Tobacco Documents Online

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Cigarette Smoking and Heart Disease The Tobacco Institute 1875 I Street Northwest, Washington, D.C. 20006 1983

Cigarette Smoking and Heart Disease Introduction Eighteen years ago, the first Surgeon General's report reached a narrow and simple conclusion about smoking and heart disease*: "Male cigarette smokers have a higher death rate from coronary artery disease than non-smoking males, hiit it is not clear that the association has causal significance." A nd : "...rTlhe basic cause or causes of coronary heart disease are obscure..."1 Four years ago, in his 1979 report, the Surgeon General revised those conclusions: "...It can be concluded that smoking is causally related to coronary heart disease in the common sense of that idea and for the purposes of preventive medicine." *For the purpose of this paper, heart disease, coronary heart disease (rHD) and ischemic heart disease (IHD) are assumed to he synonymous. With the exception of direct quotation, the text uses "heart disease" only. i

And in another passage from the same report: "There is no reasonable doubt that cigarette smoking as a risk factor for...cardiovascular diseases has been proven."2 Early in 1983, the Surgeon General is expected to issue a further report, devoted entirely to this subject. While we can speculate on what it may say, it seems proper to consider the sig- nificance and meaning of what has already been said and to indicate some of the subsequent contributions to scientific knowledge. The operative words in the previous conclusions are "associa- tion," "causally related," "cause" and "risk factor." A few com- ments on these are appropriate. On the first of those words, the 1964 Surgeon General's report said that "results of investigations must be considered to deter- mine first whether an association actually exists between an at- tribute or agent and a disease....The causal significance of an association is a matter of ,judgment...."1 That first report listed "consistency of the association" as a major criterion for such a,judgment. As will be seen, there are many inconsistencies in results of investigations of smoking and N) cn heart disease. o ~ -p -~ ~ 0 The meaning of the phrase "causally related" is obscure. The N ii

advisory committee that prepared the first Surgeon General's report said the meaning of "cause" was "discussed vigorously" in "debates" among the members, and that no member "used the word 'cause' in an absolute sense." The concept of "risk factor," perhaps the most gentle of these operative words in heart and other diseases, arose mainly from the Framingham study. Tn 1949, the U.S. Public Health Service began a close surveil- lance of more than 5,000 adult men and women in the community of Framingham, Massachusetts. Tts major objective was to attempt to determine why individuals would develop evidence of heart disease. The Framingham researchers were to utilize direct observation and questionnaires to record the variables -- genetic traits, environ- mental characteristics, lifestyle and any other factors -- believed to be related to heart disease. They were to look at which of these variables were most common in those persons who did develop symptoms of heart disease. And they would attempt to determine statistically the relative importance of each in the occurrence of those symptoms. Those deemed important would be called "risk fac- tors," in the sense of common presence, not necessarily cause. The Framingham study originally found "relationships" between heart disease and high serum cholesterol level, high blood pres- sure, obesity, low lung capacity and cigarette smoking.3 These ~ were adjudged to be "risk factors." o F-4 44 ~ V W

Sixteen years later, the Framingham director, William Kannel, wrote that elevated blood pressure had been confirmed as the "dom- inant contributor" to heart disease in the study, but that re- searchers were continuing to study the possible role of other "risk factors" in the development of heart disease.4 It must he remembered that by 1978 "risk factors" were no longer thought of merely as statistical "relationships" by many in the medical community. In the years between the publication of these two Framingham reports, the role of high blood pressure in heart disease had been elevated to "dominant contributor." The possible role of smoking as one "risk factor" among many was con- tinuing to be studied. In 1979, the author of a chapter in a medical textbook wrote that all known "risk factors" taken together could account for approximately 50 per cent of an individual's "risk" of developing heart disease in the United States. He added that important risk determinants remained to be discovered.5 In 1979, the Surgeon General's report said that relatively little was known about the mechanisms by which smoking was alleged to enhance atherosclerosis* or to increase the "risk" of heart attack. *Atherosclerosis, a form of arteriosclerosis, or thickening of the arteries is thought to be a principal factor in the development of heart disease. rv cn 0 ~ .p .P. w a ~ .P iv

The 1979 report also said that smoking was not a necessary condition for atherosclerosis and heart attack, as these occur in nonsmokers, and that correlation is not synonymous with causation. It is generally recognized that statistical correlates derived from studies such as Framingham could identify certain characteris- tics that might possibly be related to an individual's risk of de- veloping heart disease. Identification of so-called "risk factors" does not necessarily mean that the cause or causes of heart disease have been discovered. Although the 1979 report alleged smoking is "causally related" to heart disease in the common sense of the idea and for the pur- pose of preventive medicine, it suggested that additional research on mechanisms and on a more precise quantification of certain "risk factors" through epidemiological studies* was an important topic for medical science.2 It would be difficult to find fault with these suggestions for additional research. Without understanding of and knowledge about disease mechanisms, there can he no certainty about what causes disease. In fact, the entire concept of "risk factors" might well deserve reevaluation by the medical and other scientific communities. *F;pidemiology is a statistical science in which a group of people is studied to determine how often a disease occurs and what factors might be related to or associated with it. nj rn 0 ~ -p ~ w 0 v cn v

The material that follows examines whether smoking has, in fact, been established scientifically as "causally related" to heart disease. It looks also at whether support for the claim that smoking is an important "risk factor" is as strong as some have suggested -- all in light of some of the scientific evidence presented mainly since 1979 and reviewed here. N CJ1 O ~ ~ -p W 0 V ON vi

