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Auerbach and associates have reported on the effect of the chro inhalation of whole smoke through a tracheostomy apparatus in be dogs. A hyaline thickening of myocardiat arterioles was found in the the degree of change being related to the duration and amount smok (16). At the present time, animal experiments on atherogenesis and have provided conflicting data and must be regarded as unsatisfacto Experiments have variously employed continuous: and intermit'ten exposure, have estimated lesions biochemically and morphologicall and have used' diverse short- or long-term dietary loads so tha~ comparisons of results are difficult. Animal experiments remain to done in which CO or nicotine are varied in a setting of whole smoke administered by inhalation without aversive stress and in a suitable atherogenic context. Research Needs While current autopsy data on humans leave no reasonable doubt tha smoking promotes atherosclerosis of the aorta and coronary arteries ii 4 men, equivalent data do not exist for women or for other major arterial beds. Within practicaL limits of study, it would be informative for pathogenetic concepts to have better information on multiple-ris factors, including oral contraceptives in conjunction with smoking and with smoking cigarettes of different potential hazard, in autopsy; studies. In particular, it would' be of great interest to know the influence of smoking on the development of the common fatty streaks and occasional fibrous plaques found at autopsy in adolescents and young adults. The mechanisms by which smoking enhances atherogenesis require` elucidation. Such information might assist in the fabrication of a cigarette less hazardous in terms of atherogenesis and its conse'- quences. Conceptual frameworks and biological systems exist within which to study the mechanisms by which smoking enhances atherogen- esis: They include effects on the arterial endothelium, which may alter its permeability to macromolecules; effects on end'othelial-platelet interactions which influence thrombogenesis or affect the proliferation of intimal, cells; effects on the metabolism of the vessel' wall; and systemic and local effects on lipoprotein or sterol metabolism. With~ respect to the monoclonal hypothesis, research to identify mutagens or promoting agents at the level of the vessel'wall is feasible. A necessary step in such research will be the use of animal models and biological systems that have a high level of analogy with man and that are credible both in terms of experimentalL atherogenesis and in their exposure to cigarette smoke. 4-18

Conclusions Cigarette smoking has been shown to enhance the prevalence and extent of atherosclerosis of the aorta and coronary arteries in men. Experiments on the effects of nicotine or carbon monoxide on experimental atherogenesis in animals have produced conflicting result's and~ are inconclusive. Chronic inhalation of whole smoke is associated with the development of hyaline thickening of myocardial arterioles in dogs. In man, cigarette smoking is associated with fibrotic and hyaline changes in small arteries and arterioles in the myocardium. t i Myocardiai Infarction The Nature of Myocardial Infarction Heart attack as generally understood can comprise nonfatal or fatal myocardial infarction, cardiac arrest or asystole, and cardiac standstill or ventricular fibrillation. Asystole and fibrillation result in sudden~ cardiac death. These conditions are: generally the result of cardiac ischemia which, in turn, is generally attributable to coronary athero- sclerosis, although other conditions may uncommonly precipitate heart attack. Myocardial infarction is that condition in which a volume of heart muscle fibers in~ a discrete part of the heart dies because of inadequate circulation. It is generally larger than 5mm in diameter and may be several centimeters in major diameter. It may vary from a small subendocardiaU portion of the heart to the full thickness of the myocardiali wall. It may, particularly when subendocardial in location, impinge on the conducting system of the heart an& be conducive to disturbances in conduction. The infarction may affect primarily the pumping capacity of the muscle an& lead to acute or chronic circulatory failure. The most common location of infarction involves the left ventricle, but involvement of the right ventricle and atria is common. If the myocardial infarction does not prove to be fatal, it may be subject to local extension during the acute episode of illness. Healing is by scar formatiom The patient is at high risk of a second attack. The association~ between atherosclerosis of the coronary arteries and myoca.rdial infarction is close. Most cases examined at autopsy show an involvement of about 70 percent or more of the surface of the major vessels, an& more than 50 percent stenosis of the lumen with or withoutt recent thrombosis. However, a small minority of cases show less extensive lesions and narrowing, and it has been speculated that these infarctions may have arisen because of vascular spasm, or because of transient vascular occlusion by thrombi that have dissolved after obstructing the coronary circulation. Ischemia of a local mass of heart muscle initiates a complex chain of biochemical, functional, and structural events at the level of the heart muscle: cell that continues to be a subject for intensive research. A 4-19

