- Email: [email protected]
Coronary disease: Risk factors, age, and time
American April,
Heart
1979, Volume 97, Number
Journal
4
Editorial Coronary
disease:
P. R. J. Burch,
Risk factors,
age, and time
Ph.D.
Leeds, England
Because of its enormous toll-ischemic heart diseaseclaimed some 26 per cent of all deaths in England and Wales in 1975-the urge to identify causesneeds no further justification. Indeed, the sense of urgency is so strong we may well be in danger of accepting identifications that are superficially plausible and emotionally satisfying before they have been thoroughly investigated. Epidemiology abounds in pitfalls and only by the most careful choice of paths can we hope to avoid stumbling into danger. By diligent studies of large populations epidemiologists have discovered various so-called “risk factors.” A person possessing a given risk factor has, on the average, a higher risk of dying from ischemic heart disease than an otherwise similar person without it. The main risk factors are hypercholesterolemia, hypertension, cigarette smoking, obesity, lack of voluntary exercise, diabetes mellitus, and a family history of heart disease. Men suffer a markedly higher mortality rate than women and age-specific death rates in both sexes rise rapidly with age. Although by definition each risk factor associates positively with the risk of ischemic heart disease, it by no means follows that risk factors are causal. One hesitates to say it again but association does not necessarily imply cause. Having identified “risk factors”-the term is unfortunate and tendentious-we can formulate
hypotheses such as: “high levels of dietary cholesterol cause ischemic heart disease,” but we then have to try to devise tests that distinguish between that and other possibilities. An alternative to the causal hypothesis allowed by the logic of some of the epidemiological evidence is that the disease,or a pre-disease condition, causes the risk factor. For example, damage to arterial tissues might give rise, directly or indirectly, to hypercholesterolemia. Another alternative states that a third factor “causes” both the risk factor and the disease.A person’s genetic constitution, for example, might predispose him or her to, say, both smoking and coronary heart disease. These three main possibilities are not mutually exclusive and hence the task of trying to distinguish between them, singly or in any combination, is not easy; generally, ineradicable errors in the evidence will render absolute distinctions unattainable. To complicate matters further, it should be mentioned that a neutral, or even a negative, association between a factor and a disease does not in itself preclude the possibility that such a factor causes the disease. Thus a strong negative association between the genes that predispose to the factor and those that predispose to the diseasecould, in principle, overwhelm a causal effect giving only a weak positive association.
From the Department of Medical General Infirmary, Leeds, England.
An investigation by Hammond and Garfinkel’ has given valuable quantitative evidence for the relation between certain risk factors-cigarette smoking, relative body weight, physical exercise, hypertension, and diabetes mellitus-and sex-
Received
for publication
Reprint University England.
requests: Prof. of Leeds,
0002~8703/79/040415
Apr.
Physics,
University
of Leeds,
The
11, 1978.
P. R. J. Burch, The General
+ 05$00.50/O
Ph.D., Dept. Infirmary,
0 1979
of Medical Physics, Leeds LSl 3EX,
The
C. V. Mosby
Co.