Intervention Studies Multiple Risk Factor Intervention Trial (MRFIT) If elevated cholesterol level, hypertension* and cigarette smoking were "risk factors" for heart disease mortality,** then re- ducing them in people presumably should lower the mortality rate. However, results reported from recent intervention studies, such as KRFIT, raise doubts as to whether the concept of "risk factors" carries the significance the medical community has ascribed to it up to this time. The results of this "massive, expensive, and lengthy clinical investigation termed 'Multiple Risk Factor Intervention Trial (hRRFIT) "'6 were reported in the Journal of the American Medical Association in September 1982. MRFIT was designed to test the effect of "risk factor" reduc- tion. From among more than 300,000 volunteer American men, 12,866 healthy but "high risk" subjects were assigned at random to one of two groups. "High risk" was determined by smoking history, serum cholesterol levels and diastolic blood pressure readings. *Hypertension is high blood pressure. N vn 0 ~ **Mortality rate and death rate are used synonymously in this 4:k paper. w a ~ ~ 1

Figure 1: Results from Multiple Risk Factor Intervention Trial (MRFIT) Percentage Reported Smoking at Beginning and End of Study 63.8% 63.5% 45.6% Beginning End ® SI is Special Intervention group ~ UC is Usual Care group Death Rates per 1000 at 72 Months All Causes 22.5 CVD* including CHD** CHD** *Cardiovascular Disease **Coronary Heart Disease Source: From Multiple Risk Factor Intervention Trial Research Group, "Multiple Risk Factor Intervention Trial: Risk Factor Changes and Mortality Results," JAMA 248(12): 1465-1477, Sept. 24, 1982 The special intervention group (SI) received special treatment for high blood pressure and physician counseling on smoking and diet. Members of the usual care group (UC) were left to their regular sources of health care. It was anticipated that at the end of six years the death rate from heart disease in the special intervention group would be reduced by 26.6 percent below that of the usual care group. Although there was, after almost six years, a 46 percent re- duction in smoking among the SI group and a 29 percent reduction among the UC group, there was no significant difference in mortali- IV cn 0 ~ ~ 4N w 0 ~ 03 2

ty rates between the two rg oups. In other words, the death rates were almost the same for both groups. Yet there was a difference 17 percentage points between the groups in the rates of smoking reduction.7 of As a British cardiologist noted in the British Medical Journal, this trial "ended with inconclusive results," leaving many unanswered questions.8 It should be clear, therefore, that the results of this study do not demonstrate that reductions in "risk factors," including smoking, lower the risk of death from heart disease. It may in fact be time for the medical community to reexamine the significance of the "risk factor" concept. Oslo The results of another intervention study, aimed at examining the effect of reduction of serum cholesterol and smoking on the in- cidence* of heart disease in Norway were reported in 1981 and 1982. The Oslo study group consisted of healthy middle-age men pre- sumed to be at "high risk" for heart disease. Men in the interven- tion group were counseled on diet and smoking to see if this could lower the incidence of first heart attacks, including those that are fatal. The authors found heart disease incidence was signifi- *Incidence is the number of new cases of disease that develop in a selected period of time. It is used to illustrate the rate at which diseases develop. 3 I

cantly reduced in the intervention group. The authors attributed this lowered risk of disease largely to reduced cholesterol levels. They said their calculations showed no statistically significant decline in risk as a result of reduced cigarette consumption.9 When these data were reanalyzed in an attempt to separate the possible effects of smoking reduction or cessation from those of improved diet on the incidence of new disease, the results were even more striking. Neither smoking status when the study began nor changes in amount smoked were found to be signficantly associa- ted with heart attacks. In fact, changes in amount smoked were "unassociated." In this update, even though the investigator speculated that smoking may play some role, smoking was found to be a "non-signifi- cant risk factor" for new cases of heart disease.l0 There is only one study in the literature of the results of intervention against smoking alone. In preliminary findings pub- lished in 1979, Geoffrey Rose and P. J. S. Hamilton reported no evidence of any reduction in overall death rates in a group whose smoking was reduced. The authors described this finding as disap- pointing.11 4

Four years later, they reported their 10-year results. Now the death rate for heart disease in the intervention group was not significantly lower than the rate for the normal care group. The heart disease mortality rate for the entire study population was higher than the national rate.12 It is difficult to understand', therefore, how the results of this study could be cited as support for the hypothesis that smoking causes heart disease. It should be clear that the findings from these "risk factor" intervention studies are inconsistent with the claim that smoking is causally related to heart disease. The results from Rose and Hamilton and from baseline studies like Friedman's, discussed be- low, suggest that the "risk factor" concept may have been misinter- preted. It is simple to do so, but it is highly suspect from a scientific point of view. There are those who, like the Surgeon General, label smoking as a cause of heart disease. They claim support in reports that former smokers experience significantly lower risks for heart dis- ease than continuing smokers. They conclude that smoking cessation is the reason for the lowered risk of disease, because they assume that former smokers are comparable to continuing smokers except for the change in their smoking habits. This is only an assumption. Such studies generally have N failed to compare the smokers and the former smokers at the same o ~_, 0 5 CO

baseline -- when all were still smokers. Comparing a variety of health, social and personal factors among continuing smokers, never smokers and former smokers before they stopped, Gary Friedman and co-authors found that the smokers who would stop later were different from continuing smokers in many characteristics believed to be related to the development of heart disease. In other words, the smokers who later stopped already may have been at a lower "risk" for heart disease than those smokers who would continue to smoke. Smokers who later quit showed statistically significant dif- ferences from continuing smokers in a number of physical symptoms, personal characteristics and miscellaneous traits. For example, when compared with that of persistent smokers, their prevalence of reported heart disease symptoms such as chest pain on exercise, shortness of breath and leg pain was more like that of the never smokers. In fact, those who would stop in the future were, overall, more like the never smokers than they were the continuing smokers. The authors concluded that smokers who later quit were not a typ- ical group of smokers.l3 But the study became controversial. In a 1980 American Heart N) cn a ~ ~ Journal editorial, Carl Seltzer, a co-author of the Friedman ~ w 0 m r_j 6

