Preventive cardiology: A progress report

PREVENTIVE

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19, 78-96 (1990)

Preventive Cardiology: A Progress Report’ KALEVI PY~RALA, M.D. Department of Medicine, University of Kuopio, 70210Kuopio, Finland The progress to the current era of preventive cardiology covers a period of more than 40 years, beginning with epidemiological studies on coronary heart disease and other forms of atherosclerotic disease and related factors and progressing through prevention trials and community demonstration projects to the actual implementation of preventive measures by combined population and high-risk strategies. The scientists of the United States have played a leading role in the data collection which forms the scientific basis for preventive cardiology and the fruitful collaboration in the United States between the scientists and governmental, as well as nongovernmental, organizations in the implementation of preventive cardiology has served as a good example for other countries. The Section on Epidemiology and Prevention of the International Society and Federation of Cardiology and the Cardiovascular Diseases Unit of the World Health Organization, working in close liaison, have had key roles in the worldwide promotion of preventive cardiology. The rapid progress in preventive cardiology during the past 4 years, since the 1st International Conference of Preventive Cardiology, has been dominated by a “snowballing” movement toward more intensive application of cholesterol-lowering measures at both the population and the individual level. Promising progress has also been made in the field of nonpharmacological control of elevated blood pressure. 6 1990Academic press, IN.

INTRODUCTION It is more than appropriate that this 2nd International Conference on Preventive Cardiology is being held in the United States, because cardiovascular epidemiology and preventive cardiology started in this country. Soviet scientists under the leadership of academician Evgeny Chazov had a good sense of the future direction of the winds, when they took the initiative for the arrangement of the 1st International Conference on Preventive Cardiology, held in Moscow in June 1985. That conference proved to be a great success and U.S. scientists, under the leadership of Dr. Jeremiah Stamler, took as their task the organization of the next conference. Now, here we are, assembled in the capital of the United States, at the roots of preventive cardiology. I shall in the latter part of this progress report review some major steps in the field of preventive cardiology during the last 4 years since the 1st International Conference on Preventive Cardiology, but first I shall review some earlier developments extending over a period of more than 40 years that laid the groundwork for modem preventive cardiology. I will try to take a bird’s-eye view, as a nonAmerican, on the role of the United States and its scientists in these developments, not only within the borders of this country, but from an international standpoint.

’ Presented at the 2nd International Conference on Preventive Cardiology and the 29th Annual Meeting of the AHA Council on Epidemiology, June 18-22, 1989, Washington, DC. 78 0091-7435/90$3.00 Copyright Q I!?30by Academic Press, Inc. All rights of reproduction in any form reserved.

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I shall also highlight the role of international organizations in the development of the current era of preventive cardiology. THE ROLE OF THE UNITED STATES AND ITS SCIENTISTS IN THE DEVELOPMENT OF PREVENTIVE CARDIOLOGY The first prospective epidemiological studies on coronary heart disease (CHD) and related factors were started more than 40 years ago, the Minnesota Businessmen Study in 1947 (1) and the Framingham Study in 1948 (2). During the 1950s several other new prospective studies were started in the United States and Ancel Keys carried out the first pilot studies in a number of other countries on betweenpopulation differences in the occurrence of CHD and related factors which then led to the initiation of the Seven Countries Study (3). That study served as a stimulus in many of the participating countries for national research on the epidemiology of cardiovascular diseases (CVD), and, at least in my own home country-Finland, its results also gave rise to an awareness of the possibilities for the prevention of these diseases and that was of great importance for later developments. The International Atherosclerosis Project (4), a comparative autopsy study on the occurrence of atherosclerosis carried out in 19 populations from different parts of the world, was another major international study initiated from the United States in the 1950s. The pioneer cardiovascular epidemiologists in this country and elsewhere had as their goal to identify changeable factors causally related to CHD and other forms of atherosclerotic disease and to acquire the scientific basis for the prevention of these diseases. As critical scientists they were, to begin with, rather reluctant to use the word “prevention” in their papers and talks, as has been pointed out by one of these pioneer scientists, Dr. Frederick H. Epstein, in a recent review on the history of CHD epidemiology over 40 years (5). In 1953 Dr. Ancel Keys gave a lecture entitled “Prediction and Possible Prevention of Coronary Disease” (6), but according to the notes of Dr. Epstein he did not actually use the word “prevention” in his talk. Furthermore, according to Dr. Epstein’s notes, in a Symposium on Epidemiology of Cardiovascular Disease, held in 1954 in Washington, D.C., as part of the 2nd World Congress of Cardiology and chaired by Drs. Paul Dudley White and Ancel Keys, only one of the speakers, Dr. Jerry Morris from London, mentioned prevention as the ultimate goal of the research in the field of cardiovascular epidemiology (7). The initial call for prevention of CHD and other atherosclerotic disease was the “Statement on Arteriosclerosis, Main Cause of ‘Heart Attacks’ and ‘Strokes’ ” (8), coauthored in 1959by a group of cardiologists and cardiovascular researchers in this country, including Drs. Paul Dudley White, Louis N. Katz, Samuel Levine, Irvine H. Page, Howard B. Sprague, Frederick J. Stare, Irving S. Wright, and the President of this Conference, Dr. Jeremiah Stamler. This document, written 30 years ago based on early clinical and epidemiological observations called attention to three traits-elevated blood cholesterol, elevated blood pressure, and cigarette smoking-later designated to be the major CHD risk factors, as well as to overweight and a positive family history of premature CVD. I quote from the statement aimed at the public: “You can’t change your heredity, but you can intluence

