: 458-466, 1962. A 684 - REUSE J J and BOURGAIN Rc Influence de la reserpinisation prealable in vivo . sur la reponse des oreillettes isole'es du lapin et du cobaye aux substances excito-ganglionnaires. Arch Int Pharmacodyn 125: 227-231, 1960. A 685 ROMERO T and TALESNIK J: Influence of nicotine on the coronary circulation of the isolated heart of the cat. J Pharm Pharmacol 19: 322-328, 1967. A 686 SCHEUER J and STEZOSKI S W: The response of the isolated rat heart to .. anoxia and positive inotropic agents. Circulation 38 ,(Suppl 6): . 173, 1968. . A 687 VERESS L: Blutbilduntersuchungen bei nikotinvergifteten Ratten . Dtsch Gesamte Gerichtliche Med 56: 62-65, 1965. A 688 WEISSLER A M, KRUGER F A, BABA N, SCARPELLI D G, LEIGHTON R F and GALLIMORE J K; Role of anaerobic metabolism in the preservation . of functional capacity and structure of anoxic rnyocardium. J Clin Invest 47: 403-416, 1968. . A 689 ZEITLIN L A and TELEPNEVA V A: Intracellular localization of processes '. of transformation of nicotine amide coenzyrnes in cardiac muscle. _ Vopr Med Khim 17: 583-587, 1971. A 690 T10 30 2-1 245
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X. Circulatory Effects of Smoking - 28 BIB LIOGRA PHY IX. CARDIOVASCULAR EFFECTS OF SMOKING - -- ~ -. -D. B1oodCoa¢ulation. _. .:-'-°- Page 251 Reprint AMBRUS J L and MINK I B: Effect of cigarette smoking on blood coagulation. Clin Pharmacol Ther 5: 428-431, 1964. - 844 ASHBY P, DALBY A M and MILLAR J H D: Smoking and platelet stickiness. Lancet 2: 158-159, 1965. - -" 845 EL-EBRASHY N, EL-ASHMAWY S and ALY A: Effect of smoking on the index . of platelet adhesiveness and blood glucose level in atherosclerotic patients. J Egypt Med Assoc 50: 157-168, 1967. 846 EISEN M E and HAMMOND E C: The effect of smoking on packed cell volume, -red blood cell counts, haemoglobin and platelet counts. Can Med Assoc J 75: 520-523, 1956. 847 ENGELBERG H: Cigarette smoking and the in vitro thrombosis of human blood. .. . -JAMA 193: 1033-1035, 1965. . .. . . - . . _ -: --~-"---848 ENGELBERG H, and FUTTERMAN M: Smoking and acceleration of the ~ thrombotic coagulation of blood. Circulation 33-34 (Suppl 3): 96-97, 1966. 849 ENGELBERG H and FUTTERMAN M: Cigarette smoking and thrombotic coagulation of human blood. Arch Environ Health 14: 266-270, 1967. 850 ENGELBERG H and ENGELBERG L P: The effect of cigarette smoking on various - clotting time tests. Vasc Dis 5: 226-230, 1968. . 851 FACCHINI G, SEMARARO S, DI BIASE G, TABARRONI F, SPAGNOLO D, . AUTORE A and BONAVITA E: Modificazioni nel soggetto anziano della - reattivita al fumo di sigaretta: Ricerche sull'equilibrio emocoagulativo e fibrinolitico e sul circolo periferica. G Gerontol 19: 779-784, 1971. 852 KEDRA M and KOROLKO A: Tobacco smoking and blood clotting. Bull Pol Med Sci Hist 8: 145-148, 1965. . " LISIEWICZ J: Badania doswiadczalne wplywu palenia papierosow na czas krzepniqcia krwi i osocza uwapnionego oraz czas protrombinowy i - trombinowy osocza u ludzi. (Experimental studies on the effect of • smoking on the blood and calcified plasma clotting time on the plasma prothrombin and thrombin time in normal subjects). PolTygi Lek ." 18: 1471-1473, 1963. 853 854 MURCHISON L E and FYFE T: Effects of cigarette smoking on serum-lipids, blood-glucose, and platelet adhesiveness. Lancet 2: 182- 184, 1966. 855 MURPHY E A and MUSTARD J F: Tobacco and thrombosis.. Am J Public Health 56: 1061-1073, 1966. 856 .,.,wmT10302-1240
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X. Acute and Chronic Effects of Nicotine - 1 Page Z53 X. ACUTE AND CHRONIC EFFECTS OF NICOTINE C16ARETTE SMOdINC F / \ STIMVLATMM OF YELdSE OF ~ AVTOMMMC 6AN6LlA CATECNOLAMINEf X NICOTINE Yl. Mode of Action on the Heart---264 B. Experimental Coronary :IneoCfieienc9----------------- 270 C. Experimental Hypertensioxr---.275 D. Experimental Atherosclerosis- 277 E. Experimental Hyperlipidemias- 280 F. Experimental Thrombosis----'- 282 The most important and widely investigate3constituent of cigarette smoke is nicotine. The experimental use of this alkaloid has failed to produce coronary heart disease in animals that is similar to the human form. The pharmacologic action of nicotine can be attributed to stimulation of autonomic ganglia and the release of catcholamines. However, each mode of action taken singly has not been demonstra'.ed to produce coronary insufficiency, experimental hypertension, atherosclerosis and thrombosxs. IIyperlipidelnia can be induced by catecholamines or nicotine but these same agents do not produce atherosclerosis unless the animal has also received a diet high in cholesterol. The cardiac effects of nicotine do not in lude coronary vasoconstriction. However, it produces stimulation of the heart, which is potentially dangerous to a patient with coronary heart disease. The dose of nicotine used in the YICOTINE .,,,,s.T10 30 2-1 242
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X. Circulatory Effects of Smoking - 29 Page 252 Reprint MUSTARD J F and MURPHY E A: Effect of smoking on blood coagulation and . platelet survival in man. Br Med 3 1: 846-849. 1963. 857 GLYNN M F, MUSTARD J F, BUCHANAN M R and MURPHY E A: Cigarette - smoking and platelet aggregation. Can Med Assoc J 95: 549-553, 1966. 858 BLACKBURN H Jr, ORMA E, HARTEL G and PUNSAR S: Tobacco smoking and blood coagulation: Acute effect on plasma stypven time. Am J Med Sci . 238: 448-451. 1959. 859 SCHOENDORF T, WILKENING J'and CLIFF.TON EE: Influence of cigarette smoking on some blood coagulation tests. J Med 1: 117-128, 1970. 860 SOGANI R K and JOSHI K C: Effect of cigarette and biri smoking and tobacco chewing on blood coagulation and fibrinolytic activity. Indian Heart J 17: 238-242, 1965. . . 861 ..T10 30 2-1 241
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C. Acute and Chronic Effects Page 259 of Nicotine - 6 List No. 26 . . Reprint WESTFALL T C: Effect of nicotine and nicotine analogues on tissue and . urinary catecholamines in the rat. Acta Physiol Scand 63: 77-83, 1965. A 719 WESTFALL T C and ANDERSON G P: Influence of nicotine on catecholamine metabolism in the rat. Arch Int Pharmacodyn 169: 421-4Z8, 1967. A 720 WOODS E F and RICI-LARDSON J A: A survey of agents producing cardiovascular manifestations of epinephrine discharge. J Pharmacol Exp Ther 114: . - 445-452, 1955. .. . A 721 YOSHIKATA M: _ Folia Pharmacol Jap 60: . , 139-149, 1964. A 722 T10 30 2-1 248
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:. Acute and Chronic Effects Page 257 of Nicotine - 4 . X. CARDIOVASCULAR EFFECTS OF NICOTINE Additional Bibliographic List No. 26 RELEASE OF CATECHOLAMINES..~ FROM THE HEART Reprint ARMITAGE A K: Effects of nicotine and tobacco smoke on blood pressure and release of catechol amines from the adrenal glands. Bi J Pl:armacol 25: 515-526, 1965. A691 BAGWELL E E, WOODS -E Y a.id RICHARDSON J A: Effects of reserpine , on adrenal responses to nicotine. Proc Soc Exp Biol Med 103: . 467-469, 1960. . A 692 BHAGAT B, BOVELL G and ROBINSON I bL• Influence of cocaine on the uptake of H3-norepinephrine and on the responses of isolated guinea-pig atria to sympathomimetic amines.. J Pharmacol Exp Ther 155: 472-478, 1967. A 693 BISCARDI A M and WASSERMANN G F: Release of catecholamines from adrenalinogenic and noradrenalinogenic tissue by the action of nicotine 'Sn vitro". Arch Int Pharmacol Ther 159: 424-433, 1966. A 694 BLASCHKO H, HAGEN P and WELCH A D: Observations on the intracellular granules of the adrenal medulla. J Physiol 129: 27-49, 1955. A 695 BRAUNWALD E, CHIDSEY C A, HARRISON D C, GAFFNEY T E and KAHLI:R R L: Studies on the function. of the adrenergic nerve endings . in the heart. Circulation 28: 958-969, 1963. - A 696 BURN J H: Antidiuretic effect of nicotine and its implications. Br Med J 2: 199-201, 1951. - A 697 BURN J H and GIBBONS W R: The release of noradrenaline from sympathetic fibres in relation to calcium concentration. J Physiol 181: 214-223, 1965. A 698 BYGDEMAN S and EULER U S: Resynthesis of catechol hormones in the cat's adrenal medulla. Acta Physiol Scand 44: 375-383, 1958. A 699 FAWAZ G: Cardiovascular pharmacology. Ann Rev Pharmacol 3: 57-90, 1963. A 700 FOLKOW B and VON EULER U 5: Selective activation of noradrenaline and adrenaline producing cells in the cat's adrenal gland by hypothalamic stimulation. Circ Res 2: 191-195, 1954. A 701 FRIEDMAN M, ST. GEORGE 5, BYERS S 0 and ROSENMAN R H: Excretion of catecholamines, 17-ketosteroids, 17-hydroxycorticoids and 5-hydroxyindole , in men exhibiting a particular behavior pattern (A) associated with high incidence of clinical coronary artery disease. J Clin Invest 39: . 758-764, 1960. . A•702 GATGOUNIS J and AYCOCK J: Effects of monoamine oxidase inhibitors on adrenal medullary responses to nicotine and tetramethylammonium. J Pharmacol Exp Ther 141: 50-57, 1963. . A 703 T10 30 2-1 246
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{. Circulatory Effects of Pagc 249 Smoking - 26 Reprin ' KERSHBAUM A, BELLET S, DICKSTEIN E R and FEINBERG L J: The effect of cigarette smoking on serum free fatty acids. Clin Res 8: 241, 1960. 829 KERSHBAUM A, BELLET S, DICKSTEIN E R and FEINBERG L J: Effect of cigarette smoking and nicotine on serum free fatty acids. Clin Res 9: 631-638, 1961. . 830 KERSHBAUM A, BELLET S, JIMENEZ J and FEINBERG L J: Differences in effects of cigar and cigarette smoking on free fatty acid mobilization and catecholamine excretion. JAMA 195: 1095-1098, 1966. 831 KERSHBAUM A, JIMENIZ J and BELLET S:Suppression of the free fatty acid response to cigarette smoking by the ingestion of whiskey. Clin Res 12: 273, 1964. 832 KERSHBAUM A, KHORSANDIAN R, CAPLAN R F,. BELLET S and '. FEINBERG L J: The role of catecholamines in the free fatty acid , response to cigarette smoking. Circulation 28: 52-57, 1963. 833 KERSHBAUM A, PAPPAJOHN D J, BELLET S, HIRABAYASHI M and SHAFIHA H: Effect of smoking and nicotine on adrenocortical secretion. Clin Res 15: 261, 1967A. .. 834 KERSHBAUM A, PAPPAJOHN D J, OSADA H and BELLET S: The influence of tobacco smoking on the crystallization of cholesterol. Clin Res . 15: 322, 1967B. 835 KERSHBAUM A, PAPPAJOHN D J, BELLET 5, HIRABAYASHI M and SHAFIIHA H: Effect of smoking and nicotine on adrenocortical . secretion. JAMA 203: 275-278, 1968. - 836 KONTTINEN A and RAJASALMI M: Effect of heavy cigarette smoking on post- prandial triglycerides, free fatty acids, and cholesterol. Br Med J 1: 850-852, 1963. . - 837 ~ . MITURZYNSKA-STRYJECKA H, WIDOMSKA-CZEKAJSKA T and RUPNIEWSKA Z M: . Wplyv+ palenia papierosow na lipemie po posidku ttuszezowym. (The effect of acute experiment of cigarette smoking on lipaemia following . fat meal. Pol Tyg Lek 25: 251-253, 1970. . . , 838 MODZELEWSKI A and MALEC A: Zachowanie sie niektorych lipidow we krwi u palaczy, (Patterns of certain blood lipids in smokers). Wiad Lek . 22: 229-233, 1969. " 839 MULCAHY R and HICKEY N: The role of cigarette smoking in the causation . of atherosclerosis. Geriatrics 22:165-174, 1967. 840 PAGE I H, LEWIS L A and MOINUDDIN M: Effect of cigarette smoking on . • serum cholesterol and lipoprotein concentration. JAMA 171: 1500-1502, 1959. 841 REHDER K and ROTH G M: - Effect of smoking on the fasting blood sugar and , pressor amines. Circulation 20: 224-228, 1959. 842 TAGERT J: Folgerungen aus einem Querschnittvergleich von Gesunden und Kreislaufkranken fUr epidemiologische Langsschnittstudien. ' Z Kreislauflorsch 597 744-756, 1970. .. 843 T10 30 2-1 23 8
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C. Acute and Chronic Effects Page 25ti of Nicotine - 5 List No. 26 . Reprint '.GATGOUNIS J, RICHARDSON J A and CLAYTON J A: Effect of an MAO inhibitor on adrenal catecholamine content to nicotine stimulation of the adrenal glands. Fed Proc 23: 230, 1964. . A 704 GRAY L, BOOKER W M and OXHOA L: Comparison of the blood pressure responses_to nicotine in normal and ascorbic acid deficient guinea pigs. Fed Proc 26: 682, 1967. A 705 GREWAL R 5, LU F C and ALLMARK M G: The release of posterior pituitary hormone in the rat by nicotine and lobeline. J Pharmacol Exp Ther - . 135: 84-88, 1962. A 706 HANSSON E, MASUOKA D T and CLARK W G: Effect of nicotine on the catecholamine and the serotonin level in some tissues. Proc West Pharmacol Soc 6: 36-37, 1963. A 707', HANSSONE, MASUOKA D T and CLARK W G: Effect of nicotine on the . catecholamine and serotonin levels in vivo. Arch Int Pharmacodyn 149: 153-160, 1964. A 708 HOLLANDS B C S and VANOV 5: Localization of catechol amines in visceral . organs and ganglia of the rat, guinea-pig and rabbit. Br J Pharmacol 25: 307-316, 1965. . . .. A 709 . KAUFMANN H and BENSIMON L: Le sevrage du tabac. Vie Med 41: 1139-1140, 1960. . A 710 KIRSHNER N, SAGE H T, SMITH W J and KIRSHNER A G: Release of . catecholamines and specific protein from adrenal glands. Science 154: 529-531, 1966. A 711 LICHTMAN M A and WOODS J W: Catecholamine excretion in young white and negro males with normal and elevated blood pressure. J Chron Dis 20: 119-128, 1967. . A 712 McKENNIS HJr, TURNBULL L B and BOWMAN E R: N-methylation of nicotine and cotinine in vivo. J Biol Chem 238: 719-723, 1963. A 713 ~ NAGAI K: Nicotine. Folia Pharmacol Jap 59: 442-451, 1963. A 714 SILVETTE H, LARSON P S and HAAG H B: Action of nicotine and tobacco- g smoking on the adrenal medulla. Arch Intern Med 107: 915-931, 1961. A 715 THIENES C H, CANGELOSI J and SKILLEN R G: Nicotine and thyroid effect on adrenal catecholamines. Proc West Pharmacol Soc 5: 5-6, 1962. A 716 WATTS D T: The effect of nicotine and smoking on the secretion of epinephrine. Ann N Y Acad Sci 90: 74-80, 1966. - A 717 WEINER N, DRASKOCZY P R and BURACK W R: The ability of tyramine to . liberate catecholamines in vivo. J Pharmacol Exp Ther 137: 47-55, 1962. A 718 -.-T10 30 2-1 247
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X. Acute and Chronic Effects of Nicotine - 11 Page 264 X-A. Mode of Action on the Heart -_ The most important constituent of cigarette smoke that is responsible for its cardiac action is nicotine. The amount of nicotine absorbed in the respiratory tract ranges from 63 to 95%, depending on the duration of the period between inhalation and exhalation and the depth of the former (Larson, 1960). The'percentage was derived by analyzing the content of nicotine in the smoke prior to and after the puff. The total amount of nicotine absorbed has also been estimated by analysis of urine for nicotine content (Beckett, 1967; Kershbaum et al. , 1967; Cederldf and Edfors, 1968). The mode of action of nicotine is as follows: 1. Nicotine effect on autonomic ganglia. Nicotine stimulates both groups of autonomic ganglia, the parasympathetic and the sympathetic. These .ganglia are recorded as containing cholinergic fibers, a term introduced by Dale (1933) to indicate that acetylcholine is the chemical mediator. The result is either bradycardia from stimulation of parasympathetic ganglia, or tachycardia from stimulation of sympathetic ganglia (Aviado, 1972). 2. Release of catecholamines. The term nicotinic includes not only ganglionic stimulation (see above) but also the release of catecholamines in the adrenal medulla and in the area of adrenergic nerve endings in the heart 0 (see Additional Biblio ra hic List No 27) Th l t l g p . . e re ease occurs no on y following the administration of nicotine, but also following cigarette smoking (Westfall and Watts, 1963; Klensch, 1966; Klensch et al. , 1967; Schievelbein and Werle, 1967). The end result is stimulation of the heart similar to the - ..__.._.--------- _. _.,_ ____~TI0302-1253
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X. Acute and Chronic Effects Page 260 of Nicotine - 7 - X. CARDIOVASCULAR EFFECTS OF NICOTINE Additional Bibliographic List No. 27 RELEASE OF CATECHOLAMINES FROM ADRENAL MEDULLA ASSMANN H:. Ueber Nikotinschaden. Munch Med Wochenschr 86: 457-460, 1939. BRINKMANN W H: Experimentelle Untersuchungen zur Pathogenese der Harnsteine. Langenbecks Arch Klin Chir 300: 363-400, 1962. BRITMAN N A and LEVINE H J: Contractile element work: A major . determinanant of myocardial oxygen consumption. J Clin Invest : 43: 1397-1408, 1964. CHIDSEY C A, BRAUNWALD E and MORROW A G: Catecholarnine excretion and cardiac stores of norepinephrine in congestive heart failure. Reprint A 723 A 724 A 725 ' Am J Med 39: 442-451, 1965. A 726 CHIDSEY C A, SONNENBLICK E H, MORROW A G and BRAUNWALD E: Norepinephrine stores and contractile force of papillary muscle from ' the failing human heart. Circulation 33: 43-51, 1966. . , A 727 CLANCY R L, GRAIiAM T P Jr, POWELL W J Jr and GILMORE J P: . - Inotropic augmentation of myocardial oxygen consumption. . . . Am J Physiol 212: 1055-1061, 1967. .. A 728 DODGE H T: Hemodynamic aspects of cardiac failure. _Hosp Pract 6: 91-103, 1971. . , A 729 FERREIRA I J, ANDERIZ M, FIGUERA E L and CEBOLLADA J: Factores - adrenergicos en la patogenia de la insufficiencia coronaria. Rev Esp Cardiol 21: 321-339, 1968. - A 730 GAEDE D: Nikotin und Koronarekrankungen. Dtsch Med Wochenschr. 67: . 933-934, 1941. ' . A 731 GAZES P C, RICHARDSON J A and WOODS E F: Plasma catechol amine - concentrations in myocardial infarction and angina pectoris. Circulation 19: 657-661, 1959. A 732 GRAHAM T P Jr, COVELL J W, SONNENBLICK E H, ROSS J Jr, and BRAUNWALD E: Control of myocardial oxygen consumption: relative ., influence of contractile state and tension development. J Clin Invest 47: 375-385, 1968. A 733 HASSENCAMP E: Die Wirkung des Nikotins auf den Kreislauf. Munch Med . . - W ochenschr 86: 1381-1383, 1939. . . A 734 KAKO K, CHRYSOHOU A and BING R J: Storage of catecholamines in the heart. Effect of amine oxidase inhibitors. Am J Cardiol 6: 1109-1111, 1960., A 735 -T10302-7249
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X. Acute and Chroriic Effects of Nicotine - 13 Page 266 Makin, 1966, 1967). The responses to stimulation of chemoreflexes iri the heart and the chemoreceptors in the carotid and aortic bodies are variable and include tachycardia or bradycardia and coronary vasoconstriction.or vasodilatation. 1n the pulmonary circulation, the response to nicotine is the outcome of stimulation of chemoreflexes and release of catecholamines (Larson and Murray, 1963; Stern and Braun, 1966; Saman€k and Aviado, 1966). It has also been demonstrated that smoke inhalation in the dog causes the release of histamine which may in turn,influence the heart (Aviado et al. , 1966). T10 30 2-1 255
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X. Acute and Chronic Effects Page 268 of Nicotine - 15 Reprint - LICKINT F: Nikotin und Kreislauferkrankungen. Landartz 35: 470-475. 1959. 876 LARSON P S: Absorption of nicotine under various conditions of tobacco use. Ann N Y Acad Sci 90: 31-35, 1960. 877 LARSON R K and MURRAY. J F: Effect of nicotine on the pulmonary circulation in the dog. Clin Res 11: 89, 1963. .. 878 HASHIMOTO K, IGARASHI S, UEI I and KUMAKURA S: Cartoid chemoreceptor reflex effects on coronary flow and heart rate. Am J Physiol 206: 536-540, 1964. 879 PAPP M and SOLTI F: Influence of dibenamine on nicotine-induced egg changes. - Acta Med Acad Sci 14: 297-301, 1959. 880 PAPACOSTAS C A and REED J P: Influence of beta receptor blockade on certain cardiovascular actions of nicotine. Arch Int Pharmacodyn 164: 167-172, 1966. 881 ROBIN E, RAVENS K G and BING R J: Die Wirkung von Alkohol, Nikotin und Zigarettenrauchen. Dtsch Med J'5: 19-29, 1969. 882 r SAMANEK M and AVIADO D M: Cardiopulmonary effects of tobacco and related substances. Arch Environ Health 12: 717-724, 1966. 883 SCHIEVELBEIN H and WERLE E: Mechanism of the release of amines by nicotine. Ann N Y Acad Sci 142: 72-82, 1967. 884 SHANKS R G: The pharmacology of beta sympathetic blockade. Am J Cardiol 18: 308-316, 1966. 885 ' SHIBATA S, HOLLANDER P H and WEBB J L: Effect of nicotine on the , . transmembrane potential and contractility of isolated rat atria. . . Experientia 24: 236-237, 1968. 886 SLEIGHT P: A cardiovascular depressor seflex from the epicardium of the left ventricle in the dog. J Physiol 173: 321-343, 1964. , 887 STERN S, FERGUSON R E and RAPAPORT E: Reflex pulmonary vasoconstriction due to stimulation of the aortic body by nicotine. Am J Physiol 206: 1189-1195, 1964. 888 STERN S and BRAUN K: Effect of chemoreceptor stimulation on the pulmonary veins. Am J Physiol 210: 535-539, 1966. 889 STERN S and RAPAPORT E: Comparison of the reflexes elecited from combined or separate stimulation of the aortic and carotid chemoreceptors on myocardial . contractility, cardiac output and systemic resistance. Circ Res 20: 214-227, 1967. . . . 890 ' ' WEBB W R, WAX S D and SUGG W L: Cigarette smoke and fibrillation • threshold in dogs. Clin Res 16: 74, 1968. 891 WENZEL D G, MacCARTHY J D and RUTLEDGE C 0: Evaluation of caffeine and ouabain as permissive agents in the production of myocardial necrosis. J Pharm Sci 53: 567-568, 1964. . 892 710 30 2-1 257
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K. Acute and Chronic Effects of Nicotine - 17 Page 270 X-B. Experimental Coronary Insufficiency The early experiments showed that nicotine causes coronary vasoconstriction in the perfused isolated heart (Laubry et al.,, 1933; Wegria, 1951). In the dog coronary vasoconstriction could not be elicited by nicotine injected directly into the coronary artery of an intact heart (West et al. , 1958, 1962; Bellet et al. , 1960a), intravenously in the intact animal (Kien et al. , 1957; Forte et al. , 1960), or in the perfused canine heart (Leaders and Long, 1962), and in the heart-lung preparation (Folle et al. , 1966). Bing and his collaborators have systematically examined the effects of nicotine on the coronary circulation. Their experiments relating to the acute effects of cigarette smoking on the human heart are discussed in Section IX-B. In the animal heart, they measured capillary blood by means of radioactive iodinated albumin. Nicotine did not influence coronary capillary blood flow in the dog heart, unless the dose was large enough to influence blood pressure (Rakuson et al. , 1968; Rival and Mathes, 1969). By means of radioactive Rubidium for estimating effective coronary flow, Leb et al. (1970) noted that after nicotine injection there was a significant correlation between supply of oxygen (effective blood flow) and oxygen demand of the myocardium. By direct visualization of the coronary capillaries, an increase was noted in the movement of red blood cells on the surface of the cat heart following the injection of nicotine (Bing et al. , 1971; Hellberg et al. , 1972; Pachinger et al. , 1972). There is no evidence that nicotine causes coronary insufficiency in the normal heart. T10 30 2-1 259
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:. Acute and Chronic Effects of Nicotine - 10 Page 263 List No. 28 Reprint YAMAMOTO I, NAGAI K and INOKI R: The contents of dopa and catechol- amines in several rat tissues and.nicotine-induced convulsions. . . Jap J Pharmacol 16: 295-305, 1966. . .. . A 760 ZEJMAL E V: Pharmacological study of the central nicotine-sensitive cholino- receptors. Act Nerv Super 8: 60-67, 1966. - - A 761 ;A,.,=w,c~; 7•, TI0302-1252
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i. Acute and Chronic Effects of Nicotine - 16 Page 269 . Reprint WENZEL D G and STARK L G: Effect of nicotine on cardiac necrosis induced "-- by corticosteroid-electrolyte-stress. Am Heart J 69: 780-784, 1965. - 893 WENZEL D G and STARK L 0: Effect of nicotine on cardiac necrosis induced by isoproterenol. Am Heart J 71: 368-370, 1966. 894 WENZEL D G: Drug-induced cardiomyopathies. J Pharm Sci 56: 1209-1224, 1967. 895 WENZEL D G and RICHARDS M H: Effects of chronic nicotine, acute hypoxia, and their interactions on myocardial enzymes. Toxic Ap 1 Pharmacol 16: 656-667, 1970. 896 WESTFALL T C and. WATTS D T: Effect of cigarette smoke on epinephrine secretion in the dog. Proc Soc Exp Biol Med 112: 843-847, 1963. 897 WESTFALL T C and WATTS D T: Catecholamine excretion in smokers and nonsmokers. J Appl Physiol 19: 40-42, 1964. 898 *sxc;,=,-sT10 30 2-1 258
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C. Acute and Chronic Effects Page 261 of Nicotine - 8 List No. 27 , ; Reprint KAKO K, CHRYSOHOU A and BING RJ:Factors affecting myocardial storage and-release of catecho:amines. Circ Res 9: 295-299, 1961. . A 736 LAUDA E: Nikotinschaden. Med Klin 56: 679-685, 1961. A 737 MUSCHOLL E; Der Einfluss von Pharmaka auf den Katechinaminstoffwechsel des Herzens. Acta Biol Med German Suppl 1: 193-Z01, 1961. A 738 OTT G, KAULBACH W and TERSIDES C: Tabakteer-Derivate und Nicotin in . ihrer wechselseitigen Bedeutung fur Bronchialcarcinome und . Herzkrankheiten. Lagenbecks Arch Chir 300: 324-362, 1962. . A 739 RUDOLPH W, DIEZEL R, SEBENING F and DIETZE G: Der Einfluss von Adrenalin auf den Stoffwechsel des menschlichen Herzens. I. Unter- suchungen uber Koronardurchblutung, Sauerstoffaufnahme und • - Kohl.eidioxydabgabe des Myokards, Arztliche Forschung 22: _ 82-89, 1968. A 740 RUDOLPH W, DIEZEL R, SEBENING F and DIETZE G: Der Einfluss von . Adrenalin auf den Stoffwechsel des menschlichen Herzens. II. Unter- suchungen iiber die myokardiale Aufnahme von Glukose, Laktat, Pyruvat, . nicht veresterten Fettsauren und Aminosauren. Arztliche Forschung - 22: 90-104, 1968. A 741 SHARMAN D F, VANOV S and VOGT M: Noradrenaline content in the heart -, and spleen of.the mouse under normal conditions and after administration ' of some drugs. Br J Pharmacol 19: 527-533, 1962. . A 742 SONNENBLICK E H, ROSS J Jr, COVELL J W, KAISER G A and BRAUNWALD E: . Velocity of contraction as a determinant of myocardial oxygen consumption. Am J Physiol 209; 919-927, 1965. A 743 SWAINE C R, PERLMUTTER J F and ELLIS S: The release of catecholamines . from the isolated cat heart by mephentermine. Naunyn-Schmiedebergs Arch Pharma.kol 248: 331-342,. .1964. . A 744 TAYLOR R R, CINGOLANI H E, GRAHAM T P and CLANCY R L: Myocardial oxygen consumption, left ventricular fibre shortening and wall tension. . Cardiovasc Res 1: 219-228, 1967. . '. A 745 VOGEL J H K, JACOBWITZ D and CHIDSEY C A: Distribution of norepinephrine - in the falling bovine heart. Circ Res 24: 71-84, 1969. A 746 T10 30 2-1 250
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Acute and Chronic Effects of Nicotine - 25 Page 278 normocholesterolemic rabbits (Adachi et al., 1965). Nicotine was shown to change the lipid patterns of the perfused dog aorta and coronary artery (Kupke, 1972). The results were regarded by the author as supporting the hypothesis that nicotine may impair oxidative enzymes by damaging the mitochondrial structures, thereby leading to lipid accumulation. Experiments on the atherosclerotic dog aorta and the human aorta are needed. ._,..~TI0302-7267
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X. Acute and Chronic Effects of Nicotine - 14 BIBLIOGRAPHY X. CIRCULATORY EFFECTS OF NICOTINE A. Mode of Action on the Heart Page Z67 Reprint AVIADO D M, SAMANL°K M and FOLLE L E: Cardiopulmonary effects of tobacco and related substances. Arch Environ Health 12: 705-711, 1966. . • 862 AVIADO D M: Ganglionic stimulants and blocking drugs. In: Pharmacologic principles of medical practice. Williams & Wilkins Company, Baltimore, pp. 365-376, 1972. 863 BECKETT A H and TRIGGS E J: Enzyme induction in man caused by smoking. . Nature 216: 587, 1967. - - 864 BERGEL D and MAKIN G: Circulatory changes produced by chemical stimulation of the surface of the left ventricle in dogs. J Physiol 184: 74-75, 1966. 865 BE RGEL D H and MAKIN G S: Central and peripheral cardiovascular changes following chemical stimulation of the surface of the dog's heart. . . . Cardiovasc Res 1: 80-90, 1967. .. 866 BRACHFELD N and ORAN E: Effect of nicotine on myocardial metabolism. Clin Res 14: 240, 1966. . . . 867 BRACHFELD N, KUEHN P, KAWADE M and ORAN E: Nicotine mediated release of myocardial cell and lysosomal enzymes. Ann Intern Med 66: 1034, 1967. 868 CEDERLOF R and EDFORS M-L: Hur mycket tjara och nikotin fnneh&ller . cigaretterna? Lakartidningen.. 65: 5003-5011, 1968. . 869 DALE H H: Nomenclature of fibres in the autonomic system and their effects. J Physiol 80: 10-11, 1933. 870 FROMMEL E: L'action de la nicotine sur 1'excitabilite et la conductibilite du eoeur. J Physiol Path Gen 26: 384-388, 1928. 871 GREENSPAN K, EDMANDS,R E, KNOEBEL S B and FISCH C: Some effects of nicotine on cardiac automaticity, conduction, and inotropy. Arch Intern Med 123: 707-712, 1969. 872 KLENSCH H: Blut-Katecholamine und -Fettsauren beim Stress durch Rauchen und durch korperliche Arbeit. Z Kreislaufforsch 55: 1035-1044, 1966. 873 ' ' KLENSCH H, SPECKMANN K, MAETZEL F W and MEYER J D: Der • Plasma-Noradrenalinspiegel bei Koronarkranken in Ruhe und im Nikotin-Stress. Z Kreislaufforsch 56: 1164-1169, 1967. 874 KERSHBAUM A, BELLET S, HIRABAYASHI M, FEINBERG L J and EILBERG R: Effect of cigarette, cigar, and pipe smoking on nicotine excretion. Arch Intern Med 120: 311-314, 1967. 875 T10 30 2-1 256
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;. Acute and Chronic Effects of Nicotinc - 26 . BIBLIOGRAPHY CIRCULATORY EFFECTS OF NICOTINE D. Experimental Atherosclerosis Page Z79 Reprint ADACHI T, ADACHI M and POLLAK 0 J: Nicotine effect on oxygen consumption of tissues from normal and hypercholesteroric rabbits. Fed Proc . 24: 721, 1965. 945 ADLER I and HENSEL 0: Intravenous injections of nicotine and their effects upon the aorta of rabbits. J Med Res 10: 229-239, 1906. 946 GROSGOGEAT Y and ROUBELAKIS G: Action experimentale de la nicotine sur la paroi aortique du lapin. Etude en microscopie optique et electronique. Patbol Bio1 13: 1140-1155, 1965. 947 HASS G M, LANDERHOLM W and HEMMENS A: Production of calcific . athero-arteriosclerosis and thromboarteritis with nicotine. Vitamin - ' D and dietary cholesterol. Am J Pathol 49: 739-741, 1966a. 948 HASS G M, LANDERHOLM W and HEMMENS A: Nicotine induction of arteriosclerosis and thromboarteritis in rabbits. Circulation 34 (Suppl 3): 14, 1966b. 949 HASS G M, HENSON D, LANDERHOLM W and HEMMENS A: Prevention of nicotine induction of atherocalcific thromboarteritis in rabbits. Circulation 38 (Suppl 6)c 8. 1968. . 950 HUEPER W C: Experimental studiesin cardiovascular pathology. VII. Chronic nicotine poisoning in rats and in dogs. Arch Pathol 35: 846-856, 1943. 951 KUPKE I R: Biosynthesis of lipids in perfused dog aorta and coronary artery. J Mol Cell Cardiol 4: 27-38, 1972. 952 LANDERHOLM W, HEMMENS A and HASS G M: An experimental inquiry into nicotine-induced thromboarteritis.. Fed Proc 26: 359, 1967. 953 LELLOUCH J, JACOTOT B, ANGUERA G, GROSGOGEAT J and BEAUMONT J-L: Action chronique de la nicotine sur 1'intima aortique du lapin. Influence . d'un inhibiteur de la mono'amine oxydase. J Atherosclerosis Res 8: 137-142, 1968. 954 SCHIEVELBEIN H, LONDONG V, LONDONG W. GRUMBACH H, REMPLIK V, SCHAUER A and IMMICH H: Nicotine and arteriosclerosis. . Z Clin Chem Klin Biochem 8: 190-196, 1970. 955 STEFANOVICH V, GORE I, KAJIYAMA G and IWANAGA Y: The effect of nicotine . on dietary atherogenesis in rabbits. Exp Mol Pathol 11: 71-81, 1969. 956 THIENES C H: Chronic nicotine poisoning. Ann N Y Acad Sci 90: 239-248, 1960. 957 WENZEL D G, TURNER J A and KISSIL D: Effect of nicotine on cholesterol- induced atherosclerosis in the rabbit. Circ Res 7: 256-261, 1959. 958 _T10 30 2-1 26 8
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Acute and Chronic Effects of Nicotine - 18 Page 271 In some investigations performed on the dog heart with ischemia, Bellet et al. (1960b) observed that the increase in coronary blood flow in response to nicotine was considerably less in the ischemic heart as compared. with the normal heart. A reduction in capillary blood flow of the ischemic heart following nicotine injection has been observed by Corsini et al. (1968) and Mathes and Rival (1971). A reduction in response to nicotine has also been observed in the atherosclerotic rabbit heart (Travell et al. , 1960) and in the heart with pitressin-induced spasm (Kareva, 1963). The avian hearts show only a vasoconstrictor response to epinephrine, whereas the hearts of other species show a.vasodilation (Juhasz-Nagy et al., 1965). The increase in coronary blood flow following nicotine injection is accompanied by an increase in cardiac output in the dog (Corbascio and West, 1960; Larson et al., 1965). This effect is the outcome of positive chronotropic (Nadeau and James, 1967; Ross and Blesa, 1970) and positive inotropic action of nicotine (Puri et al. , 1967, 1968). The phenomenon occurs also in man following t he injection of nicotine (Boyle et al., 1947; Schweizer et al. , 1960; Dock, 1963; Valori et al. , 1964; Solti et al. , 1964). ____T10302-7260
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K. Acute and Chronic Effects of Nicotine - z-} Page 277 X-D. Experimental Atherosclerosis In the course of investigating the toxicity of nicotine, Adler and Hensel (1906) discovered lesions in the aorta of rabbits. The lesions were degenerative and aneurysmal; they were similar to those induced by epinephrine and unlike the human form of atherosclerosis. Degenerative lesions were.later seen in rabbits by Grosgogeat and Roubelakis (1965) and Lellouch et al. (1968) and in dogs by Hueper (1943) but were not seen in rats by Thienes (1960). The chronic administration of nicotine alone caused a transient increase in blood lipids but the level approximated the control level towards the end of the experiment (Schivelbein et al. , 1970). Although the calcium conhols of the aorta of nicotine-treated rabbits was increased, there were no differences in histological changes in the blood vessels between nicotine-treated and control rabbits. The rabbit has been the favaiite animal for experimental induction of atherosclerosis. The initial attempt of Wenzel et al. (1959) failed to establish an increase in severity of atherosclerosis in rabbits on a high cholesterol diet. Two other groups reported an increase in extent of dietary- induced atherosclerosis in nicotine-treated rabbits-one group from Chicago (Haas et al. , 1966a, 1966b, 1968; Landerholm et al. , 1967) and another group from Boston (Stefanovich et al. , 1969). The oxygen uptake of tissues from hypercholesterolemic rabbits has been reported to be more sensitive to the depressant action of nicotine than that of tissues from T10302-7266
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C. Acute and Chronic Effects of Nicotine - 30 Page 283 Aft fibrinolysin in the guinea pig by chronic administration of nicotine (Belli et al., ~ 1965), and nicotine-heparin antagonism when added to human blood in vitro (Singh and Oester, 1964a, 1964b). These observations suggest that nicotine influences coagulability by several mechanisms other than the release of epinephrine. ,x,.,TI0302-7 272
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X. Acute and Chronic Effects of Nicotine - 20 Page 273 Reprint LARSON R K, FUKUDA P and MURRAY J F: Systemic and pulmonary vascular _ effects of nicotine in anesthetized dogs. Am Rev Resp Dis 91: 556-564, 1965. 912 LAUBRY C, WALSER J and DEGLAUDE L: Action experimentale du tabac et de la nicotine sur le debit coronarien. Bull Acad Med Paris 109: 595-598, 1933. 913 LEADERS F E and LONG J P: Action of nicotine on coronary vascular resistance in dogs. Am J Physiol 203: 621-625, 1962. 914 LEB G, DERNTL F, ROBIN E and BING R J: The effect of nicotine on effective ` and total coronary blood flow in the anesthetized closed-cheat dog. . . J Pharmacol Exp Ther 173: 138-144, 1970. 915 MATHES P and RIVAL J: The effect of nicotine on regional blood flow in the canine heart. Proc Soc Exp Biol Med 138: 361-364, 1971. 916 NADEAU R A and JAMES T N: Effects of nicotine on heart rate studied by direct perfusion of sinus node. Am J Physiol 212: 911-916, 1967. 917 PACHINGER O, HELLBERG K D and BING R 3: The effect of nicotine, propranolol, phentolamine, and hexamethonium on the coronary microcirculation of the . cat. J Glin Pharmacol 12: 432-439, 1972. . 918 . PURI P S and BING R J: Influence of cardiovascular drugs on the force-velocity - relation of the intact heart. Physiologist 10: 285, 1967. 919 . PURI P S, ALAMY D and BING R J: Effect of nicotine on contractility of the intact heart. J Clin Pharmacol 8: 295-301, 1968. - . 920 RAKUSON K, de ROCHEMONT W M, HANLON J, BRAASCH W, TSCHOPP H ' and BING R J: Effect of nicotine and vasopressin on the terminal vascular bed of the heart. Clin Pharmacol Ther 9: 24-30, 1968. 921 RIVAL J and MATHES P: The effect of nicotine on the distribution of capillary flow in canine left ventrical. Circulation 40 (Suppl 3): 171, 1969. 922 ROSS G and BLESA M I: The effect of nicotine on the coronary circulation of dogs. Am Heart J 79: 96-102, 1970. .- 923 SCHWEIZER W, PLANTA PV, BATSCHELET E and PLETSCHER A: Tabak und Kreislauf. Cardiologia 36: 49-54, 1960. - 924 SOLTI F, ISKUM M, ZOLTAN E T, PAPP M and PREISICH P: Untersuchung der durch Nikotin verursachten Ekg- und Kreislaufveranderungen bei Menschen. Z Kreislaufforsch 53: 607-614, 1964. 925 TRAVELL J, RINZLER S H and KARP D: Cardiac effects of nicotine in the ' rabbit with experimental coronary atherosclerosis. Ann N Y Acad Sci • 90: 290-301, 1960. 926 VALORI C, INNOCENTI P F, SORBINI C A and SOLINAS E: L'azione della nicotina sulla portata cardiaca nel soggetto normale. Minerva Med . 55: 2162-2170, 1964. . 927 TI0302-1262
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X. Acute and Chronic Effects of Nicotine - 32 Page 285 Reprint SINGH J: Effect of nicotine on blood clotting time of albino rats fed atherogenic.diet. Arch Int Pharmacodyn 154: 221-227, 1965. 984 WENZEL D G and RICHARDS M H: Decreased thrombus formation in rats after chronic nicotine administration. Eur J Pharmacol 10: 143-144, 1970. . 985 _ WERLE E and SCHIEVELBEIN H: Activity of nicotine and inactivity of kaffikrein and kallidin in aggregation of blood platelets. Nature . 207: 871-87Z, 1965. 986 T10 30 2-1 2 74
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X. Acute and Chronic Effects of Nicotine - 27 Page 280 X-E. Experimental Hyperlipidemias Epinephrine is known to mobilize free fatty acids from fatty tissue and this was followed by elevation of cholesterol and triglycerides in the blood (Kaplan et al. , 1957; Sussman et al. , 1958). A similar response was noted to nicotine administration in dogs (White et al. , 1964; Kershbaurn et al. , 1965, 1967a, 1967b). There is also an accompanying elevation of blood glucose related to the release of epinephrine which has a glycogenolytic action (Tsujimoto et al., 1965; Milton, 1966). Hyperlipidemia induced in dogs by nicotine can be prevented by prior injection of adrenergic blocking drugs (Kershbaum et al. , 1966). Animals with hypercholesterolemia show an interaction with nicotine. The administration of nicotine and ergonovine produces necrosis in the heart (Wenzel et al. , 1961). Grosgogeat did not find lesions in the rabbit aortic wall with nicotine treatment alone (Grosgogeat et al., L965). There is a diminution in the rate of synthesis of cholesterol in dogs that have been subjected to chronic administration of nicotine (Gudbjarnason, 1968). The relationship of cholesterol to atherosclerotic lesions is discussed in the preceding section. _.-_-._.,-a,-TI0302-1269
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{. Acute and Chronic Effects of Nicotine - 29 Page 282 X-F. Experimental Thrombosis The release of epinephrine from the adrenal medulla has been known to increase the coagulability of the blood in vitro (Cannon and Gray, 1914; Cannon and Mendenhall, 1914a, 1914b). More recently, this phenomenon regarding epinephrine has been demonstrated by techniques involving experimental thrombosis (Rosewell et al., 1966) and platelet aggregation (Shimamoto and Ishioka, 1963; Ardlie et al. , 1966; Hampton and Mitchell, 1966; Besterman et al. , 1967). That nicotine releases epinephrine does not necessarily mean that all its reported effects on blood coagulation are mediated through this mechanism. Platelet aggregation results from the in vitro..addition of nicotine, which must a significant amo.int of act directly on the cells not containiug/epinephrine (Werle and Schievelbein, 1965). In the rat, the thrombosis induced by a single subcutaneous injection of carragenine and nicotine can be simulated by substituting'epinephrine for the nicotine (Jan et al. , 1969)= Chronic injection of nicotine in the same animal species caused decreased thrombus formation, indicating that there is no experimental support for the statement that habitual smokers are susceptible to thrombus formation (Wenzel and Richards, 1970). In rats maintained on a hypercholesterolemic diet, the administration of nicotine shortens coagulation time (Singh, 1965). In other species, nicotine has varied effects, such as: reduction of toxicity of nicotine injected intravenously by increasing the number of platelets by transfusion in rabbit (Schievelbein and Schirren, 1964), decrease of T10 30 2-1 271
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{. Acute and Chronic Effects of Nicotine -23 BIBLIOGRAPHY 0 X, CIRCULATORY EFFECTS OF NICOTINE C. Experimental Hypertension Page 276 Reprint AIITEE L and MATTILA M: Effect of ganglionic stimulants and sympatholytic ' drugs on white mice. Ann Med Exp Fenn 44: 388-394, 1966. . 931 ALBERTINI E, MARTINESI L and GANDINI A: Effects of nicotine poisoning on microcirculation: Comparative biomecroscopical, histological and histochemical researches. Biol Anat 9: 197-202, 1967. 932 BALOURDAS T A: Microvascular hyperreactivity to vasoconstrictor amines induced by nicotine. Fed Proc 25: 690, 1966. 933 BHAGAT B: Reduced accumulation of H3-norepinephrine (NE) and nicotine- - induced hypertension. Pharmacologist 10: 194, 1968. . 434 BHAGAT B, RUEHL A, RAO P,RANA M W and HUGHES M-J: Effect of . cigarette smoke on the cardiovascular system in dogs. Proc Soc Exp Biol Med 137: 969-972, 1971. ' 935 MARTZ R C, YOUKILIS F J, HARRIS P D, FORNEY R B and NICOLL PA: Effects of nicotine on the subcutaneous microcirculation of the bat. Proc Soc Exp Biol Med 133: 153-159, 1970. 936 RAKUSAN K, de ROCHEMONT W M, HANLON J, BRAASCH W, TSCHOPP H - and BING R J: Effect of nicotine and vasopressin on capillary blood flow and capacity of the terminal vascular bed. Med Pharmacol 17: . 119-128, 1967. 937 ROTTENSTEIN H, PEIRCE G, RUSS E, FELDER D and MONTGOMERY H: . Influence of nicotine on the blood flow of resting skeletal muscle and . " of the digits in normal subjects. Ann N Y Acad Sci 90: 102-113, . 1960. . . . , . _ . _ . 938 SAPHIR R and RAPAPORT E: Cardiovascular responses of the cat to . . - mesenteric intra-arterial administration of nicotine, cyanide and venous blood. Circ Res Z5: 713-724, 1969. 939 SOLTI F, PETER A, OLAH I, ISKUM M, REV J, HERMANN R and REFI Z: . The acute effect of nicotine on cerebral blood flow and cerebral venous pressure. Cor Vasa 5: 197-202, 1963. 940 SOLTI F., KRASZNAI I, REV J and NAGY J: II6er die akute wirkung des nikotins auf den extremitatenkreislauf. Acta Med Acad Sci Hung - 22: 325-334, 1966. - - 941 STROMBLAD B C R: Effect of intra-arterially administered nicotine on the blood flow in the hand. Br Med J 1: 484-485, 1959, 942 WENZEL D G, WATTANAPONGSIRI A and VEDRAL D: Nicotine and renal - hypertension in the rat. J Pharmacol Exp Ther 145: 315-316, 1964. 943 WHELAN R F: Alcohol, nicotine and man. Mcd J Australia 1: 77-83, 1968. 944 --^^T10302-1265
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:. Acute and Chronic Effects of Nicotine - 31 BIBLIOGRAPHY X. CIRCULATORY EFFECTS OF NICOTINE F. Experimental Thrombosis Page 284 Reprint ARDLIE NG, GLEWG and SCHWARTZ C J: Influence of catecholamines on nucleotide-induced platelet aggregation. Nature 212: 415-417, 1966. 971 BELLI C, ALBERTINI E, MARTINESI L and PELLEGRINIG F: Studio sperimentale di momenti dell'emocoagulazione e della fibrinolisi in corso d'intossicazione nicotinica cronica. Arch Sci Med 120: . 460-478, 1965. . 97Z BESTERMAN E, MYAT G and TRAVADI V: Diurnal variations of platelet stickiness compared with effects produced by adrenaline. Br Med J . 1: 597-600, 1967 ' 973 CANNON W B and GRAY H: Factors affecting the coagulation time of blood. II. The hastening or retarding of coagulation by adrenalin injections. Am J Physiol 34: 232-242, 1914. " . 974 CONNON W B and MENDENHALL W L: Factors affecting the coagulation time of blood. III. The hastening of coagulation by stimulating the aplanchnic nerves. Am J Physiol 34: 243-250, 1914a. 975 CANNON W B and MENDENHALL W L: Factors affecting the coagulation time of blood. IV. The hastening of coagulation in pain and emotional excitement. Am J Physiol 34: 251-261, 1914b. . . 976 JAN F, LACOTOT B and BEAUMONT J-L: Phenomene thrombo-hemorragique declenche par la nicotine. Patbol Biol 17: 501-504, 1969. , 977 HAMPTON J R and MITCHELL JR A: Effect of aggregating agents on the - electrophoretic mobility of human platelets. Br Med J 1: 1074-1077, 1966. 978 ROWSELL H G, HEGARDT B, DOWNIE H G, MUSTARD J F and MURPHY E A: Adrenaline and experimental thrombosis. Br J Haematol 12: . 66-73, 1966. . 979 SCHIEVELBEIN H and SCHIRREN V: Abschwachung der Toxizitat von Nicotin durch Erhohung der Thrombocytenzahl. Experienta 20: 432-433, 1964. 980 SHIMAMOTO T and ISHIOKA T: Release of a thromboplastic substance from arterial " walls by epinephrine. Circ Res 12: 138-144, 1963. . 981 SINGH 7 and OESTER Y T: Nicotine antagonism with heparin possible mode of action on human blood coagulation time in vitro.. Arch Int Pharmacodyn 149: 354-361, 1964a. . 982 SINGI-i J and OESTER Y T: Effect of nicotine on prothrombin time and its possible mode of action. . Arch Int Pharmacodyn 150: 435-441, 1964b. 983 ,.710 30 2-1 27 3
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X. Acute and Chronic Effects of Nicotine - 28 Page 281 BIBLIOGRAPHY X. . CIRCULATORY EFFECTS OF NICOTINE E. Experimental Hyperlipidemias Reprint GROSGOGEAT Y, ANGUERA G, LELLOUCH J, JACOTOT B and BEAUMONT J L: Intoxication chronique par la nicotine chez le lapin-nourri au cholesterol. . J Atherosclerosis Res 5: 291-301, 1965. . . . 959 GUBBJARNASON S: Effect of chronic nicotine administration on cholesterol metabilism of liver, serum, heart and brain. J Pharmacol Exp Ther 161: 47-54, 1968. 960 KAPLAN A, JACQUES S and GANT M: Effect of long-lasting epinephrine on , . serum lipid levels. Am J Physiol 191: 8-12, 1957. 961 KERSHBAUM A, BELLET S and KHORSANDIAN R: Elevation of serum cholesterol . after administration of nicotine. Am Heart J69: 206-Z10, 1965. 962 KERSHBAUM A, BELLET S, HIRABAYASHI M and FEINBERG L J: Regular, filter-tip, and modified cigarettes. JAMA 201: 545-546, 1967a. -. 963 KERSHBAUM A, OSADA H, SCIABINE A, BELLET S and PAPPAJOHN J: . Influence of nicotine on the mobilization of free fatty acids from rat . . adipose tissue in vitro and in the isolated perfused dog limb. _ ' Circulation 36 (Suppl 2): 20, 1967b. . . 964 . KERSHBAUM A, JIMINEZ J, BELLET S and ZANUTTINI D: Modification of . nicotine-induced hyperlipidemia by antiadrenergic agents. - J Atherosclerosis Res 6: 524-530, 1966. ~ - 965 MILTON A S: The effect of nicotine on blood glucose levels and plasma non- . esterified fatty acid levels in the intact and adrenalectomized cat. . Br J Pharmacol 26: 256-263, 1966. 966 SUSSMAN K E, SHAFRIR E and STEINBERG D: Mobilization of lipids by - . epinephrine. Circulation 18: 486, 1958. . 967 TSUJIMOTO A, TANINO S and KUROGOCHI Y: Effect of nicotine on serum potassium and blood glucose. Jap J Pharmacol 15: 415-422, 1965. 968 WENZEL D G, TURNER J A, JORDAN S W and SINGH J: Cardiovascular _ interaction of nicotine, ergonovine, and hypercholesterolemia in. the rabbit. Circ Res 9: 694-699, 1961. 969 WHITE H J, GORE I and LARKEY B J: The antagonism between nicotine and mucopolysaccharide activity. Biochim Biol Sperimentale 3: 107-116, 1964. 970 T10 30 2-1 27 0
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Ri. Carbon 1; ono,;idc - 3 Yaq[. blood levels for controls who were nonsmokers. The following generalizations can be made from the published results. a. The 30 investigations summarized in Table XI-A were per- formed in various cities in the United States and Europe. . The highest mean level is 16. 2% for a group of 6 U. S. Army enlisted men (Meigs,. 1948). This represents an error in the analysis, since the blood levels for nonsmokers were also high. All. the other mean levels were below 10% carboxyhemoglobin. b. The overall mean level for 2, 054 subjects reported in the 30 investigations is 3.76%. This represents the average blood level for smokers in the morning, 4 to 12 hours after they smoked a cigarette. c. The contribution of atmospheric pollution to the increased blood levels of carboxyhemoglobin can be derived by subtracting the blood levels for controls who were nonsmokers. Twenty-one of the investigations included nonsmokers, so that it was possible to subtract their mean levels from those of habitual smokers. The net difference between 2 groups repre- sents the contribution from smoking alone; which amounted to a mean of +2. 19% of carboxyhemoglobin for 2, 781 subjects. This mean value was calculated regardless of the number of cigarettes consumed. d. Ten investigators related the amount of cigarettes consumed daily to blood levels of carboxyhemoglobin. The consumption of 20 or less cigarettes per day showed the following net change in blood carboxyhemoglobin levels in each case: +1.6% (Schmidt, 1939); +2.4% (Schrenk, 1942); +2. 1% (Parmeggiani and Gilardi, 1952); +1. 0% (Goldsmith et al. , 1963); +1. 9% T10 30 2-1 27 7
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XI. Carbon Monoxide - 4 Page 289 (Curphey et al., 1965) +0. 3%a (Balbo et al. , 1966); and +0. 9% (Rouch et al., 1971). The net changes in blood carboxyhemoglobin levels for subjects consuming one or more cigarettes were respectively:; +Z.9% (Schmidt, 1939); +3.7% (Schrenk, 1942); +3. 5% (Parmeggiani and Gilardi, 1952); +1. 1% (Goldsmith et al. , 1963); +3. 6% (Curphey et al., 1965); +2. 0% (Balbo et al. , 1966); and +8. 0 (Yacoub et al. , 1970). The last-mentioned value represents the highest net level of carboxyhemoglobin, next to the +11. 0% referred to above as reported for the U. S. Army enlisted men. (Table XI-A appears on the next page; ) T10 30 2-1 27 8
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K. Acute and Chronic Effects of Nicotine - 19 . Page 272 BIBLIOGRAPHY X: CIRCULATORY EFFECTS OF NICOT'INE B. Experimental Coronary Insufficiency BELLET S, WEST J W and GUZMAN S V: Cardiac effects of intracoronary arterial injections of nicotine. Ann N Y Acad Sci 90: 156-160, 1960a. Reprint 899 BELLET S, WEST J W, MANZOLI U C, MULLER 0 R and ROSSI P: ' Effect of nicotine on the coronary blood flow in the presence of coronary insufficiency: An experimental study in dogs. Ann N Y Acad Sci . 90: 317-326, 1960b. 900 BING R J, WAYLAND H, RICKART A and HELLBERG K: Studies on the coronary rnicrocirculation by direct visualization. G Ital Cardiol 1: 401-408, 1971. .. ., 901 BOYLE M N, WEGRIA R, CATHCART R T, NICKERSON J L and LEVY R L: Effects of intravenous injection of nicotine on the circulation. Am Heart J 34: 65-79, 1947. . 902 CORBASCIO A N and WEST J W: Nicotine and smokixg on the dog ballisto- . -- cardiogram. Ann N Y Acad Sci 90: 249-258, 1960. - 903 CORSINI G C, PURI P S and BING R 3: Effect of nicotine on capillary flow and vascular bed of the heart in presence and absence of experimental coronary , .. a.rtery insufficiency. Fed Proc 27: 632, 1968. . , . . 904 DOCK W: Ballistocardiographic patterns and nicotine. Arch Intern Med 112: 467-475, 1963. . . . 905 / FOLLE L E, SAMANEK M and AVIADO D M:' Cardiopulmonary effects of tobacco and related substances. Arch Environ Health '12: 712-718, ~1966. 906 FORTE I E, WILLIAMS A J, POTGIETER L, SCHMITTHENNER J E, HAFKENSCHIEL J H and RIEGEL C: Coronary blood flow and cardiac oxygen metabolism during nicotine-induced increases in left ventricular work. Ann N Y Acad Sci 90: 174-185, 1960. . . 907 HELLBERG K, WAYLAND H, RICKART A L and BING R J: Studies on the coronary microcirculation by direct visualization. Am J Cardiol 29: 593-597, 1972. 908 JUIiASZ-NAGY A, SZENTIVANYI M, RACZ S and DEAK G: Coronary circulation of the avian heart., Arch Int Pharmacodyn 157: 360-378, 1965. - 909 . KAREVA G F: Effect of drugs on coronary circulation during experimental spasm of the cardiac vessels. Fed Proc 22: 866-868, 1963. 910 KIEN G A, LASKER N and SHERROD T R: Action of cigarette smoke on cardio- vascular hemodynamics. Fed Proc 16: 312, 1957. , 911 T10 30 2-1 261
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Carbon Monoxide - 16 Page 301 caused a decrease in exercise performance that initiated the onset of angina (Aronow et al„ 1972). The mean blood levels of carboxyhemoglobin in % were 1. 12 t 1. 20 before, 5. 08 ± 1. 19 immediately after leaving the freeway, and 2. 91 t 0. 93 two hours later. Any one of the pollutants other than carbon monoxide may be responsible for quicker development of angina after less cardiac work. Ten patients with angina pectoris were examined by Aronow and Rokaw (1971) and Aronow et al. (1971) following the smoking of low-nicotine cigarettes. After each subject had smoked 8 cigarettes, at the rate of one every 30 min, the carboxyhemoglobin level in the blood rose from 1, 58 to 7, 79%. This was accompanied by a decrease in exercise tolerance. The only direct proof would be to repeat similar observations on patients inhaling carbon monoxide mixture. De Bias et al. (1972) exposed dogs with myocardial.infarction to 100 ppm carbon monoxide for 14 weeks. The elevation of the blood carboxyhemoglobin level to 14% did not influence the electrocardiogram nor the serum enzymes that would be expected to accompany increasing severity of hypoxia. Carbon monox- ide alone, producing up to 14 %u saturation of carboxyhemoglobin, does not appear to exaggerate myocardial infarction in dogs. Exposure of rabbits for up to 14 months, resulting in a blood level of 15 to.40% carboxyhemoglobin, causes myocardial damage (Andersson, 1972). The effects of inhalation of 0. 1 or 5% carbon monoxide, sufficient to raise the carboxyhemoglobin level to between 5 and 25 % in dogs and humans, were reported by Ayres et al, (1969, 19701, There was an increase in coronary blood flow and alteration of lactate and pyruvate metabolism. Most of these changes would be accounted for by hypoxemia, although a direct effect of ~TI0302-1290
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Carbon Monoxide - 19 Page 30-1 effects, it is reasonable to suspect that this may also apply to the heart. The rabbit heart shows cardiac necrosis, which could be interpreted to be the result of hypoxemia rather than the direct effect of carbon monoxide (Veith, 1940). T10 30 2-1 29 3
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Carbon Monoxide - 23 XI-D. Experimental Atherosclerosis ~ associated with cigarette smoking has been reported, there have been repeated suggestions of cause and effect relationship. The facts are as follows: I. In patients with thromboangiitis obliterans or Buerger's disease, Page 308 Cigarette smoking causes vasoconstriction of most vascular beds. These effects are brought about by nicotine contained in the smoke. The carbon monoxide absorbed during smoking does not contribute to vascular effects. In animals, the pattern of action of carbon monoxide is vasodilatation with elevation of body temperature (Binet and Burstein, 1948; Coret and Hughes, 1964; Nielsen, 1971). In man vasoconstriction of the hand reflexly induced by cold is reduced by levels of 19 and 25 % carboxyheino.globin (Heistad and Wheeler, 1972). The influence of. carbon monoxide on capillary permeability has been investigated in humans and animals. In man, exposure to carbon monoxide for 8 days caused an increase in the permeability of the capillaries to albumin (Siggaard-Andersen et al. , 1969). The increase in permeability could not be demonstrated in the calf muscle (Petersen et al., 1968). In rabbits, guinea pigs and rats there is an increase in' permeability in the peri- toneal cavity (Gothert et al., 1970) and subcutaneous tissue (Van Liew, 1968 a and b, 1970). Although no specific case of arterial disease caused by carbon monoxide Astrup (1964) pointed out a connection between smoking and increased affinity of hemoglobin. Astrup (1966 a and b) and Astrup et aI.(1966) showed the increase in affinity for oxytien to be associated with carbon monoxide present T10 30 2-1 29 7
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Carbon D.,"unoxide - XI-C. Coronary Circulation and Myocardium t-age Dvv In recent years there has been an increasing number of publications associati,ng coronary heart disease with the carbon monoxide contained in cigarette smoke (Jaffe, 1968; Dinman, 1969; Robin et al. , 1969; Goldsmith, 1970; Szollosi et al. , 1970; Tibblin, 1971; Schievelbein and Eberhardt, 1972; Maryland and Bersay, 1972). The evidence for stating that the carbon monoxide content of cigarette smoke causes coronary heart disease is indirect. A review of the investigations concerned reveals that the levels of carboxyhemoglobin in unlikely to Y the blood of habitual smokers are / cause coronary heart disease. 1. Coronary circulation. The effect of exposure to lower concen- trations of carbon monoxide in high-pollution areas of Los'Angeles has been examined by Cohen et al. (1969). The case fatality rates for patients ad- mitted with myocardial infarction to'35 hospitals during 1958 were examined. The results indicate that there'was an increase in fatility rate in high-pollution areas and that this difference was evident during periods of relatively increased carbon monoxide pollution. However, it was not possible to prove cause and effect relationship between carbon monoxide and high fatality rate, since there are other pollutants involved. In the same city, Haywood et al. (1972) examined 34 patients with acute myocardial infarction and 35 control patients with diverse diseases. Carboxyhemoglobin levels averaged 5. 14% for the infarct patients and 4. 8% for the controls; there was no clear-cut relationship between carbon monoxide and acute infarction. For patients with angina pectoris, exposure to the heavy morning freeway traffic in Los Angeles '"~T10302-1289
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Carbon Monoxide - I0. Page 295 Xi-B. Influence of Smoking on Alveolar Air and Blood Levels of C;arboxYhem()TJ_obin Jongbloed (1939) analyzed the carboii-monoside content in alveolar air. A trace of carbon monoxide (about 0.0004°/0 or 4 prm) was detectable in the alveolar air of nonsmokers. In one smoker the content was 10 ppm in the morning before smoking. Then the subject was given 4 cigarettes, each one taking 12 min to smoke with an intervening 12=rriinute rest period. The results wcre as follows: before lst cigarette 14.0 ppm after " " 1?.9 " before 2nd " 19.4 " after " " 23.2 " after 3rd " 27.1 " after 4th " 31.5 " 32 min after 4th cigarette 29.0 " 52 min 26.6 " 72 min 23.1 " There was a progressive increase in the level of carbon inonoxidc in the alveolar air up to the end of smoking the 4th cigarette. Then a fall occurred in the concentration of carbon monoxide in the alveolar air. Other investigators have confirmed the observation of Jongbloed. Ringold et al. (19G2) analyzed the expired air after a 20-second brcath-holding period. The m ean t SD levels of carbon monoxid e wer e as follows: Nonsmokers (93 subjects) 0. 8 :L 4.7 ppm t Heavy smokers (4l1 subjects) 16. 4 t 12. 6" Light smokers (25 subjects) 7. 7 t 10. 9" Pipe or cigar (9 subjects) 3: 8 t 4.9 " Cohen et al. (1971) reported similar observations and correlated expired air levels of carbon monoxide with blood levels of ca.rboxyhemoglobin. The results of invcstigations relating to blood carboxyhcmoglobin T10 30 2-1 2 84
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Carbon Monoxide - 17 carbon monoxide on the coronary vessels has not been excluded. One of Page 302 the five subjects that inhaled 0. 14% carbon monoxide developed evidence of mild left-ventricular dysfunction (Ayres et al., 1965). 2. Cardiac output. Exposure to carbon monoxide resulting in carboxy- hemoglobin levels of 10% saturation does not influence cardiac output in sub- jects after a few hours (Brody and Coburn, 1969, 1970) or after 8 days (Klausen et al. , 1968). With levels exceeding 15% saturation, there is either an increase or a decrease in cardiac output (Diamant-Berger et al. , 1970; Katzschmann, 1970). The response of the heart to muscular exercise has been assessed during exposure to carbon monoxide. Guillern et al.(1907) exposed 12 subjects to a concentration of 50 to 100 ppm and noted an increase of cardiac acceleration during effort. Chevalier et al: (1963).previously reported a lower heart rate for exercising subjects exposed to carbon monoxide, but the concentration was not stated. Pirnay et al. (1971aand b) reported cardiac acceleration due to muscular exercise during exposure, with carboxyhemoglobin saturation of 15%, but no comparison was made with exercising subjects not submitting to carbon monoxide inhalation. Vogel and Gleser (1972) and Vogel et al. (1972) investigated blood levels as high as 20% saturation and failed to show a difference in cardiac out- put response, although there was an exaggerated tachycardia during exercise as compared with subjects not experiencing hypoxia. The pumping capacity of the heart is not influenced by carboxyhemoglobin blood levels of up to 20 %m Krumholz et al., (1964, 1965) reported a greater oxygen debt in smokers during exercise than nonsmokers, but there are no measurements of carboxyhemoglobin to explain the difference. The changes in heart function associated with cigarette T10 30 2-1 291
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Carbon Monoxide - 18 Page 303 smoking discussed by Roskamm (1964) and Anderson (1971) related to con- stituents of cigarette smoke other than carbon monoxide. 3. Myocardial effects in animals. The rat has been the laboratory ani- mal most extensively used to investigate myocardial effects of carbon monoxide. Asmussen and Paulsen (1953) exposed immature rats for 60 days to an atmos- phere containing carbon monoxide. The blood levels were kept at 50 to 60 % carboxyhemoglobin. Compared with control rats, the carbon-monoxide-treated rats were inferior in their ability to swim till exhausted and to withstand low oxygen tension. The carbon-monoxide-treated rats showed cardiac hypertrophy and a sligtt but significant increase in the relative number of coronary capillaries. Suzuki (1969) administered 1% carbon monoxide for 10 min to mature rats and the animals were sacrficed from 10 min to 24 hours after cessation of in- halation. The electron microscope examination of the heart revealed intra- cellular edema, swelling of mitochondria and sacroplasmic reticular, dis- ruption and reduction of cristae, disappearance of mitochondria, appearance of lipofuscin pigment granules and lysosomes'and increase of glycogen granules and fat droplets. The author concluded that the effects of carbon monoxide on the heart result not only from hypoxemia but also from the direct toxic effects on the specific respiratory enzymes. Holczabek (1971) arrived at a similar conclusion following exposure of rats to 3 % carbon monoxide. Slater (1950) demonostrated inhibition of dihydrocozymase oxidase of heart- muscle exposed to carbon monoxide in vitro. The direct effects of carbon monoxide on the monkey heart have not been investigated. Since there is a species difference relating to pulmonary T10 30 2-1 292
