TABLE 2.—Coronary heart disease mortality (Actual number of deaths CSM = Smokers Author, year, Number and Follow- Number country, type of Data up ©: Cigarettes /day reference population collection (years) deaths Hammond = 187,783 Question- 314 5,297 NS ......... 1.00 (709), and white males naire and Allsmokers .1,70 (3361) "{P<9-901) Horn, in 9 states follow-up <10 ........1.29 (192) 1958, 50-69 years of death 10-20 ....1.89 (864) U.S.A. of age. certificate. 20-40 ..... 2.20 (604) (77, 78). >40 ........2.41 (118) Doyle 2,282 males, Detailed 10 93 NS ......... 1.00 (20) etal, Fram- medical Allsmokers .2.40 (73) 1964, ingham, examina- <20 ........2.00 (17) U.S.A. 30-62 years tion and 20 ........1.70 (20) (54). of age. follow-up. 8 >20 ........38.50 (36) 1,913 males, Albany, 39-55 years of age. Doll and Approxi- Question- 10 1,376 NS ........1.00 Hill, mately naire and Allsmokers .1.35 1964, 41,000 follow-up 1-14... £1.29 Great male British of death 15-24 ....1.27 Britain physicians. certificate. >25 «1... 1. 148 (50), Strobel 3,749 male Question- 9 162 NS 1.00 and Gsell Swiss phy- naire and 1965 sicians. follow-up 1-20 .......1.48 Switzer- of death | a 1.76 land certificate. (180). Best, Approxi- Question- 6 2,000 NS ........1,00 1966 mately naire and Allsmokers .1.60 (1380) Canada 78,000 follow-up om 10 ........1.55 (387) (24). male Cana- of death 10-20 ......1.58 (766) dian certificate. 320 oo... eee 1.78 (277) veterans. Kahn U.S. male Question- 8% 10,890 NS ........1.00 (2997) 1966 veterans naire and Allsmokergs .1.74 (4150) U.S.A. 2,265,674 follow-up 1-9 ........1.89 (489) (93). person of death 10-20 ...... 1.78 (2102) years. certificate. 21-39 ......1.84 (1292) >39 Lo... 2.00 (266) Hirayama, 265,118 Trained in- 1 @l1 NS ........ 1.00 (17) 1967, Japanese terviewers 1-24 .......1.138 (69) Japan adults over and follow- 25 ow... 1.00 (5) (84). age 40, up of death certificate. Kannel 5,127 males Medical ex- 12 52 NS o.oo... 1.00 (27) et al., and females amination SM>20 ....2.20 (25) ; mt? 1968, age 30-59. and U.S.A. follow-up. (94). 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 26 ratios related to smoking—prospective studies shown in parentheses )1 NS = Nonsmokers] Cigars, pipes Age variation Comments Cigars 50-54 55~59 60-64 65-69 NS. .1,00 NS -- 1,00 (90) 1.00 (142) 1.00 (204) 1.00 (273) SM. .1.28 (420) Allsmokers .1.93 (765) 1.85 (962) 1.66 (921) 1.41 (718) Pipes <10 --1,38 (35) 1.88 (50) 1.17 (49) 1.27 (58) NS. .1,00 10-20 .......2.00 (213) 2.04 (258) 1.91 (235) 1.58 (158) SM. .1.08 (312) >20 .-2.51 (2038) 2.47 (199) 1.92 (129) 1.56 (73) Data apply only to males aged 40-49 and free of CHD at entry. NS include pipe, cigar and ex-smokers. 35-44 45-64 65-84 NS ......0.. 1.00 1.00 1.00 1-14 20.0... 3.73 1.40 1.71 15-24 2.00... 4.45 1.73 1.27 D265... 1.36 1,92 1.58 NS. .1,00 SM. .1.45 Cigars 30-49 50-69 70 and over NS. .1,00 NS .........1.00 1.00 1.00 SM. .0.98 (16) <10 ........0.97 (18) 1.56 (220) 1.71 (99) Pipes 10-20 - 1.45 (115) 1.67 (557) 1,29 (94) NS. .1,00 >20 --1.85 (65) 1.76 (184) 1.73 (28) SM..0.96 (95) Cigars NS. .1.00 3M. .1.04 (623) Pipes NS. .1.00 3M. .1.08 (886) Prelimin- ary report. * ">" values specified only for those provided by authors. 27 TABLE 2.—Coronary heart disease mortality ratios (Actual number of deaths [SM = Smokerg Author, year, Number and Follow- Number country, type of Data up © Cigarettes /day reference population collection (years) deaths Hammond 358,534 Question- 6 14,819 Males Females and males naire and NS ........ 1,00 1.00 Garfinkel, 445,875 follow-up 1-9 1.27 0.84 1969, females of death 10-19 1.60 1.22 U.S.A. age 40-79 certificate. 20-30 1.73 1.52 (76). at entry. >40 »1.77 0.61 Paffenbar- 50,000 male Baseline 17-51 1,146 NS ~+++1.00 ger and former interview matched 3M .. 1.50 (385) (P<0.01) Wing students. and exam- with 1969 ination and 2,292 U.S.A. follow-up controls (146) by death certificate, Paffenbar- 3,263 male Initial multi- 16 291 NS and <20 1.00 (137) ger et al., longshore- phasic SM >20 ....2.08 (154) (p<0.01) 1970, men 35-64 screening U.S.A, years of and follow- (144). age. up of death certificate. Taylor 2,571 male Interviews 5 46 NS ........1.00 (4) et al., railroad and regular <20 ........1.97 (20) 1970, employees follow-up >20 -. 3,60 (22) U.S.A. 40-59 years exam- (183). of age at ination. entry. Weir and 68,153 Cali- Question- 5-8 1,718 NS ......... 1.00 Dunn, fornia male naire and Allsmokers .1.60 1970, workers follow-up #10 ........1.89 U.S.A. 35-64 years of death +20 we. 1.67 (205). of age at certificate, 230 Le. 1.74 entry. Pooling 7,427 white Medical ex- 10 239 NS .... 2... 1.00 (27) Project, males amination 1G woe. 1.65 (34) American 30-59 years and 20 ........1.70 (86) Heart of age at follow-up. >20 -..3.00 (68) Associa- entry. tion, 1970, U.S.A. (88). 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 28 related to smoking—prospective studies (cont.) shown in parentheses)! NS = Nonsmokers] Cigars, pipes Age variation Comments Males tBased on 4H-49 50-59 60-69 70-79 5-9 deaths. NS . 1.00 1.00 1.00 1.00 1-9 - 1.60 1.59 1.48 1.14 10-19 .......2.59 2.13 1.82 1.41 20-30 . 8.76 2.40 1.91 1.49 >40 - 5.b1 2.79 1.79 1.47 Females NS .........1.00 1.00 1.00 1,00 1-9 ». 1.31 1.15 1.04 0.76 10-19 . 2.08 2.37 1.79 0.98 20-30 .......3.62 2,68 2.08 1.27 >40 .......48.31 3.73 $2.02 _— 3O-44 45-54 55-69 NS . 1.00 1.00 1.00 (p<0.01) SM ......... 1.80 (88) 1.60 (163) 1.20 (184) Data apply only to those free of CHD at entry. 