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the other factors and hence lessen your chances of being a victim of cardiovascular disease. If there is a history of cardiovascular trouble in your family, it just means you should be especially careful about factors you can control. On the key factors of overweight, cholesterol count, blood pressure and cigarette smoking, you should without fail consult your physician.” The term “risk factor” for CHD was evidently used for the first time in a publication from the Framingham Study in 1961 (9). The importance of the three major risk factors-elevated serum cholesterol (TC), elevated blood pressure (BP), and smoking-became clear during the 1960s from many prospective epidemiological studies carried out in the United States and elsewhere and the era of primary prevention of CHD by risk factor modification trials followed. Table 1 lists the major trials of primary prevention of CVD carried out in the United States, by the year of publication of their results. Early trials on primary prevention of CHD through intervention (cholesterol-lowering diets) were already being planned and launched in the late 1950s including the Los Angeles Veterans Administration Domiciliary Facility Diet Trial which reported its promising results in 1969 (12). Another pioneer trial of primary prevention of CHD by dietary fat modification, the Finnish Mental Hospital Study, was going on in Europe at the same time and reported its positive results in 1972 (17). Meanwhile, a feasibility study of a major unifactorial diet trial, the National Diet-Heart Study (ll), had been completed in the United States, but this feasibility study did not lead to the start of the trial itself for practical reasons and planning was switched to a multifactorial primary prevention trial carried out later with the name Multiple Risk Factor Intervention Trial (MRFIT) (15). Simultaneously with MRFIT, two major multifactorial trials of primary prevention of CHD were carried out in Europe, the Oslo Study (18) and the WHO European Collaborative Trial in the Multifactorial Prevention of Coronary Heart Disease in the United Kingdom, Belgium, Italy, Poland, and Spain (19). The Veterans Administration Trial on Drug Treatment of Moderate Hypertension which published its results in 1967 (10) was actually the first controlled trial of CVD prevention ever published. This trial and its extension, the Veterans Administration Trial on Drug Treatment of Mild Hypertension, the results of which were published in 1970(13), were of decisive importance for the worldwide development of hypertension control. The Hypertension Detection and Follow-up Program trial on the drug treatment of hypertension (14) and its counterparts on TABLE 1 MAJORTRIALS OF PRIMARYPREVENTIONOF CARDIOVASCULARDISEASES CARRIED OUT IN THE UNITED STATES,BY THE YEAR OF PUBLICATION OF THEIR RESULTS 1967

1968 1%9 1970 1979 1982 1984

V.A. Trial on Drug Treatment of Moderate Hypertension (10) National Diet-Heart Study (11) Los Angeles V.A. Diet Trial (12) V.A. Trial on Drug Treatment of Mild Hypertension (13) Hypertension Detection and Follow-up Program in a general population sample (14) Multiple Risk Factor Intervention Trial (15) Lipid Research Clinics Coronary Primary Prevention Trial (16)

