Cardiovascular Drugs and Therapy 1992;6:131-136 © Kluwer Academic Publishers, Boston. Printed in U.S.A.

Cholesterol and Coronary Disease Outstanding Questions Michael F. Oliver Wynn Institute for Metabolic Research, London

Summary. The role of raised blood cholesterol in causing coronary atheroma is established, and a high dietary intake of saturated fat is a leading cause of coronary disease. Reduction of hypercholesterolemia in middle-aged males reduces CHD incidence, mostly nonfatal myocardial infarction. But there are many unresolved questions that should lead to a selective and moderate approach to the management of hypercholesterolemia. These include lack of the exact knowledge of how raised cholesterol leads to atheroma, equivocal evidence of whether reduction of hypercholesterolemia causes regression of atheroma, uncertainty about how far down cholesterol levels can safely be reduced and whether the cost-benefit always justifies action, the fact that reduction of hypercholesterolemia does not reduce total mortality and may increase noncardiac mortality, and insufficient evidence as to whether the same policies should be adopted for women, the elderly, and adolescents as for middle-aged men. Cardiovasc Drugs Ther 1992:6:131-136

Key Words. hypercholesterolemia, atheroma, coronary heart disease, total mortality, women, age

There have been impressive, fundamental, and farreaching advances in our understanding of the causes and management of vascular diseases over the last 30-40 years, and a short review of unresolved or outstanding questions should be prefaced with a brief summary of this progress.

Areas of Agreement An unassailable body of evidence exists to indicate that, experimentally, raised blood cholesterol causes atheroma in the aorta and coronary arteries in many species. In general, the higher the concentration, the greater the extent of atheromatous involvement. This is usually true also in humans. Raised low-density lipoproteins (LDL) and reduced high-density lipoproteins (HDL) are separately and jointly responsible. A second fact, very strongly supported by many epidemiological and experimental studies, is that a high dietary intake of saturated fat is a leading cause of high blood cholesterol and coronary heart disease (CHD). A third area of agreement is that inheritance is a potent determinant of blood cholesterol/lipoprotein

concentrations and lipoprotein receptor activity: indeed, genetic influences probably determine more than half of the plasma lipoprotein concentrations. Fourth--but finally for the moment--there is the impressive congruity of the benefit of reducing hypercholesterolemia. All five major primary prevention trials [1-5] have shown that it is possible to reduce the incidence of CHD in men with initially high plasma concentrations of cholesterol and LDL, and there should no longer be any doubt about the need for aggressive treatment in such men. This is an important economic and therapeutic advance.

Outstanding Questions There are many unresolved issues (Table 1), and some of these have been reviewed recently [6]. The zeal of many health educators for lowering everyone's cholesterol, backed by the U.S. National Cholesterol Education Program [7], in order to reduce CHD, carries the danger of closing the book on the cholesterol question prematurely and in the absence of adequate proof. Problems that the scientific community should address with urgency may be submerged or overlooked, particularly with the commercially based enthusiasm of pharmaceutical companies. These problems need to be identified clearly and include the following. Cholesterol and atheroma While the relationship between high plasma LDL and atheroma is undoubted, the influences that determine how LDL is taken through the arterial endothelium and how its transfer is modulated are mostly unknown. How important is the uptake by macrophages of unmodified LDL through the B/E receptor system? Or is most or all of the LDL taken up in an oxidized, modified or acetylated form [8]? How do reactive oxygen radicals arise locally and from what cell types? Is oxidized LDL present in plasma? To what extent are these processes amenable to control by antioxidant

Address correspondence and reprint requests to Michael F. Oliver, MD, FRCP, Wynn Institute for Metabolic Research, 21 Wellington Road, London, NW8 9SQ UK.