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Carbon Monoxide - 27 15age 312 Reprin CORET I A and HUGHES M J: A further study of hypoxic smooth muscle. Arch Int Pharmacodyn 149: 330-353, 1964. 1098 GIBBONS G F and MITROPOULOS K A: Inhibition of cholesterol biosynthesis , by carbon monoxide: Accumulation of Lanosterol and 24, 25-Dihydrolano- sterol. Biochem J 127: 315-317, 1972. 1099 GOTHERT M, LUTZ F and MALORNY G: Carbon monoxide partial pressure in tissue of different animals. Environ Res 3: 303-309, 1970. . 1100 HEISTAD D D and WHEELER R C: Effect of carbon monoxide on reflex vasoconstriction in man. J Appl Physiol 32: 7-11, 1972. 1101 HELLUNG-LARSEN P, LAURSEN T, KJELDSEN K and ASTRUP P: Lactate . , dehydrogenase isoenzyme of aortic tissue in rabbits exposed to carbon monoxide. J Atherosclerosis Res 8: 343-349, 1968. , 1102 HUEPER W C: Arteriosclerosis. Arch Pathol 38: 161-181; 245-285; 350-364, 1944. 1103 KJELDSEN K: Smoking and atherosclerosis. Investigations on the significance ' of the carbon monoxide content in tobacco smoke in atherogenesis. . Munksgaard, Copenhagen 1-145, 1969. 1104 . KJELDSEN K: Carboxyhemoglobin and serum cholesterol levels in smokers correlated to the incidence of occlusive arterial disease. Atherosclerosis Proceedings of the 2nd International Symposium, R. J. Jones (Editor), Springer-Verlag, New York, 378-381, 1970. .. 1105 KJELDSEN K: CO-eksposition og aterosclerosefrekvens. (Smoking and coronary disease. CO exposure and frequency of arteriosclerosis). Lakartidningen 67: 262-265, 1970. . - 1106 KJELDSEN K, ASTRUP P and WANSTRUP J: Reversal of rabbit atheromatosis . by hyperoxia. J Atherosclerosis Res 10: 173-178, 1969. 1107 KJELDSEN K, ASTRUP P and WANSTRUP J: Ultrastructural intimal changes - . in the rabbit aorta after a moderate carbon monoxide exposure. . Atherosclerosis 16: 67-82, 1972. 1108 1S.lELDSr.iv ri and r: iniluence oi proi-nged carooi. i~.onoxid~ vspoaure and altitude hypoxia on serum lipids in man. Scand J Clin Lab Invest 22 (Suppl 103): 16-19, 1968. 1109 KJELDSEN K and MO2ES M: Buerger's disease in Israel. Investigations on carboxyhemoglobin and serum cholesterol levels after smoking. . Acta Chir Scand 135: 495-498, 1969. . 1110 KJELDSEN K, WANSTRUP J and ASTRUP P: Enhancing influence of arterial hypoxia on the development of atheromatosis in cholesterol-fed rabbits. • . J Atherosclerosis Res 8: 835-845, 1968. 1111 MULIIAUSEN R, ASTRUP P and KJELDSEN K: Oxygen affinity of hemoglobin in patients with cardiovascular diseases, anemia and cirrhosis of the liver. Scand J Clin Lab Invest 19: 291, 1967. , 1112 T10 30 2-1 301
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Page 299 MeILVAINP. P M, NiCLSON W C and BARTLETT D,: Ton poral variation of earboxyhemogl•i'jin concentrations. Arch I•.nviron Hc•alth 19: 8 -91, 1969• ME1GS J 1Y : Carbon monoxide poisoning. Bull US Army 8: 542-6, 1948. • 1003 .7%MOTLEY 11 L: Environmental a & irpollution effect on pulmonary function. Acrosp Med 4 1 1.0Q 42: 1108-10, 1971. PARME• GGIANI L and GILARDI F : Rilievi sulla ossicarbonemia fisiologica. Med Lav 43: 1005 179-83, 1952. - ROUCH Y, RIOUFOL F and BOURI3ON P : Oxycarbonemic spontancc et apres exposition pen- t dant quclqucs minutes a une atmosphere a un pour mille d'oxydc de carbone chez 43 su- jets. jets. (Carbon monoxid"c content in blood: normal and after a few minute exposure to an atmosphere containing 0, I p. 100 carbon monoxide/13 subjects). Arch Mal Prof es lu f006 Paris 32: 2"71-$:, 1971. RUEL M 11 and BARTHE M R : Examen systematique de 132 ouvriers d'usincs a gaz avee do- sage du CO sanguin: Arch Mal Profes Paris 15: 234-5, 1954. 1007 RUHL A and LIN P : Zur frage der Kohlenoxydintoxikation bei starken Rauchern. Deutsch ~ 1008 Med Wschr 62: 493-7, 1936. - ~ . . SCHMIDT O; Der gasanalytischenachweis von Kohlenoxyd im Blut,i nbesondere bci Rau- ' 1009 chern. :Kliri IS schr 18: 938, 1939. . . SCHMIDT O: Der Kohlenoxydgehalt des Blutes bei 'Rauchern. (The CO content of the blood of smokers). Rcichs-Gesundhbl 15: 53-8, 1940. 1010 ®SCHRENK H H: Results of laboratory tests. Determination of concentration of carbon mo- " noxide in blood. US Pub Health Bull 278: 36-49, 1942. 1011 SIEVERS R F, EDWARDS T I MURRAY A L and SCHRENK H H: Effect of exposure to known c7oncentrations of carbon monoxide.• JAMA 118: 585-8, 1942. 1012 TRINDER P and HARPER F E: A colorimetric method for the determination of carboxyhaemo- n globin over a wide range of concentrations. J Clin Path: 15: 82-4, 1962. 1013 VALIC F and D.URIC D : Concentration of carbon monoxide in the blood of smokers and non- smokers. Arh Hir Rada(Jugoslav) 5: 49-56, 1954. 1014 WEISS E• B, SLAWSKY P and DESFORGES J F: Oxyhemoglobin affinity in chronic pulmonary granulomatosis (sarcoidosis) and fibrosis. Am Rev Res Dis 104: 694-702, 1971. . 1015 WENNESLAND R: Erfaringer fra kulloksyd-gengass-undersokclser hos norske sjafforer og arbeidere• (Experiences from carbon monoxzde -producer gas- investigations on . . Norwegian auto-drivers and workcrs)• Svenska Lakorliden 42: 397-408, 1945. 1016 YACOUB M, FAURE J, MALLION J M and CAU J: Peut-on determiner 1'origine tabagique de 1'oxycarbonisme chronique? (Is it possible to demonstrate chronic carbon monoxide '" intoxication specifically caused by smoking? )• Med Ler, I)omm Corpor ('i r.ris 3: 262-5, 1970. 1017 T10302-1288 :
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Carbon Monoxide - 21 Page 300' Reprin DIAMANT-BERGER F, GAJDOS P, RAPIN M and GOULON M: Aspects hemodynamiques de 1'intoxication oxycarbonee aigue massive humaine. (Hemodynamic aspects of acute massive carbon monoxide poisoning in humans). Eur J Toxicol 3: 211-226, 1970. 1060 DINMAN B D: Discussion. Toxicological appraisal of carbon monoxide. . . J Air Pollut Contr Assoc 19: 727-729, 1969. 1061 GOLDSMITH J R: Carbon monoxide research -- recent and remote. . Arch Environ Health Z1: 118-120, 1970. 1062 GUILLERM R, BADRE R and GAUTIER H: Effects du sejour dans une ' atmosphere a faible concentration d'oxyde do carbone sur les reactions . circulatoires et respiratoires a 1'effort musculaire et sur 1'acuite visuelle . nocturne. Biometeorology Tromp Pergamon Press, London 2: 306-313, 1967. . . - ~ .. ~ .-_.-114: 83-89, 1971. 1063 IiA.YWOOD L F, WALBERG C B, KERR F,MOHSENIN M and MOHLER J: ,. Carbon monoxide levels in acute myocardial infarction. J Na Med Assoc 64: 114-146, 1972. 1064 ~ HOLCZABEK W: Uber die zyanochrome myolinige Entmischung des Herzfleisches - nach Tod an Kohlenoxydvergiftung und nach Tod an Hypoxamie. (Cyanochrome myelin disintegration of the myocardium after death from . .. carbon monoxide poisoning and death from hypoxemia). Zentralbl All Pathol 1065 JAFFE N: Role of carbon monox-ide in coronary disorders. N Engl J Med -. 279: 111, 1968. 1066 KATZCHMANN R: DasHerz.-Kreislauf-System bei Schwererbeitenden (Physiologic-Pathologic-Prophylaxe).(Cardiovascular system in workers;- - •Physiology-Pathology-Prevention). Z Gesarnte Inn Med 25: 738-746, 1970. 1067 KLAUSEN K, RASMUSSEN B, GJELLEROD-H, MADSEN H and PETERSEN E:.Circulation, metabolism and ventilation during prolonged exposure to .... carbon monoxide and to high altitude. ScandJ.Clin Lab Invest 22 :.. (Suppl 103): 26-38, .1968. .. . _. . ~.... . . 1068 -KRUMHOLZ R A, CHEVALIER R B.and ROSS J C: Cardiopulmonaty function _ isyoung smokers. A comparison of pulmonary function measurements and Sotiie caruiupuill:u[iut'y LeaYuunca wwt;.uoc va....c,,. a ~: '1p Of . young smokers and a comparable group of nonsmokers. Ann Intern Med . 60: 603-610, 1964. . . , - . KRUMHOI.Z R A, CHEVALIER R B and ROSS J C: Changes in cardiopulmonary functions related to abstinence from smoking. Studies in young cigarette - smokers at rest and exercise at 3 and 6 weeks of abstinence. Ann Intern Med _----62: 197-207, 1965. . . . MARYLAND P and BERSAY C: De 1'intcret d'etre coronarien. (The advantage of being a coronary patient). Nouv Presse Mcd 1: 1097-1098,. 1972. . 1069 1070 1071 T10 30 2-1 295
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Carbon Monoxide - 22 Page 307 Reprint PIRNAY F, DEROANNE R, DUJARDIN J and PETIT J M: Exercise musculaire maximum sous intoxication oxycarbonec. (Maximal muscular exertion under carbon monoxide poisoning). J Physiol Paris 63: 87-88, 1971.1072 PIRNAY F, DUJARDIN J, DEROANNE R and PETIT:J M: Muscular exercise . during intoxication by carbon monoxide. J Appl Physiol 31: 573-575, 1971. 1073 ROBIN E, RAVENS K G and BING R.J: Die Wirkung von Alkohol, Nikotin und Zigarettenrauchen auf das llerz. (The effect of alcohol, nicotine and . cigarette smoking on the heart). Dtsch Med J 20: 19-29, 1969. .1074 - ROSKRAMM K: Vermindert das Rauchen die sportliche Leistungefahigkeit? ' (Does smoking lessen the capacity for athletic activity?). Med Klin 59: 591, 1964. • 1075 -SCHIEVELBEIN H and EBERHARDT R: Cardiovascular actions of nicotine and -. smoking. J Natl Cancer Inst 48: 1785-1794, 1972. 1076 SLATER E C: The succinic oxidase and dihydrocozymase oxidase systems in - . heart muscle and kidney preparations. Nature 165: 674-675, 1950. . 1077 SUZUKI T: Effects of carbon monoxide inhalation on the fine structure of the ." rat heart muscle. Tohoku J Exp Med 97: 197-211, 1969. - . 1078 . ..: n.._. . . - . - _ . . .. . . . .. . SZOLLOSI E, MEDVE F and JENEY E: Angaben zur Wirkung des niedrigen Kohlenmonoxyd-Gehaltes in der Luft aufden Menschen. (Data ontheeffect of a.low carbon monoxide content in the air on man). Z Arbeitsmed . 20: 263-268, 1970. 1079 _ ,...,,.. TIBBLIN G; Hjartinfarkt och rokning. (Harmful clinical effects of smoking. Myocardial infarct and smoking). Soc Med Tid 2: 65-67, 1971. ~. 1080 VEITH G: Experimentclle.Untcrsuchur,gcn zur Wirkung von Adrenalin auf den Herzmuskel. (Experimental investigations on the effect of epinephrine - . on cardiac muscle). Arch Kreislaufforsch 6: 335-360, . 1940. 1081 ':VOGEL J A and GLESERM A: Effect of carbon monoxide on oxygen transport - " -- . . . during exercise. J Appl Physiol 32: 234-239, 1972. . , .. 1082 VOGEL J A, GLESER M A, WHEELER R C and WHITTEN B K: Carbon monoxide and physical work.capacity. Arch Environ Health 24: .. 198-203, 1972. 1083 T10 30 2-1 29 6
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Carbon Monoxide - 31 Page 316 0 ~ 1964; Tkachenko et al. , 1966; Glass et al, , 1968; Kjeldsen and Damgaard, 1968; Bethlenfalvay, 1971a). The erythrocytes manifest some differences from normal erythrocytes in staining (Blackmore, 1970; Bethlenfalvay, 1971b), denaturation of hemoglobin (Perrelli et al. , 1970) and a change in the shift of the oxyhemoglobin dissociation curve to the left (Brody and Coburn, 1969). 2. In dogs, exposure to carbon monoxide increases hemoglobin concentration (Asmussen and Vinther-Paulsen, 1949). This change is re- garded as an important mechanism for tolerance of acclimatization to carbon monoxide (Otis, 1970). A similar increase in hemoglobin and the red cell count has been noted in other species, such as rabbits (Truhaut et al., 1968), rats (Ramsey, 1969), rhesus monkeys (Theodore et al., 1971), and squirrel monkeys (Jones et al. , 1971). 3. Cigarette smoking caused an increase in the red cell count and hemoglobin, whereas abstinence caused a fall in the content of these in humans (Eisen and Hammond, 1956; Pincherle and Shanks, 1967) and in hamsters (Reckzeh and Dontenwill, 1970). In another investigation in- volving smokers, the elevated hemoglobin and red cell count were correlated with carboxyhemoglobin levels (Petrovic, 1970). A shift in the oxygen dis- sociation curve to the left has been noted in cigarette smokers (Gutenkauf et al., 1967; Birnstingle et al„ 1967). 4. Patients suffering from myocardial ischemia with normal coronary arteriograms have been shown to have abnormal hemoglobin-oxygen dissociation T10 30 2-1 30 5
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Carbon ,vi nox1dL - BIBLIOGRAPHY . XL CIRCULATORY EFFECTS OF CARBON MONOXIDE C. Coronary Circulation and Myocardium . Reprin ANDERSSON A: A study of cardio-vascular alterations in animals exposed to . carbon monoxide during a long time. Opuscula Med 17: 203-209, . 1972. 1046 ANDERSON W H: Acute exposure to cigarette smoke as a cause of hypoxia. Chest 59: 33-34, 1971. . .1047 ARONOW W 5, DENDINGER J and ROKAW S N: Heart rate and carbon monoxide . _ level after smoking high-, low- and non-nicotine cigarettes. A study in . male patients with angina pectoris. Ann Intern Med 74: 697-702, 1971. 1048 ARONOW W S, HARRIS C N, ISBELL M W, ROKAW S N and. IMPARATO B: . Effect of freeway travel on angina pectoris. Ann Intern Med 77: 669-776, 1972, 1049 ARONOW W S and ROKAW S N: Carboxyhemoglobin caused by smoking non- . nieotine cigarettes. Effects in angina pectoris. Circulation 44: 782-788, 1971. 1050 ASMUSSEN E and PAULSEN N V: Cardiac hypertrophyy in CO-treated young rats . , .. and their ability to withstand stress. _Acta~Physiol Scand ~ 29: 307, 13, ~ ~ - - ~ 1953. 1051 AYRES. S M, GIANNELLI S Jr and ARMSTRONG R G: Carboxyhemoglobin . hemodynamic and respiratory responses to small concentrations. _ Science 149: 193-194, 1965. .. 1052 AYRES S M, GIAN£LLI S Jr and MUELLER H: Myocardial and systemic .. .. . . responses to carboxyhemoglobin, lil.n N Y Acad Sci 174: 268-293, - 1970. 1053 AYRES S M, MUELLER H S, GREGORY J J, GIANNELLI S and PENNY J L: -. . . Systemic and myocardial hemodynamic responses to relatively small _. ~ concentrations of carboxyhemoglobin (COHB).Arch Environ Health 18: 699-709, 1969. 1054 BRODY J S and COBURN R: F: Carbon monoxide-induced arterial hypoxemia. . . - Science 164: 1297-1298, 1969. . . . 1055 BRODY J S and COBURN R F: Effects of elevated carboxyhemoglobin on gas exchange in the lung. Ann N Y Acad Sci 174: 255-260, 1970. . 1056 CHEVALIER R B, KRUMHOLZ R A and ROSS J C: Effect of carbon monoxide . inhalation on the cardiopulmonary responses of nonsmokers to exercise. . -' J Lab Clin Med 62: 867,1963,- 1051 COHEN S I, DEANE M and GOLDSMITH J R: Carbon monoxide and survival from myocardial infarction. Arch Environ Health 19: 510-517, 1969. . 105E DeBIAS D A, BIRKHEAD N C, BANERJEE C M, KAZAL L A, HOLBURN R R, GREENE C II, HARPER W V, ROSENFELD L M, MENDUKE H, - WILLIAMS N and FRIEDMAN M il F: The effects of chronic exposure to carbon monoxide on the cardiovascular and hematologic systems in . dogs with experimental myocardial infarction. lnt Arch Arbeitsmed +n. oc1 ILp 1e77 T10302-1294
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Carbon Monoxide - 29 Page 314 Reprin VAN LIEW H D: Interaction of CO and O2 with hemoglobin in perfused tissue adjacent to gas pockets. USAF Aerospace .bfed 212-220, 1970. . 1125 WANSTRUP J, KJELDSEN K and ASTRUP P: Acceleration of spontaneous - intimal-subintimal chanoes in rabbit aorta by a prolonged moderate carbon monoxide exposure. Acta Pathol Microbiol Scand 75: , 353-362, 1969. 1126 WHEREAT A F: Is atherosclerosis a disorder of intramitochondrial respiration? Ann Intern Med 73: 125-127, 1970. . 1127 T10302-1303
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. Carbon Monoxide - 24 S . compared with normal smokers. The possibility that carboxyhemoglobin in- creases blood viscosity and therefore reduces the velocity of blood circulation and hastens the tendency to thrombus formation, has been excluded by measure- ments performed by Solvsteen arid Kristjansen (1968). 2. That exposure`to carbon monoxide could lead to atherosclero'sis was proposed by Hueper (1944) as part of his anoxemia theory. Astrup and his collaborators have attempted to find experimental support for this theory in cholesterol-fed rabbits - see reviews by Astrup (1967, 1969, 1970, 1972) and by Astrup and Kjeldsen (1970). The exposure to carbon monoxide enhanced the development of atheromatosis (Astrup et_al. , 1968, 1970 a and b). The develop- ment of the lesions was enhanced byhypoxia ani reversed by hyperoxia( Kjeldsen et al., 1968, 1969). The appearance of lesions was accompanied by elevation of serum lipid levels (Truhaut et al. , 1968; Astrup et al. , 1970 Kjeldsen, 1970a), change in lactate dehydrogenase isoenzymes of the aortic arch (Hellung-Larsen et al. , 1968), increased endothelia permeability (Wanstrup et al. , 1969), and ultrastructural intimal changes (Kjeldsen et al. , 1972). In human subjects exposed to carbon monoxide, an increase in capillary filtration rate (Siggaard- Andersen et al. , 1967) and elevation of serum lipid levels (Kjeldsen, 1970b) T10 30 2-1 29 8 ag~e 309 in tobacco smoke, since higher carboxyhernoglobin levels were observed in smokers with thromboangiitis obliterans than in healthy smokers. Mulhausen et al. (1967) confirmed this observation in another group of patients. Kjeldsen and Mozes (1969) and Kjeldsen (1969) noted in a third group of patients that the carboxyhemoglobin saturations and cholesterol levels are higher in controls. Birnstingl et al. (1966) demonstrated that patients with thromboangiitis obliterans did not show a greater alteration in oxygen affinity produced by smoking than did
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I Carbon Monoxide - 25 Page 31 0 ~ . have been demonstrated. It has been suggested that carbon monoxide in- hibits synthesis of cholesterol, leading to accumulation of lanosterol (Gibbons and Mitropoulus, 1972). Another effect of carbon monoxide is an increase in mitochondrial enzymic activity, which stimulates lipid synthesis within the artery (Whereat, 1970). Webster et al. (1968) aggravated atherosclerosis by carbon monoxide exposure in monkeys fed with cholesterol containing diet. It has not been possible to develop atherosclerosis in animals exposed to carbon monoxide without supplemental cholesterol feeding. 3. Examination of individuals who have been exposed to an environ- ment of up to l, 000 ppm carbon monoxide with carboxyhemoglobin levels of blood between 2 and 26% for an average duration of 10. 5 years did not re- veal any early development of arteriosclerosis (Prerovska and Drdkova, 1967 a and b; 1971). The average values of serum lipid levels did not exceed the normal range. The results of experiments on rabbits do not apply to epi- demiologic surveys in humans. T10 30 2-1 29 9
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Page 321 PART SIX PUBLICATIONS AND RECOMMENDATIOiVS XII. Secondary Publications on Smoking and Heart Disease XIII. Publications in Defense of Smoking XIV. Commentary on US Public Health Publications XV. Recommendations to.the Council for Tobacco Research The last group of sections is largely a commentary on the US Public Health Publications on "Smoking and Health. " Following the appearance of the first Surgeon General's Report in 1964, several secondary publications have appeared accepting the statement that smoking is causally related to coronary heart disease. There are only a few publications which challenge this statement. A list of recommendations to the Council for Tobacco Research concludes this report. T10 30 2-1 31 0
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Carbon Monoxide - 32 ® Page 317 (Likoff et al. , 1967; Eliot and Bratt, 1 969; Guy et al„ 1971 ). There is no evidence that these patients sustain carboxyhemoglobinemia, nor is the is- chemia associated with cigarette smoking. The above examples are clearly different entities. Cigarette smoking is included only in situation 3 and carbon monoxide 1 to 3. T10302-1306
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Carbon Monoxide - 30 XI-E. Blood Cells and Plasma ® The most consistent effect of the carbon monoxide component of cigarette smoking is the appearance of carboxyhemoglobin in the blood. The molecular basis for the formation of carboxyhemoglobin has been reviewed by Rossi-Fanelli and =tntonini (1958), Wittenberg and (1966) Keyes et al. (1967), Oski et al.(1970), Bunn / Jandl (1970) and Page 315 Brewer et al (1970, 1971 ) There is a change in oxygen-dissociation curve of blood of smokers (Gutenkauf et al. , 1967) and patients with acute myocardial infarction (Eliot and Mizukami, 1967). There is an increase in oxygen affinity of the hemoglobin presumably unrelated to carboxyhemo- globin. The consequences of the presence of carboxyhemoglobin to the circulat6ry system have been reviewed by Lilienthal (1950), Bartlett (1968), Goldsmith and Landow (1968), Grut et al. (1970) and DuBois (1970). Exposure to carbon monoxide causes an increase in platelet adhe- siveness in atherosclerotic patients (El -Ebrashy et al. , 1967) and in rab- bits (Birnstingl et al. , 1971). There is also an increase in fibrinolytic activity in patients suffering from carbon monoxide poisoning (El-Attar, 1968 a (Cii:ia"ia Four groups of situations are characterized by hematologic changes. They are as follows: - 1. Exposure to carbon monoxide in man causes an increase in the red cell and reticulocyte counts and the serum globulin fraction (Coscia et al.. T10 30 2-1 304
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Carbon Monoxide - 26 BIBLIOGRA PHY XI. CIRCULATORY EFFECTS OF CARBON MONOXIDE Page 311 D. Experimental Atherosclerosis ASTRUP P: An abnormality in the oxygen-disociation curve of blood from Reprin patients with non- specific myocarditis. Lancet 2: 1152-1154, 1964. 1084 ASTRUP P: Den Kliniske betydning af forskydninger i oksihaernoglobinets . dissociationskurve. Nord Med Stockholm 76: 1039-1041, 1966a. 1085 ASTRUP P: Haemmet iltafgift fra blodet og udviklingen af oblitererende . arteriesygdomme. (Impeded oxygen release from the blood and the development of obliterating arterial diseases). Ug Laeger 128: . . 701-706, 1966b. 1086 ASTRUP P: Carbon monoxide and peripheral arterialdisease. Scand J Clin Lab - Invest 93: 193-197, 1967. ---~ 1087 ASTRUP P: Effects of hypoxia and of carbon monoxide exposures on experimental . atherosclerosis. Ann Intern Med 71: 426-427, 1969. 1088- ASTRUP P: Karbeskadigende virkning af CO og hypoxi. (Smoking and coronary disease.Vessel injuring effect of CO and hypoxia).. Lakartidningen , 67:. 256-261, 1970. 1089 I ASTRUP P: Some physiological and pathological effects of moderate carbon _monoxideexposure. Br Med J 4: 447-452, 1972. . . . 1090 ASTRUP P, HELLUNG-LARSEN P, KJELDSEN K and MELLEMGAARD K: The effect of tobacco smoking on the dissociation curve of oxyhemoglobin. . Investigations in patients with occlusive arterial diseases and in normal subjects. Scand J Clin Lab Invest 18: 450-457, 1966. 1091 ASTRUP P, KJELDSEN K and WANSTRUP J: Enhancing influence of carbon monoxide on the development of atheromatosis in cholesterol-fed - rabbits. J Atherosclerosis Res 7: 343-354, 1967. . 1092 ASTRUP P, KJELDSEN K and WANSTRUP J: The effects of exposure to carbon monoxrae, iiypoxia and hyperoxia on tiie ueveiop:nent of experimeuiai . atheromatosis in rabbits. Atherosclerosis Proceedin!~s, 2nd International Symposium, R.J.Jones (Editor), Chicago, Springer-Verlag 108-111, 1970. 1093 ASTRUP P, KJELDSEN K and WANSTRUP J: Effects of carbon monoxide exposure on the arterial walls. Ann N Y Acad Sci 174: 294-300, 1970. 1094 ASTRUP P, PAULI H G, KJELDSEN K and PETERSEN C E: Introduction and general description of the study and of the procedures for prolonged exposure to carbon monoxide and hypoxia. Scand J Glin Lab Invest ' 22 (Suppl 103): 5-8, 1968. _ 1095 BINET L and BURSTEIN M: Intoxication par 1'oxyde de carbone et tonus des vaisscaux pcriphcriques. (Intoxication by carbon monoxide and peripheral vascular tone). C R Soc Biol142: 1487- 1488, 1948. 1096 BIRNSTINGL M A, COLE P J and HAWKINS L: Variation in blood oxygen dis- sociation with age, smoking, and Buerger's disease. Br J Surg 53: T10 30 2-1 30 0
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T;a.rbon Monoxide - 34 • - Page 319 Reprir EISEN M E and HAMMOND E C: The effect of smoking on packed cell volume, red blood cell counts, haemoglobin and platelet counts. Can Med Assoc J 75: 520, 1956. 1142 EL-ATTAR 0 A: Effect of carbon monoxide on the whole fibrinolytic activity. ' Ind Med Surg 37: 774-777, 1968a. 1143 EL-ATTAR 0 A: Effect of carbon monoxide on the whole fibrinolytic activity. J Egypt Med Assoc 51: 591-597, 1968b. 1144 EL-EBRASY N, EL-ASHMAWY S and ALY A: Effect of smoking on the index of platelet adhesiveness and blood blucose level in atherosclerotic patients. J Egypt Med Assoc 50: 157-168, 1967. 1145 ELIOT R S and BRATT G: The paradox of myocardial ischemia and necrosis in young women with normal coronary arteriograms. Relation to abnormal hemoglobin-oxygen dissociation. Am J Cardiol 23: 633-638, 1969. 1146 ELIOT R S and MIZUKAMI H: Oxygen affinity of hemoglobin in persons with acute myocardial infarction and in smokers. Circulation 34: 331-336, 1966. 1147 GLASS H J, GARRETA A C, LEWIS S M, GRAMMATICOS P and SZUR L: Measurement of splenic red-blood-cell mass with radioactive carbon monoxide. Lancet 1: 669-670, 1968. 1148 GOLDSMITH J R and LANDAW S A: Carbon monoxide and human health. Science 162: 1352-1359, 1968. 1149 GRUT A, ASTRUP P, CHALLEN P J R and GERHARDSSON G: Threshold limit values for carbon monoxide. Arch Environ Health 21: 542-544, 1970. 1150 GUTENKAUF J J, BRATT G T and ELIOT R S: Effect of cigarette smoking on the hemoglobin-oxygen dissociation curve. Circulation 36 (Suppl 2): i29, 1967. 1151 GUY C R, SALHANY J M and ELIOT R S: Disorders of hemoglobin-oxygen release in ischemic heart disease. Am Heart J 82: 824-832, 1971. 1152 JONES R A, STRICKLAND J A, STUNKARD J A and SIEGEL J: Effects on experimental animals of long-term inhalation exposure to carbon monoxide. ToxicolApp1 Pharmacnl 19: 46-53, 1971. 1153 KEYES M, MIZUKAMI H and LUMRY R: Equilibrium measurement in the reactions of -hemo-proteins with gaseous ligands. Anal Biochem 18: 126-142, 1967. . 1154 ELIELDSEN K and DAMGAARD F: Influence of prolonged carbon monoxide exposure , , and high altitude on the composition of blood and urine. Scand J Clin Lab _ Invest 22 (Suppl 103): 20-25, 1968. . 1155 LIKOFF W, SEGAL B L and KASPARIAN H: Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. N Engl J Med 276: 1063-1066, 1967. • 1156 T10302-1308
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X11. Secondary Publications - 2 XII. SECONDARY PUBLICATIONS ON SMOKING AND HEART DISEASE A. Review Articles . page 323 Reprint 1879 DECAISNE D E: Les femmes qui fument. Rev d'Hygiene Police Sanitaire 1: 914-922, 1879. . ' 1883 S 1 VALLIN E: Sur quelques accidents cause's par le tabac. Rev Hyg " 5: 223-237, 1883. S 2 1885 POTAIN : De 1'empoisonnement par le tabac. Sem Med 5: 159-160, 1885. S 3 1887 FAVARGER H: Chronische Tabakvergiftung und ihren Einfluss anf das - - Herz und den Magen. Wien Med Wochenschr 37: 324-326, 1887. S 4 1892 CHAPMAN W C: Tobacco as a cause of hypertrophy and dilatation of the _. heart: "The tobacco-heart" with a report of cases. Med News - 61: 733-735, 1892. . . S 5 1902 COUGHLIN R E: The use and abuse of tobacco. N Engl Med Month 323-326, 1902. ' S 6. 1905 BRUNTON L: The effect of tobacco in health and disease. Practitioner 75: 54-57, 1905. - S 7 1906 BRUNTON L: The effect of tobacco in health and disease. Med Exam Pract 16: 148-150, 1906. - - S 8- KAKOWSKl: Ueber den direkten Einfluss verschiedner Substanzen auf das Herz. Arch Int Pharmacodyn Ther 15: 21-139, 1906. S 9 1917 SIEBELT: Tabakmissbrauch in ursachlichem Zusammenhange mit Kriegsneurosen, vor allern des Herzens. Med Klin 13: 68-69, 1917. S 10 T10 30 2-1 31 2
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XII. Secondary Publications - 1 Page 322 XII. SECONDARY PUBLICATIONS ON SMOKING AND HEART DISEASE The publications listed in this section are secondary to those which describe the original investigations covered in preceding sections. Since 1864, there has been an increase in the number of publications accepting the Surgeon General's statement that smoking is causally related to coronary heart disease. The number of review articles, editorials, letters and special articles has increased so rapidly that the total number appearing since I970 approaches the number of articles appearing up to 1964. The total number at various periods is as follows: F. 1879-1949 1950-1964 1965-1969 1970-1973 Review articles (p. 323) 22 22 14 6 Special articles (p. 328) 1 14 29 17 Letters to the Editor (p. 332) 1 17 14 26 Editorials (signc3) (p. 336) - 14 14 6 Editorials (unsigned) (p. 339) - 14 18 15 Miscellaneous articles (p. 342) - - 23 7 Total number of articles 24 81 112 77 T10 30 2-1 31 1
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Carbon Monoxide - 33 ASMUSSEN E and VINTHER-PAULSEN N V: On the circulatory adaptations to arterial hypoxemia )Co-poinsoning). Acta Physiol Scand 19: 115-124, 1949. 1128 Reprin BARTLETT D Jr: Patbophysiology of exposure to low concentrations of Carbon Monoxide. Arch Environ Health 16: 719-727, 1968. - 1129 BETHLENFALVAY N C: Resistance of reticulocytes to oxidation by nitrite: A cytologic demonstration. J Lab Clin Med 77: 361-365, 1971a. 1130 BETHLENFALVAY N C: Cytologic demonstration of carboxyhemoglobin. Clinical and in vitro studies in man. J Lab Clin Med 77: 543-550, - 1971b. 1131 BIRNSTINGL M A, BRINSON K and CHAKRABARTI B K: The effect of short- term exposure to carbon monoxide on platelet stickiness. Br J Surg 58: 837-839, 1971. 1132 BIRNSTINGL M A, COLE P and HAWKINS L: Variations in oxyhemoglobin dissociation with age, smoking and Buerger's disease. Br J Surg 54: 615-619, 1967. 1133 BLACKMORE D J: Distribution of HbCo in human erythrocytes following inhalation of CO. Nature 227: 386, 1970. -- 1134 BREWER G J, EATON J W, GROVER R E and WEIL J V: Cigarette smoking as a cause of hypoxemia in man at altitude. Chest 59: 30-31, 1971. 1135 BREWER G J, EATON J V and GROVER R F: Studies'of red cell glycolysis and interactions with carbon monoYide, smoking, and altitude. Adv Exp Med Biol 6: 95-114, 1970. 1136 BRODY J S and COBURN R F: Carbon monoxide-induced arterial hypoxemia. Science 164: 1297-1298, 1969. .. 1137 BUNN H F and JANDL J H: Control of hemoglobin function within the red cell. N Engl J Med 282: 1414-1421, 1970. - 1138 CANDURA F and CRAVERIA: Valore e significato della fibrinolisi ncll'ossicar- bonismo sperimentale. (Degree and significance of fibrinolysis in experimental carbon monoxide poisoning). Rass Med Ind 33: 404-406, 1964. 1139 COS CIA Page 318 BIBLIOGRA PHY XI. CIRCULATORY EFFECTS OF CARBON MONOXIDE E. Blood Cells and Plasma G C, PERRELLI G, GAIDO P C and CAPELLARO F: Il comportamento - del glutatione del glutatione stabile e della glucosio-6-fosfato-deidrogenasi in soggetti esposti ad inalazione cronica d'ossido di carbonio. (The effect - of glutathione, stable glutathione and giucose-6-phosphate dehydrogenase in subjects exposed to chronic inhalation of carbon monoxi3e). Rass Mcd Ind 33; 446-451, 1964. 1140 DuBOIS A B: Establishment of "Chreshold" CO exposure levels. Ann N Y Acad Sci 174: 425-4Z8, 1970. . 1141 T10302-1307
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{II. Secondary Publications - 3 XII A: Review Articles 1921 BRIGHAM R 0: Heart failure and tobacco as an etiological factor. Ohio State Med J 17: 226-228, 1921. 1923 FURBRINGER: Uber die Schadigungen durch Tabakrauchen. Z Aerztl Fortbild 20: 697-703, 1923 . 1926 FURBRINGER: Zur Wurdigung der Gefahren des Tabakrauchens. Dtsch Med W ochenschr 52: 2021-2025, 1926. S 13 1929 JOHNSON . W M: Tobacco smoking: A clinical study. JAMA 93: .. 665-667, 1929. S 14 1930 PLENGE K: Tabakabusus und Koronarsklerose. Dtsch Med Wochenschr 56: 1947-1948, 1930. 1937 MIIQNI-IAAR T C: Rol patogene'tico del hurno del tabaco en las afecciones del aparato cardiovascular. Rev Med Roasario 27: 706-732, 1937. 1939 Page 324 Reprin S 11 5 12 S 15 S 16 HEAD J R: The effects of smoking. Ill_Med J 76: 283-287, 1939. . S 17 BRIESEMEISTER R: Vom Rauchen und vom fruhzeitigen Tod durch - Tabakmissbrauch. Med Welt 17: 759-762, 1943. S 18 KUTSCHERA-AICHBERGEN H: Genussgifte. Wien Klin Wochenschr 56: 46-49, 1943. . S 19 1944 'MARIS R: The facts about smoking. Hygeria 22: 740-741, 1944. S 20 1943 1946 ROSS P H and IVY A C: Tobacco smoking and coronary artery disease. . . 4 Bull Norwest Univ Med Sch 20: 424-440, 1946. 1949 S 21 VON AHN B: Elektrokardiogrammet vid tobaksrokning. Nord Med 41: 451-455, 1949. S 21 T10 30 2-1 31 3
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r; l Carbon Monoxide - 13 R epr i ARTURSON G, GARBY L, ROBER'1' M and ZAAR 13 : CbI1nL04 in carbon monor.idc content on f whole blood during gas cqui!ibration in the radiometer dissociation curve analyzer (DCA-1). Upsaln J:Sed Sci 77: 22-4, 197Z. 987 AYERS S 1.2, GIANNELLI S and ARMSTRONG R G: Carboxyhemoglobin: Hemodynamic and respiratory responses to small concenlraLions. Science 149: 193-4, 1965. 988 BALBO W, biARUCCI V and RONCHI G U : Les valcurs de 1'oxycarbonemic en differcntes . conditions individuelles et de milieu recherches preliminaires. (Values of blood car- bon monoxide under various individual and environmental conditions. Preliminary studies). Acta Med Leg Soc Liege 19:187-9, 1966. . 989 BARTISE R, PARIS J, DUCHEMIN M and THO~.SAS F: Valeur et interpreLition des taux d' . oxycarbonemie obtenus par la methode Nicloux-Endiometrie. Deuxieme note. - Oxy- carbonemie et intoxications exogenes: L oxycarbonemie des furneurs et des etltyiiqucs. Arch htal Profes Paris 14: 288-90, 1953. • 940 BHOWN A S, MAITRYA B B and HAQ I U: Blood carboxyhemoglobin level in Beedi smokers. Ind J. Med Res 57: 1313-5, 1969. 991 BREWER G J, EATON J}'d, WEIL J V and GROVER R F: Studies of red cell clycolysis and - interactions with carbon monoxide, smoking, and altitude. Adv Exp Med Biol 6: g5-114, Aft 1970. 992 BREWER G J, EATON J W, GROVER R F and WEIL J V : Cigarette smoking as a cause of . hypoxemia in man at altitude. Chest 59: 30S-1S, 1971. - 993 CURPHEY T J, HOOD L P and PERKINS N M: Carboxyhemoglobin in relation to air pollution and smoking. Arch Envi ron Health 10: 179-85, 1965. 994 S . - DAHLSTROMH,NORDSTROM-OHRBERG C and ROTHSCHILD A: The influence of tdbacco .' ' smoking and increased initial carbon monoxide concentration on results of Sjostrand's method of total hemoglobin determination. Acta Physiol Scand 42: 174-84, 1958. 995 GAENSLER E A, CADIGAN J B, ELLICOTT M F, JONES R H and MARKS A: A new method for rapid precise determination of carbon monoxide in blood. J Lab Clin Med 49: 945-57, -' . 996 1957. . GETTLER A 0 and MATTICE M R:. The "normal" carbon monoxide content of the blood. JAMA 100: 9Z-7, 1933. 997 GOLDSMITH a It, SCHUETTE-F and NOVICK L: Appraisal of carbon monoxide exposure from ' ' analysis of expired air. Ex Med 1ut Cong Ser 62: 9•18-52, 1963. ' 998 HANSEN 0, W ILKE H, MALORNY G and GOTHERT M : Absorption and release of carbon mo- .noxide durino breathing of low CO concentrations by smokers and nonsmokers. Chem . Abstr 77/6: 43-6, 1972. 999 % ., •~iARTRIDE, H:: CO in tobacco smoke. J Physiol Landon 53: L•:xxii-lxxxiii, 1919-1920. .1000 HOFREUTER D-I1, CATCOTT E J and XINTAR:IS C: Carboxyheinoglobin in men exposed to carbon monoxide. Arch Environ Hcaldt . . 4: B1-5, 1962. , . 1001 T10 30 2-1 28 7 Page 298 BIBLIOGRA PHY XI. CIRCULATORY EFFECTS OF CARBON MONOXIDE A. Carboxyhemoglobin Blood Levels
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PCII. Secondary Publications - 10 XII B: Special Articles FREDRICKSON D T: Cigarette smoking: Questions patients ask doctors. Chest 58: 147-151, 1970. LISZEWSKA D and MICHALSKI E: Czynnik ryzyka choroby wieacowej. . Pol Tyg Lck 25: 1140-1142, 1970. MUSHIN W W: The normality of the abnormal. Anesth Analg 49: 667-679, 1970. . TIBBLIN G and WILHELMSEN L: 1913 ars man - - rokare och icke- r8kare. L'$kartidningen 67: 278-281, 1970. 1971 BOSE A K: Economics and dangers of smoking. J Indian Med Assoc 56: 320, 1971. FLETCHER C M: Environmental hazards. The hazards of smoking. . Mod Med Gt Britain 16: 723-726, 1971. HEDRICK J L: The economic costs of cigarette smoking. HSIAHA Health Rep 86: 179-182, 1971. HIPSLEY E 14: Med J Australia 1: 1146, 1971. KEMP R: Patients and cigarettes. Practitioner 207: 215-220, 1971. MEIJLER F L: Arts en roken. Ned Tijdschr Geneeskd 115: 511-513, 1971. PUNSAR S: Tupakointi ja sepeivaltimotauti. Suom Laakarilehti 26: 27-32, 1971. TERRY L L: The future of an illusion. Am J Public Health 233-240, 1970. UDRY J R: A spoonful of sugar helps the medicine go down. Am J Public Hcalth- 61: 776-785, 1971. 1972 . BALL K H: Cigarettes and the prevention of heart disease. Rehabilitation 25: 17-20, 1972. SELTZER C C: Critical appraisal of the Royal College of Physicians' report on smoking and health. Lancet 1: 243-248, 1972. ® WYNDER E L and HOFFMANN D: Less harmful ways of smoking. J Natl Cancer Inst 48: 1749-1758, 1972. Page 331 S 113 S 114 S 117 T10 30 2-1 320
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KII. Secondary Publications - 4 Page 325 XIIA: ReviewArticles . Reprint 1950 MILLS C A: Tobacco smoking:Some hints of its biologic hazards. Ohio State Med J 46: 1165-1170, 1950. 1952 SCOTT R B: Some medical aspects of tobacco-smoking. Br Med J 1: 671-675, 1952. 1954 VAN REENEN J F: Tobacco: The effects of its use with special reference to the mouth and dental elements. A survey of the literature. J D A S A 9: 334-347, 1954. 1955 HEGGLIN R and KEISER G: Uber Rauchen und Coronarerkrankungen. Schweiz Med Wochenschr 85: 53-55, 1955. S 22 S 23 S 24 S 25 SIGLER L H: Tobacco as a contributing cause of degenerative coronary disease. N Y State J Med 55: 3107-3113, 1955. , S 26 1956 COFFIN G J: The effects of tobacco smoking. Bull N Y Acad Med 32: 133-156, 1956. . JOULES H: Tobacco and smoking. Postgrad Med J 32: 226-231, 1956. 1958 ROTH G M and SHICK R M: Effect of smoking on the cardiovascular system of man. Circulation 17: 443-459, 1958. -. 1959 KUMLIN T: Tupakan vaikutuksesta verenkiertoon seka kokemuksia - . tupakanieroitushoidosta. Duodecin 75: 1-9. 1959. - BRONTE-STEWART B: The relationship of smoking to ischemic heart disease. S Afr Med J 34: 511-512, 1960. MONASTERIO G: Un grave pericolo per la salute; il tabagismo. Riforna Med 74: 989-996, 1960. _ ROTH G M: Recent developments in the effects of smoking and nicotine on the cardiovascular system of man. Mod Concepts Cardiovasc Dis 29: 605-610, 1960. . . 1961 BRONTE-STEWART B: Cigarette smoking and ischemic heart disease. Clin Med 8: 1359, 1361-1362., 1364, 1961. _ . S 27 S 28 S 29 S 30 S 31 S 32 S 33 S 34 T10 30 2-1 31 4
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Secondary Publications XII D: Editorials (Signed) LITTLE D M Jr: Physician, heal thyself. Anesthesiology 35: 1-3, 1971. PAGE I H: A personal view on diet and atherosclerosis. Mod Med 39: 49-52, 1971. 1972 BENNETT J S: Smoking: Time to practice what we preach. Can Med Assoc J 106: 276, 278, 1972. Page 338 S 217 T10 30 2-1 32 7
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4,, Secondary Publications - 7 XII. SECONDARY PUBLICATIONS ON SMOKING AND HEART DISEASE B. Special A rticles Page 328 Reprint 1939 HARRIS S: Medical and public health needs and advice to young doctors. J Med Assoc Ala 8: 369-386, 1939. S 64 1951 MORRIS J N: Recent history of coronary disease. Lancet 1: 1-7, 1951. , S 65 1958 REID D D: The epidemiology of coronary disease. Practitioner 180: 184-190. 1958. S 66 1960 BLACKBURN H, BROZEK J, TAYLOR H L and KEYS A: Comparison of cardiovascular and related characteristics in habitual smokers and nonsmokers. Ann N Y Acad Sci 90: 277-289, 1960. S 67 1962 PRESCOTT F: The smoking problem in Britain. Appl Ther 4: .. 1018-1023, 1962. S 68 1963 WHITE P D: Heart disease -- a matter of concern to executives. , . . Arch Environ Health 6: 309-311, 1963. S 69 1964 ALIMURUNG M M: Conspirators of the heart. Santo Tomas J Med . 19: 290-292, 1964. S 70 BLAKE J M: Self-induced air pollution: smoking. N Y State J Med 64: 806-810, 1964. S 71 British Medical Journal: Deaths from smoking. 1: 451-452, 1964. '. S 72 36: 51-53, 1964. S 73 FLICK J B Jr: The cigarette smoking problem. Delaware Med J KANNEL W B: Cigarette smoking and coronary~heart disease. Ann Intern Med 60: 1103-1106, 1964. S 74 I T10 30 2-1 31 7
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Secondary Publications - 14 XII C: Letters to the Editor Page 335 Reprint HOWELL R W: Smoking and vascular disease. Br Med J 2: 232, 1972. S 175 HOWELL R W: Serum-cholesterol and smoking. Lancet 1: 931, 1972. S 176 REDGRAVE T G: Oh, Mr Snedden. Med J Australia 1: 196-197, 1972. S 177 SPITTLE C: Atherosclerosis and'Vitamin C. Lancet 1: 798, 1972. S 178 WAKEHAM H R R: Smoking and health. Lancet 2: 275-276, 1972. . S 179 1973 DALDERUP L M: Coffee drinking and acute myocardial infarction. Lancet 1: 104, 1973. S 180 ELKELES A: Coronary artery disease. Br Med J 1: 51, 1973. S 181 SELTZER C C: Smoking and coronary heart disease. N Engl J Med 288: 1186, 1973. S 182 YUDKIN J: Coffee drinking and acute myocardial infarction. Lancet 1: . . 211, 1973. . . S 183 T10 30 2-1 324
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Carbon Monoxide - 28 Page 313 Reprin NIELSEN B: Exercise temperature plateau shifted by a moderate carbon monoxide poisoning. J Physiol Paris 63: 362-365, 1971. 1113 PETERSEN F B, SIGGAARD-ANDERSEN J, KRISTENSEN J H and KJELDSEN K: _ Capillary filtration rate on the human calf during exposure to carbon . monoxide and hypoxia (3454m). Scand J Clin Lab Invest 22 (Suppl 103): - 49-54, 1968. . 1114 PREROVSKA I and DRDKOVA 5: Vliv chronickeho pusobeni kyslicniku uhelnatebo na biochemicke zmeny v seru vzhledem k ateroskleroze. (The eff+ct of chronic exposure to carbon monoxide on biochemical change in the blood with respect to atherosclerosis). Prac Lek 19: 1-4, 1967a. 1115 PREROVSKA I and DRDKOVA S: Vliv chronickeho pusobcni prumyslovych skodlivin na exponovane pracovniky vzhledem k rozvoji aterosklerozy. (Influence of the chronic action of industrial anoxious agents on exposed workers in relation to the development of atherosclerosis). Cas Lek Cesk 106: 754-759, 1967b. 1116 PREROVSKA I and DRDKOVA S: Der Einfluss der chronischen Einwirkung von Kohlenoxyd auf den klinischen Zustand und biochemische Veranderungen im Serum exponierter Personen in Hinsicht auf die vorzeitige Ent- wieklung der Atheroskler ose. (Influence of chronic action of carbon monoxide on the clinical status of biochemical changes in the serum of exposed persons on development of atherosclerosis with influence to the premature). Int Arch Arbeitsmed 28: 175-188, 1971. 1117 SIGGAARD-ANDERSEN J, KJELDSEN K, PETERSEN F B and ASTRUP P: A possible connection between carbon monoxide exposure, capillary - . . filtration rate and atherosclerosis. Acta Med Scand 182: 397-399, 1967. 1118 SIGGAARD-ANDERSEN J, PETERSEN F B, HANSEN T I and MELLEMGAARD K: Plasma volume and vascular permeability during hypoxia and carbon ' . monoxide exposure. Scand J Clin Lab invesi 22 (Suppl i03): 39-4fi, 1968. . 1119 SIGGAARD-ANDERSEN 7, PETERSEN F B, HANSEN T I and MELLEMGAARD K: - Vascular permeability and plasma volume changes during hypoxia and carbon monoxide exposure. Angiology 20: 356-358, 1969. 1120 SOLVSTEEN P and KRISTJANSEN P F: Carbon monoxide. blood viscosity and development of Buerger's disease. Z Kreislaufforsch 57: 790-792, 1968. 1121 TRUHAUT R, BOUDENE C and CLAUDE J R: Sur quelques reflets humoraux de Vintoxication chronique par Poxyde de carbone chez le Lapin. (On . . some humoral effects of chronic carbon monoxide poisoning in rabbits. .. Ann Biol Clin Paris 26: 1249-1260, 1968. 1122 VAN LIEW H D: Interaction of CO and 0, with hemoglobin in perfused tissue . adjacent to gas pockets. Res Physiol 5: 202-210, 1968. 1123 VAN LIEW H D: Coupling of diffusion and perfusion in gas er.it from subcutaneous pocket in rats. Am J PhKsiol 214: 1176-1185, 1968. . - 1124 T10 30 2-1 30 2
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---- -- - --- XII. Secondai y Publications - 8 Page 32 , 9 XII B: Special Articles Reprin. LEAMAN W G: Tobacco and heart disease: Is further research necessary? Pa Med J 67: 22, 1964. ' • 5 75 . OCAMPO OTERO A: Efectos perjudiciales del tabaco. Med Segruided Trabajo Madrid 12; 78-82, 1964. S 76 PLATT R: Public persuasion in health matters with particular reference to smoking. Proc R Soc Med 57: 449-458, 1964. S 77 WILENS S L: Relation of tobacco smoking to cardiovascular disease. Natl Conf Cardiovasc Dis 2: 360-361, 1964. S 78 1965 FARBER R E: Cancer deaths rise in 1964. Md State Med J 14: 81-82, 1965. S 79 KISTLER H J: Coronare Herzkrankheit und Zigarettenrauchen. . Schweiz Med Wochenschr 95: 436-437, 1965. -- S 80 NAHUM L H: Smoking and thrombosis. Conn Med 29; 853-854, 1965. S 81 RAVENHOLT R T: Cigarette smoking: Magnitude of the hazard. CA 15: 187-188, 1965. 5 82 SCHMIDT F: Zigarette und Lungenkrebs. Med Welt 35: 1948-1956, . 1965. S 83 WILLIAM-OLSSON L: Rokning och blodsocker. Lakartidningen 62: 3810-3811, 1965, . S 84 1966 BLOMSTRANDR and LUNDMAN T: Serum lipids and heredity. . Acta Med Scand Suppi 455: 51-60, 1966. .- S 85 HINKLE L E, BENJAMIN B, CHRISTENSON W N and ULLMANN D.S: Coronary heart disease. Arch Environ Health 13: 312-321, 1966. S 86 MULCAHY R: Public health aspects of cigarette smoking, with a note on public and professional attitudes, J Ir Med Assoc 58: 82-88, 1966. S 87 1967 BIENER K: Rauchen und Coronarsklerose. Schweiz Med Wochenschr . 97: 59-60, 1967. S 88 CHAPMAN J S: Smoking and health. Am Rev Resp Dis 96: 613-622, 1967. S 89 SIRTORI C: Analisi scientifica e sociale del fumo. Minerva Med 58: 299-300, 1967. . S 90 STUBER R V: Smoking -- where do we stand? Mich Med 66: 324, 329, 1967. S 91 T10 30 2-1 31 8
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I XII. Secondary Publications - 5 XII A: Review Articles Page 326 Reprin LUPU N G, POPESCU I and ENESCU V: Actiunea fumatului asupra aparatului cardio-vascular. Med Intern 13: 347-351, 1961. S 35 SACHDEV J R and WAHI P L: Tobacco and heart disease. Indian Pract 14: 717-723, 1961. S 36 1962 DELARUE N C: Cigarette smoking: A clinical and public health challenge. Can Med Assoc J 87: 961-969, 1962. S 37 HAMMOND E C: The effects of smoking. Sci Am 207: 39-51, 1962. 1.963 S 38 PAUL 0: Cigarette smoking and cardiovascular disease. Public Health News " 44: 223-224, 1963. S 39 1964 DOYLE J T: Tobacco and the circulation apparatus. Natl Conf Cardiovasc Dis 2: 361-362, 1964. . S 40 GIOVANELLI E: G1i effetti del fumo di tabacco sul cuore e sue possibili , influenze nell'insorgenza e nel decorso delle affezioni cardiache. Minerva Med 55: 1529-154Z, 1964. . . . . S 41 PAUN D: Tabak und Koronarinsuffizenz. Z Aerzfl Fortbild 58: 690-693, - 1964. 5 42 SCHIRGER A and SHICK R M: Tobacco in cardiovascular disease. Minn Med 47: 129-132, 1964. S 43 1965 CRAMER K: Rokning och coronarsjukdom. Lakartidningen 62: 2532-2540, 1965. - S 44 RAAB W: Origin, prediction and prevention of ischemic heart disease. J Circ J 29: 113-122, 1965. S 45 1967 ANSELMINO A and BOSCO M: Tabacco e cuore. Minerva Med 58: . 1298-1308, 1967. ' S 46 _KREYBERG L, DABLE T, POPPE E, EFSKIND L, PEDERSEN E, ELDJARN L, and DEVIK F: Tobakkroking og helse. Tidsskr Nor Laegeforen 87: 1007-1013, 1967. S 47 1968 ANONYMOUS: Il fumo di tabacco nei suoi aspetti dottrinali, clinici e sociali. Minerva Med 59: 2262-2264, 1968. S 48 DOYLE J T: Tobacco and heart disease. Postgrad Med 44: 188-191, 1968. " S 49 T10 30 2-1 31 5
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KII. Secondary Publications,- 9 Page 330 XII B: Special Articles Reprint 1968 CHIEF MEDICAL OFFICER OF THE MINISTRY OF HEALTH: Smoking and - health. In: On the State of the Public Health, Her Majesty's Stationery Office, Vol 1, pp. 241-245, 1968. . S 92 FISHER G R: Associated clinical societies. Delaware Med J 40: ' 364-365, 1968. 5 93 FREDRICKSON D T: How I help people stop smoking. Hosp Physician . 4: 52-56, 1968. ^ S 94 FODOR J T, GLASS L H and WEINER J M: Smoking behavior, cognitive . skills and educational implications. J School Health 38: 94-98, 1968. 'S 95 GREEN D E and HORN D: Physicians' attitudes toward their involvement . in smoking problems of patients. Dis Chest 54: 12-13, 1968. S 96 HARKEN D E: Smoking.... The masochistic massacre. Dis Chest . 54: 47-51, 1968. _ , -.S 97 OCHSNER A: Prevention of executive obsolescence. J Am Geriatr Soc 16: 1077-1082, 1968. S 98 PAUL 0: Smoking and youth. Ind Med Surg 287-288, 1968. - S 99 ORAM S: Smoking and ischaemic heart disease. Br Heart 3 30: _ - 145-150, 1968. S 100 PAUL 0: Stimulants and coronaries. Postgrad Med 44: 196-199, 1968. S 10'1 SCHUMANN L M: Epidemiology of sYnokfng related diseases which physicians encounter in their office practice. Dis Chest 54: 8-11, 1968. . S 102 TERRIS M: A social policy for health. Am 3 Public Health 58: 5-12, 1968. . . . S 103 1969 DLIN B M: The doctor, his emotions and his heart. Minn Med 52: 369-374, 1969. S 104 DOYLE J T: Cigarette smoking. The associated cardiovascular risk. Minn Med 52: 1311-1313, 1969. . S 105 `FOX W: A homeopath looks at coronary disease. J Am Inst Homeopath . . 62: 6-9, 1969. S 106 SACKETT D L: Cigarettes, alcohol, hospitals, and atherogenesis. Am Heart J 78: 423-424, 1969. S 107 1970 DIEHL H S: The physician and cigarette smoking. New Physician 19: - 231-234, 1970. S 108 T10 30 2-1 31 9
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Carbon Monoxide - 35 Page 320 Reprint LILIENTHAL J L Jr: Carbon monoxide. Pharmacol Rev 2: 324-354, 1950. 1157 OSKI F A, GOTTILIEB A J, MILLER W W and DELIVORIA-PAPADOPOULOS M: The effects of deoxygenation of adult and fetal hemoglobin on the synthesis of red cell 2, 3-diphosphoglycerate and its in vivo consequences. J Clin Invest 49: 400-407, 1970. 1158 OTIS A B: The physiology of carbon monoxide poisoning and evidencefor acclimatization. Ann N Y Acad Sci 174: 242-245, 1970. 1159 PERRELLI G, PREVOT P A and SULOTTO F: Recenti contributi in tema di patologia enzimatica del globule rosso nelle intossicazioni professionali. (Recent contributions on enzymatic pathology of the erythrocyte in occupational poisonings). Minerva Med 61: 2620-2625, 1970. 1160 PETROVIC D: Uvecanje broja eritrocita i kolicine hemoglobina u krvi pusaca. ~ (Increase in the number of erythrocytes and in the amount of hemoglobin in the blood of smokers). Med Glasnik 24: 470-473, 1970. 1161 PINCHERLE G and SHANKS J: Haemoglobin values in business executives. Br J Prev Soc Med 21: 40-42, 1967. 1162 RAMSEY J M: The immediate haematological response in the rat to experimental , exposure of carbon monoxide. J Physiol 202: 297-304, 1969. 1163 RECKZEH G and DONTENWILL W: Effects of cigarette smoke on hamsters. Arch Environ Health 20: 7-15, 1970. 1164 ROSSI-FANELLI A and ANTONINI E: Studies on the oxygen and carbon monoxide equilibria of human myoglobin. Arch Biochem Biophys 77: 478-492, 1958. 1165 TIIEODORE J, O.'DONNELL R D and BACK K C: Toxicological evaluation of carbon monoxide in humans and other mammalian species. J Occup Med 13: 242-255, 1971. ' - 1166 TKACHENKO Z A, TISHCHENKO A N, ZATSEPILIN A T and DIMITROVA E Z: External respiration and blood morphology in persons working in conditions . with an insignificantly increased concentration of carbon monoxide). Vrach Delo 12: 78-81, 1966. . 1167 . TRUHAUT R, BOUDENE C and CLAUDE J R: Recherches sur les effets de Vexposition prolongee du lapin et du rat a de tres faibles concentrations d'oxyde de carbone. Arch Mal Prof 29: 97-103, 1968. 1168 WITTENBERG J B: The molecular mechanism of hemoglobin-facilitated oxygen diffusion. J Biol Chem 241: 104-114, 1966. 1169 T10302-1309
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:II. Secondary Publications - : a2,c 32"; XHA: Review Articles . ' Reprin; DOYLE J T: Importance of dose response in terms of total cigarette smoke, "tar", and nicotine: Cardiovascular system. Natl Cancer Inst Monogr 28: 43-46, 1968. JAMES G: Summary: Highlights on smoking and the heart. Bull N Y Acad Med 44: 1559-1565, 1968. KOLL ER S: Lebensverkurzung durch Lungenkrebs und Kreislaufschaden . als Folge des Zigarettenrauchens. DA 4: 191-206, 1968. S 50 S 51 S 52 OETTEL H: Toxische Gefasschaden und Durchblutungsstorungen. Kippokrates 8: 285-295, 1969. S 53 SANTRU EK M and VACEK M: Kouienii a ischemicka choroba srde~ni ve sv6tle epidcmiologickych studii. (Smoking from the aspect of epidemiological investigation). Cas Zdrav 16: 66-75, 1968. S 54 1969 " DOYLE J T: Smoking and myocardial infarction. Circulation 39-40 (Suppl 5): 136-143, 1969. S 55 FITZGERALD p: Arterial disease and tobacco. _Anesth Analg 48: . 412-417, 1969. S 56 SCHWEIZER W: Die medizinische Behandlung der koronaren Herzkrankheit. Dtsch Med Wochenschr 94: 2646-2649, 1969. S 57 1970 FLETCHER C M and HORN D: Smoking and health. WHO Chron 24: 345-370, 1970. S 58 GODBER G E: Smoking disease: A self-inflicted injury. Am J Public Health 60: 235-242, 1970. S 59 1971 JAN F and GROSGOGEAT Y: Tabac et coronaires. Vie Med 52: 3019-3026, 1971. S 60 SWARTZ H: Tobacco smoke: A noxious air pollutant. Rev Allerg 25: 397-405, 1971. S 61 1972 HAY D R: Smoking and health: The.1972 situation. N Z Med J 76: 4-12, 1972. S 62 SCHIEVELBEIN H and EBERHARDT R: Cardiovascular actions of nicotine and smoking. J Nat1 Cancer Inst Monogr 48: 1785-1794, 1972. S 63 0 T10 30 2-1 31 6
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r, XII. Secondary Publications - 12 XII C: Letters to the Editor 1964 ANONYMOUS: Smoking and the heart. Br Med J 2: 296, 1964. RAVENHOLT R T: Cigarette smoking: Magnitude of the hazard. Am J Public Health 54: 1923-1926, 1964. . WAKELEY C: Deaths from smoking. Br Med J 1: 1634, 1964. 1965 DORMANDY T L: Abnormal oxygen-dissociation curves. Lancet 2: 80-81, 1965. RICHARDSON R D, WALKER A R P and WALKER B F: Glycosuria and coronary heart-disease. Lancet 2: 594-595, 1965. ROTHERMICH N 0: Work after a "coronary". Br Med J 1: 860, 1965. WILLIAM-OLSSON L: Smoking and platelet stickiness. Lancet 2: 908-909, 1965. 1966 BURGH P R J and ROWELL N R: Smoking and atherosclerosis. . Br Med J 1: 1050-1051, 1966. Page 333 Reprin S 14 S 1 -S 14 S 1 S 14 S 14 S 1 S 14 SZANTO S: Smoking and atherosclerosis. Br Med J 1: 984, 1966. S 14 1967 SALTER A J: The anti-coronary club. Lancet 1: 336, 1967. S 14 SZANTO S: Smoking and atherosclerosis. Br Med 3 3: 178, 1967.. S 15 1968 ASHER R: Trial of unsaturated-fat diet. Lancet 2: 1191. 1968. S 15 GRANT B J B: The nicotine habit. Lancet 1: 645, 1968. S 15 LACY B S: Smoking and the coronary arteries. Am Med Assoc 204: 1009, 1968. S 15 MAGNUSON W G: Smoke screen. 55: 1102, 1968. S 15 1969 DENHAM R M: Smoking and the coronary circulation. GP 39: 129, 1969. S 15 WALKER A R P: Sugar intake and coronary heart disease. Lancet 2: 1071, 1969. S 15 T10302-1322
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Secondary Publications - 21 ' XII. SECONDARY PUBLICATIONS ON SMOKING AND HEART DISEASE C. Letters to the Editor .. rnKc :»r. Reprin 1934 BLUMER G: The relation of the use of alcohol and tobacco to coronary ' occlusion. JAMA 102: 1177, 1934. S 125 '1951 . PARNELL R W: Smoking and cancer. Lancet 1: 963, 1951. S 126 1953 LEVY R L, KNIGHT G F, MYERSON M C and ROSEN F L: Effects .. of tobacco smoking. Mod Med 21; 120-IZ1, 1953. S 127 1955 OLBERT T: Smoking and the heart. Lancet 2: 1041, 1955. S 128 1958 FISHER R A: Lung cancer and cigarettes? Nature 182: 108, 1958. S 129 1960 ACHESON R M:. Atherosclerosis and coronary heart disease. Lancet 2: 706, 1960. 5 130 CHARTERS A D and ARYA B P: Incidence of ischaemic heart disease among Indians in Kenya. Lancet 1: 288-289, 1960. S 131 - RIGDON R H: The smoking controversy. JAMA 173: 293-295, 1960. S 132 1962 GARLAND L H: Smoking and health. N Engl J Med 267: 627-628, 1962. S 133 .HECHT S D: Cause and effect. N Engl J Med 267: 312, 1962. - S 134 HUGHES J P W: Civilisation and peptic ulcer. Lancet 1: 322, 1962. S 135 . LUKE E: Addiction to mentholated cigarettes. Lancet 1: 110-111, 1962. S 136 RIGDON R H: To the editor, lnd Med Surg 31: 235, 1962. S 137 1963 OPSTAD E T: Smoking and heart disease. N EnFl J Med 268: 903, ' 1963. S 138'~ T10 30 2-1 321
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XII. Secondary Publications - 15 XII. SECONDARY PUBLICATIONS ON SMOKING AND HEART DISEASE D. Editorials (Signed) 1957 . WHITE P D: The patient leads the way. Dis Chest 32: 368-376, 1957. 1958 Page 336 Reprint S 184 FORBES J: Danger! Doctors at work. Lancet 2: 1226-1227, 1958. S 185 . 1962 NAHUM L H: Smoking and physiological age. Conn Med 26: 593-594, 1962. S 186 PEABODY J W Sr: Role of cigarette smoking in the causation of disease. - Med Ann 31: 702-703, 1962. S 187 KOSHY M C: Diet and vascular disease. ' 437-439, . 1962. . . S 189 RENTCHNICK P: Is tobacco harmful? Appl Ther 4: 926-927, 1962. 1963 S 189 ALVAREZ W C: Smoking and heart disease. Geriatrics 18: 879. 1963. . S 190 DOCK W: The ballistocardiographic smoking test. JAMA 186: - - 509-510, 1963. S 191 MacDONALD I: Physicians -- not physicists. Bull Los Angeles Coll Med Assoc 5, 1963. . , S 192 OVERHOLT R: Observations on smoking. N Engl J Med 268, 54, 1963. S 193 1964 CARRUTHERS W: Hazards of smoking. Nature 203: 221-222, . 1964. S•194 FLASER L F: More on smoking and health. Chemistry 18-19, 1964. S 195 COOKE A: Cigarettes -- The final indictment. C,A 14: 35-36, 1964. S 196 HISLOP H J: That cloud d smoke. J Am Phy'•Ther Assoc 44: 155, • 1964. ~ +~+ T10302-1325
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Secondary Publications - 16 Page 337 XII D: Editorials (Signed) . Reprint 1967 HAMMOND E C: Intelligent debate or demented fiddling? Can Med Assoc J g6: 679-680, 1967. S 198 PAGE I H and ALVAREZ W C: Cigarettes and the ambivalent American. - Mod Med 35: 59-61, 1967. , . S 199 VELA J E: Tabaquismo y corazon. Arch Inst Cardiol Mex 37: -- 539-540, 1967. S 200 1968 ABELSON P H: Changing attitude toward smoking. Science 161: ' 319, 1968. S 20I PAVITT L: Cigarettes (Health hazards). R Soc Health J 88: 223, - 1968. 5 202 REID D D: Smoking and the heart. Health 5: 176-177, 1968. S 203 SCHATTENBERG T T: Exercise -- The heart and the doctor athlete. . Minn Med 51: 1577, 1968. . - 5 204 1969 ADAMS S I: The stresses of urban living. Health 19: 12-15, 1969. ADAMS C W: Prevention by aggression. Dis Chest 55: 95-96, . 1969. ANONYMOUS: Serum-uric-acid and coronary heart-disease. Lancet 1: S205 S206 358, 1969. - - S 207 CARTER L J: Smoking and health: Closing the ring on the cigarette. Science 164: 1258-1261, 1969. S 208 . DIEHL H S: Opportunity unlimited. Minn Med 52: 699-701, 1969. . S 209 MUELLER M: Anti-smoking forces gain ground. Science 165: 569, 1969. S 210 I OETTEL H: Krebsgefahrdung durch Rauchbestandteile? Med Klin 64: 463-464, 1969. S 211 1970 GREENBERG S R and WHEREAT A F: Atherosclerosis and mitochondria. Ann Intern Med 73: 861-862, 1970. S 212 1971 ADAMS F H: Prevention of coronary disease -- Let's begin with the children! Am J Cardiol 28: 745, 1971. S 213 LISTER J: Smoking and health now. N Engl J Med 284: 656-657, 1971. S 214 T10 30 2-1 32 6
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XII. Secondary Publications - 20 XII E: : Editorials 1971 Medical Journal: , Coronary deaths. 4: 64, 1971. S255 British Medical Journal: World action on smoking. 4: 64, 1971. S 256 British Medical Journal: The smoking disease. 1: 61-62, 1971. S 257 Journal of the American Medical Association: Exercise and the heart. 215: 974-975, 1971. S 258 Journal of the American Medical Association: Prevention of CHD: The fat's in the fire. 215: 1813, 1971. S 259 Iancet: Counterblasts to tobacco. 1: 69-70, 1971. . S 260 New Zealand Medical Journal: The coronary problem. 74: 332-335, 1971. S 261 1972 . British Medical Journal: Predicting coronary artery disease. 4: 3, 1972. S 262 - British Medical Journal: Smoking and vascular disease. 2: 3-4, 1972. S 263 Canadian Medical Association Journal: Smoking and health. 106: 313, 1972. S 264 1973 American Journal of Clinical Nutrition: Diet and coronary heart disease. . 26; 53-54, 1973. S 265 Page 341 (Unsigned) - Reprin T10302-1330
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~IL Secondary Publications - 19 Page 340 XII E: Editorials (Unsigned) Reprint Journal of the American Medical Association: The martyred meal. 198; 1362-1363, 1966. S 236 1967 1968 Boletin de la Association Medica de Puerto Rico: Cigarette smoking and health characteristics. 59: 293-295, 1967. S 237 Food and Cosmetics Toxicology: The scourge of the tobacco industry. 6: 797-799, 1968. S 238 Journal of the Medical Association of Georgia: Coronary heart disease and smoking. 58: 440, 1968. S 239 Medical Journal of Australia: Social status and coronary heart disease. 2: 635-636, 1968. S 240 Medical Officer: Royal institute of Public Health and Hygiene conference, . . Bristol. 120: 187-190, 1968. S 241 adelphia Medicine: Cigarette smoking -- A call to arms. 64: 587, 1968. S 242 1', :9 American Journal of Public Health: Life styles in the prevention of coronary heart disease. 59: 1568-1569, 1969. . S 243 1970 British Medical Journal: Menace of smoking. 3: 753-754, 1969. S 244 British Medical Journal: Coronary disease and competitiveness. 1: 1-2, 1969. S 245 Lancet: More effects of cigarettes. 1: 1012-1013, 1969. S 246 Lancet: Blood-groups and serum-cholesterol. 2: 625, 1969. S 247 Medical Journal of Australia: Smoking and health. 1: 84, 1969. S 248 Public Health Report: Smoking and health. 83: 225, 1968. S 249 Circulation: Some problems. 41 (Suppl 1): 184-185, 1970. - S 250 Lancet: The longshoreman`s life. 2: 87, 1970. S 251 Lancet: Medical Journal of Australia: Myocardial infarctioii andberebrovascular accidents. 2: 1106, 1970. ' S 253 Medical Journal of Australia: To smoke or not to smoke. 1: 346-347, 1970. S 254 T10302-1329
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~II. Secondary Publications - 21 • XII. SECONDARY PUBLICATIONS ON SMOKING AND HEART DISEASE F. Miscellaneous Articles Page 342 Reprint 1963 Journal of the American Medical Association: Cigarette smoking and blood lipids. 184: 201-202, 1963. . , S 266 Medical Science: Cardiology. 13: 720, 722, 1963. Coronary disease in young people. . S 267 1964 Pennsylvania Medical Journal: 67: 36, 1964. Predisposing factors in coronary heart disease. S 268 Pennsylvania Medical Journal: 67: 24, 1964. Pulmonary emphysema and the heart. S 269 1965 Medical College of Virginia Quarterly: Panel on atherosclerosis. . 1: 36-39, 1965. S 270 Quarterly Journal of Medicine: 34: 484, 1965. - S 271 1966 Journal of the Medical Association of America: Smokers' blood clots more rapidly. 197: 36, 1966. S 272 - Journal of the Medical Association of America: Coronary disease prognosis sought from 100,000 persons. 197: 46-47, 1966. S 273 Pennsylvania Medicine: Public health aspects of heart disease. 66: 41, 1966. S 274 1967 El Dia Medico: La costumbre de fumar. 265, 1967. S 275 1968 British Medical Journal: Smoking habits. 1: 64-65, 1968. - . S 276 Bulletin of the Los Angeles City Medical Association: Smoking and chronic . bronchopulmonary disease. 98: 57-58, 1968. S 277 Bulletin of the Los Angeles City Medical Association: The health consequences of smoking. A public health review: 1967. 1-2, 1968. . S 278 Disease of the Chest: Formal recommendations of the National Forum on office management of smoking problems. 4-5, 1968. S 279 I T10 30 2-1 331
