CHAPTER 1 Cardiovascular Diseases Contents Page Introduction_---__-_--------------~--------------------- Coronary Heart Disease Epidemiological Studies 3 Smoking and Certain Risk Factors- _ _ _ _ _ _ _ _ _ _ _ __ _ _ BloodLipids_-__-____--_--___________-_______--- Electrocardiogram_----.- ____ ---__--_ _-__ - -___--- Experimental Studies 4 11 12 CigaretteSmoke---------- _____ -__- ___________-_ 13 Nicotine-.. _______ -_-- _____ ---_---- _-_- ---- __--__ 15 CarbonMonoxide_--_---___--------------------- 17 Smoking and Thrombosis-- _ _ _ - _ - - _ _ _ _ _ _ _ _ _ _ _ _ _ _ - - 19 Cerebrovascular Disease------- ______ --_----__-__----- ____ 19 PeripheralVascular Disease-..-- ______ ---_---_--_-__--- ____ 19 Summary of Recent Cardiovascular Findings------....------- 23 References ______ -----_-__-_- ______ -_-_- _____ --_-----___ 24 List of Figures Figure I.-Age-adjusted incidence rates of CHD by body weight and cigarette smoking (white males) ____ __ _ _ __ _ _- - - Figure 2.-Age-adjusted incidence rates of CHD comparing farmers who smoke cigarettes with nonsmoking farmers- - - - Figure 3.Atandardized mortality ratios for arteriosclerotic heart disease for males and females by age at initiation of rigarette smoking (Prospective study 1966-1970) - - - - - - - - - l%ure 4.-The effect of cigarette smoke inhalation on the ven- tricular fibrillation threshold (VFT) of normal dogs and dogs \rith experimentally produced acute myocardial infarction `~?lII)-..-__________---____-_-_--__----_--F_----_------ l$ure 5.-Eff ec s t of smoking five consecutive cigarettes on Pkrla nicotine concentration-------_-- -_-_---------- --- piFXre 6.-Relative risk of developing arteriosclerosis oblit- (`rans (ASO) for males by amount of cigarettes smoked- - - l'%Wre 7.-Relative risk of developing arteriosclerosis oblit- prws (ASO) for females by amount of cigarettes smoked--- 6 7 8 14 16 20 21 1 Introduction In the United States, coronary heart disease (CHD) is the leading cause of death and is the largest contributor to excess deaths among cigarette smokers. The following is a brief summary of the major relationship between smoking and cardiovascular diseases as outlined in previous reports of the health consequences of smoking (62, 63, l;& 65,66,67). Many prospective and retrospective epidemiological studies have identified cigarette smoking, elevated serum cholesterol, and high blood pressure as major risk factors for t,he development of coronary heart disease. Cigarette smoking acts independently of and synergis- tically with the other CHD risk factors to greatly increase the risk of developing coronary heart disease, The risk of developing CHD for pipe and cigar smokers is much less than it is for cigarette smokers, but more than it is for nonsmokers. In the United States, cigarette smoking can be considered the major cause of car pulmonale since it is the most important cause of chronic nonneoplast.ic bronchopulmonary disease. dutopsy studies have demonstrated that aortic and coronary athero- sclerosis are more common and severe, and myocardial arteriole wall thickness is greate.r, in cigarette smokers t,han in nonsmokers. Those who stop smoking cigarettes experience a decrea.sed risk of d&h from coronary heart disease compared to that of continuing smokers. Experimental studies in humans and animals suggest that cigarette sllloking may contribute to the development of CHD through the :l(`tion of several independent ok complementary mechanisms : The folmation of significant levels of carboxyhemoglobin, the release of "@cholamines, inadequate myocardial oxygenation which may result from a number of mechanisms, and an increase in platelet adhesiveness \vllich may contribute to acute thrombus formation. There is evidence th;lt cigarette smoking may accelerate the pathophysiological changes "f I'reexisting coronary heart, disease and therefore contributes to *II&n death from CHD. liecently published epidemiological, autopsy, and experimental in- "`%ations have added to the understanding of the association be- t'\-& smoking and cardiovascular diseases. 