Risk factors:
quantitative
evidence
American
Heart
Journal
415
Burch specific and age-specific mortality from CHD. The degree of risk connected with a particular risk factor is often defined in terms of a mortality ratio, which usually varies with age. (A mortality ratio is given by the death rate from the disease in question in persons with the risk factor, divided by the corresponding death rate in a suitably matched group of persons without the factor.) Mortality ratios for CHD decrease with increasing age for cigarette smoking,‘-i excess relative weight,’ hypertension,’ diabetes,’ and hypercholesterolemia.“. j By contrast, when non-exercisers are compared with heavy exercisers, the mortality ratio rises with increasing age.’ Also of theoretical importance is the relation between the mortality ratio and, for example, the rate of cigarette smoking within a given age group. Whereas this relation is approximately linear for bronchitis and lung cancer, we find for CHD that, after an initial rise that appears to be more or less linear, a near plateau is reached at a smoking rate of about 20 cigarettes per day, especially in the higher age group~.‘-~ To achieve a satisfactory synthesis the over-all evidence-epidemiological, observational, and experimental-needs to be accommodated within a unifying framework. Because risk factors are usually identified from epidemiological evidence we have to ensure that it is exploited as rigorously as possible. Age-dependent
disease:
theory
The various associations between risk factors and CHD receive a simple interpretation6 in terms of a unified theory’. 8 of growth, cytodifferentiation, and age-dependent autoaggressive disease. This unified theory derives in part from Burnet’s forbidden clone concept? of disturbedtolerance autoimmune disease and also from Burwell’s viewlo that the growth of target tissues throughout the body is regulated by components of the lymphoid system. A brief description of the pertinent features of the unified theory will suffice to explain the different types of association between risk factors and CHD. To become the victim of a specific autoaggressive disease a person must first possessa specific genetic predisposition. Occasionally, diathesis takes the form of a simple autosomal dominant or recessive inheritance, but more commonly, polygenie predisposition is involved. In that event, the chance of one polygenic disorder being associated
416
with another may become appreciable; numerous recent studies have revealed the complexities of the associations not only between one diseaseand another but also between diseasesand the major histocompatibility antigens. These latter associations, predicted by us, make the genetic basis explicit. If, therefore, we study a group of persons with a specific genotype-say maturity-onset diabetics-the proportion of persons predisposed to CHD in this selected group may well differ from that in the general population. The genes that predispose to maturity-onset diabetes mellitus might associate, positively or negatively, with those that predispose to CHD. Furthermore, the type and strength of the association might well differ from one population to another. But given a genetic predisposition to CHD, many years usually elapse before the disease develops: the risk of death from CHD, small at the age of 20, increases very steeply with age. One of our main tasks is to describe, in biological terms, the striking characteristics of this steep age-dependence. From studies of hundreds of age patterns, relating to many types of disorder, an unexpectedly simple and unified interpretation has emerged.‘. * The kinetics of the disease process can be divided into two distinctive phases: initiation and development. (In certain diseases-neoplastic and non-neoplastic-qualitatively distinctive stages of progression can also be distinguished but this phenomenon need not detain us here; it has been analyzed elsewhere.“) Initiation is a purely random process involving the occurrence of a specific set of spontaneous somatic gene mutations in one or more central growth-control stem cells. In the example of fatal CHD it appears that six somatic mutations need to occur in a single growth-control stem cell to complete the process of initiation. The steep age-dependence of CHD-age-specific initiation rates increase with the fifth power of age up to about 75 years of age-is a consequence of this multi-step random (stochastic) process. I have seenno indication that extrinsic pathogens, at the levels encountered in ordinary environments, have any detectable influence on the rate of occurrence of the initiating somatic mutations in CHD or any other autoaggressive disease. However, different rates are often observed between, for example, Caucasoid and Japanese populations and they, presumably, have a genetic basis.x
April, 1979, Vol. 97, No. 4
Coronary disease and the risk factors
