Tobacco Documents Online

~ionary and ~e contribu, posed to the inated with SMOKE and in ciga- I to be con- tituents are fiese health tar'''), su' ach are sus Xn this are stituents i. , most 1ike1 utors to th I the consen ect to modi. ~e become I CHAPTER 2 Cardiovascuil6r Diseases

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/ Contents Page Coronary Heart Disease Introdhzction ................................... 13' Epidemiological Studies ..... . ........... . ........ 14. Interaction of Smoking, and Other Risk Factor& ....... 16 Autopsy Studies ................................ ]i9 Experimental Studies .............. . .... . ...... . . Nicotine and Cigarette Smoke .............. . .. Carbon Monoxide ............................ Stnoking and Thrombosis .................... Cholesterol Content of Tobacco and Tobacco Smoke: Cor P~ulmonale (Pulmonary Heart Disease)~ . . ........... Cerebrovascular Disease ................................... , Peripheral Vascular Disease . . . ......................... Oral Cbnt'raceptives, Thrombophlebitis„ and Srnoking....... Highlights of Current Cardiovascular Information . ........ References ............................. LIST OF TABLES Table 1.-Incidence (1963-1970) of heart infarct in relationn to tobacco consumption, ini "'The Men Born in 1913,,' Goteborg,Sweden ...................................... Table 2'. Cigarette smoking at entry and'subseqnent 20-year CI-IiD incidence, among Minnesota men .................. Table 3.-Human autopsy study. Comparison of the thick- ness of' myocardial arteriole walls in smokers andl non- smokers ................................................ Table 4.-Average values of carboxyhemoglobin and serum cholesterol in Danish smokers and nonsmokers in control group and'l gxoup, of patients with arteriosclerotic cardio- vaseular disease .......................................... 21 21 21 23 24 24 24. 25 26' 27 27 15 15 19 23 0 ~. 1 Y 4+ V C~^~ W I

LIST OF FIG'[JItLS' ii L Page Figure 1..-C'anihe autopsy study. Comparison of the thick- ness of myocardial arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsrnoking, dogs ........... 20 . 12 00w

ek- )gs Page 20 IhTTRO!DUCTIION In the United States more people die from coronary heart disease (CHD)'~ than from any other disease; furthermore; CHD is the single most important cause of excess death among cigarette smokers (54, 57). The 1'9'71 report, "The Health Consequences of Smoking" (56) , outlined the growing magnitude of t'his problem and summarized the relationship between smoking and coronary heart disease as follows : 1. Data from numerous prospective and retrospective studies confirm the j udgment that cigarette smoking is a sigmsficant risk factor contributiilg to the development of coronary heart disease including fatall CHD' and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers, 2. Analysis of' other factors 'associated with CHD (high serum cholesterol, high blood pressure, andl physical inactivity) shows that cigarette smoking operates independently of these other factors and can act Jointly with cert,'ain of them to in- crease the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing, coronary heart disease and't'herefore contributes to: sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is: associated w ith a significant increase in atherosclerosis of the aorta, and coronary arteries. 5: The: cessation of smoking is associated with a decreasedi risk of death from CHD. 6'. Experimental studies in animals and' humans suggest that cigarette smoking may contribute to the development of CHD: and/or its manifestations by one or more of the followTingg rnechanisrns : a. Cigarette smoking, by: contributing to the release of cat'echolamines, causes increased myocardial wall tension, cont'ractioni velocity, and heart rate, and thereby increases the work of' the heart and the myocardial demand for oxygen and other nutrients. 1'3