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other continents, the Australian (20) and the British Medical Research Councils’ (21) trials on the drug treatment of mild hypertension, then further extended the scientific basis for the current policy of the use of drugs in the treatment of hypertension. The Lipid Research Clinics Coronary Primary Prevention Trial (16) added important confirmatory information on the beneficial effect of serum cholesterol-lowering in the prevention of clinical CHD events and the publication of its results in 1984 was the final stimulus for the development of an intensified policy for cholesterol-lowering in the United States. Translation of scientific information into preventive practice and public health policy is a complex process that requires the active participation of leading scientists. The president of this conference, Dr. Jeremiah Stamler, is an outstanding example of a scientist who along with his leading role in research has also dedicated his work to the development of public health policy for the prevention of CVD. He was apparently the first to use the term “preventive cardiology” in its broad sense-in the same spirit in which we have assembled at this conference in his book Lectures on Preventive Cardiology published in 1967(22). At that time most clinical cardiologists, including myself, trained for catheterization laboratory work, could not conceive of the potential for prevention of cardiovascular diseases and raised our eyebrows at the thought that prevention would somehow relate to cardiology. Stamler’s Lectures in Preventive Cardiology pointed out the widespread occurrence of increased CHD risk in the population and the need for a wide scope of action in prevention. Dr. Frederick H. Epstein in his George C. Griffith Lecture in 1971 further developed the concept of prevention strategies and described the principles of the “clinical-individual” and “community” approach to prevention (23). According to his review article on this subject (24), he used the term “clinical” deliberately to draw attention to the role and responsibility of practicing physicians in prevention. During the 1960sand the 1970sthere was an increasing exchange of experiences between U.S. scientists and scientists working elsewhere in the field of cardiovascular epidemiology and prevention. In 1979 the leading British epidemiologist, Dr. Geoffrey Rose, published his famous paper on strategies of prevention and introduced the terms “high-risk strategy” and “mass strategy” (25). “Mass strategy” later became changed to “population strategy” and this became a key term in the further development of preventive strategies. The first public health trials and community research demonstrations testing the overall feasibility of CHD prevention in the population were launched in the United States and Europe in the early 1970s. The Stanford Heart Disease Prevention Trial took the initiative in the United States in the form of the Three City Project under the leadership of Dr. John Farquhar (26). At the same time, in Europe, the North Karelia Project was started in Finland (27). Experience from these pioneer projects gave background to the Five City Project in California, the next phase of the Stanford Heart Disease Prevention Program, and simultaneously other community programs for CHD prevention were launched in the United States, in Minnesota under the leadership of Dr. Henry Blackburn, and in Rhode Island under the leadership of Dr. Richard Carleton. These community

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programs had counterparts in several European countries and also in other parts of the world. We non-Americans have always admired the efficiency and practicality with which existing scientific information has been translated into preventive practice and public health policy in the United States. Progress in prevention has not been blocked by too much skepticism; when information available from basic sciences, clinical and epidemiological research, and prevention trials has been judged as substantial enough evidence to justify action, action has been taken. Table 2, which is by no means comprehensive, lists the major steps taken in the United TABLE 2 MAJORSTEPSINTHEDEVELOPMENTOFPUBLICHEALTHPOLICYFORTHEPREVENTIONOF CORONARYHEARTDISEASEANDSTROKEINTHEUNITEDSTATES 1959 1960 1%1 1964 1970 1970 1971 1971 1972 1977 1977 1979 1980 1980 1981 1984 1984 1985 1985 1988 1988 1989

Statement on Arteriosclerosis; Main Cause of “Heart Attacks” and “Strokes,” by a group of leading scientists (8) American Heart Association’s Statement on Cigarette Smoking and Cardiovascular Disease (28) American Heart Association’s Statement on Dietary Fat and Its Relation to Heart Attacks and Stroke (29) Report of the Advisory Committee to the Surgeon General on Smoking and Health (30) Inter-Society Commission for Heart Disease Resources: Recommendations for Primary Prevention of the Atherosclerotic Diseases (31) White House Conference on Food, Nutrition and Health (32) Task Force on Arteriosclerosis of the National Heart and Lung Institute (33) Inter-Society Commission for Heart Disease Resources: Guidelines for the Detection, Diagnosis and Management of Hypertensive Populations (34) National High Blood Pressure Education Program launched Select Committee on Nutrition and Human Needs. U.S. Senate Dietary Goals for the United States (35) Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (36) The Surgeon General’s Report on Health Promotion and Disease Prevention (37) U.S. Department of Agriculture and U.S. Department of Health, Education and Welfare: Nutrition and Your Health (38) Bethesda Conference on Prevention of Coronary Heart Disease, sponsored by the American College of Cardiology, American Heart Association, Center for Disease Control, National Heart, Lung, and Blood Institute (39) Report of the Working Group on Arteriosclerosis of the National Heart, Lung, and Blood Institute (40) Inter-Society Commission on Heart Disease Resources: Optimal Resources for Primary Prevention of Atherosclerotic Diseases (41) Consensus Development Conference Statement: Lowering Blood Cholesterol to Prevent Heart Disease (42) National Cholesterol Education Program launched National Heart, Lung, and Blood Institute Smoking Education Program launched The Surgeon General’s Report on Nutrition and Health (43) Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (44) National Academy of Science and National Research Council Report on Diet and Health (45)