35-44 45-54 55-64 65-69 NS includes NS ......... 1.00 1.00 1.00 1,00 pipes and x10 . 4.22 2.05 1.41 1.17 cigars. +20 . 6.14 317 1.64 1,26 SM includes +30 .....,..8.57 3.33 1.66 1.36 ex-smokers. >40 woe... 7.93 3.15 1.42 1.42 All . 6.24 2,95 1.56 1,24 1.00 (27) 1.20 (24) 29 TABLE 3,—Sudden death from coronary (Mortality ratios—actual number Author year, Number and Data Follow-up Number country, type of collection years oO. reference population deaths Pooling 7,427 white Medical 10 145 Project, males 30-59 examination American Heart years of age and Association, at entry. follow-up. 1970, U.S.A. (88). TABLE 4.—Coronary heart disease (Risk ratios—actual number of CHD {SM = Smokers NS = Nonsmokers PROSPECTIVE STUDIES Author, year, Number and Data Follaw- Number of country, type of collection up incidents Cigarettes/day reference population years Doyle 2,282 males Detailed 10 243 myo- NS ............1.00 (52) etal, Framingham, medical cardia] All smokers ... .2.36(191) 1964, 30-62 years examina- infare- <20 ... eee eee 1.98 (44) U.S.A. of age. tion and tions and 20 .. 2.05 (64) (54). 1,913 males follow-up. CHD >20 - 3.04 (83) Albany, deaths. 39-55 years of age. Stamler 1,329 CHD- Interview 4 46 CHD NS ............1,00 (2) etal., free male and examin- <10 cigarettes. 2.92 (6) 1966, employees of ation with <5 cigars....{° U.S.A. Peoples Gas clinic <5 pipes..... (177), Company follow-up. 10-19 cigarettes.3.67 (8) 40-59 years >20 cigarettes . } 3.83 (29) of age. > 5 cigars.... > 5 pipes..... Epstein, 6,565 male Initial 4 96 male, Males 1967, and female medical 92 female 40-59 U.S.A. residents examina- CHD in- NS seceee 1.00 (1) (61), of Tecumseh, tion and cluding EX ............6.53 (10) Mich. repeat deaths, Cigarettes .....5.20 (36) follow-up angina, and Females examini- myocardial NS -. 1.00 (21) tions. infarctions, EX ............0.89 (3) Cigarettes ..... 1.02 (14) 1 Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 30 laurt disease related to smoking of deaths shown in parentheses ) Cigarettes/day Cigars, pipes Comment Never smoked ...........1.00 (13) 1.00 (15) See_table 1 for description of LO eee e ee eee eee ee 90 (23) 1.86 (13) Pooling Project. BE ccc ccc n veneer eee AGO (50) BD eee ene ee 8,86 (44) morbidity as related to smoking manifestations shown in parentheses)! EX = Ex-smokers] PROSPECTIVE STUDIES—Continued Pipes, cigars Age variation Comments Data include CHD deaths, only on males 40-49 years of age and free of CHD on entry. NS includes pipes, cigars, and ex-smokers. NS includes ex-smokers. Includes all CHD. Males—Continued Males Reexamination 60 and over 40-59 of patients 1.00 (7} SM ....1.80(2) was spread 1,27(41) 60 and over over 114-6-year 1.96 (28) SM... .0.86(6) period, but Femates—Continued data are re- 1.00(47) ported in 1.31 (5) terms of 0.42 (2) 4-year inci- dence rates. Actual number of CHD inci- dents derived from data on incidence and total in smok- ing class, 31 TABLE 4.—Coronary heart disease (Risk ratios—actual number of CHD [SM = Smokers NS = Nonsmokerg PROSPECTIVE STUDIES Author, year, Number and Data Follow- Number of country, type of collection up incidents Cigarettes/day reference population years Jenkins, 3,182 males Initial] 4ly 104 myo- NS weeeee 1.00 (21) etal., 39-59 years medical cardial EX cece ee 2 AT (15) 1968, of age at examina~ infarctions. Current .......2.78 (68) U.S.A. entry. tion and 0-15/day ......41.39 (45) (90). follow-up S16 Lo. e ee 3.08 (59) by repeat examina- tions. Kannel, 5,127 males Medical 12 228 myo- Myocardial Infarction etal., and females examination cardial Males 1968, 30-59 years and fallow- infarc- NS ..........--1.00 (21) U.S.A. of age. up. tions. All SM ........1.51(153) (94). 380 CHD. Heavy SM ....1.85 (59) Risk of CHD (overail} Males NS ............1,00 (61) 1-10 .. 1.34 (25) 11-20 .1.80 (90) >20 ..2.41 (76) Shapiro 110,000 male Baseline med- 3 Total Males et al., and female ical inter- unspeci- NS we... 1.00 1969, enrollees view and fied. All current ....2.14 U.S.A. of Health examination cigarettes (p<(0.01) (172), Insurance and regular <20 ween ee 150 Plan of follow-up. >20 Lees 2.336 Greater >40 wee 6.36 New York (HIP) 35-64 years of age. Keys 9,186 males Interviews. 5 65 deaths. NS, EX 1970 in 5 coun- and regu- 80 myocar- (SM <20) ...1.00(305) Yugo- tries 40-59 lar follow- dial in- All current slavia years of up examina- farctions. (>20) we... 1.31(108) Finland age at entry. tion by 128 angina Italy local pectoris. Nether- physicians. 155 other lands — Greece $428 total. (111). 1Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exelusion of either oceasional, miscellaneous, mixed, or ex-smokers. 32 morbidity as related to smoking (cont.) manifestations shown in parentheses )+ EX = Ex-smokers] PROSPECTIVE STUDIES—Continued Pipes, cigars Age variation Comments tIncludes nen- (p<0.001) 39-49 50-59 smokers and NS......1.00 (4) 1.00 (6) ex-smokers. (p<0.001) Current 4.23(35) 2.26(33) NS includes (comparing former pipe 0-15 and 16+) and cigar smokers. Myocardial infarction—Continued Females 1.00 (31) 1.71 (23) Risk of CHD (overall) —Continued Females 1.00 (89) 0.86 (18) 1.29 (18) 0.93 (3) Females Males only Males Females Total myo- 1.00 NS 165-100 85-44 45-54 55-64 35-44 45-54 55-64 cardial in- 2.00 SM ......1.82 1.00 1.00 1.00 1.00 1.00 1.00 farction in- (p>0.01) (p<0.01) 2.47 3.06 1.69 2.25 2.87 1,80 eludes those 0.52 2.15 1.32 dead within M7 3.04 3.29 aie 125° 2.81 165 je hours. 