report, cited the Friedman study and the 1978 report by Rose and Hamilton as evidence that "the reversibility of the claimed risk of cigarettes to the smoker's life has not been demonstrated. "Accordingly," the editorial said, "it is reasonable to be- lieve there is no proof that stopping reduces the risk of heart disease."14 Friedman took another look at his study population and in a subsequent article claimed that further study showed that baseline differences between the groups could not explain the differences in heart disease mortality between persistent smokers and quitters.15 Seltzer and Philip Burch criticized the Friedman "update" for the methodologies employed and the conclusions reached. Seltzer noted Friedman's second analysis ignored the possible effects of other factors associated with risk of heart disease that are impor- tant for reaching conclusions that are accurate.l6 Burch concluded that there was no valid scientific evidence to prove that stopping smoking reduces the risk of death from heart disease. He wrote: "The conclusion that quitting smoking results in a substantial reduction in mortality is not established by the study of Friedman et al."17 IU t3} It should be clear that the results from the intervention and 0 ~ ~ ~ w 0 7 - w

the Friedman studies do not scientifically demonstrate that reducing smoking reduces the risk of death from heart disease. The MRFIT authors, in trying to explain the seven-year results of their study, wrote that "multifactor intervention received a less than optimal test" because of unexpected declines in "risk factor" levels and lower than expected mortality in the usual care group. They suggested that the recent reduction in heart disease mor- tality in the t1.S., "the reasons for which are still not totally understood," might explain the unexpected mortality decline in the usual care group.7 Time Trends In the U.S., heart disease death rates have been reported to be declining since 196R. This, however, has not been demonstrated to be attributable to changes in smoking habits. Attributing the decline to improved medical care or "risk fac- tor" change is open to criticism. "The truth of the matter is that we are uncertain as to the precise reason or reasons for the de- cline," a prominent government scientist conceded in 1982. "It has not been possible to obtain national data that would support an ex- planation," he admitted.1R - 8 -

Figure 2: "What underlies the recent decrease? While this question has been addressed by a number of authorities, no consensus has emerged. The question would be easier to answer if answers were available to a number of other questions. "Has the incidence, as well as the mortality rate, from CHD [coronary heart disease] been decreasing? "Have the presenting symptoms become, on the average, less severe? "Is there a lower case fatality rate following an initial myocardial infarction? Follow- ing subsequent infarctions? "Has the reinfarction rate decreased? "Has there been adecrease in the incidence of myocardial infarction following angina pectoris? "Is the ratio of sudden to nonsudden CHD death changing? "Data on these subjects are sparse and equivocal, but unless we know, or presume we know, answers to some of these questions, it becomes difficult to decide what to explain, let alone to apply tests of relevancy to proffered explanations." These are statements from a letter to the editor, American Heart Jour- nal, January 1982, by Tavia Gordon, consulting biometrician and former longtime supervisory statistician, Biometrics Research Branch, National Heart, Lung and Blood Institute, National Institutes of Health. Heart disease mortality did drop markedly between 1968 and 1978 in the TJ.S. Participants in a Conference on the Decline in Coronary Heart Disease Mortality, convened by the National Heart, Lung and Rlood Institute (NHLRI) in October 1978, agreed on one thing--that the decrease was real, not a result of artifacts or changes in death certificate coding.lA Their report said the reasons for the decline were not clear. And they remain speculative today. Last September, the Framingham study's Kannel noted that "the case for either improved treatment or risk-factor modification is difficult to sustain" in providing explanation for the continuing mortality decline.210 Two papers from the 1978 conference analyzed epidemiologic - 9 - N tJ1 0 ~ ~ .Q w 0 m cn

data to determine whether a decline in the percentage of smokers was related to the decrease in heart disease mortality rates. Roger Williams and co-authors suggested that recent trends in stopping smoking might be partially responsible for changes in U.S. males' mortality rates, but that change in smoking habits could not explain the substantial decline in the largely nonsmoking population of Utah. Nor could it explain why younger U.S. women showed the largest percentage decline in heart disease at a time when their smoking rates reportedly increased.21 These views were reinforced in Joel Kleinman's conference pa- per. He looked at the possible impact of smoking trends on heart disease mortality and reported that changes in smoking habits among women were not consistent with the decline.22 A year later, Klein- man and his co-authors wrote that changes other than smoking must account for the bulk of the decline in heart disease mortality.23 A principal problem in understanding the decline is the rela- tive lack of current U.S. data on heart disease incidence. The 1978 conference report called for additional research on heart disease rates to determine whether there had been changes in the frequency of nonfatal heart attacks. As Kannel commented, it is unfortunate that incidence data are "sparse" and "inconsistent."20 ~ .a 0 CO - 10 - oN

Figure 3: Smoking Prevalence and Rates Among Middle-Aged Females: United States, 1965 and 1976 Regular Cigarette Smokers Smokers of 15 or More Cigarettes/Day White Females 35-44 45-54 55-64 Black Females 35-44 45-54 55-64 Age 1965 LI 1976 ® Source: Reproduced from Kieinman, J.C., et ai., "Trends in Smoking and ischemic Heart Disease Mortali- ty," in Proceedings of the Conference on the Decline In Coronary Heart Disease Mortality, Havlik, R.J. and M. Feinleib (eds.), U.S. Pubiic Health Service, Department of Health, Education and Welfare, DHEW Publication No. (NIH) 79-1610, May 1979