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States during the last 30 years on the road toward the current era of preventive cardiology. A remarkable feature of this impressive list is the joint involvement of the scientific and public health arms of the American Heart Association, other scientific and professional organizations, as well as governmental organizations, with the strong and leading involvement of the National Heart, Lung, and Blood Institute (NHLBI). The 1980 Bethesda Conference on Prevention of Coronary Heart Disease (39), cosponsored by the American College of Cardiology, American Heart Association, Centers for Disease Control, and National Heart, Lung, and Blood Institute was an important landmark toward more intensive involvement of physicians in preventive practice. The development of an antismoking policy and a nutrition policy, and the successful implementation of the National High Blood Pressure Education Program and more recently of the National Cholesterol Education Program and the NHLBI Smoking Education Program have set excellent examples for other countries to follow. THE ROLE OF INTERNATIONAL ORGANIZATIONS IN THE PROMOTION OF PREVENTIVE CARDIOLOGY Two international organizations have been of decisive importance in the development of preventive cardiology worldwide, the International Society and Federation of Cardiology and the World Health Organization. The International Society of Cardiology was established in 1950 and after merging with the Intemational Cardiology Federation became the International Society and Federation of Cardiology (ISFC). At the 5th World Congress of Cardiology, held by the ISFC in New Delhi in 1966, eight Scientific Councils were established to function as the official scientific arms of the organization. One of these was the Scientific Council on Epidemiology and Prevention. The recognition that primary prevention is a key strategy in the control of epidemic cardiovascular diseases, particularly CHD, was one of the basic ideas in the framework of this Council. From its very beginning the Council on Epidemiology and Prevention was organized to form as its background a Section open to physicians and other scientists interested in the epidemiology and prevention of CVD. Dr. Ancel Keys was the first Chairman of the Council, followed by Dr. Jerry Morris, Dr. Jeremiah Stamler, Dr. Geoffrey Rose, myself, and Dr. Henry Blackbum. The Section on Epidemiology and Prevention now has more than 800 members. Promotion of training in the field of cardiovascular epidemiology and prevention has been one of the central activities of the Council and this has been carried out by holding annual IO-Day Intemational Teaching Seminars on Cardiovascular Epidemiology and Prevention. The first lo-Day Seminar was held in Makarska, Yugoslavia, in 1968. I had the privilege of being a participant in that Seminar which changed the direction of my scientific work and professional life, as these seminars have done for many other physicians and scientists since then. To date, twenty-one IO-Day Seminars have been held in different parts of the world and more than 700 physicians or biomedical scientists from more than 70 countries have participated. The example of the IO-Day International Teaching Seminar has stimulated the initiation of regional and national teaching seminars and courses, but the international seminar still continues to attract large numbers of qualified applicants.