5.92 10.09 7.69 5.30 20.25 11.79 4.07 NS include ex-smokers. Includes all CHD incidence including EKG diagnoses. Covers all countries in- vestigated except U.S.A. t Difference between total CHD and the sum of smoking groups is due to difference in figures presented by authors. 33 TABLE 4.—-Coronary heart disease (Risk ratios—actual number of CHD {SM = Smokers NS = Nonsmokerg PROSPECTIVE STUDIES Author, year, Number and Data Follow- Number of country, type of collection up incidents Cigarettes/day reference population years Taylor, 2,571 male Interviews 5 46 deaths. NS and EX ....1.00 (62) et al. railroad and regu- 33 myocar- All} current ....1.77(150) 1970 employees lar follow- dial-in- U.S.A. 40-59 up examina- farctions. (183). years of tion. 78 angina age at pectoris. entry. 55 other CHD, 212 total. Dayton 422 male U.S. Interviews upto8 27 sudden <10 .+ 1.00 (25) et al., veterans par- and routine deaths. 10-20 ~-1.04 (22) 1970, ticipating as follow-up 44 definite >20 .1.17 (18) U.S.A. controls ina examina- myocardial (48,49). clinical trial of tions, infarctions. a diet high in unsatu- rated fat. Dunn 13,148 male Data only up to14 Total un- et al., patients in on new specified. 1970 periodic health incidents U.S.A. examination extracted (55). clinics. from clinic records. Pooling 7,427 white Medical 10 538 Project, males 30-59 examination includes Never smoked ..1,00 (53} American years of and follow- fatal and <10 .-1.65 (72) Heart age at entry. up. nonfatal 20 «2.08 (205) Association myocardial >20 . 8.28 (154) 1970, infarction U.S.A. and sudden (88). death. Pauletal., 1,989 Western Screening 1963, Electric Co. examinazion Coronary US.A. male workers and cases (87) (148). participating history. NS oo... eee 23 in a prospec- 7 Lee eee 2 tive study 8-12 9 for 444 years. 13-17 6 18-22 ........, AT 23-27 3 >28 9 1Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 34 morbidity as related to smoking (cont.) manifestations shown in parentheses)! EX = Ex-smokers] PROSPECTIVE STUDIES—Continued Pipes, cigars Age variation Comments All CHD including EKG diagnoses. No data on NS asa separate group. 30-89 40-49 50-59 + Includes tLow NS, EX, and SM 1.00(25) =1.00(125) 1,00(157) <20 cigarettes/ tHigh day. SM 2.17(¢10) 0.90 (81) 1.41 (53) } >20 ciga- rettes/day. Includes all CHD but excludes death, No data avail- able comparing smokers and nonsmokers. 1.00 (53) 1.25 (54) Noncoronary 88 developed controls clinical (1,786) coronary 33 disease, q 47 angina 11 pectoris, 12 28 myocardial 30 infarction, ; 13 deaths CHD. (p<0.005) 35 studies have shown an increased risk of this manifestation among smokers, others have not (see table 5). From these longitudinal studies, it has become increasingly clear that cigarette smoking is one of several risk factors for CHD and that it exerts both an independent effect and an effect in conjunc- tion with the other risk factors. The basic concept may be ex- pressed as follows: The more risk factors a given individual has, the greater the chance of his developing CHD. The importance of the constellation of coronary risk factors which include cigarette smoking, high blood pressure, and high serum cholesterol in pre- dicting the risk for CHD is illustrated in figures 1 through 3. Other risk factors are included in certain of these figures and are dis- cussed below. Knowledge of the effects of cigarette smoke on the cardiovascu- lar system has developed concurrently with the knowledge derived from the epidemiological studies. Nicotine, as well as cigarette smoke, has been shown to increase heart rate, stroke volume, and blood pressure, all most probably secondary to the promotion of catecholamine release from the adrenal gland and other chromaffin tissue. This release of catecholamines is also considered to be the cause of the rise in serum free fatty acids observed upon the in- halation of cigarette smoke. Studies concerning the effect of nico- tine on cardiac rhythm have also suggested that smoking might contribute to sudden death from ventricular fibrillation. In addition, research efforts have also been directed toward the effects of smoking on blood clotting and thrombosis; since many cases of sudden death and myocardial infarction are associated with thrombosis in a diseased coronary artery branch. Cigarette smoking may be associated with increased platelet aggregation in vitro and thus might play a role in the development of such throm- bi or platelet plugs in vivo. Other mechanisms have been investigated. Because cigarette smoking has been shown in some studies to be related to the prev- alence of angina pectoris as well as to the incidence of myocardial infarction, it has been suggested that smoking enhances the de- velopment of atherosclerotic lesions. Autopsy and experimental studies have shown that cigarette smoking plays a role in athero- genesis. The administration of nicotine has been observed to in- crease the severity of cholesterol-induced atherosclerotic lesions in experimental animals. Attention is presently being given to carbon monoxide, which is present in cigarette smoke in such concentra- tions as to cause carboxyhemoglobin concentrations in the blood of smokers as high as 10 percent. Based on research in animals, it is reasonable to conclude that the atherosclerotic process may be enhanced, in part, by the relative arterial hypoxemia in cigarette 36 Ze AuLnor, year, Number and Data Follow-up Number Cigars country, type of collection years of Cigarettes/day and pipes Age variation Comments reference population incidents Doyle 2,282 males, Detailed 10 81 NS . -1.00(30) NS include ex- et al., Framingham, medical All .........