If "risk factor" changes had played an important part in the decline in heart disease mortality, then they should also have had a role in reducing the incidence of the disease. By 1982, there was little evidence that the incidence had declined at the same time as the mortality rate. It has been suggested by some researchers that if there had been no actual decline in the incidence of heart disease, the re- ported decreases in the levels of "risk factors" might be far less important in reducing mortality than improved medical care. A 1982 editorial in the British Medical Journal added a signi- ficant note -- that the decline in TJ.S. mortality rates was appar- ent before there were substantial alterations in many factors, in- cluding smoking.24 This observation appeared in a discussion of findings from one of the very few incidence studies to appear in the scientific lit- erature, an examination by a group at Mayo Clinic of heart disease incidence in Rochester, Minnesota, over a 26-year period. The Mayo authors noted that the decline in the mortality rate there was similar to that observed nationally but that the decline in incidence preceded the decline in mortality by approximately 10 years. N Ln 0 ~ ~ ~ w 0 m w - 12 -

Figure 4: Per-Capita Cigarette Consumption, 18 Years and Over, and Age-Adjusted Death Rates for Maior Cardiovascular Diseases: United States, 1950-1979 450 400 350 300 • • ~N."a, Per-Capita Cig arette Consumption, 18 and Over Age-Adjusted Death Rates, per 100,000 population, 250 Major Cardiovascular Diseases -~2500 01 1 1 1 1 1 1 1 I 0 1950 1955 1960 1965 1970 1975 1980 Death Cigarette Rates Consumption Sources: Economics, Statistics and Cooperatives Service, U.S. Department of Agriculture Rosenberg, H.M. and A.J. Klebba, "Trends in Cardiovascular Mortality with a Focus on Ischemic Heart Disease: United States, 1950-1976," in Proceedings of the Conference on the Decline In Cor- onary Heart Disease Mortality, Havlik, R.J. and M. Feinleib (eds.), U.S. Public Health Service, Depart- ment of Health, Education and Welfare, DHEW Publication No. (NIH) 79-1610, May 1979; National Center for Health Statistics, Monthly Vital Statistics Reports 2501443089

They looked at the survival rates of those who developed heart disease between 1950 and 1975. They found a significant reduction in the death rate in the heart attack cases between 1965-69 and 1970-75 and an almost 50 percent improvement in long-term survival of those patients who had a milder form of heart disease. They concluded that the improvement in "survivorship" in the incidence group during the 1970s contributed to the decline•in the mortality rate.25 This study demonstrated that the decline in incidence was apparent before, as the editorial in the British Medical Journal noted, there were major changes in "risk factors." It follows that the subsequent decline in mortality may he more reasonably attrib- uted to improvements in treatment than to changes in "risk fac- tors," including smoking. Other countries have reported drops in cardiovascular disease mortality similar to that in the U.S. For instance, a Swiss re- searcher noted declines of 22 percent in males and 43 percent in females between 1951 and 1976, suggesting that the reasons were un- clear. The decline in Swiss men occurred while they were smoking approximately the same number of cigarettes, and the dramatic de- cline in women occurred at a time when they smoked more cigarettes, ate more animal fats, started ~ extensive use of oral contraceptives, and increasingly 0 ~ ~ w 0 - 14 - o

left the peace of their villages for the stress of big towns and the warmth off their homes for the hard com- petition of occupational life.26 British scientist Philip Rurch compared trends of heart dis- ease mortality in five different populations, in Fngland and Wales, Scotland, Japan and among U.S. whites and nonwhites.27 He found internal consistency in the patterns of heart disease mortality in various populations and in both sexes. He asserted that most of the traditional "risk factors," including smoking, could not explain the mortality decreases in the U.S. Changes in levels of traditional factors, his work suggested, could not explain the U.S. decline. Geographical Inconsistencies There are geographic inconsistencies in data on smoking and heart disease. A number of scientists have commented on these. For example, Ancel Keys' seven countries study was a long-term investigation of the epidemiology of heart disease in six Western countries and Japan. Sixteen groups comprising 12,763 men, aged 40-59 at the start, were followed in Yugoslavia, Finland, Italy, the Netherlands, Greece, the U.S. and Japan.?R N cn 0 ~ .~ ~ w 0 ~ ~ - 15 -

The groups were observed systematically for 10 years. The important analyses of the data involved comparisons among the groups in different countries and offer new insights into the rela- tionships between cultural conditions and the operation of some of the usually accepted "risk factors" for heart disease. j Keys' conclusion, derived from his own findings and from other studies, is that the big three "risk factors" are age, blood pres- sure and serum cholesterol. The findings about smoking illustrate the complexities of at- tempting to determine the "cause" or "causes" of heart disease. Keys noted that neither the percentage of heavy cigarette smokers at the beginning of the study nor the percentage of non- smokers when the study began was related to either heart attack or mortality rates in the groups. Keys found an insignificant difference in heart disease mor- tality rates between smokers and nonsmokers in the Italian and Greek groups. Among Japanese men, the lowest death rate after 10 years was among the heaviest smokers, those smoking 20 or more cig- arettes a day. Keys noted that cigarette smoking is not as important a "risk N ~ factor" for heart disease in Japan and southern Europe, compared 0 ~ .~ with northern Europe and the U.S. ~ w 0 -a N - 16 -