131

132

Oliver

Table 1. Some unresolved problems concerning lipids and atheroma

What are the mechanisms through which raised plasma cholesterol causes atheroma? How does cholesterol leave the arterial wall? Can reduction of hypercholesterolemia cause significantregression of atheroma? How is measurement of atheroma regression best undertaken? How much should cholesterol be reduced? Why does reduction of hypercholesterolemia not also decrease total mortality? Does reduction of hypercholesterolemia increase noncardiac mortality? Why is the relation of cholesterol to vascular disease different in women from men? Why does the relation of cholesterol to vascular disease decrease with age?

vitamins or drugs? How might lipid uptake by macrophages and their conversion to foam cells have a chemotactic effect on circulating monocytes? How do "scavenger" lipoproteins, such as HDL, remove cholesterol from the arterial wall? While transfer enzyme systems are well described, little seems to be known about the kinetics or influences that lead to the removal of cholesterol from deposits in the arterial wall. What is the role, in this regard, of phospholipids, such as phosphatidyl choline [9], facilitating apoA 1 removed of cellular or extracellular cholesterol? Can crystalline cholesterol be mobilized? Regression of atheroma

A particularly important issue is whether it is possible to cause regression of cholesterol-rich atheromatous deposits in coronary or other arteries by lowering LDL cholesterol or raising HDL cholesterol. The preliminary reports are encouraging. One small controlled clinical trial [10] in advanced femoral atherosclerosis, using cholestyramine to lower elevated cholestrol levels, reported nonprogression of lesions over a 13-month period between femoral angiograms. Another [11], comprising 20 treated and 25 control hyperlipidemic men, showed regression of femoral lesions in nearly half of those given fenofibrate and nicotinic acid (see later). Two trials, one using cholestyramine [12] and another using a high polyunsaturated/saturated diet [13], to lower LDL also showed nonprogression in coronary arteries between coronary angiograms. More recently, there have been two trials of the effects of lipid-lowering drugs on coronary atherosclerosis. These suggest that progression can be slowed and that a small degree of actual regression may be achievable over a 2-year period [14, 15]. Another longer trial of 8 years duration, using partial ileal bypass to reduce hypercholesterolemia, has also indicated that reduction of hypercholesterolemia is associated with regression [16] of coronary lesions. More,

larger, well-controlled trials are needed using quantitative coronary angiography. Another unresolved problem is how to interpret changes that may occur in the arterial wail during regression trials [17]. What is the most sensitive index of regression? Is either a change in mean luminal or minimal luminal diameter better than changes in degrees of stenosis? Is it more important, for example, in relation to the primary function of the coronary arteries in supplying blood to the myocardium to achieve a 50% regression of a 30% occlusive lesion (one that is not normally associated with clinical symptoms) or a 20% regression of a 70% occlusive lesion (usually regarded as clinically important)? It is more likely that the former would be able to be demonstrated, while the latter may be the really important test of the regression hypothesis. Will successful regression, as distinct from nonprogression, necessarily be associated with restoration of the arterial wall to a more or less normal state? Successful reduction of arterial lesions presumably would be associated with an increase in platelet-fibrin thrombus formation, and this might carry an increased risk of small emboli passing downstream into the tissues supplied. Many regard the current regression trials as surrogates for clinical trials, because of the expense, large numbers, and duration of clinical trials. But regression trials and clinical trials address very different questions. It is entirely possible for regression or nonprogression of atheroma to be demonstrated, yet, because of continuing or even worsening thrombus formation, no improvement occurs in the incidence of clinical events. Therefore, both are needed. A related issue is to ensure that pharmaceutical companies are not too hasty in interpreting what would appear to be a positive result from regression trials as an indication that the clinical manifestations of heart disease will regress to the same extent. There appear to be many who do not understand that the relationship between coronary atherosclerosis and its clinical manifestations is weak [18]. Cholesterol as a risk factor

While the relative risk of developing CHD in those with elevated plasma cholesterol concentrations, and particularly LDL cholesterol, is four or five times that of those with low levels--and greater when other risk factors are also p r e s e n t - - t h e absolute risk is not so greatly increased: thus, less than 20% of those with marked hypercholesterolemia will develop CHD over a 10-year period [19]. Nevertheless, the public health approach to the cholesterol problem is that everyone in developed nations has concentrations that are too high [20]. This view is even advanced in explanation of the fact that the commonest cause of death in individuals with the lowest concentration of plasma cholesterol is CHD, since it is argued that even these individuals have levels that are unacceptably high. Those who hold this view believe that everyone should