-.... -1.09 (51) smokers and 1964, 30-62 years examination <20 . 1,17 (15) pipe and U.S.A. of age. and 20... .. 0.99(18) cigar (54). 1,913 males, follow-up. 8 >20 vee eee eee ee AL15 (18) smokers. Albany, 39-55 years of age. Jenkins 3,182 males Initial medical 414 29 NS ......... ..1.00 (9) NS include et al., aged 39-59 examination All current former pipe 1968, at entry. and follow- cigarettes ..1.44(16) and cigar U.S.A. up by repeat >16 .. 1.63 (14) smokers. (90). examina- tion. Kannel 5,127 males Medical 12 107 Males et al., and females examination 1S 1.00(16) U.S.A, years of age and follow- Heavy SM, >20 (94). 30-59 up. cigarettes ........2.04(17) Femates NS oo. e eee ee «1,00 (58) Cigarette SM ......0.65(16) Shapiro 110,000 male Baseline 3 Total Males Females Males Males T(p<0.01) et al., and female medical Unspec- NS wee 100 1.00 NS,..1,00 35-44 45-54 55-64 F(p<0.05) 1969, enrollees of interview ified Current SM. .$1.71 NS weeee e100 1.00 1.00 NS include U.S.A. New York City and examina. cigarettes 11,91 1.20 Current cigarettes ..3.40 1.57 2.06 ex-smokers. (172). HIP 35-64 tion and <40 steee -1.51) 1.20 <40 «22.35 1.40 1.54 years of age. regular >40 . 4.85 § . >40 . 1015 2.58 6.15 follow-up. Females NS . «1.00 1.00 1.00 Current cigarettes ..1.56 1.67 0.97 <40 os . 167 1.53 1.04 DAD cee eee ee — 4,12 _ 1 Unless otherwise specified, disparities between the total number of manifestations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. smokers caused by the increased carboxyhemoglobin level. With respect to the acute event of myocardial infarction, atten- tion has been focused on the role of nicotine. Nicotine stimulates the myocardium, increasing its oxygen demand. Other experiments have demonstrated that in the face of diminished coronary flow (due to partial occlusion from severe atherosclerosis in man or to partial mechanical obstruction in the animal), nicotine does not lead to an increase in coronary blood flow as seen in the normal individual. These effects exaggerate the oxygen deficit when the supply of oxygen has already been decreased by the presence of carboxyhemoglobin. Thus, a marked imbalance between oxygen demand (which has been increased) and oxygen supply (which has been decreased) is created by the inhalation of CO and nico- tine. This imbalance may contribute to acute coronary insufficiency and myocardial infarction. EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in various countries in order to iden- tify the risk factors associated with the development of coronary heart disease (CHD). Many of these studies have included smok- ing as one of the variables investigated. Tables 2 to 4 present the major findings. CORONARY HEART DISEASE MORTALITY Table 2 lists the various prospective studies concerning the rela- tion of CHD mortality and smoking. These studies demonstrate the dose-related effect of cigarette smoking on the risk of developing CHD. For example, the Dorn Study of U.S. Veterans as reported by Kahn (93) reveals progressively increasing mortality ratios, from 1.39 for those smoking 1 to 9 cigarettes per day to 2.00 for those smoking more than 39 cigarettes per day. Although the data are not detailed in the accompanying tables, several of these stud- ies have also shown that increased rates of CHD mortality are associated with increased cigarette dosage, as measured by the degree of inhalation and the age at which smoking began. Although not as striking, the data for females reveal the same trends. In most studies, the smokers’ increased risk of dying from CHD appears to be limited mainly to those who smoke cigarettes, Some studies that have investigated other forms of smoking have shown much smaller increases in risk for pipe and cigar smokers when compared to nonsmokers. However, the recent study by Shapiro, et al. (172) of a large population enrolled in the Health Insurance Plan (HIP) of New York City showed a significantly increased 38 risk for the development of myocardial infarction and rapidly fatal myocardial infarction for a group consisting of both pipe and cigar smokers. Table 3 details the findings of the American Heart Association Pooling Project on sudden death. The Pooling Project, a national cooperative project of the AHA Council on Epidemiology, is de- scribed in table 1 (88). Cigarette smokers in the 30 to 59 year age group incurred a risk of sudden death from CHD substantially greater than that of nonsmokers. Pipe and cigar smokers were observed to show a risk slightly greater than that of nonsmokers (table 3). The relative risk of CHD mortality is greatest among cigarette smokers (as well as among those with other risk factors) in the younger age groups and decreases among the elderly. In table 2, Hammond and Horn found that for those smoking more than one pack per day, the risk is 2.51 in the 50 to 54 year age group and 1.56 in the 65 to 69 year age group. Although the relative risk for CHD among smokers decreases in the older age groups, the actual number of excess deaths among smokers continues to climb since the differences in death rates between smokers and nonsmok- ers continue to rise. CORONARY HEART DISEASE MORBIDITY Tables 4 and 5 list the prospective