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The lO-Day International Teaching Seminars have not only stimulated epidemiological research and public health policy development in the participants’ home countries but have also led to the development of collaborative international research activities, e.g., the WHO European Collaborative Trial in the Muhifactorial Prevention of Coronary Heart Disease (19) which was initiated by participants of the Blessington Seminar held in Ireland in 1970, and the International Collaborative Group joint analyses of data from 15 population studies in 11 countries on the relationship between hyperglycemia and CHD (46), as well as on the relationship between serum TC and the risk of death from cancer, in pooled data from 11 prospective studies in eight countries (47). INTERSALT-an intemational study on electrolyte excretion and BP (48)-was the most recent and the largest of the international research activities of the Council and its Section, covering 52 population samples from 32 countries. The idea for the INTERSALT Study was conceived at the Tuohilampi Seminar held in Finland in 1982. The World Health Organization’s Cardiovascular Diseases Unit, established as part of the WHO Headquarters in Geneva in 1959, has had a leading role in the international promotion of prevention of CVD. The WHO Cardiovascular Diseases Unit has had a series of capable scientists and leaders as its chiefs; Dr. Zdenek Fejfar was the first chief, followed by Dr. Zbynek Pisa, Dr. Silas Dodu, Dr. Siegfried Bothig, and Dr. Ivan Gyarfas. The main approach in the WHO work has been to arrange expert committee, study group, or working group meetings involving known experts representing different parts of the world. WHO has also initiated and stimulated international collaborative research and promoted the development of public health policy for CVD prevention. The WHO’s Cardiovascular Diseases Unit and the International Society and Federation of Cardiology have had a close and fruitful liaison throughout their existence. Table 3 lists some landmarks in the activities of the WHO in the development of public health policy for the prevention of cardiovascular diseases; these activities started in the 1950s (even before the formal creation of the Cardiovascular Diseases Unit) with the assessment of the possibilities of prevention of rheumatic fever and rheumatic heart diseasea great problem in many parts of the world. During the 1960s and the 1970sthe emphasis of the WHO work switched to CHD and hypertension and in the 1980s the road toward public health policy for CVD prevention became clearly marked. The 1982 WHO Expert Committee Report on Prevention of Coronary Heart Disease (58) was an important landmark, because it laid down the main guidelines of a comprehensive plan for CHD prevention among entire populations. These guidelines have become widely accepted and endorsed by regional and national groups of experts and now form the basis of national plans for CHD prevention in many countries. In 1982, in connection with the Ninth World Congress of Cardiology, held in Moscow, the International Society and Federation of Cardiology and WHO decided to launch a new intensified effort to develop model programs for rheumatic fever/rheumatic heart disease prevention on a population-wide basis. The progress in this field has been evaluated at a recent WHO Study Group meeting reporting in 1988 (65). The titles of other recent WHO report-primary prevention of essential hypertension, prevention of CVD among the elderly, hyperten-

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TABLE 3 LANDMARKS IN THE ACTIVITIES OF THE WORLD HEALTH ORGANIZATION IN THE DEVELOPMENT OF PUBLIC HEALTH POLICY FOR THE PREVENTION OF CARDIOVASCULAR DISEASES

1954 1957 1962 1966 1971 1973 1974 1977 1979 1982 1983 1983 1985 1986 1987 1988 1988 1989 1989

Expert Committee Report on Rheumatic Diseases (49) Expert Committee Report on Prevention of Rheumatic Fever (50) Expert Committee Report on Arterial Hypertension and Ischaemic Heart Disease (51) Expert Committee Report on Prevention of Rheumatic Fever (52) Working Group Report on Methodology of Multifactor Preventive Trials in Ischaemic Heart Disease (53) Working Group Report on Methodology of Multifactor Preventive Trials in Ischaemic Heart Disease (54) Report on a European Conference on the Prevention and Control of Major Cardiovascular Diseases (55) Working Group Report on the Prevention of Coronary Heart Disease (56) Expert Committee Report on Smoking Control (57) Expert Committee Report on Prevention of Coronary Heart Disease (58) Expert Committee Report on Smoking Control Strategies in Developing Countries (59) Scientific Group Report on Primary Prevention of Essential Hypertension (60) Report on a WHO Meeting on Primary Prevention of Coronary Heart Disease (61) Expert Committee Report on Community Prevention and Control of Cardiovascular Diseases (62) Report of a Meeting on Prevention of Cardiovascular Diseases among the Elderly (63) Report of a Meeting on the Development of Methodology for Prevention and Control of Hypertension in Developing Countries (64) Study Group Report on Rheumatic Fever and Rheumatic Heart Disease (65) Expert Committee Report on Prevention in Childhood and Youth of Adult Cardiovascular Diseases (66) Study Group Report on Diet, Nutrition, and Prevention of Non-Communicable Diseases (67)

sion control in developing countries, prevention of adult cardiovascular diseases in childhood and youth, nutrition and prevention of chronic diseases, including cardiovascular diseases-outline the future directions of the worldwide developments in preventive cardiology. MAJOR STEPS IN THE FIELD OF PREVENTIVE CARDIOLOGY DURING THE LAST 4 YEARS Against this background of 40-year progress from early epidemiological studies toward preventive cardiology, in both clinical practice and public health policy, I shall, in the following pages, offer some reflections on more recent developments. Progress in the Application of Cholesterol-Lowering Measures A “snowballing” boom of interest in the cholesterol-CHD question has dominated the scene in preventive cardiology for the past few years. This movement was initiated by the NIH Consensus Development Conference Statement Lowering BZood Cholesterol to Prevent Heart Disease in 1984 (42). This statement emphasized the need for a combined population and high-risk strategy and thus reinforced the recommendations of the 1982 WHO Expert Committee Report on Prevention of Coronary Heart Disease (58). The National Cholesterol Education Program was launched in the United States in 1985and as part of this program the