b. Among individuals with coronary atherosclerosiis; ci~ga- retite smoking, appears to create an imbalance bet'ween, the increased needs of the myocardium and an insufficient in- crease ini coronary blood flow and oxygenation. c. Carboxyhemogl'obin, formed from the inhaled carbonn monoxide, diminishes the availability of oxygen to ~the myo- cardium and rnay: also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxernia, thus reduc- ing, the amount of oxygen available to the myocardium.e.. Cigarette smoking may cause an increase in platelet adhe- siveness which might contribute to acute thrombus for- mation. Recent epidemiological, pathological, and experimental studies add to the understanding of the relationship between smoking and, CHD. These studies point to cigarette smoking as one of the major risk: factors leading to CHD and help, clarify some of the biomech- anisms through which t'his occurs. EPIDiE1VDI0'1LOGTCAL STUDIES A prospective study of 973' men born in 1913 in Goteborg,. Swed~ens was, undertaken in 1963~ (51, 52) ~. The proportion of myo- cardial infarctions among cigarette smokers was sigpRficantly greater than among nonsmokers (P <.05)', and the incidence of myoeardial infarction rose: with increasing cigarette consumption (tab1E! U. afthe 35indivildu~alswho experienced a myocardial in- farction between 1963' and 1970, only two, had been nonsmokers ; in the whole population of: men borni in 1913, 56 percent were smokers. Although angina pectoris was more common in smokers than nonsmokers, the difference was smaller than for myocardial in.- farction and was not statistically significant (52) 1. Paffenbarger, et al. (.42) reported on the health experience of. 3,263 longshoremen st'udied' over the past 18 years. During this in- terval 1,098 were known to have died, 350 dying from CHD'. Long- shoremen who smoked more than 20 cigarettes a day faced al risk of coronary death which was more than twice as great as that of: the group:made up of both nonsmokers and smokers of less than 20 cigarettes a day ( P' < .0i1)' . Keys, et al. (30) analyzed the 20-year CHD incidence among 279 Minnesota, men aged 47 through 57 years who were CI-ID free at entry into the study. The relationship of cigarette smoking habits at the start of'the study to the subsequent incidence of CHD was examined. The originally: published' table of results was incorrect 14

i. sis, ciga- ~ween the Ficient in, : i I carbon i the myo- pment of cigarette us reduc- rdium. ~let adhe- ' abus for- t1 studies oking, and he major biomech~- Goteborg, ' k of'myo- nificantlly idence of Isumption ardiall in.- kokers ; in j smokers. • ~ers than ardial in- I E"rience of ug this in- ~D: Long- : eed a risk m that of is than 200 mong 27'9I Dfree at ng habits CHD was incorrectt and the authors have supplied a corrected table which appeared in a later issue of the', same jaurnal (table 2). The morbildity! ratio for "'hard CHD"' (CHD deaths pius myocardial infarctions not resulting in death) among those smoking more than ]0 cigarettes a TABLE 1.-Incidence (1963-1'9?'n)~ of' heart infarct in relation to tobacco cons2urnpt'ion in ".T'he Men Born in 1913," Goteborg; Siveden.n = 855 clAssification Sinoking Heart infarct Never smoked n= 207 Stlopped' smoking n=168' Cigarette smokers 1-14 cig/day n = 234 15-24!cig/day n = 138 ?2'5cig/,day n=33 Pipe/cigar n=75' Number Percent ( 2') 1.00 ( 2'), 1.00 (13) 6~0 ( 9) 7:0 ( 4) 1i2:0 (,5) 7A SOURCE:: 'Eibblin, G., Wilhelmsen, L, (51).. TABLE 2.-Cigarette smoking at entry and'subsequent' 20-year CHD incidence : among Minnesota men.l Iwl~umber. Smoking~habit (cigarettes/day)~. A'gee of'men~ Item Never~ Stopped. C1A. 10~-19~ }20~. 47,48 53 % with, habit 23' 19 9 19 30 49,50 51 % with habit 33 20 14 10 23 51,52 69 % with habit 33' 26I 14 14 13. 53„54 53' % with habit 36 30 8 13 13. 55-57 51 % with habitl 24 33' 8 18 17 47-57 277 Number of'men 83 71 30 41 52' 47-57 277 Hard CHD rate (~c)' 12.0 15.5 10:0 17.1 21.2' 47-57 277 Hard CHD rate (SE) ± 3.6 + 4.3' ± 5.5 ± 5.9 ± 5:7 47-57 277 Hard CHD Morbidity Ratio 1.00 1,29 .83' 1.43' 1'.77. -17-57' 277' .!Y11 CHD:rat'e (~lo) ±2r.7 ±21.1 ±16.7' ±19.5 ±26.9' -17-57' 277, All CHD rate (SE) ± 4l5 ± 4.8 ± 6.8' ± 612' ± 6.1 47-57 277: All CHD1 Morbidity,Ratlio 1.00 .97: .77 .90 1.24 t Cigarette, smoking habits~, by~age~at.start of'the~.20-year~follaw-up~„ 20-year~..incidence rates (per.100 men)~.,,and.st'andardlerrors (SE)', of thexates.,"Hard CEID"-CHD death~and~h myocardiali infa~reta,. "All1'~-angina pectoris and other CH~.D~D diagnoses.. "Deaths"-from all causea except~ I ~i6lence:. SOURCE: Modified from Keys, A.,,et al., (i30). 15. GJ