On completion of initiation the appropriately mutant stem cell propagates a forbidden clone of descendant cells, the peripheral members of which, in the example of CHD, probably comprise T-lymphocytes. These mutant T-lymphocytes attack specific target cells (perhaps particular mosaics of endothelial cells) that carry complementary recognition proteins. When damage to the target tissue reaches a certain level, death ensues. We describe the process from the formation of the forbidden clone to death as the development phase; we call its duration the latent period. In general, the development process may be affected by extrinsic factors-causal and therapeutic-but its average duration is dominated by genetic inheritance. In the England and Wales and the United States “White” populations the average latent period for CHD is 10 years in males and 20 years in females; in the United States “Blacks” the corresponding intervals are only 5 and 10 years, respectively. However, this latter disadvantage is more than compensated by the fact that a smaller proportion of “Blacks” than of “Whites” is at genetic risk to CHD.” (It should be mentioned that CHD belongs to a general class of autoaggressive disease in which the average latent period in women is double that in men; in another class the average latent periods are the same in both sexes.‘. “) Risk factors: CHD
the nature
of the association
with
Analysis of suitably accurate sex-specific and age-specific death rates for a sub-population of persons, selected as possessing a particular risk factor, enables the nature of the association between risk factor and CHD to be determined.” With cigarette smoking, relative weight and, probably, hypercholesterolemia, the association in each instance is only with the duration of the latent period. Thus, in non-smoking United States males,‘. ” the average latent period for non-smokers is 15 years, but the interval shortens progressively to 5 to 6 years for those smoking 20 (or 21) to 39 cigarettes a day; and to 3 to 4 years for those smoking 40 or more cigarettes a day.” Among United States women’ this inverse association between latent period and smoking rate is weaker: in non-smokers the duration is 24 years and for those smoking 20 to 39 cigarettes a day it is 18 years.” For the risk factors hypertension, diabetes
American Heart Journal
mellitus, and lack of voluntary exercise, the association with CHD has a dual basis.” In the first place, hypertensives, diabetics, and non-exercisers are more likely to be genetically-predisposed to fatal CHD than “normal” controls. The second aspect of the association between these particular risk factors and CHD involves the latent period. In hypertensives and diabetics the latent period is shorter than in the general population but in non-exercisers it is longer. This latter phenomenon explains why the mortality ratio for nonexercisers versus heavy exercisers increases with age,’ whereas for all the other risk factors analyzed6 it decreases. Are the associations
causal?
The findings’ and interpretation” in connexion with exercise raise a particularly interesting and important issue. A heavy exerciser is 3.3 times less likely to be genetically predisposed to fatal CHD than a non-exerciser, and exercise has no effect on the initiation of a forbidden clone by random somatic mutation. However, once the forbidden clone has been initiated, the latent period is markedly shorter (5 years for men, 18 years for women) in the heavy exerciser than in the nonexerciser (10 years for men, 24 years for women).6 If this shortening of the latent period is caused by strenuous physical exertion then heavy exercise (or even moderate and slight exercise) should be regarded as a risk factor in those persons that are unfortunate enough to have an initiated forbidden clone. Although the over-all evidence, showing an effectively constant latent period both in time and with age, favors a genetic interpretation of the connection between latent period and the degree of exercise (especially voluntary), I am unaware of any evidence that bears directly and decisively on the problem. Overwhelmingly important in view of the social and political consequences generated by enthusiasm for preventive medicine is the cause of the short latent periods in cigarette smokers, hypertensives, the obese,and in persons with hypercholesterolemia. Fortunately where smoking is concerned, the properties of the age-dependence of mortality from CI!ID and of the secular trends (1921 to 1973) in sex-specific and age-specific death rates, enable reasonably confident conclusions to be drawn.” (Seltzer’? has given independent reasons for doubting the causal interpretation.) If the short latent period is caused by the
417
Burch