Other anomalies related to smoking turned up in the seven countries study. For example, in Yugoslavia heart disease rates were higher in the men who had never smoked than in those who smoked fewer than 10 or between 10 and 19 cigarettes a day. What is more, the rate of heart attack or death was slightly higher among the never smokers than among those who had stopped or who smoked fewer than 10 cigarettes a day. What does all this mean? Keys himself discussed an important and unanswered question: What accounts for the regional differen- ces in the relative importance of smoking as a "risk factor" for heart disease? Keys found that variations in duration and amount of smoking and in percentages of nonsmokers or heavy smokers "were equally unrelated to the subsequent incidence rates of the disease." And so he concluded that the relationships between smoking habits and heart disease are not as simple as first proposed. In fact, in some of the groups studied,no statistically significant associa- tions between smoking and heart disease were found. Other scientists have commented on anomalies in data on deaths from heart disease. Kleinman and co-authors studied regional and urban differences in U.S. heart disease mortality in relation to serum cholesterol - 17 -

level,.~blood pressure and smoking. They found that differences in these-"r-isk factors" could not explain why death rates have been lower in the West than in other regions or lower among suburban than urban residents. They concluded that other characteristics of environment, lifestyle, medical care or genetics must be considered in trying to explain the geographic variations that have been observed for many years.?9 Tavia Gordon, writing early last year in American Heart Journal, wondered why Japan, which has had changes in lifestyle that are usually thought to increase risk of heart disease, has experienced a decrease in heart disease mortality comparable to that in the U.S.30 How can this he explained in view of indications that levels of "risk factors" had generally decreased in the U.S. but increased in Japan during the same period? Could it be that some other "factors" played a role in the U.S. mortality decline? Other "Risk Factors" Genetics Family history of disease, the so-called "genetic" or "heredi- tary" factor, has been found in some studies to be related to heart disease. - 1R -

For instance, Rune Cederlof has found that differences in smoking habits of identical twins are not associated with their heart disease symptoms.31,32 When, in the fall of 1977, the final Cederlof monograph on the twin studies was published, its authors stated that their data "may just as well indicate that other factors than smoking play an es- sential part in the etiology of coronary heart disease."33 Aware that the chief drawback in using the twin studies to do epidemio- logic research was in the somewhat limited numbers of twins, they suggested that this limitation was being overcome by cooperation among several research centers that were using the same "twin method." Further evidence that heredity plays a major role in develop- ment of heart disease comes from Finland, a country where the mor- tality rate from heart disease is very high. Researchers there, in a study of the arteries of deceased children, concluded that there is a genetic component in the causation of heart disease.34 And genetic make-up may help explain why men in northeastern Finland have the world's highest rate of early heart disease, according to the authors of a recently published report.35 In James Nora's study of a Colorado population, a positive family history of heart disease was the most important factor in U; 0 ~ predicting the development of heart disease at an early age. -p ~ w 0 ~O cn - 19 -

Nora wrote that analyzing "risk factors" such as smoking, diet, obesity, cholesterol and hypertension as if they were inde- pendent of hereditary predisposition may be misleading and that the contribution of heredity appears to exceed that of environment.36 One of the most recent analyses of Framingham data reports findings that suggest family history of heart attack may be impor- tant in predicting heart attack in siblings and that the clustering of heart disease in families may result from a genetic predis- position that is independent of the usually accepted "risk factors."37 A British physician wrote in 1981 that genetic influences ap- pear to be more important than habits of life and work in explain- ing the extent of degenerative changes in the arteries of young men in military service who had died suddenly from heart attacks.3R Finally, with the exception of family history of heart dis- ease, no individual "risk factor" was, in and of itself, a predic- tor of the degree of atherosclerosis in heart disease patients in a recently reported Harvard Medical School study.39 These are only some of the studies that appear to lend support to the importance of heredity as a possible "risk" for heart disease. N 01 0 ~ ~ .~ w 0 ~ - 20 - o~

Diet Dietary factors have been related to the development of heart disease. Among these are the amount of saturated fats and the amount of fiber in the diet. A greater amount of fiber has been reported to be protective in some studies, while a greater amount of saturated fats has been reported to lead to increased risk of disease. The authors of a 1982 report from the Netherlands suggested that a diet with sufficient amounts of fiber might be protective against heart disease in Western societies.40 Among Keys' significant findings in his seven countries study was that among men who had no evidence of heart disease at the start of the study there were higher heart disease death rates at the end of 10 years in those who had consumed a higher percentage of caloric intake in saturated fats. In 1981, Keys wrote that the percentage of dietary calories supplied by saturated fatty acids is significantly correlated with death from heart disease.41 Although aware of the implications of diet as a "risk factor" in heart disease, Keys did not claim a cause-and-effect relation- ~ti cn a ~-A ~ .~ w 0 ~ ~ - 21 -

ship. He wrote: FFpidemiological studies, even prospective ones like the Seven Countries Study, cannot prove cause-and- effect when the end-point, 'effect,' is an outcome of a chronic non-communicable condition. He said this limitation is often forgotten in discussions of preventive programs and that one should only cite epidemiological evidence as being either consistent or inconsistent with the hypothesis being examined. In this instance, Keys found the data consistent with the hypothesis that diet is a "risk factor" for heart disease.41 Keys did not find smoking to be one of "the big three risk factors" for heart disease. Behavior Another hypothesis is that stress, psychosocial and behavioral influences may be involved in the development of heart disease. Several recent scientific articles have underlined their signifi- cance. The association of an overt behavior pattern with heart disease was initially proposed by Meyer Friedman and Ray R.osenman in 1959. Intense ambition, competitive drive, preoccupation with deadlines and a sense of time urgency identified the behavioral pattern they associated with an increased "risk" of heart disease.42 N ~ ~ .~ ~ a a ~ - 22 -