495-028 O-73-2 3 Coronary Heart Disease Epidemio2ogicaZ Studies SXOKING AND CERTAIN RISK FACTORS A prospective epidemiological study of the factors associated with cardiovascular diseases was conclucted among the 4,847 white and 2,434 black men and women of Evans County, Ga. ($8). The investigation was initiated with a private census and preliminary examinations beginning in 1960. Followup examinations were conducted after 7 years. Cassel (23) reported that high blood pressure, elevated serum cholesterol, and cigarette smoking were major risk factors for the development of coronary heart disease. Increased body weight, an elevated hematocrit, and ECG abnormalities were additional fact,ors that were associated with elevated CHD rates. A significant finding of this study was the very low prevalence and incidence of coronary heart disease (myocardial infarction and angina pectoris) in black men. The age-adjusted prevalence rates among black men were only half those of white men. The study showed that blacks were affected by the various risk factors for CHD in a similar fashion to whites but at a lower level of disease. This appeared to be true for any level of any risk factor or any combination of risk factors. Greater physical activity of blacks as compared to whites appeared to account for part of the observed dif- ference in rates. In this study, subjects were classified on the basis of their smoking history at enrollment and both current smokers and exsmokers were considered smokers. Both black and white male smokers had a higher incidence of CHD than did nonsmokers, but white males had a higher incidence than blacks whether they were smokers or not. The age- adjusted incidence rate for white nonsmokers was 52.7 per thousand compared to 9.8 per thousand for black nonsmokers. White smokers had an incidence of 101, whereas the rate in black smokers was only 3G. The prevalence of CHD increased with the number of cigarettes smoked per day in both groups. The combined effect of body weight and cigarette smoking on t.he incidence of CHD was also examined (~3;). The "Quetelet index" 1 \yas used to determine relative weight. The risk of developing CHD did not change with increases in relative we.ight among nonsmokers, but smokers experienced a substantial risk of developing CHD with increases in weight (fig. 1). The relabionship of smoking to occupat,ion and CHD was examined I 1-i). Farmers who performed sustained physical activity had lower Mes of CHD than nonfarmers. Figure 2 shows that, while smoking inc*reased the risk of CHD in bot.h farmers and nonfarmers, farmers ha.d lower rates than nonfarmers whether or not they smoked. weight ' W?telet index= - height ,x1oo' Figure 1 .-Age-adjusted incidence rates of CHD by ' body weight and 1 cigarette smoking (white males). 160 , 1 Nonsmoker 140 ' Smoker 120 - 110 - 100 - 90 - ' Rate 80 - m'ales lP& 70 - 60. 50- 40. 30 - 20 - 10 - 0 ' Distribution by weight 80 Lower third (lean) Number 90 183 99 161 127 119 Cases 5 15 3 14 16 9 1 Smokers excluding ex-smokers. `67 months follow-up period. I Based on Quetelet index. SOURCE: Heyden, S., et al. (26). 6 Figure 2.-Age-adjusted incidence rates of CHD comparing farmers who smoke cigarettes with nonsmoking farmers. Farmers 100 Rate per 1,000 males 50 0 Cases . . . . (8) (9) Nonsmokers Nonfarmers El 158.2 (11) (39) Smokers and Ex-smokers SOURCE Cassei. J. C., et al. (18. Hirayama (27) reported 5-year followup data on smoking in &a- tion to death rates from a large prospective epidemiological study of %,118 men and women in Japan. This investigation was the first of its kind to be conducted in an Asian population. During the followup Period, 11,858 deaths occurred during 1,269,382 person years of obser- Wion. Male and female cigarette smokers experienced higher mor- tnlitv rates from arteriosclerotic heart disease than did nonsmokers. .