studies carried on in a num- ber of countries to identify the risk of CHD morbidity incurred by smoking. Here, CHD morbidity includes myocardial infarction as well as angina pectoris. Certain studies, notably those of Doyle, et al. (54), Keys, et al. (111), and Taylor, et al. (182) include a number of CHD deaths in their data that could not be separated out using the information provided in their respective reports. As noted in the discussion on CHD mortality, the CHD risk ratio increases significantly as the number of cigarettes smoked per day increases. Similarly, the HIP data of Shapiro, et al. (172) show that the elevated morbidity ratios declined with increasing age as has been shown for mortality ratios. A recent monograph edited by Keys (11 1) dealt with the 5-year CHD incidence in males age 40 to 59 from seven countries. As summarized in table 4, cigarette smoking was found to be associ- ated with an increased incidence of CHD in the U.S. railroad worker population, 2,571 individuals (183). None of the differences in ratio between smokers and nonsmokers was statistically signifi- cant for the 13 other population samples which varied in size from 505 to 982 individuals, from the five other countries. (Smoking was not considered in the two Japanese populations.) When more cases 39 become available to provide greater statistical stability to the rates, this intercultural comparison should prove illuminating. The results of those studies which have separated out angina pectoris as a manifestation of CHD are presented in table 5. Doyle, et al. (54) found no relationship between this manifestation of CHD and cigarette smoking. Both Jenkins, et al. (90) and Kannel, et al. (94) observed increased risk ratios among male cigarette smokers although these differences were not statistically signifi- cant. More recently, Shapiro, et al. (172) found a significantly increased risk for angina among their male cigarette smokers as well as increasing risk ratios with increasing dosage among both males and females, particularly in the younger age groups. A variety of hypothetical explanations have been advanced to account for this seeming contradiction. Among these are the relatively small number of cases, the difficulties associated with the definitive diagnosis of the syndrome, and differences in the methods of clas- sifying those cases of angina pectoris which are followed by myo- cardial infarction. RETROSPECTIVE STUDIES Table A6 presents data from the various retrospective studies of CHD prevalence. Most of these are case-control studies and show an increased percentage of smokers among those with clinical CHD when compared with a selected control population, usually without apparent CHD, Two of these studies include data on mortality. THE INTERACTION OF CIGARETTE SMOKING AND OTHER CHD RISK FACTORS The preceding section has reviewed the epidemiologic evidence which supports the judgment that cigarette smoking is a signifi- cant risk factor in the development of CHD. Many of the studies discussed above have identified a number of biochemical, physio- logical, and environmental factors, other than cigarette smoking, which also increase the risk of developing CHD. These risk factors include elevated serum lipids (particularly serum cholesterol) and hypertension, which, with cigarette smoking, are considered to be of greatest importance. Other factors are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as well as asympto- matic hyperglycemia), electrocardiographic abnormalities, and a positive family history of premature CHD (88). A number of these studies have also found that these factors, when present in the same individual, exert a combined effect on the risk of developing CHD. Figures 1 through 3 depict this inter- action of risk factors. As may be noted in Figures 1 and 2, the 40 additional factor of smoking greatly increases the risk of develop- ing CHD among those people already at high risk because of other factors. Furthermore, these studies have shown that the effect of smok- ing on the risk of developing CHD is statistically independent of the other risk factors. That is, when the effect of the other factors is statistically controlled, smoking continues to exert a significant effect on increasing the risk of developing and dying from CHD. Smoking and Serum Lipids The interaction of smoking and serum lipid levels in the develop- ment of CHD should be considered in the light of information con- cerning the relationship of smoking to serum lipid levels. Table A7 presents studies which deal with the association between smoking and lipids, notably cholesterol, triglycerides, and lipoproteins (con- cerned with lipid transport). While some of the studies have indi- cated that smokers show increased serum levels of these lipid con- stituents, others have not. The populations investigated and the methods of the various studies show significant variation. This lack of comparability makes interpretation of the findings difficult. It is clear, however, that in the presence of high serum choles- terol, cigarette smoking increases the risk of CHD. Figure 4 de- picts the data from the Chicago Peoples Gas, Light and Coke Com- pany study which show that smoking greatly increases the risk of CHD in each of the cholesterol groups. Smoking and Hypertension Some epidemiological studies have indicated that smokers tend to have lower mean systolic and/or diastolic blood