Almost two decades passed before this pattern, now known as Type A behavior, received widespread acceptance. In 1977, the National Institutes of Health (NIH) scheduled a forum to investigate the role of behavioral factors in heart dis- ease. The NIH scientists were interested in the relationship be- tween Type A behavior and "traditional risk factors," and whether Type A behavior might be "independent" of other "risk factors." And they speculated about biological mechanisms that might help explain the association between the Type A behavior pattern and heart disease and at the roles that genetic or environmental factors might play in originating Type A behavior. They concluded that additional research, using carefully de- signed studies, was "critical to develop, test, and validate inter- vention strategies to determine whether alteration of the Type A pattern will, in fact, reduce risk for CHD fcoronary heart diseasel."43 Twenty-one years after he and Rosenman proposed the associa- tion, Friedman again described the Type A pattern and its associa- tion with heart disease. The medical community resisted the association, Friedman wrote in a publication of the New York Academy of Sciences, because "we were taking what is widely believed to be just the sort of behavior and personality necessary -23-

for successful living in Western society, and calling it a disorder." Although the personality pattern is now generally recognized as a "risk factor," Friedman wrote, that does not prove that Type A behavior causes heart disease.44 In 19R0, two physicians wrote that the traditional "risk fac- tors" cannot explain the cases of clinical heart disease encountered on a worldwide basis and that it is difficult to separate the role of behavior and environment from the "accepted risk factors." They said that each "risk factor" is a genetic, environmental and behavioral components. composite of They noted that a large number of animal studies have implica- ted psychological stress in precipitating both sudden death and ir- regular heart beats. They concluded that behavioral and psychological factors are involved in the development of atherosclerosis and heart disease. And they noted that the mechanisms by which Type A behavior might operate as a "risk factor" in development or aggravation of the disease remain conjectural. They wrote that even the accepted nonbehavioral "risk factors" are composites and cannot be separated from their behavioral and psychosocial underpinnings.45 N cn 0 ~ -p w ~ - 24 - o a

In their emphasis on the interrelationships of the behavioral with other more traditional factors, Buell and Eliot appeared to agree with Rune Cederlof's concluding comments about research methodology. Cederlof wrote in the 1977 monograph that the results of his study clearly demonstrate the importance of genetic, several behavioral and psycho-social factors which have not been considered in conventional epidemiological studies. 8uch factors should as far as possible be included in future epidemiological research, not only in the context of smoking and health, but also in studies on other similar exposure factors that may be linked to risk factors of this type or to genetic predispositions.33 A late 1982 editorial in Arteriosclerosis by Harvard scien- tists David Hamburg and Glen Elliott appears to lend support to this call for renewed emphasis on behavioral factors in the study of heart disease.46 The lead article in the same journal was about the relation- ships of atherosclerosis in monkeys to social status and environ- ment. The authors, J.R. Kaplan and colleagues, concluded their results "suggest that social dominance ran individual behavioral characteristicl is associated with increased coronary artery ather- osclerosis, but only under social conditions that provide recurrent threats to the status of dominant animals, (i.e., under behavioral challenge ) . ,T 47 -25-

The Hamburg and Elliott editorial reviewed some of the biomed- ical and behavioral literature on heart disease. They discussed the traditional "risk factors" and urged further experimental anal- yses of social and behavioral factors. The authors noted: Clarification of the mechanisms underlying the results reported by Kaplan, et al. will require a combination of approaches that properly fall within the domain of the biobehavioral sciences, as do studies of the behavioral and neurophysiological aspects of other risk factors such as hypertension and smoking. Hamburg and Elliott concluded that the field of heart disease would be well served "if some excellent biomedical scientists would expand their interests to include behavioral problems and if behav- ioral scientists would pay greater attention to atherosclerosis."4(3 A number of recent published materials lend support to the importance of behavioral factors and psychosocial disturbances in heart disease.48 Mechanisms The mechanisms by which smoking may relate to heart disease are not known.l4 ~ cn 0 ~ .~ ~ w ~ 0 -26- ~

There is a critical need to explain how heart disease develops in humans. Substantial research has gone into the effort. Some investigators have suggested that either carbon monoxide (CO) or nicotine may be involved. However, no mechanism involving either of these substances has been scientifically established. Carbon Monoxide Suggestions about CO rely mainly on animal work of Poul Astrup and Carl Hugod in the 1960s on the possible effects of Cn exposure on rabbits. They reported that CO from tobacco smoke played a ma- jor role in the development of atherosclerosis in smoke-exposed rabbits.49 Other researchers, however, reported only negligible effects of CO exposure on the development of atherosclerosis in other ani- mals,50 so the Astrup group repeated its earlier experiments. After correcting a methodological deficiency that had been present in their work in the 1960s, they were unable to reproduce their earlier findings. They concluded, therefore, that CO was not responsible for atherosclerosis in rabbits51 and have reiterated these results regarding CO (and certain other cigarette smoke gas- phase components) in several recent publications.52 - 27 -