\nlong cigarette smokers, the mortality ratios for arteriosclerotic heart ~hise were 1.56 (PO(liurn pentobarbital, and respiration was maintained using a Harvard V~`l~tilator attached to an endotracheal tube. In one group the electrical iInl)ulses used to precipitate ventricular fibrillation were delivered tllrough the chest wall, and in another group the impulses were deliv- `~4 directly to the heart through electrodes implanted in the myo- Qrcliurn. The experimental group of dogs were exposed to the smoke `)f three cigarettes over a IO-minute period. Each cigarette contained :`lWosimately 2 mg. of nicotine. With acute myocardial infarction, the "VT was significantly (P of sudden death observed among coronarv patients who are `l";lVY cigarette smokers (65). Y 13 Figure 4.The effect of cigarette smoke inhalation on the ventricular fibrillation threshold (VFT) of normal dogs and dogs with experimentally pro. duced acute myocardial infarction (Ahll). 0.8 r 0.6 t t o ? o ?? =. `* %. smoking (normal) . . . . . . . - . . . . . . . *I-.- 0 15 30 45 60 75 90 Time in minutes following cigarette smoking SOURCE: Bellet, S.. et al. (6). The effects of passively inhaled cigarette smoke on several measure of cardiovascular function in treadmill-exercised dogs were examined by Reece and Ball (52). The experimental dogs were trained on the treadmill for approximately 1 year before exposure to cigarette smoke began. Each dog was passively exposed to the smoke of 36 cigarettas over a 3-hour period 5 days a lveek in a 2.2 m.3 chamber ventilated at the rate of seven exchanges per hour. The dogs were exposed to this cigarette smoke and were continued on their exercise program for an additional year. Exposure to cigarette smoke was associated with cadiac enlargement, ST segment depression, and an increase in post- exercise serum lactate concentrations. 14 Studies in Man Isaac and Rand (98) have recently described a method for the assay If plasma nicotine. An alkali flame ionization detector was used with a !a.+liquid chromatograph. The test is sensitive to 1 ng./ml. of nicotine In a 2.5 ml. sample ; 30 minutes elapsed between end of one cigarette md start of next. Blood samples were taken before smoking and at 5, 10, and 30 minutes after the last puff of each cigarette. Plasma nicotine lrvels increased rapidly during cigarette smoking (fig. 5). The post- making decay curve consisted of two components: an initial rapid I)hase which may be due to the uptake of nicotine from the blood by various tissues, and a slower phase which may represent metabolism :md excretion of nicotine. Some accumulation of plasma. nicotine 00 rarred during a day of smoking, but the background level never ap- proached the peaks attained during and immediately following active L8igarette smoking. The rate of elimination was rapid enough to prevent :Iny appreciable accumulation of nicotine from 1 day to the next. The dWelopment of sensitive tests of plasma nicotine levels will allow a greater understanding of various dynamics of smoking. Inhalation Patterns can be objectively measured, and the role of nicotine in habituation to cigarettes can be evaluated. 15 Figure 5.-Effects of smoking five consecutive cigarettes on plasma rhOtin@ concentration. 60 50 Plasma nicotine 40 (w/ml.) 30 20 10 0 Smoking period . . . . 0 1 2 3 Time (hours) 4 5 SOURCE: Isaac, P. F., Rand, M. J. (28). Studies in Animals The effect. of nicotine on regional blood flow in the canine heart w&s exan1ine.d by Mathes and Rival (42). The effects of nicotine were examined in normal hearts and after partial coronary artery occlusion. I-rider normal circumstances, as well as after infusion of nicotine in normal hearts, the subendocardial portion of the myocardium had II !I..`-percent greater capillary flow than the subepicardial fraction. Partial ligation of the coronary arteries resulted in a 22.Cpercent reduction in left ventricular blood flow ; however, the subendocardial portion remained X.6 percent higher than in the epicardium. After 16 coicnary artery ligation, an infusion of nicot.ine resulted in a signifi- cast (Pi'l~cl to have AS0 if both the dorsalis pedis and posterior tibia1 !"I~w were absent in one lower extremity and the examining physician `Il:l(l~ :I diagnosis of XSO. Patients we.re asked the age of init,iation `If sMiing; the daily number of cigarettes smoked: the amounts .`liC)k~~d at ages 30. 