smoking then: (1) the post-1921 changes (mainly increases) in cigarette smoking in England and Wales should have generally shortened the latent period in both sexes; (2) because the average rate of smoking decreases with increasing age above about 55 years of age, the latent period in older men and women should be longer than in younger persons. The Registrar General’s mortality statistic fail to confirm either expectation.6 Although large increases have been recorded in death rates from CHD, and although changes in the International Classification of Diseases have introduced some interpretational difficultes, the data give no indication of any systematic shifts in the latent period between 1921 and 1973. Over the age range yielding the most reliable and consistent data (below about 75 years of age), the average latent period has remained close to 10 years in men and 20 years in women throughout the era.6 We could always argue that, although cigarette smoking has generally increased in the post-1921 era, especially in women, other causal factors affecting the latent period have decreased so as to compensate for the adverse effects of tobacco. Until such hypothetical agents-with their requisite and improbable time variation and their equally improbable sex and age dependence-can be identified, such arguments must be regarded as suspect to the point of absurdity. The consumption of foods such as eggs, fatty meat, milk, and dairy products that are supposed to raise serum cholesterol levels has also changed’” since 1921: the changes have generally been increases, although from 1970 to 1976 total fat, butter, and total egg consumption decreased,‘” Because the latent periods have failed to reflect these secular trends, the hypothesis that dietary cholesterol causes CHD is not supported. McMichael’” and MannI have also given reasons for rejecting this hypothesis. Hypercholesterolemia, obesity, and hypertension all increase in prevalence with age and the finding of effectively constant latent periods for CHD with age indicates that none of these conditions causes CHD. Nevertheless, the large increases in recorded death rates (about a factor of 15 between 1921 to 1925 and 1971 to 1973, depending slightly on age group) remain to be accounted for. There is little doubt that at least some part of these increases can be ascribed to better recognition of the disease; the mathematical characteristics of the
418
age patterns throughout the era indicate that the degree of under-recognition, up to the age of about 75, was very similar in the two sexes. However, these same mathematical characteristics allow another general type of interpretation. They are consistent with the idea that part of the recorded increase was genuine and caused by a precipitating factor that increased in prevalence in the course of the century and acted uniformly on men and women of all ages.” A precipitating factor, of which infective microorganisms and allergens are the best known examples, is an extrinsic agent that releases an initiated forbidden clone from restraints that are normally exercised by the host’s endogenous defence mechanism.‘, s No evidence for such a factor has yet been uncovered in connection with CHD but should it transpire that part of the secular increase in recorded death rates is genuine, and not merely the result of better ascertainment, then search for such an agent might prove rewarding. In spite of the consensus among many experts,17 the secular increases and age-dependence of recorded death rates from CHD cannot plausibly be reconciled with the view that cigarette smoking, consumption of cholesterolcontaining foods, hypertension, obesity, and diabetes actually cause the disease. The evidence indicates that for each of these “risk factors” the observed associations, with all their subtle but readily interpreted features, have a genetic basis. This is probably true also of exercise, although as yet it cannot be conclusively ruled out that physical exertion might hasten death from CHD. If this analysis is substantially correct it follows that intervention programs-unless they involve by accident or design a reduction in the purely hypothetical and unidentified precipitating factor-are not only doomed to disappointment, they are likely to create unnecessary misery and anxiety. And what should one say about a publication,‘” in a highly reputable journal, in which the economic consequences of “smoking and alcohol abuse” are calculated to six (sic) significant figures? REFERENCES 1.
2.
Hammond, E. C., and Garfinkel, L.: Coronary heart disease, stroke and aortic aneurysm, Arch. Environ. Health 19:167, 1969. Kahn, H. A.: The Dorn study of smoking and mortality
April,
1979,
Vol.
97, No.
4
Coronary
among U.S. veterans: report of eight and one-half years of observation, Natn. Cancer Inst. Monogr. 19:1, 1966. 3. Doll, R., and Peto, R.: Mortality in relation to smoking: 20 years’ observations on male British doctors, Br. Med. J. 21525, 1976. 4. Chapman, J. M., and Massey, F. J., Jr.: The interrelation&in of serum cholesterol, hvnertension, body weight, and &k of coronary disease, -J. Chronic. Dis: 17:933; 1964. 5. Kannel, W. B., Caste& W. P., Gordon, T., and Macnamara, P. M.: Serum cholesterol, lipoproteins and the risk of coronary heart disease. The Framingham study, Ann. Intern. Med. 74:1, 1971. 6. Burch, P. R. J.: Coronary heart disease: risk factors and ageing, Gerontology 24:123, 1978. 7. Burch, P. R. J.: An inquiry concerning growth, disease and ageing, Edinburgh, 1968, Oliver & Boyd; Buffalo, 1969, University of Toronto Press. 8. Burch, P. R. J.: The biology of cancer: a new approach, Lancaster, 1976, Medical and Technical Publishing Press Ltd.; Baltimore, 1976, University Park Press. 9. Burnet, F. M.: The clonal selection theory of acquired immunity,.Nashville, 1959, Vanderbilt University Press; London, 1959, Cambridge University Press.