Writing in 1981 in a chapter of a book called Smoking and Arterial Disease, Astrup and his co-author noted that there was no longer evidence for considering CO or several other tobacco smoke constituents to be components of major importance for the alleged enhanced atherosclerosis in tobacco smokers.53 Nevertheless, the earlier Astrup work continues to be cited by some investigators as evidence that smoking causes athero- sclerosis. Fven the 1981 Surgeon General's report failed to cite their updated work on atherosclerosis.54 It is inexplicahle that these strikingly different results are ignored. Studies of workers exposed to relatively high amounts of car- bon monoxide on the job generally do not support the claim that CO causes heart disease. For example, auto tunnel workers and blast furnace workers, known to be exposed to high levels of CO on a regular basis, have not been found to have more heart disease than the general population.55 In 1982, Francis Weir and Vincent Fabiano reviewed the litera- ture on CO and heart disease, concluding that there was no evidence to support the suggestion that exposure to low to moderate amounts of CO accelerates the development of atherosclerosis and added that there was, in fact, enough evidence to conclude that CO does not cause atherosclerosis.56 rv tn 0 ~ .~ -~ -28- ~

Nicotine Those who claim nicotine causes heart disease have also relied principally on the results of animal experiments. Yet the Surgeon General's report of 1979 pointed out that experiments on the ef- fects of CO or nicotine on experimental atherosclerosis in animals have produced conflicting results "and are inconclusive." Based on available data, the report said, nicotine does not appear to affect atherosclerosis in animals.2 Two years later, the 1981 Surgeon General's report again pro- posed that nicotine and CO may play a major role in the development of heart disease. But it came to no conclusions on causality, per- haps because it admitted the available information is "scanty."54 Anatomy and Autopsy Studies If cigarette smoke or any of its components enhance development of atherosclerosis and, thereby, the risk of heart disease death, anatomy and autopsy studies should generally confirm the association. However, the results of these studies have been contradictory. A case in point comes from the Oslo study. The most recent analysis from that intervention trial attempted to measure the ~ i ° l t d t " k f t " i o ev - were re a ors e r ac s extent to which the separate f" -R .p w ~ 0 - 29 - cn

dence of atherosclerosis obtained from autopsies. The authors found no significant relationship between smoking and the extent of atherosclerosis observed at autopsy.57 Other recent anatomy studies lend support to these findings.58 Seltzer has criticized the 1979 Surgeon General's report for its conclusions on mechanisms and for ignoring other studies that do not support the causal hypothesis. Seltzer said that in spite r of the report's claims to the contrary "there is no established proof that cigarette smoking is causally related to coronary heart disease."14 Clearly, the mechanisms by which smoking has been said to contribute to or aggravate heart disease in the smoker have not been scientifically established. Public Smoking The claim that environmental tobacco smoke or any of its con- stituents causes or aggravates heart disease in the nonsmoker has been criticized on scientific grounds. A number of researchers have concluded that environmental

tobacco smoke has not been shown to cause heart disease to develop in nonsmokers. For example, a cardiologist, after reviewing the scientific literature, rejected contentions that tobacco smoke has been shown to cause heart disease in nonsmokers.59 She added that to her knowledge there were no statistical studies suggesting that tobacco smoke or any of its constituents causes or aggravates atherosclerosis in nonsmokers.59 Opponents of smoking have claimed that ambient tobacco smoke in the air may be especially harmful to persons with serious heart problems. Much of the support for this claim comes from work published by Wilbert Aronow. In 1978, after studying only 10 patients, Aronow reported that heart pain developed sooner after exercise when the patients were exposed to cigarette smoke during the exer- cise.60 There are a number of published criticisms of the Aronow work. In addition to finding the study's sample to be extremely small, scientists have faulted the basic experimental design and Aronow's failure to allow for the possible effects of psychologi- cal stress on patients' reactions to cigarette smoke. For example, a Los Angeles chest physician, after describing - 31 -

such deficiencies, called the study "questionable."61 A pathology professor described the study's scientific design as "exceedingly poor."62 And, in 1982, Roy Shephard, a Canadian researcher with strong anti-smoking views, called the endpoint of the study --the reported onset of pain -- "subjective." He added that it is difficult to imagine that enclosure in a very smoky room did not have some emotional impact upon patients who were subject to heart pain. He noted that psychological disturbance may have done more to bring on the pain than the carboxyhemoglobin* levels in the 10 patients.63 Finally, a physician who now heads the American College of Cardiology, after reviewing the scientific literature, including the Aronow work, told a Congressional committee that available studies do not establish that under realistic conditions atmospheric tobacco smoke adversely affects nonsmokers with preexistent cardiovascular disease.59 *Carboxyhemoglobin(COHb) is the substance formed when carbon monoxide combines with the oxygen-carrying substance in the blood. -32-

Conclusion Unquestionably, many gaps remain in medical knowledge about the origin, development and prevention of heart disease. Science has not satisfactorily explained how the disease progresses, how to interpret the decline in mortality, or the effects, if any, of reduced levels of factors that may be related to heart disease. This review should make it clear that there remain too many anomalies -- too many unanswered questions. Heart disease is far more complex than was thought in 1949, when the government-funded Framingham study utilized the concept of "risk factor." Despite all the unknowns surrounding heart disease and its beginnings, many of them enumerated in his 1979 report, the Surgeon General would appear to have ignored those gaps in knowledge when he singled out in that same report as the "major goal" in heart disease research "the development of long-term effective methods of smoking avoidance and cessation".2 This document has attempted to take a look at what some re- searchers have had to say about their own and others' work as it relates to heart disease. It has suggested that some scientists are taking a new look at - 33 -

the concept of "risk factor" and the questionable use to which it has been put by some others in the scientific communities. In fact, the term "risk factor" itself has been described as being "vague and deceptive" by Carleton Chapman in the foreword to the seven countries study.28 This paper has attempted to review some of the recent litera- ture on the "risk factor" intervention trials that sought to deter- mine whether reduction in some or any of the factors may, in fact, result in lowered risk of death from heart disease. It should be clear that the findings from these studies are inconsistent with the claim that smoking is causally related to heart disease. It has looked at a number of inconsistencies in data on "risk factors" and heart disease. Among these are the significant geo- graphic inconsistencies and those that show up when deaths from heart disease are looked at in different populations over long periods of time. It has looked at how scientists have attempted to explain the continuing decrease in the U.S. death rate from heart disease and concluded that there is no satisfactory explanation. It has examined what some scientists have said about other factors that might be related to the development of heart disease - 34 -