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Page 347 XIV. COMMENTARY ON US PUBLIC HEALTH PUBLICATIONS After the text of this review article was completed, the seven volumes relating to "Smoking and Health" issued by the Surgeon General was examined. The pages relating to cardiovascular disease are reproduced on yellow paper and commentaries appear on the succeeding pages. It can be noted that there are differences in interpretation of the state of knowledge at the time the Surgeon General's Reports appeared in 1964, 1967, 1968, 1969, 1971, 1972, and 1973. Commentary starts on page 1964 The Health Consequence of Smoking pp. 315-334 348 1967 Smoking and Health pp. 45-86 356 1968 Smoking and Health pp. 15-61 372 1969 Smoking and Health pp. 9-134 394 1971 Smoking and Health pp. 15-134 405 1972 Smoking and Health pp. 11-34 460 1973 Smoking and Health (draft available) 471 T10 30 2-1 33 5
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'!I. Secondary Publications - 22 Page 343 XII F: Miscellaneous Articles . Reprint Hospital'Medicine: Axioms on coronary heart disease. 4: 71, 1968. S 280 Missouri Medicine: Miscellany. 65: 711-71Z, 1968. S 281 1969 British Heart Journal: Dietry sugar intake and ischaemic heart disease. 31: 792-793, 1969. S 281 British Medical Journal: Cigarette advertising. 2: 833, 1969. S 282 El Dia Medico: Las enfermedades de la civilizacion. 856, 1969. S 283 Journal of the American Medical Association: Call for cigarette curbs. 210: 2293, 1969. S 284 Journal of the American Medical Association: Researchers say smoking . causes aortic atherosclerosis. 207: 664-666, 1969. S 285 Medicina Sociale: Congressi e riunioni di interesse medico-sociale. 19: 73-74, 1969. S 286 Pediatria de Actualidad: Aterosclerosis en Pediatria. . 1969. S 287 1970 . British Medical Journal: Labelling of cigarette packets. 1: 312, 1970. S 288 Canadian Medical Association Journal:. No smoking signs at WHO Headquarters. 102: 996, 1970. S 289 Journal of the American Medical Association: The good life and long life just may go together. 214: 1636, 1970. .. S 290 1971 Schweizerische Medizinische Wochenschrift: Xrzte als Zigarettenraucher 101: 1420-1421, 1971. - S 291 1972 Journal of the American Medical Association: Psychiatrists shrink from giving up cigarettes. 219: 823, 826-828, 1972. S 292 Journal of the American Medical Association: Carbon monoxide linked to .. heart disease. 221: 456-457, 1972. , S 293 I Modern Medicine: Heart research offers a boost for exercise -- and a warning. 40: 26, 28, 1972. - - S 294 T10302-1332
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. - ._ ...-- ---- .. -~ Secondary Publications - 13 XII C: Letters to the Editor Page 334 - Reprint 1970 BALL K: Hospital beds and cigarette smoking. Lancet 2: 48, 1970. S 157 DAYTON S and PEARCE M L: Diet and atherosclerosis. Lancet 1: '473-474, 1970. S 158 1°AFFENBARGER R 5: Occupational preselections. N Engl J Med 283: 100, 1970. . ' S 159 YUDKIN 3: Sugar, cigarettes, and heart-disease. Lancet 1: 1111, 1970. S 160 1971 BLACKET R: Coronary heart disease and diet. Med J Australia 1143-1144, 1971. S 161- CLEAVE T L: Sugar intake and myocardial infarction. Lancet 1: . 43, 1971. S 162 DALDERUP L M: Mutants, hyperlipoproteinaemia, and coronary artery disease. Br Med J 2: 771, 1971. S 163 GILDER: Smoking and the physician. Can Med Assoc J 104: 476, 1971. 5 164 GRANNIS G F: Cigarettes and heart disease. N Engl J Med 284: 1384-1385, 1971. _ , . S 165 HIPSLEY E H: Diet and heart disease. Med J Australia 2: 219-220, 1971. S 166 MORGAN L: Diet and heart disease. Med J Australia 2: 282-283, 1971. S 167 SELTZER C C: Cigarettes and heart disease. N E:ngl J Med 284: 557-558, 1971. S 166 TURNER R W D and ILLINGWORTH D G: Preventiori of coronary deaths. Br Med J 4: 228, 1971. S 169 1972 BALL K P: Preventable smoking deaths. Lancet 1: 201, 1972. S 170 CHERRY W H and FORBES W F: Smoking and health. Lancet 2: 824-825, 1972. S 171 FLETCHER C M: Smoking and health. Lancet 1: 386, 1972. S 172' FRIBERG L: Smoking and health. Lancet 2: 973, 1972. .. S 173 FURST A L, GREAVES DA, HAWTHORNE V M, McCARTNEY H and STEWART G T: Candidates for coronaries. Br Med J 4: - 366-367, 1972. S 174 T10 30 2-1 32 3
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1964 Page 349 (a) • This section on pharmacology of nicotine is so brief that it does not do justice to the considerable amount of information available in 1964. The opening paragraph cites (57) Larson, Haig and Silvette (1961) which is the most extensive monograph on Tobacco. The cardiovascular effects of nicotine are discussed in pages 14 to 232, and the relation of tobacco to cardiovascular disease in pages 653 to 686. However, the monograph is mentioned only in reference to the amount of nicotine absorbed. T10 30 2-1 33 8
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Page.331. rIL Secondary Publications - 18 XII. SECONDARY PUBLICATIONS ON SMOKING AND HEART DISEASE E. Editorials (Unsigned) . 1955 British Medical Journal: Smoking and coronary thrombosis. 1: 91-92, 1955. .. S 21F 1956 British Medical Journal: Smoking and the cardiovascular system. 2: 90, 1956. -S 21; 1963 British Medical Journal: Prevention of myocardial infarction. 2: . . 1351-1352, 1963. S 22C British Medical Journal: Smoking and blood clotting. 1: 833-834, 1963. . S 221 Journal of the American Medical Association: Tobacco, pollution, and . pesticides. 155: 31-33, 1963. S 22 1964 American Journal of Public Health: Cigarette smoking and health. 54: 32Z-324, 1964. . . S 22`. British Medical Journal: Work after a "coronary". 2: 703-704, 1964. S 22i British Medical Journal: Healthier life. 1: 1267-1268, 1964. S 22` British Medical Journal: Smoking and death. 1: 192-194, 1964. - S22E Canadian Medical Association Journal: Smoking once more. 91: 353-354, 1964. S 22. Journal of the American Medical Association: Childish habit. 189: 850, 1964. . S 221 Lancet: Haemoglobin changes in Buerger's disease. 2: 1164, 1964. . . S 22~ Lancet: Coronary-artery disease in the young. 2: 628-629, 1964. S 23C Medical Journal of Australia: The United States report on smoking and health. . 51; 201-202, 1964. . ~ S 237 1965 Medical Journal of Australia: National health. 1: 205-206, 1965. . S 232 Public Health Reports: Relate heavy cigarette smoking to angina. 60; iZl, 1965. S 233 1966 British Medical Journal: Smoking and atherosclerosis. 1: 755-756, 1966. S239 British Medical Journal; Cigarette smoking and heart disease. 2: T10302-1328
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FIESSINGER C: Tobacco angina pectoris. JAMA 60: 1473, 1913. Page : Repz S 3 HUTCHISON G B: The nature of epidemiologic evidence: Smoking and health. Bull N Y Acad Med 44: 1471-1475, 1968. S 3 JORES A: Arzt, Tabak und Alkohol. Dtsch Arzt 13: 752, 754-755 , 1964. S 3. KASPARIAN H: Ethanol, smoking evaluated with coronary blood flow . JAjv1A 190: 33, 1964. . S 3i MAJEKODUNMI M A: Seventeenth World Health Assembly. WHO Chron . 18: 117-127, 1964. . S 32 OSTER K A: Predisposition to atherosclerosis. JAMA 222: 704, 1972. S 32 OSTER KA: Prevention of atherosclerosis: Fact or fiction? Med Counterpoint 4: 13-27, 1972. S 32 SAIGER G L: A critique on the report of the Surgeon General's advisory committee on smoking and health. Bull Int Stat Inst 41: 856-860, 1966. ._ S 32 SCHOENBERGER J A; Mass screening identifies high-risk coronary patients. PostQrad Med 48: 37, 1970. - . S 32, SELTZER C C: An evaluation of the effect of smoking on coronary heart disease. JAMA 203: 193-200, 1968. 5 32( SELTZER C C: The effect of cigarette smoking on coronary heart disease. .: Arch Environ Health 20: 418-423, 1970. , . S 32( SOMMER R M: Nonspecification of tobacco smokers. JAMA 222: 487, 1972. S 327 STERLING T D: A review of the claim that excess morbidity and disability can be . ascribed to smoking. J Am Stat Assoc 66: 251-257, 1971. S 328 WALXER A R P: The prevention of coronary heart disease. Am Heart J . ~ 72: 721-724, 1966. . . . . S 329 T10 30 2-1 334
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SMOKINGaJI-d HEAL~.~~ ~ do REI'OIIT OF T1IE ADG'iSOPY COMMITTEE TO THE SU1:CE0\ GE\1:PaI. OF TIIE 1'UBLIC III:ALTII SEIIVICE US DEPART\IE\T OF FIEILTH, 1:DUCaTIOV, AND WELFARE Public IlczltL Servicc Chapter 11 0 Cardiovascular Diseases Contents IAT1tODliCT1O\ . . . . . . . . . . . . . . . . . . . . 317 PERTINENT PJI AR]fACOLOGY . . . . . . . . . . . . . 317 GENERAL OLSElt1':1TIONS ON CORONARY I[16AP,T DIS- EABE . . . . . . . . . . . . . . . . . . . . . . . . . 320 SMOKING AND COJ(O\:1CY 11P:AR1' DIS1iASI•: ..... 322 SMOKING A\I) NO\.CORO\ ll(Y CARDIOVASCULAR DISEASE . . . . . . . . . . . . . . . . . . . . . . . 325 C1IAR,1CT61ilSTICS OF CIG+.R}TTF: S\fORLRS .... 326 PSYCItO-SOCIIL F:1C1'ORS OP S\IOi:I\G /\' REiATIOY TO CdRDI01'ASCGL:IR DtSC.tSl: . . . . . . . . . . . 327 SUNDfAi:Y . . . . . . . . . . . . . . . . . . . . . . . 327 . COYCLtiSIOY . . . . . . . . . . . . . . . . . . . . . . 327 REFEREnCLS . . . . . . . . . . . . . . . . . . . . . . 328 - List of TabICS . TiBLF.1. Ucadr uttcs per 100.000 frum artcriosclcrutic and dcpsnaratise Luart di.ca, by eca and agc, linited Slatca 1?,3-60 . . . . . . . . . . . . . . . . 32] T.tDLE2. liatioe of m-)rlalily ratrs (or cotcnarv Lcari discasq rnalr, sumS.•re to nnn-sumkcra. Li agc an1 amount amukcd, in sclcct.d etwlicx . . . . . . . . . . . 324 1964 PPage 348 T10302-1336
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1964 Page 350 (c) The vaeodilatation reanlta from liberation of catechol amines from stores in ornear the blood•vesa,el salls, including the chromarbn tissue along the coronary teaeeLs themeelves. Catechol amines cannot be liberated as a result of ntimula- tioa of eympathetic gan¢fia by nicotine, aa the blood level of nicotine attained dry amoking is too low for this purlKrae. It is, ho}cever, auf3icirnt to liberate eatechol amiaee from bfood-vesrei ealLs. Theerplanation of the rarity of tobacco aogim is not clear. Preanmably a kw indisiduala are ia aome way hypereen:itive. The investigation of.kin sensitivity to tobacco should be made by using fractionated extracts of tobacco smoke rather than extracts of tobacco itself. We have been unable to demonstrate any sensitivity to either. • To test the theory that release of catechol amines by nicotine leads to tobacco angina, we tried six druge which n.ight be expected to block the nicotine eifect, and four which might be expected to aggravate it. The former group consisted of dihydroergotaatine, antiverotonin, reserpine, hydrocortisone, gaanethidine, and methyl dopa, while the latter comprised serotonin and three monoamine oxidaso inhibitors. The results are given in detail. Surprisingly, the monoamine oxidase inhibitors had a proteetive effect in all three patients. None of these drugs blocked the effect of exercise. Ournesutta support the belief, previously based on animal esperimenta,that nicotine exerts an action like that of the sympathetic stimulants because it liberates noradrenaline. If it is thought by the patient that his angina is induced more easily during the time he is smoking, he should be peiauaded to abstain for one month, and the electrocardiogram should then be repeated. If clinical improvement is reported and the height of the T wave has also improved, he should be per- manently discouraged from smoking. Indiscriminate advice against smoking, as far as a 6^ina is concerned, is not josti6ed, and each patient needs individual assessment. ® 11 T10302-1342
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1964 Page 351 (a) a Some of the articles cited in this page discuss the interrelationship between smoking and other risk factors. One example is (81) Russek and Zohman, who described hereditary predisposition as well as other risk factors in coronary heart disease of young adults. Although smoking was prevalent in the coronary group, it appeared to the authors to be an indication of heightened emotional tension rather than a predisposing or causative factor in coronary heart disease. TOBACCO. Prior to the attact. 9Q-, of jthc coronary patients induh,d re,u- larlv in the use of tobacco, %d6ife ItY: were either nonsmokcrs or participated on rare occasions. Among mutrole, on the other hand, 627 were ha6itnatrd while 38< smoked occosionalk or nnt at all. Heasv smkers were al>o found to be far more frerluent in the v:ronan• group. Thus, :0'F of their nunJ.,r h:A smoked at least 30 cigarets i' r d-p prior to their attack as cnmpar, a s%ith unlv 357 in the omtratcst grou;,. Thrse obscrvations indir.itt•, thercfr,r., th.it smoking was not onk- more p, .ak'nt in tiie coronan group but a: n tL.a the coronan• p;dicnts Mho had -nnkirl were more helu,ilv addicted to •'ie u><' of tobacco. Xevrrthclcss, it is u t dezr from these findiu;;s %chctha•r :, otinc is a prcdispo.in" f,rctor in e,nsn' heart discase or whrthrr ih m.• fn'- tluent and rzcc•ssivc use amim'r' 0mn, annSid.~hw is mrrrh• a n•fhwtiun uf the lni~htr~:,tl emutiunal teusion so irret•• aknt amnn,, thrm. ---' T10 30 2-1 344
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1964 Page 352 (a) E E When selected groups are examined, there is no relationship between cigarette smoking and an increased death rate from coronary heart disease. The report by Cohen and Heimann (1962) is a good example. It is reproduced in its entirety. Cohen J and Heimann R K: Heavy smokers with low mortality. Ind Med Surg 31: 115-120, 1962. T his paper extends mortality rates of cigarette division employees of The American Tobacco Company to cover the period 1cJa7-19G0. Previous mortality studies of the same population were made by Dorn and Baum of the National Insti- tutes of Health, embracin-, October, 194G, through 195?,1 and by Haag and Hanmer, for the years 1953 through 195G:' An intensive in- vestieation of this pcpuintioa's smokinc hahits was made in 1956 by Finkner et al? of the In- stitute of Statistics of the University of North Carolina- The 1D57-19G0 data confirm the findings of Dorn-Iiatuu and Haag-Hanmer that the age-, color-, and sex-adjusted mortality rate for all causes, for cancer, for re~piratm-}- cancer, and for cardiovascular disease in this population are average or lower than average trhencompared n•ith the general population rates. The significance of this finding relates to the determinations of Finkner et at,3 who found that the population under study had a markedly hic-her percentage of regular cigarette sntokers than the general U. S. population. Fink- ner's study also indicated that the percentage of these factory employees consumin.- upwards of 20 cigarettes daily was tYVice that in the general population. This series of studies thus establishes a dis- tinctly heacier-than-acerage smoking population svhich has, over a period of 1-ll:i years, mani- fested fewer deaths of all kinds, and fewer deaths from cancer, lung cancer, and heart disease, than the expectancy for an average population of its age, sex, and racial composition. These results are Dr. Cohen is nlao eoruuttant to the Dupartment of Resmrch "d Dreelopmcnt of the Americen ToLacro ComDnny- in direct opposition to the hypothesis that ciga- rette smoking per se causes higher mortality rates generally and for lung cancer and,or heart disease. The three consecutive longevity investigations covered 70,532, 45,455 and 41,967 person-years respectively, or a total of 157,954. The average size of the population during the 171 month, under study was slightly over 11,000. Mortalify Rates for 1957 through 1960 Table I compares the observed deaths in the population studied with the expected number based on age-sex-color-specific death rates for the general U. S. population. This table and the method af its calculation are patterned after those published by Dorn-Baum and Haag-Han- mer. T.+er.E 1. ODSERYED AND EXPF.CTED Ntil1BEPR oF DEATHS FROM SPECIFIED (;AGSEi .al'os0 FULL-•rDIE ASD RETIRED EMPLOYEES OP QC-RETTB PLANTS AND STEMMERIES OF TLIE A11EF.KAS ToB.tCCo L:0>iPd\Y JANUARY 1957. - DECE}IBLR 1960 Eapected Ob.ened Cause No. of D<aths No. of DeatAe Observed to Ezpecttd All tauses 42S 325 46 c Caneer - nll forms (140-205) 75 - 4T .63q'o Cancer - respiratory syslem UG9-16A) 14 6 43% Canc<r of bronchus and traehea. and of lun6 . 6peCnicd al Pri4lan' s~l 7 0 0 Cardioa•sscular (JOp-J631 1Ad 154 86% Coronan' disea•;c (420) 116 100 867. NOTE: NumLers in pa-enlF.e+es are cauaeo(-d•ath aatecori.'.y of Seventh Y.eri.iua of The Intarnational Lis4 as uned In 19toi S.areti<. of The U. S. _ TI0302-1346
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1964 PPage 353 (b) -4 6RE7rF.{C OF ~SNORI\O AND rrF.ALTA" 723 for a eausrettect relatlon,hip will be greatly strengthened. To refute effectively the hypothesis that smoking is a cause of lung cancer n-ould then require a reasonable explanation, other than causation, for tha consistently observed association bctween smoking and lung cancer." In 1957, Sir Ronald Yi=hcr (0] otiercd such an esplanation: "that cigarette mroking and lung cancer, though not mutually causative, are both influenced hc a common cause, in this case the individual genotyye." Rerksmr in a series of papers, og. [I0] and [111, expressed doubt regarding the demonstration of caustitiou. lie ernphasiced that a higher death rate was ahown for almost all disrases, and that if this i; acccpted as rcflectingthe escess deaths due to smoking then about 40 per cent of all deaths among cigarette smokers must be attributed to their smoking. In 1959 Cornfield ct at [121 concluded that "the consistency of all the epi- demiologic and elperimental evidence also supports the conclusion of a causal relationship (of lung cancer) with cigarette smoking, while there are serious inconsistcncies in reconciling the evidence with other hypotheses which have been advanced." Of the comments of statisticians, the above scem to be among the more unportant. In 1962 the Surgeon General of the Public Health Service of the U. S. Depart- ment of Health, Edue:aion, and Welfare moved to appninba committee to 'assess available kaoniedge in this area [smoking vs. health] and make appro- printe recammendations" (pa-e 7). It is stated (page 8) that the function of this committee was to make "an objective assessment of the nr.ture and mag- aitude of the health hazsrd" and `this committee would producc and s•abmit to the Surgeon Generai a technical report containing evaluations and eon- tlusions." However, "Reconemendations for action were not to be a part" of thecommittee's responsibility. The formation of the committee was a formidable operation. The Surgeon -Gencral met on July 24, 1962, with represerdativesof the American Cancer Society, the American Collece of Chest Physicians, the American Iieart Asso- ciation, the American \Icdical Association, The Tobacco Institute, Ine., the Fond and Drug Admiuistrstion, tls \ntioucil Tuberculosis Association, the Federal Trade Comrni,;ion, and the i'residcnt's Olllcoa ofScience and '1'cch- aology. It is noteworlhy that no statistical society was represented. Also the lat of organisations nppears to lie heavily racighted towards government agencies and organisations lnr-ge, general, and active in public relations, and to have low represcntation of soe.iet.ics with spcciGcally scientific outlooks. The participants of the July 21 meeting compiled a list of 150 scientists and physi- irians. This list was thcn screened by thcsc participants, eneh orgnnisation represented having a power of veto. From the intersection of all the ects of ~ tron-vetocs (which might, but apparently dirl not, have turned out to be the rmpty sct, though wc are not told its size) len were selected fer the Committee. Of tho ten, only one is listed as a statistician. Since a substxntial fraction of the relevant issues are statistical, one might question whether a one in ten representntion for statistics was sufficient. ]lowever, one further member of the Committee is listed as an epidemiologist. I T10 30 2-1 354
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1964 Page 350 (b) F Tobacco angina. In 1963, Oram and Sowton reviewed the literature and his experiences on tobacco angina. Although the condition is rare, its occurrence has been ignored in prospective and clinical studies of angina pectoris. The subject is discussed in pages 15 to 18. Since the article does not appear in the 1964 or subsequent reports, the summary is reproduced below: Bsmmary The term tobacco angine aa previously used has become meaningle~, and covers at least five teparato s}md:cmes to tchich we have drawn attention. A$e8nition of toba~to an;-i:za is offerecL Angina as a resul: of smoking is a real entity, but rare. IncIuding onr three patients, only 17 con::nci:. ; examples, confirmed electrocardiooraphieally,have been recorded. The commonest type occure in patients who already have typical $eberden e angina due to coronary di: case and precipitated by the moro usual -tauses. A cery rare type is that occurring in apparentlS healthy young peopa in whom electrocardiographic changes charactetistia of coronary irsutlicienoy appear within a few seconds of smoking a cigarette, accompanied or unaccom- panied by cardiac pain, but in whom the electrocardiographic changes and pain are said not to be induced by other causes such as exertion, emotion, and cold. We feel it is likely that follow-up studies of these rare patients might later ieveal coronary disease. . It is important when searching for patients suffering from tobacco angina to investigate them not only while they are smoking, but after smoking followed by exercise, and after exercise followed by smoking, othericise ezampiea will be missed. Of 309 smokers with ane na questioned concerning the possible role of cigarette smoking in causing cardiac pain, 20 claimed to have angina on amoking. These were re-examincd clinically, and elect:ocardiograms Rere taben at rest, after smoking, after smoking followed by exercise, and after exer6e followed by smoking. Only two examples of genuine tobacco angina were found by this means. Our three patients bad isebaemie heart discase .cith chest pain, and electro- tardiographic evidence of coronary insuff:ciency was produced by exer@ix and bysmoLingcigarettesorcigars. Nosignificantchan5einblood-presvureaccom-panied the cardiac pain and electrocardiographic changes which resulted from emoldna. These eSecta induced by smoking were invariably accompanied by taehyeardia, but were not secondary to tachycardia as induced by intravenous atropine. Fieither smoking herbal cigarettes nor the intravenous injection of normal saline induced angina or electrocardiaeraphio changes. The most satisfact.ory explanation of tF.e cardiac pain and electrocardiographie changes appears to be that nicotine gives rise to coronary inanmciency not by coronary vasoconstriction as previously suppoeed but by coronary vasodilata- tion. In spite of this vasodilatation t he blood sunply to the myocardium becomes lnsu$ieient because of the concomitant increase La cardiac work, resulting from an increisei cardi w rate, rise in blood-pressure, or both. Possibly also the h'bcration of catechol amines has a deleterious effect on the metabolism of the myocardium. T10 30 2-1 341
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1964 Pag'e 353 (h) A nEVIEW OF ~61fOAr\G AND NEALTn" 729 (d) The next section, `Temporal Relationship of Associated Yarinblea," msk-es the point that people smoke and then have cancer, rather than vica versa. Ttte point of coursc, is that if B occurs later in time than A then it is difncult to maintain that B is a cause of A. This is obviously a necessary condi- tion, but not sufficient. (e) The final criterion is the "Coherence of the Associstion" which covers e number of points as follows. ' (1) The historical increase in cigarette consumption is correlated tcith the historical increase in lung cancer. .(2) The sex difference in smoking is in the ssme direction as the difference in lung canccr rates. (3) Page ISG reports that "althougb adjustment for smoking history does not equalize the urban-rural lung cancer mortal .y ratio, control on the urban-rural residence factor nevertheless leaves a large mortality risk - dificrence bcticeen smokers and non-smoker." This seems to imply that correlation of residence with smoking cannot account for the obsen-ed association of lung cancer rate with smoking, and, vice versa, correlation of smoking wiflr re=ider.ce cannot account for the observed association of lune cancer with residence. (A) A scetion on socio-ccononrie differentials in lung cancer mortality re- marks (page 187)"it rcill be neccrthe.lcss noted that the professional and farmer and fann manager groups had hiohcr proportions of non-smokers mnon,^, them than did the laborcrs and crafts'nten. This finding is in the proper direction for cnn:pntlbilltv Ncit.h the sociorr,onomic differential in fnng cancer mortality but the disparity does not appear to be suf- ficient to provide a satisfyinq correction." (5) This section comments on the dose-response relationship and relcrs to the muddled position Nvith respect to inhalation. A seotion on the histopathologic evidence (page 1 S9) refers mainly to work by ?nerbaeh on epithciial changes in the trachea and bronchi: 'These changes were rarely scen amoqq nmr-smoker.s, but incrcascd in fre- qucncy and intensity rvith the number of cigarcLtes smoked daily by indi- s xiduals without cancer and were most frequent and intense in patients dying of lung cancer." Tlm opinion is espressed {page 172) "it secros probably tbat sonte of the lesions found in the trachcobronchial tree in cigarette smokers are capable of devcloaino into lung cancer." It is difficult for onc not a=-pcciali~t in this area to assess the significance of these obsercations. Tle Report concludes (page 189) "Thus, the histopatho- •logie evidence derived from laboratory and clinicaltnaterial support the ciczrcttc smoking-iunq cancer }y; otl:c_is" so thc Committee does not appear to re-,ard this time as crucial. Presumably having established to its ratisfaction that smo}:in, causes lung cancer since the criteria of the "epi- demiolo„ic mcthod" are allef;edly satisued, the Rcport in paces 190-193 die- cnsses the "Coustitutional lfVpotbcvis," i.e. "the alternatice hypotimsi, that hnth smokinr; of ciy;arcttcs and cancer of the lung harc a conmmn eause . . . " and concludes 'that genetic factors play a minor role" (page. 192). Tbe main T10302-7360
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1964 1'agc 3~3 (e) 726 A1,II:RICA\ STATISTICAL ASSOCIATION IUliR]AL, SEPTEf1nFn I'.cf - Ilabit," eoncludes that smoking is a AaLitualion rather than an addiction, "siner dnce establisLcd there is little tendcncy to incrcase the dose," etc. (page 351). Chapter 1-1, "i'sycho-rzocial Aspects of Smoking," states that "Tl:e 0vcr- whelming cridence points to the conclusion that smokir.- is to a large extent psychologically and soeially detertnined" (pa-,e 377). The "psychologically' part of this conclusion is apparently based on Ecsenek []6] r;ho found that cigarette smoking, was positiccly associatcd nith cxtrolersion, and that both non-smokers and pipe smokers (the study uss made in England, so presumablr there were too few eigar smokers to consider) were less extroverted. The evidence for the "socially" part of the conclusion seems in its summarized form to be uot very quantitative. Thc $epmt forms the conclusion that "u-hite collar professional, mana-erial and technical occupations contain fewer smoker• than craftsnren, salesperaons, and laborers" (page 363), but does not give any figures. HmreN cr, ":Ss to separate class-linked variables, income does not seem to be related in a consistent mmnner to prevalence of mioking." The Report finds "The relatonsbip between smokin; and education is unclear," and "Thr proporGon of smokcrs is rounhly the same amon; whites and non-whites." I1fon smoke more than women, thou~h the di;crepancy has been decreasin- in recent ycars3 Also, "Smoking (of any kind) is most prevalent among the di- rorced and widowed and least amonl; those who have never been married, except tlat among persons over 45, never married are as likely to be smokers as the marricd" (page 3G1). Some religions affect smoking, and the rural farm populatiovn smoke less than the rural non-farm population. There is little dir- fcrence between the latter and the urban population. Pev: figures are quotr1 inthis discus.;ion, so one cannot assess how important these carious factors are. . Chapter 15 deals with the morplrolo-;:cal constitution of smokers. \llmt eeems the most useful information is from Seltzer [17], who in 1912 obtainec anthropomctric mcasuremcats on 922 Harvard undergraduates and in 19:f.aseertaincd their smoking habits (mith an SI per cent respons). He found that cigarette only smokers were statistically larger in a number of anthropmnelrir indices than non-s:nokers, areraving 4.3i pounds hcavicr, pipe only smokcn larger still, and eioar smokers the ]argest. The Report concludes, however. *The available evidence suggests the existence of some morphological di(ter urces between smokers and non-smokers, but is too meagre to permit a con clusion" (page 357). The Report does not give reasons for declining to aecep: Seltzer's results. 1Ce turn nolr to a detailed consideration of Chapters 8 and 9. Chapter S reviews the secen major prospective studies and concludes thn' the orerall dcath rate for cigarettc smokers is about 70 per cent higher tha, for nmrsmokcla Yor cigar and pipe smokers the e(icct was minor. The mory tality ratio, i.e. the ratio of the dcath rate for ci; arette smokers to the deatli -„r r ..,... ..._ .- ...... . r. -~.. . ~. .- . the lung (10.S), bronchitis and emphysema (G.1), etc.,Por coronary arter•I disease the mortality ratio was 1.7. It seems that for cucctivcly all causes r death (eeen uccidruts, suicide, mrd violence) the cigarette smokers had tL higher death rate. Thouh cancer of the lung had the hi_hcst mortality ratio "coronary artery disease is the chief contributor to the e.ccss number of deattr '----- . .~ ,""sT10 30 2-1 357
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A ItEYIEW OY °5StO1:I1G d.1'D HEALTnn 727 of cigarette smokers over non-smokcrs" (page 113). This chapter makes Do ezplicit claim that cigarette smokicg is the cause of the nrortulity ratios being greater than 1. Chapter 8 reaches its conclusions solely on the basis of seven prospective studies, presumably (though nothing is stated) for the reason P.tat its authors wereae•arc of the hazards in attemptingto make r'gorous infcrena~s from rotro- spcctive studies (possible biascs in rctrospective studics are di.scussed in t'hapter 9, paees 1 SO-1 S 1). The main d ifacult v, it =_eems to me, is that it is Aery difficult to deLue accurately the population from trhich the hospital sample of, r•.i'v., cancer patients has been drawn, and even more dift9cult to draw a sample of controls from that population. In some of the prospective studies a cleariy dcfir.ed population ezisted, e.g., policy holders of U. S. Covernment Life Insurance Policies, and the intention . nns to take a 100 per cent sample of this population, but in general for these sti:dies non-response avera.ged 32 per cent. Biascs in the non-respondents could play havoc with inferenccs based on the respondents. Appendix I to Chapter 8 considers this, and on various assumptiau ahout the behavior of the non- rcpondents concludes that such biases could, under rather extreme assump- tions, make an actual mortality rat io of, for example, 9.0 be observed as 5.0, or an actual 7.0 be observed as 10.0. The possinle c.ects of the non-respondents are tricky, however, as Doll found (page 97) that for British doctors the non- respondents had a higher death rate and relatively more smokers than the respondents. The cross-classiGcation is, however, not given. In other prosp~ctive studies, e.g. t!:e 19G3 Ilanr,,;oad study, tLere is no dcarl}• dcfined pcNCfation and hence the concept of percentage response is im- possible to evaluate. Bias could csist in the rccruitmer.t into the sample, but it is stated (paoe 1S1) that its cfCects, if any, should decrease with tium, and this is not observed. Mainland and iferrera 17] bad previously wondered about the effects of biases in studies of this type, hut the lieport cites the gradual in- trease in the mortality ratio tsith time az neaLening their criticism. The 1963 Ilammond study speci i cally excluded °persons too ill to answer a questionnaire" (also illiterates, and persons who could not have been traced). Presumably these exciusions are responsible for the age adjusted death rate of the.lTanrmond aample being substantially below that of U. S. nmles 3enorally. In fact, for all +ercn prospective studies the sarnples arc hcalthicr than U. S. nmlcs (page'J5). This may be largely due to the probable fact that the surveys are drav; u from rdatis•ely high socio-economic groups. In specific surveys other reasons mny also operate. Even though cancer contributes only ^_G per cent to the total excess numbcr of deaths of ci;arette smokers, it receives the most attention in the Report, as Chapter 9 being 13G pages is substantialty the largest. Lung cancer, which contributes 16 per ecut to the total number oi cxte,s dcaths, receives the greatest emphasis and we will confine our attcntion accordingly. Chapter 9 first reviews acNadjusted Ittortalit}• rates for various countries, , for various times (1 J06-19iA), by site, by ses, iucome class, occupation, and rtlmio group. It theu discusses various carcinn;~cus, sonte of which are present iu tobacco smokc. '1'ltcn follows pugca 1d9-19G on lung canccri reaching the I
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1964 Page 352 (c) ® on leave) was taken as of July 1 in each year. Expectancies throughout were calculated for each single year and summed for the period studied. Dleasurement of the subject population's smok- ing habits by Finkner et al. was methodological- ly similar. Independent incesti-gatots recurded individual smoking histories and classified them by age, sex, color, and rate of cigarette consump- tion. These were ranged against the cairrespond- ing findings for the general population of i:ie Lr. S. by subgroup, as reported by Haenszel, Shimkin, and Miller of the U. S. Department of Health, Education and Welfare,6 based on a Census Bureau -study. The above procedure follows that of Haag and Hatmter, who compared employee smoking habits with those of the U. S. population, and employee mortalitp rates with tho<e of the C. S. popula- tion, both stratified by age, sex, and color. No sampling or estimating was involved in any of these studies. Smoking habits were measured by applping pretested procedures in- dicidually to virtually every member of the population under study Data on age, color, sex, and mortality were available for each individual member of the population and were summed as above described. - Characieristics of tire ?opulaiion The population under study was that defined by Dorn and L':wm of the \ation. l Institute> of Health. It consists of full-time employees in factories and leaf departments of The American Tobacco Company in Virginia, Sorth Carolina, and Kentucky. Tw-nocer in this emploree group is negligible. On July 1, 1960, approximately 66<< of the population had service records of ten years or more, and 20'c had service records of 25 years or more. On ,lugust 1, 1953, .48'i had been employed ten or more years, and 10'~, 25 or more years. As reported by Dorn and Baum, employees who are unable to worke-entuallc are carried on the payroll as on leave without pay but remain covered by insurance so that they remain part of the population for purposes of these studies. Retired employees retain insurance coverage and also are included. Thus the population is a coherent „roup for purposes of mortality investigation. The degree of this coherence is indicated by its average age, which increased almost precisely threc cears between July 1, 1957, and July 1, 1960 - from .a°_.8 Ve:u•s to •Ia.7 years. respecticely. White nude~ nccomited for 13',o to 16~0 of the population during this period, these pcrcentagcs being minimunt and maximmnt. Males white and nonwhite accounted for 57'o to 01;c of the sutr ject population. \Ieu over 45 accounted for'31','C' of the employee group on July 1, 1960. Comment The health history of this pop ulation of heavy- smoking tobacco company emptoYees tends to disprove the hypothesis that cigarette smoking causes higher mortality from all causes, from cancer, from lumg, cancer, or from heart disease. This interpretation is =trene heued by the fol- lowing data of observation: - 1. The subetautiai deorec to which the. studied population's cigarette consumption exceeds the national rverage: In the per- centage smol:ine more than 20 cigarettes daily, the Finkner study group recorded the ratio as 2:1 or more in every subgroup and in virtually every age group. In view of the population's cocational interest iu the product it manufactures, and the provision of a free package of cigarettes each work- ing day, this characteristic of the group studied is not astonieiung• 2. The unusuaCyy stable nature of.this employee group, as indicated under "Char- acteristics of the Population" aboce: Sta- bility of the population for purposes of these studies is also insured by the fact that employees on leave, retired for disability, or retired for age, continue to be covered under the group insurance plan. These em- ployees or former employee; were included on the July 1 rosters used to compute ex- pected deaths; and actual deaths among them were reported by the Metropolitan Life Insurance Compan}-. 3. The extended nature of the mortality research, covering a continuous time span of 14?:.i years. 4. The consistently lower-than-average mortality of the studied population for each of the three mortality studies (Table II). 5. The consistenec of the degrce to which this mortalit~ for the entire 1-Ir4 year period is lower than the national rate, as between the various causes of deaths (Ta- ble II, Column 4). Other Sfafistical Sfudles A number of studies, of which those of Doll- HilF and Hammond-fiorn` are representaffie, hace yieldect a stati;tic:d a-sociation in individuals between cigarette :mokint! and hi;:her mortality rates. Other studies, including Ea~tcott, Dean, and the present itud}-, hace :hoorn no such as- sociation. A number of ciistincti,.ns may be noted in connection with the ciiamelric opposition be- hceen the resulta of the t\co groups of studie:. Statistie:G as<ociation studies of the Ham- " T10302-1345
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1964 Page 353 (o) i36 , . AlIER1C.l\ .STATISTICAL ASSOCI-eTIOS 7OUR\AL, SPTTEMBFR 1943 TABLE 3 Tranquiliren Do not nx IIse Fried Food \ ever s moked regularly 755 1:308 TABLE 4 ~ever smokrd regulnrly No Fr;ed Fuod Eaten Fried F-d 3-4 times a wk. 1208 642 Cigarettes 20+ a day 1501 2286 ('igurrttes 20t e day 2573 1714 o(Len in a"socird" environment, it is probable that some tranqnili;:er users did not admit to this habit, arni therefore appear in the "do not use' row, hence raising the dcath ratrp for this row. The real "eficct" of tranquilizers is therefore probably even u.ore dramatic than the table sho~-s. Tables 4, 5, 6 are from Ilammond; the first two are not quoted in the Report. Nammond's data also show the r:ell 1:noun, but as far as I know, never satis- (actorily esplaincd, dilTerences in death rat es between married, sint le, widowed, and divorced persons. It also shon-s a marked hereditary effect, a marked height effect, and a moderate education efiect. lianmrond does not give cross- classifications, other than on smoking. It is notenrorthy that in all the aSovc two-way cross-classifications, and others in ]Ia^}mond's report no: quoied irerc, the smoking catcgory always has TABLE 5 Sleep Never smoked regularly . Cigaretlrs 20+ a day <5 bra. 2029 393G 5 bn. 1121 2656 6 hrs. 805 1601 7 brs. G20 1426 8 brs- 813 1562 9 hn. 987 1729 10thre. 1&98 2694 TABLE 6 Exercise T-ever smoked regulsrly Cigarettes 20+ a day None 834 1416 Slight 579 1347 Moderate 486 30115 Reevy 474 945 I "~`"-TI0302-1367 ~
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1964 Page 350 (a) 4 The information on the effect of smoking on coronary blood flow in man was sufficient to show that there was no harmful influence. The conclusions of (2) Bargeron et al., 1957 and (74) Regan et al., 1961 were similar to those obtained by six groups of investigators administering nicotine in dogs (see page 270). At the time Bargerson et al. and Regan et al. 1961 completed their experiments, their conclusions were accepted because the nitrous oxide technique was the only means of measuring coronary blood flow and myocardial metabolism in man. The observations by Regan et al 1961 have not been disproven by subsequent reports. The Discussion quoted from the article is as follows: - - Discnseion ,. The esperimenta! conditions of this stn tserelitnited to ecaluation of the su,tair _. effects of ei;arette smnkinz _ up•m the m: rardiuni of nntn afi,-r,the peripheral he'- atnLli+b: • dfnamic ehan-~ h,hl b,.•nme well - Conswqoently. lntrrpretati,m of thr data ca.nbt~be applied wiil:.ut n,•r..Ytion to ti . acute ehan_n o,•currinc imm..iiatetv aathe onset of smoking, which may Icell be qualitatively dif<erent" If one as.unns, how- , ever, that nicotine is the principal pharma- cologic ao~ent in tobacco smoke, then the elfects ,of intracoronary infusion of this substance are of some interest. In the intact dog it has not been found to modify coronary blood flow when injectisl into the anterior descend- - ing artery, despite substantial increase in myoeardial contractility:° Left coronar}• per- fucion with nieotine aho has faibNl to increase flow in the atherovhcrotic rabbit h,•art. d"pite eardiae. aeceleration and enhaiwe,9 cuntract- ility:30 These studi.ti, in l.hi,,h ditFcreut methods of determining coronary flow have been emploved,tend to rednre the pn~ibilita• - that the.e re+ults in man repr,,eut an artifact of the nitrou; ocidc mcthod. Aug-mentaticn of coronary hhr-3 fl„w mac usually b.t anticipat,vl when there i. an in- crease in heart rate, systemic artrrial pres- sure, cardiac output, and left ventricular work. In this manner, the apparently greater oxygen requirement of the myocardiunt would . be severed. Failure to find such increases of myocardial b1orn.I flolc and oxygen ~con- sumption in the coronar.- subjects during cip trette sntokin; may- plausibly be related to the "fired coronary nyi.tance" alle.-e,l to exist in snch pati,nts.'t That the abnormal corouarc vaurulanae is not responsible be- comrs apparent frnnn the similar response in the subjLs:ts withnut evidence of coronary- di.case. In view of the evidence that ventric- ular contraction acts to impede coronary f'.ota-. Rithin the left ventricular wall,'= the en- hanced ventricular contractility as reflected . _ by left heart arorkmay have produccd such an effect. This view is ditTicult to accept, since the failure of coronan- flow to meet the need for greater oxy~ •n usa;ze should be ac.oei,.el with ano lentel o_:c,e n extraction. .. Although mauly of the effects of smokinZ and nicotine infusion mimic thoae of cate- - eholamine adtninistratiot,° au evaluation of endogenous catechols in plasma in response to smoking too small to affect the coronary , vasculature appears unlikely.On the contrary, small graded doses of cat<•cholamine induce ehanees in eoronarc• fl,,cr before increments in rate and pressure." •lnother humoral agelt possibly rcleasel duru:e svolcin,, is anti- diuretic hormone.° It, poteqt coronary casn. eonstrictor properties rai;e the possibilit}- that any undesirable edeYts of smoking could - be effected through its activity. Even though the plasma levels of easopre.~,in probably are not sufficient significantly to restrict coronary blood flow per se, the lack of ulcreased flow despite increments of rate and pn~sure may represent a restrictive eff«•t of low hormone concentration upon the response to these stim- ttli of coronary vauxlilatation. . It would appear that an enhanced ratio of left ventricular work to oxygen uptake may be maintained for some time without cardiac dysfunction. Such is the caxe in animals with chronic complete heart bluefc°/ or in those subjected to eipan,ion of intr;na,cular vol- amcl' Such disprolwrtion in coronary sub- jects, however, if laq;c enou"h, could pre- sumably producc isJn•mia sgmptomv. Thi.a. eireo:nstae.,-e, as su... ,>U•d by this studp, ~ would aplMar tn be an uncommon o,•currence.1e T10 30 2-1 340
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1964 35" (k) ~ 7.32 AliF.RiCA] StATISTiCAL ASSOCIATIO\ 7OVR\AL, 6EPTEMIDER 1a63 Positions (a) and (c) may present the feteest difficulties. If one ndopts position (a), then one is under sorne obl ~ation to provide hypotheses as to possible mechanisms, or to hold out hope that future research sill provide these hr- potheses. The difficulty with the smoking hypothesis is that it has not really got to first base on even lung cancer, let alone the other °L causes of death, even though the matter has been under intensive incestigation for ten years or more. The rnost potent carcinoecn identified in tobacco smoke is bcnz (a) pyrene (page 27) and "it is present in much larger qnautitp than any of the other carcinogens listed." Cigar smokc has almost 4 times as much benz (a) pyreme, and pipe smoke about. 10 tlrnes as much as cigarette smoke (pa;,c 5S), yet pipe, and cigars are prcttv iscll innocent of tiie charge of association with lun; tancer. (Ilowecer, the Committee does conclude that the smoking of pipes is causally related to cancer of the lip (pa^e 20d).) Apart from the above specific measurements on smoke, the difference be- tween cigarettes and cigars (vld pipes) is a puzzling feature of the indictment --of tobacen. It could be, of course, that the variety of tobacco used difiers si^- nificantly, that the tobaccos are cured dIl-icrentlp, that cigars and pipes do not use cigarette papcr, that posibly pipes and cigars burn at lolcer tempera- tures, or that many cirarette =_nmkers inha!o-nLcreas few pipe or cigar smokers do. But if inhalation is the crucial item, then it should show up strongly when cigarette smokers are analyzed into inhalcrs and non-inhalers, and as reported above, the present cN idence on this point is not clear. As stated earlier, animal ezperiments to demonstrate carcinogenic effects of tobacco smoke have proVed unsuccessful. \Philc hppothe~es f or a cau=atice effect f or luno cancer are still unsatisfactorp after a decade of researnh, thr eitustion i=_ even emptier for other diseases. The degree of one's bclicf in the plausibility of the smoking hypothesis thus is considerably affected by the extent to which one thinks it probably that satisfactory mechanisms rill be provided to account for all, or most, of the diseases. If one adopts position (h), then one is in the unenviable positionof admittin; that concealed correlations account for diseases D;, i=k, k} 1, •••, n, but are -not responsible for diseases D;, i=1, 2, - •-, F.-1. It seems to me that once one admits that concealed correlations account for a substantial number of the observed associations, then one has to nork very hard to disprove the hypotbe=is that they may- account for all the observed corrdations. The Report uses the historicnl correlation of rise in lun;, cancer mortalitc with increase in per capita consumption of cigarettes as one factor to suppod the coherence of the association (pa,_e iS5). All statisticians know that the presence of a positive, zero, or negative correlation behoeen tico variablc, observed over time has bccn the basis of more ludicrous nonscnse than un5 other statistical procedure. For esample, the inc,idence of cancer of the stomach hns bcen declining for mncV 7cam (Dorn and Cutler [181), but only a madmar. would infer that the increased smokinF has caused the decreased stomarl canc;:r. Incidentally, it is surprising that the lZeport makes no mention of thi; fact in the seaion on stomsch cancer (pages 22fr2^_D) though it is mcntionci ,..,rs.T10 30 2-1 363
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1964 Page 353 (a) The statistical method used in the prospective studies have been reviewed by Brownlee (Am Stat Assoc 7 60: 722-738, 1965). This article is so important that it is reproduced in its entirety. A REVIEW OF "S,1fOKI4G AND IiEALTII/e•j' K. A. S80N'NLCE U"isenir y of CAicnpo A n'ruoccu there were earlier papers in the medical literature, e.g. htuller (1 [, J-k the possibility of an association between cigarette smoking and lunE cancer first became common knowledgn. among statisticians generally vrith Doll and Iiill's [3] retrospective paper published in 1932. A retrospective study is one in which a group of, e.g., cancer paticnts is classified by their smokin; habits, and a second group, the controls, known to not have cancer, but sampled from the same population as the cancer patients, is also classified by their smolcing habits. The resulting ?X2 table, in tchich in principle the two sample sizes are fixed, can be tested for indepeidence.'fhe evidence for the association became more convincing Nt'ith tlle pnblication in lf).i4 of two reports on pros- pective studies, one in England by Doll and IIill [:3] and one in the United Statcs by Iiamrnond and IIorn [d]. In a prospective study, a populntion ii sampled and then each individual is classified by, e.g., his smoking habits and by his experience with respect to cancer after an interval of time sufficient to allow a reasonable number of cases of the disease to develop. I have ohserved amongst sornc statisticians a.oistfulness that statistics has not so far played a larenr part in science generally. Since this association bo ttceen smoking and lung cancer, interpreied by many as one of causation, is of pri^c imp;,rta°ca, one nrgLt ha, e e.cpected it to be grceted with enthusiasn and loud ac: :irnticn. On tim cuatrary, ti!c conm!l-:.',s and re-aotinns of the sta-~ tistical profession have been very restraincd. By and large, in fact, the silence has been deafening. In 1955, 1\eym:ul [5] pointed out a possible fallacy in retrospective studic±,I but carefully asserted in a footnote that hc had uo direct information on tLe~ association betwccu smoking and cancer. Incidcntally, this footnote containe~ the curious remark: I! "A referee tvarus me that in spite of the fictitiousnes.c of the figures in Table li and in spite of the emphasis ou the methodolo~ical character of my rernarks.i the 'tobacco people' may pick up the argument and use it for publicitc~ purposes." Also in 1955, Rerkson [G] and Mainland and lierrera [7] pointed out eertair.{ type; of bias which could alicct prospective studies. ~ In 1955, Cutler [R] reviewed the literature. Ilk overall conclusion at thaf timc was "r'I'Lcrc is dlsagreemcnt tcLcthcr the ecideuce at haud warrants t conclusion that smoking aud lung cancer are causdly related." tie also re tnarked `7f lung caucec should cousistt•ntly occur more froqueutly in smokec tha1: in non-smel:ers, ilt various subgroups of the populations studied, the case • Ao In.ikd ev,;ew enicle on 'Sm~l.inr nnd nnnlrl~' Rr~nn ef tAe .Sd.i.ary Gunm{uee tn pm 6.e¢roa Om ed d We PoL'.~a n.~!tl, c,.r.i,., 0. S. Ira„nn.ua ut 14.irb, Gdnr.ern..nd IGli.r.. Pablie nuuWSer.ien re! aretlun Nw LW. tiu,.a:ums3cnt ul pu.auenu.4wtnmrm f`ri.uwnp 03ce. t\'ul.iuewn, U. Q:O5a2 nii, Ja u.^-s. e.R,. tl.ubbJ.enkJ.nrtl.w,L..1.nwJinnn,QVV.llepy end\Y.ILErnet-0forcoinment.Wefn,eL .w eneuGu d•n uf d,u rs.le..I eleu.uL re tl,enkwrcnl rtrciew far tSrireue¢eWou, T10 30 2-1 353
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0 Eastcott found a parallel difference in lung cancer mortality behveen imntiFrmlts from Great Ilritaiu to \etc Zealand and native-born New Zealanders; at the same time tobacco consump- tion for the two oroup; uas observed to be com- parable. Eastcott concluded that "Differences in habits of tobacco-smoking are unlikely to con- tribute to this picture;' and "The environmental factors concerned are unlikely too to be of a personal kind related to the way of life of the. imntigrant" In 1960, hia data were extended to cover.ten years' compa)'ison of the mortality ex- perience of 250,000 immigrants from the U. K. against that of 2,S00,000 native-born New Zea- landers. Neither Dean nor Eastcott nor the present study offers a correlation between a single fac- tor and mortality t'ates. They merely indicate that the higher mortality, whether from lung cancer alone or from thia and other causes, does not associate «-ith higher tobacco consumption. Rigorous interpretation of these findings as op- posing the tobacco theory does net require the assumption that other factors remained constant. Actually, the results indicated that other factm•s did not remain constant, since important death rate differences were recorded despite similar or contrahypothetical rate, of smoking, although - the precise identification of these other factors is not germane to this inquitti•. . Bearing on both types of study is the observed tendency of many seiecteti popuiatimi subgroups to manifest lower mortality rates than the popu- lation as a whole. Hammond-Horn, for example, estimated that "the death rate of our study population would stabilize at about S1't to $51~ of the rate for white males in the general United States population," attributing this favorable comparison to selection of subjects from coun- ties with lower death rates and to "a slight de- gree of socioeconomic selection." - Emplocee populations, such as the one studied by Dorn-Laum, Haag-Hal;mer and the writers, also represent a tle"ree of selection resulting from the initial medical •'screeninfi° of appli- cants for employment. This eriect, according to H:mmtond-Horn, ";limini-hes rapidly with time, is relatively slight after the third year, and for African-Lnro men amokin¢ 1-?V ciFaretR•; a dar xhawed Iuxer lunf; ranrcr ortulit> ratca than nommo:ery in euch U-K. Ineatione as Li+-erp(ol. L..n.a>hire. DenLich S.E.. Flint anJ eheshirn dlso. "In Seuth Alnranrural orca• the lunr csncer tnortnlit> rate for men aced J; to •;t yearo ., ver, lo.r for buth nnrnninke:, and mnJerv.- amoker=. andfncrcued nnly With heazy c., retre <,nkine." nd "Th.- hirhen lane c+neer ntnrtality rate, aere fuund here heavy mo:inc ar com- ' bincd with e.posure to nir Pnl!utian:' ICnt. Jf.d. l.3J599, 1^61) Dean'e wtimates euccea ehe Po..IhiGb' that e •,t oanukinF nfay be rliarnu;tlc n( athcr (aetnn Pr..li-pn~inctohi,:her mortalltv n,tr,: thi. c,:JJ , nf fu, thc a au.,n, faund b, Dull-)Iilf : nA . . ,. .md .vwld : ..l be e~nq.ti61e lrith thc findin,; of lo.v mi-nLq' fur Inntc c,vtqs of amoker7 in beun. Ewtcott, and the pre.ent .rudy. lfarck,196° 1964 Page 352 (e) all practical purpose, ticea t's off within five years." Although the exact duration of this screening effect would not be important in a study extend- ing 141a years, the significance of the present study does not lie in the fact that the tobacco employee population (like other selected groups) shows lower-than-average mortality. Rather, it ties in the fact that this lotcer-than-ati'erage mor- tality exists concurrent with a pattern of dis- tinctly heatiy smoking and in the fact that . respiratory cancer mortality - alleged to be specifically and causally linl:ed to cigarette con- sumption - is as much below average in this heavy-smoking population as is mortality from other causes or from all causes. It has been pointed out that employee groups enjoy better-than-average medical care and forr this reason are likely to manifest lower-than- average mort ality rates. In the first mortality study in this series, Dorn-Eaum noted the find- ings""are not surprising in view of the medical care program provided by the company for its employees.'r To the extent that medical care favorably affects the mortality rates of the em- ployee population, the postulate is denied that cigarette smoking in and of itself is a major cause of respiratory cancer, or heart disease, or decreasedlmlgecitc. The previous study in this series' was criti- cized on several grounds by Caset' who, in turn, was quoted by Cornfield et aIJ", This criticism if valid, also would apply to the present report: 1. Case questions the comparability of the tobacco workers with the general popu- lation in reg,ud to characteristics other than smoking (and age-sex-color, which is allotaed for in the deternr.nation of expected rates). On grounds such a, these all sta- tistical studies in this area may be called into qucstion, but the present study less than most, since it represents a cross-sec- tional population with regard to socioeco- nomic-occup:.tional levels. Further, the basis of Case's argument, that mortality, particularly from primary lung cancer, is associated with other factors, calls into question the specificity of the tobacco hypo- thesis. 2. Case applies a Hammond-Hotafactor for inereased lung cancer mortality expec- tation (ba;ed on the tobacco workers' great- er smoking rate) of 1.7 to the previous 'study and arrices at an expected number . of luntt cancer deaths of seven. He then demonstrates that the sampling error of this studsis such that 0-S such deaths could orcur at the P=.03 level, and that since this include; the atiiustat freqneccy of seven the results cannot refute the 119 T10 30 2-1 350
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1964 Page 353 (d) ~ A REYIErf Or "S110r.INn A\D 1IEALT/r" i.~.5 ~ Chapter 3 also has a section on "Causality," (pages 20-21), the essential • pa : nf which nppears to be "It is recognized that often the coexistence of eecersl factors is required for the occurrence of a discase, and that one of the : factors may play a determinant role, i.e. without it the other factors ... are f impotent... . The word cause is the one in general usage ... and is capable of conveying thc notion of a significant, effectual, relationship between un agent and an a>sociated disorder or disease in the host." Presumably in the lung cancer situation cnusc must be defined probsbilidi- ally. 9 cery ovzr-simplified sketch might be as follows. Suppose that each iadh-idual and his circumstances and environment can be classified diehoto- mously on each cf rs claaiGeations, so that he is either an El or an Ei, an F,a or an E,•, etc., where F.r• is the complement or T:r, etc. Suppose now that ~ Pr{EtI EaEj ...Ei{ 3-`Pr{Er{Fx`Ej ...Ee}, where E, -•• Ek is some speci(ed subset of conditions Er; •••, E.. Then, for . that act of conditions F.; -•- Er, the probability or E, given F7 is diirerent from the prebability of E, given E,t Since the presence or absence of Er a7ects thcprobability of E,, it seems reasonable to say that E: is a cause of E,. The practical significance of Ee as a cau,e of Pt r ilt depend an two conditions: (a) If the left hand side of the aboac inequality, though not exactly equal tathe right hand side, is numerically quite close, then for that set of E; ••• E& - (lie caueatire associatian may he of =msii pnctical importance. -(b) If the inequality holds only for, say, one particular subset EJ, --•, E., .. and for all other subscts equality holds, and if the subset E...... F,, occurs in the population with low probability, then Pr{E,{E,1, while not strictly equa] to Pr (Er{ E,•i, u'ill be mlmericnlly close to it, and then E, as a cause of E, may be of small practical importance. These considerations are related to the Committee's responsibility for as=_essment of the nmgnitudc of the health hazard (page S). Further complesitics arise when we distiag7aish between cases m which one of thc rcqnired secondarp conditions E..... Et is, on the one hand, presumably controllable by the individual, e.g. the eating of parsnips, aruncontrollablq c.F. the presence of some genetic propcrty.In the latter case, ~d further makes a tli;icrenee w-hetlsr the genetic property ie identifiab!e or non-identifiable: for e.<smple, it could be brown eyes aAich is the significant ;subsidiary condition E;, and we could tell everybody with not-brown eycs it a-as s:de for them to smoke. Chapter 4 is a set of Summaries and Conclusions. Chapter L gives consump- .tion of tobacco prochicts, including- chewing tobacco and snuff, for the linited States for selected yeacs from 1950 to 13G2. Chapter 6 is on "Chemical and Physical Characteristics of Tobacco and Tobneco Smoke." Chapter 7, "Phar- macology and Toxicology of \icotinc," concludes that nicotine is unlikely to he important. In Chapter 8 we come to a discussion of the relationship between smoking and mortality. Subscquent chapters deal with speciGc groups of diseases: 9. Cnneer; 10, a;on \er,plastic Re~piralory Diseases; 11, Cardiovasc•,lar Diseases; 12, Other Conditions. Chapter 13, "Characterization of the Tobacco I T10 30 2-1 3 56
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1964 Ya[-;e 353 (r) ,\ IIl:Vt6A' OF °6]fOA"I\G AND HEAL78" 739 (101 Ikrksun, J., 'Smoking and lung cancer: some observntione on two recent reporte,' Journal of the Americaa Slclistirct Aasaciation, 53 (1853), 28-38. 1511 Berkson, J.,'Smoking nnd lun¢ canrcr," {nari<un SJCti.stipcn, 17 (1903), 15-^"2 (1.1 CornSeld, Jerome, et al., "Sn:oki::G and lung ranrer: Recent evidence nnd a dier'is- sion of conte questians," Jeurnal qr the .\'ational Cenccr IvsG:utr, 22 (1959), 173-203. (131 Ifammand, E. Culdcr, "~nakir5 in rclaC.nn to mnrlnLty and morbidity: Findings in first 34 montns of follow-up in a prospcctire stuJ' started in 19i9." Ststistical Ito- uareb Bectioq uiedical A17:r.rv, Lepartmeut of the American Car:cer Society. (171 Tervshslmy, J., "Statiaiol considcrations and etnluation of epideminlogical evi- denee,' in Jaraes, George, and linsenthal, Theodore, To3ac<o and Jlraiih. Spring- feeld: Charles C Thomas, 306=, 205-30. 1151 Peuslulmy, J., and Palmer, Carroll L'., "On the methodology of investigations of etiologic factors in chronic dismses," Journal of Clvanic Diuasre, 10 (10i9), 27-40. (16/ Eysenek, Il. J., Tarrant, 11., 1loolf, ]L, and Lngl,nd, I.., 'Smo:ing and pcr- eonslity," TrHisfi ,7fcdiaal Joun:c7, I (I9G0), 1i50-G0. ([7] Seltzer, Carl C., "Norpuoloqic ror.stitufion and smoking,' Journal aJthe American Jledical Associa:ion, 193 (19Q3), 639-45. . 116] Uorn, lfaro!d F., and Crder, SiJncy J., "Nforhidity from cancer in the United States,' Public lfealth >fonogrs.ph So. 56, 1959. 119]Fisher, I:. A., Letter to the Etitor, 3aA.re, 13G (1935), ;74, 1'0/ Yule, G. V., 'The function of sclenti&e method in scienti0c investigalion,' Industrial Fatigue Iicsearch Board Report, 26 (1924). (2lf Irwin,J.0.,'The plxre of n:~,rSrmstirs in medical and biolugienl elntietita,' Journal of the Royef Slatiet{eaf Sociely, Svice A, 120 (19G3), 1-45. (22] Fisher, R. A., 'Csncer end smoiing," Letter to the Editor, Rclurc, 192 (1955), 590. ('3/ Friherg, L., Xsij, L., 17encker, 3. J., and Tonssoq L., `Smoking habits in monnzy- 6olic and diaJgotic tnins,' BritisA ,tfrdiral Journal, 1(1t199), 1090-2. - -710302-1370