American
Heart
Journal
10. 11.
disease and the risk factors
Burwell, R. G.: The role of lymphoid tissue in morphostasis, Lancet 2:69, 1963. Burch, P. R. J., and Burwell, R. G.: Self and not-self. A clonal induction approach to immunology, Q. Rev. Biol.
40:252,1965. 12.
Seltzer,
C. C.: Smoking
and cardiovascular
disease,
AM.
HEART J. 90:125,1975. 13.
14.
15. 16. 17.
18.
Drummond, J. C., and Wilbraham, A.: The Englishman’s food. Five centuries of English diet, London, 1969, Jonathan Cape, Ltd. Florey, C. du V., Melia, R. J. W., and Darby, S. C.: Changing mortality from ischaemic heart disease in Great Britain 1968-76, Br. Med. J. 1:635, 1978. McMichael, J.: Dietic factors in coronary disease, Europ. J. Cardiol. 5/6:447, 1977. Mann, G. V.: Diet-heart: end of an era, New Engl. J. Med. 297644, 1977. Working Party of the Royal College of Physicians of London and the British Cardiac Society: The care of the patient with coronary heart disease, J. R. Coll. Physicians Lond. 10:213, 1976. Lute, B. R., and Schweitzer, S. 0.: Smoking and alcohol abuse: a comparison of their economic consequences, N. Engl. J. Med. 298:569, 1978.
419
Heart
1979, Volume 97, Number
Journal
4
Editorial Coronary
disease:
P. R. J. Burch,
Risk factors,
age, and time
Ph.D.
Leeds, England
Because of its enormous toll-ischemic heart diseaseclaimed some 26 per cent of all deaths in England and Wales in 1975-the urge to identify causesneeds no further justification. Indeed, the sense of urgency is so strong we may well be in danger of accepting identifications that are superficially plausible and emotionally satisfying before they have been thoroughly investigated. Epidemiology abounds in pitfalls and only by the most careful choice of paths can we hope to avoid stumbling into danger. By diligent studies of large populations epidemiologists have discovered various so-called “risk factors.” A person possessing a given risk factor has, on the average, a higher risk of dying from ischemic heart disease than an otherwise similar person without it. The main risk factors are hypercholesterolemia, hypertension, cigarette smoking, obesity, lack of voluntary exercise, diabetes mellitus, and a family history of heart disease. Men suffer a markedly higher mortality rate than women and age-specific death rates in both sexes rise rapidly with age. Although by definition each risk factor associates positively with the risk of ischemic heart disease, it by no means follows that risk factors are causal. One hesitates to say it again but association does not necessarily imply cause. Having identified “risk factors”-the term is unfortunate and tendentious-we can formulate
hypotheses such as: “high levels of dietary cholesterol cause ischemic heart disease,” but we then have to try to devise tests that distinguish between that and other possibilities. An alternative to the causal hypothesis allowed by the logic of some of the epidemiological evidence is that the disease,or a pre-disease condition, causes the risk factor. For example, damage to arterial tissues might give rise, directly or indirectly, to hypercholesterolemia. Another alternative states that a third factor “causes” both the risk factor and the disease.A person’s genetic constitution, for example, might predispose him or her to, say, both smoking and coronary heart disease. These three main possibilities are not mutually exclusive and hence the task of trying to distinguish between them, singly or in any combination, is not easy; generally, ineradicable errors in the evidence will render absolute distinctions unattainable. To complicate matters further, it should be mentioned that a neutral, or even a negative, association between a factor and a disease does not in itself preclude the possibility that such a factor causes the disease. Thus a strong negative association between the genes that predispose to the factor and those that predispose to the diseasecould, in principle, overwhelm a causal effect giving only a weak positive association.
From the Department of Medical General Infirmary, Leeds, England.
An investigation by Hammond and Garfinkel’ has given valuable quantitative evidence for the relation between certain risk factors-cigarette smoking, relative body weight, physical exercise, hypertension, and diabetes mellitus-and sex-
Received
for publication
Reprint University England.
requests: Prof. of Leeds,
0002~8703/79/040415
Apr.