day is similar to that reported from the large prospective studies. However, with the small number of cases in each smoking, cat'egc,ry,, there are no statistically significant differences in the incidence of CHD between the categories, either singly or combined!. Retrospective studies of CHD have recently been reportedi fromi Czechoslbvakia, Sweden, Norway,, and India which, corroborate earlier studies linking cigarette: smoking with excess CHD morbid- ity and mortality. The Prague study (19) included 443 men between the ages of 600 and 64 years. Significantly more (P <.05) ) individuals with a. "probable" myocardiali infarction were found among, cigarette smokers than among nonsmokers or pipe and cigar smokers. The smoking habits of 120 patients with myocardial infarctionn who were hospitalized in Gateborg were compared with those of thee entire "men born in 197 3" population sampUe (17, 62). A signif- icantliy (P <.01)~ greater number of smokers and heavy smokers (more t'han 15 cigarettes & day) were found in the myocardial in- farct'ioni group than in tlie population sample., The Bergen, Norway, cross: sectional study of 2,117 women and 2,472 men documented a relationship between smoking and CHD1im men, which was most marked in the 5'0' to 59'. year old age group (16). No effect of smoking, on the prevalence of CHD' in women was demonstrable in this study, and the effect in men did not appear to be related to the daily number of cigarettes smoked. In! New Delhi, 100 "well 'documented" cases of ischemic heartt disease were compared with an equal number of control cases (8)',.. In this study, significantly rnore ( P' <.01) of the case group smoked cigarettes regularly than the control group, (1WTorbidity Ratio = 2.1) . Mu1'cahy,et al. (40) recently foundla positive associatibn between coronary heart disease mortality rate and calculated per capita cig- arette consumption in 21 countries. He interpreted the results as being, consistent with the hypothesis that cigarette smoking is a significant risk factor in CHD': mortality. Stamler, et al. (50) found that for both men and women the 1964 CHD mortality rates in 17 7 developed countries were.related to aver- age annual per capital cigarette consumption. INTERA:CTION OF SMOKING AND! OTHER RISK FACTORS The Report of'the Inter-Society Commission for Heart Disease Resources summarized the evidence indicating that three risk fac- tors (hypercholesterolemia, hypertension, and cigarette smoking) are properly designated major risk factors for premature CHD (,28)i. Other possible risk factors including, obesity,, physical inac- tivity, diabetes mellitus, elevated resting heart rate, electrocardio- i W ,6