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1964 Page 353 (i) 730 AMERICAN 6TATISTICAL Aa50ClATION JOURNAL, BEPIEMBER rPod reasons for this conclusion appear to be (a) the presumption that the genetic hypothesis would have to be very complicated to include the dose-response relationship, etc., and (b) the rapid historical rise of lung cancer. Finally, sundry factor, such as occupational hazards, urbanization, air pollu- tion, etc., are mentioned, and on page 196 the conclusion of causality is un- equivocally stated. This rev icm has so far bcen largely restricted to a summarization of the rele- vant arguments leading to the above important conclusion. I xill now discuss the question of whether the available evidence justifics the Report in reachin- that conclusion. lt is possib;e of course, for the conclusion to be in fact correct but for the evidence in its favor to be inadequate. We are all familiar with the accused ww has to be found not guilty, because of insufiicicnt evidence, though we arc personally certain of his guilt. Let us now comment on various parts of thc Report's position. . In my opinion a key factor in determining onc's opinions is one e iuterpre- tation of Table 26, pages 10D-I1Q which shous the mortality ratios, individu- ally by separate study and also jointly, for 25 causes of dcath, ordered from cancer of lun, with a total mortality ratio of 10-8, bronchitis and emphysema with a total mortality ratio of 6.1, down to cancer of the rectum (1.0) and cancer of the intestines (0!J). The l:ctter cause of death is the only one out of the 25 to show a total mortality ratin of Icss than 1. The total over all studies column of Table 26 is reproduced herc as'lablc 1. The median of the?3 total mortality ratios is LE, asd E are gruate. tfian 2.0. One could adopt aa c::trzme null hy- pothes'.s attitude and admit that only those causes of death for V;hich the total mortality ratio was statistically significantly greater than 1 arc genuinely asso- ciated rrith cigarette smoking. The technical details of this statistical problem would be difficult on accouut of the various "sampling" procedures involved, allowances for po,sible Lis=ia and dependencies, the varying sample sizes, and the multiplicity of the tcsts being made. If xe take the tnenty-firsl cause of death, "accidents, suicides, and violence," with a total mortality ratio of 1._', it is noteworthv that in ca,h nf the cmvrn L xtcdie; the ;;:urtality ratio is greater than 1. In my opinion virtually every tabulated cause of death shows a mortality ratio greater than 1. I do not rcl,ard even the twenty-fifth cause of death, cancer of the intestinrs, as significantly an exception to this, as if " look at c;timatcs of 25 paramuters the sm:dlest of the 25 is likely to be smaller ~ than its populatimn value, and at 0-9 it would not take much of a samplingl error to Lrinl; thc ratio orcr 1. IIo%% ever, «9tclbcr one fecls that p:obably all 25 eauses of death hace mortalit}• ratios greater than 1, or mercly the first ?I out of the 25, or the first 15, makes little dificrence in my opinion. In the dis-I eussion I gice beloc, I shall rse the phrase "eirtually all causes of death" but it could be replaced by some such phrase as °21 out of 25 causes of death' without changing appreciably the import of the discussion. One's interpretation of Table .90 determincs Nrhether one accepts the Rr port's conclusion (page 1S3) "Thus, it is reasonable to conclude that the asso- ciation bet~sceu cil;arctte >m.nkiug and lun; caucer has a high degree of; slkcilici,y" as, on the ene hsnd, reasonable, or on the other hand, as an ez- traordiuary etatemeodt completely in violation with the facts. The Report T10 30 2-1 3 61
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1964 pPage 353 (j) A AF.ViRW O£ °SHO6ISG AND nEALTH' 731 TABLE 1. ;\i1MRI:RS OF F.\PECTED AND DEATII FOR S\IU&F.RS OF' CIGAItf:7Tt.> U~LY, AND NtOf:TALITY P,ATIOS, TUThIJ.ED OCIiR ALL cP:cl:'; P1t11S1'IiCTl1'li STi;UIP.S. TAKEN FROM TAIILF. 20, t'AGE 110, OF TIIE ItEPORT Cause of death Deaths Mortality E.pected Observed ratio Cancer of lung 170.3 1,533 10.8 Bronchilis, emphysema 90.5 546 6.1 Cancer of larvux 14.0 75 5.4 Cancer of oral cavity 37.0 152 4.1 Cancer of csophegus 33.7 113 3.4 Stomach and duodenal ulcers 105.1 294 2.8 Other circulatory discuses 254.0 649 2.6 Cirrhosis of liver 169.2 379 2.2 Cancer of bladder 111.6 216 1.9 Coronary artery disease 6,430.7 1I,177 • 1.7 Other hesrt diseases 526.0 866 1.7 Hypertensive heart disease 409.2 631 1.5 Ceneral erterieselerosis 210.7 310 1.5 Cancer of kidney 79.0 120 1.5 All other cancer 1,061.4 1,524 1.4 Canccr of atomach 255.2 413 1.4 InOucnza, pneumonia 303.2 415 1.4 All other causes 1,509.7 1,948 1.3 Cerebral vascular lesions 1,4G1.8 1.844 1.3 Ca^cer or prostate 253.0 318 3.3 Accidents, suicides, violence 1,OG3.2 1,310 1.2 \ephritis 156.4 173 1.1 Rheumatic heart disease 290.0 309 1.1 Cancer of rectum 207.8 213 1.0 Csncerof intestinea 422.G 395 .9 All causes 15,G53.0 26,223 1.68 accepts `spcci6city^ as one of the criteria of "the enidec~i~rnric m^.thod" (paecs 20, 1S3), and in my opinion the way it claims the facts are in conformity with the critrrion is to flatly ignore the facts. In my opinion, thercfore, T able 20 raises difi'wultics which the Report totally fails to face up to. The Ji"iculties are as follows. ' If one believes that the observed association between smoking and lung cancer is substantially real, and iiot an artefact of biased sampling, then one would seem required also to accept the ob<crved association between smoking andalmost all causes of death as substantiallv real. If one believes that the oh;crred associatinn betnccn cigarette smoking and Virtually all causes of death is substantially real, then one must take one of the following positions: (a) All the acsociations are due to causation. (b) Some of the associations are due to causation and others to correlatious, concealed or othencise. (c) All of the associations are due to correlations, concealed or othereise. '"710302-1362
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1964 Fare 353 (0 A REY3ER' OF a6](OIC7N0 A>rD HEALTIIa TABLE 2 X X• Suma over X aod X• S s• s - s• s s• C C• D.a0a:o 0.44550 0.00050 0.04950 o.nono5 o.0i99; 0.00045 0.44955 0.00455 0.o0osa 0.49545 0.49905 Sum, 0.45010 0.05000 0.05000 0.45000 field et a] 1121 that if the mortality ratio for smokers to non-smakere for a particular diseasc is k, then factor X must be present at least k times more frequently among smo}:crs than among non-smokers. The Report does refer tothis result, without citation of source, in the section on specificity (page 184), nhcrc its relevance escapes me. It is clear, however, that Cornfield ct al regard this result as one of the key arguments sgainst thp constitutional hypothesis, a.s they cite it prornir•.ent]}' in the Summary to their paper [12): "The magnitude of the ex cess lung canccr risk among cigarette smokers is so great that the results enn not be interprcted as arising from an indirect acwcia- fion of cigarette smoking with some other agent or chcracteristie, since this hypothetical agent would have to be at least as etronely associated with lung cancer as cigarette use; no such a,ent has been found or suggested." :1 simple nrithmetical illu=_tratiorn of this (:nathematical) phenomenon is de- arlapcd below. Suppose that the population is divided 50:50 into X and X•- Suppose th±t arr.onrrst .`.- peopie the proi,+biiity of being n smoker is 0.9 sr.d the proF,abil:ty of getting cancer is 0.01, and that these protmhilitics arc inde- pendent. Suppose further that among %' people the probabilit,v of being a smol:er is 0.1 and the probability of getting cancer is 0.001, and that these prob- abilities are independent. Then the resulting probabilities are in Table 2. The cancer rate among smokers is 0.0015.i/(D.0043L-I-0.4D545)=0.0091 and the cancer rate among non-smokers is 0.00005/(0.00005-I-0.49005)=0.ODl9: the mortality ratio for cancer for smokes/non-snrokrrs is thus 0.0001/0.0019 =9.79-The X rate amone smokors i~ n.h!lp.q.i-~0.05) --0M and among non- smokers is 0.05/(0.05-i-0.55)=0.10; the ratio for X for smokers/non-smokera is thus 0JJ0/0.10=9.0. This illustrates Cornfield ct al's point that the X ratio for smokers/non-smokers must be grcater than the mortality ratio for amoker/non-smokcrs. I do not feel that the numericnl valucs of the parameters inscrtcd in this simple model are ridiculous, yet ni;h independence of S and C for S and for X• mee came out rcith a lar„e mortality ratio for the population as a ahole. T do not see why the fact that the X ratio is larger than the mortality mtio is any embarr:asment to the corstitutional hypothesis. The Report qnates vario us results frnm i lammond's Intest report [13] which illustrates carious phenomenc rihich csn bc attributed to various constitrd.ional h}-pothese:, though one could nlso easily construct other causal hypotheses in eeh case. The °eGect' of the use of tranquilizers, for example is shown in Tah1e 3. (All mm•.heis quoted in TnLles:h0 are nge standardized death rates from nll causes for mnle-,) Recalling that this data was collected by volunteens, ;
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1964 Page 352 (b) ® F1 ® Table I indicates that the observed number of daaths during the 1rJa7-1'JG0 period was 76Ci of the number that would be expected to occur I in an arerage Lr. S. population similarly stratified : as to age, sex, and color. The number of cancer deaths was G3', of the expectancy. Respiratory cancer deaths were 4V, of the expectancy, car- Ziovascular deaths 36% of the expectancy, and coronary deaths 36Sc of the expectancy. No deaths from primary lung cancer occurred dur- jing this period, although an expectancy of '. seven such deaths was derived from vital statis- tics tics for the U. S. as a whole. ~Previous Mortality Rates for the Same Population ' Similar percentages of observed-to-expected ~ deaths in the seve]al chissification, were observed by Dorn-liaum for the period October 1936-1952 and by Haag-Hanmer for 19a3-19-a6. Percentages of observed-to-expected deaths cov- ering .the results of all three studies as well as the complete time span of 1dl,y years are ar- rayed in Table 11. Allowing for the random fluctuation in the number of particular causes of death that is observed in most population sub- groups, and espeei:dlp for thoset•au-e; fromwhich the number of deaths is small (e.g., respiratory ia:e;ti;r._:ions cancer), the results ef the threc show internal consistencp. Escept for the afore- mentioned cause involving few deaths, the per- centages front one study to the next show no radical variation. The over-all percentages in Column 4, Table 11, characterizing the obserced- to-expected ratio for the several cause cate- gories during the entire 1d1.'t year period, fall within a range of nine percentage points. Ob- jserved deaths ranged from 7V, to 79<< of the expectancy for all causes, for cancer, for respira- tory caneer, for cardiovascular and for coronary disease. Since Dorn-Eaum did not compute a separate expectancy category for primary lung cancer as distinct frem the general category of respiratory cancer both primary and secondary, this cate- gory does not appear in Table il. In the two TABLE II. -PERCESTAGE OF ODSERVen TO ESPECTED DEATHS lIi THREE SGCCEiBtCE STUDIES OF 'FULL-T11IE dVD RETIRED E?IetOVees OF CIGARETTE PLANTS AND STE]IHEDIE3 OF TnE A?IERICA.\' - ToaACCO Co]IYA\r ' Dorn- Raum (OCL 1946- 195_1 Haap- ttnnmcr (19it- 11150 193]- 1560) TaLI Period (Oct. 19J6- 1960) AAll caunw tiM a 69~'o i6!-o Cencrr - ull furms :] c - ` 63G 70 n funcer-nzpinu.n.-.rsrem 6G' } 1J9 '~ J:rc Y1'-e Cnrdt:rvavcul:v Cornuary di.ruc 67% S0q'o 761b 6S($ SG% 6G o :p^e latter studies covering eight years, fotr deathx from this cause were recorded, representing 3G;; of the normal expectancy of 11. Smoking Habits of the Population under Study As previously reported by Finkner et al., the proportion of regular cigarette smokers among the tobacco employees studied was much greater than that in the general U. S. popUlation. Among white males, 77.2~~~ of the tobacco emploYee.+ were regular cigarette smokers, compared with 49.9rc for the general U. S. population; for ; nonwhite males, 33.Vc compared with 43.-1', for white fenmles, -1-4.4~~ compared with 23.6r, ; and for nonwhite females, 61.7<< compared with - 22.Vr. The tobacco employee population also included a considerably higher percentage of smokers consuming more than 20 cigarettes daily than the general U. S. population. Amone white males, 52.8~0 of the tobacco employees smoked more than 20 cigarettes a day as against.13 .3rc for the general U. S. population. Nonwhite males among the tobacco employees included 16.5(~ smoking more than 20 cigarettes a day as against 6.91, in the general U. S. population. For v.-hite females the proportion was 6.9(, among tobacco employees :.S :g..:St o.1rp .: the ne nCr:.: p Opq- lation, and for nonwhite iemaies d.0`c a; against 1.7rr•In each category, the proportion of tobaeco.tcorkers smoking more than 20 cigarettes a day is of the order of two and a half times that of the comparable segment of the U. S. population. Methodology In all three mortality studies, ob;erced deaths were tabulated from reports of the Metropolitan Life Insurance Company, which underwrites in- . surance policies on all emplocees of the group studied, including those on leave, those retired for disability, and those retired for age. Death rates for the general U. S. population were cotn- puted by dividing total deaths, as reported in Yitad S'tati.,(ics of tlre U. S., Tolume ll { by the population estimate, issued by the Bureau of the Census for July 1 of each year (Series P-26).° For the 1937-19G0 period, rates for the year 196S were used to compute expectancies for 1957 and 1953, and rates for the cear 1959 tiwere used to compute expectancies for 1959 and 1960. Rates were computed separately for male white, male nonwhite, fen:ale white, and female nolr white, and for all the ale groups 1=r'_,, 2.i Z4, 36- .14, d5-5-1, 6-I-0-1, G5-7.1, 75 and oser. These rates were a1'Iplied to the number of per' son-years of exposure in each age, color, and 'ex alte~-ory of the pu•^hdion undvr stutiy. The roster of enr plocees tincluding retired employees and those T10 30 2-1 347
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1964 Pag;e 353 tg) 728 AMERICAN STATISTICAL ASSOCIATIOV JOURNAL, FEPTE9nER IW I i eonclusion (page 190) "Cigarette smokino is cau=ully related to lung cancer in men." We will now sumnrarize the arguments that led to that conclusion. Pages 150-161 rceieu"29 retrospective studies and, briefly, the i prospective studies that had been discuxscd in Chapter S. There follows a discussion of at- tempts to induce lung cancer with tobacco e~tracts and tobacco smoke in e<- perimental animals. These have not been successful. However, industrial car- cinogens were efectice. Another section (page 10i) reports that "genetic factors e.crt a detenninino influence on :he spontaneous development and in• duction of lung tumors in mice." 1'ages 1Tu-I7G discuss the correlation of national crude male death rates for lung cancer with per capita consmnption of cigarettes. Using a 20 year la, Doll obtained r=0.73 w ith I I countries. The "population" from which these 11 countries were "eampled" is not described. Pages Ii8-1S2 discuss possible biases heiug responsible for the obsen•edassociation, and coocludes that the observed association is real. ~ The Report then moves to cstablish the cau sal significance of the association, its argununrs fol;owing the five cr:teria that Chapter.3 lisled as being patl (or all?) of the "cpidemiologie metlad." . (a) The first criteriou is "consistency." The 29 retrospective and the i prospective studies all demonstrate the sanu association. (b) °The most direct measure of the strength of the association betwcen smoking and lung cancer is the ratio of lung cancer rates for sntokers to non amokcrs ..." It is hi;;h, of tbc order of 9 to 1. aso "Import^.nt to the strengtt as well as to the coherence of the association is the doso-uGect phenornonon. Iu every prospective study that provided this intionnation, the dose-enecs ara apparent . . . " (c) The specificity of the association "implics the precision n ith .vhich om component of an associated pair can be utilized to predict the occurrence u the other." This :ecros a curious use of the word "specificity:" A more sntS- y factory definition would seem to be Ycrushclmy and Palmer's (I5] "The bas( assumption of such a test for specificity is that ii the characteristic is not rclatcN to the disease in a causal way, then the rclationship should not be reslricto. to the disease under study but should also be present with other discase cutitics If the charactcriaic can be shown to be related only or mostly to the disear under atudy and not to many other disease entities, then our confidence tha' it is a cause-carrying vector for that discase is grcatly inereased." This section of the Report discusses both these interpretations, its own nni Yerushslmy and Palmer's, of "spccilicity." On the first, it comments that wit'; diseases Irith multiple causc> one cannot expect high specificity in this scus, On the second, the Hcport states "The number of diseases in which tC. ratios rcnmiu ..:::..:. "..... .. ,,.. r:r,a :.^ bt: 3s not great enough to cast serious doubt on. the causal hypothesis." It furt.ller conrrnents that even a singlesu6stance might cause several diseas' and a miaure of suLetnnces, such as occur in tobacco smoke, might "pred•u more than a si~gle disoasc." The Iicport concludes "'1'Ims, it is reasonable I eonclude that the aa:ociaLiml between cigarette smoking and lung eanccr ha a high degree of specificity." -~,,T10302-1359
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1964 Page 353 (q) 738 AILERICAS STATISTIC.\L ASSOCIATIO\ JOURNAL, eEPTENLER 1:W Paasing over the qurstion of m I iether any governmental action is warranted. each indiridual cigarette smoker L:u to decide whctlicr to mako the effort to give up cigarettc smoking. To make this dccision he would need to knoir (a) the change in his expectation of life assuming that lung cancer alone is causally connected with ci;;arctte smoking, (b) the change in his expectation . of life essuuing that virtually all causes of death are causally connected with cagarctte smokin;. The Report does rtot appear to provide these figqres (scarching in the Report for any part.icular topic is somnetimes difficult as the Report has no indes), which ia ratLcr surprisin, in victc of tLe fact tlmt an assessment of the magnilude of the health ha zard was one of the Committee's prime responsibitities (page 8). The individual cigarette smoker would then have to weight the above changes in cxpeetation by his assessment of the question of whether the _ cigarette smoking was a cause. He would have to rclate this expected chanee in cxpcctation of life to the analo¢ous probable expected changes in expectation of life caused by various other of hi; activities wldch probably cause decreasei ~ in expectation of life, such as over-eatin;, undersleepinfl, under-exccisinc. travelling by aetomobile, etc. He would also have to weigh the possibility of such adverse consequences of giving up smoking as in due course bccoming ap- preciably ovenrcipht% lle would have to assign utilities to the expected change in expectation of life and to the pleasure and satisfaction he gets from cigarette smoking. It is unfortunate that the Report does not give a table of changes in ez- '; pectation of life, for if the change at, say, age 30 was 10 years, then even if one ; assigned a probability of 1/5 to the cigarette smoking causality hypothesis i being true, the net cl+nng,e of 2vlars would give one pause to censidc:,-sl:c:ra' if the clrange at age 30 is only 2 years, then the net change of 0.4 years on an.: average expectation of about 40 years might not be taken too seriously by ~ some people. i~ !.. REFEHE\CEa (1) hi811er, F.J.,'Tabakrnissbrauch und Lungenenrcinom,' Zeitamp fur %n6afcrscAvn•~ Pen, 49 (1939), 57-84. - (^_) Doll, It., and 11111, A. 13., `A study of the aetiology of carcinoma of the lung,' Brd41AJcdicat Jounml, 2 (1052), 1271-SG. (3J Doll, R., nml 11i11, A. Il., "The mortality of doctore in relation to their emukin{' . habita; a prcliminsrv report," P,rilirF Merlicol Journal, 1 (1954), 1451-5. . (4) Ilamrnood, 1:. C., and llorn, D., •The relationshin betmecn human smoang babin' and death rates: A lolloT-•up etudy of IS7,7G6 men,' Jormwl of the Americnn dhd•' trol.laaocialion, 155 (195a), 1310,49. (51 Ke~-man, J., 'Statisliao-servane of all scieneee,° Sciance, 122 (1955), 401-B. i (6) Iicrkeoo, J.,'The eiatistieal study of a=sociation hetwcen nmokin6 and lung cancer; 1 Yroctcdinp ql the StafJ 1•fr:!inr,s o,f 1he .11ayo Clinie, 30 (1955), 319-4&. . (7) Dlninlv~!, 11., and [?errera, L., "fhe ri,k of biaeed selection in forxard-going survepl wilh nanpmfcviounl inlcrsiexcrn," Journnl of Chrmrie Diseasra, 4(I95G), 240-4. 181 Curler, Siducy J., 'A revie+v of the xtatistical evidenee on the aesociation betweeu smoking nnd lnnC cnnccr,' Journat oJ the Americnn Sfalialical Associalion, 53 (1955), 267-8^.. (91 Finher, II. A., Lattcr to the Bditor, Jbiliah h7edirnl Journal, 2 (1957), 297-8. T10 30 2-1 369
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n mond-IIorn, Doll-Hifl type compute expected deaths on the basis of mortality rates shown by professed nonsmokers. The professed nonsmoker is taken as the norm or "average" against which various types of smokers are compared. This raises two qucstions: ,1) whether those smok- ers who manifest higher mortality rates do so as a direct result of the effects of smoking, or syfiether the smoking habits of some of these higher-ntortality smokers are diagnostic of other factors that predi: pose to shorter life, and (2) whether the professed nonsmoker with his low mortality rate can be taken as a norm. ) ~ Tho former question cannot be ansttered from the statistics themselves, since this would re- quire that all relevant or predisposing factors other than smoking be held constant. \o attempt was made in tl:e Doll-Hill, Hammond-Hortt, or their counterpart studies to do this, since all relevant factors affecting mortality and• or can- cer cer mortality are not known, and since some of the suspected factors -,:precious medical his- tory, genotypic differences, constitutional pre- disposition, exposure to various encironmental agents, "rate of living," the "stress" factor, etc.' - are difficult if not impossible to reduce to mathematical terms, even if they could be gath- ered for populations large enough for statistical study. Touching on the latter question, Berkson' has noted that ... persons who are nonsmokers, or rcla= tirel}- light smokers, are of a constitutional type that is biologically disposed to self- protective habits. ... It is not implausible that they should be, on the acerage, rela- tively longevous, and this implies that the - death rates generally in this segment of the population will be relatively lou•. The extent of this difierence between death rates of professed nmumosers and average U. S. citizens was indicated by Hammond-IIorn, who computed mortality rates of 777, 1,253, 1,781, and 3°S0 per 100,000 for nonsmoking white males in their 50-:5-1, 6.i-59, 60-G1 and 66-69 aare groups, compared with rates of 1,-139, 2,210, 3,402, and 4,593 per 100,00 for white males of the same age grouns in the general population. These mortality differences between the profes~ed nonsmoker and the~•average" white male reported by Hammond-Ilorn were great - 801.,, 76~f, 91<<, and 4P(c. Should Befkson's characteriza- tion of nonsmokers be correct even for a num- ber of persons in that category, the Hammond- Horn interpretation that cw:reette smokers incur e'excess'r mortality rates becomes meaningles;. That is, the association their data shotced re- (lects only the choice of an abnormally longevous group :u a criterion of what is "normal." The 118 1964 Page 352 (d) same would be true of a number of other statisti- cal association studies patterned on the Doll- IIill model. The influence of this choice of criterion on their final calculations is evident from Ham. ntond-Ilorn's own comparison of death rates among their "heavy - cigarette smokers" Nrith death rates among C. S. white males generally. In a 20-month period these rates were 1,222; 2,140; 2,707; and 3,356 per 100,000 for "heavt• cigarette smokers" against 1,288; 2,000; 2,991; and 4,354 per 100,000 for U. S. white males iu the four age groups. These rates hardly differ. In a subsequent 21-month period the "heavy cigarette smokers" showed slightly higher death rates than the U. S. average. Apart from the question whether nonsmokers constitute a valid criterion of "normal" mor- talit}'-and Hamntond-Horn's figures strikingly suggest they do not - a basic difference exists between the two types of studies mentioned. Those patterned after the Doll-Hill model (in- cluding Hammond-Horn) attempt a correlation between mortality rates and smoking habits in individuals. This requires the assumption that no unmeasured other factors exist that might account for or eiplain any correlation that is found. The number of such factors investigated, alone or in conjunction with smoking habits, is thus far small - the so-called °u:'ban factor" (assumed by some to be air pollution), cert-in special occupational exposures, and alcohol con- sumption. By contrast, studies of population subgroups including this series, those by Eastcott,ln and that by Dean,ll deal with mortality rates and smoking habits of groups. Dean compared native white male South Africans with British mate immigrants to South Africa 45-64 years of age. Between 1947 and 1956 the death rate from lung cancer among the former was 50 per 100; 000, and among the latter, 112. At the same time, white South .lfi-icans are amongg the world's heaviest cigarette consumers, with a per capita usage reported 6S1< above that in the United Kingdont in 1)50 and d0Cc higher than the U. K. figmT in 195.5. Dean found urban resi- dence to correlate with lung cancer incidence among South African whites, and concluded that "bronchial carcinoma must result from the total effect of genetic and environmental fac- tors."* •Dean later C,ithered smokinR habit dpta for about haff the lun[ enncer dasthr hi, 1tudn Ucing theye and e set of mauh..l "cuntrdt' -- death, (rom other eausr~r - he ~limakd mortnlitv r.,trs by ara rrv.n+• by cuunt4 of oricin, by rural- urban rt~id<nce, b> w'cupatwnsl eir Gollution, and by tate of amotimr. Thc crv:,tatit re6ti.e a-. iaiun aith hmx eanecr in thoe e.timame inrolrad cm,ntryof oripin itCk. vs. Union nf South dfrieal• L••rt nrban rsi!.ere ubo rhowad eou..i,tent areocintinn. OccuPUtion ahe..ed no m,ucfation. ds to anwkinr, rurnl South lndustrial nlcdicine and Sur9crg T10 30 2-1 349
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1964 Page 3s3.(c) 724 AMERICAN STATISTICAL JOURNAL AS.SOCr.1T[O\, SEPTEMREn Itua The committee met for nine sessions of from two to four days between November 1962 and Decernbcr 1903, and in addition there were "uncounted' meetings of subcommittees. The committee had the assistance of a professional stafi of ci0ht, nith a secretarial and technical staff of fifteen. The committee lists 1S9 individuals or organisations who made "contributions." The iiterature surveyed was enor:nous. A basic blbliagraphy of more than 0000 articles from 1200 journals tlp to 1050 nas supplemented by an additional 1100 titles pro- vided by the ;`Iational Library of .l7edicinc. The Report lists in the references to its various chaptcrs about 900 references. Some of the individual studies eonsidered were thcrosclces enorrnous. For Ilammond's latest report [13], G8,11G volunteers enrolled 1,078,594 men and women. The Report represcnts a tremendous silting, by a large group, of an enormous literature into 397 pa~es, and this review will confine itself to a brief summary of its contents and an assessment of its major conclusions, with emphasis on statistical and mcthodoloaical aspects. . The front matter contains no trace of a statement of date or publication. The very last paoe (pa,e 387) does have as a footnote the notation "U. S. Government 1'rintinp 0Mce: 10G-1 0-71d-?22' in which I presume the '19Gt' is the year of publication. Chapter 1 reviews the evolution of interest in the possible deleterious effects of smoking and the procedures for the establishment of the Committee. Chapter 2 describes the operation of the Committee through its subcommittees, con- sultants, etc. Chapter 3, "C'riteria for Judgment," discusses 'the T•.pidemiologic Tfettmd." It renarks (pages 20-21) "Statist ical methods cannot establish proof of a causa'. :c!ataaship in an r.ssocintion. The causal signiBcance of an nssa eiation is a matter of judgment ... To judge or evaluate the causal si;• nificance of the association between the attribute or agent and the disease, or effect upon health, a number of criteria must be utilized, no one of which is an all-sufficient basis for judgment. These criteria include: . (a) The consistency of the association (b) The strength of the association (c) The specificity of the assoeiation - (d) Tim temporal rcla:ionsSip of the association (c) The coherence of the association" "' . The Report docs not define these terms nt this point, though they nrc discussci in pages 1S2-189 in connection with lung cancer. The Report does not state whether these are jointly sufficient. Nor does this rliscussion of "the epidcmio- logic method" give any mcntion of the f actor of sclf-selcction, as discussed b) Ycrushalrny [l4], Ycrushnlmy and Palmer [1u]. Later in the Report (pagcr I80-131), there is a mention of selection bias, both by the operator of the survey and by the indiridual whose cooperation is bcir.g sought. The subsc quent discussion (page iSl, last paragrap!I) is coneerned .cith the results o: selection of the type caused by exclusion, or decreased probability ofinclusion of persons sick or about to be sick: the discussion does not bear on the well known fact that volunteers (or equivalently, cooperntivo persoru) mny, ant often do, differ in their disease experience. T10302-1355
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a ~ Chapter 11 INP1i0llIIC170N It han been suggested reprtrdly that nnokiur mav have at7verse eCecls on tho eardiavasrulur systen:- licecutly. -tudlrs uf larse gn,ops of peuple have shown that ci; nrrttc sma'sera in pnrtieular are nwm nnnm to <lic carly of certain cardio.asculxr disordrrs thnn num.ntokcrs Chirf anvniq thrsc di+- orders is eorucnrv artrry disna,e• ar:d ll:e prescnt chrq.te•r deals wo=tly with this subject. ll,c chapter bepins with n snmmar.' af infonnatioer about the o<utceCecLa uf sn,ukin~ an the canlinva-cular systcm. Tiris is fullm.ed by a brief account of coroenry disease. ite frequnicy in different kinds of People, and the many fa,:tors knorvn or limu~rLt lo afiect the iikelibood of its develop. rnent The aim hore is not to raic,r criticallv our knnt,6•d;;e of coronary dix.ti+e but an, tr give barkeround for whnt follow'•. lrxt is svmmarized the fnforr.iatiurn currcntly arailaLlr hnm study of large p:~prdY.ion groups on the associatiou oi cicarette smukinl~ with an increas<d tendency to have coronary diacase. lhere follows a bricf .3iscusslun of stnokino and non- eoronary cardiovascular disease. Finallg there is a short review af evidence .ielating to the question of whether cigarette smokers ma., a; a group, differ from nun-smo!Xrs in xars not cavscd by smoking itself. Mortality ralios sltuwing the association between ci~arette smoking aud deaths from cardio- raseular dlscese, e=pecially cornnurp olsea=c, do no: indice.te the ma;nitude of f1m lmrden. This ran be bettcr appreciated fronr consideration of the following facts: cardinvascular disease dcsths now total more than 700,000 annually in the United J'tmes. Of thrsc more than fi6Q(100 erre due to heart discase, witlr more than 500.000 due to arteriosclerotic hcart disease includ- ing coronary disease. The remainine approxiutately 40.000 ne:a ascribed to disease of other parts of the cardiovascular system. Deaths from lung Wnccr total approximately 39,0U0. A mortalil•v ratio of 1.7 for coronary heart disease among ci~arette smokers in thr. seven pros,ocetive studies repre- senls from 32.9 percent to 51.7 percent of all escess dea0u, whereas the much higher lung emrcer ntoemlirr ratio of 10.8 from the same studies repre- settta only 13.5 percent to 24.0 percent of total excess deaths (Chapter 8. Tables 19, 25). PENTINENT PHARMACOLOGY The acute cardiovascular effects of smoking in man and experimental ani• mals are like tlrosc caused by nicotine atone. A smoker who inhales gets ssually 1-2 nm of nicotine from a ci_arclte 156,57). l.ow eonccntrations of nicotinc stimul:,te sympathctic oan~lia, and hish bnecntralions paralyze lhem. Parasmpathetic eanclia respond in the same aay but are Iess scnsiti.e. Nicotine ean also have a srmuat!•.umiu:etic effect by causing the di<charge of nnrepinep6:ine and epinephrine Irour chronra0in eells in ruriaue tL=suas, induding huart, ve__els, and skin (9, 10, 11). In addf1 tion, rnieoGtm prodeccs e:':eats refexly by stimulating tfrc c!:emoraceptors of the carotid and aortic Lodics. 1\ hev nicotine is given intracenuuslv in in- ereasiug doses to do;_> or cats the first effects. at aLout 1 micropram~kg body KYfght, erc increased hrcathin.- and srr.rpathctic stimulatinn, with predn:ni- uant vasoconstriction, carrlioc accele;atimr, and rise in hbod pressure,re- eulting from stimulatiun of the sortic and carutid hodics I1 7). Doses of 4 to 8 micrograms%kq can stimulate pulmona.ry and coronarc ehemorcllcxes srhich produce opposite c6ecG. If a!I these recuptors are inacdvated, much higher dotu are necded to a'oke the cardin+accular eGncb of syrnpathetic stimulation, presum:rhlv thrnueh aetinn on ±ytnpnthetie 'an:_lia or chronmiTin tissue. Intmvrnous zi{mini•tratinn ~.d nirotinr• in thc evoerimcntat animal causes a dischar~e of cpin^p6rico from the adrena n,edulla, and in man ]teavy cigarette smkingg produces an increased urinary exeretion of, catccholzminrs I&f,991. Smoking 1-2 ciiarettes causes in most persoas. hath smokers and non- smokco, sn incrcase in resting heart r:rte of I5-2S hcat per minute, a rise in blood pres<cre of 10-20 mmf L s.=tolic and 5-IS mmFl- diastnlic (76, 73, 85, 86), end an incrcas< in cardiac output of about 0.5 1.'min rsq.m ( i51. There is a decrcas: in dip_ital blood 7o,v and a consequent drop in Ro,er and tattemperuturv 131, 73, 1031. l1e d,crcase in peripheral blood Pox w'hih aormnlly fclloa s. okinc dnes not occur iu x sympatltcctomired limb. in dieating tiut lhe etL<t is mediated primarilg by Ihe s)'mpathctie nervous system rather thas thrnugh the rdease of eatecholamincs frnrn nthrr sites or the direct eCrrt of nicotine uporn tl:c smooth mn=cic of tbe blood ressa•Is themsefves (103). Intravenous nicotine, and prohahly cicarcne snwking na wxll, can produee a sli~Lt transitory incrcasc in thc blood IIJW to resting calf musclc (59). 1964 Page 349 9. Bum, L II. Action of nicotine on the heart Ann N Y Acad Sci 90: 70-73, 3960. 10. Burn, J. II., Leaeh, fi Il., Rand, Ai. J., Thomnson, J. W. Peripheral effeets of nicotine and acetyleholine resernbling those of sympathetic . atimufztion. J Phvsiol 110": 3 32-3 52. 1959. . 11. Burn, J. II., Rand, M. J. Actimt of nieotine on the heart. Brit Med J 1: 137-139, 1958. 17. Comroq J. Il., Jr. Thc pharmsalogicxl setions of nicotine. Ae.n . N Y Aoad Sci 90: 48-51, 1960. 84. Silvrltc, fl., laroon. P. S., llaag, If. B. Action of nicotinr and tt•hacro- smoking on the adrerml medulla. Arch Intern \fed 107: 915-9a1. 1961. 99. Walts, D. T. The ctfert uf nirotine and snmd:ine nmthP•r•rt{•lidi:',z+epinephrine Ann N Y Acad 3ci 90: 7130• l7nU. . 85. Simon, 1). L., lglauer. A. The acute etfect of chc,.fn~ tnhacro smoking in habitual uses. r1nn N Y Acad .'•ci 90: 1f0-1.72. 1ILU. 86. Simon, b. L., Vauer. A. Circulatory effects of pipe and ci_ar smoG.-. ing. Aracr J Ned Sci .41: 22-;0, 1961. 31. Freund, J-, Ward, C. 7Lc aeute et:ect of dgarette smokin, on the diei- ta[eirrnlatiau in health and disease. Ann N Y Acad 7ci 90: 8r101, 1960. 103. Wood, J- E. Effect nt smnkmg on tne penpheral circulation in rela- '- t'ron to envirmmtrntal Iempcrature. Ann N Y Acad Sei 90: 114-113. 1960. 79. Rotteutrin, If., Peirce, C., Russ, E-, Feltlcr, f)., lfuntpumcry, I7. Iufluccce of nivotinc on dre Llood Oorv of rrstinl: skelvt.d mu>clc a.•i of thte diotts in normal subjrcts. Am N Y acad Sci 9'J: 102-113. 1960. = 1~ 75. Regan, T'_ J., lldleno, 11. K., fGnr, 11. J. EB,ct of d,^.amtte snroAii, on coconmy nrcuhtton xnJ cndiac work in pati•utr -ttb artrn,.- . aclcmtir cormiary discasc. Ann N Y Arad Sci'J0: ISb-177), 17i•I] -. S 76. Rchder,'n., Rotl,, G. 3L IQferl nn srnokine on thc ta<nnryLlnoA su;:nr • and peu•ur mninrs. Circ:daiiun 20: 221 4-. ,(T1Q',102-1',j',I]
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1964 pPage 353 (p) a R£YI£IY OF °S1tOS1\G A]D NEALTH" 737 the higher death rate. The Rcport mentions an unpublished analysis supplied to the Committec bc Ip_en and Pfaelzer, with the conclusion, "Further, the cor- rclation of any of these rariablcs with cioarette smoking lrastoo weak to reduce markedly the correlation of cigarette srnoking with mortality after adjustment for the other i ariablc.' It is a pitc that the Report does not give any detail oa this analysis, as it nroy hc that this anaivsis would have carried the greatest eom'ictiou. llonerer, this is spectdation, a•od we can onlc jttdce the Report by what it contains and b%- its references to the published literature. One can interpret the results of Tables 3-4 in various ways. The association nitb longevity of parents and grandparcnts probably has a genetic interpre- tation, though it is poe>iblc to interpret it ern-iromncntally: it could be that the grmndparents settled in an cenirmnmrnt or adopted habits and customs that were favorable to ]ongecity, and lrhich tLcy passed on to the later generations. The association with tranquilizcrs could be interprcted as causal, as is the associatinu with cigarcttn, but it appcnrs equally plausildc to hypothesize that the need for tranquilizcrs, and/nr cigaretles, is merclc a rcfleetion of an under- lying facet of the human orgmtisms iurolced. Likewise, the associations with fried food eating, slecp, and esercise can bc interpreted either as causal or as concealed correlations. It will be recalled that the Committee's assignment was °if possible, to reach some definitive conclusions on the relationship between smoking and health in '"nernl" (page r). "Tbis committee lvouhl prod,.tre snd =ubmit.t to the Fu e^on General a tech- nical report containing evaluaiCions and conclusious" (pnge 8). The Committee's "Jud,me,ut in Brief" was `Cigarette smoking is a health hazard of sufficient importmire in the United States to warrant appropriate remedial action" (page 33). 'fhe detailed conclusiens cqcer pages 37-40; the most important are "Cigar- rttc smoking in causally rclaled to lung cancer in mon." "\falc cigarette smokers have a higher death rate from coronary artery dicra,.c thsn nan-smnking r`l!es, but it is not clear that the associatioa has eausal significanceP NIy opinion is that thc Committee has not established the case for causality in lung carr.cr. ]fy rrasons for this opinion are, to recapitulate; (a) This conclusion ran only be justinrd by proving the genetic hypothesis Ln be false, and this thc Committee has failcd to do. ' (b) Even if there c: as no cpmpetinF hypothesis, the case for causality is at the preeent time significautly h't•akcurd by the gross nonspecificity of the atsocia- tion and by the a6:ence of hypotheticd physical-chemical mechanisms. My opinion that thc Convitt.ce has failed to offer a satisfactoq• proof of the ln-pothesis of causality docs not imply that I believe that the rml=ality hypothe• sis has been proved false. It implies nothinr rnore than I believe that it is not possible to reach deflnitire cmiclusions at this time. Although "Recmnmendations for actions were not to be part of the Phase I eommittec's respon=.ihility" (page S), yet as noted above the Committee did conclude that °appropriatc remedial action" rcas warranted. I tnke this as an excuse to append sonle personal rcflections. 310 30 2-1 36 8
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1967 361 (a) Smoking and hypercholesteroletnia. This subject has been alluded to in the commentary of 1964 document, page 354a. There are several studies indicating that there is no relationship between smoking and cholesterol levels (page 207-210). The cited article (13) Benson et al. does not show that smokers generally have higher serum cholesterol levels than nonsmokers. The Results quoted from the article are as follows: The mean -serum cholesterol was also _ higher in urban men in both age groups . (Table 1). Twenty-one per cent of the younger urban men and 12 per cent . of the older urhan men had serum eho- . lesterol Ieveh of greater than 2G0 mo . _ , per cent in contrast to 11 per cent of . the younger and none or the older rural . . ctalc:.. f . . . . Urban men smoked h>s than thrir rural cohorts. The pcrrcutage of ciga- ~. . . .- .. rette sntokcrs in urban men was less in both a;,e Froup,, but was s1ati<tically . significant only in the younger age . group (TaLlr 1). Howe.er, the-re was a . . higher percentage of "hea.y" (greater ~ than one pack per day) ci;.arrtte smok• . ern in the urhan men in eaclt age group ' . (TaLle 1). Table l--Cnmparison of urban and rural nmles Number ' of Subjects • AgeGroup Urban Rural Urban Rural Mean systolic and 4551 33 28 139/87 121/76 <0.001' - diastolic blood pressure (mmllg) Sri6t 17 16 154/90 127/76 <0.001' Relati.e xeight 4SSi 33 20 107 98 <0.02t ' 5S6t 17 16 ' 100 95 <0.03t Mean serum 4553 33 28 231 211 <0.02t cholesterol (mg/IOOce) 55-64 17 16 ZW 199 <0.10 . Per Cent cigarette 45•SS 33 2.8 42 96 <0.001t woken 5561 17 16 29 56 <0.12 Per cent "heary" 45-54 141 23I 64 , 35 - , (grcatcr than 1 pack/day) eigarene smokers 55-64 51 9I 80 55 , ~. Per cent "a6normal" 45-54 33 28 1s - 7 <0.42 tlectrocardiograma 55bi 16 16 6 12. <055 btean 6ematocrit (;'S) 4554 33 28 - 45 44 <0.42 SSbI 17 16 43 45 <0.11 •Snq.Ue.:y r.n'~M1ucr br s<<~ mwu..ad dwr.tu. 1 nn~Lw.nr o.ni6..m. .,,,.,,,TI0302-1396
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a] 1967 Page 360 (a) Sudden Deaths. This paragraph implies that sudden death occur more frequently among smokers, Schor et al. (86) specified one group of sudden deaths, i. e. those who die from coronary disease undetected. The incidence of sudden deaths of smokers compared to nonsmokers cannot be dcrived from the article. A portion of the Discussion is as follows: The person who dies from coronary heart disease which has escaped detection constitutes a special problem. In our popu- lation 427, were in this category. Our find- ings show that, by our present technidqes, such a person more closely resembled his alive counterpart without evidence of heart disease than he did the person cho ctied with the diagnosis of the disease. rurther- morc, this person died somewhat sooner after his last examination than did the man in schom the discasc had been identi- fied- The lethal process can, therefore, be presumed' to have been advancetl at the time of Gsamination. Clearly, new or im- proved methods will be required to distin- guish this man from normal persons. Re-cent studies (2) suggest that difiefntccs may reside in social, persoaaliq', or other factors that are not now tested in the usual pe- riodic hcalth examination. The one fineling that, in our study, distinguisbed this man from his licing counterpart, ivas heavy cigarette stnokiug. \1-hcthcr this, as such, is an impm"taut factor or simply a ref[ection of some other factor sce are not in a posi- tion to say. "T10302-7394
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1964 Page 353,(:) ' A. A6PIEIY OF '6MOSISO AND HEAVfII" 733 on page 135. The Report omits any comment on the tveakness of this item in its discussion of the "Cohcrcuce of the 1ssociatiou" on page 185. Simi.lar considerations apply to spatial correlations, wldch arn presented on page 178. The fact that the hcpothesis that ci;,arette smokin~l is a eause of cancer appears by and lurge to be in conformity with the data, and hence that this hypothcsis is acceptabic, does not rule out tlic possibil!ty tha.t there arc other hypotheses also in conformity with the As Sir Ronald Fisher (IJ] wrote afmost thirty years ago: °Por the logical fallacy of bcliccin,~ that a hypothesis has been proved to . betrue,merelybecauseitisuotcmttradictedbytheavailablefacts,hasnomore right to ir.sim;atc itself in statistical th^u in other kinds of scientiLc reasoninq:' And as Yule [_^0], quoted by Irwin [31], wrote about forty years ago: °`lou ean prove anything by statistics' is a common l;ibe. Its coutrary is more nearly truc-you eau never prmc auything by statistics. The statisticiau is dealing with the most complex cases of multiple causation. Iie may shotF that thee facts are in accordance with this hcpotheeis or that. But it is quite another thine to show that all other possible hypotheses are escludcd, and that the facts do not admit of any other interpretation than the particular one he may have in mind." It is not clear to me tehat are the optimal, or even sat isf actory, procedures for inference. In the case where there are tno competing hypotheses, one might estimate the "plausibilit7 ratio," analogous to the likelihood ratio, and if it is very•small,<Cl,orverylarge,»l,onecanreachaconclusion.If theplausibility ratio is in the neighborhood of 1, then no decision can be reached. One would further icislr tlmt if the more plausible hy'potheais is chnsen as a null hypotiiesls, then a test of this null lrypothcsi: can be necopted at a large P value, for other- wise one would suspect that neither hypothesis was correct, and if the less plausible hypothesis is tested as a null ip'puthesis one xould Ncant to it be re~ jetted at a small P value. - Tho main altcrnal.icc to thc smokinq causcs-canccr hypothesis is the genetic hy'polhcsis, and there are several odd pieces of information that give plausi- bilftc to it. (1) 91,ere is somc csidoncc that non-smokers, ci-arctto smokers, and pipe and cigar smokers are morpholopically different (Chaptcr 15, reference to Seltzer [17]). (2) There is some evidence that the various classes of smokers and non- arookers are psychologirall-v dil`icrent (Chapter 14, refcrcnce to Eysenck [IG]). (3) There is some evidence that identical twins are more alike than non- identical twins in their sn:oking habits (page 100, references to Fisher [22], Friberq et al [13], and l;^.aschou-Siclsen [24)). (4) "P'oreign-born mi5rants to the Lrnitcd States as a group have age- d adjusted death rates for eancerof the esophagus and stomaeh about tnicethoso recorded for native-born white nmles and females," etc., (pare 134). (5) "The sevcral ctimic groups in the United Statca di=play thcir own char- acteristic patterns of succcsses and dcficits iu risk by site" of cancer (paee 135). It is true, of course, that these phenomena ((9) and (5)) could be the result ------_. ._T10302-1364
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1964 Page 353 (m) r I 734 ANERICAA STATISTICAL ASSOCIATION JOURNAL, SEPTE)inER P141 of social, dietary, or other customs imported by the immit;rants and main- ~ tained for one or more generations, or could be a confoundingg of tieee3ects of the environment of thc rr~,inn of the U. S, in which each eP.mic group tended to settle. Tlms these phenomcna can hc interpreted in terms of environmentat effects rather than genetie efTeets. (6) Yerushalray [i,] pre=cnteddatastron-lysuggestingthat whether ornot the husband smokes is associated with the incidence of premature births. (7) Hammond [13J gives results showing marked association of death rate with longevity of parents and grandparents. On rny reading, the ma!n reasons the Report gives for rejecting the genetic hypothesis are (1) the necessary complezity of the genetic hypothcsis, and (2) the unlikelihood that the genetic pool can have changed sufficiently in the past 5fty years to account for the historical rise in lung cancer rate. For the first difficulty, dlf-;crent genotypes need to be h}pothesized for the - various classes such as ciearette smokers, cigarette smokers nho give up cigarette smoking, cigar sme'.:crs, etc. It seems to me that an enormous number of traits are transmitted genetically, from color of skin and tendency to diabetes and tendency to baldness, and it is completely plausible that the tendency to be a cigarette smoker in varying degrces, a pipe or cigar smoker, and so on can be carried by the genetic code. The second objection referred to above seems to me to overlook a possible fallacy in tl:e i::terprctatio : of `Sstorioa. chaugc in death rates. Yirstly, pessiblv part of tbe long term app:acot rise may be an iliusion causcd by fashions iu diagnosis and by improvements in diagnostic techniques. It is quite probable that several decades ago many cases of lung cancer would have been diaqnosed as tuberculosis. The Report claims (page 140) that over the shoder term, from 1947 on, particularly for data for Connecticut arld \ew York, the increase in genuine as there have been "no signLScant advances in dia,,nostic methods" and in these regions "a high percentage of the cases reported have microscopic confirmation." This comment does not quite bear on the point at issue. The suggestion of the skeptics is not that cases of tuberculosis are now being falsely dir.gnosed as luno cancer but on the contrary that in the past cases of lung cancer were falsely diagnosed as tuberculosis. The second argrrment is more complex. The generation born in ISSO reached the age of 20 in 1900, and a substantial fraction, 24 per cent, had died by this time, presumably Inrgel- v due to the traditional infectious diseases of childhood. The generation boin in 1900 reached the a_m of 20 in 1920, and a lesserfraetion of this genecatiml had dicd by that age, namcly 15 per cent. Tberefore, the 1rJ0`J cohort at the ngcof 30 reprc euts quite a different stratum from the ISS0 col:ort at the same age of 50, since the former iucludes the "a-caklings" .%ho were eliminated from the latter. The relativel,v large number of cases of lun; cancer obsened in thc 1000 cohort can merely be largcly those who reould not have survived to ruu the ri,k of luri,; cancer if they had been borrr 20 years earlier. On this model the allened hi,torical inercase in rate of lung cancer can be readily accounted for. The model is spoculative, however. Ra.her strangcly, the Report does not include in the section devoted to re futmg the con.,titutional hypothesis (pages 190-193) the observations by Corrr .! T10 30 2-1 36 5
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1967 Page 367 (a) M r] Exercise and oxygen debt. It should be noted that the subjects were healthy without heart disease. The increased postexercise oxygen debt was observed in subjects using a a bicycle ergometer which increases the oxygen consumption 20 to 25 fold: (not cited) Chevalier et al. (1963) from 300 to 5, 833 cc/min (64) Krumholz et al. (1964) from 300 to 7, 9D0 cc/min. Such enormous increase in oxygen consumption is not encountered in ordinary work. This paragraph implies that since carbon monoxide inhalation increases postexercise oxygen debt and smokers also show the effect, that carbon monoxide is the cause in smokers. Reference (21) Chevalier et al. specifically stated that the pathogenesis is unknown. Their summary is as follows: Differences have b^_en found in the cardiopulmonary responses fo e:ercise h-aween young ma!e ci;;are!te smo- kers and nonsmo~ers. Thx present stcdy Vr.s u-_-:taken in an atinmpl to dc!erm:na taa cause of such d76_rences. Since smokers carry a chresically e!erated caruox;6a:o- globin kvtl (>4°'A, carton monoxid= vas irhaled by nonsmo',ars to raise Iheir cartexyyemc--!?' ~:n leret to the range seen in a control group of sn:c:csrs. This ma- neuver ezsscd the devc!opnsnt in ncns.ru!.ers of an in- creased oxygend•Lt aitS exercise and a r.dccod pulmo- nary diC:;slne ctp::ity "~I r.st. Tiie afi_r carbon moraxiit ir,h=lation rrare sini!ar to t'ms= found ehen eomparing sm"ers to wr;mckers. The pi1no„er.esis of these chznLes are un:ccen, Lot &,JFport c, rtcn monoxide as a posiu;e eils!°-ic factor c:counting for the less etfic:nl eaarcix aad poorar pcinc:':ry function per- formance of smckers coaryared to r,on;mckers. In the articles cited above, there are differences in responses to exercise of smokers and of nonsmokers inhaling carbon monoxide. The latter show slowing of the heart rate and decreased oxygen uptake during the working period; smokers show tachycardia and increased oxygen uptake. T10 30 2-1 40 6
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1967 Page 368 (a) El H The first group of cited references relate to the acute effects of smoking and do not compare smokers and nonsmokers. Even (72) Mustard and Murphy did not compare smokers and nonsmokers but used the same 7 subjects, all heavy smokers who refrained from smoking for at least three weeks• The interpretation of the results should consider the emotional factors involved in abstaining and resuming smoking which are known to influence platelet adhesiveness. The authors accept this possibility which they could not exclude. Su6fafs.--A varied group of seven white mile rcterans wnv studied. Their ages (given in Table IU nnged bet..ccn 35 and 72. Three had sustain:d m)roeardial jnfaretions, two cefebrovSscL'lar accidems, and one had had recurrent thrombophiehitis, but there ' hzd been no os'ert episodci of vascular disease in any of the patients for some months before the experimc:it was done. The so•euth subject had chronic bronchilis and emphvsema without evidence of vascular disea.c. All were moderately hcasy sntokers (at least ]) cigarettes a day), but all acreed to refrain frnm smokina for three aeeks immediately prior to one test as sxc11 as during the 10 days during which the test was done. Although ee cannot be abiolutcly certain that none of them 6pmd occasionally, we are at least certain that their cigarette consumptions svere greatly reduced. Dict.-A diet of uniform composition and caloric content uas r•..Sinnincd thrvu_':oct. The wci5ht of c>:h subject was maintained conaznt to within 21b. (0.9 kg.l. The diets had the following conrposition: Lt 2?'", ot . ealories, protein 15.°:, earbohydratc 63^;,. The dict, contained no dairy fst or ecg yolk ezcept foc 7 or. CW m}.) of skim milk daily; 30;Y, of [he fat was dcriscd - from segetable sources. - Ezperirrtrnlal Deign.-This was a simple cros•oscr detignM three of the sublects selected at random beiog studied durin3 the non-smking pcriod first and the unoking period second. and the remaining four in the Ieserse order. S;nceihe same mbjccts Nere studlcd in 'the two periods no problem of comparability ari.es, and IeomDansons can be nude by piiring the results. T}tese considerations by no nxans exhaust the povi• bilnies shout Il:e mc.ns by whlch wwkinr inlluences platelet survival. For exantpla, p.ychomotor activity is ~ one of the (actors wh:ch ve ha.e not been able to': control. We hase no evidcnce bearing on tttis or an 4 xhat etfect (if any) tho may have on platelet economy. ~ ~- .-.-+ T10 30 2-1 40 8
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1968 Page 377 {a)' Hypertension and Smoking. The article by (107) Mulcahy does not contain any information on hypertension. There are 77.women reported to have coronary heart disease and their smoking habits were matched with statistics of the general female population. The relevant paragraph and Table are as follow s; Table 2 illustraies the smokin- experience of the 77 female patients with cla.:sical CHD under. 61) vears who were seen by ~ us. The numbers are sma,f and further study is clead~~ needed. . but alre:idr we can identify a~i~ni~eant deficiene_r of non- smoker. and ez-.mn;cet, anwnc nur. fec:n;e taatirr.ts rompared Tahle "_ Ralin of .mnkers to nnn.mukere in 77 female patientx onder GO years r-ith l'11t1 eontpareJ to estimatrd r:+tin in gen<rnl (emale population for a¢e group 31 tu i9 in 1961 1 I Prea.nt etquiry I Fenw(e pnp,datimt• (f/ (age group J5-59) Cafrpny - No, of r. h'n- o f r. i . pntienfa ntbjecte i ° 3mokers . ~ 49 ~ 64 261 ~ 45.6 . Es-smokers 1 ' 1 52 9.1 IQonsmokerx ' 27 . 35 259 45.9 Total j 77 I 100 572 I 100 Sleulfe.nt at the P: 1.10 . •io°rtr: '3utiaio d nnwkins in the Iri.h Republie:' Nnorcb..ie u,nited. nuhtin. 156: ca. to the generaI female populatinn. Also, our 77 patients are on average more than' 2?.;,) times heavier mbkers than the gen- eraI IriSh female population of the same age group. Our finding of a significant association between cigarette' smokino and CHD in women confirms the findings of M. F. Oliver of Edinburgh' who noted an excess of smo!:ers and a. deficiency of nonsmokers and e.-smokers among 50 women less than 45 years of age with cardiac infarction. He found little or no connection between ciearette smo'~in~ and nn.-ina pectoris among your.,- women. Our 23 females with angina pectoris had a lighter smoking experience than the 54 with cardiac infarction or acute coronary insuf;ciency; but nevertheless they had a heavier experience than the general population. 9 T10302-1419
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1967 Page 365 (a) 0 Cigarette smoke on coronary vascular resistance. The interpretation of the perfusion experiments by (8) Aviado et al and (38) Folle et al is not complete. The authors mention a second explanation in that the amount of nicotine absorbed in the lungs is not sufficient to influence the coronary vessels. The quotation from Folle et al is as follows: The perfused coronary artery behaved in the following mantier: no imnurliate change when blood exposed to cigarette smoke was perfused into the coronary artery but an increase in coronarv vascular resistance when nicotine was injected directlv into the vessel. There are two possible explanations for this discrepancy: (a) that the amount of nicotine absorbed from the left lower lobe was less than the lltg/kg injected directly into the perfused artery; or (L) that blood exposed to cia rette smoke did not act in the same manner as pure nicotinc. In regard to the latter possibilihY, nicotine may be in the blood in sufficient quantities but there was an additional amount of substance re- leased %thich antag_ onizes the primarv actions of nicotine. Such a substance may be hista- mine which is known to reduce coronary vascular resistance;=' and this may serve to reduce any effect of nicotine. These possi- bilities can be verified by determination of nicotine in the blood. Until a sensitive method becomes available, it is important to question the exclusive use of nicotine in the under- standing of the coronarv effects of tobacco. The systemic absorption of substances from the lungs exposed to cigarette smoke initiated stimulation of the svmpathetic ner- vous system with an elevation in aortic blood pressure and positive inotropic action on the heart muscle. The latter Aras accompanied by an elevation in cmronarti- vascular resistance, although the perfusing blood Ncas not exposed to cigarette smoke. Poth the changes in coronary vascular resistance and ntvocardial contractility are indications of generalized increase of sympathetic nervous ac[ivitv. If the coronar' v artery was not perfased, the eorona r_v vasomotar effect Irutdd have been masked by an actual elevation in aortic pressure and the entrance of catecholamines relcased from the adrenal medulla so that the end result umdd have been au actual increase in coronary blood (low. This con- forms to the generd conclusion in an earlier paper" tLat the cardiac effects of tobacco arise almost entirel_v irout the extracardiac actions of sntokin~l- instead of a direct re- sponse of the ]tc:u t. T10 30 2-1 40 3
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1967 Page 369 $LiOIU1G AND CEitEIIROPASCUL.17t DISEASE - An incrcasing amount of evidence has accumulated in the past fetr yesn rclating tho derelopment of clinieal ccrchrot'nscular disease to eigaret.te smoking. \fo.,t of this information has come front tlm pros- pntivumortalitystudics. ~ Ifamnond has reported the following data fram his large prospec- 'tivestudy (j7)rnotedintaUle 15. .TAaLe 15.-Cerebral rvscular lesions. dge-slandardized.decid rates, by type of smo.Cing (tifetime history) ond agz at star: of s.udg - Ai. uw ssa ~I as.r4 rsar CYL death rates per 100.000 persoo-y¢ere lISK Nevrr emokcd regulnrly________________ 28 92 349 1,358 PiPC.rigar__------------------- _______ 25 100 369 1,371 Cigarcltc u.d othcr____________________ 28 129 361 900 Cigarctlc onlr_________________________ 42 130 477 1, !OS ~ TotaL__________________________ 35 110 391 1,272 \tlYtn Nettr amoktd regiduly__ _________ _____ 18 57 228 3,082 Citvettc_______________--_--.--._--. 38 as 315 1,277 Tatd____________________ 25 64 238 1,091 BO:N C4'L mortality ratioa \e.ersmoked regulsrly---------------- 1. IXI 1:00 I.00 1.00 Pipe, da.r............................ .89 1. 09 1. 06 1.01 Cigevatc antl other-------------------- 1.00 1. 40 1.03 .73 Cigurette on1-y_________________________ 1.50 1.41 1. 37 .86 Aarr[Y Ne.xr emoked regvlarlp ....... ..... ) 1. 00 1. 00 ', 1. 0U l. 0[ ... Cigerette__________________________ I I S.It 1.54 ~ I 1.38 L1f - mcar_ c. C. u.mmo-n lann fietween the ages of 45 and 74 the death rat¢s from stroke for male mtokors.vere 37 tn 50 percent hi; uer than tiwse for male nonsmokers of . comparable nge. In fe..oale snokets the death rates from stroke were 38 to Ill parcent erester than those for nonsmokers. Above the age of 74 the diQerences hch.ecn the tlro g*oups v:ere n•mch less. The data in TaLle 1G concerniaq smoiieg cnd death rates from stroke aro derived from tho U.S. veterans study (52) . TAEt.c 1B.-Tfortality ratios and death rates for etroke as underlying eauee among cUment smokers of cigaretles only 0 Morw(tY mlio (sll egcs)___.___ Death rotee: Age 55 to 64_____ Age 65 to 74 .............. 1. 00 S9 280 Qumuq ut C¢-ue .a.otm o.r a.y t-a 1.61 92 323 1.42 112 312 nav 1.70 125 332 eat L59 130 502 bosa: Q.s. remuu rzudy trr. . ' Nlwn stroke t~es certified as the principal emtse of death, the death rates for smokers nere higher th:a for nonsnmkers; ho«e.er, no pro- nounced iucreuo was noted in the mortality ratios as the dz„ree of emoking incrrused_ The de;dh rnta.; frorn strok0 for all oges .ras 57 percent hi.~her in heavy smokers (40 or more citrarettes) than in nonsmokers.