Physics,
University
of Leeds,
The
11, 1978.
P. R. J. Burch, The General
+ 05$00.50/O
Ph.D., Dept. Infirmary,
0 1979
of Medical Physics, Leeds LSl 3EX,
The
C. V. Mosby
Co.
Risk factors:
quantitative
evidence
American
Heart
Journal
415
Burch specific and age-specific mortality from CHD. The degree of risk connected with a particular risk factor is often defined in terms of a mortality ratio, which usually varies with age. (A mortality ratio is given by the death rate from the disease in question in persons with the risk factor, divided by the corresponding death rate in a suitably matched group of persons without the factor.) Mortality ratios for CHD decrease with increasing age for cigarette smoking,‘-i excess relative weight,’ hypertension,’ diabetes,’ and hypercholesterolemia.“. j By contrast, when non-exercisers are compared with heavy exercisers, the mortality ratio rises with increasing age.’ Also of theoretical importance is the relation between the mortality ratio and, for example, the rate of cigarette smoking within a given age group. Whereas this relation is approximately linear for bronchitis and lung cancer, we find for CHD that, after an initial rise that appears to be more or less linear, a near plateau is reached at a smoking rate of about 20 cigarettes per day, especially in the higher age group~.‘-~ To achieve a satisfactory synthesis the over-all evidence-epidemiological, observational, and experimental-needs to be accommodated within a unifying framework. Because risk factors are usually identified from epidemiological evidence we have to ensure that it is exploited as rigorously as possible. Age-dependent
disease:
theory
The various associations between risk factors and CHD receive a simple interpretation6 in terms of a unified theory’. 8 of growth, cytodifferentiation, and age-dependent autoaggressive disease. This unified theory derives in part from Burnet’s forbidden clone concept? of disturbedtolerance autoimmune disease and also from Burwell’s viewlo that the growth of target tissues throughout the body is regulated by components of the lymphoid system. A brief description of the pertinent features of the unified theory will suffice to explain the different types of association between risk factors and CHD. To become the victim of a specific autoaggressive disease a person must first possessa specific genetic predisposition. Occasionally, diathesis takes the form of a simple autosomal dominant or recessive inheritance, but more commonly, polygenie predisposition is involved. In that event, the chance of one polygenic disorder being associated
416
with another may become appreciable; numerous recent studies have revealed the complexities of the associations not only between one diseaseand another but also between diseasesand the major histocompatibility antigens. These latter associations, predicted by us, make the genetic basis explicit. If, therefore, we study a group of persons with a specific genotype-say maturity-onset diabetics-the proportion of persons predisposed to CHD in this selected group may well differ from that in the general population. The genes that predispose to maturity-onset diabetes mellitus might associate, positively or negatively, with those that predispose to CHD. Furthermore, the type and strength of the association might well differ from one population to another. But given a genetic predisposition to CHD, many years usually elapse before the disease develops: the risk of death from CHD, small at the age of 20, increases very steeply with age. One of our main tasks is to describe, in biological terms, the striking characteristics of this steep age-dependence. From studies of hundreds of age patterns, relating to many types of disorder, an unexpectedly simple and unified interpretation has emerged.‘. * The kinetics of the disease process can be divided into two distinctive phases: initiation and development. (In certain diseases-neoplastic and non-neoplastic-qualitatively distinctive stages of progression can also be distinguished but this phenomenon need not detain us here; it has been analyzed elsewhere.