pressures than nonsmokers, while other studies have not found this to be the case (table A8). Reid, et al. (155), in a study of 1,300 British and American postal workers, found that the blood pressure difference between the smoking and nonsmoking groups was eliminated after controlling for body weight. Tables 9 through 11, derived from the study by Borhani, et al. (27), demonstrate the following associations: That for both smok- ers and nonsmokers, the risk of dying from CHD increases with increasing diastolic or systolic pressure, and that the risk of mor- tality from CHD is higher among smokers than among nonsmokers in each blood pressure group. Cigarette smoking, therefore, has been shown to elevate CHD mortality independently both of its effect on blood pressure and of the effect of hypertension on CHD. Smoking and Physical Inactivity The recent study by Shapiro, et al. (772) of more than 110,000 41 TABLE 9.—Death rates from coronary heart disease, by systolic blood pressure; ILWU mortality study 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Systolic blood Person-years Death Person-years Death Age group pressure in 1951 of observation ratel of observation rate! 45-54 <130 1,877 27 2,413 8 130-149 2,066 34 2,912 17 150-169 740 95 1,177 26 >170 369 109 672 45 55-64 <130 1,067 84 1,550 26 130-149 1,380 94 2,401 325 150-169 647 93 1,558 45 >170 524 210 1,117 125 1 Rate per 10,000 person-years of observation. 2 p<0.025, 1 p<0.01 Source: Borhani, N. O., et al. (27). TABLE 10.—Death rates from coronary heart disease, by diastolic blood pressure: ILWU mortality study, 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Diastolic blood Person-years Death Person-years Death Age group pressure in 1951 of observation ratet of observation ratel AB-B4 ce ce eee <80 1,527 26 1,700 6 80-— 89 2,115 AT 2,947 17 90- 99 961 52 1,507 33 >100 448 89 1,020 20 55-64 oe ee eee <80 1,059 104 1,447 221 80- 89 1,521 59 2,704 15 90-- 99 669 194 1,521 246 >100 369 163 954 147 1 Rate per 10,000 person-years of observation. = p<0.05. 3 p<0.01. Source: Borhani, N. O., et al. (27). TABLE 11.—Death rates from coronary heart disease, among hypertensives and nonhypertensives: ILWU mortality study, 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Blood pressure Person-years Death Person-years Death Age group status 1 of observation rate? of observation rate? 45-54 ......... Hypertensives .......... 883 125 1,871 $32 Nonhypertensives ...... 4,169 29 5,303 13 55-64 ......... Hypertensives .......... 931 150 2,219 95 Nonhypertensives ...... 2,687 93 4,407 316 1 According tu the WHO recommendation, the following cut-off points are recommended for the definition of hypertension: (1) Normotension—below 140/90 mm. Hg. (2) Hypertension—systolic blood pressure 160 mm. Hg. or over, or diastolic 95 mm. Hg. or over, or both. (3) Borderline—the residual category. In this analysis, Normotensives and Borderlines were combined and the population was grcuped into ‘Nonhypertensives’ (1 and 3) and ‘Hypertensives’ (2). 2 Rate per 10,000 person-years of observation. > p<0.01. Source: Borhani, N. O., et al. (27). 42 INCIDENCE PER 1,000 MEN 80— — 80 70— — NON NON SMOKERS SMOKERS SMOKERS SMOKERS SMOKERS SMOKERS <225 225-274 2754 <225 225-274 275+ CHD 46° 1 5 2 9 16 12 N 1329* 187 235 71 336 317 151 AGE 49 49 50 51 50 49 50 SYSTOLIC 13 139 131 133 135 PRESSURE 133 8 WEIGHT 1.16 1.19 1.21 1.18 1.12 1.15 1.17 RATIO Figure 4—Relationship between smoking status and serum cholesterol level at initial examination, and incidence of clinical coronary heart disease in men originally age 40-59, free of definite CHD, and followed subsequently without systematic intervention, Peoples Gas Light and Coke Company study, 1958-1962. *For 34 men, no information on smoking status was available; one of these men had a coronary episode. Source: Stamler, J., et al. (177). persons participating in the Health Insurance Plan of New York City has further identified and elaborated upon the interaction of the various risk factors. Physical inactivity, both in employment and during leisure time, was found to be a potent risk factor for the development of CHD, particularly for rapidly fatal myocardial infarction. Figure 5 depicts the effect which smoking exerts on CHD in combination with physical inactivity. Of note, also, is the observa- tion that within each activity grouping, smoking greatly increases the risk of myocardial infarction, thus exerting an independent effect. Smoking and Obesity The analysis by Truett, et al. (190) of the risk factor data from the Framingham study revealed that weight, while a significant risk factor, had a considerably smaller effect on CHD incidence than serum cholesterol, cigarette smoking, or elevated blood pres- sure, The results concerning the interaction of smoking and obesity from the San Francisco longshoremen study are shown in table 12. 