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Ll 1964 1- age An apparen[ inMrplav of (aclors reLiting to enwl.in; aud orcvpari.m ' lutnad op iu a slmrtbnu stndc of tho drrrlnpmrnt of rarnnurv hrnrt die- tas^ in a lrnrnrl Aorrii I1I•mml,,ti-, , Z•i'.rl It al., 1D7L Farrnecn In dfarmrr', clmukin.r1ri 1 c ~af t 1 1 rc! cu r II' - r len. of mhre- 107. 2u1.e1, W. J., Ieni., (?. ff. Enledine, P. F., lainter, B. C., flal-tan, r I I I. rfl' t n tl InnI~r 1r`- lion, but in othrrs tbr. t ad Iv uf infareti+l wa. n r. as ( r•.II ar.wnF L- S., Fewectt, I( 11., \I,rc lith, A. 1'., pclcr>rrn, !S A•T +rt a n smokvs as ammrR the nomsnmkecs. The (arnlrrs whu ~rnokedaiearcur+ eommunity etudx of ti+r epideminlr•'y of coron.vv hrart dbro-r. rA smuked lesc hearlbthan in other occupatinnal grmrps, preliminaq'repnrt art tire lorth Dakota sludy. Amer J Pu! ~lirc lleaL'h In Chaptcr P, \f•+nallh" tltrre is summarimd Ihe cnost rerrnt infar- 49: 1630-1639, 1959. metion nrailaLle frnm 7 larce complebed nr currcnt pro-pectira• sinnking . . end death ratrstudice tllnll and llill: Hnrnmm..rl and Iloru: Dorn; Dunn, ' Lindcn and ISveslow; Duno, Buell nnd 6ruaow: G,qL Josie, and tt ~Iker, and 1(nmmond). The mrdian mortalitb' ratio fur ruronarv disease of corrcnt - eigateRe snrnkars to onrv,m••l:ers is 1.7 t range 15-?.01, Teble 2 presrnH dota frc.:n some of the largr• prospeclire studies an the telin of tnortality ratts ducto coronarn mort rireaee of male ~maknrs to non-smol:crs, by aee and anwunt ~mokcd, The ratios tend in general to Uinereasas with amount mnnb~d and to decreai,e wit1L adranr.ing a,•e, . _ The duta (roan Nie Lr>t 22 mnntbs of llammond's t111 eurrent stvdy help to show the sixe of thccoronary prnhleni For this parPu=c, ai:tual ,(~J' llammond, P:, C. sFenat report to the Svrgeon General's Adrisor7 DulnLers of deaths may Lc nwrc in(ormatrve than mortalitp ratros. Of uearly , Committee on Srn,al,ing and Hcalth, . . TARI•E 2--Ralfnr uf rnmroliry rares /or cornnnry hcnrr discnse, nrnfc smokers to non;smokere, by are and mnount arrmked, in selected aturlius .. DAMM(SD AND NUn\-1•ei9 (ta) Are lhwp CIr°•@n smoieG per dy Lev nran ta to-lG ux------------------- ---------- ----- --.. 4 to u-s9.......- --.-.-... -. -. - .................. 1.9 to __ _ _ _ _ .................................... L] 1.9 aW ....._..._ .............. ._. 1.3 I.e M1btat 4p alusmJl------------------------ LA I.aa BURCrILEY, DRAKE, 9RESLOIV-tvss fel' SYN-,_- .......... _._---------------- /HL,,,,,,,,,,,,,,,,,,,,----•.-..._..--... •Sel. . _. .................. Y,x._ -.. -. -, . . ................ ~__ ........ .. ... ._--I IRAxrNORAM eTUDY-cYA pD 1a LnJ ceet is 16 1.4 le f9N3) 115I (ta+19.n ia iE La U.1 L 4®1Ten9n I [PMde.M . DOLY~W9 (aa _--- 1b414GRLdpxted).... ---.... --------- ---- LIS I Lla I L1e DOLL AND nILL-19Y, @0 an crr.p s-x a.nrs IWx, / - - a,a k] ___ L9 ae 9 l.o Ll Sai........ . ... -,---------------- „- 1 ) ( LC 15 tW14re9ElueteE) _. - . , . LI LI 1./ ePmam f:noklnr I piet Vrr•lrycr mare murPareJ x41r tame amotlnr teu rlom t(aek µ. b.Y nneWJinr nnsinoterD. 10,000 deaths of men agnd 45-79, 46 percent aere ascribed to coronary . . disease. 51.7 percent of thc 2,630 "rsccss deal6s• associaled witlr aQarette xnoLing were caused bv co:unary diecase. In approsimate tenus, ncarly . • half of ntidd!en~~ed an(1 clded, males in Ihe Lnited Jtatrs die of c.rnrunary ' discase. AboWlolf of tLc:e vw!es ~muke ci„Irrucs. Cigarette sn:okors hevc brcn fnuud in su.cra! smdio: to husc 1.7 timus zs hl}h o cururmr. death ' ralc as nonomukcr.. If r yuctb,s acto:rll - cau,ni thc additionzl coronarr, ~ Uolt, R, Ifi!1, A. I'., Lung canr anrl other eause of dcath is rela5 ) 2] ce dcuths af swokert, the.r nuid accauut for many dcaths ofmiddlraced and tn snrokim•. A xcond report on the snortal(ty of liritisL dort, elderly males in lhis cuuntrv. Like olhcr s•.udics ( I). 21, 22, 23. 121 this Brit Med J 2: 1071--1081, 1956. , anc shows that thc ratio of snrnkere' coronarr, death rntes to tlw:e uf tron- - smokem iuareascs pw silrlp tritle t6tdaily r catcttc rnnsunrption. In , - ' - edtlition, at czrh lr.rl nf cumoniptiun tUc r,rtln incrra"s s.itb Ibc amnunt of inhalntion reportcd br tIre s wkcn, Othcrs 1~1, .3, 26, 891 lur.- indicared that Ihc ri>k of rL-ath (ront coronary di=ra=e in nralz rig:rrette sntokcn nrL•tire ' to Ihal in non-snm{.cr: is prcmer in rnidrite ace thm old and lizmmmnd's ,' rurrcnt study supl+nrts tlds, The mnrtatitrra0u was 3,09 in the age range ' 4U-49, and in socccs.kc Jt<rlc= was Y°0, I.I$., ad 1.33. • •h hTcn ehn rtop nroAin" /ia.e n lower death r:dc (ron( coroncrrv dlsease 47- Kannel, W. R. Special reporl tn lhe $utgcon General's ddvieory C•+ titan tlwse who ccmtimrc 121. •12, b'), 6t lhc study a( Ilanmwnd and Ilorn mitlee on Srnoking and F3calth, . ,. (42) sLc drrreaer in dr,iIli appcxred unly aft•-r a ycor, ' ' Angina pectnris is Ir,s rb,.dy rolaled It cizar, tt. vno(:ine than nunrardial . In(arrllnn aml ~uddcu drrdh. In (ic raud~iaol .111muvFromin-leun crtpe- ' rlcnce (23), uugina pertnris >ho+•nl nn atrrall rrlnlinnship with sinrt~king, and the association ha, unt bccn strong in otbrr smdics iS1, 89)•._ T10 30 2-1 352 Uremf crto4.oro meked yxr abr Iraor^ma I ssamaearr~
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1964 Page 352 (f) ® Hammond-Horn tobacco hypothesis. Using exactly this reasoning on the cumulative ]9a -19G0 results, the expv~ted frequency is 11 (four iu 1953-19bG and seven in the current period), the .05 confidence interval is 11 -!- 2 V 11 which provides a range of 4.4 to 17.6. Applying the fIammond-Horn fac- tor of 1.7 to the expected value of 11 re- sults in a hypothetical expectancy of 18.7 lung cancer deaths, a value that falls out- side and above range of the comllidence in- terval. AIthough the writers have serious reservations about the procedure suggested by Case, its application to the extended series results in a rejection of the Ham- mond-Horn tobacco hypothesis. 3. The additional points made by Case are hypothetical ones regarding the possible unrepresentaticeness of the population and shortness of the period studied. Data with regard to some of these issues were lacking in the Haag and Hammer~ report, but have been included above. They indicate that the representativeness of this population, and the length of time over which relevant data have non• been gathered, cannot be called into serious quz,tion• Summary This study extends to 1-1?j years mortality data of appro.imately 11,OU0 employees of cigarette factories and stemmeries in Richmond. Virginia; Durham and Reidsrille, \orth Caru- lina; Loui>rille, Kentucky; and other location.<.. It confirnls the findin~'s of previous studies that this population sholvs lower mortality rates for all causes, for cancer, fot' respiratory caacer, for heart and coronary disease, than the expectancy for a population of its age, sex, and color com- position based on mortality rates of the U. S. population in general. For the full period studied, the degree to which its mortality is lower than average is similar for all death causes men- tioned. lndependent measurement has indicated that the suSjoct pot,ulation includes more than twice as many more than 20-per-day cigarette smokers as the percentage in the general t. S. population. These findings, obtained without re- e course to sampling or estimates, are contradic- tory to the hypothesis that cigarette smoking per se is causally related to increaaed.nlortality, from all causes, from respiratory tract cancer, or from heart disease. . The lot•: turnover of this employee }rroup. and the inclusion of retired and disabled personnel '120 on the insurance rosters make this a relatiheh stable population suitable for an extended mnr• tality study. The margin by which its eigarelt, consumption exceeds the U. S. average make, it further suited to a.test of the cigarette theory. Analysis of statistical association studies no which the cigarette theory is largely based jll. dicates certain assumptions and criteria as tu "normal" death rates which influence the final calculations of these studies. The validity of these assumptions and criteria is called into question by the results of this and other studies that du not confirm the cigarette theory. The negative findings of these data with re- spect to the cigarette theory parallel and con- firm the negative hnding; of other extended tests of the same hypothesis: that of Eastcott, %vho studied cancer mortality of the entire census population of New Zealand and of immigrants of similar stock from the U. K. over a 10-year period; and that of Dean, te}io studied lung can- cer mortality among male white native South Africans altd male whiie immigrants from the U. K. to South Africa, also over a 10-year period. References 1. }NMrY, H. F., and BArv. W. S.: )lortality Amung \Cork- en in Cigarettc Faanris- fndn, Xrd. 8 gu.p. 2J:^-h9. 1935. . 2. }1. P.• -.-:+>:F.. H. P . ing i oivs a S[nrtality Aninsc Ko-ken in C'-earc::< Faaorin. .vfu.e. •V<d. Ssarp. :5:b59. 1D5I. 3. FtNx.ea. A. L.. Hnaart D. G.. Foeatnn,. G. T.• Ftc[sca. [t~ 7., and Sto~coe, ].: An Inre.uc~tion on the S1,•uremen[ of Current Smok:ng hy 7nd'nitieals. l.'nirersit> of lorth C.r- oltna rnaitute of >Lrneo s•riee No. 177, ehapel Hill. ,ortb care}ma• IJW„ IbS:. 4. 1'ita! S[na./fca of the LlJtnt Stnt,e, r?SF. 11: Table 41. U. S. UeGartment of H.al,h. Elucation. and Kelfare. Publle Health Scrrice,Sational 0'6re of \'itel StatL+tics. L. S. Gov. e~ment Fr/r.tie,^. O'Aea tea,F.lnr:.-.n L•^:n. 1'ite! Smtfatira a1 . the -Cnitad ctntra, tg.c?. 11: TzF);• ]l. U. S. De9+rtment af Health, Educazion, and R'e!f.ve, Public Hmlth Senire- Satinnal Oidce of Vital Ftntisurs• U. S. Go•ernment Printing OtSee, Washington. If~Ll. 5. Crrrenr TopvlJlon 6evnrte, Senea F-1i, \'o. !l2: Table 'L- U. S Department of Commera.a 6ureau of the Census. 1L'ashincton. U. C.. Jancan' "-5. L•1U. h. }Gnszet. W.. SWnx,... }l. e.. and Slnux. H. P.: To- Mc¢a Sn+n:ine Pe[te:rs in the t-nited States. Pub%ie /lrailh lfonogra}~h .\'o. :i. l:. S. Department of Health. Eduestion• and tt'elfare- In~S. 1. Dnt.y R.• ted Hat. A. lt.: smot:ing and car<inomc of the Lung. Prrlimi:an Rerort l:r;!. l]•d. J. ^_ t39. 1450. a. }fau~a~0. P.. C., and Flna.. U.: Src.nking end Dsth Rates - 1[eport on Foep-}'our Slon:hs of Follo~.t'i. uf 15:,:rt Men. J..a.u.l. l~,s:vsa. In;s. 9. Rr;neWI• J.: Smni:inF end Lun. Cencer: Some OMer.e- liona un Tn,o Reeent R+nurts. J. d-n. Statiat(ool deane. b3 :!. 19i9. 1U. Ewsrcnrr• U. F.: The Epidemiology of Lung Cancer in \eu, 2v4and. Lmad 1:3:. 19in. Il. bea~'• C.: Lung Cuncrr ).mong R-hite South dfcicans. Dnt .lfed. J. 2a5?, 1969. 12. C.tsc, R. A. bt.: 3nmkin., Habas and 3lormlity Among \Porkern in Ci4oreue Facmries. .\"afurc 15L5t, 1^+bS. 13. Con.rtstn, J., et aL: Smoking and Lung Can:ere Recent Evidence and a l/iscusaion ef Some Quations. J. .\'ot. Conon ta.t. 22:iSa, 1950. Induslrinl Dfcdici,re and Sin•9eT10 30 2-1 3 51
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1967 Page 357 (c) H 858 ' Social Statistics Further, the problem of the relation between smoking and health is one on which new data ar: continuously accumulatiae, p:rticularlv data on females, of whieh rclatiselv little was avaiLlbh to the Co.-„i, iace, and fun}:cr persoa-y.ars of cxperience in the prospective studies, which facilirate th_ tcpe of control on more rariables that Dr. 3riger and I both fsvour. The most interesting question is uot what the state of the evidence •.cns early in 1953, when the Commitcce study tc^s in proyrass, but what it is nose. This, of course, gets beyond the scope of Dr. Saiger's paper. Na'ertheless, I would like to comment, for two rcasons. Dr. Saiger's refcrences to the Comntittec's work are inaccuratc in a number of respects. I would like to quote two to reinforce mv ho,re t':at tho<c who are ir.tcrested in his ::rguments will read the relevant part of the report. S:condlv, the problem of appraising the self-selection or constitutional hypothesis - the main theme of Dr. Saiger's paper - is a challenging one for statisticians. First as re,,~ards inaccuracies. On pp. 6-7 Dr. Sai,er doubts the compctence and ability of the 10 men, and pa.r:icu!irly of the poor statistician, to cover the vast literature on this problem in the time used. I-3e omits to tell pcu of the 189 persons znd agencies used as cspert consultants, through these are listed and their contrihutions described right at the beginning of the Report. ' At tht top of page 3, Dr. Siiger rcfers to the committee's definition of a cause as being °a significant, effecm.1l, relationship benc.en an agent and an associated disbrder or disease in the host", and proceed, tc ridicule such a definition. In f.icr, the Committee lave no formal de- finition of a cause, recognizing that c.use and effect are complex ideas, but instead discussed on pp 20-21 their cvnception of causahp'. The sentence irom which Dr. Saicer purports to be quoting reads as follatvs (p.21). "The word tniire is the one in generel usaee in connection with matters cons`dced in this study, and it is capable of concecing the notion of a sigtrificant, ef- fectual, relationship bet•.ccen an agent and an associated disorder or disease in the host". The Report goes on at once to state: "no member of this Committee used the word cause in an abso- lute sense in the area ef this study" and °sll membnrs shared a common eonception of the mul- tiple etiology of biological processes". As regards the s=_Y_:e'.cc^e :`r.othesis, I ag=ce with Dr. Seiger that a welbplanned, long- term rar•demized c: , crim :nt mealfl bo r„liy;;,ning but is impracucable. In appraising this hp- pothcsis from non-re.ndemized data, u•hat can one do? To quote some of the statistical evidence for males, the death mte at a given age incrasses steadily lrith the number of cigarettes smoked. For tnen of a given a,,e who report smokin; tht same amount, the death nte increases with the number of years stnoted. For men of aai%cn age who pr:viously smeked a given amouat, the death rate is lower for those who have scoppcd than for those who have continued. In two groups of men of the same ag.e who have stopped far, the same le:r;;th of time, the group m;dch preciouslv smo)ted more have [he iugflhcr death c,.te. Dr. Saiger seems to think that the self-sclection hypothr- sis can comfortabiy aecur.todate afl these rasults and others which I could cite. !11y opinion is titat it is bainy suctcn¢d v=ry thin. Secondly, one considcrs all studizs in which differences in physique, habits, ancestry, psychological pattern and so on !r_nceen ci;ir-tte smokers and non-smokers have been examined. Dr. Saiger mentinns, as dnas the Report, rs numher of variables in which diffcrznces have been found in some sh[dies. He«cver, thesc diffcrences are at most small differences bcnteen the means of neo populations that overlap extensively. Thirdly, in thc prospeetiv^e and retrosptctive studies, one adjusts for any variables other titan smoking thzt arc known or suspected ic be related to the probability of dcin,^.. In the analyses leading to the Report, these adjustments tcere computed wherevrr the dita ulhaced it. 8xcept. for age, for which udi••isnnent is ess,ruisl, these computations produced only slieht changes in the mormii[y r.itio. On pap: 13, in maninni;tg a seven - varinble adjustmont hy IIammond, Dr. Suiger points out that the 7 d•:d include important t-ariabl--•s such a lon,cvitv of parents and grandparents, initial hezlt.h status of thc snbject, maritsl st: tus, and so on. Actually, Hammond slr,ady c.eamined the effec[s of adjustinr for each of these v, riabl:•s indicidually, again finding only slight chan,es in the nwrtaliry rbtio. From inspection of Hammond's dsta, my judgement was and is that the combination of t.vi:ibhs would give essentially the same conclusion. From all this, the Comntittees rzzclr,d the judr,ement tlrst self-selection could account for only a minor fr.taion of the observed diffcr.nce in death ra:es. It fclr in no position to put a precise figure, sav 5°„ or I•5°;,, on this fraction, and like Dr. Saiger, I loo:< forward to se:ing more d-rca bearin,, oa IIr_ constitu[ionnl hcpothesis. I feel, however, that thc extreme form of the constitutional hyoothcsis cannot be appr:)iscd by thcse mcthods. No matter for how many vsrinblas tve adjust, the ohj~ctionean be rais<d that the diffarenec in death rates is due to some futther variable not tet mcasured. Finally, my opinl.on is that the new data that I have seen since 1953 do not weaken the main conclusions of the Rcport. T10302-1387
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1967 Page 362 (a) Pulmonary Function in Smokers. The cited articles (50, 91, 96) do not relate to a comparison of pulmonary function between smokers and nonsmokers. However, this topic was investigated by (21) Chevalier et al. in an earlier publication (1963), and by (61) Krumholz et al., 1964. These articles are quoted in the 1967 document in relation to exercise (page 367). These investigators did not find any significant difference in vital capacity or airway resistance between smokers and nonsmokers. The Results from Chevalier et al (J Appl Physiol 18: 357-360, 1963) and Krulnholz et al. (Ann Intern Mcd 60: 603-610, 1964) are as follows: ltael.E ^_. /'4.Inurqnn' I "marlrri4rrr uf m:blrrlr \on:m.h El Iiters/miu Nfas. 6rrntLlnc capaeitv, ~~ iut.7 t 18 3 3 of pvetiictcd nurmnl ~ Vital capacitc, ml 5.099 - hvl j,2F4 x a. Total Ilu,g rapacitc, ml 6.920 f A58 7,r85 . sti. t i 4.9 s6.2 x S,4 Ain.ny re.i.[anc,. nn 11_U. i.A1 t.tii ..69 x r3. liter src t-Sec timrd oital capacit., 84.6 t 8 89.5 ~ 6~, r;, of rntal M1fac e.pirxmrv Oow ratc, 596 t 84 tioo t~_. 90.9 ;..i8: ~ Valncs arc r~pres•t'd a.e tkhe mcan *. su. Thrr, is m,q nifcant dfl(rrrvcr P >.ojl A'ncrcn rncan vnhirs (or ~ - ~- groups. Su6jccls lnspiratnry• Inspiralory E>piratory Tidal Vital Functional Capacity Reserve Rescrve Volume Capacity Residual Volume Volume CalHtcity I Residual Total Volume Lung Capacity Residual Maximal Maximum Aincay Volume/ Volun- Expira. Resi;t- '1'otal tary tory ance Lung Venti- Plow Capacity lation Rar,c al $mokcrs uil nrl ' orl ml rnl nrl . ml ~ lifer/min lifer/min on /I:O/ . liler/scc 1 2 3 . 4 5 6 7 8 9 3,170 2,760 3,160 2,570 3,2211 2,9-/0 2,180 3,8181 3,5th1 2,400 2,1W 2,180 1,920 2,470 2,110 1,490 2,710 2,540 1,420 2,430 2,050 2,0-00 2,170 2,580 2,600 890 1,920 770 600 980 650 750 830 690 1,0911 1,051) 4,59 5,19 5,22 4,61 5,38 5,52 4,79 4,69 5,54 0 2,600 0 4,700 0 4,400 0 3,900 0 3,600 0 4,600 0 3,4IX1 0 1,800 0 3,500 1,180 2,270 2,350 1,860 1,430 2,020 800 910 1,580 - 5,770 7,460 7,570 6,470 6,810 7,540 5,590 5,600 7,120 . 20 30 31. 29 21 26 14 16 22 147 142 168 141 168 184 142 173 206 420 1.27 570 .62 680 1.00 550 1,21 650 J17 660 1.04 520 .85 550 .83 710 1.03 Mean: 3,0-10ti00t 2,220f370 2,010f560 8203=80 5,060t 380 3,610t950 1,600f57 0 6,650t690 23t6 163*24 59of90 .98+..19 Norvsmokers ' 1 3,710 2,830 2,780 880 6,490 5,200 2,420 8,910 - 154 570 .90 2 3,650 1,950 1,400 1,700 5,050 3,200 1,800 . 6,850 26 203 610 1.02 3 3,500 2,540 1,560 960 5,050 3,500 1,940 6,990 28 177 630 .71 4 3,370 2,820 3,401) 550 6,780 6,700 3,300 10,080 33 169 640 1,13 5 3,630 3,140 2,550 490 6,190 4,100 1,550 7,740 20 146 600 .83 6 3,180 2,050 1,910 1,130 5,100 3,800 1,890 6,990 27 161 560 .74 7 4,220 3,300 2,160 920 6,380 3,800 1,640 8,020 20 166 480 1.03 8 4,0311 3,4tltl 010 2 630 050 6 3 (-00 ] 590 610 7 21 161 53 640 9 3,20 1,750 , 1,120 1,51)0 , 4,370 , 4,400 3,280 , 7,650 43 123 . 510 .82 Mean: 3,6103350 2,6.t0f610 2,1001720 1' >.115 <.10 >.80 970i390 5,720t830 4,260t1,090 2,160~690 7,870f1,01A >.SO <.05 >.80 >.10 <.05 25f13 162f22 580f60 .86zi-19 >.50 >.50 >30 >.20 T10 30 2-1 398
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1964 Page 354 (d) H cigarette smoking and the Serum linid level (Gofntan cf af., 1953 ; Karvonon « af.. 1959 ; Thomas, 1958, 1960 ; Dawbcr ei ul., 1959; Blackburn ar aL, 1960; ESrontc- Steu'arq 19G1). All these studies support the view that the serum cholesterol level is higher in smokers than in nonamokers. Thc present eonlmunie~tion shows that there was no corrclatioa betwecn smoking habits and Serum lipid pattern in a group of young men in Finland. 1lateriat and Afethodv The nuterial presentcd-eonsists of a series of 314 healthy young men who startcd military service in Finland in 1957-60. lhe subjcces were selcctcd at random. Their mean ate was 19.7 yc.lrs (range 15-:5). Blood samplcs were takcn from the arbital vcin in the moroing after oscrni~ht 6sting during the first three dayt of military s<nwe. From the speclmens Ihe scrum toc{( cholesterol (Acferson and Keys. 1956) and the Serum total phospholip ids (Fi.ke and Subb.rrow, /9251 wcre dctermincd. Scrum lipo-protcin fractions were separated with the aid of paper dce[rni:horesis, and from the (ractions so scpurnted the cholesterol content of the m and fl-lipoprotri:n was delermined. The details and evidence of Ihcir accuracy ha.e been preunlcd in a previous study (Knnttincn, 19591. Rlood-pressure azs nho measurcd a.n.d re'':nv< b.1v arfvht w~n nlculated accordingtothe Vctro,Mtlitan Life ln.urvnceCompan's (1943) tables. To be sure that the men wcr< hcailhy, determinations ncre al-.o ntadc of the blood scdimen- tation rate and b1oN hatemoglobin Icscl, and the urine svss analy~d for glrcose and prolcin. ]fasf ]-ray etaminations of the chest wcre also made. The smokin-c, hahits were reported in rasponse [n a questionary filled in by each man. 'lhere were 145 men who h.'Id never smoked The smokers, divided into subgroups aciordmg ta dail,v consumption of tobacco I,e Table), had smokcd for at lust one )ear bcfore eatering mditary ser.i.e. 1he fcw pipe smohers were -,lt included in the urks. Ne.vly all the smokers -naked American-t.pe cigarettes unh or withnut a Nter. Reaults In the different grourts the similarity in level of all the lipids studicd (sce Table) is obvious. Statistically there is no diderence betw'een the groups in total cholesterol, A-cholntcrol, or phospholipids. Analysis reveals a probable ditference (P<005) in a-cholcsterol variance, but this seems not to depend on the smoking, since this difference is Pctween light smokers end non-sntokcrs. On the other hand, betwaen non-smokers and heavy or moderate smekcn there appears to be no significant diRerence in a-cholestrtol. Divclrssion In the prescnt study the similarity in serum lipids found in smokers to those found in non-smokers is at variance with the results of prn'ious studies, in all of which the cholesterol level has been staled to be higher in smokers. The material presented here is very similar in all respects ercept smoking habits. Body build, ezprcesad as reiative body weighq was very much the same. The mcn came from the same parts of Finland and the o.cupxtional structure of the different groups was a/;o sicn:ar, The blood samples h.d been taken similarly in L.e different groups in respact of time and season. The age range of the whole series is quite narrow (13-'_5 ytars) and there is very little difference between the groups. As the men were young they had not been sn:oting very long, although one criterion in selecting tt:em was at least one year's smoking. Karvoncn e+ a(. (1959), however, obsennd a higher scrum choleste•.o1 lc,cl in smokcrs of all age-groups, except 50-59 sears- in Kest Finland ; lhe youngest age- group in their study was 20-29 years. Gofman er af. (19551 foond tl~at the dit7crence in serum lipids betweca smo.ers and nos-smokers was greatcT in their youngest ('-0-?9) age-grr::p than in the oldcrones. In the present study the sebjec<s were slightly younger than the youngcst agc-:roups mentioned above. If the esptano- tion for the di.^.erence lxtween the observations in the mentioned s:W:es and the present one lies in th:s point, the eRect ea Serum lipids of exposure to cigarette smoking seems to occur after sontc yean of smoking, but not, hoae,er, during so short a smoking period as in the present work. _ When eonsiderit•.g atherosclerotis many investigators have strec.ed the importance of the (f:e ntio in the lipaprocein fractions. /t has been noticed that an increase in this ratio is encountered in palients with atherosclerosis (Nikkda, 1953; OGser and Boyd, 1955; 3cncka er a/_ 1956). In the studies concerning the correlation betwecn smoking and s<rum lipid; in which Ilpoprotein fr ctions are included the a:a ratio has been found to fe raised in smokers (Gofman ct nl.. 19551 Bronto5tc'-art, I9Gq. In IF.c prc,cnt stc.ly, by contrast- no trcnd pmnlld with the srnoking habits could be discerned in scrum lipid Ieccla- The serum pSmpholipids hase been shown to have the important function of stabilizing other lipids in solution Sarun IJArJ/ in 314 Yauny MGn Geou('rJ AreorJinr ro Snwtine /!chlrr CIGARL•TiG SMOKING AND SERUM LIPIDS IN 'YOUNG MEN w AARNE KO?/'TTINE.N, M.D. Rutar<R A+sociarr, Wihurt Rrrra•c)t lnmlrure. 1ldrinki, FinfanJ In mortality statistics cigarette-smoking habits have been oberved to be eorrelated with coronary heart disease IHammcnd and Horn, 19547 Dotl and.ltdl, 1956; Hammond and $orn, 1958y; and dle urum hpid level end especially the semm cholesterol and I:-lipopracins are known to be rai.<d in Npulzlion group; wi!h eoranary heart disease. With these (ects in mind, many 'f- insestigators have studicd thee rdalion.hip between rJWa [[[..m4t I slm see„w. tm/.Immn --~-~~/ 11 ..aw~.{.« 1{t ,lt\/t\:{ 1-10 f /1 ~~/-tle /~.Lr.uw..l.~ - ~ I II.IV Ill~t+l V . '«qw..aa .-_--_ Y. I I f b 1[{:I I 4+um I Se.um + el.r am iwrw.:/nl In.e 1~^enn/mn ~y.l l ApfYwl Lw.aU ~ sw. o ~ -__-._- a/m I I~IO:MI Is..-4a 1 1'~~-!~S 1.-1/altl :Ila.«r J a]]\.t11 f I]:Il.{IO LO)e.1/ I Y• 6aa {]] ( M] 10l M~ l l .tl IH , :.,.,T10302-1375
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`P.rr^e./ilY 7?, ,r. . . Various invr•etigntors have long suspected a posible pathogenaic rolu of the central r.ervous system iu curm:my heart di=ease (Ju). In aseriesof reports,l',osanman (81,6J) and.Icidtins (51) 6arodescribed a personrdity pattern or ot'ea enotional eomplec ldrich, lvhile ns=m ciatcd e'ith ol.hcr knolan rLsk factor.;, aulrears to prcdict coronnry heart disease moro clFectively thsn do of ber rick factors. This entntional conr plez,10which tlrcy lu.re tarmed Uehacior Yatten: Type A, is con:posed of an enhanced competitivencss, driee, aqo ,^s+iveness and hnstility, and nn esces:bu evnse of tinw urpency." ftecent unpublished data b::: ed upon prospective ob_xrvation of rnorc than 3.000 men for a 41,~-)ear period (51) disclo-4sthatsmolo•r hFn'e a]lilrher pereentaae (:.{ versus 47 percent) of type A persmis:unong them. ]toraover, tlm incidence uf coronaq' hcart di=as.;e is slto,:'n to be relaLVl in(iependentiy to both smoking rtatus and pcrsonalit_v type. lIorbidiny ratios, tlerivcd from the incide::ce dsta, are sho•.cn !n table 13 u1r,cL ch:arly denlonstrates the independent eRecs of cigarette smoking and its interaction aith personality chnracteri>tit•s. lciu'i PaE;~ a .i (]J) Erursrv, F. Ii. The ePldemlaluES of corunnry hcart disen.e: A revlc. ' Jourvnl of CLrnnlc 1)Ise•uscr (St. Loulr) 19(9): i:L-i]-1. Aueuvt 19... . t8jl R06t_Y]rdY, R. It. Ffl[lnlrAa, 11.. JCYFrYfi, U., YTRA1:8. It.. W rn\I. 13 Kosrtc¢es, R. The predlcUno of ImmunltY to coronurJ henct Ji="aF• Jour¢nl of We Amertean \tedlcul As~lntlo¢ (Ch:cv6'0 tll5111) : 11"911L",Drc.1_'.1Jnd. (dp) Roscxsisv, R. 11" Fsamuv, 31, , S'ruce, p.. Wcnu, Dl.. Ronrrcucn. £.. Hnuv, N'., R'rHTnrss[s, N. T. -~ predlctlve rtnd) nr corrna:y Tear: dlsense.Journnluf theAmeclean 1ledlcaldssoclnttoo (ChtraEo) 15q (t)- IC.-=^. July 0, tOGi _ (`!1!Trsstsn. C. D. 1•crsoent cummunieatlao. The Coiremltj of Yoith Caro- liux, Cbutxl Ilill, APr. 10, 11h1T. TAlns 13.-dfordidity ralios o,f eigereUe stnokers as rompared to non- tmokers Ly personclify lyre eanmuq rrp. xo,•saol.ner rtean~~ C o„tr. .me.H &havior t]Te 13 ................................ Bchnviur tYVe A ................................ L0 2. 5 W vrzc: Un W btbtN Em nom 1Parrm Ccaeteutb. Gmup ewtlL Snn Rvmqw, Caa. Hr). ellnllipIc-Risk Factors • ' The method of mfalysis traditionally employed by epidemiologists, that of the comparison of rates for multinlo cro;s-dassifications of the data, gcimrnlly requires a largustudy poptaction ut rclatively high . incidence of significant events. Since coronary hcart disease incidence Istes nro los ann ttudy populations are ntcaaslrilv small because of "pigotical and practicabk.• Lmitatiots, def:nitive anulysis of tlte inde- - pendenco an<i iuteraction i,eu~een risK faeror Lave generally beenre- atricted to trro factors at a t imc. Tructt (D.i) applied a multipio locisEic fuaetiotl proposed by Cornficld to investi~ate the independent effect on the inaidence of coronnr- heart dirxase of seven risk factors: Afre, serum cholesterol, systolic blood pressure, relative nciGht, hemoglnbin, ' eigarettesperday,andECGabuonnalities.Themethod.rasumdinthe analysis of dnta compiled in the hraminqhsrn stn.dy during a 1^-cear period..'l discriminant fumction coef.icient lcss coinputed for each risk factor. Thex caeflicicuts represent t' : relatire importance of esch fae- - tor with respeet to the other six factors in thedere'.op.r.entef coronary heart disea<_z While theoretical considerations underlying the Inti=cic risk function arc not fully ~IC=iied Ly the actu,rl data, thc approxirna- lion given by tlte funct ion to cSsried r ates is rary good. ('Jonsequcntly, Truett aud CornPicld believe that the present compu- tations pmnnit the conclnsion that `the mosrt important risk factors, nsido frem a; e itsclf, nre chole;terol, cigarette smohing, ECG abnor- mality,nndblood presure' (75). ,.-T10302-1399
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1964 Page 354 (c) substances, such as saturated fats. Ihan non-amoken; he has published some evidence, which he does not claim to be conclusive, to support his view (6rontc-Steaart. 1961 ; F crrin rl al., 1961). The lack of correlation between serum lipids and smoking habits in the present sample rc<eivcv indirect support from the f3ct that smoking does not seem to be associated with coronary heart disease in them (Acheson, 1961) or in two other samples of men over the age of 65 years (ifammond and Horn. 1953; Doll , nd Hill. 1956). On the present evidence it is not possible to give a rcason for this, even less to exp(aln ` the pos:ibility of an invorsc rdltionship, but several theories suqgcst them:clves. First, as has been stated. limited financial means mi;ht have caused those wha smokt more to eat lexs, but in the present samplc thcre was nothing to suggesCthat means were so limited nar ".lhat heavy smokers a;a less. Secondly, if we accept Bronte-Stew~rts basic hypo:hesis, it could reasonably be argued that the dffci of agcing on the sense of t.Ysle -may be ntor< powerful thin any e(fect of tobacco- ~ smoking, so that the Istter is ab>ured among old people. Thirdly, it could be that uith in.rcaoiag age the pattern .. of nteubolism of fats and lipids is ehnnged. Our finding. although Jifiicclt to explain, is com.patible with our knoaledge of the aetioLtZy of coronary heart disease in old men. In youn3er agc-grcups the greater part of coronary disease Likes the form of infarction caused by thrombotic occla;ion of a major vessel, a lesion ahich has repcatedly been shown to be associated . with high serum eho:csrerol and a raised 0(n li; oprotnn ratio. L'rnnte-Stewart (1941) bclieves that the relation- ship between cigarettc-smo;in, and such disease is due to the raised serum cholesterol which smokers havt- ruther than to any pharn;acelogi,:ally induced response smoking may slicit from L.c cardiosaxular sgstem- Only 9',; of the present series had myocardial ir.Jercrian, and in them the serum cholesterol and J?In lipoprotem ratios were raised; the r<r..aining BI;;, the majori(y of whom had angina pcczoris andlor ra)ocardialisehaemia, did not dilfer from the controln in their smoking habils or their rscrum lipids or serum . eholcstetol. Dawbar rr cl. (1958), io a lon~itudiml study of younger mcn, have shown that, although eigarette-smoking and high serum cholesterol predispose to coronary thrombosis, neither predisposes to new easec of coronary heart disease prevcnting as angina pecloris. In line with this is the f..ilurc of Paterson et eL (1956, lo demonstrate a corrc6lion bat+.een cholesterol leveh during llfe and the e.xlent of atherosclerosis at necropsv. Our prescnt finding. therefore, is consistent wilh the view already expresscd (AcSeson. 1961) that coronary heart disease which preunts as angina pectnris and dcctrocardiocraphic cvidcr.cc of myocardial i:chaemu without infarction in old man is of ditlcrent aetiology from acute cnrunary thror.tMsis, which is the more usual form the disease takes in younger men. $ulmm"y It is shown in a random vmple (2.11) of a defined population of men aged 65-85 years that tobacco- smoking. whether in pipes or cig.ueltes, is not jswcieud with elevation of the scrum cholest<rol or the ff/n lipoprotcin ratio. lhe signitiuncc of this finding in the actialogy of curon.ry hc..rt diuase is dr.cu.ud. REIGlMR! Achewn, R. M. (196). 8<!r. l. prv. we. M<d.. 1!. 49. _ and AchcsnH. • F.. d(Jesrop. µ'Jl. 11956)~ G<wnrofoe(e - (lemrmn.. fBn<ieJ. 7. 557. and 1<..op• W. 1. P.. (t96ll. Ibid. In prna. Andn.on" 1. l., end KcY+• A. (1956). Clin. Chnn.. 2. 145. B,onte-ti~ewar1 am+uhn1EJB . [Rr ro•rrfirW ,(1955). f- o+in. P+rh., ro•rrfirW, W G, nJ S a. D=. Daw6<r, Gordon,<T`l14<91.x<Amu~ L P~6lcll+6'i9. US9. A., an Ib71, R.. and 7hIL A. (I. (19561. A.ir, mrd. l., 3, Inll. . Cnro,ne.yJlCambndger G<rrkr. /d. M.,+nd wLrc. P. D. (l9!i) in Yavns AJ-iu. flervard Unir<rsilY Frcu, Mass. Gu(Gmiler4 F.."e JnlCrmpiin. A. (t9ii1 wGrrBnlar. IoIJa9 ~~ Hammund, E. C., and Ilom, D. (195J). l. Anut. m<J. Arr.. (SS, 1316. K+rronen. Df..Orma. E.. Keys, A.. Fidanra, F., and Brorek, I. 51959). [nnr<:. 1. 392. OGret, M. F.(195tl). Sror. meJ. J.. 3. 225. Parcrsan. 1• C.. Comi.S, B. R., and ArmsuonC• E C. (1956). Circulario,.. 13. :v. and BromcSicwart. 6. ;1961).Brir. Penin, AI. 1.. Krut. L. H., mrd. l.. t. ]x1. Sac G. E. (19]5). 1. bluJ. Chem.. 67.'-O3. lhomaknr. s. C. B. (1958). l. chrun. Oo..7. 199. We are again plumd In.aclnur(<Jge our sratirodi to the director, ot Me..n. Anhur Gumne<a Son and Cu. LIJ. (Dublinl to Dr. Rrian Pring'e and Dr. 1. F. Fuatzce, and to our culkaCUes in the h(upne (nstitutc. 7nmty College, DubLn, far making th" study N"srhle" l(i•r 1ane Coopcr helped wrth the computalions and Dr. Richard Doll kindly read Ihe t<.t. ,TI0302-1374
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1968 Page 379 (a) Postexercise ECG Changes. The observations of (10) Blackburn et al. are very important because they relate to the incidence of myocardial ischemia in 10, Z60 men. That 519 subjects had positive ECG response should not deter from the significance of the investigation. The reference is actually an abstract which is not normally cited as a primary source of information. Hower the 1968 document is full of abstracts and personal communications. n Refation of "Positive" Postezereise Electrocirdio . graphic Responses to Other CharaMeristics of Risk - Ilenry Blarklnrnt, Ancef l:.ya, Sfinrn•apolir, - Jlirnrr.rnrq Sfarrfi Karronen, Hr•L:inki, Finland, F. S. P. Varr BueAem, 1/aarle•rn, Thr .\'rthrr/arnls, -`- anrl flrnnj L. Tmifor, .Ifinro•r.pal6, Sfirrneaata. . Lnborarorj of PLy.ioloFicaf f(y.;wna, Cnicrrsitj of Slinneaof4 Slinnra/wkr, Sfinr.cwra The dectrorard'ur_nphic respume to en"ciu fras beeomra puurrful tool for idevtrf}iniz greatly fnae.rsed risk of acute a+ron.rry cpiu.des in otherwise "hea}tby" individuals.. It is now nece:- sary to establish how much it really adds t.r information over and above already known fao- tors of risk. This was first examined by a stueiy of the interrelations of a"positive" exercise EC; response with other measurable physirvl char- acterisYics and habits. It is best studied in natural populations which contain realistic proportions of "p7sitive° and "ne¢ttive" responders and broad ranges of characteristics. Herethe &equcn• cy of 519 "positive" responses amung 30,?fNl . -men aged 40 to 59 years was plotted attnrd- ing to increasing obesity, blood pressure, aud . serum cholesterol, and activity and smoking habits. The test was a standard three-minute, ron- stant-rate step, and criteria for "positive" tests were rigtdlv dcfined. The most important aarxi- ation scas a Gncar relationship between frequencv of 'positive' ECG tes,.orues and level of sls• . tolic blood pre>crue (P G 0.0001 hetween hiscrst and highest pressure clacses). No relation of eaercise response to fatness was found thrnu-h tlre bulk of the distribution, but 'amons; t6e upper 207 of men ranked by skinfold thidms< the rate of "p.xitive' responses was si;-mificantly greater (P<0.001 bchceen lowest and hi;~he~t obesity classes). There was a decreasing rate of 'positn'ci aith increasing physical activity . class and no rel:rtiunship to scrum cholesterol . or smoking habit. E.Auation of the proguustic power of the esercise ECC requires, at tbe Icalt, consideration of age, 5ez, blood pressure, a"d obesity. - T10302-7422
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1964 Page :;54 (e) A (Ahrens and Kunkel. 1949), and it has therefore been inferred that an incrcax in the ratio of phorpholipids to eholasterol helps 1o prercnt atheroci!aroris. This view has been supported by the obscrvation that the phu+pho- pipid'ebolnterul ratio is smal!er in athcr.r+:lcro.is than in age-matched controls IGunler el uL, 195C ; Oliver and Bo)d, 19531. lim publi.hcd studies on the re!ation betwroen serum hpids and smoking do not include reports eoocuning scmnr phe~pho!ipids. In the present study phospho!iptds shuw no trend paralleling the smoking habits. Attempts bnse been made to relate the rise in serum lipids obsersed in the previous studies in smokers to differences in the diet poaib!y due to smoking. Krut etof. (1961) have not:d a (ifference in the perccption of bitUr taste betvecn sr:e:ers and non-snwl:ers. Accord- ing to those authors th:, could lead to smekea having a prefcrence fur some special ftwds. The same group of investigators (l'errin r/ ol., 1961) have obsencd that smokers consumed mo:c fat than non-smokers, but the difference was too sm.r11 to explain t)u difference in aerum hpids, and in Finland S. Punsar (uapuhli.hcd data) could not detect anr difference bclueen 1Se diet of stnokers and that of non-smokers. Even the greater amount of fat eonsumed by smokers does not nemsarilc signify that all this fat is absorbed, for a recent study (Konttinen and Raias.ilmi, to be published) has shotsn that the rix in serum trigly'cerides after a fatty meal is less in heavy smokers than in non-smakers. The eBect of giving up smoking should throw further light on the eorrelation hetwccn cigarette smoking and serum lipids, but in the only relevant rcport I found in the literature no charge in srrum cholrstcrot wav detected in the six subjects studied (lhomas and Eisevbere, 1959). The faxsibilily has also been discussed that smoking could be anolher manlfrotation of the disturbance respnnsible for the rix in the serum cho!esterol Icrcl, and in this eonnexion m<ntal tcnsion was incriminated U the ehotesterol<!e•atine factor (fhomas and llurphy, 1959 ] V/ert!ake rl al., 1953 ; Grundy and Gri15n, 1959 ; Drcyfuss and Czaczkcs, 1959 ; Peterson ct aL, 19G0). It should be remembered, hosvever, that mental tension cannot be measured but only estimated. It is evident that funiur ienouigations of the relation- ship of smoking to the serum lipids are required. Bronre-Sr~arL B. (I9G7). Bdt. meJ. l., 1. 379. U..bcr. i R. Kannd, W B- Rcvott4ie, N., 5[okrs. 1.. K.~y.'i A., vnd Gordca. T. (i97v). Awn L Gudd- lllrh, eV. I rJ ~. DcI1, R-. end IlLll. A. B. (19561. Brit J. J., 2, 1071. UreY/mt E, .nd Czirskes, J. W. (19)9). Arch. Inron, M.:.. 141. 70tl, Fukr. (. Ii...nd SuDb~rrow, Y. (1915). J. 61aL AlN., 66, 171 Grnrr, M M_ Gvm, S. M., and t<rman, 1. (1950). Ctrc.fnu.~n. 2. :US. W., IiuA¢rm, F. T.. Strisowcr, B., drf_ilkt, O- ' Glaxin, F.,.nd Innplin. A. 119551. Gour.ur. 10, 319 Grvna•. A 6t., end Gr: tn, A. C. (1959). Cirru.ariun. 19, <•K• Hum^.ao1 L. C., and lWm, D, (1954). J. Amo. nvJ. An.. 155, 1316, - (1958). fbid . 166. 1159. fenc4t W- P.. HYun, M_ It, Jrnnn. M. R, Maniaely. T. N'., end Durrum, E. L. (Ia55). /. rlin_ 11,111. .. 3!,'J+tl. Knrvar.m, hs., Orma. F., Kryr, A., Fidanra, F., end Broxk, 1. U45d1, Lanrrn. l. 412. Kennlnm. A. (1959). Acn- AIrJ. e+p. Frnn., 37. Supnl_ 7 Kmn 1., II.. Purnn, At. 1., and eron[c-StrM-at, B. lprol). R•ir" nrJ. J.. t. 3tlJ. Mctru; e6tm Li(e Insurance C'ompany (1943). Srurie. e-1)_ J. 6. J(it4Ji, E. f199) Sruni. l_ dLi. Cah. )wrc+t_ 5, Suppl. 8. Gh.<r, N. E, end Bo.d. G. S. (19531. Brit. ffrurr J., 15. JS7. - {1957). ICrd_, 17. 29Y. Pcrrin, M1f. 1., Krut, L. H., and Bronlo-StcwarL B. 11^bll. Brir. wrrJ. J., L 337. Prtrnon. 1, E., tXJCoa, A. A.. IIJ1eY. St. 1. and Keith. ft. A. 11960L Cirt~u(~tion, 23. 247. 7hum+c C. B. (19731. L vAvn. OL.,7. 199. - 5/9:d). Ann_ lr.:nn_ AtrJ., _eJ. 697. - and Eumhre. F. @(IS59). 913. Johro IfuyA. lfurv.. 105, 14. - cnd bturphv, E. A. (I958). l_ rhron. Ois„ a, 661. R'r.d~kc. P. T_ k'ilcoe, A. A.. Wley, S1, I., and Peterwn. J. L SIY'bl. A<r- Sa- cry. BroL (N-YJ, fl, IM1J. Suntmary Serum total cholesterol and the cholesterol content of Ihe a- and je-lipoprotein fraction and scrum phnspho- lipidf bave been determincd in a series of 314 hea!thy young men (range 13-25 years) starting military service, prouped according to stno;,ing habits. There were no diQrrences relating to smoking habits in any of the lipidsstcdicd. ' ASderu/ur.r.-$intt the present study was made Achcwn and )cswp (19(i1) ha•c published thcir .cork on scrum lipids in old men groupcd according to snwkmy habits. They could lind no association bcMecn eigarcae or pipe smoking and serum cholesterol or P:a-hpoprutnn ratio.- Rurv.crs A<he.«,, R. St. and Jc.+op, W. J. E (1961). Brn. mrJ. J_ 1 tlox. Ahrene E lL, lun. .nd Konkrl. H. G. (19<9), J. r+v. AlnL- fa, 40M. Andervm. J. L and Keyl A_ (19561 Clin. CA.m., 2, te5, BLCkr•um, ft. Bro.d, l, L)Wr, H. L. snd Kpl, A(19E0). Ana ,v.r, Arai. Sd.. fq 7N. T10302-1376
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1967 Page 368 (b) Smoking and Atherosclerosis. The Letter to the Editor by Burch and Rowell (Br Med J, 23 April, 1966) would be pertinent to examine,lrelevant to the association between atherosclerosis and smoking. Smokiny and Atherosderous Sn,-You diseuss in Tcur 2nder 06 6farch, p. 755) the [+s.itis. a••e:iaion between dz'+rette s^.wk{n,2 and nrv'invaw!ar disease. We +Fafl so: ;est that ISis i+ J rar- ti<vlar easmple of a sriJes-,rcad The sex- am1 aGcli¢r.`ur'nm' of tltegories of oNinva•c:!.v Ci•n•e 'Ir:rr- -n+ti.r.:ot AhriCeed Lin, 1955: Ac<, R'I. ICf. 8:6-->r,criu+c:crosie and dc:er.entiv< Sun di•tae-fl37, 1129, and.II?9) are all .rn- si+tcnt siLS the ricwl a Lhat the<t se::nl diseJU+ have a disturSed-rolenece -=o' inaune .efmlogy. Thi+ 'c,tcr^reLl if tupported by tSe oHixnr,re n+,.vlar e"-'tt+ that are obwryeJ L-1 kwrncY lv+rmtnn•S':"!sL and rhich hare been ann~uted tn a M•t- vehur-"wrJft rnGlon.a Acmrdini <n the- lutJlnl-nIL'le theV 1y L•le CJ rV 4T'J4ti IJi i. "a4 ' prucev is ini:iaeC bY a r. afl nm:!r[ :"er' ally le+. th.n /0) of gcne m_: n- -Vs in I/sy+!.~d etan cd;+ F.c.c sp • ten%eG:e.e+ m::e --~,e pr.r:h of r. e or rl.+re torbiJden-don<+c' nf celtf tnal sYn- thc. a; uutountibndle•. ahvn the target tis+ut lio hdund a blmd-tiwue F~r.icr the primary auro:nnSvlin erc necc+vrilY humnral, and y ap;ors11 that they grnmllY mignte on ' dcsr+phn¢ds with the n;-glohulin serum proKin factbn when the targct tissue is ncrmdlY IralY Infilrratcd by .mnll lYSplw- <s;.. moe •elle wrspr~y cdI-IvunJ :vto- an;:>sJ:a :'a s the primary pethogenic ag.nn. Gnen thi+ ap; rosch, disturbenccn fn d:c cl- and y-globalin fntlions do nnt mr rawn[ the primary nusc of spontancoos - (as rppncd to experimental) autoisnmune drc,s; but the h•s1Y's complcc response t0 Ie.• H Bcrwren the initiation of a forbidden-clone and the first manifcs[ion of +ymptoms or si<n. t Iaant ptriod inevirably intervcnn. Ghen the prinl.rY auto.n[ih~_+its are « Il-bolml (IYm7hog'tic), then on the average this imerral, fur a gis'en a.vironmcnq is ahnlt tuia cr goly) in lrnvltc as in malcs: hut .hcn thc brgct tissue Ilcs bchind a bLrod- ti+w[ barritr the a'unRe latent period in uswlyof e"out eqcal dura[ion in the two seae•.'sr From the elini;al es'nlcnce ae dedwztef1 thnt the length of the letent pcriod is determincd in port by the opcntion of an intrinsic d4cnce mcch.inism, which in the asc of IYmphoqtic autortnrnunitY at Icast is mcdiated through immunoKlnbolim. For- biJ]<n-dnnn att "form ,,n" and antoanti- gan:c. and they elicit a classinl immunt re•t,onu that restrJins their proliferation. Pmbably all divNrFd-tolcranac auto- ecmune ditcases can be prccipiuted and evcubted by estrimic facton such u eer- tim infective cgcntf and ccroin drogse ,lknUl strea uro,:oces cETecu!s We hn'e prc'i^ISe,1 that the.c scvcral f,ctors either cvnp<te for or adect the lesel of the defence ag.+itnt forbiddcn-clonts." SmNsir.g proS- ab.y arts in the same way. Anti;enic and noosclf mater-v6 entrrirg the body haee to be opsor.iaed and phagocytized, and they therefore mmpete fnr the finite defence resuurcn. Consequentlg the tff:cicncy of the defence againa anro.ntlgenic forbiCden- elevrs is dunlnished. AutoJntibWics inere:se in r.u-.bcr, :nd the Iztcnt or chronic acto- 6rne une mndition is precipiuted or tr,arbJtcd. Tha idea that the iatrinsiC dden<e olechanism rtl amoimmunitv is vulntnFle to vuriuun exttinsi: fa.^.ors alvs ecmun[+ fcr Ihe u:}an-runl dl5eea«+ that are foend in e^nncxexl with nan chrovie ennditicm: C,: groter pollution of she urbm atmn+pSere arJ the gr atcr etre+s of urFan Lfc ancounge the :n.ah uf forbidJm<lone+. In eur sll lhl Ci4Ct UI aKOren<-v.uaw/n~ On urdio- scacbr distase procw•es is more appmpri- slc!Y de+cnbd a+ eaxcerbating rather than oc.Jl.-Re arc, eccJ , ,s of P. R. 7. 8tiest. . Cec:r...,lln8rnure. N. R. Rowttl. Lnda 1. Rnnrun '..M. P. R. T.. Ln,.r. r.ns. x. ]vs. • Coner. K A_ d P R. 1_ .N h.,om. (t 4. V•wr. Rm. H1,41.- +~.M kow..~. ~R. .{.u Lr.r.wJVnrl. 'Se..M „ Iwl ai .Nt fAr <:1,.u( $.r..rle.< TAs.y./ ta~...d l.n.nvn -bm ..d I. Fn• 1. ln • M-rA. P k I.N R,..<::. N. 0.. A.v.. J. .4.f, fYf. ]a, bl T10 30 2-1 40 9
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I 1968 Page 373 INTRODUCTION The primap' purpn;e of the 190 Snpplrnteutal Itepnrt is to trvierr . the pertinent liter:nmv th:d has bcoute at'aila6le sul.;rqncnt to the _ 1907 72rpnrt. lirief mrution of the ronclusions of the 1061 Report and theltighlighisofihelDSSltepurtismadetefncilitatealtundclsemdLng ' . . ofthesilmilicancenflhemostrecentinfnrm:ttinu.Thecurrentreanrch . ' findings should b, cuusidert•d in the perspectit'e of tb.c ra;carch eri- ~ dence preeiou5ly presentetl iu tile 30Gi (I:S) and 1BIiI (1yl.') Iteporis. L'/J U'S. Fceuc ile.terrt Srnvice. Smolleq and Health. Sepnrt of the ddrL+ory Commltttt to the SurSNn Ger.ent of the Public Ilraitb S••vke, Vt ¢eb- C.08CLII3IO\S OF TIIE 1064 Rr:HD1T (145) . [nstou, U.S. Department of ftealth, Eduratloq end VL'elfaee, t'ublh: Heelth Servi~e I'uLlicatlan So-1If13.I9G15~4 pp. Male ei,~arette smokers hace a hieher death rare from coronary lqt6 U.S. pwuc ltearv St'xrtoe. The Henlt6 Con~lnrnren or SvmAmz. A artery diACaie flem non3mnlcinr, males, but it is not clear that (ha pubtle Ileulth S?rrke Rerie"w: 195L 6'ashiutitou, U.3. Dcpurtment of aSSOCiationha9eaus:il5lgn':icance. . Health, Educutloo and St'elfere, Publie Heolth Service FuLlicatioo --~---- IhcnLtonra or Tlce 1901 Rerrotrr (1a6) 1. Additional evidencennt onl,v conFlrms the fact that. cigarette stnokers hare incrcased dcutlt r:tros from enror.ary heart di=eare, Lut also su¢gsts ]mtr [hc=e deatiu mav L,.• caused by rirarette smoFina. There is an inerea=ir.•,cnnverifencr of m:mc tcpee of evidence enncern- ing ei¢arette :mnltinu aud cnronarc hrart disease nhfr•h seron_ly . suggesls that cigalette smohing can cause death front coronary Ireart dlsease. 2. Cigarette smokine males hsce a hieher comturv heart disease death rate than nat~mnkin_ Inalr=. This death rate mqr, on the averagoe, hc 70 percent _reater. and. iu some. even ?n0 percent greater • or more in the preeore nf orher kttovcn "risk iaetor: ° for cornnarcy beatt di=ee.e. P'emnle rivarrfte amnAers also hnre a hi¢_her cor"narv heart di.rase death r.lte tlr.m d.+ u~,~tsmnkin~ female?• althoach not ss high as that for male:, In ~renernl. die death t'^tes from titi.s disease inerease v:itlt amount =mnke.L ('e-±atinn' of ri?arutte smnkiu; is folloaed by a reduction in tile ri,k of «rin~ from cornnan' heart disease ~9ten cmnpared +cith tile risk incurred by thoee nito continue to5tnokc. 3. A greater freqnency of advanced comnary arteriosclerosis is noted in male cigarette smokers, eslmcialk in those who smoke bearily. 4. Addilionalevidence=trenathens thenssncintinnMts<'eencic_arette amokinlr and rerehrorasrnLtr di=easa nnd sur^ests thnt snme of the pntho~onetie coueideratinna pertinent to coronarv heart di=ease may also apflly to ceiebror:c,cular deeax. •Thone nt,o M.e etoened smoNnc e1~r•tt•s bnr< n toaer d+[ or drtne from eeroneer wn m,ceu rnan tno...ho.onunoe to.mote. - E SMOKING AND COP,OS.IRY ITF..t,RT DISEASE - Conovanr ITenrrr Dtsc~tse Mor.rwrrx As in Ihe pi°t t.cn r7rrnrle=, roronnrv hrnrt di,ease in the L'nited Stntes cnntimles as the lead ing cnu.=e o f deaih, 6cin;; re=ponsible in 1967, for 5G7,710 deatls or 31.0 percent of tile total of 1.833,900 deaths. Since aee specific d:da are nnt yet arallnblr (nr 14G7, table I elmacs the mlmLer of d^aths due to coronarc hntrt disease and the death rntcs pct' 700,G00 persons hy aoe ior 19GG. TASLV 1_-Cnranbrg heart d%scase t(<n16.s and deatA rates per 100,000 population, by age: Lrrtited StaLes, 1966 lvu...enivcwr•viom.mnv_nmi,rilsl lp NumLer ut d•.m. n.,th Totel______________________________ __________ 573,191 292.7 Under 25 ycnr_____-------- ________ _ ________ __ ________ 250 0.3 P5-34 pran__________________________________________ 1,469 G6 a5-11 ytere------------ ~---------------------------- 32,527 52.0 45-SS yeun--------------- --'-'-----------'---------- 45,997 200.3 55-W yr.n__________________-_._.__.______________. 99,647 577. 3 a5-79 ycsn__________________________________________ 162, 535 I, 40.5.2 75-61 yc.vs--_------------------- ____________ ______ 171, 737 2,979.5 85 and e.ror-.,_._•___________________________________ Nutalated___________________________________________ 78, 354 I6D 7,OtS5 (X) i-Nx eyvti...ele. tue.6:6tuna.lr YIta19blSCCf. Satbml Cenrrr tut ma;tE Stathtlc./[n/. . Th~e data ilhr•trate tile dr,nnatic iucrease in rleath ratea as a5e advances, with the inetr:uo Is•in, particularlc marked after a,e -lb. Tho tleat h ratv+ fn r cnr,~ua n' Leart d i+e:ce i~,r nmtutnd t~ nmrn cnnr in ne to shott" n couspimmUs ditirreucr. In l'Jr.e it m;t-c.^.G1.G for males and 226.5 for fcumles twr lUi ;./Je lwpnlat ion, Nc. IG9G,19i,7. 227 pp. U.9. Fneue Iirnt.rn Stxv"tee. Nallnnal Centur for 111.10, Stntlxtlesm btontLly 19tut Starl~dc Itepart Final Rortslit] atatUtlcs 1dl_) (SUP ptcmenp :1-12. )IS rch 12. 11iG'i T10302-1414
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1967 Page 364 ' DfwNtn•srenoN OF CCROY.rRL }Islaz Dtsuee Coronary henrt rliseaso is essentinlly comprised of three major mani- fL'9tattonsoVsulFatef,orlfs: 1. Fatal myncardia) infuretions, including sudden deaths attrib- uted to corona ry heart d isease; . 2. Tonfatal myocardinl infarction; and 3. Angina pectoris. " Generally, investigator in their analysis of the relationship of risk factors to the incidence of coronary heart diseav: have not subdivided the observed coronary events into the three major snUcategories pri- marily l.ecattse tIm paucity of erents in each cntelgory did tmt permit definitice conclusions on an: cifi.rences obseried. ]Iotcm-eq the pool- ing of data froln sonte of the lar; cr pro=pertire studies llolds pro:nisc of a more enmp]etu annlcsis of the indepcndent and scncrgistie effects of each risk fartnr on e.^.c.h of the sabcategories of coronar_v disease. Findingr~ from these nnnly_=es might prnvide somc insight.s into the underlying pathnph~=io!n_ icll o:echauisms throu,•h u'hich a risk fartor operates. The poolcd datn ftom the Albany and Frxmingltanr studies and data from the 1111' sturly inc]ude the ouser,ed associations of cigarette smoking with each of the three major manife.statious. 3for- bidity ratios have been derived from these studies and are presented . . in table 14. TAU1.E 14. Age-adjusfed morbidily rafios for suLeofegories of coronary . Avart disease among srr.ol_era and nonsmo!•era nbr.ee ehrorr Nee- C~ -,tte Noa. ®atm ef matee Enukaet 1qve{le C G{vatu l ~ ea Fatel myocvdial in(arction----- ._._ LO 2.4 L0 2.1 Non-fatd myocardiai iafarctio¢----_ LO 2.3 L0 L8 Anginn pc c torb .................... 1.0 L1 10 L7 l4ve,r: E<med Repntt artDe Camtiaed Eupvke<etmm Altrour.ad Framlarh.matadb 49). Vm paG16T.G Dae 4am nmlth ine~na[e etn Sludr ff2]. The association of cigarette srnoking to angina pectoris is not a con- eistent one. A clear-cut association lras found in the }]ealth Iasurancer Plan Study (ratio of 1.4) ; a similar association is alw found in un- published data from F'raminghant considered separately. I}owever, no assoeintion between cigarette smokin', and the incidence of angina toris was found in the Albany eyperience. Cederlof (19), in his analysis of prevalence data on anaina pectoris obtained by question- naire, found no statistically sigmitcant difference in prevalence rates between 453 mor.nzvgotiq twin pairs with disaimilar smoking habits. I:n e larger study of about'J,OC0 persons irorn the twin register where genetic factors were uncontrolled, Cederlof (l9, 20) did find a sio nificantly hi.,her preca]cnee of nngins pectoris amon., smokers than noasmokers, particu]nrly in men (ratio of 1.6) (C7)_ Friedman (,'9) and Epstein (J;) have clcarlv described the in- herent bi:ws in prevalence sutdics u-hich may lcad to findings of risk gradients that are different from those obtained in prospective inci- dence studies. One of these lielitations is that fatal casses are under- represented in a prcraletlce sun-ev. Thus, since it appears that cigaretta smokino is more cln=e!y related to the incidence of fatal myocar- dial infarctions than to other fnrns uf coronary heart dieease, it is ex- pacted that niorbidity radns rlcriced from preralence sun-eys.vould be lower than those computed from incidence rlata. With these restrictions in mind, Fna+ck (8.7) in a surrey of 19.OUD men in 1-k ocenpntiomd groups fouod that t]m morbidity ratio of coronaty heart disease preva- . lencu amnng ci_urrttc smokcrs tcas as high as LS. In contrast, in a study of 77 ideutical and H'J frateruul twins in Ftcec!en, comparing smokers with t!wir respectil'e non=makin;; trsins Lundrnnn (r;7) reported no eacess prevalence of overt or silent coronary heart dixase. However, the prevalence of thM' eondltious, as Ltmdmon concluded, "was too lowtoperntitofdeGuitirecunclusions." . , rnmmrh.m.alawr I sar¢wm..neun (fa) C~rnwr, R., FaraM, 4, yoseso.r, E, ltera. L Sforbldlty ¢monS mono- rygotic ttaus. Archivea or F.evlroumxotal ]tmlth (C.`.[ea6o)-1oi_): . a;63i0. Februarr 1DG. (!o) Ceneawr, R. Frrano. L, yoreso., E., t:ev, 1. Resniratory symVtoms aad "aaglaa pectorls" 1. brins with reterenae to amoklo; habltc Ar ehl.ee or Ea.tronmentat IIeatth (Chicago) 13(0): i21rT37, December ` 19c0. yS.:) Fanovas, C. D. Ciperette smulioC a¢d 6eo5raph!c variatiou lu caroav ~f beert disease mnrtatity In the Cnitttt States. Fresented at Coafere:, : . on Eptdemiolrny or Cartlio+'aeceizr Discases, imerir:m Heart As•~ tloa, Chtrngo,_I11iao1•, Feb. 5, 1^Gi. [Gnpnbilsbed.! °-3 pp. (!6) Ersvuv, F. li. Seme uses of praspec[ivc ohserr¢tlons In the Tecum.~ Commualty FfesRh Studr. Croceediegs of Ihe Royal soclety of \ICi el¢e (Londoa) C,O: IiG-rq. ya¢uary lihii. . T10 30 2-1 40 0
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1967 Page 359 (a) Prospective Study of British Phvsicians. The original articles of Doll and Hill contain important details which have been omitted from the 1967 document, Table 5 has grouped all arnounts of cigarette smoking, whereas the original articles have specified the quantity from 1 to 14, 15 to 24 and 25t cigarettes. "There is no clear gradient with number of cigarettes smokedtl quoting from (25, 26) Doll and Hill. Altanatitclc, eigarctte smo{:ing and coronary throtnh]sis m:iy , be related to one another only indircaly throu6h seme umer . factor, It may be, for ec]m..ple, t!wt nxn with a raised scrum ' cholnterol or of a puticular physical constitution (Scl(:cr, 1963) or who tend to take ldtle physicnl exercise also tcn.: to take up eigarcire smoking, and that these factors romnSute , to the production of the diacose. Sudl a hypothcsis is not, at first sight, uruttrJctisq since the ratio of thn mortality rarr of smokers to non-smokers is relatiscly smalL Iiut it hcuma dif(icult, to a rept when all the nidencc is takm into a,murt- namcly, the much e(o•,a r<htionship at yovng e,e,es, the incnJtt , in mortality with increascil cmcent se:oked, The diffecale between ei~.lrette and pitr smnking and between inhaling zad not inhaling, the taduaion in mortaliry with incr.asinl, r:n< sfter smoking h.ss lncn stopp'd, and The many physiotog.-al eQects of smolina ea The cardiorasrular aysrm. In ahert, tlal cigarette smokir.g is a cause of roronary tl¢ombosis is not, ax think, proved ; but it is the most reasonable intcrprctation of the asadabk facts. f In short, we would conclude from these data that the only Czraliovascular cause of mortzlity tn show any aawciation with smoking habits is coronary damx, unrelmcd to hy.•trrrension, and that evcn hcrc the differenm in rates arc not very marked. . The death rate of all smokcrs (4.03) is 23,;; higher t!'an that of non-smekm (IJ1), a nd this ezcuss app can to be limited to the ei,^rcttesmokers (4.79, or 33'.; aSov< the nnn-sntoken, Table 18). There is cavinly no clur gradicnt with number of agarcttcs smol.ed but The h ql st mortality is found among the hnsi<st smokas and thcre n~,eus to Fe a fall in mortality on grs ,g up .1- lTabl 19), p'e rnmir,e nc,x findings morc closely in Table 20, which shous The a5e spceifie death rates from coronary discase. Thcs^ fi5um show that a rising gradient of mortality fnoln non-smokr.s to hrasy ciprcttt • smoken is elearly present at ags under 65, doubtful at agts 65-74, and abscnt at age 75 years and o•'r. We have rnt sought clinical information about the targe number of deaths in this eardiosascular group and eonsequently have noe frh justified io tning tn scpJrate a group of deaths which might bc ascrii4si to"cor pulrnomlc" We notnl tarhu that 55 eardlorasular daths inc!udcd a tsfren.z ro chrunic bronchitis on tlu death catitiatc (corolnrv thromvsis 24, mpocsrdul dcgcncretion 15, h}p'rtamiun 2, other heart dr~ 4, and ttrchrovasn:IJr accidents 10), and it was sho•sv in Tables 16 and 17 that these dcaths v.er< eloxly asvxurcd with smoking. It is posslble that in a few of them the primary cause was reJlly chronic brocchitrs--particularly perhaps among those attributnf to mpwnrdisl dc;eneration or "othcr hnrt disease"--an,l that ttzsc tvnstinne another prdiosascular group which is also associated with smoking. On the c+idcno: avaiLble, houcsrr, this group aould no( appcar to be large enou>;h to have nvtcrially af(tt-tn1 the mults. Possrbly mout such deaths among doeton are attributed directly to chronic -brorlchitie. . . ... Trslt i!.-SranJmJi~J Wnrh Rmr, frurCmJlucJI<vL Are'rsr t)<nh lt.rc 9<r 1.0.V Gc.r. I P,;•c ar FIi.N Uur d r'I A!1 ano- A1I t>'>A! ~'~' At<n .. .1<n Sm~en~ 5.~„y`c„ Sm,~trn~- ~~ ~~la lOl 045 D51 OH U50 OU I OJ •°~ ~Aa /45 M ~I-~--1-6 ~ Ia5 191 ldl 13x ___-- • I,xF] ]Da )].. I ]ti Or.:r,q fAdV bi O:d) P1r ~i, 0.6 I OJ) PII fAU 1•]]6 e:6( 361 ({]6 I{es r:5 Jrl µad~ Dn o-Vx oso I lUx Im o04 I xm H.MC.um Ise o1• oas PU O+s o 9a n]7 Q~.n!.an w l55 O{t 041 041 OU PU O)) 011 e16 o-]5 P)S Lr:.+c..n V.I I]5 OU ' y, l ~ O 0'll OC) PI• Ola ! Orl PV ]n Teu1 .',x.t6DIl s1!' 732 e6r wl 624 Sae+ary<no.i•e 1 TrC I HS Fb f lii I tdl T1x ` Pal p uni5a+te ,1 tr_1.n nfamc la hWp<nev ,M S N t•) Ilrp<+tv~mu z!.nN o Ve C rE a•n:.iaa. Tu:[ 19.-SaoJmJud Dr+rA F,:u hom CJ.Jf..c:mvl.~ IXwu.{, dl R.Iutml In rM b'~.mA.. ef Ciuna/o 5~«Pi.d t5nm it+4 v<r 1POO _ AadCir•m,n5~:,.1,Jn.]v ` G^m '{Pf°b . M I Se+.rMa ib NS 14H ~.~~I IOSi hH ow o _ ^ ,43 1 l9~ ( xxa , xaV ,.YI •..DS .:n {-- -{-V-x }}}I~~~ {~'''5- ).1 c+mur ~thrtl P:, a16- ~j.r:l 019 4~~ (AL ~ S ! .9 ( 516 1 .M I ]rI H..`...LI trc.. ,u~Ym x.uA,y.....•e.. ' 1T] ~ u: Itn ( 1n tl0 n. J.1s onm.w. T.err 16.-1H.,4 Rne hon Caro.vy Tr.n.mbudr by Af.• a.ul+n1.W ~ ~ - Dndh s.. Y.~.n 11-N 55+1 N-0e [5 • ., 1.. .!t .4..ln uv,l.vuJ b .. r..urv N,vn~A.u, erq4 Y..e 4r .4.1 1>n<ti Sn I4G /ra S+Y II{ oa I o.• I le] I oyv I 0oi15 oax + o-11 ou PS{ on ~ 4N O.ri on uw ( v-,a-I as 1 at 1 >a 1-14 Is x+ c~nn,r [fnrc5te s.*.ulm amdmr Uulr Ptl PLL O+i a u l t 6nl IV.1 1oM 11J1 lF. :1 ]I 15,4 ]I 35 >5 W ]I 51 xs. t4 II54 tT ]Q -t M AL..•. ( IYt ~ lll 1•M .Y 4fT 1 4 :.,,na.,,,,.T10302-7 392