“) Initiation is a purely random process involving the occurrence of a specific set of spontaneous somatic gene mutations in one or more central growth-control stem cells. In the example of fatal CHD it appears that six somatic mutations need to occur in a single growth-control stem cell to complete the process of initiation. The steep age-dependence of CHD-age-specific initiation rates increase with the fifth power of age up to about 75 years of age-is a consequence of this multi-step random (stochastic) process. I have seenno indication that extrinsic pathogens, at the levels encountered in ordinary environments, have any detectable influence on the rate of occurrence of the initiating somatic mutations in CHD or any other autoaggressive disease. However, different rates are often observed between, for example, Caucasoid and Japanese populations and they, presumably, have a genetic basis.x
April, 1979, Vol. 97, No. 4
Coronary disease and the risk factors
On completion of initiation the appropriately mutant stem cell propagates a forbidden clone of descendant cells, the peripheral members of which, in the example of CHD, probably comprise T-lymphocytes. These mutant T-lymphocytes attack specific target cells (perhaps particular mosaics of endothelial cells) that carry complementary recognition proteins. When damage to the target tissue reaches a certain level, death ensues. We describe the process from the formation of the forbidden clone to death as the development phase; we call its duration the latent period. In general, the development process may be affected by extrinsic factors-causal and therapeutic-but its average duration is dominated by genetic inheritance. In the England and Wales and the United States “White” populations the average latent period for CHD is 10 years in males and 20 years in females; in the United States “Blacks” the corresponding intervals are only 5 and 10 years, respectively. However, this latter disadvantage is more than compensated by the fact that a smaller proportion of “Blacks” than of “Whites” is at genetic risk to CHD.” (It should be mentioned that CHD belongs to a general class of autoaggressive disease in which the average latent period in women is double that in men; in another class the average latent periods are the same in both sexes.‘. “) Risk factors: CHD
the nature
of the association
with
Analysis of suitably accurate sex-specific and age-specific death rates for a sub-population of persons, selected as possessing a particular risk factor, enables the nature of the association between risk factor and CHD to be determined.” With cigarette smoking, relative weight and, probably, hypercholesterolemia, the association in each instance is only with the duration of the latent period. Thus, in non-smoking United States males,‘. ” the average latent period for non-smokers is 15 years, but the interval shortens progressively to 5 to 6 years for those smoking 20 (or 21) to 39 cigarettes a day; and to 3 to 4 years for those smoking 40 or more cigarettes a day.” Among United States women’ this inverse association between latent period and smoking rate is weaker: in non-smokers the duration is 24 years and for those smoking 20 to 39 cigarettes a day it is 18 years.” For the risk factors hypertension, diabetes
American Heart Journal
mellitus, and lack of voluntary exercise, the association with CHD has a dual basis.” In the first place, hypertensives, diabetics, and non-exercisers are more likely to be genetically-predisposed to fatal CHD than “normal” controls. The second aspect of the association between these particular risk factors and CHD involves the latent period. In hypertensives and diabetics the latent period is shorter than in the general population but in non-exercisers it is longer. This latter phenomenon explains why the mortality ratio for nonexercisers versus heavy exercisers increases with age,’ whereas for all the other risk factors analyzed6 it decreases. Are the associations
causal?