Figure 5 202.2 194.4 ~ 142.7 7 ~ 292.5 13 . 1 4 106.9 20.3 M N=~ 90. 91 1 8 .5 70.3 369.0 111111111 149.2 af• 108.0 52.3 37 .4 362.0 162.6 101.9 4 56. 3 0.9 343. 18 6.3 76 6 . f• 47. 9 25.1 00 3 50 3 00 2 50 2 00 1 50 1 50 C 00 4 Rates per 100,000 Population 1900 1. Pneumonia (AII Forms) and Influenza 2. Tuberculosis (All Forms) 3. Diarrhea, Enteritis and Ulceration of the Intestines 4. Diseases of the Heart 5. Intracraniai Lesions of Vascular Origin 1940 1. Diseases of the Heart 2. Cancer and Other Malignant Tumors 3. Intracranial Lesions of Vascular Origin 4. Nephritis (All Forms) 5. Pneumonia (AII Forms) and Influenza 1960 1. Diseases of the Heart 2. Malignant Neoplasms 3. Vascular Lesions Affecting Central Nervous System 4. Accidents 5. Certain Diseases of Early Infancy 1970 1. Diseases of the Heart 2. Malignant Neoplasms 3. Cerebrovascufar Diseases 4. Accidents 5. Influenza and Pneumonia 1980 1. Diseases of the Heart 2. Malignant Neoplasms 3. Cerebrovascular Diseases 4. Accidents 5. Chronic Obstructive Pulmonary Diseases Source: Excerpted from Levy, R.I. and J. Moskowitz, "Cardiovascular Research: Decades of Progress, a Decade of Promise," Science 217(4555): 121-129, July 9, 1982 Heart disease is the leading cause of death in the United States. Its relative importance is demonstrated in this chart of the five leading causes of death, 1900 to 1980, expressed in death rates per 100,000 population.

and whether the mechanisms leading to heart disease have been elucidated. From this review, it should be clear that the cause or causes and mechanisms of heart disease are not known and that further re- search is needed on the disease, which although apparently declin- ing remains the leading U.S. cause of death. Summary This review of some of the recent literature on smoking and heart disease can be summarized as follows: The results of a recent U.S. "risk factor" intervention trial do not show that reducing "risk factors," including smoking, reduces the risk of death from heart disease. Because of frequent failure to compare smokers and former smokers when both groups are smokers,-conclusions that former smokers have a reduced risk of heart disease because they stopped N a ~ -~ smoking may be unreliable. ~' W Changes in smoking patterns do not explain the significant de- crease in heart disease mortality in the U.S. between 1969 and 1978. The mortality decline in U.S. women came, as it did in Swiss women, at a time when there was a reported increase in their smoking. - 36 -

There are geographical anomalies in data on smoking and heart disease. In a major international study, differences among popula- tions in heart disease incidence and death rates are not explained by or related to differences in smoking habits among the populations. Other "factors" have been thought to play a role in the devel- opment of heart disease, and heart disease occurs, of course, in nonsmokers. Hereditary factors have been considered to be significant in the development of heart disease. Diet, especially the amount of saturated fats in the diet, has been related to the development of heart disease. Psychosocial and behavioral influences may be involved in the development of heart disease. No mechanism by which cigarette smoke might produce or con- tribute to heart disease has been demonstrated. The roles, if any, ~ Cn of nicotine and carbon monoxide in the initiation and development ° ~ 4_4 of heart disease in smokers and nonsmokers have not been shown. W ~ w Whether cigarette smoking is causally related to heart disease is not scientifically established. - 37 -

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57. Holme, I., et al., "Risk Factors and Raised Atherosclerotic Lesions in Coronary and Cerebral Arteries: Statistical Analysis from the Oslo Study," Arteriosclerosis 1(4): 250-256, 1981. 58. Dimsdale, J.E., et al., "Predicting Extensive Coronary Artery Disease," J Chron Dis 34: 513-517, 1981. Vlietstra, R.E., et al., "Factors Affecting the Extent and Severity of Coronary Artery Surgery Study," Arteriosclerosis 2(3):, 208-215, 1982. 59. Knoebel, S.B., Statement, U.S. Congress, House Committee on Agriculture, Subcommittee on Tobacco, Effect of Smoking_ on Non- smokers, Hearing, 95th Congress, 2nd Session, Washington, D.C., Sept. 7, 1978, pp. 49-55. 60. Aronow, W., "Effect of Passive Smoking on Angina Pectoris," NEJM 299(1): 21-24, 1978. 61. Niden, A., "No: Environmental Smoke Can Irritate, Not Injure Others", Los Angeles Times, Oct. 29, 1978. 62. Fisher, E.R., Statement, U.S. Congress, House Committee on Agri-culture, Subcommittee on Tobacco, Effect of Smoking on Nonsmokers, Hearing, 95th Congress, 2nd Session, Washington, D.C., Sept. 7, 1978, pp. 2-20. 63. Shephard, R.J., The Risks of Passive Smoking, Croom Helm, London, 1982. ~

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