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N H IfeL\Tto]sttle9 OC Ctc]neTRl S]torlYO TO OT}trR iastc FACrous The orlgoin,~ pro.;pectiro and otlter epiderniolo~ric studies have y ielded frnd ings wlrclj permit nnalv~i; o f I Iec intc rclat iaush ips antong cigarette snrnkiqtt and other factors con~idered to increnso the risk of coronary heart discase. Age Generally, tlw findings show that tlw incidence rate of coronary heart discase increses vcith age, bnth amonw smokers and nonsmokers. Tho morbidity ratio of coronaqhe:ut dieesso in -moLars vct5us nonsmokers decre:rs-s with aGe thnu,qh the uLsolute number of escess denths amono smokets increases with age. IIigA Blood Pretsu re Recent reports on the relationship between =_moking, and blood pressure appear to support tbc findiues in the 1067 report: Although tbo inlmLttion of ci¢nretm =-nmke is ftrqner:tly necom- panied by ncute trwsit eletarlons In 61nnd ~ nr=anr, Irnhlhial snokers tend to lmre ln.rer blual pre-umn tLmr du nnu-mnkec. 1Scr, "iven tbe pre.mrree of hiab 6!„0,l preso,rc in nn indiridtcd, snnkiue auts_ as nn additional risk factor for the derelnpmcid of coronary hc:trt disease. Ifeyden-Stucki et ul. (91) repotY thct anrnnq 300 trnt$cr<_ in Srcitzer-land, smckers, pnrlicultrlv heavy smokcrs, have lower blond pressuro as a group tlmn (to nonsntokers. Smokers also were fcunrt to have normal or snhnormal .ceiehts in contrast to nonsmol<ers who had a greater mean .reifrht; thus, cronfoundi:,_ the relation;hip between snrokino and blood pressura level. TiLblin (144) in a cohort study of Scandinavian men born in 1413,fomtd a lower mean bloud pre+:ure among sntokers than amonz nonsmokers. As the populntion was clas- sified accordiug to levels of blood pre=sure, a step-wise tlecrease in the prevnlence of smoking mas noted as thc lecel of blood pressure in- TAAts 3-1lfean ag+ and mean systalic and diastohc 6lond pressnre, dy imoking eategory: i.os dngeles Ilearl Shtdy, 11161 ~~ Worl or ., l amnt elr.n[n eaetW .[etm (~^- nL t' a mnt Fu0%~otl Y~ ut Spm-~c I Dlaautk w Smnkere________________________ S07 54 I 133.8 82.5 2ioramoaen---------- _________________ 728 57 I 137.0 83.8 bvres:CWS, V.r..rpt). creased..1 similar trend for both systolic and diastolic pressures was eLn teported br C'1^ rlc, et nl. (?.9) ns=hwt'n in table 3. In the study of G;a ariators (.9q smnkin'm inteusity, alrhouci[ not found to be associated siznificmrtlv with srstolic or dinstolic bload" pressures, was po>itirely nssocinted with pulse preszure. Ecid, et al. (1B3) in a trornparative =_tud}' of workers in Great Rritain and the United States noted lo,rer diastolic blacd pre'snres among =_r,tokets than among non=nroken in both Froups; adjustment for e'eight variations reduced this ditTerence appre:iably. ~ Dfuleah}' ( IUY), in o retrmpert ive etudc of 100 n'omen cor onary heart disease patients under GO years of aqe, reported that .''9 to fi0 percent had diastolic hyperten=.ion (>Pu nun. Ilcpet=ension and ci_~- ,, tog.ther or separately, nere pre=ent in over 60 percent rettosmoking f lhe=_e patients. In the major prospectire snrdie, when both smokt.nt; and hyper- tension were present, in internctive inrren=e in the risk of deceloping coronary heart disense was noted. \Chen to thc,r two rislc factors elevated chole.=terol levels were ndded, tlu tislr of devc:upin, coronary heart discaso ras further incrcased (figures 3 and 4). 1968 Page 3'17 (141) 1YVUUa, G. High blood prrssure In men aged 5)-A Ipprrtation studr of men lroro ]n 1913. Acta Stedica Scaodioa.ica (Supplemeatnm 470): 1-84, 1967. (23) Cuam, Y. A., Crre>ntes, 1. )I.. Cocr_aov, A. Il. ERecte ut rarious factors on ey.tntic enL diuxtolfc blond prrs.ure in tLe tns An6eles l[eort Stndy. lournai ef Chronic Li.eases CU: eT1~l, Ivth, (ffi:) Rcru, D. D.. llov.asu, \t-. R'- Rosr, G. A. An AnBlo-Amcricnn cardiovas- cular eomperisan. l.ancet i(4a.11): 13Vn-1379, December 30, I9cT. T10302-141 S
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1964 Page 354 (a) H The two reports that did not describe a relationship between cigarette smoking and serum cholesterol levels are (1) Acheson and Jessop (in old men) and (54) Konttinen in young men. These are well executed studies and are reproduced in this report. This subject is discussed on pages 207 to 210. Subsequent to 1964, ten additional reports appeared indicating no relationship between cigarette smoking and hyperlipidemia.. TOBACCO SMOKING AND SERU)1 LIPIDS IN OLD R/EN ar ROY Nf. .1CIfFSZ)S, NLA., D.\1. Senior Lecrvrer in Son.d ar.d Prnauire Afrdicinr, Cuyi Hospircl Sftdur.l Srl:oaf and Lnndnn School of Hygiene and Tropical Afedicinr {Y. J. E JESSOp, JLA.. \l.D., F32.C.p,I. Profiuor of Saeiul Afrdieine. Trinity College, puFBn The intcrreiationships between coronary heart disease serum lipids, and eigarel:c-smoking have becn demon. straled by authors from several countries in recent years (Hammoad and itorn, L454; Gertler and Rhi:e. 1957; Gofmn rr cf., 1955; Doll and Hi;(, 1956: Thomas, 1953; y(arvoncn er a1., 1959; Dawber «nl.. 1959; IbrontoSter.art, 1961). 7heir work has. howevcr. been ehicfly concerned xir.h men below or durinb middle tge, v.hertss it sccros that o:er the age of 65 years there is littte relationship beturen tf ath from coronary hnrt - disease and a prcvious hi,lorp of smoking (Doll anu Hill, 1956) or bctwccn clir.icai esidcnce of nryocardial isehacmia and raised scrum cholesterol (Oliver, 195S: Aehcwn, 1961), It is thcrcfure a nutter of somc imere.t whether serum lipids are rcl:.led lo smoking habits u: mcn aged 65 and over. llaaerlal and \lethod TAe Scmpfe.-Thc men aere all prnsionen on thc list of }fessrs. Arthur Guinne.c Son and Contp..ny Lid (Dublin), and their a..mn wcre mleated in a randor' manner as foliov.s: every man aged between 75 and S` was ehoscn. hete<en t.; agcs of 70 and 74 escry thir, name aas omitted front the ha, and bctween the a¢cof 65 and 69 altcrnile n.,ruz v.ere omitrcd. lTu method of scleclion pradc<cd 267 names in all, an: each nun uss sent a Mt,l:.,rd mviL•ng lum lu altcron in the .umpan,v's medir..l dnputmmnt for dmi::. txamin.nion; Ihc actu.rl aucnd.mac. (:-'I) are shu+w: y hy age in Table 1, topethcr with the numbers for whom ' Klimations of serum cholesterol and an analysis of the ecrum proteins by gaper eleclruphoresis were satisfactory. Txps f.-TM1e Sample Aer tnn IY+,ntw nf Mtn Ivd,ed I m Ane+deJ I rvanComvas c~l ~n 1 g~..mmu w;in I fomN+m 4rvm Elm~~r~r~n Q r2 b 74 I rJ I t3 Te 1Q) rM1 36 ll ' Sl n ln s0 $9 72 V 13 `t rx l1 2{ 69 _-' il a6 I i) 6h ]6/ 1 T-1 1 R )i ~ Wt ~ 71 Clinical Examination and Lipid Earimarionr.-Full details have already been published of clinical pro- ttdures (Achcson and Acheson, 1953; Acheson, 1961) and of bioch:mical and electrophoretie techniques (Achcson er aL. 1958; Acheson aa9 Jessap, 1951); accordingly only an outline will be given here. The clinical esamination, which was carried out by one of us (R; M. A.). included a history of smoking habits and a note about die[ that permitted a rough appraisal of wheLhcr or no; these old men fcd themsel.es adequatzly. Blood was taken in a dry syringe between 9 a.m. and II a.m., after breakfast, and xithin 90 minutes the serum was separated by centrifuging. The ser::m cholesterol was estimated by three independent observers, one of whom used the method of SnckeLL (1925) and two that of Anderson and Keys (195R); and since the findings by the two methods did not di0rr systematically the results wcre averagcd, when the threc estimations wr.c aitha IC ;, of the hi5he;t of the :hrcc. In the relatively few cases v,here thcy wcre not, assess- ments were rep'-aled until Ihe required agreement Icsc( was reached. Paper electrophoresis, ..ilh certain minor modifications, was carricd out by the technique of Dangerf¢Id and Smith (1955), using a horizontal EEL apparatus and a b.3rhitone butTer (pH 3.6). Each strip u'aa divided in two, light green S.F. (" lissamine" green) being used to stain the serum proteins and sudan black for the lipoproteins. The intensity of staining in the . various bands was measured uith an automatic rciist- ance scanner which incorporated its oxn integrn:or. Tobacco and Dicmry lndicer.-For certain of the calculations tobacco and dir.ary indices have been used. For the tobacco-index I oz. (23 g.) of tobacco a week and 5 cigarcttes a day were taken as unity. Thus a man wha smoked 20 eigarcnes a day had an index valut of 4, and another who smoked 10 cigarettes a day and 3 oz. (S5 g.) of pipe tobacco a wcck had a value of 2tJ=5. The dictary index simply enumerated the number of times a man ate meal, fish, or egg in a aeck ; it nng-d from 0 to 19, and, althouch it is obviously a very rough measure, the scrum albumin was signifi.antly higher in those wiyh an indez of 14 than in those with an indcx of Icss thm :; and men with an index of 2 or under hsd slgnificanlly Iezs subcutaneous adipose liswclhan the renuindcr of the sample (.jcheson and Jntop, 1961). Reaufts Rrbdun.hlp af Srvrn C6otaurd aed Sa.N.fn{ Nhh Ase The disnibulSon of serum cholesterol in the sample is shown by 6vcytac agc-groups in Fig. I and that of J3ja lipoprntcin ratio in f~lg. 2. There tended .-.eT10302-7372
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F 1968 Page 387 (a) Sudden Deaths < The incorrect statement in the 1967 report on sudden death is discussed in page 360 (a). The additional references relating to sudden death have no smoking data but contain information of risk factors whire orted th t contribute to sudden death. For instance (94) Kuller and Lilienfeld~app~oximate~y two-thirds of coronary deaths had a history of at least one of the following: diabetes, hypertension and cerebrovascular disease, and heart disease. The relevant table from the article is as follows: TnLlc 8 drllyditm of hr/rdustlrroNc lirarf Dtse•ase Drallhs fry Rate, Sex, and Ntunber and Perecnlage tdth a 1flstory of llear! Diuaae or Scural Odter mdiucasealar Dheases (C%'D) . ro ' ' - Airtorr of a ara .- ' Ilirtuq uf 111.mry nf lliaoq of - Iraa unr d:.A ' Tulal 6r.n J1.eaa - Jubw. - ~prrtnul~m e..em CVU r4 Cat.ywr JranLr \-'a. -^w~ \u. - % ' a !G^ SCu. '.5 4M Sndd,-n 40 Nut .uddrn t•F Suddrn Not suddeu '\I Suddrn Not suddrn 'F Suddcn . ' I:rrt .. . suddrn . Tutd 5uddrn . Not sudd.•n 392 :A7 53.3 46 11.7 03 .23.7 128 32.1 193 133 08.9 35 18.1 54 28.0 . . . 89 - 30 43.8 - 7 7.9 . . 37 ' 41.6 42.7 70 49 01.5, 29 38.3 47 61.8 114 64 50.1 18 14.0 29 25.4 37 32S 00 33 55.0 . 14 23.2 20 33.0 . 71 27 38.0 7 9.0 26 36.0 ~. 30 42.3 52 34 05.4 17 32.7 15 28.8 . ' . . . Ofifi 339 50.9 70 - 11.4 185 27.8 231 34.7 381• 249 05.3 95 24.9 . 130 35.7 •F.xdudoa 51 nul-.udden dratha wLen dte patlent had Ixron adnJtted to the hospital with a noncardiovasrular disease and subsrquenlly had a new roro- t•ary ra•ul iu tIH• Im.pital. T10 30 2-1 449
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P Ll Data from the Fr,unin,;hntn Ileurt Studv (00) rer enled tlurt"beavytl cipnrette sntal:il.., I.+nrr thrn )T) ,;. n.r d.i-,.^ ciated \vith uurontplicated auvina in males Lut not in females (figure 2). . Similnr findings nere reported by lCcinblatt. (155) in a study of mnlosni/jects in tl:e I6^rlth ILI.,+lrancc I'Ir.n with tLe ns:ociations more pro3munced ntvnn„ tho;c rncu uhn slnokd two or more pac)rul,+es of cigatcttes per day. As can bo roen, in table 2, the aritLmetic diticr- entres in rates tx4,ceen smokcrs and nonsmokcrs are greater for myo- cardial infarction than for aneina; howeveq the risk ratios are similar. In a retrodtective sturly, Ireyden-Stncla et al. (6'1) found no asso- ciation of smokine n'itil alminn or othcr chest complaints. The inconsi,tencies in data on the n5eocintion betmeen smokine and lho dcrelopment of nuaina may be duc in part to differences in methods used to dia;mosre and cla=siiy snqina and to record smo3cing habi(s in these epidenliolo_+ic =tadics. Tw-ther standardizlttion in this arra mny help to detcrnline more accurately the relatiousLip of snlok- ing to angina. Im- ILr OID 0.M Nen l,uo.w eV.. r,.OS..cr.M e92 1.}p >]U Cirn.,u5mc..n . 08] 14O ~.b Cqrnu3nc..n I Fmcac 2-Anglea pectoris morbtdtty ratios among perwns aged 30.i0 years at en[q into Framia5ham llcart Study, claasi5ed by se: aod number of cigorettes amoked:125ears exp<•rieacu. Soous: Sennel.etat. (G9). _ TASt.e 2.-Age-ndjusled-incidence rates per 1,000 males aged 35-64, and morbidity ratios, fnr spvr,fted rnuni/estatians of eoronary heart di.tease, by smol.-ing category: Ileul.'A Insurance Plan Study auuklug nteeurr b rw oexrv.non mt.l Currcnt nnnsmokcv.--.-.._......-..__ Currentcigarctte amokers ..............s f.ee.s than 2 pack=------------------ R or more Packs ................... 6ryx»nnJ In62tluu Incnd.:.ae 3.27 7.01 5.05 20.80 )[aR'!r1:f9 rono 1.0 2. 1 1.5 6.4 Aattns Inr:'1mSa 1LR1{Iry rae I r=r10 1.37 2.62 2. 05 6.64 1.0 1.9 1.S 4.8 aeura: W<InLlat• r. (nli. In the Western Collaborative Study, Rosenrnan et a1t reported hifIher rates of silent ntynrordial inf.urlions in yulm_er men, and higher rates of rerurreut nprornrdial ia6trctinns at all ages umong thoL who suroked mofe than 93 cipzrcttrs per dny (1°.J. Friedemnnn, et al. (1-{) reported relnl'arctions occurred mora fre- qmnttt)'nnlne•!=rnll-Ir: thsiun 1 mo crs. Dor6en (]7) fnund nn n>erle of ;0 nwn of all ntes, in IlmnburC, w'Ln surritrd at lrn>t L and up to G~e;us n fh•r tln Ir ti-:t m+ocardial infarctiou, tlntt 172 (:C prrrcnt) }md atopped =u:okinz completel)' after thc Grst infut.Iu cnntraet, nt ti, subjects Irhn hnd dicd from aFCeond mt-nrnrrllal utfuntiou or sud,i: u cm'oiuu-v dv:ttb afmr leuriin the bo>pltnt, t,ulyl~ (:%9.71 percent) had given ttp snokiua cmnpletely f P<0.D01). 1968 Yage 376 L9 n.o It n R. Cns , w r.. St ~ r+. I'. df r c r. re/p, a•,oklrn; r , ., l tk r •. . . . . . , . .. . r iLe )'rum,usl¢ICt .~.IJ>. cu. 1C.~ !vr. 1':. L.. lln..uml,u. ll.. u~ 1'.eN A I.ror f/nrm[ut Cicorrnc fa.l1u•_.lu. C3 I'uLli,, lic-.lti, 5.r lee. Xutlunul Can,r In.titute )I~ni~erauh '21. June t o, (n55 w'srsacnrq f3. Pervnud rnnununlcarinn. April 11M1R. Flesncs-SrecsT. S. SauetEt6crcn, 5. Cardiologlschc Siislkofsktorea 1,01 Schu'elzar lfannern. Fch++eivrieahe ltrdlzinische R'ochenscrift 07 (1):20-27•Janunry7,3007. . - (JPS) Imar.a'sux, R. )i.. Fxu:ruun, 31., J^.<rtr+s, C. D., Sra.cs. R.. W cn4 31.. Soslrensu. R. Cllnicully onrecognized myocardlal lnrarctloo In. the w'este[n Cntlabor.lti.e Graup '`vtudTAmericnn Journal of C+rdiulogT IO(G): 7YG-:~'!. Jc~c 1P:T. tJlU Ro.ersana, tl. )I., kau.wtas. N., Jr+hlss, C. U.. STrtnc's. Ft., \vt;e.>q \f., %nsrrcucr. 11 R t ring end fami u+nr.rrL~l Llarano, in tho lYeeteru CcIP,I ,ratl Cr+,up •tvdy. AmerIleo Journal of Carl,toer _ 19,E):7I1 :•e,Jmu.1.G.. Cfdli F`sm~cvxa, Sf.. Sno,r. )t.. C,utatnr. J.. )oa.nn.l., 11. lter IL~rir.fnrkt V' In Atlelo:.l+cer ond kntmmervti..cCrr SIrLt. Deuhches .\« tliv rur Sllnluhc Sfnlb.lu 211: ::1 ."nl. ln .r. (f9) llfrssv. 11-'1'Le a,ht•.r-. nf mru ,rJl.'ll Ildnratlnn-alth spvqal r.frr- enve In riclnite n wCInG nninn¢ Sunl,4 ~r , mry pat,• wl Il:n.e nlut ', ,t u,-nrr ,_, .- In: +c"nm.r. e.rl.. m,IrT10 30 2-1 41 7
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1 - CIGARETIF. SMOKING AND CORONARY DISEASE 71 Cigarette smokers had substantially greater anxiety scores= titan nonsmokers; heart rate and artxiety showed the greatest discriminatory po»-ers among the seven variables used. Cholesterol and pulse pressure contributed to the diTer- entiation to a lesser degree, with anger close behind. These findings, taken with those of others cited above, suggest that outstanding characteristics dif-- ferentiating civrette smokers front nonsmokers reside in the realm of per- sonality. It was, therefore, intri;uing to find that anxiety was the most important vari- able in a similar tliscriminatory anal)sis based ou parental history of coronary . heart disease (13). Virtually the sante population and cariables were used; in particular, the measure of anxiety employed in the two analyses was identical. Again, the ovet-all differentiation was highly sionificant. On the average, the group with fathers affected by coronary heart disease reported a higher anxiety level than did tile group with both parents unaffected, whereas the o oup whose motlrera had coronary heart disease had lower anxiety scores than the group With two unaffected parents. Depression was significantly less evident in both positfYe-parent groups. Although they aided in the discrimination, anger, dia- tlolie pressure, height and cholesterol level made much smaller contributions. From these two disaiminatory analyses, several striking points emerge: - 1. the same psychological characteristic, anxiety, was an important single variable in differentiating cigarette sntd.ers from nonsmokers and in _ distinguishing subjects with a positive parental history of coronary dis: ease from subjects without such a history, 2. the two criterion groups of smokers, which were selected on a quanti- lative basis in respect to nu:nber of cigarettes smoked a day, did not have significantly different characteristics from each other, and 3. the two groups with a positive parental history of coronary disease fell on opposite sides of the n oatice parental coronary disease group in respect to their niean anxiety scores. Since a rather simply-dericed anxiety scale proved to be a highly signiLcant variable in both the smoker-nonsmo':er differentiation and the discrimination between groups with and without parental coronary disease, the interesting possibility is raised that the link bettveen cigarette smokino and coronary heart diseasc has to do with auxfety under stress. Does other re;earch about the coronary personality tend to support this hypothesis? More than ucer.ty years a^o, Dunbar described the personality profile of pa- tients with coronary ocdusion as ene of counlntlsi.e striving, with an urge to get to the top through Lird v:ork, self-dixiplioe and mastery of o,hcrs (d-i). IIer sub- " Anxiety scores rxr< 6:•ttl on the answen given by 1095 s^.edical stud- nts to a questionnaire ap<tiallv dcsircd f.,r d:c Study of the Pr:ur~:n of liyrsrr:cn.:on and Cmonn' Diuase (11, 42). The quraiumuice cnn.icts of a Iiat of _7 l::iun of ncnous tcnkinn (il.VI)I tl:e subject was asked to tltrck all thc rc: cr.nas or npc+ of hahavior eharcterintic of hint tils<n under snesss. Patterns of rt±pense tn srrr~; s+ere drtrr:r.l,"l bv mon of a phi cr.•nclati~n nutrlk; scafes w'ere dcrissd from the tl\7' ncros dwwin; the hi.h.~t drqrc«s of aswci.r,i~xt v;i[h cach other. The nectium MnsPrisin" the ansict)' antr ~consist of anaio:u (triin.rs, Ccr.nat rensioa, Ei~~nJty sfarr in~, rosa of appcti:e, 1rnr:uturanesr an.l uri;e to rnniirfe, all of ehiJt showed slqni5ant pnsitise conch- lions, and nr~e tu rr.t, v:hich was nraeively asrrclatsYt (11, P. IbJ). The anzicty acate scota, lheeforq ranrcd from +6 to -1. . . . 1968 Page 381 (c) T10 30 2-1 42 7
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Ihancntne1lertsnftc mokmgul Ilpntmalaryfimcnonnro oN1•.ia 1) tl,.rn... , r.<.e m s r.a=I:urr. 'i'lt,. ~iif- foronces in ptdnlonnry L:uuinn betu'scn s,aolers:msl nnuslndaers ap- pear to Fhe (,I'cIter than rnu be nr%onnted for hp acute ~•Brels frorn a reeentSy smoked cimarrtte ?l L'rim rel:~timi!iip of corouarv hr.irt dix:rti to t:r.ccred pnlwon:trr lnor.tiun tu ni~rrhd I•r lu,c v-itnl c:tpadny and eigaretto smukin, is o'u+cn'ed in the datn pablished by the Nn- tio»al T nsl ktttes of lreafth ba,,d on tlln 12 ycnr c zpet'ietme irr Frnlr ing- ham (9i;), llarbidity rntios derived from tJus publicatian are shonn in L1e 10. . •. ( TAnte l0. .9ge-adjusfed mm8idity rutius for toronary Acart dCttast among smokers and non.mlalers according to ltctl of rifat eapacity vlw [[wa[r Undcr]Iltrts...................... ------ -...... 9litere ormorc........ ------------------------- a[u<il[ m~erm 1.7 2.4 .6evuansrr.[w„pb- u..rnmavt.'sl. . ( Hero again, lho independent and combined effects of civare_tte snuk-~ ing are ob=er.'ed ff- Physical lnacticity A physically inaetive or sedentary india'idual =_eems to run a hit hcfr iisk of devcloping coronan-heart diseaso (dD, i0, 41, 76). Spain i8.4) re(qrtcd tltat, in his prospec[ice study of a,GOU men the reln- tionship of occupational phys'tcal aeticity to smeking hahits tecealed that one of six t'edentan' tcorkers mere heary s:noters and one of fire strennnus vorl:ers rera l:eacy smokers:' R-tinbintt. in reporting t:re experieuce of the IIealllt ILSurnuce Plan of Gre.ltec.Setv York (11f) also found that n higher proportion (41.9 versus 36.0 percent) of cig- atello smokels .cere classified Sn the "most active" physical activity cstegory. The independent and the combined effects between cigarette smok- ing anrl physical nctieity mo shown in table 17. The morbidity ratios for rny'ocardial infnrxifions are deri+ed from published dati. TAnI-rl 11:-.4gaadjusted morbidity ratios for myoccrdict inJarch'ons among smakers and rmnsmekrrs aecurd£ng to rl,ysicaL acfirity Ieret PW[Inlcurltr ~' -LNw..mubeU rtt[p [Ia dlnst nclivc ' 1.0 Leest aetice------------------- . - I 2.4 ewetva 26 r4e¢q HenLMt. E. tIW,. Sociaenrirmunenta7, $trese Since 1055, resenrdt on socioenvironmentni strcy in relation to coo onaty henrt disea=e has incren=_ed ',reatly (•4J,1+3). _lmong the factms sludicd th•rt inlli,ate a>ruom:p ¢snqiatiou tvilh coronarv heartdi_eve Ineidenca mul prrc:dume is cr„-incultoral a•.~,bility, tLat is, moving from one axinl settin~ to almther. The iuternrtian of this fcetor and cigarette smeking, hzs bren. rcported by 9y'n:c ('.Y), ef) in both an ur- ban and rural setticr!'. ?_'...arently in Mth arcas clqarette smmketa .veren:ore aulturnll,v 11,1111 L: til:.n nonvmokers.'I'lic independent eu'c'et of cigarette smokin, on tlm incidenco af coronary heart di-raeo is shown in the morbidity ratios in table 12 derived from the North pakotastudy (91). TABLE 12.-Ape-edjcrttd morAidity ratios for cnronnry heart ducase among emmFers and nonsmokers aceordiny to soeiaculfuret mc6itity ttatua lalu[ultunlWtu[ 81nb1<---------------------------------------- Rlehly m~bilc-------------- •--------- •-----_-. t<VUr, Nom, nanr.[tuar. Pn Nrm o te1 Eruelln L0 23 If[un ..,r,e rn'ate~[ e (9f) 9ruq S. 1., tirvap', 31. M., Esrcar.rac, P• li.'Vnme sncinl nnd culhirnl factor.+ ¢sxodateJ MtL tbc occurrenee of ouuonrry heurt disense. Jonr. nal of Cnroulc Dlsenscs (St. Louls) 17: ^_li-_n9, 1904. td9) Fos. S.SS., 311, Sr.LSZra, J. S. Phrstcni ectlsity atd cardiovnsceln Dealtb, American Journnl of Cardiology (Nerr Ynrl) 13(6): i21 ~d' Decerober 1'N.A. (a0) t§ess, C- W, 6'vssut; E:., Strarteo. 8., S.cen, R. V. )lyocar0inl trn fermllon ln men. ftote of physiml ectirity nnd s:ooKioS lu i .•..., tad mortnlity- Jovrent ef the Emerlcan Jlcdical 3ssodaHou IC;ICir-nc., 195(12) : 12i1-1^_15, Dce. 19, =~r'n tU) l~tnr, C- \1'., \4'tx.'surq E., Snertxq S., Secsx, R. V. Pbrsinl h:ar drity as a letbal f:¢Nnr In mTOCardial Inr,irrtlen amoo; n[ c. Circ, Ue¢; Iammnt of the dmerican lleart Associatlou (New York) 3I: 1C'^ IQ1'h De<ember 1f". 476) PAnT_1eaxcea, R. S., Ju., 6'uLq F. A., NorEls, J.-Tnonsr, >1. C. Chr•ie diseasc Infarmer eolleec s:nuenln, 1. Early precurwrr vf furL c -,_t beart disease. Americnn Jourual of Epidc¢~iolc6y fisallimorrl.°.1V r-. 314 "' 1vC& -'tl00) ICmat rx, F I`ersonal cummuulention. Hcnlth Insurana Plan of Grrctr 1l New York, Apr.37,19G4. (gJ) Raseex, li. 1. Stress, tobacco, und eorunary dlsense /0 1nrG wmer-rn prafesstonol groups Saucey of 1_^,r}}} me¢ 1¢ 14 accuptinnnl gron; lou[oal of the Ametlcun )fedleal Sasociutlun (Chica[o) 19^_(3): tEL 141,Aprt119,19r.u. ' `93) Sxsre, S. L., A rnca, L. G., e[Iltors. Soeiol stress and carJioeascular'tll ~ eux. Froreedloge of tLe Nurim:ol R'arkshop Cm,!ereuce on Socio-er.nro. mental Strees nn1 CvrUlova.rnivr Dl=psse, PLOenlr, \rla., Feb. II :o? 4 1BCG. The Jlllbank >]cr:mrinl Fued Quarterly (Serr York) 45 1No. . pt 2) :149^_, Apri1 I0U]. ;(90) Strrz, S. L., ], O.. Rorcxzcz, It. 1V, Cultural mcSility v v roranary heart disen5e in an nrban nrea. \merlrau Joutml of E; demtole:y (llo111moce) d3(3) : 3344116, Norember 19r,9. ~rrT10302-1397
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f 1968 Page 389 (a) Anomalous hemoglobin-oxygen dissociation. The 1968 document has misquoted (9) Birnstingl et al. The authors explain the increased hemoglobin affinity for oxygen in smokers as almost entirely due to carbon monoxide. Portions of the Discussion and Summary are as follows: FThe L•tCect of Smoking.-The increase in ~ oxygen atlinity found in smokers appeared mainlc ! due to high concentrations of carbon monoxide in thc ; blood of the smokers (Haldane-Smith effect). When ~ the oxygen saturation values had been corrected for { HbCO content, the mean oxygen affinity of the ,I group of smokers was much reduced, but it remained ~ significantly above that of the group of non-smokers. ` This small residual increase remains uncxplained. ~ It is unlikely to be due to methaemoglobin, as this i was estimated in a few of the samples and the con- s eentrations were found to be low (less than 2 per ._cent). . H SUMMARY A study has been made of the effects of age, smoking, and Buerger's disease on oxyhaemoglobin dissociation. Healthy male subjects over;o years of age have a blood oxygen affinity which is greater than that of a ~similar group under this age. This would result in a shift to the left of the oxyhaemoglobin dissociation curve. Cigarette smokers also have an increased oxygen affinity, but this is almost entirely due to a raised carbon monoxide haemoglobin level. T10 30 2-1 453
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1968 Page 381 (a) Review of Psychological and Personality Variables. The sentence describing the ( 143) Thomas article does not do justice to her excellent discussion. The article is reproduced in its entirety because it discusses another way of interpreting association between cigarette smoking and coronary heart disease. ON CIGARETTE S>fO1:ISG, CORONARY HEa£.T DISEASE, A\D THE GENETIC HYPOTHESIS' G&ROt.T-E BEDELL THO)LlS - . Dcfarfment oJ.trcdici:<,Tht JaAnr lforkinr Cni,eruts Schcutof Utdicize , . Recci.xd for pubtiation Scpcember 14. 1%'7 . 1Chat is the basis for the azsociation benreen cigarette smoking and coronary heln discase: :>._lthou~?r coronary disea,e is the most frequent cause of dcatlt in tlu Cnited States todac, and the majoritl of n:en smo:.e cigarettts, the ans,cer to this question is still ob>cure. In 19~6, Doll and l:ill teported a si, riGcant statistical relationsaip bet.ceen cigarette s:nolia, and death from coronary dis- ease u•hich has been cunGnned by other pro~pectire studies (1-S). The diiierence betsren smo.ers and non,mokers in respect to coronary di;ease mortality is relativel}• small, hoa-esrr, com;r=.rcd to the ten- to nrentsfotd difrcrences often noted in respect to deaths frc:n luno cancer in the prosr),xtis-e stttdies resiewed - by the .acri•or;- Co:rnnittc, to U:c Surseen Ger.eral of the Public Health Ser.-- ice (9, page 161, Table 5). In contrast, the median mortality ratio for coronarv diseax rras 1.7 (range 1.5 to °..0) for seven prospective stuuies of smo:cers and nonsmol:ers (9, pa,;e S?3). \fanc Fcol:le have concluded that a cansal relationship betkeen cigarette - . smd:in.- and coronar}' disease has, therefore, been c5tablished, but some have pointed out that sucft an association could- be equally Well e.plaiaed on the - groune'> that I) smo.e;s are ccu,titutionally di1<erent from nansmd:ers so that smokino cigarettes o rrs them more of a p`oaiole,icat or ps.chologica 1 b<ost and 2) eiprette scIo,ers are r.:ore often tbe precoronary npe of individual than nonsmo;.ers. There hace tieen scattered pieces of evidence that tais map, i.n- dced. be the case (10-16). At the time of tl:e Surgeon Gencral•s report. thex srere suGlcient to erarrant the statement that "rnale d^,arett. >moken hace a higher death rate frotn coronary arten- disease than non-smol:in3 males, but it is not clear dtat the association has cawJ si`uificance." i9, page 527). In eve:ninie- the ecidence that the statisticll assexiation bemeen cigarette . smoking : nd coronar y i:eart disea` na ay not be a simple caur-and-c:iecc reladon ;:iy, n+o facetc of the; enetic h~pc:4e>is. 1) that cinrette smolxrs are constitutioaallv different from nonsmokers, and - - 2) that individu:rls v:i[h a hi"h riv: of devcloping coronary heart disease are eonstitutinnallc di:ir•rent f3or:r tl:~_e %:ith a Imc ri,k, s can proGrably be eonsiderrd together. Although the implications are basically ~ +genetic, the term "con,titutionaP" is utid here nther than "ocnecc•" because trwst n:easurements of adult men, vrhetL•er ph%eieai or p,,cholog-ical. repreicnt the ht~nn[cpe, or inrnifest cltaractrti,tics of t!-.e inclicidual resultim;; fro:n cnot}pe, or genctic make-[:p, and Q-:e enciromr.ent. The dte intcraction of his - degree to u':'sl[ the einirot:mc•nt inte:~rts tcith the "ene[ic comi-;r.:nt rarirs gready accuce!ing to t!ie trait under c;^.i,3rratiua and t'.x• p.rrticv'.ar eNterr•.al eitcvr.!sunies. Csr0in tr.tits, such as t:ic blua3 groups, a:e oot l.no'vn to be modifiable by natural mr1ns. Othcrs, sudt as stature, are ruodi5ed only unr'.er tT[tir 4'cet Km luP1qrtvd b) t[ruJrch Gnnt ItI.01591, \a8onat In,timta of H<x!t!i. T10 30 2-1 42 5
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PAy.tknl lnocficity physieul acaicity, us describcd in the IDa7 repnrq continne-m be denonstmted n, morc datt nre ari'urnubltad. The appm,nt ptotectit'e efTect of phyeienl nati':ity uplrt'ars to be twtrc prm[uunovt , 'irh regttrd to tnyoeurdial infnrction Ihun nugin:t [Ctbla 4, (l35)]. Dlllerences in metiiods of nase:mncut of bistory of plqsical actirity iu case versus am- am- ym- nr tm- oaa ~wo~+ ]nvM r.n M,np.,OrRwurmyrr.v ea].•,Y..breWrvp w.•..,m.a H 7toC.r.4-)tyaerdial lnfsretion mrrrbidity ratlos emong men aoed 30-39 yean at entry into FraminCham Fleart 5tudy, classi5ed accordine to presence of eelected ri±l fo.ctoru: 12 years er,mr,ence (lisk factors nre! cholesterol le•el urer 250 mg/100 ml., systotie blood prussure over 160 mm. IIg., smoking over I paet ot eigarettes per day). . Bomca: Xsnnel, et aL (70). control groups may account for some difLerences in the incidence rates noted. I3lackburn, et al. (10) found no rclationship of smoking to the prev-elenw of po;tesercise ECG changes in a study of 10,=C0 nicty a:e 40 to 0 years Aowetrq there were only 510 (3.1 petcent) subjects with a "uositive" ECG re;ponse. Socioiagical, PsgcdoZogJcad and Personadity PardaLles Two studits (.$,i, 64) demonstrated an in.'er=e relationship between . the frequency of comu::ury hrart a::d the edue:.Gcr:rl '.ecel of the subjects. In the IRell Telephone Sy>tent (Q5), those men without a coltege educatinu had higher coronsq' heart disease rates than those with a eollee education. Also, those not attendin.g cottege tended to smoke more. In a study of factors related to coronarv heart disease amnng Cleve- land attorneys (a4), the quality of t6e law schools attended by the sub- '(eets 4-:Srrnpal age-adjv.sted incidrnce rales of specff.eL maaUe.sta- tiuns of toronary heart dicraae per 1,000 mafes apef! 35-Cy' and eor- mxponding nmrbilfey ralios, by ,m,oking habfts and pdysicat acfiri:y elass: LlealtJt Insr<rance F'!an Sfwly n re~ ehxnmioa mt,tl ltraeudtLrnbrttbn I Anelnw pmnih,a.r6m.nd phv+kel ¢t1atY rl.u tmurt"r. k sbrbhatr i Inna.na ~, GmrUbnrr Allcurrent nonsmakers--------- -...... - 3. 27 110 1.37 1.0 $ut cl5urettc smokero: Least ectivc------------- ---------- 6.33 1.9 2. 14 1.6 Intcrmedlatc-------------------- -- 3.07 0.9 1.67 1.2 ~ Dtost activr----------------------- 3.01 0.9 1.32 1.0 AB current rlg:,rcnc snmkers: Leu+t activc----------------------- 10, 69 3. 3 231 1.7 Intermedlate---------------------- ~~ 5.80 1. 8 2. 83 2. 1 bfmt pc[iec..---.----_.._-...-.-. Lco tLan 2 yxrfln: 5. 77 1. 8 2.74 2.0 Lex,t scCGve.-..................... 7.61 2. 3 2 oi 1. 5 Inlermedio-te_---__-------------- 4. 71 1. 4 231, L7 htast nclive----------------------- 3.85 1. 2 1.95 1. 4 7 er more pncke: Lc>st neti.e--------- -............. 39.00 12.0 4. 97 3. 6 lntermcdistc---------------------- 11.27 3..5 5, 09 3.7 6tost activc----------------------- 2109 7. 4 12.20 8. 0 196s Page 379- (10) Br..csma.c, II., Kevs. A., Sam'os[::, .lt., t'.x Bnc¢rcx. F. S. P.. Tnar.o; Id. L Retption of "insi[h'e" Imreserri~ elntrorprdin~rapbic rn atqneea to otter cLnracteris[itv of risl. Clrculation 3G(J) ( supplerr:ect II):40, October PJC]. ' 'j' Flttnvei, F.. FI., ires.txnrms, It. K. (lecutvtlonal stres.. Inv sclool birenrchy, and cvrouarT srterf dlxease iu Clrvelnnh nttorneyn. 1'sy'cCO.~o- mntic Jledieinc 8)(1) 3suuary-Fehruery SO88. 6{„ llrxzu: 4 F.., Jr.. n'ntrsn, L. Ii., Lcnana, E. W., Ur.'.. J.. Bcv- - .reru:r, B., 6rxo. R., Fr.rea+, A., Fcu[rscca, B, Fersonal rp,u:mupira. tloo. 19G9. ' T10 30 2-1 421
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1968 Page 392 (a) P © "TriggeY" Mechanisms for Cigarette Smoking. The impressive list of 8 mechanisms is not. supported by sections in the 1968 document. It shoula be noted once more that for each mechanism, cigarette smoking was not used as the stimulus. In most instances, catecholamines, carbon monoxide and large doses of nicotine were used to elicit the "trigger" menchanism. The brief comments for each of the 8 in the list are as follows: 1. Increase in myocardial walll tension was elicited by doses of nicotine and cigarette smoke large enough to cause a rise in blood pressure in anesthetized dogs. 2. There are no observations that nicotine or catecholamines can reduce collateral blood flow. 3. The amount of carboxyhemoglobin in an ordinary smoker is about 5°Jr. 4. Smokers have no impairment in pulmonary function unless they are suffering from chronic lung disease. 5. The lipidemia and hemoconcentration demonstrated acutely following smoking is not intense enough to impair blood flow. 6. The increase in platelet adhesiveness is not consistently found in most smokers. Furthermore, thrombosis has not been noted in animals receiving toxic doses of nicotine for an extended period of time. 7. The predisposition to acute cardiac arrhythmias was observed only in dogs exposed to huge quantities of cigarette smoke for 30 minutes. 8. The role of cyanide in cigarette smoking has not been proven. T10 30 2-1 458
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6 While several studic-" of rnrioua nspects of the utstciation bettrmn 1968 Page 374 CAtvnaq' Ite:u't disnnsr morl.J,ly. ;tn1 ,~:trctlo :nm¢in; ns i;ct . tnported dnrin, tlte pu.<t roar, !ho mrnt. sig uilicnnt studles of this eS;ocintion tur eout:tilled in the 1967 report. . Tlto sevetul netr sludicsof rarians a?lxr-td of thc nssaci;ttion between eoronary henrl J i<es , mott nlity mt<I ciga rette smokin,G fol lmc, ' Friedntnrt (.fr) rehot'tcd a.itron~ p[mitice correl:rtlon between per (46) tBlrnu:.~, G. IP. C15arett< smnqtug and gmgrnphlc r¢rlatinn Io corannry hcart dfsense mortelity In t6e Dulted Stntes. Journal ot Chconic Dlecnses capita cig~amtte stles and conncvy heart direase de.tth rates hy states. yp; ;ury7;9,1ser. . . T)reeorrelntiunis0.76trbenditnottlyfi'uttlio.eaatestlithrclaticely accurate information of ci~:vette coqsmnption are mmlyvad. Relnted factors sueh a. ut•}mnizatinn or snftness of the locil water supply do noteaplainthisde;imteofx-tsocintion. . . Other studies dcal n'itlt tbe escess deaths assxiated .vith snoking. gtrolMl, el al. (l.j11) R•pOtted lliat nmonl~ :};17P s(lllysici2t6, Drer I110) Steor.v:, 11., GSn.r, 0. ltortellt]t ln Is¢fehang zVm Tobakfau<Len: 9 JnGre Reobadtunen Ind.lrzten in dee Schrcriz. Hcbetica-ltedlnt irn 50 petrent of the rsee.s death, uccurring over a Oy'ear periorl nmono Decemberlsw. amokers v::u duc to comnarr Ire:t r, tii.a:se. ]n trontrut to the =tudc sbove nnd data from the United States in ' which nppror.utntcl)oucAh:,lf of lLe exces; dcaths n=wciated with - smoking are uttriLuted to canfioctiFulsr cau~s (1:/3) prolitninar-V data from lliracame. (G.: ) shovv that the escev dcxths in Japan aswci- ss lLaarn>rn, T Smoklvg In relation to the death rnte, of xs,vs men and oPotl srith stnnhin; tcelC pritnnrily esplainetl by r.;utccr of caTious si[es. V wvmrn in Jaton. TokSo. Satinnal Cannr Centcr Resenrch Instltute. September 199. 14 pp. Onl)• 12 percent of the esees dcttlts trere aaociated .rith eardio- -_-. --- -„ -- ,. vasctdaT cuns-cs. This pro?pectire study of o_I1F,113 adulte over tbe age ' ' of 90 encompnssd a follovnp period of 1-a months..ltlditional follo,,- . uphy 111r•lrnwa shouLl yi Jd u=eftd data tcith re-)lect to snrokin;; and . 'oaccas mortality from cardiorasculnr di=ca=cs in this J:rp,mese popu- . lation group, particularly ivith regard to the younger adults in the . study. Iljams, et al- (67), on the other hand, speculate tlmt theapparcnt (e7) etxer,s, [... Sua ll., Anc¢so, N, xyocnrdlm ~ntzr~-t9ou In tt,,• increlse in the ocCunCnPe of coronary heart di5r.tse among JnpanArte A retrRR'cttre study. AmeriCm Journal of Cardioiot„ ]0(4) ; 51:?mnles, espcci:Jly under the a_e of nin•, runy be tluc to a trend toward Westernization in both diet and smoking habits among )•oune r Japanese men. ~ IInmmond (5i), in his ptospectice study of over I million men and Sbl Iiaznmsn, E. C. Smoking In relallon [o the dcath vntes of 1 millluu cea AUmCn, shot+etl a positlre relationship betrceen the duration of the aod aomen. In: Hnenael. ll-.. editor. F'.ptdemiulogicat Apprunrhes to smoltin, habit nntl Cotonarn-heart disease mortaiitv, In the Framing- the Study of C'ancer and Other Dlscasez. Bcme=na, t's. Puhuc Ite:;!u, ]tnnlAeartStttdy(71),noassrciationaasfoundb!rw'eentheduration 8errice, Sational Cancer Instltute Efonograon 5o. 15, January 1G;c. Po. 1'4-.^(N. o£ thesmokingbnLit atld the ittcitlenceof mortnlity from heart attacks (71) Sens,:q `V- It., Dno-m:a, T. R.. II~S.>taaw, P. ]f. Drteatinn of the .vru- smon(,r men who tvere."ItCar)- 3moke15' (motC than one package of aery-prone adult: TTe FnmingLam Study- Journat of Qme Imva \led4 itgnrettes perday). .. cal Soctets sc(1): aG-31, Janwry Ixu- These discrepancies behreen the relationship of smoking to the ._ incidence of total coronarv_ heart disease and mortalltv from acute . toronary heart distnm msy be sc<ounted for, in part, by the ditTerences in population groups studied and by the poyibility that duration of . smo[dnr mav P.at'c a greater association with the fatal forms of . ~ toronaryheartdiscase. Knnnel, et nl. (T0), in motE recent data from the Fruminglmm (p0) HASeq {V. R.. CsreuA W. P., 1(c\auea. P. H: The corenary pro- study, hidicate tltat the fntal and morn severe fonns of cotonary rtle: 12-Jear rouow-up in the ]tamtngnsm enniy- Journal of Oceuoa- drsease 9r9 mot2 s[ronQly as_soCiated with cigarettA Smo6-inp that the qon8t Jtedfdnn 9(12) t el1LID. ne.enmer IOiIr. less:overe forms (figure 1). T10302-1415
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F 1968 Page 380 ject were ranked independently by n law school professor. Lawyers attending schtxds in the "b.i~hc,t la]r scl]ool quality "roufi' Imd lower ra:e; of caronsry heart di~•ase tkun thosc actcudin-.1 se4ools in the "lotrer la:v scluwl qunlitc :;roup.'-.11sn, tLt~ in tlm Intter group had started suokiniv at mi earlier a_•e. :jince additional differences were noted for ot6er ribk factors, snwkinr aloue urar not be responsiblr. for tlte tatal dilfetm:ces in IL,~_e rates. ln both studics, it tcxs hypothe- sixed that with respect to st~,lptiLilit-r to derelupnteut of coronary heart disease, Lchacior pattcrns and attitude~ establishe<t prior to profession:d traiuiu.~ aud Ireior to>tres:rs res]Itin_ front joh mohility aad joL te:sion, tvere tnore >i:naicant than the !ater stresses which aesulted Lnn]thcir prc=ent jobs. ILecent data from the Spcstern CuILtLoratire Grottp 8trldy (F'_-9) appear to show that anton, mcu :3D-4'J years of age, ci~arette stnoking was associated trit lt seceral roronarr heart di=rast risL- fxctors (tahle 5). ThongL theee findin^s may be statistically =i~nificant, the diLrer- ences betnecn smokers and noaemokers were smal. TAaLe 5.-fige-adjusted means Jur selected coronary deart disease risk fadors and personal elmra<Irrisfics, by smoking eategory: Bistern (kllaboratire Group Study, n:a(es 33-w3 years of a N8 se.n.ros. ahu,.auac ext.l ge 8.13e, ureem r YW.pre e.Kne N<.a me[<S P-na pae pe] kH 3r < Es~~o $etamehOleitCtOl ____ ___ _ ______ 217.2 231.8 +6. 7 Bcls/alpha tatio_____________________ 1.9 2.1 +10. 5 Linnlhumin__________________________ 21.1 10. S -&1 6ystolie blond 4reuure_______________ 126 3 1219 +2 9 llisatolic blood prMSure--------------- 82 0 8L 3 -0.9 Pondcrslindex_______________________ 12.6 187 +0.8 PhysiralectivitY on lob_______________ 1.95 L 95 0 0 Amount of e.er<iee___________________ 2 18 2. 05 -e. 0 Iosome_____________________________ 2.76 2.75 0 aYaq: RM<u¢.4 R. H. nrJ). Tnat.e 6.-Perrene d'utriF.rdion by beAnvior type of smokers and non- amokers: Rrestern CoAaboratice Group Study, molea 89-49 years a<h«tur LrP^ (e5/ Rosrssus, R. H.. Fnrtnv.n, ffi., Jem¢ns, G D.. ZxznresRr, 3. J. 1' `') soosl Cowruvuication, 19G8. . T10 30 2-1 42 3 ef ege TOtd 100.0 Type A.-_ . 4]. 5 41.3 45.0 4S3' 7ype B___-___-.i 52.5 58. 7 ~ S.i. 0 5L7I SotarQlRere.e<a(1]Inbut,ON: V - I/. i',N- ];p-P]L aaV.q: RaenmeE, R. H. Wfl. +ti pet GatY 100.0 4i8 55.2 Behavioral pzttern type .\ is chsracteri>ed bv an enl]nnced com- petitil'ene.;, drire, ag, 'ressivenc:s and Iwstili[r] and an excessire sense of timo urgn,nce as c(ntr,tsmd to typo B. Theiv uas a difference in the distriLucon of personality types A and ii zrnono smokets and nonsmoke> 1 taLle 6). The foregoing, dnta refer to conctrrent ober-ations gathered in 1860-1901 ou 3,L2 men mlw n-ere then free of manife;tatimu of toronary heart di=ca.e. A follow-up of this populatio]t diaing the ne5t 4t_, y-ears di~-Lµtd thut cigitYttc =mnlsrs ecperien.ed substan- tially' highct• ratc nf rmonnrc heart disea=e ILan tiw:e trlto bad necrr emokrd. 1'Li.; fiudin7 , ia bn-rJ tln tluta fbr tnrn ".?-1:1 t'ear:s of ai•c, u'hiclr hsre Lcen adin,ted it,r the confowtdiw- iut;uenccs of rciand risk factors, sucL ns nge, chale.,terol, etc. (table 7). IaQ 0 tolr<u.a.o.c.ca,en.unca«.I emnklue<nteeon ro, c.:rer.e on vor tieu Ny too: 0
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'r1 0 Cerbon .1JonorLlu E)Jrrt Tlm pa~'us; 1.nu cf eizarette sln,dm cunta'm+ nbout; pertel:t ear bon ntonnxide. This qwullity crut in.reose the Ievels of rurhosyhemo- globin saturation of ciqaretto smn6cn from 2 percent to 10 percent (21). The averuioe nonsmokr, depeodinZ on errvironnicntd cxposure, ustmlly has lese than 2 percent carlrocyl'.cn:ngtobin saturation (10). Since smokers of one pack or morv a day may hace chrunwa I Iy elevated carbuxyhemo;-,lobin levels of more thart 4 prrcent (r), tbere muy' be appreciabin dilie:rncrs in the ezri.rxyhenlnglobin levels between some heavy cigarette smokers and nonsnld:ers. In addition tn disnlneinq osyhemn¢iobin, carbon monoaide eQects a shift in the as}';7t, n-bcrnoglobin diz sociation curvc (?, 3, /, 5, 6). Thie may result in a decreased release of oxy'gen at the tissue level. A serics of studios (61, 6J) bas bc.n pcrfor.r:rd on young adults to analcze the effect of ci,azetto smnkin¢ on cnrlraxyhemoplobin levels, and tite eonsequent efficct on como paremeters of cardiopulmonary function. An intreasod post esercisc oxygen debt was observed aiter cicare.te smoL-;ng n,s compared to controls. Tlds, in part, nm.y reflect noc only ventt'atory distucbances but also a decreased supply of ozygen in the plood duo to the carbon monoxide eQect, resultin~ iu ]t>s available oxygen to meet the increased tissue demand. Similar post-exercise oxygen debts have iwen noted aitcr inhalation of elmugh catvon monoxide to produce comparable blood levels of carbosy!lemoglobin E1). - The consequence of the smoking/carbon monoxide eRect appears to be especially im)nrtant in the myocardium where. relatirely- morv oxygen is nornr sily extracted from the coronary eirculatiot as com- paled to other organ systems (Co:nnary vesocs blood usuaflv has an oxygen saturation of less than 25 percent, whereas bloorl leavu\,q aome other ar-sns is about 75 percent saturated with oxygen (y'S).) Dogs were exposed to carbon monoside to elevate their carbo<y- hemoglobin satnrntion levels (9). In response to inhalation of enrbon monoxide there n'as an increase in coronary blood flotv but a decrease incoronary arterial-venous oxygen di2crences. Patients n'ith coronary heart disease were alsa studied following inhalation of enouqlr carbon nronoxide to clevate their carUosyhelnoglobin saturation levels to the range of 5 to 19 pert'ent (9). In responc, to carbon monoxide there was generally an increnw in the cardiac output and ti,e coronary blood ' flow in most of tho patients R-hile the sy=iemic arterial-cenousosye n differences raried, either increasing . or decreasing, the cbronary' ar- terial-venous oxygen difietences decn•ased, indicating a decreased oxygen extraction by the my'oeardial tissuo despite the myocardium's increased demand for oxyre.n.1•hes: decrease> in rnyoeaniial oxygen extraction are related to increases in the carboxyhemaaoSin saturn- tion levels. Jt tras obser,ed that some patients eciderdly could com- pensale by increa=.ing their coronary blond flolrs adequurelv to suppiy the myocardial ti,ue ..ith suoicicns oxygren, as inaicated by a rise in myoealdial oxpF,-n uptake in thew iudividuals, Ho\ceccr, the other patients with coronary heart di;cax, evidently n.oro severe, could not inaesso their coraiury blood flo\r rrto enouch to compensate for the decreased osygcn carried by the blood. Thislatter grnup of patients, eveur, tthough they Lad inereased cardiac output, had Ie,s si;ni6cant increases of corouury blood flmv than thosu noted in the first oroup of patients. The coronary arterial-venous ox}'gen diiTer'cnces and the ti]yocardial tissuc o~ygen uptake, both derreased, indicatine tlmt the myotardial tisouo oxyleu demnud r:as nat bein' met mlticele, Tho tcduction in the amnlmt of un,_en :a':tilable to the myocardial tissuo caused by the nlsorption of carbon mmtosidc from tobacco suwke may iw expecially critical iu per.~ns rvitlr pre-esistinp coronary' heart diseak, e inccially when ther cannot simficantly ineretie coro- nary blood flm~ to ro:npensate for incrcased myocardial tissue oxygen demand. Tho c•trbon monoxide eliect may, in part, contribute to the increased incidence of myocardial infaretions that occur in cignrette stnoken. Addit ional nsearch is necd 1. ~ 1967 Page 367 tifl Cnrretss, R. R„ Sntomov., R. A-, Rosn, 7. C. Reactfon ol nm+mnhern to carbon tnonnxldr 1nt:nlatlon. ('ordlopvlmonnry reslnn•es nr rest nnd durtng escrrLe. Journul af tLe Amertcan Nedical Assoyal lon ( Chlca4o) 198(30) : 1M1-tt>Gl, Uce 5, 1'F3G. 10 Asar9, S. 1f., Cr.\iaerir, 9., Js., Asusr6ol0, R, G. Cerbas;tvcm¢loblv: LemolyuanJC vnd tvspiratnrD resrorscs to smll co¢eeotrallens, icience ( We+hlnetoro 1{n: July 9, SG:;. (^7 Arz£a, S. )C Prrsoral Comuruuirarln¢. -l'rm LorL, St. Ylnrent'a IIospltat _ and'lledlcal Ceoler.,fb'vpublished.} JuueYJG7, J) Asrs.-r, P. Len k1i:SSt.e b?tSdalug ot forzLrdnin6cr t okslhanc:eytoLlncts tllssoclotloos6ur~e. \nrdL=k >ledldn (stockLOlm) 16:10.:;LLJU. 1;GG. A52aer, P. Variatlone. I olralLaemoglablveb dissoetattnnelrurrr. Cgeslrrlft ^~ for Lacger (sone:a.u.nl 1_SU"1l: uD~7V1, 15v,i. t_y AeTBCP, P. 1Llemciet IHafSitt fra Ltodet aG nd\ildingcu aP nWkererende unerlesyGdenime. t'seshvift for L,cger (&obenharv/ 1"5t°4):'ilt-709. r(l'.~A6i8CP, P„ fsr,14'.\n-L~RSE,I', P., 1.J£4sE'.Y, R-, ]fEGr£~[C.\AN'J, effeCt Ot tobacco sr6nklnS on tbe dlsaxlatlon curve of o%,Themogtohiu. Inrestigatinnr h, pa:tents "ltl, eccluslre nrterlul dlseosce ia normat s\b- Jee[i Seaadlnari:m Jnurnai or Cllnl.al aod Ia6omtory IuresCSatlov . (Oslo) ISbq: a:A-1G7, 19ui. - ~DSscsrrrort, R. A., Curvscru, R. 5. Ross. ]. G. cerdiopulma:ary fane- (tu¢ lo young emn6ers, A cnmarison of pulmooory funclisn measurE- mevte enA mme ranlioputmn¢sry res;,ar.<es to eaercl<e be.t,ece a group of Tuneg smnkes and a\vmpsrnhle rroup o[ eoosoc',;ecc Senals ~ of laternul \lydicine (PL11nde1Phia) r)(-I) : 6031,10, dPVit 1?ih 6~3) Aavssnou, g. -q., Cn.ur., It. n., Rocs, J. C. CL¢nges ir. cnrd:opvl- manaty fOnctinO9 rPlateA to ntvStlnence from smnkiaG. 3tudi,K in rUUn.C eigarette xnmlrcrs ut rest and exereise at 3¢nd C neeks of ob;tive: ce. Auvals of Interual )ledlcine (PuitadelpLiu) 6^-(^-): 19: .G1• S\-0ruary lo&S. 7 ($,-) Gr.cee, D. E., Ftsn+s, L. C.. Editnrs. Rlnod supply to the hea;r, tn: De,. P editor. ]lantbook of physiolooy. Circulatlou. 5er. :. 6'¢sbtng'ao, American I'Lysiolopy Society. Y.1GZ. 11, 1;d:J. T10302-1405
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1968 Page 381 (d) iJ 72 C.tRO1JNE BEDELL THOMAS ' jects were hospitalired patients under tfre age of 55. She came to her conclusions through psydiiatric intervieres supplemented by tlu ftorschaclr Test. Since that time, there has been little agreemetrt in regard to a psychodynamic personality pattern associated with coronary-disease (15). There are sonic indica- tions, Iroweser, that there may be hrri major coronary pc•rsonality patterns uhich are diantetrically oppo,ed to each other. 13ahnson and l1•ardsaell, u,in,q home interviews plus sclGaclminixcrcd check lists, studied 32 whiee merr aged 3.`r61, who had survived their first attacks of myocardial inLurtion, and compared them wi:h a control group (16). They found some dillerences between the cor- onary patients and the conurol goup in respect to their feelings and attitudes tox•ardtheir parents. •1-he coronary gtnup, howeser, resohe•d itself into two discrete subgroups which were almo>t the oppasite of each other: the self- oriented, regressiee type corresponding to the mother-oriented coronary paticnt (~ e 19) and the socio-centric and controlled type corresponding to the father- oriented patient (N = 13). The mother-oriented group showed the following characteristics: l. they identified ssith their mothers in terms of :rer personal manners and intimate beLasior identification - 2. they were amono the younoer coronary paticnts 3. they were passiee, stating that they frequently day-dreamed or "sat and - did nothing", often lacking interest in and commitment to work '- 4. they showed dependency by tending to turn to others for help tchen in trouble 5. they were not contpulsive and slio:ced little concern over "face" 6. they had strong sucrorant needs . - 7. they had low ego strength and self-acceptance 8. they were unstable in that they often felt mixed-up, tense and worried 9. they showed a trend toward anxiety aud depression . - 10. they frequently made usc of rc•gressice defens;s - 11. they showed insufficient control of a;;;re>,sion. The (athcroticnted patients, on tlte other hand, showed the following char- acteristics: - I. they identified with their fathers through somatic and social iniage - identification 2. they sscre among the older coronary patients - - 3. they were active and seif-teliant 4. they slrus.ed strong comfxnsatory soc io-centric nceds for achicvenr.:nt 5. they had considerable self-control and ego strength, with hieh self- - -aceeptanceandse46caieem , 6. they clun ; to social norn» - 7. they had concern ocer "face" . 8. they resorted fre<lucntly to the ur of mmpulsire and reyxc.cite de• fenses in order to pcrfornr as solid citiiens in spite of an unsati,factory tmdcrlying scl6image . 9. their social commiunetu repre.entrd a flight front dternsares. - Both tlre ruodreroriented and tlte father-oriented coron,ny patirnts a•ere con- tidererl by the amhors to Iwse failed in eatablishiug their or.n iclentitin iu a 33tiffactory ntamler. T10 30 2-1 42 8
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1968 Page 386 (a) li Experimental Studies on the Heart. The lengthy discussion on cardio- vascular response to smoking and nicotine which started in the preceding page and continued to the next page does not relate directly to the question of cigarette smoking. Most oi the cited references are on catecholamines, carbon monoxide and hypoxia. There are only two references on cigarette smoke: (15iS) W estfall et al. and (3'_) Edmundowicz et al. re.acing to the release of catechoPamines bat the amount ot c.g.:rette smoke admimsterea was'excessive, since there was a significant rise in blood pressure ( t 1y to 176) and slowing of ne neart rate. There is no cil.ed reference that catecholamines can be released by administration of ordinary amounts of cigarette smoke which does not influence blood pressure. ~ -GtDlWAr0.'L.V! tL5PU5[9 TO RLAa-tF S,~ 4vD ~ILOTl%2 0 UOCS LOLt/i.u: J-/.^.eC\Epl.IC LIA'vaC_ :^.'N ixOVrA~OILC (I.C.l. afAlu). A. c[ s,~.=lcc.. p. f. Civotlnnt•. .m L. r. . eP--°ruL. Sa: Vtre'~^ie Un1v. Sah: of Yee.. `W: Vnewn. W. V.. Lqht ..[Mtued dny r.re u e to SnI.l. -e fren 1r il{ [tet C'.te'aih .[u1(ed end.,tr..F..t Nn.; r9tr.tto't Yetl.E Gr : VW :n.LVter. .l frm I19 [n L16 m. Nt . d.cr u( .t. (n larc ro. .nd ln. of ]S.Yn reYe vuWv (S,Y,J .nJ J:: le e~rdlaa wipa (CpJ (alL x v.tu..), ne.n level. c! .yb eephrlne CT) .m mqplnryhrin. (Y) fn !leod frw the Alth lnGrmr v . ll.v.C.) tncr....d fr- 10.2 tn tl! t-.d lro.<O.I ee 27 )/C re[Vecttyely. stelbr e.penu. (etl...ed La. ln;«ifoa of nleuelm. AR.r d-aJ[en.[61c 33n«ttn. vtCh O.I q[Jt[~ yropr.nolcl I.V., rstln6 d.cttu.C 3.s, q:: 3.V. Gy 9f. ..d C9. Gy J4S. 4..n A.A. tncna.d fr- LlO~ta L95 ell. p[ .-d r a.t day. d.v.leyed crtn.unc lelt v c(t- t..W Aitur.. tutn levfb of t.nd N tn ohe hl[h .VeC_ (natw.d (re.a e0 1 to 145 end fr- N.'. to IO./L. {.qonwr ta .ICOtlar fetluvm[ Etnck.d, r lcu.r, cu^vt~_.lcc: ~- carr.rsfa nf.,.k.d. ty p.wr.-nmf daa n malty t r.tr... nf n.. tn. eerc.+t rm: n( e„d. Sn • .mYly ud alcu[L^..: vu.klni o( • .u[ur catMq c . n ,.tnc..f.m ndre ~~nu !.a .m crsa..t.. mncu.e. i (iappureed Ey c5PM5 er.ne o:i)d-c1). 1 The other experiments cited relate to nicotine. The significance of measu.ement of nutrient. btuod itow was not'mentioned. Nicotine increases nutrient flow in a dog with coronary constriction indicating that there is adequate blood flow in the ischemic area following nicotine injection. T10 30 2-1 447
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r 1968 Page 381 (b) 70 CAROLINE BEDELL 7nOS1AS such adverse conditions as severe tmdernutrition, w•hile t4e proportionate roles played by genetics and encitanment in such characteristics as body teei,At, ar- terial blood presure, total scrunt cholesterol level and personality structure are still being vigorously debated (li ?9). While the genetic hyirtthesis does not necessarily contradict the sarious enviromnental hypotheses, it does limit ,hent and diminish their importance by asserting that not all indiciduals ..re equally susceptible to adverse environmental influences. Reportsof actual ge•netic studies in this area are limited in number. Ditfrrences have been found in the distributions of such genetic markers as die blood groups and the ability to taste pltenyltltiourea (P.T.C.) in populations of smokers •and nonsmokers; these- findings are in harmouy with the generic hxpothesis (12, 15). Twin studies carried out abroad point in the same direction. \Iono- zygotic twins showed a higher degee of concordance than dizygotie tt,ins in regard to smokin~ habits (30). In monozygotic twins with dixordant smokino habits, coronary disease was not more frequent among the stuokers than among the nonsmokers (31, 32). The numbers involvea in these eomparisons uere too ' small, however, for definitive statistical evaluation. Somatic variables reported to show statistically significant smoker-nonsmoker differences range from a series of anthropmnetric measurements to resting heart rate and blood pressure (13, 14, 16). The mean ditIerences in all of thex com- parisons have bcen small, however, and at times have varied in direction from study to study, as in the case of weight (1d, !b). \loreorer, the small circulatory differences obser.ed could well be the resuhof the smoking habit rather than aa true constitutional di0erence. Perhaps the most thouoht-proNoking smoker-nonsmoker differences lie in the psychological area. There is a.considerable bocly of evidence to show titat the personality of smokers differs from that of nonsmokers in imf~rtant ssass (JPr- 36). In the words of Eysenck, 1) "smokers tend to be more emotional, more neurotic, more gicen to anxieties, more tense, tuore likely to suffer f:nqt the so-called p<ychasontatic symptm,:s" than nons:;:a':ca, and 2) "s:itokers tend to be more extrosetted, nonsmokers more introeerted.-Extrovertcd pcoplc tend to be sociable, to lii:c parties, to value good food, drink and the good tbiq;> of life generaliy-to t: ke riAs tnore readily, to act tritbout regard to consequencei, and to find it di ucult to stick to the same task day e:fter day" (:i9). Schula_rt i:as emphasited the point that tLe smoker seeks phy~_u'.ooical, social and eal arousal (IU). 41is fmdiu;s amort„ eoIle"e students, based on the }fi:::rqta 1lfultiphasie Pcr>atality Incentory, ress:iled that, compared WitJt nu~n~cokcrs, smokers more frequcntly dr,aibe tlicm:cl%e,as 1) b_in, borc:' .ind sceliu{ thrills, 2) bcltaring in a~ocially unaeccptnble 6shion, aud 3) havinn m.txulinc traits. 5mo'r.ers abo scotcd higher on an impulsicit} sctle. Work frotn our own laboratory indiratcs that psydtola•inl sntuker-tton- smoker tliEferenco are of considerable importauce. As pnrt of a lon;-terns prospective studc of the precur~crs of hs.r.eten>ion and coronary disea,e, dis- eriminant function a nalysis was esed to test thchylwthesis that cigarette smo.crs are different from uon>uto:.-ers in a numbc•r ofp:}chobidogical so:~ss (d1). The overall difiereutiation betNtrn non+nmkers artd two oroups of cigarette ernukcrs in a population of male medical students was found to be hiohly significant. T10 30 2-1 42 6
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r Ll IIigASernm CAolre[erol and Sdderd DO (i..i n u; t: r ., r.i ! rn:.. ...I rh.,r.-. (f , i;t) have, in Fener•tl, dtmnn=trarod himher chnl :t.rol Icrei.s in .uokers than in uonimnkern. 1'iu, Lerlr, et sl. (110) and Lmte, et nl. (Hr7) nport similar f ndin,=..1 studVlrc f@cdmo~nicki (Cl ) of 50()Stciss tt'orlcers found a similnr trend Lut tlo, rtuPcrenees Imttreen smnhers and nor,• smokers with respect to rholrsterol lerels aud other lipids were not statistically significant. A recent report (3f) descritks some of the rnriahilitp of interrela- tionships amon7 smokiu_, blaod pre'st¢c and cholesterol lerels in different populrtinn ~roups tl:rou-Lout the trorld. It conchldes that thoueh nonanolceritend lo be I:eavier nud hace hielter blo«I presure levels timn cigarette svmkers, heavy smokers tend to be in the top rso- a I : aa- >:_ t a a M t61 Yp plmrze 3~Inet2ence nf corovary besrt dises+e smanp men aged 10.59 Sears at entr) tutu F'eopl•s Gas l.icht and Coke Compan' Study, vlasstaed fls to prea- euce uf speci6ed riek factors: 1DSSID6^_ SnIDCr: Stsmler, et al. (118). . deciles for blood pres_sitre nnd relatire wei;ht Cholesterol-smoking telntionships described in these studies do not show a consistent pattern. In nenntroller1 rlietnrc intonlntian <_htdc of noatinfnretinn patients Leren (97) fotmd that smoking habits did not influence the eernm cholesterol level or ehe coronar., he:nt dises:e relnpse rate in the control group. Among the stud_r _roup of dieter, there was a su~•,e<tion, although not staticti.allrsi27tiiiicaut at the 0.l).l level, thnt smokers had a higher coronary heart di-ease relep=_e rate dlan nonsmokers• ]Vl a 139 TM 12 H. f17 .~, .: o. . tr vv e II] iba er 1968 Page 378 JfedYWlseLe t1-nche "htiLG J.JL'd : 1SY. 1et0, \o•-emLer u, L'M;.l. (Ilfl) f7ecnr_utr, G., R•amur, iT. il. Screnn[ng In the early tllncnnsls ncd Drv. revtlon or cnrd[ovneculur tllsrose. ]ouruol of the Cai]eSe of Genurat Pr:mt!Gnnrrs 13: ^+o _^v. 1`.u7. (SG) Epidemlvim,;lrnl stndie. rcl'leQ to rornnary henrr dLee.+ee Chnrorlcriatler of omen serrl io-19 Ia ceren c~•antrie=. P. Sninking hnb!4. .{.qs Ncdtca Scsndlnnrtra (Suppter.ieut irA): snl-315, I•,1u7. (P!9) Srssrtee, I., Bnsso3, D. >L, Ln2ssos. )L. f.euvswn. IL A.. Alntoss¢r. L., Nui[s, W. A., ll.tt., T., A~'n[utes, S. L. Coronur9 arrerp divr.,r. 6mtus o[ prerentlre eCorts. Arcbires of Enrlrvnmeutal Health 13131 : 32-335, Sel'temLer 190. - 197) Lxu:~, F'. Tbe eCect of plnsma chnlesternl lowerine diet In male snrsi.rors of myoczrulal lufarctinn. A rvntroilerl rllnicsl trinl. Oits ltedirn F•yi: ~ dlusrica (Supplement iG6) : 1-92. 1066. t,I t T10302-1420
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r , The Health Coiiseqnences of SMOKING i969,SUPPLEMEN7 TO THE 1967 Public Health Service Review U.S. DEPARTMENT OF IfEALTIf, EDCCATION, AND WELFARE Public I(ealth Service C6"iAP'i'ER 1 Smoking and Cardiovascular Diseases - Contents Summary---------- ____________________________________ f.a. 1I 'pidenuolooical _________________ 12 Bh_________________________ 25 ChrumLus Formntien cnd Blood Flow_____________________ 27 arhon 9fonuxide--------- _------- _________________ 28 Cited References_._____________________________________ 29 Cardiovuscular Supplemental BibGcgruphy_________________ 31 1969 Page 394 T10 30 2-1 46 0