50, and 70; the age at which they stopped smoking; 455--028 O-73-~ 19 and, for males, whether they smoked cigars or a pipe, A total of 214 male cases, 206 male controls, 390 female cases, and 913 female controls were studied. The control group was composed of patients with peripheral vascular problems other than aSO but who had dorsalis pedis pulses present on initial examination. In each age and sex group, cigarette smoking was more prevalent among cases than controls. In both sexes, risks were high for smokers of less than one pack a day, and increased with the amount smoked (figs. 6 and 7). It was esti. mated that 70 percent of nondiabetic AS0 in the United States is related to the use of cigarettes. Diabetes mellitus is a major risk factor for the development of AS0 ; however, cigarette smoking appeared to act independently of diabetes. Figure 6 .-Relative risk of developing arteriosclerosis obliterans (ASO) for males by amount of cigarettes smoked. 15.0 10.0 Cases 18 21 33 69 Controls 53 15 26 37 Amount smoked Non- smoker 1 pack day SOURCE: Weiss, N. S. (73). 20 Figure 7 .-Relative risk of developing arteriosclerosis obliterans (ASO) for females by amount of cigarettes smoked. 1 Fernal& 15.6 cases Controls Amount smoked 79 50 60 41 429 83 69 33 NOW 1 pack smoker day SOURCE: Weiss, N. S. (731. Preuss, et al. (-50) examined the relationship between several factors including cigarette smoking, blood pressure, weight, and history of diabetes and the development of occlusive disease of the peripheral arteries in a population of 300 patients in Germany. Group I consisted of 150 patients with a mean age of 59 years who had intermittent claudication. Most of these patients were ambulatory. The 150 patients in group II had a mean age of 60 years and had far advanced periph- eral arteriosclerosis with ischemic pain at rest or evidence of gangrene. There was no control group of patients free of vascular disease. There Wre few nonsmokers in either group of patients, but. the group with 21 the more severe disease had a higher average daily consumption of cigarettes t'han did group I. The influence of cigarette smoking on late occlusion of aortofemoral bypass grafts was examined by Wray, et al. (75). A series of 100 patients who had aortic reconstruction for aneurysmal or aurtoiliac occlusive disease between 1965 and 1968 were studied. Of the patients who had bypass grafts for occlusive disease, 30 patients smoked ciga- rettes and 16 did not. 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Sota II: Incidenza in rapport0 all'abitudine al fumo e all'alcool. (On the incidence of cardiovascular disease among the workers of the mining industry of Sardinia. Second communication : Incidence in relation to habitual smoking and consumption of alcohol.) Rassegna - *edi? Sarda 71( Supplement 1) : lQl-200,1968. m>J. C. Summary of major flndings of the Evans County cardlo vascular studies. Archives of Internal Medicine 128(6) : 887-339, De cember 1971. 24 (14) OASSU, J. C., HEYDEN, S., Baarxr., A. G., KAPLAN, B. H., Txaom!x%, H. A., COBNONI, J. C., HAMES, C. G. Occupation and physical activity and coro- nary heart disease. archives of Internal Medicine 123(6) : !%?&%X$ De- cember 1971. (15) CIAMPOLINI, E., DBINBOLI, R., RAVAIOLI, P. Azione de1 fumo di sigarette su aleuni parametrl de1 ricambio lipidico. (Action of cigarette smoking on several parameters of lipid metabolism.) Atti dell'Accademia dei Fisiocritici in Siena ; Sesione Medico-Fisica 17 : 47m, 1968. _ ---- (fG~-c'o~s~ocx,~. W. Fatal arteriosclerotic heart disease, water hardness at homeyand socioeconomic characteristics. American Journal of Epidemi- ology 94(l) : l-10, July 1971. (17) E~TANDIA CANO, A., ESQUIVEL A~Iu, J., Jim CAMACHO, II., Fzazz SANTANDER, S., LEON MONTANEZ, E. Infarto juvenil de1 miocardio. (Myo- cardial infarction in the younger age groups.) Archives de1 Instituto de ardiologia de Mexico 41(Z) : 137-150, March-April 1971. (18) FACCHINI, G., SEMEMRO, S., DI BIAS& G., TABARBONI, F., SPA~NOLQ D., BUTORE, A., BONA~ITA, E. Modificazioni nel soggetto anziano della reattivita al fumo di sigaretta : Ricerche sull'equilibrlo emocoagulativo e fibrinolitico e au1 circolo perlferico. (Modifications of the reactivity to cigarette smoke in old subjects: Research on the hemocoagulative and fibrlnolytic equilibrium and on the peripheral circulation.) Giornale di Gemlql lS( 10) : 77f+784,1972. 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