43 11.0 10.0 9.0 8.0 7.0 6.0 5.9 4.0 Rate per 1,000 (age-adjusted) 3.0 F 2.0 1.0 0.0 Not dead within 48 hrs. Dead within 48 hrs. 10.89 5.72 (57) 5.78 4.48 (166) 5.18 (46) 1.30 (1) Least More active active NONCIGARETTE SMOKERS 6.33 3.76 (47) 3.03 2.34 (118) 2.57 G)) 0.69 (33) Least More active active Note: Both for cigarette smokers and noncigarette smokers differences between rates among the least and more active men are statistically significant for total MI and rapidly fatal Mis at the 0.99 confidence level. For other Mls the difference is statistically significant only for the nonsmokers (confidence level 0.95). Figure 5—Average annual incidence of first myocardial infarction among men in relation to overall physical activity class and smoking habits (age-ad- justed rates per 1,000) (Actual number of deaths or myocardial infarctions are represented by figures in parentheses) Source: Shapiro, S., et al. (172). This table shows that cigarette smokers in the 55 to 64 year age group were observed to have higher CHD death rates than non- smokers in all weight categories. Similar findings, although not in all weight groups, were observed for the 45 to 54 year age group. Cigarette smoking is thus shown to be a CHD risk factor indepen- dent of body weight. 44 TABLE 12.—Death rates from coronary heart disease among men without abnormalities related to cardiopulmonary diseases by weight classification in 1951: ILWU mortality study, 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Weight Person-years Death Person-years Death Age group classification 2 of observation rate = of observation rate? 45-54 ......... Not overweight ........ 388 21 279 q Slightly overweight .... 962 28 1,096 0 Moderately overweight . 1,383 28 1,574 28 Markedly overweight .. 1,055 22 1,797 9 55-64 20.2... Not overweight ........ 222 43 247 0 Slightly overweight .... 536 75 605 36 Moderately overweight . 855 109 1,320 411 Markedly overweight .. 735 . 88 1,653 312 >The four classes are defined in the text. * Rate per 10,000 person-years of observation. *p20 Smoked 1-19 cigarettes/day cigarettes/day Hammond Never and Garfinkel, smoked regularly ......1.00(1,841) 1.00(1,841) Male data only 1969, Current U.S.A. cigarette smokers ....... 1.90 (1,063) 2.55 (2,822) (76). Stopped <1 year .........1.62 (29) 161 (62) V4 eee cece eee ee 122 (5TH 1.51 (154) BO cece eee cee ee ee L26 (55) 1.16 (135) LOG oe cece cee eee 0.96 (52) 1.25 (133) S20 Lee ce eee eee 1.08 (70) 1.05 (80) All ex-cigarette smokers ..1.16 (263) 1.28 (564) Total definite myocardial infarction Shapiro Never smoked 1.0.0.0... 00 eee eee eee en een etnies 1.00 etal, Current cigarette smokers ........-:ee cess ee ee eens 1.87 1969, Stopped 5 years 2... ... cece cece ee ee teen e eee 0.76 U.S.A. (172). Pooling Project, American Heart Association 1976, U.S.A. (88). Al CHD deaths Never smoked ........-..+5 1.00 (27) >, pack/day ....-----.565 1.65 (34) 1 pack/day wae eee oL.70 (86) >1 pack/day wee es 3.00 (68) Ex-smokers ween ee 0,80 (19) First major coronary event 1.00 (53) See table 4 1.65 (72) for description 2,08 (205) of Pooling 3.28 (154) Project. 1.25 (51) TaBLe 16.—Annual probability of death from coronary heart disease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking Age started smoking 15-19 20-24 Discontinued Discontinued Maximum daily Current for five or Current for five or Age number of ciga- smokers more years smokers more years rettes smoked (Probability x10 5) BB-64 oe eee 0 501 — 501 —_— 16-20 798 568 811 551 21-39 969 766 872 698 65-742 1. ee eee 0 1,015 — 1,015 — 10-20 1,502 1,169 1,478 1,213 21-39 1,710 1,334 1,573 1,098 1For age group 65-74, probabilities for discontinued smokers are for 10 or more years of dis- continuance since data for the 5-9 year discontinuance group are not given. Source: Cornfield, J., Mitchell, S. (45). Based on data derived from Kahn, H. A. (93). 46 Smoking and Electrocardiographic Abnormalities Electrocardiographic (ECG) abnormalities such as T-wave and ST-segment changes as well as a number of arrhythmias are use- ful indicators of CHD and may, therefore, be predictive of the development of clinically overt CHD manifestations. The results summarized in table 13, from the prospective study by Borhani, et al. (27), reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smoking and Heart Rate Recent analysis by Berkson, et al. (23) of the data derived from the Chicago Peoples Gas, Light and Coke Company study of middle-aged men revealed that resting heart rates of 80 or greater were associated with an increase in the risk of death from CHD. These authors found that this association was independent of the other major coronary risk factors. Table 14 presents the interaction between smoking, blood pres- sure, and elevated heart rate in increasing the risk of CHD mor- tality. This study shows that cigarette smoking increases CHD risk in the presence of elevated heart rate as well as in its absence. THE EFFECT OF CESSATION OF CIGARETTE SMOKING ON CORONARY HEART DISEASE A number of epidemiological studies have been concerned with the CHD incidence and mortality among ex-cigarette smokers as compared with current smokers (51, 76, 88, 90, 93, 172). These studies are listed in table 15. Table 16 presents the data derived by Cornfield and Mitchell (45) from the Dorn Study of U.S. Veterans (93). Ex-cigarette smokers show a reduced risk of both myocardial infarction and death from CHD relative to that of continuing ciga- rette smokers. The Pooling Project (88) and the Western Collab- orative Study Group (192) which adjusted for the other risk fac- tors of elevated serum cholesterol and blood pressure observed this relationship. Hammond and Garfinkel (76) noted that cessation of smoking is accompanied by a relative decrease in risk of death from CHD within 1 year after stopping. This decreased risk of CHD among ex-smokers further strength- ens the relationship between smoking and CHD. It must be noted, Owever, that the group of ex-smokers is composed