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1964 Page 354 (b) to be absalulcly and relatively fewer men with a serum eholesterol in excess of 220 m;. among the older age- groups, with the result that the mean value fell slightly hlfb C1_F_1a CMOEER[RIX. (+IrOO~Q I>-tfistoEnms ahowing, d'svihutian of mm eholeavol in sample by nvo)ear aac-yrouq, ~30 L tnl act 4)-[9 m aCE T0-71 1GE )Y)V aCE 6n. Y ~~rtih OAr ttrovnortiv asrro Fw- 3.-Distributinn of 9/n Gpoprotein ratio by five-year /SCSronnl. - but significantly with age (r=-0.19; P<0.01). The pattern of smoking varied in a far more striking manner with a;c (ste Table II): 66 - of the men agcd 75 years and over were p'pe smokers and 9" cigarette smokers, as compared with 27% pipe smokers and 53', cigarette smokers in those who were less than 75. Taat[ ll -5mo.tinq Nabiu by Aer Amonq Fhn .{Ih Chorcraor Arvo+ snu Tm 1 Arc fn Ye.rs y[ u~ ' IfnM r) ~-I t) NJ O+n NonC .. 'R tl Gpr.+r<ovtl I ]) ]) 39 <aV 1ar .. I 45 24 acE 1f-n aG[ [O. r. 27 Wsa ' C~ran~uNJpi.e i Taal ..' 1)b I 100 Retatbn+dP Bet.cee Serum [)plds it Snollnt The nature of the relationship between smoking and both serum cholesterol and /1/a lipoprolcin ratio is indicated in Table 111. This shows that both mcaeures of serum Upid are just a little hi,her in oon-smoi:cn or very llphl smokers than in Ihe hcavier smokers of cigarette or pi('e tobacco. 7his tcend is confirmed hy the eottelzlion analysis shown in Table IV, uhere it T.LLa IIL-Frlanon+5iy nf Ctemrrrr cnd F:, 5mo47nt wirh Serum CAOru~nol anJ .+ln (i~.uprorein Rmio_~ 'ryye or Totvew Etw1 I ]reN Yrvm ]/un a'a (~,.~Mtm~l(nC.) LWtNK~nltup I 1aw ' ]IeN ~ r:a 1 ](_-u Nu,+. s 10 Mwwh: ~a:.«a: 2 )a I] 34 n ean be secn that all the coefficients of correlation are negative, but with the exception of fl/a lipaprorein ratio in pipe smokers and non-smokcrs the trends are not statistically significant. Taau tY.-Car.rlctlon Bmwn Serum Up'Ji and SnroFlnt In the Ennre samn+e sen,m s.,vnt avme,m.,t [t„~nn~~elm (me.loomL) P+x.~w PtaMbunolTrnJmn-.mWOr,. -0-07 ' _OIn hw eTAien NJ nan.molm -OIt 1 -OJS• ToWavbJn.. .: r' -oat -o-tt V<PGd: ouw or rM other ewnun era eiyni~ic.m et L1le Jy, knt . Bronte-Stewart (1961) believes that the proved relationship bet•seen serum cholesterol and cigarette- smoking in younger men may be due to dietary preferences. it is possible that these ald people living on pensions cannot aiford to smoke hcavily and to eat well, and therefore a comparison was nsade bctween the dietary indices and some other charactaistis of, . on the one hand, the heavy sntokers of both cigarettes and pipe tobacco and, on the other, the nomsmokcn (rable V). It can b< seen that Ihc heavy cigarctte- smokers are significantly younger than the other two groUps-a finding which reffects the dilference tktwecn the smoking habits of the generation which reached maturity before and after 1914. In the sample as a -Taate V.-Serunr UpiJy ABe. enJ Dlercry InJez of Non-rmo.Een end fleuvy Sn;u4rrr nl Ci;u•ene um.! YiM Toba,vo ,r jI Aae O.,asmt ~ 4'+Llc.+ ~ orwy 1~1 6.YUn (m¢./ pammRnro tweA aren SO He<n~5n-Ipf~ya~5b.'N;ai15D. Noe+mok la >34 I]1 ' 2143 e29 i 30 I Ot rq 36 M/~lpI d. 'y ' ] ~,~ 1[>q• 19 b)r )r] li I oJ 70 1) tvt+um~ • 3 I roor. ,; tl YS0 f al ~ H6[ + 6)O I t=) 1 PI Sa 149 ~asipii/ tlY T*~nSO .amue a4ri t~ ///~,p_~<04])p m otau owuJ,rts,N.~eer.,,¢n~ va,:r,ei. whole there was a significant negative regression of serum cholesterol with age of 1.7 mg./ycar (A.hesan u ol., 1953), buL even allowing for thl.,, the dntrrcnces between the mean serum cholesternl valuos are not significant at the 5'~ Ievel. The dietary indcc used in this study does not measure preferunces- but it has aheady been shown above that Ihere is reason to believe that it measures the general lercl of nutrition and there- fore would show whethcr the heavy smokers go without food. The analysis in Table V indicates that this is not the ease ; ind<ed, the hea.y pipe-smokcrs eal rather more lhsn the non-srnokers, although tlte diIIercnae is got quite significant (t=1-69: O.I?P>0.05). Discusion There ean be little queriion of the rdatinnship between serum /ipiJs and cigarctte-smoking in mtddlcagcd men. It has been demonstratcd in rhe U S.A. (Go(man er al., 1955; Thomas, 1953: Dswt><•r rt al_. 195'i), Finland (Karvonen cr al.- 1959), and South Africa (Orunte- $tew'art, 1961), yct in tFs prescnt data based on old men there is no eviJence whatsocver of such a relation..hip -in faet, there is a suggestion that non-snmkers may bave a mcan acrum cholcaerol and fdla /ipoprotcm ratio which arc higher Ih:m in smokers, Bmnfc-Stcwart (19611 believes Ihsl the re,son serum fipidc are ni.ed in youn6cr snWtrrs it bcauv< L+sle preferences indu:e them to at more cholcatcrulagcnic T10302-7373
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1967 Page 361 aims -° ...................I ]s.x ss.i ~a i.o 2.4 bprGa: ps. Punik Rmah3mltt, 9nmin:h.w Studll.el. (Ctaatd 1W:1 . - 196) U,S. Pueuc Iluun SLSttea The Yremiusham Ileart ffiudy 11nblts and L-' Cotonary Itcart Diseaso. Washmrtou, U.S. Deparmmnt of Ilcaitb. F.da- 14e effect of ngu ou the incidencu of eorotuay he:lrt dlsease sci0h regerdto ciEptrrlte s:nnking in =hmcn in tnble 7 hnsed on recent datn frontthoFract in~hsnlStudyau•lpnbtisi,e. l. I Txors 7.-Incidence rates and morbidily ratios fur coronary ib<art dtitease by age and amod~ing a:ofus of uten J3-year aperirncei k}a- tninghant, 3fcss• ' . I . rtrlEt.mt wpnlhn~ P.mm~to P/ LWl rlwnlUy ntb tN B t '' Won ametm mo c a nonut ao . i evwten . r m es t n mestn ma ,» nonsntokers, the rate is seen to triple every 10 years. This marked increase in ineidence amono nonsmokers reflects the cliect of other important ris.l- factors and perhaps accounts for the decrease in mor- y bidity ratio as age advances. The independent e!1'ect of snlo4-ing on the incidence of coronary heart disease is believed to be more appro- priately reprssenled by 1he excess morbidity rates, wiacit increase flrom 2.7 lxr 3,000 smakers in t)IC age group 35-44 to 9.2 per 1,000 mlokers 55-64 ycars of age. . «rhen the incidence rate of coronary heart diseaso among mnle non- eatlen, aud vVelfure, Pvblic Ilenlnt Serrieq Publhatlon \o. 1515. 106i "smokersbetireen33-1iyer.trsofa;ciscomparedwithtltatamongolder Sig1.BloodPres.rure Although the inhalation of cigarette smoke is frequentlyaccom- panied by acnte transient elevations in blood pressure, habitual smok- ers tend to llavc lower blootl prcuures than do nor.smoLets (//S). But, given the prewncc of high blood pressure in nu indiridual, smoking.._ aots as.nn add ition al risk factor for the deeelopmrnt of coronary heart disease (17, 28, :.7, ,40, 53, 05, 95. 96). Both the indepcndent and the combined effect of cigzrette smokiq~g is clearly shown intnble S de- rised front the experience of the Yraminghnm and Albany studies (so). Tast.c 8: Age-edjuated morbiditg raHoa for coronary luartdiaeaae amory amnkers and nonsmokers according to iuel of systolic blood . . preaaure ~ . . ~ .. aTtelk Lbae ee®en n dyenuu or imu~ltne tlader 130 mm. 71R_____________________________ 1J0 mm./1g nnd o.ror .......................... aWrir: taytV rnminrn.q rad Lre.rAllenr ereeat,rce nW. 1.0 1.8 2.1 3.8 8iyh Servm Cholcstercl - It is not 1•.ow conclosively ktawn if cigarette smoking by itself can rauu increases in scrunt cholcsterol. Dietary influences as welll as en- dogenors production and elimination of cholesterol must be evaluated in grepter detail with simnitanenus analysis of the roles of other risk fdetors, including smoking. OTIC study of a smsll population of twin9Jin Streden, as reported by f.undmsn (G7), sngqect that smokine monqrygotic twins te.nd to have lower cholesterol levels than their nsrnoking control twins, although the diL'I:rences are not statistically l significant. Other studies sug9est that smokers Penerally have higher serum eholesterol than nansnu§crs (13, G:,88). fIoweveq given the teseoee of high serum choksterol, smoking increases the risk of car- onaryheartdiscaso (?d,9G). . The indopendeut'and synergistic eReet of cigarette smoking is dem- tmatnted by the data in table 0 derived from the combined experience of the Frnntinghnm and .11Lany studies (90). ' . TAar.r: 9.-Aye-adjusfed morbidity ratios for tarnnnrt,/: heart diseaseatnong am,okrrs and nonamokrcr aetordiny to lcrrl of scrum ehulesteroi eavmACletncllmn . nnn,:eetaeel~~tal.n. ce.rtr.a e.n Lowr ......................................... Hfaht........................... (t8) DorLr, J. T. Etiology of eorooary disease: &Isa factora lnfluencint cor- 4nary disease. Modero Coocept+ of Catdlotveculnr Disease (Saltimore) ffi: WkG. AprL11fIGG. . (rA) Ilonr., J. T.. DAmacs• T. B., t:Arrxrt, 1F. B„ ffieua, A. S., ICAR.. H. A Cigarette smolaag and ouronnry heart dlsesse. Comb[ned es,nerience of the Alhany and 1'raminaham studies. Sew England Jaurual of yftdleine (Bostun) 20606) : TJfi601, ,1pc 10,196Y. (J0) DartS J. T.. DAU'sut, T. B•. SAxrrJ. lv; B.. Arscu, S. ii.. 8sus, H. A. The s<Inllonsmp of cl5arette smoking to ooronarJ heart dlic:tse. The eerond relart of the mmt'med zxperleoee of the AlGonr. >.Y., and Ftemtnglinm, Raxs., atudle.t. Journnl of the American Ltvlnal Assoela- Ilan (Chicago) 140(10) : W.fiiU. Dee. T. 10Gt. .(SS) Sanacy {V. B. Clgarette smoking and romnary heart disease (editorial). Annals of Iuternnl )iedicine (Phitadelpbb) 60(6): 1103-110Q June Io6L BAn.m, n'. B., DAmrq T. R.. ?fc\.uASA, P. H. Deleetien nf the eoro- C nary-prone adult: The Framinehant study. Jourvat of the ioxn )Iediwl aoclety pxs Notnes) G6iD : 2r.5t, January 10G6. .. _ ..~9S) rhtrtir. 7.; CAenrvin, J., C.AS.Lt. 6'. A mulnraAete ana45sla of the nae of eoroaary heart disease in F'raminahaol (Unpubtlshed.l 2G trp. (67) Lb..aval, T. SmoYinq in relatiou /o coronarr heart dlsease andlung function In tNns. A co-twin control etudy Aeto 3Ir.lica Scandlna.ICa (Stnekbolm) 1S0 (Supplement iw): 1-75, 10GG. ( (tJ) 8cxsos, IL. Cost.s. B., JA., GARCIA-PACRlLRr, SI. ]t., FTLmLRTI. M.. ArsuA, B., BLA:ITOx, l. lt.. (:oLOS, A. A. Coronary bcaa divasc rlsk fanturs: A eumparison uf two Puerto Bh-+n pepulatioar. .\meriean Journal of Pnblic Hemlh and the p'etlon's Health tNe.v Torl) ' 56(t) : 1037-10PA, luly 1}GG. r"LOV•'bEelovmNmn.^/l4n'•b.P,.en~rv:I.e.aa.Mxmm<nn6.nmL . . . . . a<uafe;l6fNtrta,nnieMmaMlarmrAllu.nr.awien[t/rU). T10302-1395
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1968 Page 388 (a) N Exercise and Smoking in Post-Infarction Patients. The statements relating to (43) Franl- et ale are incorrect. A fall in output was noted in 2 patients (-2 and -18°je) and a rise in 6. The authors state "Smoking failed to produce the striking increase in output seen in young, healthy, habitual smokers." Furthermore, exercise and smoking caused an increase in output less than that seen in pre-smoking state. The Results and Summary are as follows: Finding.t before Snwking Findin,~,s after Smoking Patim[ Ate SA CO Re+t er ' Stl HR CO E..rc've CI SV 1IR S.C.• 64 1.55 2.81 1&1 50 57 457. 2.92 54 86 N.E.• 62 7.90 3.82 3A-1 57 66 5.10 2.71 57 90 E.F.• 53 156 3.s.i 2.46 64 60 6.88 4.41 8? 84 G.C ` 69- 1.51 2.55 1.67 35 72 4.0.1 . 2.67 46 87 \LH.• 55 1.&! 2.69 1.61 45 60 3.62 -^_'0 38 96 A.J.• 48 1.92 3.&3 1.99 71 54 7.87 4.08 82 96. A.Lt 56 1.99 3.50 1.70 56 63 7.66 3.85 91 84 F.L/ 68 1.75 3.44 1.97 60 - 57 5.44 3.11 60 91 • Chronic nnokerr. 1 Nonsmokers. " SA, surface area ut M.2; CO, cardiac output in L./min.; Cl, cardiac index in L/min./M.'-; SV, stroke vnhmac in ml.; Hll, heart reto in beats/min. Table I Table 2 Rnt E.nciu ° P.r:rnr CO °.A Ci Rs SV .'S! HR CO .°.1 Cl :.f 59 . ros HR S.C.• 2.78 -2.1 L79 -3.2 44 -13.0 83 J 93 -1.i.6 ?.Si- -10.6. 4.i -nn.° 93 \V.E.• 4.10 }71 ^ °0 +7.8 52 -8.8 78 5.90 +15.7 3.10 +14.4 58 +1.75 102 E.F.• C.C.• 4.10 4.E:4 +6.5 +45.5 -.6.3 3.10 +8.9 +~16.1 57 46 -10.9 +23.9 72 5.5? 102 ~1.4s -19.8 +10.1 3.5-1 -.9S -19.0 +10.5 68 48 -17A +-f.4 81 93 Df.1L• 2.19 -185 1.33 -18.8 37 -17.7 60 --- A.7 • 4.44 ~" 15.9 2.31 +16.0 55 -".5 81 7.47 -.i.1 3.89 -4.6 57 -34.1 132 A.Lt 4.03 +15.1 20-2 +14.9 58 +3.6 63 7.9-1 +.3.6 3.99 +3.6 95 +4.4 84 F.1..t 3.9^u +15.1 2_"6 +14.7 55 -12.0 72 6.48 +19.1 3.70 +19.0 58 -3.3 111 •Chronic satokrn. 1\on.mn1crs. CO, cardiac output in L./min.; Cl, c:rrdiac indea in LAnin./\f.2; SV, stroke volume in ml.; HH, heart rate in Ixats/min.; Y], PrT tcnt a'funlre from nonsmoking state. Summary Smoi:ing by subjt-cts %~itll healcd myocar- idial inFuction: in nmtract to iis effects on the ' '. nomlal subjtrt, lails to procoke an increase in ~ C cardiac output or in strukc eolunre. On the other hand, smoking docs iucrca..r the heart I rate in subjects with hraled mt'ocartlial in- farction. This tliaaociatioo beturcn the rQcct on heart rate and on cardiac output and I stroke columq ahich was nlso t.oted in thc ! healthy subjcet pretreated with ylucvse, indi- cates that incrcase in heart rate is mes!i.rtcd by different factnrs than those that incrcase stroke voiume aud cardiac output. .T10 30 2-1 451
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1968 Page 381 (e) pGARETTE SMOAI\G AND CORONARY DISEASE 73 In 1964, Ostfcld and his co-workers reported a four-year follow-up of a prospec- tive epidemiological study of coronary heart disease in which the \finnesata Multiphasic I'ersonality Inventory and the 16 Personality Factor Que;tionnaire were used to obtain measures of personality in men 40-55 years of age at the start (47). They found personality differences between the 48 tnen who, since being registered in the study, had deceloped symptonu of anpina pectoris and the 37 men who had had myocardia] infarctions. (Ihey did not give the mean ages of their groups). On the aeerage, the 1771 men who had remained free of clinical coronary disease showed personality profiles which lay betmeen the angina peetoris group and the myocardial infarction group. Their findings indicated that the men in the angina group complained significantly more about somatic symptoms of all sorts and worried signiGcantly more about the state of their health, even in the absence of objective findings, than the, men in the infarct group. The ane na group also reported greater lability in cardiovascular func- tioning and greater emotional lability and sug;estibility. Zllten the non-cor- onary group was compared with the totzl coronary group, no significant dif- ferences were found in their \fMPI scores, but the 16 PF indicated that the coronary group were more independent in their socual relationships, more suspiciotts of the motives of other people, and had greater feelings of inner tension. A prospective study of coronary heart disease was initiated in 1960 by the 14'estern Collaborative Group (3). Friedman and Rosenman, the leaders, had previously described an oral psycho'.coical questimmaire by which the specific behavior pattern of a subject could be classiLed as Type A or Type L. They con- sidered that Type A was the coronary behavior pattern. It is characterized by excessive drise, ap;ressiveness, ambirion, competitiveness and a sense of time urgency. They described Type B, on t':e other hand, as the relative absence of these characteristics. Ans:acrs to t.';is questionnaire were part of the eomprehen- sive data collected at intake on over 3,OCD sub;e_cts After two years, 54 of 1,534 . Type A men and 16 cf 1,593 Type B men ha:': devclop.d coronary heart dis- ease, more than a tl:recfold difference. A.ftcr four and a half years, there - is still a predominance of the Tl'pe A behavior pattern among the subjects who developed eoronary di>ease, but the difference is less strikin- (48). It should be noted that a sub,:.mial number of Type B men did develop coronary dis- ease; again dte evidence sua-ests that at least two precoronary jxrsonality tytxs areinvoleed. That thcre are'at least two major types of coronary disea;e has been sug.-ested by clinical studies, also. lu two groups of men d)ino from coronary heart disease, for examp'.q thosc dia-:msed a; IIarin cotnnary discase at their last periodic health e:camina:ion were co:npared witir tho+e whose heart disease was uo- detected at tl:at time (1'J). The latter group was younger, and contained nearly tti.•ice as many heavy eigatcrte s:nokers and nearly.haice as many men with hypercholestncmia as did the group w'ith diagnosrd heart disease. The facts thac 1) both hyl~rchodcsteremia and heavy cigarette smokine ttavc bcen more closaly assoeiated w•itly de.:th from eoronary di~.ease at younocr than at older ages (cf, Table 20, p. 1105, ref. 6, 8, 49), 2) the ansicty-linl.ed "coronary fxrsonality" was more often found in younNer coronary patients by Bahnson and Ward%ell, and 5) the preponderance of new coronary events in Tylx 'A subjects was greatest in T10 30 2-1 42 9
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® specific eorunary Lrart dr+~u-w nwrtality rates for cz-sumhnrs nnc. current cii~.vr(tr sr,nker_v (tnhlc 4\). Fro:u these d:,t:,, it : mnrnrs tLnt ces.utLc:, af c rc[Lc s,c,,~;inq is toaou.d by :r tcaluetion i~,i ris's of corottan, Lcutt discase morlallty ns comtmrcd 10 lhn:a who continue - to smoke cijnrettes, Tesl.E 2A. Aanual death rate per 100,000 from coronary heart disease b age, eigerelre-smoking status and num5er oJ eigareLea +maked per day, U.S. ceterans study ' ud/ e5-0/ I ei'le Nw+tvrmotMye.Geye -' ewrev a cm.nt rt- om elb er. elCyetb mobn, nLeo nav mnknet Muke,a nokPa o 1 to 9 ............... 195 ':15 504 432 1.374 3,105 10 to 20_____________ 297 133 830 557 1,577 1,260 91 to 39------------- 390 - 57 012 743 1,701 1,366 40+ ................ 502 -------- 1,IOl 646 1,955 1,482 I Thn n ttm eueenvmo ete-+otinr t'+e a,r.<nt dcveoe.moYen e^d Ihe m Wmumreu a41aM ke ee- u.tm ~ CeIt~otrn.eo 11.,,4 me rc.uum eene tnen Ux'ne'r rJen. leeeco. t1.5..cle,.roae~Jy (1r). . The Hammond study findings swnntarized in table 3 are based on coronary heart discase deaths reported over a 4-year period among approximately 1 million persons (•4s1,000 men and 563,000 women). • TABLE 3.-Carenary heart disease mortality ratios among current eigare@e amokers only, by amount smoked daily . lret.e.n. Men: ~ 45 to 5t .................. 65to 64 .................. 65to 74 .................. 75 to 84 .................. Women: 45 to 54__________________ 55ta 84 .................. 65 to 74 .................. 75to 84 -................. 1.0 1.0 1.0 1.0 1.0 1.0 1.0 10 u rn 2.4 L5 1.3 1.2 09 1.3 1. 1 etn,eetm rmntm mnr 3.1 19 L6 1.4 2.0 1.6 3.1 2.0 1.6 L1 2,7 ao n+ 3.4 2.1 (9 tatye6MdAha.Pehm0.n10. . eoGacs: r[b¢ona. E. c. a>). . Tables 3 and 4 show that bbdi men and women who smoke cigarettes haee relatively higher death rnles from coronary heart disease tlmn aousmokers, although men have higher rates thnn Iromen. For each sex and for each age group, the mortality ratios for coronary heart dicwasc gzncra'.P: iucr.a_-• ~ritVr ine:acad irtcnsity of cinsrcttc =_:::ol> ing (lablo 3). Thu highest mort:dity ratios for both men and .comen are observed in tbe d5-54 yeur age-group; the coronary beart diiease doath rates among heavy smokers in this age group are three timcs the death rates for nommokers for luth s.xes. T'ne mortality ratios for both men and women decrease tcittr advancing age in each intensity eategory. This trend may reCect the effects of selective survival of smokers who have survived the c:evat.ed risks at yomhar ac7es of eur- ennry heart disease and other diseases associated with cigarette t:moking. Another ciplanation of the decrease in mortality ratios with aging is that the effect of smokicg, while substnntial in increasing death latesr'cannot be expected to be proportianate to all other causs of eorqnary heart ducasc as aee advance.s. Considering the advanced de- gr I of atherosclerosis ecnerally found among non=.mokers over age 6, tbc deletcrinus e:^,cat of smoking is inore approprinrcly rtepresentad the eacrw iu death rates among smokers. Table 4 belotv shows e observed dcatlr rates from coronary heart disease among lrrsous tudicd by Ilammond and dussifind by age, sex, and smnking status. Although the mortality ratios ei:•creased.vith age, ditTetenres in death rates, .chich reCiect the uumbers of 1'eru>ns slw die in each age group, inercase. This could Im interpreted to memr that, althmhh relative to other faetors, the role of cigarette snwking tends to diminish with ad- vanting agc, t ho tm mber of esce.~deaths per 1fiJ,000 snwkers continues torisexithadcancin~ nge. 1967 1'ap;e i5t9 TABLE 4. Ageapeeifte death rates from eorancr',1 heart disease p: 100,000 persvns by age, sex, and sntok(ng slat:!s _ aperMra lmerenot e ~,tn Nnwmnten Eec.v .m~oia'~,~- )tom:::r r~--, Mela: 45 to 54 .................. 422 150 273 2- 55 to 64----------------- - 996 542 454 / 65 to 74 .................. 2,025 1,400 625 1. 75Lo 8A .................. 3,571 3,132 739 1. Females: •AS to 5f------------------ 66 33 33 SS to 61 .................. 275 103 ' 112 1 65to 74 .................. 941 653 288 ) 75+ ..................... 2,349 1.973 376 3 , C.INIMM GOm lha Eell . ' auceR~ u.mmne. E. C. It/n. G. :rt-1 The rclative decrrase iu dcatir rates from coronary heait di..d essociated with the cessation of cigarettc smoking is illustrr.ted table 4A. Tente 4A.-Cnrunary heart disease (men). efge-stunrlardied dect': rafes for ez-efgarette smokers toith Aisturj of cigarette smuking by former number of eigardtes emoked per dey ard years eince i•vo ngarette smoking. Death ratee J"or a<rrert rparettt smokers ¢ith A,sicr~ of cigarette smoking only and men who net'er smoked regularly cre rhown for eomparison. blen aged 50-6.? ui~i,'i~w. o~,oq Undet I yesr.-..-.--. 1 to 4 yeen _..... _ _.. 5 40 9 ycan..-...-.._ E0+ yeare_..-..-.... Totel ez- smoken..... Current ciq.rct[c emokers........... Never emoLed regu- larly .............. emntee o-u e~r+rntm e eer smnrea v+r:r,.an.. m. nrm.er ~ fEex e ~ nn:.h oI me~Cr w'umo-r a:.:+a D.::] 749 27 t 1,005 ( 2,."44 77 1,844 51 718 5,435 195 l,nC 1,770 48 725 5,803 152 73 4,209 84 498 8,142 206 67 8, 569 2i0 635 21,624 630 81 22,808 181 947 55,888 1,805 t.0'1 $5,728 1, 114 502 55,728 1,114 50 t rav er m.,re enue:, mm tn nrerbI e.veenn in wn,e xtne c=anew. me.c.. aemon=n. a. c.010. n.:al. _ -°"'T10302-1390
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I 1968 Page 382 (a) Seltzer's criticisms. The questions raised by (129) Seltzer have not been adequately answered by the 1968 document. The article is reproduced in its complete form.- An Evaluation of the El ffect of Smohing on Coronaz-y Heart Disease 1. Epideutiolosical Evidence Carl C. Seltar, PLD n In January 19Gt, the Surgeon General's Advisory Committee on Smol:ing and Health' in conzid- ering the available infannation on smokin., and c»ronary heart di..cae (CHD) (International Sta- tistical Classifcation [ISCJ 420) reported that "male cigarette smo;<ers have a higl:er decth rate from coronary artery• disea>e than non<mokinar males, but it is not clear that the asoc•iation has casual sigtificance." Three points should be not~d. First, the comrnit- tee left no doubt that there wa: a consi;tent statis- tically significant association amon,, ci;arette xmokers of increa,ed n:,ri.ilitv and morbidit_c from CHD in men, pcrticuiarty tiurina midd!e life. Secen lane completed or current prn+pectice studies of smokin,gand death rate;,ivc a CHD mcdian m•.nrta!i- (y ratio (current ci-,arette smnkers to non,mokers) of 1.7, v,ith no si;niFr:,nt eue:; de..a:s among cigar and pipe smo:-:er<. Sccund, the coramittcB recnwniud that cerYairr factors ot!-,cr than ~mo'in, were known or thnu;;ht to pnr'i~p::~e to the cnndi- tion or to be al.;n a:<cc:a;ed ::ith an incrc•ascd incidenre. Iceicd,l ar.:+s; th.•=e were a;tc•I sex, mnr- pholn~oical cor.<titutb.)::, l:,rerhty, occap:+tinns in- cnlcin~ rc:pon.ibilitv aca .tre.:• low !ccela o' r.hes- ical activity, diet; F.!;:h in ~atur.:u-ti fat<. hi:'l idotd pre--ure, hi;h t,rum c!:olc=trrol and esces- ei.e otn-sily. Third, the pvint wa; made that if it cuuld be nimwn that eigarrtte ~nrofic:,l and non- smoken had si;mifirant cn:,titutional diiTrrcnrttv apart from any dili,r~-nce; that might he rauxs: by .1mnkinn it<elf, tb:n the 1„+•ihility w'ou!d esi~t th.^,• +onx pn-di,pt,itinn of rmol:cr, to the di,<.i-er might d 1'WAr rb.lih t4~ aL=o be of constitutional origin and not caused by smoking. After revieuin, some of this evidence, the committee concluded, "In spite of =ome bits of sua'e>tice evidence the esistcace of basic constitu- tional diiferences betwcen sc:ukers and nonsmokers is not presently estnLliehed." The Surgcon General, Luther Terry, DID, on Jan 29, 1961, speakirn of C'rID stated, ". . . the corrunittee was mtaa:= to reach a firm condu=ion as to the ro'.e emokir.,; plays in cau_in~ or precipi- tatino a death from taia di,easa We nced to Gnd out for sure wheti;•r sctc'cno is a factor in this di=case or whether it shou:..' be esnnerst.;d ... we luve no real clues es to what it is in tobacco that in~uence; coronary artery disease, if indeed it doc.."• Since pub;ication of the Sur,eon General's Re- port on Sm::in; and Health in early 1554, there hac'e appear,d many ststetncnti x'tth re;ard to the Sre ul.n /~es,•r 1,,°.9 r.nd ;'lif. rcl:ition=hi,n of ci;arettc sr.:nv;,:rg and CIID which go far h,:vnnd the lir.:ited con:lu-ior.; of the Sur- „con Cenera!'s A&.'.-nry Cnr_^.mittcti anrl the thcn Sar-,on Ge;,-raL of the=e :stnter^.,ents come from US Public Ha,!th oEr.cir.ta, from respnn<ible pur-on; in m,Jicinr and =ch•nce, and frmm mutner- ou~ medic:d sncietie~ thrnu-',,ut the eountry, as well as m:rr:v othrr ,aurcr-. F•a esamr•P•, in 1965 it wa; statcd, '•L-Itimatc ch~•.i.^.ation of cigarette smokin~ .., wmdd m,an the ±a%in, of some 2.50.000 Ans•ricmv fmm ptemature de.rths cau<ed by or as- vsrciatrd wit!: ci;tarette <moking . . hilf of tha<e prerr~ture a.-ori.rted with ci;;arutte ,rnnk- Ing are due to cnrdun'a~[tlar particularly T10302-1433
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1968 Page 393 , P E sMos7S(3 Sxn cFltrBSOC:ASCUt,AH DISEASES Many of lhc putbnphtsinlqqical cocaiiieratitnt.; noted in the above section tnay- oho pcrtain to dte relatimtsbip of smohin', nud cerebro- vascular di>case. A mortalilp study in Japan by Riray~mna (C.5) reports findings different frmr tlmse cited in tLe DIGT Report (Ial1), in whicb smokers under age Si Istd a rnortt4itv ratirr of I.40r ur more, for stroke. Hirayatnn found that dvath.; due to l'a;cular lesions of the central nervons svstem, after age +0, w,•re oue-third Ics frequent nmon,g smokers than amnn,g nonsmoker. Seceral factors ma}' account for these different findinits. One is thst the etiologic spectrum for strnl:e in Jspnn includes more hemorcfm~~ic snrokes th,ut in the United States. Atmther is that tbe Japunese =_tudc inclnded all stroka deaths or'cr age 40,.chereas the stutliea in tlm Lnitetl Rtates found tlre positir-e nssocia- tion betaren srunkinq and etroke nrnrtal itp occnrrrd nnder a:e 75 (a.j). In a study repnrted by Anlm {?;), ^_0 Labittmi smokets refrained from smokin~ for one-half dup and bseline retro;;rade brachiocere- bral angioeratns trere taken: then tltey'smokud one ciourette, inhaled deeply, nnd had repeat anqic,`,rsms. Outp those over 60 cears of aqe failed lo hace signifrant acccleration of f1o,, in cerebral precapillary vessels and markedly incrensed tessel counts as in carbon dioxide inhalation experiments. - As iu coronary hentt di.:ca.e, it mae be thut snwkinr bas diRereut effects depeudiu;; upon the degree of nndcrlyin,~, urteriosclerotie discusc present.Ammrg patients wit!t strol<e, nr.uw have orteriosclerotie heart disease and a significant nurnberdie of myocardial infarcts (104)- The tate of oxygen uptake in the brain is rery Etigh, being apptoxi- nrately S cc. oxy',1en/1UU g. braiu/nriu. (10$). .\s discussed in the cardiovascular aevtion, if c:v'bou uronoside emses a shift to the left in the oxygen hemoglobin disociatian curve, !t would urake less osvgen available to tim brain tissue. Tbose people with an :rrteriosclerotic eerebrocnsculnture who cannot.increa;e their cerebral bloord flomv in re5ponsc to :makingmap therefore more easily tlet'clop a state of rela- tive cerebral hpposia; a situstion which could be a factor in the etiolo¢y of stroke. , '(9J fftax. 1t. A. Slode of action of tobaico smoke inhalatton npon the rnrebrel etmulation. Anmta of the New York Aoudemi of Scieoces 142 (Article ' 1) : 07-71, Dismh 15. 1067. (to; l[nrntt, J. S. Per.onnteommunlcallon. 1968. T10 30 2-1 459
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TAnbtT-Llc:';relJr.e_. 'vivtcl ~r''yn:.. Ury caHp.ry: IYestarn Callaboraliee Group Shrdy, rnales yD-iy years of age (qy r•nra evernse nurervmmn mrel . emnln.¢c.trcarr NownMr af inen Rnta per In,aW poputatlnn .lnl'n~lr.at ( Nusnn .yWln Nevernmoked ............................. 640 36 29 FYrnser ciqnrcttesmokcrs ------ ....:........ 241 67 92 Pipe end ciEar, or.ly_________________________ 406 27 16 1-15 eigareetes____________________________' 212 51 52 16-25 eigsrcttas---------------- ____________ 436 89 92 26 elgarcttes and orer______________________ 425 98 104 enaaca: Rarrnmra. 6.H.(!tt). . The coronary heart di=ea=_e rate for those men smoking 26 or mnro cigarettes a day is zeen to be about three times greater tLan for thosc :chu never smnked. Tite rate for former smo!:ers is still rather high, even after adjuslmmnt for cm•,cn:nitttt variables. The ]argest impact of the adjustnaild procedure is noted amonp this group, and sul~gests that those who quit may have rlnne so because they u-ere already a relatively hi-gh-ri?ic group for retions other than smoking. The rela- tia•cly low rate nmon~, mcn smoking only pipes and cigats is noted inthis as in ot6er prospectico=_tudies. The nature of the association of sntokin, and cotnnary heart disease incidence among type A mtd type 11 per:ouality groups is not easy, to characterize or interpret..\mong tho type A gronp, the pipe and cigar smokers and the li_ht ci~arette smokers had the lowest rates of incidence of ne.v coronary heart dizease, while the highest rates were found among tho;e sn:okiny ?C or more cinlrcttes a day. For the type B group, the lowest rates occurred atuou_ those who had never sntok-ed, and the highe=_t nmonz thc light cigarette smokers. The age- adjusted rates of ne, incidence of coronary heart disease per 10,000 men 39-19 years of age afe shwrn in table 3. Additional data to permit concomitant analysis of these variables and thoae in table 7 are needed. . TARSH S.-Incidence of new coronary Acard disease by smok[ng tategory and brJ.acior type: fl esfern Coltaboratiue Group Study, males 5J-y.9 years of age 14Vi yesrs .rerese obserr.nou Latnl Rate y.r W.eoo paV+lrtlon saeamreatecar BeM1e.Wr tsTn A £.en B tYne r Totd_____________________________________________ 91 33 Never amoked----- _-------- ________________________ 53 13 Fnrmersmokm____________________________________ 107 36 Pipe and cigars unlY________________________________ IB 36 Cigarcttes: 1-15---------- ________________________________ 18 60 16-25____________________________________ 135 33 26 and over_________________----------- ________ 149 51 lqeaei:Re,emnna•R.H. Ilftl. Lnne, et a]. (9B) found siqnificant relationshi ps of smokin1w intensity and duration rrith personality factoc,-impulsit-cness, emotional instn- bility and belligcrer.e.e ;cales. Thomas- (i:.)') after nr-imring various studies of psycholocical variab[es relab~d to coronary heart di<ease, concltnies that smokin, tnsy have ditivrart eGccts on ditierent personality types and at differ- ent anxiety lelelsi ttltiple Fisk Factors The acceptance of a multiple factor causation hypnthesis for coro- nary heart di=cast empha=ims the nmd for more snphisli; ated stntis- tieal analy.x•s nf appropriato data. Our undcrstandiu, if tte trLetive impnrtance of carinus risk factnr? Prom the limitrd mnnber of auch special arndcsrs h.u nnf 6een allrrrd =i••nitlcantly irow dmt obtained bymotecolu'eutiouaL=trtisticllan:lic-ei (Jn'). Clarification of tho appatent rmiependencc of sereral of the nrnjor risk fuclor,;h.)s rvsnl.•cd. Truett, ct al. (1 ~i) emphnsiza thnt tlte major risk fnctatv arc nnted to have a dilivlznt nrdcr of inlparl:u)rn bs-:tre and ":. Ciz•arette etnnkinrr i, n:uti,-ulsrlv imnnrL)id amun" voun^_cr mnles as noted iu 1968 Pagc 381 (f73) Tuuu.as, C. R. un ci3arette smoe~ne. mronsry nenrt msra=e. ena mc genetic hypoth.Kis. Johns Iiopkins SLdical Joumal 1_'121: Fehruery n.i9. (.i8) tirsrrrs, P. II. Prcdleling amnuury heart d!.en1e. Journnl nf tho AmerF cen 3lediral A.s.istion :011i11: 7u:.2ir), &aPmmbcr ll, lfu,i. tlJS) ltrzrr. J., Cnemr.v,, J.• F.nNsa; W. A multirnrlate nnnlrsb uf el:r risk of cnrrnmrr L•~ert Alleoxc tu Framincham. Jouranl of Chronlc Plseas°.sa:slt-"c1•'u"' T10 30 2-1 424
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r s H Srunlrs ore Tm:mmcs Fcnx.trmN The 1967 RReport recielced the ell'rets of srnnkinp nn in r~[ro throm- : bus fnrtnatinn, rarnim~ :,hltelet chartlrteri-tiro and nther=rrmn factors associated trith Llaod cn:t,ulntion. It is nnt in the srnpc of tl:is report - to go into u detniled :utalvsis of blaod cno_nbatinn and/nr thromhnsis. However. tba rulo of +mnking and blund lipide on [hrntnho••rnesis will bo briefly diAcu=::ed, as thcy mlatc to thrombosis and cardiovascular disease. Cafmflolnminee The role of eateclmlanlines (especially eoinephrine) in thrombo- genesis ntust ba stn'.:,ed (111). The nirotine-{udured cateo!lolanline release, which plays a major otu!e in cardiocnscttlar drnamics mi;ht also be the medmtin~, factor in the relatien brt`ceen cirnrette srrmking and thrombosis. .lnilie (1) has shnrnt thn caterllulamines enlmnce dTP or ADP induced platelet nc,re;•atinn. ,1PY and norsdrennline in low toncaLLn:tiau (up to 0.05 p¢,/ml.) ~'cre found co increase platelet mobilitv (5.;). The reser=.e tcas trnc in higher concentratiun. Rossell (1^S) has shosn incren~cs in both thrornhus formation in an estracorporeal scatem and clnrtin_~ time in silicon-coated tubee with Moderate doses of epinl=phrine. Lar~,c dnses gave valnes closer to the control state. Bestm-tnnn (8) has shocn n diurnal car!ation in 1`plate- let" stickiness which m~:ht be a,~ociaced with diurnal cariations in eatecholamine rclease. I.h-nlt (.;8) iound no di6ercnce in platelet ag~regationbettveen?nwkersandnonsmoLera Shimamnto (1&7) prnpnres that epinephrine has a prinmry effect on the arterial n'all eau;ine the rele;re pf a tilrombnphtitin-like sub- atance Rhich then Icads to increa=ed platelet n!•erecatian..ln autopsy 6tudy in hunatll> bc 3 urrhach (.;) showed iucrensed 91nntts thickenin_ in the ]calls of arterinlcs and s:nsll arteries of 5 orgnns, in smnkers as compared to noc<n:olcers T'his efTect mlr•Itt be secondary to platelet thane s which then c:m=ed tlan:aet to the arterial wall. as discussed earlier in the studv by Hass fc9), in n-Iliclt rnbbits on a hi¢h cLoles- terol and vitamin 1) diet were .1icen nicotine, at the site of the oe- currence of throndms there was usually an in9ammation of the arterial wall. 1968 Page 384 ~. (tll) Slueaar, E. 1., \(cereav, J. F. Smoklvg and fAmmoosls. .n: •ryvueq ~ E. L Flnftmnnn, D., editurs. Tonard a Irse flarm(ul Clfarette. Bethesda, C.S. I'uM1lic Ileulth SercL,e. \atlann: Cane'er InsUtute IIono- gral`h 24, June 1.x;C ( In pre.asl . (1) Aenrtc, N. G_. Cunq G., Scmvaerz. C. 3. Infiuevre of cntecLClnminea on nueleotr-Irir,dure~l plnreL¢ avircg:ttion. \uture ILnadmy ^_1°_ CHflinl a1.r-Ili. Il.t.,lirr - '. 1'e'.Ii. (35) Ilenrros, J. It., Verunr. J. R. A. Rfl'rct of aFFre¢ntins ocents on the etectroPh^rctlc n'oLilitY of human 4iatclets. British \ICdicul Joumal 1:10ii-1oii.IP'~ 1. (1Y8) Rnusu. 11. C, Ftscxeur, A, Pe.rsa, II. G., llusr.aq J. F. Mrarnr, E. d. Adremli,c snd esPerircer.tst tLromhosts. Britisu Journal ot IIaematuto;l' 1P(1) : 6c-T8, 1906. . (8) Besrevus, E., >h'.T, G.. Taarcnr, V. Dinrnnl varintinns of platelet stlcllness colnPnred with eft,rr.v Prt,ducad bT adrenafine. Briti.+h Jledl- cel Journat 1: 2nt_:Lq. ]farch 11. Laa. J G txs, ]t. F.. Jtcer.,ca. J. F.. nccsn.vxn-. >t. It.. )fcse¢r. F...1 Cigarette emoliug and Idatrlet ne:recanon. Canadian )ledical Association Journal 95:519-SSJ. S mper 10. 19LG. (1J3) Snvanoro. T., Isnlosn. T., l[elesse or a tnromao0msuc :umuu~n i.o,.. arterial n'alls by eDineDheine. Circulatioa l:euarch 1](_^): 13S-bil. . Febtvary 19':3. (3) Ar.'eanecn, Q F[xy~mso, E. G- Gnsrturceq L. Th[ekenin; of ~alls af •rtertoles and snmll arteries In relatioa to age and s:un61vg habits. ~ \ew' England ]nnrnal of Hedlcine LTnI Ib) : JNYDH. )lay =• 1'-'G5. . T10 30 2-1 443
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r 1968 Page 385 (a) S Blood Lipids and Platelet Aggregation. Most of the articles cited in this section do not relate to ci arette smoking or to nicotine. Out of the 17 articles, there is only one wlSi~l°)d sc i~e °yhen~cuKeflfeb~s of smoking on blood lipids. There were 12 patients who took smoking tests and sham- smoking test. The document quotes only one part of the Conclusions. The other statements omitted relate to the "variable effect of smoking on platelet adhesiveness". It should also be noted that sham-smoking caused the same effects as smoking. The Discussion and Summary are as follows: Discussion The significant rise in plasma-N.E.F.A. after smoking, with no sionihcant alteration in cholcstcrol and tri- glyceride, confirms the findings of previous workers (Kershbaum et al. 1961). It is interesting thatsham- 'smoking was followed by a similar rise in plasma-N.e.e.A. in 5 of the 12 tests. The fact that the rise followed a steady basal period suggests that the effect was due to sham smoking rather than repeated venepuncture, and might possibly be due to the embarrassment of pufiing an unlit cigarette. The fact that sham smoking may produce physiological changes was recognised by Irving and Yamamoto (1963) in thcir investigation of the effects of eigarcue smoking on cardiac output. An increase in unsaturated fatty acids at the expense of' saturated fatty acids has been found by other investi- gators avhen the total plasma N.E.F.A. is raised by stimuli other than smoking (Rothlin et al. 1962, Wood et al. 1965). It is somewhat surprising that the change after sham smoking was tnore striking than that after smoking, , and that the change in pattern does not correlate well with thF change in total plasma-N.n.F.A. level. 'Some earlier workers rcpoaed that cigarette smoking elevated the blood-glucose (Lundberg and Thysclius- Lundberg 1931) but Rehdcr and Roth (1959) have suggested that the risc shown was due to stress rather than an cScct of smoking. In our series the rise can be attributed to smoking per s^,. , The increased platelet count after smoking also seems to be a nicotine eff.:et. This effect has previously been reported in an uncontrolled study by Grassi audCalta- biano (1956). The mechanism is obscure, but may be a result of adrenaline release (Vaughan-Jones et al. 1963). Platelet adhcsiveness is known to be increased after myocardial infarction (Macdonald and F.dgill 1957) and in disseminated sclerosis (CasparY et al. 1965, Payling Wright et al. 1965) and, since fatty-acid abnormalities - have also been demonstrated in these conditions (James et, al. 1957, Thompson 1966), a relationship between platelet adhesiveness and serum-fatty-acids has been suggested. The proposal has been supported by the in-vitro work of Kerr ct al. (1965), who showed thatt saturated fatty acids induced greater platelet aggregation than mt<nturated fatty acids, some of which seemed to have an inhibitory effect. Our results show that when the blood-glucn:;c remained constant there was a good eorrda- tian between the ehanr,es in platelet adhesiveness and the ehanges in N.E.r.A. AAthcn the blood-glucosc also altered (in the smnkinu~-test) the relationship between the changes in platelct adhesiveness and N.E.F.A. w'as less elose. In this situation, the ri:e in blood-glucose seemed to have a suppressivc clfect on platelet adhcsivencss, since there was a negative correlation between the changes in blood- glucose aad plateict adhesiveness. Bridges et al. (1965) showed that platelet adhesiveness inereased after an oral glucose load, but he was unable to show a correlation benrren the rise in blood-glucose and - the rise in platelet adhesiveness. This situation, hot°rever, is quite different to the present one in which endogenous glucose is being mobilised. Bridges et al. (1965) also showed that the addition of glucose in vitro resulted in an increaxe in plateler adhcsivcness, hut this is contrary to the work of Hellem (1960) who was unable to demonstrate any effect within the physiological range for glucose. We have not c6nGrmed the findings of Ashby et al. (1965) of a significant inereasein platelet adhesiveness • after smoking. hIthough 7 cases showed a considerable rise in platelet ad'tcsiveness following smokitig, in 5 others in whom there slas a marked rise in glucose the platelet adhesiveness fell. This effect was more evident in 2 patients who fc)t nauseated at the end of the smoking- period and who showed the largest increase in blood- glucose in association with delay in N.a.r.A. rise. Since Ashby et. al (1965) only measured platelet adhesi veness it is not possible to explain the discrepancy benreen his results and ours. It may be, however, that in the non-fasting state the blood-glucose response to smoking is less striking. The somcwhat surprising finding of a significant increase in platelet adhesiveness after sham smoking is clearly , associated with the unopposed effect of the rise in N.E.F.A. on which we have already commented. Summary Platelet adhesiveness, blood-glucose and plasma-lipids were estimated in 12 patients before and after smoking and sham smoking. Cigarette'.smoking clevated p!asma nonestcrified-fatty-aeid levels and resulted in an increase in the proportion of unsaturated fatty acids at the expense of the saturated fatty acids. Smoking was also followed by a significznt rise in blood-glucose and a transient increase in the total platelet count. The variable eftect of sntoking on platelet adhesiveness seemed to be due to opposing actions of changes in nonesterified fatty acid and glucose levels. A rise in plasma nonesterified fatty acid was associated with increased platelet adhesiveness, whereas a rise in glucose inhibited platelet adhesiveness. T10302-1445
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GENKRrtL ORSICftV:1T10`:S 0`; COi:CNAR.Y 11I',.litT DEE.'.5.: s . 59. Lew, E. A. Some implicatiar:e of mortality stah<tm+ retavng to core nary artery disca•e. J Chronic Dis 6: 19-^-209, 1957. 46. Jo!Gffc, N. Fats, <holcsierol, and coronary heart dtscusc. A revfem of recent nroeress. Cireelatien 20: l09-127, 1959. Miller. 1). C., Stsre, F. J., White. P. fl.. Curdon, J. E. The con:mmaitv problem in curonarv heart di=ease: A ehallenee for epidmnioln~;irxl re:earch. Amer J Ued Sci 232: 329-359, 1956. Cardiovascular discases mortality, 1931-1956. 1958-1960. W11(1. Epidemiological Vital Stat Rep 16: /15-20;i, 1963. 52. Keys, A. D:et and epidemiology of coronary heart dicease. JA'ttl 164: 1912-1919, 1957. , fr5. Tlorris, J. N. Recent history of coronary disease. Lancet 1: 1-7. -1951. 83. Saphir, 0., Ohrir,oeq L., Silserstone, H. Ceronap' arterio=drru!ir heart disease in the younger age group: its greater frequencv in tlri- group arnong an increasingiy older necropsy population. Arner j died Sei 231: 493-501, 1956. . . C)Krueger, D. Special report to the Surgeon General's Advisory Lom- rniltce on Smoking and Health. Jleart disease is the most common came of d^ath in nur populatinn. and coronary diseasc is tLc commonest rarirty of fatal Lcsrt di-,•a=e (591. fn 1961 there ueto I,YOL52'3 draths frum all causrs in tire Vruted Statcs. Heart diseae deaths numbemd 663,391 of whiclr 502.i11 verc due to artcrin- aelerotie heart dieease. Tbedisorder con,ists of ob=Iru.tion or narrowing of the cnranarv arteries, redueing tire blood supplv to thr hrort mnscle. The undalyinr cause of tire obstruction is coronary atherosclerosis, hut an arutr eornuary artery occlu- tion is oftert coused by the fnrmntlun of a bluod clot in a disrascd erterv. The tomntom mani!cstatians of curuuary di=cate are aneiria pectnris, recur- rent brief atlacks of chest pain caured by inad,_qnatn hlnnd supply to the heart muscle; n:yocardial infarctinn, or ncctnsis of a portion of the heart muscle due to acutu loss of hl:;ed coneestivc heart failnrn, a chronie rlate caused 6y inabi!itv of the Ixurt to pmnp cnou~lr b!'ud to satitfy the demands of the hndv; and sndden death resultino frnm cardiac stand.till or venlricular fibrillstion. There are considerzLle differcnecs in the prevalence of coronary hcart diuase in diffucnt cownries, and oilrn in diffecnt ethnic aod sncioeconurvic groups witl:in a particular couctry 1{6, 62). The reported dtath rate of arterioselerotic Ireart di=ea=r. uhich is primarilt' eurc+:an di=eae, is bl~bcr in the United States than in other countries. It is also quilc high in \esv 7ealand, Auslralia, South Africa, Canada, and 1'inland. and wudcratctp hieh inCdeatBritaiu. ThndeathralcinAnrnny,9»eden.arrdDcnnmrkisrousWy helf that in the high death rate countries (15). 1Le dealh rate in Jupan appears to Le about one-sisth that in tire United States, ahhough )rcnons of Japanese origin livivg in the Or.itrd States are said tn hace a death rate , aimilar to th~rt nf t6e gr:neral pepulatiun of this country 1521. s ]Seeause of chan,giug diqpunstic elills and recisions io nnmeuclature of disease, it is dilLcuIt ro be certain nl the charip i r incidence of coronary disease in tire Lnited _°4ates u.er t'ue past few dccades, but there i~ a gcnural opinion that the incidence is inerea"n. in this ennntry arrd in En,dand, particularly in the youneer male group f59, 62, 65, 83). In 1955 the mortality rate from arteriosderotic heart disease was reported to be about 210 per ]00,0'J0. Although this is an increase of n:ore than 50rim over the tate in 1940, it has heen estimated that Ices than 151Z of the increase represented a real change in incidence of (he diseaseq the remainder deprnding upon changes in diagnosis, in nomenclature ar:d in the age of the population 159). Sinoe 1955 the dcath rate from cnronarv disease (ISC 4201 and frum arl<riosclerotic and drgeneratice hnrt dierase (ISG42U ai:d 422) has com Gnued to increasr grnduall). In 19C0 the ae_e-adjusted death rate front 4t10 and 422 was 330 per.100.000 for white mn les and 160 fur s.L itc fnualcs (551. Allhough the basic cause or causes of coronary heart disea=e are obscure, . uttain factors otLer than smukicg are known or thouiLt to predisposc to the eondilian or to be xsoaiated uitn an increased incidence. The incidence of coronary heart disease in men under 45 is about 5 times as 8reat as that in women ITnble 1) ( 10, 20. 59, 62). In iwlh sexes the inci- den<e increases w'ith advancing ycars. After the menopause the incidence fnRea¢s rapidly in wnm~q a,d at o~e 80 the de.vh ratce from coru:vey disease are xhout the same for the twn sc.es. Coronarv ll:romhosis plays a relativelymore important role in precipitmiug myncardial infarction in rouno men lhan it does in old men 1105:. In studies of hrrre population gruups ooronary disease has been associated xith clevation of the serum chnles[erol, hypertension, and marked o.eraeight (19, 2Q 21, 36, 45, 59, 62). Some individual eharacteristies have heen eaid to be associaled with eorm nary dis<a,e. There is a sionificant famiiial tendency to ilrvelop it f36, 69, 81, 96). Persons aith a meson:orphic mnstitotion are said ro be nmrc vul- ntnhle Ihan endnmorphs and ectornnrphs 136, 62, Fl3). A corooary-prone personality has becn d~scrihed as ti,c aupres+ive, competitive persnn . ho takes on loo many jnbs, fishts deadlines- and is obsesscd by the lack of adequate 20. Dawber, T. R. {faore, F. E., Btann, C. V. 11. Coronary heart disease in the Framinpham study. Amer J Public Jlealth 47 (Suppl.): 4-24, April 1957. 105. Yater, W. M., Wel«h, P. p.. Stapleton, J. F., Clark. M. L. Compari=on of clinical snd patholn_iczl aspects of corone.ry artery dircasc in c<m of rarions agc groups: A study of 9.i0 ar:top=icd c os fru:n rl'• Armed Forces Ltstitute of f atholopy. Ann Intern 3Ld .'.1: 3.i2-3'72. 1951. i 1;~'Dawbcr, T. A., Kannel, W. D., Revotskie, N., Stokn, J., !:agan, A., Cur- don, 7. Jeme facturs as;occaN with tire deselo(uneut ot eoronary heart disease. Six ycars' fo!!on-up cxperie:rce in the Pramin,har.t study, Amer J Public Health 49: 13d9-13.i6, 1959. Doy!e, J. T., flesGn, A. 5., Hilleboe, 11. E.. Formel, P. F. Early diaz- nnsis of ischemie heart disease. New Eng J Med 261: 109G-l101, 1959. 36. Ccrtlcr, hL M., Woodbury. 151. A., Consch, L. C., White- P. D., Rusl. lf. A. The eandidute 1nr coronary hczrl disease. Oiscriminatle;: power of biothemicat heredita,y and antbropometrie measuremenl=. J:1iiA 1.0: 149-152. 1959. 69. P oe, 1L il., I'. J..l:nrcoran..a. C.. Pollack, H., R'll4:insun. C. F. Atheru.rcleroeis and the fat content of the dict. Circulation 16: 163- meforl6e crfornunceofhisaork/33 31 35) ' p , , . 78. 1957. s 2ohn,an di H l B L Relativ si nifi dit t 81 R k f h - - ,. . . g rancc o e . us e , e ere y, -Denlh rotes TABLE 1 er 190 /P10 from arterios feroti and de eneratioe and occupatiunal etress in rornnary hcart disease of yomrg adult=. . p , g c c Aear[ dis<ase' b sex and a e brnired Stvtea 1933-i0 Amer J 1!ed Sci 23.5: 26C.--^77, 19aE. ' y g , , 96. Thumas, C. 8. F+millul pmn-ns in hylrrtension and aornrur.v heart AnrCruup bt.les Fenulen BcthSr.ea disea=e Grcvlatinn 20: ^:,22 19.59 , Utrder 35------------------------------ 3.3 1.2 2.2 88. Spain, 1).9f.-uradess, V.A.,!fuss-.C. Observatinnsonathero.clernsis 3541 --------------------------------- 90,2 ]8.3 53.3 of the coronary arteries in males undcr the a__e of 46: A necroprv 4531 --------------------------------- 353.7 79.3 213.5 study with special reference to sonratutypes. -Vnn Intcrn )!cd Sli: . . 5"1 --------------------------------- 928..5 3145 610.2 9St-977.1933. 65-74 ------- 2129 2 103^ 0 1569 5 33. Fricdrnan, Roscnn:an, Ii. H. -lssocialion of spcrihc ovcrt behavinr -------------------------- 75orovcr-------- ------------------ - . -. 4765.1 3733.4 . 4179.7 pvtcrn with hlood and cardiovascular findir:~,s. JA?I:1 I6'): 12tJo- -- - 1296.1959. •lucludae ISC numh-n 4L0 and 42:. 34. Friedrnau, )1.. Roscunran, R. II., Carrull, V."Chan~es in the aeruns n 8aurm; WHO Epdtmiolosical nd V irnl 5ratis: in ReDOn, Yol. 16, Nn.2,1963 415). eholcsterol and Idaod dottin, t6nr: in tnut subjected to eyrlie varim . tion uf oc citmional struss9 f:ircolati,m 17: 83'_'-861, I'1.3.' 35. Frb:Jcr. \I.. St Grur~:r. 5., R"m, 5. f).. R, unan. IL II. L.acrctm:: uf cao-d,olanrinus, ITken,.tctoids, 1i-hydroxl'r•l rticoids cud 5-hydroa.indnk {n n~en e.diihitip~ a parliaular 4cLarior pattorn (A) e..o:iatcd with hiyh iidcver of diuiaal coronary artery dc.- ec.e. J Gin Invest 39: ijC-7p1, 1'I6U. T10 30 2-1 343
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P b. The impairntent of enronarY blood flnw as a result of tile in- ereased bloud ri±ensity a<~oriated tt'itIt hypei{ipemia or hemoemtcen- tralion. 6. The inrrease in platelet adhasiceness which mi,~,ht contribute to thrombus fmmation or coronnrv occlu;ion . 7. The predlsposition to acute eardiae arrhythntias as a consequence of harmfnl ncurngunic rnaescs or cateclwlawino relrase 8. T9te possiblc, altttou,",h pn~cutlp speculative, eontributious to impairment of myocardial cellul:tr rrpiratinn by cyanide ion. Thus, lho intemctinn of tLe farttaa n$ieh dn•rease ox-ggen supply to the myocardiuw mtd tlm-e vchicli increase the my-ocardial demnud for oxygen tnav play a majcr role in preciditatitig the fatal outcome in some indicidnals with ent'onnrc heart disease. Ou the other hand, it is pos=ible that tlte same fm•tars. in Icas seeere clinical circumsttmces, could proripitnte tempnrarc eoronarr insulll.-iency or contribu[e to nottfatal tulocardill infarrtinns or cardiac at-rhvtitmias. ' Tho pntlmph}siolq~iral f,,rtors a==ociated ~rith ciffarette smokin„ may further interact with nthcr known epidemio!o :ical risk factors asvociated with coronarc i,cart discase such as hilrh serum cholesterol and high blood pressure. AItltough troi a"risk f.o•.tor', unusuallp bigh physical stress mnt- ulso creatc phasinlo1r*,ieal ticmmnds for additinual oxygen supply to the myocardium. Ttte finding that those niw dlscontinue ci_arette smokin,, have a lower risk of d} in, from cornnarp Iwart di:case than those wim eon- tinue to smo6-e nu;;ht be accountetl for by the potential ret'ersibility o£ many of the pathopln<iole"irnl edects of smuiciun on tile cardio- tascular scstem. It is reaaonable to expect parti:il rerersibilitc of factors that interfere ~iflt o~p~en sunnh, such zs the carbwr monoside effect,sud the increased platelet adhesirenes, h; pcrlipemin, and hcmo- coneentrntion nnted in ci'arette smalcets. )lureoserq the increa:ed myocartlial ox}'^.eu requimntents as=ocinted n'it L tlm cigarette smoking- induced calecltolatnine rtspon~e and tieurogenic rdivsea could be ¢xpected to be eiiotitvlted upnn cer.•.ation of ci,marette smolring. In sntne patients, the enrdiopulnmtmrt beucfits of <toppit5; smoking may reduce pulmonnrv lyperten=ion. An increa;ed ability to predict faturr, carrtiovascular events in itrdiridual persons a'ill depcnd ulxm more prrci~a definition and measurement of the pat6np'n<iolotie factors n'aociated with ciaa- rette smoking nnd t:reir correlation with information about tile epi- . demiological ri=L factors. Becauac of the inerecsiuq conver_ence of epidetniologicr.l and pbysioingic:d findin,~ relatins cisarette smol:in~ to coronary heart disease, it is eonclnded that ci,atctte smokiug can contribute to the developtnent of erardim-:v=cular disease and pnrticulurly to death from coronarT heart disease. - 1968 Page 392 T10302-1457
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1969 Page 403 (b) Fibrinogen Synthesis. The paragraph is written as though (Z) Pilgeram and Pickart associated their Results with cigarette smoking. The association was added by somebody else. There is no mention of cigarette smoking in Pilgeram and Pickart's article. Note that the , transposition of results is increasing by one step as follows: cigarette smoking___~ release of epinephrine--~clevation of FFA----yfibrinogen synthesis ~clotting---jatherosclerosis. btSCUSSIOY H A role for FFA in the turnover of fibrinogen could have been predicted by the correlation of a number of earlier studies. For example, incorporation of vlycine into fibrinogen is enhanced by epinephrin^'. Hower-er, epinephrine is well known to mobilize FFAIo. ACTH has been reported torai~e the plasmacontentof fibrino,entt,rx_ ACTH administration has been shown to induce elevation in plasma FFA and to . induce thrombosista. Chronic stress syndromes have been associated with elevations in plasma fibrinogent;-1a. However stress has at^o been found to induce an output or increase of epinephrine, chole,terol, and FF-4tt-=o. Stress has also been associated with myocardial infarction or coronary thrombosi.=t. Cortisone, depending upon dosage, induces an increase in fibrinogen"-'-or a decrease'-%. Cortisone also restores the mobilization of FFA in adrenakctomizcvi animals expnsed to traumat", etc. Correlation of a number of reports alr suggests a role for FFA in the formation of fibrin or fibrinogen-fibrin intermediates. Saturated lonn chain fatty acids shorten 'theclotting time and accelerate thrombus fnrmation-+--7, activate Hagemcm factoM, aggregate platclets=4, activate plasma thromboplastin antecedent30, and induce thromtxosis in r-iro=7. Although the clot promoting effect of FFA has been confirmed by a number of inve,tioators, a failure of the fatty acid salt to accelerate the clotting of native plasma irt ri7ro, i.e., plasma that had not b.rn decalcific.l, has been repnrted". ' On the ba.is of this study, the authors cnncluded that it xenied douhtful that FFA . are of impntance in the dcvelnpment of intravascular thrombi. However, this con- T10 30 2-1 47 3
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, EFFECT OF SMOKING-SELTZER study," Reid and co-workers' migrant study;" the health insurance plan (IfIY) studies,"" and the national health sun•ey." . These investigations are not always comparable, since their study designs lead to incidence rates of disease manifestations in some and to prevalence rates of disease or illne+s disability in others. Inci- dence rates of mortality or morbidity derived from longitudinal prospective or retrospective studies may be quite a difTerent motter than prevalence rates of d't.aease, illne+s, or disability derived from cross-sectional studies of whatever nature. Thc•se distinctions are important and must he kept in mind in as,e,sing the respective findings in these studies, especially in connection with mortality ra- tios computed from different base lines. The first four studies listed aboNe are prospective studies of mortality or morbidity with attendant death rates or incidence rates of disease manifestations in large populations, and hence have certain clemenG of comparability. On the other hand, for example, the national health survey is a prevalence study and does not identify the rate at which various types of morbidity develop in differential groups in the pop- ulation but simply reports the recent esistence of illness or disability, or both. As such, its findings under certain conditions may be spuriouw and at best are supportive in nature when they identify relationships previously established in incidence studies. (It is to be noted, however, that "surprisingly good agreement" behceen prevalence and incidence results was found by the Framin;~ham heart study aith respc•ct to relative risks for CHD.)" While all of the-e incesti,,ations d_~ene detailed individual analyses of their tlnciings• the limitations of space do not permit such eLaboration. Many important discrepancies or inconsi~tencies (as well as consistencies) in various aspects of the-:e studies are overlooked when the rcaufts of the studies are charactcrized solely by their main conclu~ions. A topical analysis of important aspects of the studies affords a pnxluctive approach to an ur•r'••:r<tanding~ of the relative consistency of the rc-:ults of the in- vestigations. Epidemiological Ce!a Published Since Surgeon Ceneral's "zpcrt of f°:d The more important new evidence relative to mortality and morbidity from CND i~ summarized according to the follcsing ~uhjcct catc~orfc~: (1) overall mortalitc and morhid3_v in =n:oken and non- smoker., (^_/ mnrhidity from an„ina p:ctorie. (3) mnde of tobacco smokin2, (4) age of smnker., (5) amount of cigarette moking, (61 duratinn of ci~a- rette smoking, (i ) inhalatinn• and (A) di-ea.e raten in ex-xmokers in rr!.etirrn to the duration of the cc«ation of Orrrall Sforlchtv nr.d Sfurhrdttv in Srr.nkvrs and •I'h,• S•.n_e•no G"t•rnl'v 1tPra ry.lxxt concl:;~Ld th.et n:.d,• r! ..+r.tte• •muk,n k~~r a hith- t•r drath rate tmm C'i1D Ihan nu•n who dtd not 1968 Page 382 (c) 295 smoke. All the new evidence gives the same results, a confirmation of the earlier findings. This is not surprising, since the concluSions of the 19" report were based on "seven large completed or current prospective smoking and death rate studies." Ad- ditional new prospertive studies or the extension of ohservatirrns on previously reported current shrdies on the same or similar populations would not be ex- pected to give different results. Similarly, all the new evidence on morbidity, with the exception of the Tecuntseh study of F.pstein et al," confirms the existence of higher CHD prevalence rates among smokers thar•. among nonsmokers. It is not clear why the Tecum~h study CiiD prevalence rates are higher in non;mokers than in smokcts at every age level up to 70 years. The new evidence does not change the basic nn- ture of the associatioa of higher CHD death rates in cigarette smokers. It simply confirms the pre- vious evidence. The new data, either through lon-- er observation periods of follow-up of ongoing studies or through additional studies of large popu- lations, in the main merely serve to provide an opportunity for a more precise look at various in- terrelation,hip>. Furf}:em:are, there has been no change in the intensity of the association, such as would bc su-;e>ted if the new data showed con- sistently tu;her acera;e CHD dc•ath rates for smok- ers compared to nonsmo4ers than did the older data. But this has not bc-en the ca se. The Suroeon General's 1964 report indicated a median mortali- ty ratio of 1.7 among perons c3rrently smoking cigarettcs. it is seldom noted, hoa-ever, that the Doll and }{ill study cf Beitish docton' (one of the key mortality studies) showed a 33 c greater mor- tality rate for cigarette smokers from "CtfD with- out hvpertension" r:on=mokers, a figure far be- low that of most otS:er prospective studies. But in the main, the averz~e value of the mortality ratio in the new studies is approximately that found in the older evidence. Angina Pector~s.-The Surgeon General's 1964 report makes brief mention of the fact that "angina pectoris ... is le+s doselv as,ociated with cizarette smoking thsn is mvocardfal infarction." Available new mortality data stpport lhe conclusion that cigarette s:no'<er h_a%e hi,her death rste; a~Sociat- ed with myocardSal infarction thin nonsmokers. But the new data ap;.car to be ambivalent with respect to an,ina pectoris. The combined A!'..any and Framinaham sturly'° clearly shows no si,initicant incr.a,e in incidence of angina amon; ei;arette smokrrs compared with nonsmokers. It wa, even found tlut thc morbidity ratio (Framingha:n scries) for thrre who smoked 20 or more ci;;arettt-s per day (7fi) was below that of the non-cigarette -mnkers (AF). T.`.e conclu.ion arrived at was.that "The ri='.-: of a:_aa prtoris at the sole or initial >.::mifutatinn of CHD appcar•s to Ix unrrlated to t!:e toLaccn hatit." On the other hand. f"th the aflP- and Reid and eo-wnrken' migr.mt'- -tudirr gace op{-ite resultv. The IIIF' T10 30 2-1 43 5