The findings’ and interpretation” in connexion with exercise raise a particularly interesting and important issue. A heavy exerciser is 3.3 times less likely to be genetically predisposed to fatal CHD than a non-exerciser, and exercise has no effect on the initiation of a forbidden clone by random somatic mutation. However, once the forbidden clone has been initiated, the latent period is markedly shorter (5 years for men, 18 years for women) in the heavy exerciser than in the nonexerciser (10 years for men, 24 years for women).6 If this shortening of the latent period is caused by strenuous physical exertion then heavy exercise (or even moderate and slight exercise) should be regarded as a risk factor in those persons that are unfortunate enough to have an initiated forbidden clone. Although the over-all evidence, showing an effectively constant latent period both in time and with age, favors a genetic interpretation of the connection between latent period and the degree of exercise (especially voluntary), I am unaware of any evidence that bears directly and decisively on the problem. Overwhelmingly important in view of the social and political consequences generated by enthusiasm for preventive medicine is the cause of the short latent periods in cigarette smokers, hypertensives, the obese,and in persons with hypercholesterolemia. Fortunately where smoking is concerned, the properties of the age-dependence of mortality from CI!ID and of the secular trends (1921 to 1973) in sex-specific and age-specific death rates, enable reasonably confident conclusions to be drawn.” (Seltzer’? has given independent reasons for doubting the causal interpretation.) If the short latent period is caused by the
417
Burch
smoking then: (1) the post-1921 changes (mainly increases) in cigarette smoking in England and Wales should have generally shortened the latent period in both sexes; (2) because the average rate of smoking decreases with increasing age above about 55 years of age, the latent period in older men and women should be longer than in younger persons. The Registrar General’s mortality statistic fail to confirm either expectation.6 Although large increases have been recorded in death rates from CHD, and although changes in the International Classification of Diseases have introduced some interpretational difficultes, the data give no indication of any systematic shifts in the latent period between 1921 and 1973. Over the age range yielding the most reliable and consistent data (below about 75 years of age), the average latent period has remained close to 10 years in men and 20 years in women throughout the era.6 We could always argue that, although cigarette smoking has generally increased in the post-1921 era, especially in women, other causal factors affecting the latent period have decreased so as to compensate for the adverse effects of tobacco. Until such hypothetical agents-with their requisite and improbable time variation and their equally improbable sex and age dependence-can be identified, such arguments must be regarded as suspect to the point of absurdity. The consumption of foods such as eggs, fatty meat, milk, and dairy products that are supposed to raise serum cholesterol levels has also changed’” since 1921: the changes have generally been increases, although from 1970 to 1976 total fat, butter, and total egg consumption decreased,‘” Because the latent periods have failed to reflect these secular trends, the hypothesis that dietary cholesterol causes CHD is not supported. McMichael’” and MannI have also given reasons for rejecting this hypothesis. Hypercholesterolemia, obesity, and hypertension all increase in prevalence with age and the finding of effectively constant latent periods for CHD with age indicates that none of these conditions causes CHD. Nevertheless, the large increases in recorded death rates (about a factor of 15 between 1921 to 1925 and 1971 to 1973, depending slightly on age group) remain to be accounted for. There is little doubt that at least some part of these increases can be ascribed to better recognition of the disease; the mathematical characteristics of the
418
age patterns throughout the era indicate that the degree of under-recognition, up to the age of about 75, was very similar in the two sexes. However, these same mathematical characteristics allow another general type of interpretation. They are consistent with the idea that part of the recorded increase was genuine and caused by a precipitating factor that increased in prevalence in the course of the century and acted uniformly on men and women of all ages.” A precipitating factor, of which infective microorganisms and allergens are the best known examples, is an extrinsic agent that releases an initiated forbidden clone from restraints that are normally exercised by the host’s endogenous defence mechanism.‘, s No evidence for such a factor has yet been uncovered in connection with CHD but should it transpire that part of the secular increase in recorded death rates is genuine, and not merely the result of better ascertainment, then search for such an agent might prove rewarding. In spite of the consensus among many experts,17 the secular increases and age-dependence of recorded death rates from CHD cannot plausibly be reconciled with the view that cigarette smoking, consumption of cholesterolcontaining foods, hypertension, obesity, and diabetes actually cause the disease. The evidence indicates that for each of these “risk factors” the observed associations, with all their subtle but readily interpreted features, have a genetic basis. This is probably true also of exercise, although as yet it cannot be conclusively ruled out that physical exertion might hasten death from CHD. If this analysis is substantially correct it follows that intervention programs-unless they involve by accident or design a reduction in the purely hypothetical and unidentified precipitating factor-are not only doomed to disappointment, they are likely to create unnecessary misery and anxiety. And what should one say about a publication,‘” in a highly reputable journal, in which the economic consequences of “smoking and alcohol abuse” are calculated to six (sic) significant figures? REFERENCES 1.
2.
Hammond, E. C., and Garfinkel, L.: Coronary heart disease, stroke and aortic aneurysm, Arch. Environ. Health 19:167, 1969. Kahn, H. A.: The Dorn study of smoking and mortality
April,
1979,
Vol.
97, No.
4
Coronary
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