of individuals who have stopped smoking for a variety of reasons. Those who Stop because of ‘ill health and the presence of symptoms are gen- frally at high risk and can bias the group results in one direction; 47 those healthy persons who stop as part of a general concern about their health and may adopt a number of self-protective health prac- tices are generally at low risk and can bias the group results in the other direction. Therefore, ex-smokers as a group are not fully representative of the entire population of smokers and may have limited value in predicting what would happen if large numbers of cigarette smokers stopped smoking purely for self-protection. Cer- tain incidence studies, such as the Pooling Project (88), were initi- ated with only clinically healthy individuals. The data from such studies, as well as those from the British physicians study, contain ex-smoker data less influenced by these biases. Fletcher and Horn (63) have recently presented data derived from the British physicians study of Doll and Hill. Over the past 10-15 years, cigarette smoking rates among British physicians have declined significantly in comparison with those of the general British population. The information presented by these authors concerning all cardiovascular diseases showed that for individuals between the ages of 35 and 64, the age-adjusted death rate for CHD declined by 6 percent among physicians and rose by 10 percent among the male population of England and Wales during the period from 1953-57 to 1961-65. THE CONSTITUTIONAL HYPOTHESIS The effect of smoking on the incidence of CHD has been found to be independent of the influence of the other CHD risk factors. When such risk factors as high serum cholesterol (177), increased blood pressure (27), elevated resting heart rate (23), physical in- activity (172), obesity (27), and electrocardiographic abnormali- ties (27) have been controlled, cigarette smokers still show higher rates of CHD than nonsmokers. It has been suggested by some (39, 170) that the relationship between cigarette smoking and CHD has a constitutional basis. That is people with certain constitutional make-ups are more likely to develop CHD, and the same people are more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and CHD is thus largely fortuitous and that the significant relationships are between the genetic make-up of the individual and CHD and between the genetic make-up of the indi- vidual and his becoming a cigarette smoker. Two sets of epidemio- logic data bear on this hypothesis. It has been maintained that people with a certain temperament are more likely to smoke and also more likely to develop CHD. These characteristics have been demonstrated for those with the 48 of 1.6, while those in the second group were found to have one of approximately 1.1. The authors concluded that this difference be. tween the two groups provides better support for the importance of constitutional factors as against the importance of cigarette smoking in the development of angina pectoris. A similar study was done using the responses of 4,379 U.S. Vet- eran twin pairs (approximately 60 percent of estimated available total) who completed the mailed questionnaires (38). Cederlof, et al. found a significantly increased prevalence of chest pain and “angina pectoris” among smokers when Group A was analyzed, Analysis of the smoking-discordant matched twin pairs (Group B) revealed no association between smoking and cardiovascular symp- toms among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors concluded that this lack of association among the monozygotes and its presence among the dizygotes and unmatched pairs strengthens the case for a constitu. tional hypothesis. A major problem in these studies is the small number of cases available and, therefore, the statistical instability of the results, In the Swedish study, among the 274 monozygotes, only 19 smokers and 16 nonsmokers were classified as having angina pectoris while among the 733 dizygotes, 25 smokers and 25 nonsmokers were so classified. In neither group was the difference between the prev- alence ratios found in the Group A analysis and that in the Group B analysis of statistical significance. Analysis of the data on women shows a similar lack of significance. Similar criticisms may be made of the study which utilized the U.S. Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris between the low-cigarette-exposure and high-cigarette-exposure dizygotic groups was not present among the monozygotes. The authors ques- tioned whether the excess morbidity associated with cigarette smoking found in the dizygotic group was causal as it was not pos- sible to reproduce the association when studying monozygotic smoking-discordant twin pairs. As noted above, the numbers in this study are also small so that the differences in rates do not approach statistical significance. Tibblin (188) has questioned the value of a mailed questionnaire to diagnose heart disease. The questionnaire as originally con- structed was used and validated by interview technique alone (157, 158). Cederlof, et al. (40) conducted a study to determine the validity of this questionnaire as a mailed instrument by personally interviewing and examining 170 of the twin pairs who had replied. Of the eight males who were diagnosed as having “angina pectoris” by the questionnaire. four were found to be free of symptoms on 50