Choleste~vl a~d Coronary Disease

have their plasma cholesterol lowered to levels of 4 mmol/1 or less. An alternative view is that the body requires a "balanced" plasma cholesterol concentration for cellmembrane homeostasis. There is a J relationship between cholesterol and total mortality, and there is an increase in the incidence of cancer and other diseases at the lowest end of the normal distribution. It has been proposed that most of this relates to incident cancer and is a result of this process [21]; yet there are several studies showing that low cholesterol predicts the development of cancer 8, 10, and more years later [22]. Also, there is an inverse relationship between low cholesterol and hemorrhagic (not thrombotic) stroke [23, 24]. If a large proportion of the cholesterol in the blood of a given individual is genetically determined, cellular homeostasis may also be individually modulated. It is not inconceivable that the maintenance of normal biological membrane function, in terms of immune resistance, for example, may demand in some individuals a higher concentration of cholesterol in the plasma than the exponents of the first view would find acceptable.

Reduction of hypercholesterolemia and coronary heart disease The five major primary prevention trials [1-5] and some of the secondary prevention trials indicate that in men reduction of high plasma cholesterol levels is associated with reduction of nonfatal myocardial infarction [25]. But the degree of reduction of cardiac death is less impressive, possibly because of the numbers recruited in these trials have been insufficient to have the power to show an effect. These are two secondary prevention studies (the Coronary Drug Project [26] and the Swedish Secondary Prevention Trial [27]) that have reported reduction of CHD mortality, and both used nicotinic acid. This has long been known to cardiologists as a vasodilator and, since both studies had a majority of patients with myocardial infarction, it is not impossible that the improved mortality was related to decreased left ventricular work rather than a reduction of cholesterol. We need to keep an open mind about this point. None of these trials have shown any reduction in total mortality [28]. While none had the power to examine this question adequately, we should be careful not to dismiss the problem, and the logical step is to wait for the completion of new clinical trials with such power. Clinical trials now being conducted using HGCoA reductase inhibitors, which will lower cholesterol to a far greater extent than the first-generation trials, may show a reduction in total mortality. Reduction of hypercholesterolemia and noncardiac mortality A related and potentially serious issue is the possibility that lowering hypercholesterolemia increases non-

133

cardiac mortality [29]. This has occurred in several primary and some secondary prevention trials. One meta-analysis of six primary prevention trials [30] has reported an overall odds ratio of 1.76 (p < 0.004) for nondisease mortality, and in another of six secondary prevention trials [30] the odds ratio for noncardiac noncancer deaths was 2.10 (p < 0.01). What does this mean? There are three possibilities--a drug effect, chance, or a biological effect. It now seems very unlikely that the increase in noncardiac mortality is due to a drug effect, since it has occurred in trials using four drugs--clofibrate, cholestyramine, gemfibrozil (admittedly, another fibric acid), and nicotinic acid, and a high polyunsaturated/saturated fat diet. The play of chance can seldom be eliminated, and one must recognize that none of the trials individually was designed to test the question of whether reduction of hypercholesterolemia might increase noncardiac mortality. It has been proposed that chance is the likely explanation, because the increase in mortality is spread over a wide variety of diseases, and no plausible explanation for this can be advanced. But it has recently been pointed out that the confidence limits around the adverse finding of an increase in noncardiac mortality are so narrow as to make chance unlikely [31]. Unfortunately, this is also a powerful argument in favor of the most serious of the explanations, namely, the consequences of longterm impairment of normal biological functions of cell membranes. Very little is known about the long-term effects of lowering cholesterol concentrations on the composition of cell membranes, and there are no relevant experimental studies on which to draw. It is possible that a fall in circulating cholesterol concentrations could lead to a permanent reduction of free cholesterol in cell and mitochondrial membranes. Could such a change influence their permeability, enzyme, and immunological responses, or receptor function? Presumably, homeostasis would usually be restored rapidly and would be maintained by cholesterol synthesis, preferential incorporation of cholesterol into affected membranes, or other adjustments within the phospholipid bilayers. But would such homeostatic mechanisms be effective in all patients, at all times, in all cells--particularly cells in which biological function is impaired for other reasons? These doubts will not go away for several more years. Trials of hydroxymethylglutaryl coenzyme A reductase inhibitors, which reduce serum cholesterol much more effectively than earlier agents, should help to resolve these problems, but they will not be available until 1995 or later, and may still not decide the biological importance of depletion of membrane lipid. Although there is clear evidence that some populations with very low serum cholesterol concentrations have no excess noncardiac mortality, such steadystate observations are unhelpful. The question that arises from the trials of the last 25 years is whether