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1968 Page 382 (g) EFFECT OF SMOKING-SELTZER ]99 the bins introduced by ill health on smoking habits which suggested that the effects of smoking is "dirties up" the data of ex-smokers and makes it hmited to those pec;ons with "already compro- therefore di::icult to establish clear-cut trends and mised circulations." - effects. With respect to amount of cigarette smoking, Summary the new data do not confirm the finding of the Surgeon General's report of a consi,tent rising With this presentation of the additional informa- gradient of CHD mortality with increased amounts tion since the Surgeon General's 1964 report on the of cigarettes smol:rd, but on the contrary give a subject of smoking and coronary heart disease complex and hardly corsistent picture showing a (considering the epidemiolooical studies only), we profusion of inconsistencies and inversions. The are now• able to assess the nature of the evidencenew• dats have in efiect raised serious questions as which has led to the extension and magnifirition of to the validity of the 1964 report on this point. the claims of the etiect cigarette smoking has on Duration of cigarette sm:,king has been found to be mortality and disability from CHD made by nu- unass~xiated with exccv CHD mortalitv in ciga- merous people. rette smokers in the new data, and con5icting re- The conclusion of the Surgeon General's 1964 su)ts are obtained e:ith regard to the e;iect of in- Report that male cigarette smokers have a higher halation. Finally, the new data dealing with the death rate from CHD than men who do nut smoke effect of discontinuance of cigarette smoking (a has been confirmed in the new studies published subj_^ct considered o: such ;zeat si^ni5cance in since the report was i>ued. This conclusion must lun-, cancer mortality) frequently give contradic- be accepted as an estabii,hed observation. But the tory and inconsistent G, dings, and pose a virtually question still remains as to the interpretation to insoluble problem as to valid interpretations and be given to this statistical observation. The most conciusions that mav be, drawn from such data in such an epidemiolo^ical observation " . can do the pre:;ent study dcsi^s. The bias introduced by is to demonstrate the exi;tence of a relation.,hip the in~luence of ill f:ealtL on smoking habits makes between ciZarette smoking ar:d various health char-. it extremely di:r.cult to detcrmine whether giving acteristics; it cannot estah!i>h any existing rela- up t?;e habit act:aiv rtsclt.s in a rednction of tionship as a causal one; "" snd '. . in`.erences death rates soon after. Accordinely, in some re- on causality cannot depend on the demon..'-ration sT,cts the epidemiolc;ticil ev:dence is less clear now of association alon2 ""' The first phase of the epi- than:.t the time of the 1Sed report. demioloeica l approach to a disea-e prob!ca: is the It is, therefore, diCivlt to see from the new determination of the statistical associatina; the epidcmio:o;ical data how valid causal inferences second phase is the derivation of biological in- cadbe drav.-n that ci;;arette smoF,ing is linked to ferencea from the pattern of statistical associ.3tion." excess CHD deaths or ti,at the excess CHD deaths What inferences, then, may be drawn from the . are "caused by" cigarette smoiing. We do not . additional epidemio!a;ical ecidcnce which has ap- kao:r c•::ether or not tl:cre is a causal connection peared since the 1964 report? And particularly, betvre_n cigarette mloking and increased deaths since the 1964 report concluded ". .. but it is not from ccronary heart div-.>e. clear that the association has causal scmificance;" The present state of our knowledge still sug- what new inferences may be drawn with re: r-lect to ge,ts (as the Sur~con C-neral's Advisory Com- causality? . rnittce's Report on S,r•.-,l:ing and Health stated in Our survey of the new epidemiolopcal evidence 195-1) that "male c;3arctte smd.;ers have a higher has indicated that, for all practical purposes, pipe desth rate from corer= artery disease than non- or cigar sno'.;in,-^, is not a:=ociated with exce: s snoldv:, nules, b•.rt it i; not clear that the associa- deaths and dir-bilities due to coronary heart dis- tion hn, causal si;,miEcsoce," ease (CFiD), le.aving ci~arette s ncoS:ing.aa the focus Tl,i. ~r ..eicuaon .zs .,rr~.r+^t in pnt Lr rhe eued ror Ee- of necessary attention. The v:ei~ht of evi&nce, at „r,h ,-,j T..rhinz .4 r~- !}-~~~rtr~••ne of Numunn, H.nnrd the moment, is that annna jrctoris as the sole or r0,t,c tw.ton. initial manifestation of C1iD is probably unrelated . Rrfercnees to cigarette smoking. There aro still some lin„^ering end u.rrre r.•r-••r .,1 rer Adr,,.,.y cen~.~irv. m questionc with rr;ard to the prcvatence data in this rnr s..•=-.n Grn.rnf ot re. ro-_•,r,r f+.otm s.rrt<.- vs rxnr af regard, but conclusions drawn frum previlence rr.+!,n e~..-.fMn ann iv.!e.... r-a. Ii.unnt. rror. Y.:e un T.~+rao of r6e Cu+n- data flIC generally CORtldf`SCd 1C5ti reliable than m- 2 miu.< nn i•Kna.Jrure. kb.uv M I:ryn.,,eoraVrm, .erir. 1- y 5, cidence rates. This would leave m_vocardial infare- J.n ~1. rtaI tion (arid snaden dt:aths) as the principal cendi-. x, Ft-..•ls, t•.rok a,. m camn+erce, US s.n.r., rcns. .rn.,! M'.t-5. ht..rl+ :!!. 1-.-.; tions statistically asKH•IDte/f with cigarette smokers. 4. ~;yn+kt J.: '"tiulnu..q .n•i niher..•.ir. In this cu^eectinn, Dnll and Hill have pointcd out tne-rftrs••. t'Jt rtr!1„n ns< •~.>, ta:.n4 xf. conno- that a relatinnvhi(r with smul.ing is character,stie w.u. (:n., llYa. 59 =1.e9. aI only a littlc more than nn,..hsll the to::a num- n"!~- er m, rxn.,,rwwa c..ntM'r of li•;ftflli attrlhut4,l to ca[unary thrOml+Uxls.* rm~liaq ('•t+retl~:v,c + =dlr4xa Na fntrmir~u.,al Gnm This rrmion of p+,tulat~•d CHl) ~mwaing ri:'.JS iv ,; it•1+.•!mG.+-.rM•rY=M`-•r..t,nc.Ad.frrie.dh!:.rv4v further rnhancrd by l4 1'r.+ming::..m hrart study &I T10 30 2-1 43 9
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F • 1968 Page 383 (a) Epidemiological Studies Relatine to Serum Lipids Like other types of studies in this page, the epidemiological studies comparing nonsmokers and smokers indicate conflicting results. The negative studies are not discussed. The Results of (150) Van Buchem et al. are reproduced below. The positive results of (56) Harlan et al. are described in the document. The differences in population and nature of diet may account for conflicting results. Note that Harlan et al. also identified skin folds, uric acid and weight gain to correlate with lipoprotein fraction. wor W V R w It ira t0 10 t- 1~0•4='a TAeta XlV. Serum-cholntrrol lard in smoken SD-• aIIl ' and non-smokrn l-f tso 240 nu 4lo To c7o reo W, L 5! 0-12 LICGPAOtEINS V.A.b7. C..d.n.. Ftdna. r SMORtNt: - u~-~ur 0.144 rcIwiCtDf - ecFSt .IRI VL! a'rJ .711 wd!Onl"GAIN 24 . e6 yr. ra.rep p"c•u - .1,12 1•.ny l:n.ry . f•.S.r ,2p0 Ab,a^..o^r .7l7 r.n!y A:.,.y . ae.b.r .f74 Itl t-1 ,770 Ftetr2 I. F'rcqccncy rlisuilution of values for Sf 0.12 (l:rta) ti^,r.^::;:cirs =cd f:ccrs corrd2tcd with lesels oi r:r:- ]:} ei:u. :_tars L~~. ~ a~rtc- 6tiors at~3`L levc3 or ;.rcnter aro sr:iied out in ar!tal lettc:s. v_inioi.is a:_ a neaurecaat a[ avL::cnemcs adil,r;e r-suc a1 Cm sim no.ed. PBl=proccilCac^d i-1i:c. &t tc+t fot dcsriis- 6on DI The St (.L7C (ce:a-lux)pro- tei..). ,e1 przdo:;ut:antly of cc'._,:crc; (S:;c.) and t(Vc) but lit-"c tri-lvccride (3 are rc- . ,.. :..:.. lalt;t S:.ir.fnld tsic:- nes ef t: e uric acid, ;.nd ita:e a fror,i aoe 21 to aoz :3. :i!thor'-h the nur.tb..~~r of cip rc;ta RBS .,3CCCd hy this smcki-'- also h-1 a s~.~-t::csnt corrciLtion. I::ese sariaL;cs Si:ni- larly, sFin:tald dickness of the ehcst anQ hack are do;;!y rdated, and selcction of the chect n:casuretnent escluded that of the b;:cC-. 1lutrever, sLinfotd thit.:nezs in ot!ter areas was not related to tF.ese Iilw- proteins. The utinnr omqihutiort of pro- tein-houtnd iodine (PL!) to the nmltiple earrcl:ttion i; of interot Lcew;c of the '1,•-^ .,,. ,..,..h:atrrrn !rr:itoic.•ical Non-smoken Light Imokcn Modcratc amoken . Heavy 6garctte smokcn Hcavy cigar smo4crs Heavy emoken Heasy pipc smok.n Unknow•n Total Sorum rholnterol (mg °.o) 0-209 210- >250 249 32 44 41 Is 14 to 70 76 60 Several times the nature of the diet of all men wa< ezanlined with diffcrent methods. No correlation was found betwecn the nutrition and the serum eholcsterol7cvet. T'he diet of the men before they suffered from atherosclerotic complications was not di(ferent from the diet of the whole group. No correla- tion w'as found txtwecn smoking or non- smoking, and the degree of smoking, and the serum cholesterol content. T10302-7442
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f a Qenetir-und Con.rfi(rdionaZ Srudics Ilnuc (j) futmd timt heacy aue•ken Imlou~ c~~ileye umlcs tt'rro tailur than light smokets and non=lnnkers. Lauc, et nl. I`x%) ulw frmud sig- nifscant ru-ociuti-.ns bettrern hodg size measwruieuts, including ponderal index (thou~h uot •s ith hcipht nc rcei~Lt indiriduatly), and amount of smoking iu dte .=tudy of over 675 neiaturs, TAgLE 9.-Linrar dleerinlrltanl f+nrtflon coefjicienh (in.afandarrl unita) for t'arim/s riek faNCra in coronary hrarl disease, by sex and aqe: 1PYear Fruminghant Slrrdy . I Ftur I Women Ahk terbn Ase--------------- Cholcsterol___.___- Sy'stolic bload pressurc_.-_---._ Rtletivc meight flcmoglobin-- _ _-. _ Cignrettcs smnlced.- ECG Abnormality-_ lovnaa:'nuert• r. (Iy,) cumnieee wz:, wc, 1 soe: eo v.an Kr+ >o.v. r++rs I 1-1 EP,ei re~m rm ym 0. 5B3{.0. 2391 1 0. 33-311 I 0. 2370 0. G2E) 0. 73^5 0. 2c00 4443} IO.OG13' 0.3^_03~ 0.3i9010. 1Y+1 I 0.732 2 I0, 1207 0.333i0.3t271 0_ 1660 i 0.3<-090. 5536 0. 10170, AIiO 0.L9700.19Ak 0.3610 0.10Li4nti5~i QO].it0-1391 -0. 10:,0 0. fu 13'-0. 0181: -0. °20t10. 037-' -0. 0;610. 073{ 0.I1JJ0.G)96' 0.50S1'0.3004 0.0G"5-00:310.1_19 0.+62cin.2s.55; o. 25sGi u.2l9ria 301si 0. 22310. uxe Cederlof (18) has emphasized the value of studies of twins for investigntin- e~pects of coronan' heart disca=_e and presents certain suggested modifications in metlmdolo.y. The 19Gi Beport (1i8) «is- cussed the stndics by' Cederlof on Saedish twin pairs (19. 3n)- His data on American hrin pnits was recentlv nresentetl and sho.red re- sults similar to those of the Sredish tn-ins (18). The problems with ir•terpretation of the=-c shulies are several. The small numbers of cases and the combining of data for both sexes in various subeategories make rates and ratios subject to si.mificant chance variatimt,. In ndrlitinn, use of a que=tionnaire for angina, witlr only modest levels of rel'.ablity- and rnl-iditrreqnires a larger stutly population before dennitit-o conclusions can be made. The lack of information on the distribution of risk facton other thmt snmt:ing in subsamples of discnrdant trrin pairs and the total cronp uf tnin pairs makes the cotnparivm of raties for prevalence of srmptoms difticult to evaluate. The itminsinn in the "snmkinq" group of thone who had stopped snmkin_ up to 3 ceats previons to the study, rvould also tend to diminish the ditfcrencts betneen _mokms and nonsmokers. Tkfinitions of dianrdunt snnkin2 habits mu=_t confnnn to tho=c difTer- ences identified as si,~tilicant in the large-scale populatinn studies The fact that dixord:mco for snnkin3 dncs occur amnn~ mrrluizv- gotic twins eertainh- indicttes that tlm sunking habit caunot Le deter- mined by genetic fuetotn alone. Twin studie3 rrirh further ;ophi_ticu- tion of dc;il,.n, larger ntuuber of cases, better definitions of disease, and more sienific:mt ideutifiratinn of tliccurdm:t esposnres have the potential of contrihutin¢ sn[,;tantialFr to aur nnderstandino of the inter±ctivefactorsineoronarn-henrtdi,,,ase. In an articlo revietcin_ some of the epirleeninlonical evidence in the 3% years sub;equcnt to the I9C-1 report, Sellxcr (129) concluded t6at there mus no subs0utti:Q evidence to indicate a further as,rciatimt of cigarettu snlnkin;; tci!h coronary heart disea=e bcyond that statcd in the 19GI report. Scltzer alluricd to rhnt he called "inconsistencies" in the recent literatmn rclarin¢ to dnratinu, auwunL a_Re_. inhalation and mode of lobnccosmoltiq~ trith caronnn-hcurt diee:is. . ' The addition nf manc morc perean years of experiance, from rhe nen• and continuin;; sludie:. I,roriclrs data since tlte 10G} Repott tlutt can bo analtizod a••r-=pociffoally. R-hcn dtis is dune ntost of tlre_c "in- con;istencir,r' di,;tppcar, Seltzer "S conclu.iou i, vontrarv to that of mo:d epidr•rnioln_iets rvho ero familiar aith the rurrent research. Furthermore, lie has not con- sitleted tbe impnrt:ud n•lev;tnce of tLe eaperimcntal, put Iml.,r_ ical, and clinical d:ua th:rt h•we Lern repor¢d since 1061 conrerning cigarette smokin~ and cartliovascular dLenxs I968 Page 382 (S) C.~u, IL I. I[dFLI, ueILL[. und pnuder:,l InJea ot eolla•ec mole smoArn and uon.rmolev. Journnl of Poychology 61: 101-103. Setmrmerr tor.c, r~g)li Crvssror. ]L 7he rxtue of hHn etudics In epidcminlap'. World )led:c:d ~/ Jnuniatli/G):IUS-],l,]orewber-Derewbrri(18i. 19) O:oexroq R., F'uxr.xn, L_ JoIssus, Fl., Aara. L. \torLidity amnng nnsvm zSROtIc tntnn, drcLire.c of Envirnnnental Heelth 19t21 : 31.-t~-0. Fcb. (~ runrr l:q:l. `e0) CCeCRLOr. Ft-, F-dnvLR1:. L., ]n.6[O.\', F... F.AU, F.. Recpiratnf5 ~)'IrIt4oLRi U aud alth referenrv tu n...ine haLits. Archires of F-nrironweutnl Health 13(0): isG-Y3I, Decemher 1`aiG. (1?9) Su.rzce, C. G An evalualion of theeRett of smokiog on roroonry beart diccase. 1. Epidemiolxieat e~'.dentt. Jourual of the American Stedical Assoaintiun C03(3) : 193-C00. Janunry 15, IDLB. T10 30 2-1 43 2
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1968 Page 382 (b) 194 EFFECT OF SMOKING-SELTZER coronary artery dika+e. ...In 1965, [it was affirmed that ".. . the a%;sociation [American Heart AaaociationJ believes that there is a total of ap- prosimately 250,000 excess premature deaths asso- tiated with cigarette smoking each year in the United States, and that of thn.e, about 1^5,000 am associated with cardiovascular di,casr, principal- ly coronary heart disea,e....«'e have excellent evi- dence that heavy cigarette smoking, a pack or more a day, particularly accelerates atherosclernsis, and accentuates its effects, makes it war=e. This ac- counts for the increased premature d<ath; that are associated with cigarette smokin- so far as coro- ttary artery disease is concerned.... """' °" In 1966 it was said, "In view of the mountain of evidence now available this is no longer a 'controversial' mat- ter. The massive evidence indicating that cigarette smoking is a major coronary ri.+k factor in middle- aged Americans and Briti~h men have bt~,en re- viewed in many places ..."' Again in 1966, it was . declared ". -. unforgiveable for us to write o,I the 48 million adult3 in the United States who are now cigarette smokers. After all, these are the people in whom the extra hundreds of thou~and; of prema- ture deaths will be occurring each year for the next 20 or 30 years; these are the pcop:e ,. ho suiTa from ...the 300,000 extra coronaries..."' From the statements, ". .. ft is not clear that the association hv cau=al significance" and ". . the committee was unable to reach a firm conclusion as to the role smoking play; in cau<iag or precipitat- ing death from this dEsease •.:' of the Sur,eon General and his Ad,isory Committee on Smoking and Health in January 1964, rce have since heen presented with "iJl!:i6u exccs craths," "•1'20.000 excess premature deaths," `30V00 extra coro- naries" each year that are "cau>ed by" or "a>so- eiated with cigarette :mol "ing." - Attention shnu!r] he focuaed on the phrases "caused by" and "a:=ociated with ci^nn<te smok- N&° These phrases c!earlv imply that the conse- quences of smoking ci_arettes is a variahle amount of excess premature CHD dcaths. Bit no such im- plication can Lr dnwn from the conclusion of the Surgeon General'+cnmmittce of 1781. The latter re- ported a highcr death rate front Ci3D among maL• eigarette srr:ol:,•rs L:an amon:; nor.emn;cur~. If one were to tran:crihe this statement in terms of "ex- eess death+ " then it could he stated that there was an esce:cs of C!1D deaths arnun~, cicarette smokers than amon, r.an,moker>. To =hift from eK- ees+ deaths amor:q marette smoker: to excesw deaths a'sociated r,r16 c'rgare•ttr .rnt„/::re4• is to at- tribute ccusafitp to cijarette -moking, an attribu- tion which the adci,ory committee was unable to reach. We have no n-avon for as.uming that x hat we arc dealim,,, with h, tr i: a m.rt.ter of -,mmatirs. Rother, the more likedy rccnt i, that th,- ,tatrmrnt: ra;u- ally linking mart.i'uty lrorn ('iiU smokers mu,t mprr"nr, c'onrlu•ion, n-ao 11,11 hv snme from m'w etii,lrnre avall:dde incc the I+,u- ' ance of the advisory committee report in 1964. It becomes important, then, to inquire into the natun: of this new evidence. At the same time• it is nece, sary to inquire into the availability of additiona! new evidence beanng upon the question of [mnrt;r and constitutional factors between smokers at:,l nonsmokers, particularly insofar as they ure relat- ed to the etiologv of coronary heart disease. Some readers may' object to the use of the phr:e-.• "caused by," since ahe words "cause and efiect" an• eztremely difficult to define clearly. In usin, tne>e words, we are followin„ the practice of the Surg,vn General's 19134 repnrt, which attempted to expla:n (pp 20-21) the meaning which that committee at- tachcd to the term cau>aiity. In stating "cicarcioe smokin, is causallv related to lung cancer in mn." the Surgc•on Ceneral': committee implied that ri~_.i- rette smoking incre;ur.oc the probafitiity that lung cancer will develop in a man. With reprd to card6r vascular disecse, the committee statcd, "it i.+ not clear that the a~soci.ation has cau=al significan.,.;' implying that the evidence available to them wai insuffieient to jud,e whether cigarette smokiiw i- an efTectiee a~ent in in.rcasing the probabitity of death from eardio%a rular disease or not• Furpose of the Report The purpose of this report, then, is to review th,• more important publications dcalin,, with smokint and CHD which have appeared suh-cquent to Cat Surt;eron Gen,ral's Report on Smoking and Health in 1964, to answer the followingquevtion: What is the nature of the additional ecidence on smoking and C'HD s.hich has n~ultctl in the m:cnification and evtensiun of the claims of the etic.t= of cigarette smnking on mortality and morbi,3ity from CH D? This particular communication (part 1) will co-i- sider the epidemin!nzical evidence on!y and is limi'- ed to data on mrn. Suh,eyuent report; covering ec• perimcntal and clinkA data, and constitutional aml genetic evidence are planned. This analysiu of the epidemiological evidence w-•< submltted for publication almost cimultancnu-'.with the ap{xxarance of Thr Nra/flr ('onsequemt : of .timoF.in?, a['uhlic Hr'ath Service review ps'fahrd in late 1^0;.' .Sccordin,qly, this is an indep.dent analy,Ls and doe, not contain references to-- eompari.,rm; with the 1965 report. . The Material In the SC years.ince publication of the Sun;e• Generai's report of 1961, a certain amount of e; drminlneiral rr.-larch has trrun completed or co' tinucr] in this countrv or abroad. For the purpo- of this rr-pNt, enn-6lemtinn ha1 txt•n gicen to t'I more pe:rGncnt studics as follows: D.,II and Hi':. study of Briti-,h doctnr<; ' thn eombineKf :11ba: and Framim;:ham stur!y,," D.~rn's I'S veeer:, study." H.ic.n:iad'n pro.{x-ctLvr study:" the Car: di.rn .e-t,tans tud ~. ' th• f?.an+ Counlr. 1;e-nr, study," the Tecum-,h. 1!ichigan prn•{.cti T10 30 2-1 434
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M 1C T~ . ~ iJ.Ci111.1 ln .:;llz;t'ihtt'iit;(',S of Slnohin~ A Report of the St:rgeon General: 1971 U.S. DEPARTSIEtiT OF HEALTH, EDUCATION, AIvT) WELFAILE PuLlic IIealth Service Contents Pays Introduction......................................... .. 21 - Epidemiolo^ical Studies ............................... 38 Coronary Heart Diseasc Mortality ................. 38 Coronary Heart Disease \Iorbidity ................. 89 Retrospective Studics ............................. 40 The Interaction of Cigarette Smoking and Other CHD Risk Factors ................................... 40 Smokino• and Serum Lipids ................... 41 ~ i Smoking and Hy pertension. .. , ................ 41 Smokingand i°4•:;E~al Inactivity ............... 41 Smoking and Ohc;ity ......................... 43 Smoking and Eiectrocardiegraphic Abnormalities. 47 Smoking and Heart Rate ..................... 47 The Effect of Cessatfon of Cigarette Smoking on Coronary Heart Disease..................................... 47 The Constitutional Ilypotiicsis ........................ . 48 Autopsy Studies P,elating Smcking, Atherosclerosis, and Sudden CHD Death ................................ 52 Experirnentnl Studi?3 Concernlng the Relationship of Coronary Heart Diaease and Smoking ................ 56 f Cardiovascular EfPects of Cigarette Smoke and Nicotine ...................................... 56 Coronary Blood Flasv ............................ 58 Cardiovascular Effects of Carbon il(onoxide ,,,,.;,,. 59 Effects of Smoking on the Formation of Atherosclerotic . Lesions ....................................... 63 The Effect of Smci~ing on Serum Lipid Levels ........ 65 The Effect of Smoking on Thrombosis ...........:.. 66 Other Areas of Investigation ...................... 66 Cerebrovascular Diseasa ............................. 66 Nons1'philitic aurtie dnemy;m ..........1 ..,.......,. 67 Periphrral ArterioscL,rosic ............ . 72 ..... ..... .. F;Speriment:~l [:eidanct:......... .................. 73 TitromSsan;:iiti< OLliterans........ . .... ....... 73 Sumn:ary znd Cnnclusewas ............................ 74 Coronary Heart Illsc2se .......................... 74 Cerebrovascular U'sease ...................... .... 76 Nonsyphilitic Aortic Ancuryym .................... 75Peripheral VazutLu' Uisease ...................... 76 1971 Page 405 T10302-1476
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TABLF. 9. Alule.a! incidrnee rates ef r,euv coronary heart disease, by Smoki//p babits, adjuslr' far aye and errial;rn, fcr ayrclfia: other risk foUors IR.I~.remnueu::aauco-.3':LOYIwen.ey,L]ImlOrnuaelmttYL:waendyl Dea> elvvetle BpeBled alLer rbk MClan Nen.r .moted Forn:n u o~.~} Plqe clNOr 1-15 11. M m ----------------------------- l 9] 'tl 49 L) 100 0-WS Ne4+lynsntb ........................ il It 19 19 9l Rn :001 LIIW:~ua~b .............................. 11 41 R 51 0 !U .00: ,IPta1kUP._-.._.... . .. M - 49 /S lN •0Yl DI'-•611rBP----------- ------- --------- 19 1) lE 4. 91 LO4 .001 PonJeeolLrl•a .......................... 'H 91 19 19 95 1% .Wl PLSsInl4tl.rt1... ~~-- TS 93 3e IS 93 10/ .0]I ---------------------- 'S 91 11 4a to 1. .001 Lmm.kreL.....................•...• A 11 M 49 LI 10e .011 AnaftM.bnn.................. 19 Ll 9o $l 0 9i ror TnlprerlJe._------------------------ 51 IN . 'b 10 8J 301 .Wl qReaeeal3n0e.va er P.otm la suelpb a! te.ulnvtt. Bovaa:3enlw, C. o„et et I+q TABLe lo. Annuat incidence rates of new eornnary, heart di.sease, by Smoking Aubits, a4justed for age and seriatim, Jor specified other risl.' factors [Ran en.nvvu mcideea 5er i.0a0 rcan,.5v.! ra b vl rean a eotry lna rlu]rl Neeer Pors•r Pipn md Dmimurs~¢ ma LPr36tlelknmilectate ~t~ .ma[ n t1luomr !-M It.U al or o, Ckokneral.......... • .................. u3 to MS ua 211 fw 1154 BeWJPlvmtb............ __...._.. l0/ !43 111 la) 213 XS .12r LlpelLUmi................. ............. 109 to 151 121 lt9 bi .133 BpkOe BP ............................. IM BtT lU 319 lt1 >A .118 Dtt•bIICBP . . .. .. . IW IN IM Yl/ t]] rr3 .0E3 PW,CrN InJei. . ... IVr 1]I 140 I'.'! ln "JA .031 PCrylml utlatr. . . . . . 113 to 1/9 113 213 n9 -ll9 Mnonlafeu¢ta. _._._ _ _ 113 1" 131 111 t/l 2[5 'AS lnmuekeeL .......................... U3 I14 147 121 iA 11 .159 •B ww.beee._ ................ III ue tm IW 91] 19 .1f9 ThlSmlae........_ .... .---------- _ 1l1 141 to 96 L93 lm .If1 .keelofaljuNapm af Fn[b br aneIyah el wwLw¢. bv.u: reukW, C. D.,a:aL a/1. 1969 Page 401 TAnLe l l.-Jrlcidcaee ae ncw coronary heart disease, by smoking cctegory and behacior !ype, for men aged 39-49 IRaSea ve.m.mimted.nnul InelJe+re P'r LOD menl Cu,nntanJbrver Da1lYelynr<¢eu aoii[bn Por,nerB;aretle vlpaondalareoty ------ ToW Bebnbelrq Nner.meted FLS IFUe 1Cermote - Antea Cmee Retmn'eCeeee Retee Cuau Rntn C.+ar Ratee Cue, Aetu ,CUea Rotea Ceva R........ -............ _............ 63 1 IS.B 7 Li 1 1.3 1 Inl IS 14.9 IS >3 b L1 2 1. 1 1 11 1 e.1 1 11 3 to 1 Ll M TIIW............. _...... 9 7 Ll 10 Le 3 to 3 LL 19 l44 20 13 ll bvetz: ]erd W, O. D., et LL(//). TABne 12•-incidence of new coronary heart disease, by Bmoking catcgory and behavior rype, for men aged b0-69 . IRetmv.qe.Wll++teE.nnuelinddmrteprl[tamml Currentandfmmer Dtllydprettemiuwnptbn BeWebrp'p NaeenmolM ~MmokR+ralta plv<en3clCUONY- - Tn41 1-IS IblS l0eemen 8etn C.roe R.tn Caa. Retu C.xa Retra C.!.a Ratu Cueea Ru:ee Ceme Rowe C.xf A L"1 - 1 ILS 1 91.8 B 161 1 9U 1 3¢0 14 IUJ 19 8 ..............._._.._.._..._.. 130 4 LI ' 1 LI 3 U 1 1L1 9 IRI 3 130 21 Ta41 ......................... 11.1 Y 1/.] 9 lL4 II ILa ! 51.3 te ]0.0 IY lai M BJV.a: ho5 W, C. D., e[ aL (Ip. T10 30 2-1 46 8
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1968 Page 381 (f) I 74 . CAROUNE BEDELL THOn.IS Rosenman and Friedman's yotmgest age oroup, all tend lo support Oliver's state- ment, "Indced, there may be at least two major tyJr:s of cotouary discase--one associated «ith an active metabolic disorder and another assucialed xith ad- vancing age" (50). Much remains to be done before the psycholoodcal factors tmderlying either the smokina Jmbit or the coronary di:+dtesis are fully understood, but it looks more and more as if the kind of person one is has to be taken into account. Whereas a decade ago, Hammond said, "there is as n(uclt reason m suylwse that cigarette sntokin~, causes nercous tension as to believe that nervous tension causes cigarette smoking;" it nou seems possible that both statements are true, "but for different ty'pes of men, so that one uses stnoking as an cnergizer, the other as a tranquillizer (51). Our own Gndin.gs and those of others point to the existence of distiuctite pernon:;lit)' traits in cigarette smokers, on the one hand, and in precoronary-individuals and coronary patients on the other. Inasmuch as a specific pattern of anxiety under stress was significantly telated, both to . cigarette smoking and to parental coronary dixase, anxiety appears to be one kind of common denominator (41, 43). In three studies, anxiety has been de- scribed as characterizing one of two groups of coronary patients or precoronary individuals-the motlzer-orientert group of Bahnson and Wardv'cll (16), the angina group of Ostfeld ct aJ (17) and the Type A behavior pattern of Friedman and Rosenman (8). The familial occurience of cnronary heart disease has been documented, and points torcard the involvement of genetic factors (52, 53). It seems likely that smoking habit patterr,;, too, are, to some extent. espresiions of inborn differences, intensive im'estigation of du sources and kinds of anxiety, and hots destructive fornts of anxiety can be identifieti and relierc J may be the next important step in the precention of coronary heart disease, BS.FERE\CES I. DoLL, R. AND Hut, A. R: Lung ancer arrdother [auses of death in relation to smoi,fng. Brit. Mcd. J., ^: 1071, 1556. ' 2. I/essaoND, E. C. AND HORN, D.: Smoting and death nres-report on forty~four r.wudn of follos.-up on 187.)37 mcn. Part I. Tutat mortality. Part 11. D[ath rata by cause. 166: 1159 and Ixi1, 1959. . S. Dozv, I(- E: The mortality of sinuken and nmrsmotcrv ProC Soc. StaL Stt[. Anter- stat, Assn., Sl, 19Sd. 4. Brsr, E. lV. R-, Jos¢, G. H. e.u IVALRLR, C. B.: A Cmadtan smdy of mortality in retnion to amokicg hal:in, a ptelirninary sepurt. Cannd. J. Puhiie Ifealr'r, 54: 90. I Hil. 5. PACt, 0., Lssrrx, ]L ff., Poituv, lt'. J(., Ucrratc:s, G. \V„ plec+uu.+, A., \rrtCres, 11. esD Pecc, If.: A fra^itudinJ studv of cuo.nar,r hurt dierar.. Cirru6riun, 7::: LV, E163. 6. Doct, R. AND Httr., A. B.: }fosnliry in rrl:rtinn to sn:ukir:o: Ten )cars' olr>cnations of Initish doctors, Crit. }(cd. J.. 1: IS'i9 and IdGO, I~Gh • . 7, DOVLr, J. T., Il\MPCR, T. It., K M\!L, SC. n., KI\c.n, S. }f. AND I.AnN, I(.:5.: RCtptlonShiP of rigarene srnoting to heart disca+c-. J.A.]f.A., Iri.'1: 8~41, 19G1. B, RosrNx[s, R. IL, fRnomrs.c, pf., Srpsrs. R., S1'r.xsr, Sr., Jr.r,rs, C, D.,•\Inst.r,sa, 11- B., Kosn<ns:, R., Ituts, R-. esn {ttrtrus,.rr, N. T.: turcrnry hcan di•cr.c in thc SSt•trrn Collabontisa GrnnP Studr. A ruuow.ufs cspcrirncc of tno ycan. 193: f.G, 9. Srnol-ing and tL.Adr: Retx,rr of the Adci.orp Gnnnriare tu the Sur~con Cenutal of rhe 1'ub- li[ 1loalth Sm.'ica C_i. D:pm uirtn of r[rx!tL, r'.,tuu:ariou and IYcllarc, Public flrallh Seniee Publio:een No. I b'IS, 1'.><a. 10. Tnus[es, G tf., hvcsus,J. 4,s..u Lmonur„ F_ F, with the natist(cal a.dNmce of ri.ra- NotD, If. J.: uSsr.uiuus nn rha inJividwl c!tccts of uu.,;i:ry mt rha 1,6.1 pn+.vq heart atq rnde solvnre and caldiac ouspul cf hcalthy youno dufu. Ann. lutcrn. )(cJ., 44; 871. Il. 71409141, C. D.: Fami:iJ and cpidcwiu;cry;ic alacts of [mo[urr Jiuaac and h.prncruion. ' J. Chratic Du., 7: I5i, 19J3- 12. Txmtes, C, D. AND Cmrcu, R, It.: Cnwpxrison of snotcts and OOnli110{.rn. I. A 1/rVhrDtniry report on tho abilir) m t:rrtc 1+6cnsirhiourra (P:f,C.) 15u11. Hnl,li:u Hcn1>., 100: L^ti0. IS. Tnosrs.s, C. 1f.: Clraraueriuicr.u( ,nn~.cn eump:ncd wfdr nousm•,Fcn in a 1~•pulnsi,xr of healthy ynong aduhs, inchrdir•,~ ohsrnarinn on (Amily hiuory, htav,J prv.au5r, hr~rt s.(e, body wcigirq rLulcetcrot and nrwin ps)rhnlugic naits. Ann. Intrrn. If.d., 53: 697. I'.k+J, T10302-7430
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El Corortary 1;1aod F1mn in Subj, c1e tci(A Coronarq 11csrL Discaec The c2ectt of ciP:uctto smd;in^ cn enroaarv blrnd flow n-ns studicd in pat 't: vil`t c^r 'tn' , a (7)'. 1 ..-. r: in nornt:tl eubjects, signibcnnt inercases in heart rate; artcrial pr4surG and eardiae outpnt w'ere noted. Sn contrast to the unnu:rt iodividuals studied, Intirrts with coron:tr ' v heart di.,e;tse <li-tinetly showed a much le~ si,•nific:mt comprus:dor' incrense in d'.<ir euronary blood flows. Theao resuits rtere cnnlinncd by n later studv (IG), using the Rubidiwn 81 mothod to estinutm mtnuary binorl flo.r. This study also showed that in the coronary patiours studied, there teas no adequnte com(>ensatory incrcase in cornnarv Llnod flmv to nuct the increased myocartlial tis+ne demand tor o,c_~cn. Coronary blxd flow nppnr- entlydecre:ued ns a result of cir.nvttc smoking, iu this particular study eroup of coronary patients .Illltottl~h tlic dcerzass noted were not mnrl:ed, they rrcre statisiir:tlly siqniticant, und iuriicated that n diRerence e:;'qted hetwren thr,r corcn:.ry patients as compared to thc normal subj ces shtdied. A diflereur-e in tbe cornnary 1,1os1 flow rerpou=a to nitroglycerine has also been dcnwnstrateci ut ucrmal snbjers cornpared to subjects with coronary Itoart disensc. 'l'his roas sho,u iu studies usin., the nitronsoxi(lc (18, yf) andthc I2ubidiur.l8} (10) luethods to measure coronary blood flow. tu r.::pon_c to nitroglycerine tlw normal indi- viduals gcnerally inereased thcir coronary blood Ilow significantly, but the eorcnary patients generally did not. Animal stndics have also demenstrated the decreased ability of tthetosclelnlir, coronary arteri.s to increase coronary blood flow, as compared to tlm coronary arlcrics in norntnl animalc (Dw). Dogs with experimentally produced coronar: artery iusufiiciency also show this decreasul ability (12). Similar dilCemnees between animals rvith nor- maleoror.nry atteries as contpand to atherosclerotic coronary arteries havo been demon.strated in restonx to ergonovine (M). ; The above studies indicate iLat the effect of nicotine upon thecar- diovescularsysteut, mediated in part by theaction of released catechol- amints, is "nerally to increasv bzatt late and cardLlc output, and to raise systemic arterial pressure temporarily. F'intiino concerning the effeet of nicotine on coronary idood flotv are presently thought to be largely duo to tho indirc,tt c"'ccts of nicotinc upon thc cardiovascular system.Other animal stud[es indicate that there may t>r a direct action of nicotino on the coronary vneculatnre to incma.=,e coronary vascular resistance, thus tending to reduce coronary blood flow. There aro no human studiesatr the direct action of nicatine by ic~clf on the coronary vaseulature; such studies, involrino the ditcct injection of nicotine into diseasr.l human coronanarteries, might be dcnperous. Normal individuals apparently can increax their coronnry tdocxl flows to com- pensate for the increaszd myroenrdial tiz;sue ocygzn demand, but np- parently some pat[ents iritlt cntronar-: heart dixase camtot, as shown bytheir resironse to smakine. . Thus some patierts with cm-onarc heart diseaso mae be at a prtr- ticular dicdrant"oe [vhen smoking and under other stresses since . their coronary arteries nnp.trer,dr evlnot dilatc to supple blood flosr adequate to mect the increased os.gen demand associatud .riih nico- tine-induced catecholamine relea=r. The interaction of tbe nbo.-e ef- fect with tment findings conceruino carbon monocicL, described in tha ne<t scclion, may bo eslxcinllr imperrar.t in iho-~I indiriduals w'ith eoronary ]teatt disea=_e. Tbe pre.ent star(ies indicate that the effect of cigarette smo.ir.g oa coronary blotd flow, in the pr,~ence of pre- existino coronary Lcart rliseu=r, niiy, iu pnrr, cont:Ihute to the in- creased im;idcnre of acutc tuca•::rdial infamtio:,s t6nt have bcen observed to 1.• ns~iated rrid: ci_:relte sntokinZ. Ao rdntionship be- tween tho smo!:ing el7ect on corovarr blood flow nnd tlm pathoo nesis of coronary alhernsderosis per sr, is presently sulql,,ested. Additional . D:seAreh is needed. 1967 Page 366 i:v1 nrxa.,'r. J., Fass. 31. J.. )(cCtsrq .I. F.. Zun4 E.. Il".rrvx, Il. K., G Rtsa. It J. Jlyocardiat reclronse to cl¢arette smnklnc in normal .ruSject• and Pnttenb ,rllh mronarT aiaaa•. t'ireulatwm: Jnnrnat or the .\mer- leen Ifenrt As.oelation (Sec Ynrk) ~(3): J05~W. )tnr<h PJltl. 11H) Ht,tltrvn, \., Doxes, l.. Guerss, n. Action of nltroqlycerin on coronary circnintlou In rmrnint and in mila cardiac subjecls. Circntntion: Jcur:ne3 o[ the Araericao F[eart Aesoclation /\e,r Yor6) ID: 697. 1aJ9. (f(~ Cout.. R., DceenrEr.o, \., 3LCLeoo, C„ norr, P. Aetlon of nitra7Yycrrin on <oronry clrcvlatiun in nrmal nod in mitd cardiac subje:tv. Ctreu- letloa; Journal o[ IDe 3meric•in Eicart Association 1 Sew York ) 19: 700. 19 /15) HIS4 IC J.. 1iss+tstt, A., Diecucues, 6., Cmro', A., CerJ.>cuta. J. p. J. The Aetcrminaann of coronary Oorv tvtuisalrnt with co- Incidenee rvm~tin~ technir-Circubtion; Journal of the Amerfcay Ileart Aasocia!inu (?cw ]"orl) °l:Sl1S1G, June 1•J6l. ~4) Tlyrnq J., Itrsrcrn, 3. IJ., lfesr, D. Cardlac efteets of nl<otlne In the raGDit ~itn ez{erimentul cor(,unry aWCmsctera+le. Annale of the Sev Yor4 Academy nf Sclences t0: 2130-r-t)1, 9ePt 27. 1nP). (,92) De.vr, .`,., Wvsr, J. 1F., )If'ttin. O. F., ]leszou, U. C. '=eect of nicotine - ' on thecorouory blood 5ow' aud related cl«uiatorS Lar:nce[e+e. Correln- rlre s[edy In normal deG an1 does o'ilh coronarY InsuP.ieicuvy. Cireuta- 11on Iteuurrh 10(1) :°-31, JanuarT n%=. (q0) Rrxn.r_q S. li.. 1§etur. J., I:exe. D- Dr[ectlon of <oronap atberax e- rnsts in the IIrIoE nnimal by the ersaanvioe atresa teeL Sdeoce (Wesu- ~ Instun) 121: BW. 1'!w. I T10 30 2-1 404
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1969 Page 399 (a) Prognosis of Myocardial Infarction. The article by (30) Weinblatt et al. is being criticized for absence of data indicating which patients stop smoking. The article did not mention exsmokers. Only smokers and nonsmokers are reported. Anyway, the basis for statement that prognosis is independent of smoking states is as follows: Table 4-Earl,y mortality nmong mrn (o1b/.inA Gr+t )fI in rehltinn to ph.uil eal avti.it,r le.el and emokin,~, hahitn at lime of MI, apa~adju.ted per cent dead willrin one monrh Chararteriaic at time of 3fI No. `9o dead (age-adj.) Phv<ical activity lerel' l.rael active 261 43.6 Othur rla,-ifird S29 25.0 Inlemlediate 280 28.6 Most active 243 20.5 Lrast active, no limitation . of activity prior to 1tI 200 40.4 Men without prior CIID Least active 196 3&S Other elazified 426 22.6 - Men without elanted blood prec.nre La<t active 143 36.1 Other rlavified . 365 . 19.5 ' M<n with nrither prior CIiD nor elrvated btoori pressure Lrari artive 108 30.0 Other 8a<sified 299 17.6 bGn without other C7r di_ease Isa« active 211 . . 37.4 Other classifird 466 22.7 --Smnkinit habits All rigarette .mokent 487 32.6 Two or more packc daily 177 27.1 f.r>l than rNO ' packn daily 304 352 Pipeand/orciparsmok•rw 110 275 lbn•mokrr• 237 38.0 •Dnnir~i.e d.h. <n mmlon ef IF. pSrdr.l vn.ip A....• n.eA le .Ae ~IIIP wnAr Ff• b.!e pnF. Ii.Fnl O. fAr..n, ni.. 1flid:, 1'~'.SL (a rleera. IFe tbrr InFl. .m A.M1n.d In ..ra• nr •p..ibd rembin.. tirn. nf laur ri.r. n/ Irb.enn!n.d •~i~ rnneea,!d IL.A 0 .x r~ pE .n./ ea.j..F . .. 1. e.f..v.l .. m••in!d r r .f • N.r.d ... ../ J. i.b~. 6f•W m•pm5< Ci;,arctte smoking---esprcially heatrv cigarette smokino has Lcul reported aa as.ociated with an increas<d ri=k for incidence of fir?t )iS anlon-, men in thn HIP study Fwpulation ° but no influence of snmking on early mortalitv could he dentunstrated frnm the prdiminary data.° This 6ndin~ is confirmed be ihe data show~n for dte full cohort in Table 4.
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Page 35Z ~ Certain nccupalinre have Ircen said pnrtirulady to (avor the devuupment of coronury disca~, unlaLly' those nhirh halurc respur.=il,ility auJ strns (3M1,81.87/,andnl tar el, utrvmra nrcll Odr.s1 2,901 hare nnt fnund dmt . r ut - are n re I r, In r r 1 arv dr ra. e dar nnn- cmvttve ! enurmcl 11 . ium hase L.:ad lu Lase 3 or 1 Gm,+ a+ nmch coronary d'•easr as farners or IaL re s i 7/. and general prartitioners to - havo 3 trmes as mucL a d,.rmatolnprts G.Ji. Ocarpat ons mvnlvmg mrctr, physical activity arr said to Le prutective 166, 67, 771. Cit,r' life hns been said to be morc d,,,.ly a-orialed with curonary dise:tse Qrmr suburLvn life, and mcn who drmr nrurc than 12_OIiO milcs a v-.,r srcmcd. in onc studv, nmre pronc to tile dism•. than I!ru-c who drove Ics 16-1), It hae been xi,l:le held, and occssinnaLy druicd, Ihst a diet hiph in saturated fat predi,pus,s to the decelopmrnt nf corunarv discase (46, 52, 69, 81). A corrrl:eiuu Lct„- en tile nationaI iuci,irnee 01 carona.ry dise.rse and the pertentape nf faod calories acailahlc as saturnted fat has been re- porledamongthu'•-r'mniriafnr.chirlredr^ualr•dmtesiet f-0G). Thecerum ehnlt•sterol tends l,- r. when saturaled fat is added to the diet, :u,d it falls significantly when mo,aturated 131 is sohstitvted i4Gi. It has also h+rn sug- gested that p oenar:d •,cer-nulrilinr.. ralher than c1cess salurated fat prcdis- poses to curunary un tile grnuuds tL;l tile corrclation of cnrunary dLm.ase with total a•ailable calurfes or sr:gzr consumption per capita is as good as that for pr'renta;c of calorlcs in fat (106). In general, it is aPParcnt that multiple persornal and envirunmcntal factors can markedly aRcrl tile incidence of coronary di:ca=c. SMOKING AND CORONARY HEART DISEASE Over the last txa dreades a considcrahlc numhcr of epidemioloeic studies on different populations, employing different techniques, have s}:o..n with 0" remarkable eonsistrncy a signiftcant relationshiu betueen ci,nrette smuking and an increased Jeath rate frnm coronary heart disease in males, par- tioularly during middle life. There has been little disserdinz evidence./. 'he association of e"runaqdiaease with the nsn of tobacco in otbcr forms Las not been strikin,". The dncumentation (or thes statements is given in the folloxin8 paral;raphs. Particularly important is the information in Chaptcr 8, -llortalilr. English et aL 1."t') found the incidence of coronary disease in male patients at tile Dlap, Clinir about 3 times rereater in ciearette ±mukers than fn non-smoLers in tile 40-59 year age range, hut fovnd little relation to smoking ahove 6R ltu=sck (81/ rrportcd a similnr rclntionship. hut L"s slriking, in youn~ men t.'it6 eoronar,v direas.. 3filLv (64) in a stadv oI reported rnortalily in a Cincimrti pnpu6uion found that heavy amnkers in the 30-59 year aSC rar.~c had ts.ice as high a death rate from coronary di.case as noo-sm"'kcrs. J1ale Seventh Day Adventis5, who are non- amokers, r.ert fnmr,l by Wynder and Lemon f 101) in a study based on hospital admission- lo bace sioninranrly less curonary disease and to de- velop it later in life thau tile general male hospital population. llaag and flanmer 137) rrpurtcd that employees in the tobaeco indu>trvd who . tend to smoke hraulv, haJ x lower deatlr rate for ezrdiosacular disease than tile general p..puiati,. r thcir r,.rupidr rc.ioo, lmt uo rcp-rl uas made ef m,rctality hn„s within tile nrhorrn-workrr crnup, di.idcd by smok- (ng habits. 76c snnl, lus Lrco eritirired nu this aud other cruund, i 161. Large-scalc prnrl"Tda sludirs uf mnrmlitv in British pLvaaiaas I t1n11 . and }fill, 21), C,nr,',I Sta:es males 3t1-67 recruilcd hy colwmecr workers (llan,mond and iforn. 30, 37, 10. 42) and V.A. Life lnsurance pnfic.Lnlden fDota, 22) havc rnnlirrrred the asnciatiun of death fro:u eurnnay dixase with eigarctte suwl.ine. ln the liritish study, a>(ep-ai.e ac<nriatinn was found hetween the anmunt of LuLaaco corsunred Inot eoLirely' ci_arettes) and thc mnrtalitv fcunt coronarr disease. llIc a<~nrialion eccur-rd inthe 33-54 ycar age nnoe, bet nct in o.Jcr mcn. ILn,omud ar,d 1111111 fcund a similar graded relation_hip brtvrrn cnrnnar.deitLs aod eiearette smok- ing, the death rate bcin, more tlan h+ice as ^rext in men wha smol.ed over a pack a day ~ in nnn-snrokrrs. Men who had stuppcd smnkin, for more than a year at the start of the study had a coronary deaLh rate luwer then those who rontinurd. Studies on eperial proun, of mrn, such as lonr=hnremen I Buerhlev et nl. 81 mrmbcrs af x fraternal nrd!s tSpain and Nathan. 291 and induariaf employers (Piul et al. :I) sLirh, in tile latter two instanecs. inrorporated clinical coronary di-rarc. as vrii as cmnr.arv drztbs, aleo have =-hnnn a tcfatimchip beb,reu corn;nrv disease and smokin+. Thc rclatinnnhlp Nas closer fer men undcr 51 than for older nn•n, and elo•er fur myocardial infar<Is n::d druth tlr.m G,r sv,ica I.~r;oriv ( i 0, S9). The long-ternr pros!arlire str,lies of cardioiasrular rli>oasc in Framiv=- 5am (19) and in rlll any 141 whi h hate (c rturet v} a .-takin, rarch at regular intenaL fnr Ge mzl manYe ot-n . of dl=. .. ha e. nn ponl o-t the data (D',vlr el aL :3) ikoan . tlr. f hl i rrea.c in tile rreidcnce of myocardial infarrtion anJ rnrnnarv dcaths in mrn wLn are hcarv rifa- ntte 5mnkcn ss v,mpar.d l.r nonsrn•,kors. pipc and cirar smuAcrs, and former ei~-arcttr smnkrrs, le: tile p mlol d:as Ihr i:n:idcure of aenina I••o toris did not shaw a sianiticunt u=s,.ciatinn wlth cignrettr: snn•kinu- 9he lack of this particul..r r•.I,tlnn.hip had bo,-n supg•stcd on tile basis of cliuiaalc*pcricncc IlCbitc and Slmncer, 102 1. - 7. Brunncr, D., Nxnelis, C. 6lyocardial infarclion amnng nn,mLrn of eommunal settlemnb in Israel. Lrcet 2: 11149-lllatl lY0 , 58. 1<e, II. E., Schneider, 1i F. Ilyprrlenn inn mrd srtrrm { r-is in es- t~ ecutiveandnoneseruhrepersonne!. JA\L1167 IFt, IJSO 1/5.1. 72. Pell, S., D'Alonzo, C A Ilymardial inferclion in e one-year in- ~ dustriel study.. WI.\ 166: 33: 337, 1953, 90. Slamlcr, J.. Lindher,, Il. A-, Rerkrnn. D. \l.. ShaRer, A., Sli!Irr- lC., Poindexterq A. Preealenm aud incidence nf euronarr I-•zetrt di•exsa• ' in strata of the labor fnrcc of a Chica;:o imlustrial cnrporaliun. J Chronic Dis 11: :11;-12q 1960. L~P.Smith. H. L. Incidence nf coronary sclcrn,is amnnp ph,.irians, As eompared xit6 mrn,bcrs of other occnpztions. JAMA Il)i: 1327- 1329, 1937. ' 80. Russek, IL 1. Emutioaal stress and cornnary heat diseasc in A:ncrioan physicians. .1mcr 1\lyd Sci 210: 711-721, 1960. 66. hlorris, J. N.. Heady. J. A., RaOle, P. A. B. Plnsique of Londnn hus- men. Epidrmiolo.v of unifornrs. Lancet 2: z69-570, 17;6. 67, Bfurris, J. N., Headv, J. A., (Iatile, Y. A. B., Robert.;, l:. C., P,arCs, 1. W. . Coronary heartdisease and physical activity of work. Lancet 2: 1111-1120,1953. ' 77. Reid, D. D. TLe epidrmiology of'coronary discase. 1'raclitioner 180: ' 184-190, 1958. ' 64. hfills, C. A., Porter, M. SL Tobaceo smoking and automobile doiving alress in relation to deatirs from cardiac and vascular causes. Amer J Mcd Sci 2.33: 35-13, 1957. 106. Yudkin, J. . Dict and coronary thrombosis. llypothcsta and fact. Lancet 2: 155-162, 1937. 26. E plieh, J. P., Wi!!ius, F. A., Berkson, J. Tobacco and coronary disease. JAr51A 115: 1327-1329, 1940. 101. Wynder, E. I.., Lemon, p. R. (:ancer, ccoronary artery disease zed smoking. A preliminary report nn differenres in intidence ben.een Seventh-Day Adventists end others. Cslif Jled 89: 267-T2, 1958, 37. Haag, 11. B., lfanmcr. II. R. Smokin~g 'hahits and mortzlitc amon- workers in cioarette factories. Industr dled Surg 26: 359-562, 19.i7. 16. Case, R. A. AI. Smoking habit= and mortality an,on- noel.rrs in ci,,a- relte factorics. Nature tl.ondnnl 181: P.1-8G, 1958. ~38: Hammond, E. C. The effects of amoking: Sci Amer 207(1): 3-15, _ July1962. 39.llfammand, E. C. Smoking and dcat!t rates-a riddle in cause and effect. dnter Sci 46: 331-3-s1, 1953. Also: Sci Progr 11: 239-67, 19G0. 40. Flarnmonrt.t.C. Snrokinginrelationtohcartdiscase. AmerJPuLlic Health S0: 20-26 _19G0. _ 42. Hamnwnd, E. C., Harn. D. Smoking and death rates-report on forty- four months of folluw-up of 1^7-793 men. I_.Total nwrtalitv: II. Death rates by cnusc. JAJ1A 166: 1159-1172, 1_°2N:03, 19.18. 22. Dcrn, 11. F. Tobauo consumption and martzlit,y from cancer and other diseases. Public He,lllr liep 11: 581-593, 1959. 8. Buechley, R. W., Drake, R. 8f., Rreslow, L. Relationship of amovnt . of cigarette smni.ing to cornnarv heart discose mortality rates in _ mcn. Circulation 13: 10°~-1090, 1938. " ~89.1Spain. D. )L, \athan- D. J. Pmnkinc hab!ta and coranars' athcro-` eclerotic heart di,case. 1:\SL\ 177: 687-6°3, 1961. - ,'71.)Paul- 0., Lepper, 1f. H.. f M1elan. W. H., Dupcrtuis, C. W_ 1!ac)1i!ian, A., hlcf:enn, H., Park, H. A lnnriludinal study of coranary heart _ disease. Circulation 20: 20-31, 19d3. , 0. 1'ersona coc:mmricatian to Ll,e Srrr2con Ceneralb Advisory , Conun ttee on ~mokr. xnd Health. ~ ~ 23JIb,lr, J T Dar icr 7 fi }:anncl, lti B., Ifrslin, A. S., F:ahn, 11. A. Cigarcdc snoku o n I coronary 4cart dL•wse. Cumh:m:d espcrirncn of the Albany and Framinghnm studies. Aew Eng J)led 2t:6; S~tr 801, 1'X2. 102. lS'hirr, P. D.. $harf•rr. T. Tobacco, elcohnl, and angina pcetnris. JAMA 102: 6',>-657, 1934. T10 30 2-1 345
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S v] Ylnmmood, et nlA also studicd CIID uwrtalitp nmont~ men who .reree ex-ynol:eo o[ cie,lretlr;. TLr. Jv,ttit r.tt/., i.om Cta Iere Ioo'tr C/nong,the ex-sutuLers th,ln anmug, those still smalciug nt the beginning of tho study, tho size of the diiierenee being Inr~er the lonPCr they had been oif sntukint• (table 3). jonle people stop stnoltin~ because of illness or s-mptoms and thc:o people nnuld be ezpccted to hare higher death rates than tho,o I~ho stop for other reomn=. Pnrly deaths among tho:c with preecistim- di>ea=o mny arcouut, at least in part, Ior the high death rates front CIID among cT-srnokers in the early yearsofah;tention. -- - -~ Dfortality ratios for stroke were higher nmong ci-pnrette smokers with the exception of tho;c orer 70 years of age. Male ex-cie,arette smokers hnd nmrt:Jit-v rntins for stroke approximately equal to those of nonsmokcrs. A clear increase in mortality from nonsyphilitic aortic aneurysms with insreasiu, cigarette smokin',' amon1(v men aged 50-G9 is seen in table 4. The mortnlitv rntio for heavy smokers was 5.00. -Hammond, et nlp found tLat &ldl rates from the three diseases var- ied eonsiderahly with relutire ~+eiqht, amount of esercise, nmount of cigarette smokinL•, and hoa.trs of aleep per niqliL SuLjects who were obese, took little or no exrrci>c, smoked many cil;arr.te; a daY, or slept G or more Lours per night hnd high death rates. Those with a combi- nation of these factors have especially high death rates from the three distases. . T.tsi.z 3--Obaen•ed and expected num6er of deatAs ondmortality ratios for ex<igarette emokers mith a Qistory of snoking only cigarettes, by num6er oJyears eince 7es: cigarette smoking and Jor current cigarette tmokers, <oronary heart disease and stroke; campared to persons who ntttr smoked regularly, in men aged 40-79 SYyeotsmnka Caou.r Leut duew+n eeoke OWird L.yecka astlo Onv ed Erpeei.d AaN icd{YaWrmoten(lumuwoken .rF19 dr.e.ltea. dsrl: 11opttE: Iab 14, 19'+r.............. W Mleuf_..-,,,-„-,-_.,,,,, Cr .0.k L'II ,----- .,..-- HreN_-----------------_. {6 llT Lm bt91e»-------------------- Ir at -16 ------ .~.-. .-.._ 1C.rtm.run-------------- 10 eLr Lm ...... _-,.- .__- Te!.1....................... Llvnelirvet4rnoten,. ,___.__ _ Nna.motel.+euwir....-....--_- a11 Llnf LNt 249 L».6 1,841.0 Lte 1.90 LW L19 tx! 60La ! rSlryetL smet.n / tormer.xoken •bxa.aadr.r;tto.dsyl; ~ eappM: Iswnlryr_...:.,-,-,,, f1 166 Hn.rt ..................... w 14Ls ..................... W ne6 --------------- 1J] Ydt a>mw.rwe .............. U 1L9 ToLI ....................... x4 anr CbrtntHey.ne,mek,n............ lea Llolr NIM.mokedrtNtvrlY........... _ L6e1 lNLa - toc.o:: n.mmox. s.O...t LL Wl. tu L61 Lle L31 Lm LH a WLl arl LAS UU fJlr Lrr LM 6H !]LO LW is TAxLE 4--Aortic ancurysrr6 death ratcs and mortality ratio.r for macn aged 50-69, clas.si,v:d by cignrette srno.Zing habits INrte, ur Lae "mouonl Neva t~ot.e .er~wlr Cunent Im~tent by Csny an~ao.mu.uo`unuu H io-l9 :n-:h aurmun Den/h mte---------------------- 13 34 50 59 IUf Mcrlsiity rntio------.---„------ 1. 80 2.62 185 4. 54 8.00 ba.rs: nemrnud, E. C., a aL (/0. They also found that dcath rates frotn Cf11) and strohe were lower inex-ciparettemnol:crs than in nicn l.ho t.ere curecntlv smokin, eig-t- rettes at the timc tiiry enrnllcd in thw =tudy. Tlle dr,tth r:ltes of male os- eigaretto ssu•/ker+ w6u LnJ mrt smnked fnr ll/ to YIl )c;u~ tv cre no higher or only slc,htly hi„Itcr th.ul the da:ttll ratcs of men xim Imd never emoked rr;;ul;trly. Ilcath rate. frum thc three diseasvs were lo.res't anlong subjects (ditlmnt a Ili.uorr of diubctrs or hi~ h blood pres.utce who ucre not nU.a-, tonk it 1c.1~ t ntnilerate cNcrcise, urrer smnlced reg- olarly nnd slept G lo fi 6ours per nirht. NrrertLi less, ccmt t6c=e stth- 1969 Page 397 T10 30 2-1 46 3
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1968 Page 382 (e) EFFECT OF SMOKING-SELTZER the smokers parallel those of the US general popu- tation much moree closely than do rates of the non- .mokers, with the nonsmokers parcicularly diverg- ing from the general population in a far greater in- crease in CH6 death rate from a°es 45 to 54 to ages 55 to 64. Furthermore, in Dom's study of veterans, the death rates for smokers are somewhat lower than those of the generel public, and the death rates of persons who do not smoke are still lower. While it is di ncult to make direct compar..ons of death rates from one popu+ation to another, is it po,sible that the nnnsmoken represent a very spe- cial and markedly singular group in the popula- tion, more so than the smokers? Amount of Cilprette Smo4inR: The Surgeon General's 1964 report states, " . the ratio of smokers' coronary death rates to those of non;mok- ers increases pro-'ressivcly with the dailc ci;arette consumption." This increase in CIID death.mtes with increaa,d amount of smoking was found in a number of studies. However, an examination of the new data since the 1964 report reveals a very complex and hardly consistent picture. To brgin with, a consistent posi- tive gradient of CHD mortality with amount of cigarettes smoked is found only in the Dorn study;' Reid and co-worlcer->' migrant study" (in British and Nnrwegian born hut not in native born US men), and in white men of high social class in the Evans County, Georgia study." "There is cer- tainly no clear gradient [of CHD tcutalitv] with number of cigarettes smoked" is t:,e report by Doll and Hill in their survey of British doctors (a rising gradient is apparent in younger hut not in older men), and no clear grad:ent is found in the Cana- dian veterans study," and in the Ke-ro ond white men of low social class of the Evans County, Genr- gia study." Signiticanlly, the majority of the new studies show inveraions or incon;istencics in the gradient of mortality or morbidity with a%era,e numhcr of ei-areltci sn-.eked d.cly. %Chile it is tr.e that in virtually all :h^,a ia~tanc!•s, tho~e who s^•n?red the most eigarett~s gire cor.si=tently f:fr-'i,r CIfD and myocardial in'_rction rat::s t:ian t!:r.re w:~o s^okcrt the lca;t, the consi:tcncy cf :Ir_ };r:,dicht is broken down as bet:veen the groups which smoked the least and the internted.:.a group.,, with the inter- mediate rates the samc or lo" er than the rates of the groups which smo: d the len;t Inver.-iecs bc•- lween the groups w9hich 'mokt+) L'•:c Ira>t (usually less than a pack a d ay) and the intelmediate groups (at Iea;t cee pack but le--s th: n two packs daily) are to Ix found in the corn.`>:ned Albany and Framiagh,im ~turly,"' the IL:-r.,;r.:) study," Reid and co-wor':rr; n:i,rsat study (nativc Ixlrn subjects)," tl:e )I!F in:eytigat;un," and the na- ti.mal hoalt:r ntrv, p.'. Aoron:i^ ;ly, it ca,^.::ot b,• d that t::e new dnta runl~rlo li,r rr'JI:. nf ihc iL'•ll : ~-a witll n•-lN'ct to a rnr.-i.ter:[ r:-.nt cr.:d5•::l ..: L'11D m~~rn5ty with inor•:IV-d au.of ri;:arrttrt sn:n6~-d. On 197 the contrary, the new data, with its many inconsis- tencies and inversions in the "rising gradient," in- dicate that this whole subject is not as clear cut as it appeared at first blush. Parenthetically, it is to be noted that almost identical inversions in body build measurements according to amount of cigarettes smoked have been described by Seltzer in his study of mnrpho- logical constitution and smoking habits of Harvard college graduatc;.° Duration of Cigarette SrrroF.in;.-The 19&f re- port made no comment with regard to duration of smoking and CHD rates. Since the 1964 report, therc have tr•en three important studies which have dealt with this subject. The combined Albany and Framinrharn study"' found an absence of asocia- - lion trtwtYn duration of heavy cigarette smo.'-:ing and risk of mvocardial infarction. In Dom's US veterans study there was also no significant rela- tionship b',twe-n duration of cigarette smn!cin', and risk of death from CHD; Rahn summarized this by stating that there was ". .. an almost perfect fit of the data with a hypothesis of no relationship to duration."" And in the Canadian veteran, survey there wa, no clear h adient of increasir.; CHD mor- tality with increasine years of smoking experi- ence," In fact, in this material, the morta:ily ra- . tios for heart and circulatorv diseases for tho>e who had smoked cicarettes for 30 to 39 year> (1 5) were lower thon tho;e of individuals who had smoked for a pcrind of only 5 to 9 or 10 to 14 years (1.7 and 1.8, resprcti% ely). . It is notzhle that while duration of ci0arette .smo'r:ing, i> considered an important factor in eon-. nection wdth lun; cancer mortality, the new evi- dence since the 1954 report point; to an exonera- tion of l:tis imPOrtant elec:cnt with respec: to CHD. The evidence wnu'd appcar to be consistent with the ronc?vsion of the aut::ors of the cor.rbined Al- bany and Framingham study that it is ". .. not any cumulative el:ect of inhalin; cigarette smoke which prccipitates myocardial infarction and death (rom CHD.... "'° This has led to the sugl,estion by the Framing- ham heart study i::at coronary heart di~ea,~ is only ecut,7ty connected with ci,=_rdtte smo]<in,+, not chroaiccll_v connected, acting by the "triggering of a lethal arrhythmia or thrombcsis in subjects predisp~sed by an alreadv cor..promised carnn+ry circulatioa'°' If thi: is indeed true, then the eExt of smnkin; (by their su;tCe;tion) wouid 1><' lisited solely to thosc pcrsons with "alreedy comprnmi;ed circulations." Due-s this si;nify that cigarette smokin„ i4 without dcletc:ious effect on those with a normal. healthy roronary• apparatus? jnhaletion.-Th,: Surgenn General's 1964 report statcs...... at ench lc%el of conaumption the ratio (mortalily ratio) in.•rra<es with amount of in):ala- tion re;,xted by t'x >mokurs.•' On tn- ~ :ubjeit the new dala give mnf)ictint re- +ultx. In thr poll and Hill sturry of Bnti-h duc- tnrz, thr authors stated, "Only small and statis- T10 30 2-1 43 7
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$tllullar (^./) l:us:uet)'Ir.rd 10-year mortntitv dl:ta on a total coho:t 1969 PH (5',e 398 s at' ^ 'I f 1 1'):., , 7,, . o- • P e SrAVlrs, J. Persuoul Communlcotloo. 10G0. (25) Tnox.~t; )L C.. nY.n..\. L., PArlFSnnaoe'r St. 8., Jr. Cnronlc dts.n former ttrlleCe stutlems. VIL Bar!y prrvursnrs of nor.f:,bl anr~~nar}' F disexse. Arueric.ln Journl of F.~ idemia:o.y SP(01 :311t-e:'1. \:'.ry' t^ (19) Pei~z.nanseR It. S., Jr., R'rso,.t. L. CWaractcristic~ In collr_e Soa;!; dLeS~osleS to tatd corunar5' Aeart usease in later life. (In t Amaican Joarnal of gpidcmfolue : 1(R;B. TASL11 S.--I0-ycar murta[ity rates for a~adden dcatb, coronary heart disease, stroke, cardiotlascular-rcnaL, ond alI eausea eornbincd among anen ajed y0-b9, classified according to eigarette smokimg, eAofes!crui, and b6ood pressure 1YWplm ou LIt4t Cv. stvdr,191YdS Stevarlitv"uy t^w vt wtenYr hevrt d1xi.N.na rvue.eC wa[:cur ePtemarre tvtereevuvn.) . , t0 ql tC a1111Lmrr. o t:n . 1r1._. , 0e rllefl, It^etl- G~ - n .. lt ple,Car, l.il,ht :uld Ca:' Oi ItIG,7 nwu trcn_ immd initially to bo fren of dMinitx CI[D ncd Ictve lwen follou'ed reithout eystenmtic intcrvention.llialter nverali death rates tcerefound almyng tho 5tnnkcrs in thc st ndv. Tahlc 3 sLolrs the dv'.tt h rates f ront CI I7) and fromnll caus> for men cit]t various risk factot,. Recent papets by Thorne, et til. (°5) nud hy Pndenbari;er, et al. (19) tcpurt furthar results of studics of C11U arnong, formcr collcqa students. Collrge healtL rrcords and otLer culte:;a records lrere re- viewed to sscertain thu pre=ence or ahsence of fnctors under considera- tion. Caecs were identitied from death certifuates itt tho stndp of fatal CIID (19) and frolu questionnain-s and phpaicul examinatinns in t)m Study-of nonfatal C(1 D(i5). ]Iatrlyecl conlrols were obtained for each case. In both nonfatul :r,:d fatal C1ID, si_;ulinvttv more sn:oicer:m t9ete found nmon, t6e cases thmt amnnq tLe controls. Combinations of iisk factors res•,dcad in r;rcatcr CI1D umrLid il v:md ntortaitv ratios than did single fartots. Fignure 1 shows tlre mmbidity ratios for com- binations of pnirs of risk factors in nonfatal CIID and taLlc fi shows mortality ratios for co:nbinar.ions of risk factors in fatal CfID. loYmr m-rmtnr 19ferotLrtmuu,u~leanueematln¢n0arvlaetd.r). &uaaanaette AIlCIIU 3rmte AllC~'n Au orwrtlwWtuulemlqnrvr,ustans _ - __ - m-~ Numtrr SYmEer nt1tn Nu-lvu rkam pvmL.r D.,4n Yumper ucln Nvm oer De>tn ctc, vl ntee el nte ct ~ rute or ruu nl rate Imm~eort amrnt aeYnf a¢ame 4tatnf datrlY Nerttttnc,or_..._........_.__.._...._ ....................... T!/ 0 0 a to 2 Gf 4 ItJ 13 pe ttrrurEV:mt<mkmleaEYCer4nslovaal>-Ire[b .............. 9t 4 ]26 U e>1 t 19.5 t9 T20 G1 IUL3 CI33nt1esmutln9uclY(IDOrtco:el,cM1r--------------- t0e 4 160 le 11.1 D IL3 'A LY9 ~ N 16.T . Hr4tnLsen.votauluvd~yperuvvonas!y-:fs<tvn-_........ LO 1 Af . 3 3Y.1. 1 417 tT 4 N.3 I Iite (.YtY Lse:Ol'.city90rmoeeeaayl Ynl~':IYt[^aleetemlemirOf . aimt,wtm.emi"an>r<nron~„-a.u:m........._........ mf 11 0;] li 67.1 3 /A9 30 t6e A 1e0.f C4Ynw tme¢mr no « sere I a~yy nvw..emmwmeml., erpmrem,uv-.lu........._ ................................... n f ut 3 mo. 3 z1f e tOLI u SLS. TotN....._.__....._._............................... - el,il3 S! te.i LS J9.] Y! tll tr D4! - tC Illl tRbtm:ran/telvACrenrmrdeteaaervl:r:lamw.mrMl;dlrtwllvELw1{.et- t9mullvtdtt..erevntuEeetoedtvr4ot1Ee1,3Dmto, etln9lEr6Wrer:m.ilCaOVr:nOt dsY. tAll uto Ye qe'e'yi•irnl by Yyeet aye rmuisin nu U.B.OVhpvpuletlvu, t9/Yt in ntes pn tEat•-a. BoYrti: Bt.mlep r. Ua. 7 t.t r f f:eNnlalyd eorononj heart dlsea.se deatR raAins in a 17-51 ±rear' t J ~i~tp o^I°ngforrner college st<dents, classified according to eombined :. SeK „re (}) or absence (-) of eacb af tdr<e specified rG•.k factors, .+J 6Y aye plYrmtw Ar.(mn)•aemthlrumeervnerynevtarava ePbIkNP, 2nMZrv1 Tneel l.'NOrmoee ]?el 3Uit tYd 35Ni r..e.yr mm.lle hra~av yean rJ.-a rtur rtan + + + 4.3 t(1.9) 5.7 '(4.8) + - 4• 1.8 23 L6 t(2.0) + + - 4-2 2.9 4. 5 5.6 - + + 1.9 2.9 1.6 1.8 + - - 1.7 2.2 1.9 1.3 - 'F- 1.8 1.2 1.2 1.4 - - + L1 1.4 L4 .8 - - - 1.0 1. 0 L O 1.0 tNOmEen N purtntT«e Ivalmre etyctea vumpu mmvuy pwt d4aaa Jemdevu ku tA.v 6 eacta: peE.ivuiY, p. 9.,14L (ID). T10 30 2-1 464
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1969 Pagc 400 TARtv 7.--A+:nuad iruulu:ce raf<e of coronary laarl diyease fcr men 59-49 yeare of aye, c:assifeed by snto{tirzg nietunj aud by c:rreut }:ractitas as to cigarean ernoking .Mn u eltne IrylnnL~C af tlu /I( ayr rerlu! of a Wennwet rew ' e:nnunamuoty ~ e.mntet...uel:ovuneertumner.e.aer Martldq wlm '.ubleau ti vieL rq.nona ron,,.r cur..nt xon. Iw 16-:0 90arma. y uu y <ga.elte r:Enale Nun- F+tat Num- Ov bar Rete Num- tur RaN Nu.'_n- bcr Ilete NuniRnte Gr Num- ber 4ulannnmrelna...........- qsta .... Na ..... 103 .. 2b .. 1'0:'1 ..... Lltt W lbtil numbc-CIfD u.u._.._. Sl Lt y e1p a Lu lo 19.8 u eao m Allv:yccsrdlilWhrctbn....._.. Ef 6l 4 v t 1.e 10 1.1 ]s 43 It LymMon:euc ............... sn Lt 1 .4 3 LI I t.t 31 SI tl Unre'syuD.ea ............... It LI 3 Ll I .6 2 l9 1 L7 0 ind ........................ 11 p p t a 0 1 p 6 it 1 dnLln. nciwle enlL........... ll u i 1.3 0 0 a a 6 L7 a Cu ayer.1-L Nurn- Re. ber t Annuel N. n-:1.IFq m. c Nt. a snaw/tr. rql,ew eb::a.atm.v n1 c r~ mr.wlou emntlut mresortn ere rlL.uayntiv dR • DI^.e:cau tr. CDD 4ulue::m h'