reduction in arterial blood flow such that cellular oxygen~ demand is not met by oxygen supply causes myocardial cells to shift their metabolism to anaerobic glycolysis and to accumulate lactate and other acidic metabolites: Such acidosis depresses cellular contractility. For reasons that remain to be clarified, cell membranes are damaged by ischemia. Moreover, the mitochondfia are sensitive to ischemia and rapidly lose their ability to synthesize adenosine triphosphate, and are unable to maintain the energy requirements of the cell to live and function. Cell death ensues (65, 137). The organized contraction of the heart is integrated by the sequential spread of an electrical stimulus. Ischemia, with or without overt infarction, can disrupt this integration and alter rhythmic stimulation, causing bradycardia or asystole or,. more commonly, aberrant foci of electrical activity and fibrillation. Hypoxia is not identical with ischemia since hypoxia can occur while the circulation maintains the local concentrations of other ions and substrates. However, the lack of adequate cellular oxygen is so important a part of the events summarized above that the addition of hypoxia to a marginally tolerated ischemia may initiate critical changes. Since the major risk factors can be shown to enhance atherogenesis, it is usually implied that their association with heart attack is through the ischemia resulting from coronary atherosclerosis. However, direct effects upon cardiac function may also play a role. Hypertension increases the work and mass of the heart and creates a larger nutritional demand and relative ischemia. Nicotine releases catechol- amines and transiently increases cardiac rate and! work. Carbon monoxide decreases oxygen availability to the heart. Animal models of acute myocardial infarction include embolism of the coronary arteries, slow or rapid constriction of arteries; intimal sclerosis and narrowing by various techniques and, by dietary cholesterol, atherosclerosis leading to acute or subacute myocardial ischemia and infarctionL These different models can serve different experimental purposes. Each has limited analogy to myocardial infarction in man because infarction in man is itself a pathologically variable phenomenon and~ because of anatomical differences in size and circulation between animal and human hearts. Perhaps the model creating events most like those in man is the nonhuman primatee (particularly M. fascicularis) with advanced dietary atherosclerosis. It is however, a variable one (58). Summary of Epidemiological Data The epidemiological concept of risk factors for myocardial infarction~is based' on data: gathered prospectively or retrospectively about myocar- dial infarction rather than about atherosclerosis per se. As noted in the section~ on atherosclerosis, the data that associate risk factors with humani atherosclerosis seen at post mortem are limited. On the other

hand, there is a very large body of data, suitable for treatment by sophisticated analytical methods, that associates risk factors with myocardial infarction. Usually, the data are treated in terms of fatal infarcts including both sudden and nonsudden (acute)Aeath. However, analyses have dealt with sudden death alone, morbidity, and congestive heart failure in individuals free of detectible heart disease on initial study, individuals with some evidence of disease when first seen, and those experiencing second' heart attacks. Prospective studies of risk factor associations with myocardial infarction or coronary heart disease (CHD) have identified~a number of clinical descriptors strongly associated with liability to future infarc- tion. These descriptors include age, male sex relative to female sex before age 65, blood cholesterol level, arterial blood pressure, and cigarette smoking. Other associations have also been documented, including, the "Type A personality," diabetes mellitus, obesity, blood uric acid, the use of oral contraceptives, hematocrit reading, evidence of coronary heart disease : or other atherosclerotic disease, vital' capacity, family history, and physical inactivity: Recently high density lipoprotein (HDL): has been shown to be apparently protective against myocardial' infarction (49, 92). Reports dealing with risk factors, particularly smoking, but in many studies with other risk factors as well, have been extensively tabulated in the 1976 reference edition of The Health Consequences of Smoking. (138) (Tables 1-4, pp. 19-31, Tables 9-14, pp. 38-41; Table A6, pp. 89-93; Tables A17-A18; pp. 101-102). The tables of the prospective studies of CHD mortality (Table 2, pp. 22-25) and morbidity (Table 4, pp. 26-31) are reproduced' below as Tablles 2 and 3. The major risk factors of blood cholesterol level, blood pressure,, and cigarette smoking, are indepen- dent and strong predictors of susceptibility to CHD. Each is dose- relate& to the liability to CHD, and each of about the same importance when considered independently. Cessation of smoking and reduction: of high blood pressure will reduce the risks of cardiovascular disease. As summarized in Tables 15 and 16 on page 42 of the 1976 report (138) (and reproduced below as Tables 4 and 5); it has been found that ex- smokers suffer fewer myocaridal infarctions than continuing smokers. With reduced blood pressure it has been shown that less cerebrovascu- lar disease: and congestive heart failure occur. The effect of reducingg blood cholesterol on liability to CHD remains under study. Identified' risk factors account for a major part but not all of the variance in CHD among a population. Cigarette smoking is an important risk factor, but it is not essential, nor is it, in those parts of the world~ in which people have levels of cholesterol in the range of about 160 mg percent, as strong a risk factor as in the United States: It has been reported from a follow-up study of about 265,000 adults over 40 years old in Japani (99) that smokers compared with nonsmokers have a relative mortality ratio of 1.22 for death from all causes and 4-21