134

Oliver

reducing previously high cholesterol concentrations is always safe, and not whether having a naturally low cholesterol is always harmless. Cholesterol and women In contrast to men, there is no strong relationship in women between LDL and HDL cholesterol, on the one hand, and CHD mortality, on the other: The correlation coefficient between total cholesterol and CHD mortality in 19 countries with accurate death certification (WHO standards) is + 0.67 for men and a nonsignificant + 0.24 for women [32]. Familial hypercholesterolemia may be an exception. The relationship between plasma cholesterol as a predictor of CHD in women in comparison with men and, effectively, it disappears by the age of 50. Why is this? One explanation may be that the levels of LDL/HDL needed to produce extensive coronary atheroma do not occur in women until after the menopause and that it may be necessary for such concentrations to be present for 15-20 years to produce CHD. The demonstration of any relationship between lipoproteins and CHD in women would then be difficult because of the confounding and diluting factors of other diseases in women in their 70s. None of the clinical trials have been conducted in women, and it is a false extrapolation to assume that the benefits regarding nonfatal myocardial infarction shown by treatment of middle-aged hypercholesterolemic men will apply to women. This is an important issue insofar as more than half of the adult population are women. Screening programs and health education programs directed vigorously at women may be uneconomic and unjustified. It does seem fairly clear, however, that estrogen replacement therapy has reduced the incidence of CHD strikingly [33]. It has yet to be shown whether hormone replacement therapy (opposed estrogens, as distinct from estrogens alone) have such a beneficial effect. Age and cholesterol The relation between cholesterol and vascular disease decreases in both sexes with advancing age. This may be because most of the cholesterol-related deaths have already occurred, but also because other diseases become proportionately more common. It has yet to be demonstrated that changing the lifestyle of elderly people or lowering their cholesterol reduces their risk of developing CHD or other vascular disease. Perhaps it would be less intrusive for the quality of their lives if they were left alone. Yield from reducing blood cholesterol concentrations There is a dilemma, which health educators and cardiologists/physicians tend to resolve differently. It is illustrated in Figures 1 and 2. Both of these show the relationship between the distributions of cholesterol

-40

14"~

m n

12'

-30

i:i=~~i:i:,ii

LU

ii,ii,i

1o. W n

a a o

o

i ii: I

i ~ i.ii:I

i i.ii i i i

:: ::: :

• 20

z LU W n

!

"10

i~i ~i~ 190

[]

220

N

I

!

!

I

250

280

310

340

D

[]

N

o 370 mg/dl

mmo,,

SERUM TOTAL CHOLESTEROL

Fig. 1. Prevalence distribution of scram total cholesterol (histogram) related to coronary heart disease mortality (curve). Adapted from Framingham data [34].

and CHD. Figure 1 emphasizes that the majority of the population does not have very high concentrations [34] and is the basis of the view that a population approach is the sounder policy with a numerically higher yield. Figure 2 is constructed from the 360,000 men in the control population of the MRFIT [35] and shows the curvilinear relation. It emphasizes that proportionately the greatest yield is when action is taken against marked hypercholesterolemia. Figure 2 also illustrates how little can be expected from reducing cholesterol below about 5.2 mmol/1. Education