ludies:. egory, nce of G from )orate orbid.- ~of60' 7ith a Iarette I irction of the ,ignsf- aokers ial in- mi and HDin group !n was ~ppear i heart s (8). moked. = 2.1). Aween ta cig:- ults as. lg, is a .e 1964 3 aver- TORS )isease ;k fac- Aimg') I CHD' L inac- tardio- graphicabnormalities, a positive family historyof'premature CHD, ; ~1d psycholbgic and social factors have also been, described (54, 55,56) . in the study of 973 men born in 1913! in Goteborg, Sweden, sev- eral coronary risk factors including elevated serum, chol'esterol;, ele- vatedl serum triglyceride, low physical' activity at work,, and' smok- ing were found tobe related to an increased risk for the development of coronary heart disease during the subsequent years of'the study. Failure to find a relationship between hypertension andl an, in- creased risk of CHD may have been due to the fact that all patients -,Vithi hypertension in 19!63' have been under treatment since thatt tiihue~ Tibbliniand Wilhelmsen (52)' found!that as:a patient accumulated more risk factors his chance of' developing, CHD1 became substan- tially greater. Werko (61)' reportedl from the same GReborg study that patients who were smokers; had sedentary jobs, and had both tlevatedicholesterol and triglycerides experienced a 4-year incidence ofrsew coronaryevents: of about 20 percent;, t'he4Lyear incidence arnongthose who exhibited only one or two risk factors was much lower, ranging fromi 0 to 3 percent. ECG changes andl anginal pain \vere included in the definition of new coronary events., Paffenbarger, et al.(.4.2)'. evaluated coronary risk factors in the stud~ of 3,263 longshoremen. They found that,, with the exception of diagnosedl heart disease, smoking was the most important factor predictive of'higlii risk for coronary rnortality:, I Keys, et A (30) im the, study: of 279 Minnesota men, concluded ; that al positive, cold pressor test, elevated', serum cholesterol, andd elevated systolic blood pressure had major predictive power for ('HD, death or infarction;! in their analysis smoking seemed less important. S'tamler (49) ~ has analyzed the data on 13' deaths.occurring dur- ing, the first years of the Chicago Coronary Prevention Evaluation Program,, which originally consisted of 519'. coronary-prone male volunteers aged 40, to 59 who were free from clinical CHD'. Eleven of the 13 decedents had three or more coronary risk factors at entry into the program, and at least S' were cigarette smokers at the time of death. Forty-three men, who were cigarette smokers at entry into the Coronary Prevention Evaluation Program, gave up smok- ing andl have remained active ini the program. There have beeni no~ dpaths fromi cardiovascular causes in this group. Stamler (49)) commented :°`Etven though the number of deced'ents was small,, these data, strongly suggest that continued cigarette smoking is as= sociated with very high risk of premature death for very coronary- P rone men,, and that other preventive measures are by: themselves of limited vallue for them as long as they fail to give up cigarette smoking."' i 1 17

r As described in the 1971 report, "The Health Consequences of. Smoking"' (56),, some studies have indicated that smokers show inereasedl leveIs, of serum lipids while others have not. Such contra- I dictory results are also present in recent studies from Germany, Poland~ and Sweden (,21; 39, 53). After ai patient suffers a myocardial infarction, he frequently gives up smoking (17, L6) . Only fragmentary data are avaiiable on, what effect the cessation of' cigarette smoking might have oni the '. likelihood of ai recurrent myocardi~al, infarction ( 9;,34, 43). ~Ninety- two survivors of a first myocardial infarction were studied over a 3!-year period by Paras Chavero, et all (43). During this time, 37 patients continued smoking, and 12 of them (32 percent) experi- enced a second myocardial infarction. The 51 patients who did not smoke during this 3-year period included 39 ex-smokers and 12' pa- tients who had!never smoked. Eight of the nonsmokers (16'percent) experienced a second myocardial' infarction. The smoking habits of' four of' the patients were not known. Although the continuing smokers experienced a greater rate of recurrent myocardial infarc- tioni than the nonsmokers, the difference was not statistically sig- nificant (P =.07). The role of genetic factors in the development of' CHD and' the difficulties associatedl with the use of twin studies were discussed in the 1971 report, "The Health Consequences of' Smoking" (56)~. Mailed', questionnaires were used to establish the diagnosis of angina pectoris in ai study by i,undtrnan, et all of twin pairs discordant wit'hh respect to smoking habits and in a study by Liljefors of twins with CHD. Lundman, et al. (36) recently investigated 69 male twins with the diagnosis of angina pectoris established by questionnaire. Only 22 percent of'these diagnoses could be verifiedl byy clinical examina- tion. In a study of CHD, Liljefors (35)' studied 91 pairs of twins fromm the Swedish Twin Registry ofl' 1967: The twins ranged in age' from 42'to 67 years, and 511 pairs were monozygotic. Smoking habits were not significantly different in pairs discordant for the probable presence of' CHD. However, Liljefors noted that ". .. in many pairs the smoking habits were similar and that the material included few pairs discordant with respect to~ smoking, so that it does not pro- vide a suitable basis for conclusions as to the causal importance of smoking for CHD'."' As observedl in the 1971 report, "'The Health Consequences of Smoking"' (56), it would be surprising if' genetic factors did not play a role in heart disease; however, it is open to question whether findings from twin studies can be used to dis- tinguish between ". . . the hypothesis that genetic factora govern the level of host susceptibility or resistance to the effects of an exo. genous influence such as cigarette smoking and the hypothesis t'hat't genetic factors `cause" both heart disease and smoking:"' ta ( I