TABLE 2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual number of deaths shown in parentheses)i [SM = Smokers NS = Nonsmokers] Author, Numlwr and Follow. Numla•r praq tvlw of Uata up of Cip,aretta/duy Cigan, pipe cuunlry . IVulalion colkMion (yean) deatha Hummom{ I87'93 Quv9lion- 31/2 5,297 NS ...... l.00 (709) Cipars end white malp '(p<OWI) naire and All smoken 1.7U (376q NS LW .. NS Horn, n 9 rtate~s follow-up <10 129 (192) SM . 179 (420) All snaken I958, 50 69 yean of dcath 10 20 189 (i1fi1) pipa <10 . _.. CSA if ag,, o•rtlHcate 20 40 ...... 220 (604) NS .. 1.00 10 20 ....... >40 ....... 241 (118) SM . 1.03 (312) >d1 ........ Bnyle 2,7R2 mal., 17clall d 10 93 NS ........ 1.00 (2)) et ul.. Fram- nadcal All smokera 240 (73) 964, ngham, raamina- <20 . 2W (17) C.S A. 30 62 years lxm and 20 ......... 1.70 1201 of age. follow-up. R >20 ....... 3.50 (361 1,913 mal e, Alhany, 39 .55 yean of aRe: Age variation 50-54 5559 6064 6569 LW (90) 1.00 Q42) LW (201) LW (Z73) 1.93 (765) 1.N5 (962) 1E6 (921) 1.41 (713) 1.39 (35) 1.38 (50) 1.17 (49) 127 (5H) 2W (213) 204 (24S) 1.91 I2:65) 15f1 (IiN) 2.51 IAii) 2.47 (199) 1.92(18) 1.56 (73) Doll and Approxi- Qu.tion- 10 1,376 NS ........ 100 3544 4Sb4 65A1 Hill, makdy nalm and All amoken )85 NS ......... 100 I.W 100 1961, 41,000 follow-up 1 14 ....... 129 114 ........ 3.73 1.40 1.71 Gmat malc Bntlah of dcath 15-24 ...... 127 15-24 ....... 445 1.73 IT Britam physi<ixn,. certifi<ate. >29 1.43 >25 ........ 136 192 158 0344~~;9co Data aPPlg only to malen aRr.rl 40 49 and fm of t'HD at entry. NS inelude pipc, cigar and u -nkem

TABLE 2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual number of deaths shown in parentheses)' [SM = Smokers NS = Nonsmokers] -Continued Authur, tiumlxr zn,t E'~~Ikrv:- Numt- ycnr, tylx~ nf [)aln up of CIgaretlestday Cigan, pilry Age vxriation Commrnl muntpIxgrulation callrrtion (yean) Jeaths Strolx•I and Gx•II 1965 Swit.r-_ IanA 3,749 malc Suixv phy- >iciani- Quivtlnn- naire and follaw-uy of death n~rtificutc. 9 162 NS ........ 120 ....... >_20 .....,. 1.00 1.48 1.76 NS SM 1.00 1.45 Be+t, Appro.i- Qmslinn- 6 2,0110 NS ........ 100 Cip,urs 1966 ('anada mal<•ly 78,(q0 nain~ and follow-up All smoken G10 1.60 (13N0) 1.55 (207) NS _ SM . 100 0.98 (16) male Cana_- of dcath 10-20 1.5A (766) Fipa dien vetcrane. mrtificate. >20 ....,.. 178 ('277) NS .. SM . 190 0.96 (95) Hahn 0.5. mplc Quextion- 8 I(2 10.990 NS ,.,.... . 100 12997) Cigan 1966 vcleran. neim and All smokers 174 14160) NS .. E 00 l:.S.A. 2,265,674 fallow-up 19 ..... 1.39(4J9) SM . 1.04 (623) ~ I.•rum of Aenth 10-20 ...... 1.78/2102) Npen yean. cecliGeate.. 21 39 1.64 (1212) NS .. 100 >39 .....,. 200 (266) SM . 1.08 (366) t~; t.+!: :~9C 0 30J9 fAl-69 70 and over NS ....,._. 1110 Idp 100 <10 0.97 (18) 1.56 (221)) 171 (99) 10-20 1.45111.5) 1.67(W) 1.29 (941 >20 ......., 185 5 (6,5) 1.76 (1134) 1.73 (28) . . .