Atheromatous vascular disease and coronary heart disease will not disappear as a result of lowering cholesterol and treating abnormal lipoproteins. Those who claim that it will are either naive or ignorant of the pathogenesis of the disease. Therefore, much needs to be done to educate the public correctly, and it is the responsibility of those close to the field of lipids and vascular disease to provide the right balance. The areas of agreement should be clearly and consistently presented. Excessive claims, false expectations, and nihilism must all be resisted. It is also necessary to educate our own profession. There are four risk factors, not three. They are smoking, raised cholesterol, raised blood pressure, and physicians. Cardiologists and physicians in many countries still need to be convinced of the need for aggressive action to lower high blood cholesterol. One reason for their casual interest is that their duty is to diagnose and treat advanced disease, and many are overwhelmed by the load of clinical problems. Another is skepticism. Others include a legitimate suspi-

Cholesterol and Coronary Disease

135

20 Age-Adjusted 6- year Death Rate per 1,000 Men

15

-A A=9

10

B=3

C=1

5 0

Percentile Serum Cholesterol

I

I

I

I

I

I

I

I

I

I

5 15 25 35 z,5 55 65 75 85 95 157 175 187 198 207 216 226 238 253 281 mg/dl t,.1 4.5 4.7 5.1 5.z, 5-6 5.9 6-2 6"6 7.3 mM/I

Age-adjusted CH D and total 6-year death rate per 1000 men screened for MRFIT according to serum cholesterol percentiles. Fig. 2. Proportions of coronary deaths likely to be saved according to policy regarding reduction of serum cholesterol. A relates to reduction of serum cholesterol from 7.3 to 5.0 mmol/l and might lead to 9 fewer deaths per 1000 men over 6 years. B shows that reduction of serum cholesterol from 5.9 to 5.2 mmol/l might lead to 3 fewer deaths per 1000 men over 6 years. C shows that reduction of serum cholesterol from 5.2 mmol/l to 4.3 mmol/1 might decrease the death rate by 1/1000 over 6 years. (Adapted from M R F I T data [35], with permission.)

cion of public campaigns promoted by self-appointed health educators and of the increasing intrusion into clinical judgment by pharmaceutical companies. But there is sufficiently well-documented evidence to recommend that dietary advice aimed at less than 30% of calories from fat and a polyunsaturated/saturated fat ratio of about 1.0 should be given to those with serum cholesterol consistently in the region of 6.5 mmol/1, particularly if other risk factors are present: cholesterol lowering drugs may be needed for control of concentrations above 7.0 mmol/1 and will be necessary for levels at 8.0 mmol/1 and above. Decisions to treat hypercholesterolemia should always be based on determinations using methodology with acceptable quality controls: they should allow for methodological and biological variations, as well as regression to the mean.

Conclusion The balance of knowledge favors aggressive action against unequivocal hypercholesterolemia. But the unsettled questions presented in this brief review are sufficiently serious so as to limit this advice to young and middle-aged men. It is necessary also to recognize that the cost-benefit ratio of lowering cholesterol from moderate to low concentrations may not be advantageous. The problem of an increase in noncardiac mortality is real and needs careful monitoring in the future and appropriate research.

References 1. Dayton S, Pearce ML, Hashimoto S, et al. A controlled trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 1969:39/40 (Suppl II):II1II63. 2. Turpeinen O, Karvonen M J, Pekkarinen M, et al. Dietary prevention of coronary heart disease: The Finnish Mental Hospital Study. Int J Epidemiol 1979;8:99-118. 3. Report from the Committee of Principal Investigators. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 1978;40:10691118. 4. Lipid Research Clinics Coronary Prevention Trial. I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. J A M A 1984;251:351-374. 5. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidaemia. N Engl J Med 1987;317:1237-1245. 6. Grundy SM. Cholesterol and coronary heart disease. J A M A 1990;264:3053-3059. 7. Lenfant C. A new challenge for America: The National Cholesterol Education Programme. Circulation 1986;73:855856. 8. Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol: Modifications of low density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924. 9. Stein Y, Glangeaud MC, Fainaru M, Stein O. The removal of cholesterol from aortic smooth muscle cells in culture and Landschutz ascites cells by fractions of human high-density apolipoprotein. Biochim Biophys Acta 1975:380:106-118. 10. Duffield RG, Lewis B, Miller NE, et al. Treatment ofhyper-