I ~ TABLE 2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual number of deaths shown in parentheses)1 [SM = Smokers NS = Nonsmokers]-Continued Author, Numler and Follow- NumG:r year,- tgpe of Data up of Cil;areltes!day Cigsrs, pip. Age vadation C mmenU eountry pnpulation rnllection (yean) deaths - Hinyama, 265,118 . Tnined in- 1 91 NS ...... _ 1.00 (17) Prelimin- 1%7, Japanese terviewen 124 ....... 113 (69) . ery report. J.p.n adults over and follow- - >25 ....... I W_ (5_1 . age 100 up of death certifirate. Kannel 5,127 males :Nediral ex- 12 52 NS _...... 1.00 (27) et al., and femalee _ Inatinn SM >20 ... 220125) 19NL aRc 30.59. and G.S.A. follow-up. (p<9,o5) Hammond 358,534 Qutstinn- 6 1019 Males Fumalts Males tH asal on and malee rrgimand NS 100, 190 4039 5"9 6_0-89 7079 59deaths. Carfinkel, 445,875 follow-up 19 ........ 1.27 084 NS .....,... 1.00 1.00 1,00 L00 1969. lemnlea of dealh 10 19 .,.... 160 1.72 1 9 ....._.. 160 1.59 1.48 1.14 C.S.A. aC,r40-79 rerti0catr. 20-30...... 173 1.52 1a19.__.. 259 213 1.52 1,41 at entry. >40 .,..... 177 0.61 31-•'i0 ....... 3.76 2.40 1.91 149 >40 ,...,... 5.51 2.79 1.79 147 Femalea IAO 1.00 1.00 100 1-9 ......... 131 1.15 1.04 0.76 10-19....... 20R 2.37 ~ 1.79 098 'LQ.30....... 8.62 2.6R 2.08 127 >40........ t3.31 3.73 t2.02 zs~c-s9ca ,

I.M TABLE .2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual number of deaths shown in parentheses)1 [SM - Smokers NS = Nonsmokers]-Continued Awhoq ?iumlar and Fnllnu. Vuml.•r _.. , tp{.• of Ilata up of fiqamt0.s day CiRan, pqxr Ag, rariation Commenls muntry Ixtpulation mllcctinn (r.an) dtatha Paffenhzr50,OOll male B. line 17 51 1,146 15 ........ 1.011 30-04 ~t5-54 Sa-69 ~tvand former ten~iew: (PGOFlII matched SM _.__ I.i0/~l NS 100 LOO l.W K'in4 etudenL, xnd exam. eith (PF6611 1969 ination aml 2292 SM 190 (A4) 1.60 (161) 1.20 (134) L'S.A folInw-aP mntrok 6c Acath n•rlificate. - Pe[tentwr- 3,268 male Imtixl multi- 16 291 1:S and <2U 1A0(1871 (1 <601) Qcr ct el., Innphqrq- pha.ric SM >20 ... 2(1H f1541 - 1970, men 35 64 +ttea•ning ~- GS.A vvan of aml follow- agc. up of dcath crrtifieata•. Taylnr 2,571 male Inti-iewa 5 46 M1S ........ IAO (4) Uata apply et al., railn>ad and n•gula_r <20 .. .. 1.9i (Y()) . only tu 1970• emPloyeen fnllo-p >20 --360 (7l1 t4oie free L•.S.A. 40 59 )ean crim- - of CHD . uf age at ination. . . at entry entry. C~_IllSs9£0

TABLE 2.-Coro>rtary heart disease mortality ratios related to smoking-prospective studies. (Actual number of deaths shown in parentheses)1 [SM = Smokers NS = Nonsmokers]-Continued Author, Number and Follow- Number year, type of Data up of Cigaretten/day Cigsrs, pip. Age varietion Commenta muntry population mlleetinn (yeara) deaUm --- Weir and 68,163 Calif. Qumtion• 5~ 1,718 NS ........ 1.00 3SJ4 /.551 55-U 6569 NS includee Dune, forni. m.le naire .nd AII smokers 160 NS ......... 100 100 1,00 1.00 pp. and 1970, workera tollow.up 210 ....... 139 210........ 472 2.05 141 1.17 cigarn. U.S.A. 36u yean of death 220 ....... 1.67 !20 ........ 6.14 3.17 164 1.26 SM includes of age at certifiatc >30 ....... 1.74 ±30 ........ &57 3.33 1,66 1.36 e:amuken. entry. >40 ........ 793 3.15 1.42 1.42 All ......... 6.24 295 1.56 124 A Pooling 7,427 white Medinl ez- 10 29 NS ........ 1.00 (27) 1.00 (2T) PrnJeet, nulea amination <LO ....... 1.65 (34) 1.20 (24) American 30.59 yeux and 20 ......,., 1.70 (66) Heart ol age at follow-up. >20 ....... 3.00 (68) Aaocu- tion, 1970, entry. U.S.A. 'Unieee othervri.e epaeified, diqparltiee between the total number of deathe and the .um of the individual emoking eategoeen are due to the exclueion of either ueueional, mieeellnneorra, mixed, or ex- .. .moken. a"p" values apecified only for thoee provided by.uthon. SOURCE: U.S. Public Health Service (138). V_ItIS;y9C0

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