136

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

Oliver

lipidaemia retards progression of symptomatic femoral atherosclerosis. A randomised controlled trial. Lancet 1983; 2:639-642 Olsson AG, Ruhn, G. Erikson U. The effect of serum lipid regulation and the development of femoral atherosclerosis in hyperlipidaemia: A non-randomized controlled study. J Intern Med 1990;227:381-391. Brensike JF, Levy RI, Kelsey SF, et al. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: Results of the NHLBI Type II Coronary Intervention Study. Circulation 1984;69:313-324. Arntzenius AC, Kromhout D, Barth JD, et al. Diet, lipoproteins and the progression of coronary atherosclerosis. The Leiden Intervention Trial. N Engl J Med 1985;312:805-811. Blankenhorn DH, Nessim SA, Johnson RL, et al. Beneficial effects of combined colestipolniacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 198;3233-3240. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323:1289--1298. Buchwald H, Varco RL, Matts PJ, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolaemia: Report of the Programme on the Surgical Control of Hyperlipidaemias (POSCH). N Engl J Med 1990;323:946-955. De Feyter PJ, Serruys PW, Davies MJ, et al. Quantitative coronary angiography to measure progression and regression of coronary atherosclerosis. Circulation 1991;84:412423. Oliver MF. Prevention of coronary heart disease--propaganda, promises, problems and prospects. Circulation 1986;73:1-10. The Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events. J Chron Dis 1978;32:201-306. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults. Arch Intern Med 1988;148: 36-69. Epstein FH. The effect of coronary heart disease prevention on the prevention of non-cardiovascular diseases. In: Prog. 7th International Meeting on Atherosclerosis and Cardio-

22.

23.

24.

25.

26.

27.

28. 29. 30.

31.

32.

33.

34.

35.

vascular Diseases. Bologna 1991, Kluwer Academic Publishers. In Press. Isles CG, Hole DJ, Gillis CR, et al. Plasma cholesterol, coronary heart disease and cancer in the Renfrew and Paisley survey. Br Med J 1989;298:920-924. Iso H, Jacobs DR, Wentworth D, et al. Serum cholesterol levels and six year mortality stroke in 350,977 men screened for MRFIT. N Engl J Med 1989;320:904-910. Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989;20:1460-1465. Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction. N Engl J Med 1990;16:1112-1120. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: Long-term benefit with niacin. J A m CoU Cardiol 1986;8:1245-1255. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988;223:405-418. Oliver MF. Reducing cholesterol does not reduce mortality. J A m Coll Cardiol 1988;12:814-817. Oliver MF. Might reduction of hypercholesterolaemia increase non-cardiac mortality. Lancet 1991;337:1529-1531. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: A quantitative review of Br Med J 1990;301:309-314. Naylor CD, Basinski A, Frank JW, Rachlis MM. Asymptomatic hypercholesterolaemia: A clinical policy review. J Clin Epidemiol 1990;43:1029-1121. Simons LA. Interrelations of lipids and lipoproteins with coronary artery mortality in 19 countries. A m J Cardiol 1986;57:5G-10G. Ross RK, Pike MC, Mack TM, Henderson BE. Oestrogen replacement therapy and cardiovascular disease. In: Drife JO, Studd JWW, eds. Hormone replacement therapy and osteoporosis. London: Springer-Verlag, 1990:209-222. Dawber TR. The Framingham Study. The epidemiology of atherosclerotic disease. Cambridge, MA: Harvard University Press, 1980. Martin MJ, Hulley SB, Browner WS, et al. Serum cholesterol, blood pressure and mortality: Implications from a cohort of 361,662 men. Lancet 1986;2:933-936.