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Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in 1987 gave its guidelines for the high-risk strategy of cholesterol-lowering (44). At the same time a Study Group of the European Atherosclerosis Society formulated its policy statement on the recognition and management of hyperlipidemias in adults (68, 69). These two recommendations are very similar with regard to the classification of adult individuals into risk categories based on serum TC levels and have formed the basis for national recommendations in many countries. The publication of the 6-year follow-up data on almost 360,000 middle-aged men screened for the Multiple Risk Factor Intervention Trial (70, 71) ultimately had a great impact on the wide acceptance of the cholesterol-CHD hypothesis. Basically, the same information had been available for a long time from numerous population studies, in particular from the so-called Pooling Project, combining data from several prospective studies from the United States (72). Due to the huge number of men included in the MRFIT screenee follow-up study, this study was able to look at the cholesterol-CHD relationship with better precision than any of the earlier studies. This study demonstrated beyond any doubt that the risk of CHD has already begun to increase at TC levels below 200 mg/dl(5.2 mmole/liter) and becomes about two times higher at cholesterol levels of 250 mg/dl (6.5 mmole/liter) and four times higher at cholesterol levels of 300 mg/dl (8.0 mmolefliter). The MRFIT screenee follow-up data also presented a better opportunity than ever before to demonstrate joint effects of the three major risk factors-serum TC, blood pressure, and smoking-n the risk of CHD. For any given level of serum cholesterol, coexistent hypertension or smoking was shown to increase the risk of CHD death; the coexistence of all three factors was shown to be associated with a significant increase in the risk of CHD death (73). The best-off group, non-smoking, normotensive men in the lowest serum cholesterol quintile had an age-standardized CHD death rate of only 1.6/1000 in 6 years, whereas in the worst-off group, smoking, hypertensive men in the highest serum cholesterol quintile CHD death rate was as high as 21.4/1000 men in 6 years. An important point was that the lowest risk group constituted only 10% of the U.S. male population. A large prospective population study carried out in Shanghai, Peoples’ Republic of China (74) has extended observations on the cholesterol-CHD relationship to TC levels below 200 mg/dl (5.2 mmole/liter). This study confirms that even at these low TC levels, the risk for CHD increases with increasing cholesterol levels. Another set of data which has had a great impact particularly among cardiologists comes from studies using their own tools, repeated coronary angiograms, in the assessment of the effect of serum lipid levels and their lowering on the progression of coronary atherosclerosis. The National Heart, Lung, and Blood Institute Type II Coronary Intervention Study (75) and another angiographic study carried out in Finland (76) published in 1984 had already shown that progression of coronary atherosclerosis may be retarded by cholesterol-lowering drug therapy. An important additional piece of evidence came from a study carried out in Leyden, The Netherlands (77). That study was a 2-year intensive diet-intervention study and it showed that there was a direct relationship between the serum K/high-density lipoprotein cholesterol (HDL-C) ratio and progression of coro-

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nary atherosclerosis. The most impressive demonstration of the effect of cholesterol-lowering on the progression of atherosclerosis came, however, from the so-called Cholesterol-Lowering Atherosclerosis Study (CLAS study) carried out in this country (78). In this 2-year randomized study the effect of lipid-lowering by combined cholestipol-nicotinic acid treatment was compared with placebo in diettreated non-smoking men who had undergone coronary bypass surgery. In the drug-treated group serum TC decreased by 26%, serum triglycerides (TG) by 22%, and low-density lipoprotein (LDL-C) by 43%; HDL-C increased by 37%, whereas serum lipid levels remained essentially unchanged in the placebo group. Repeated angiograms showed that regression of atherosclerotic lesions occurred more often among the drug-treated group than the placebo group, 16% vs 2%, and there was less progression of lesions in the drug-treated group. With respect to both native and grafted vessels, lipid-lowering treatment significantly reduced both the appearance of new lesions and progression of already existing lesions. It was of great interest that this benefit from cholesterol-lowering was not confined to those with exceptionally high TC levels, but was observed also in patients with serum TC levels around 200 mg/dl (5.2 mmolefliter). Dr. Richard Peto and his co-workers in Oxford have carried out very useful overview analyses combining the results of randomized controlled trials of serum cholesterol-lowering by either diet or drug treatment (79; Peto, personal communication). These analyses have shown that the reduction in CHD incidence in these trials has been directly proportional to the size of the serum TC difference achieved between the treated group and the control group. Furthermore, the reduction in CHD incidence from a 10% difference in serum TC has been greater-22Yein “longer” trials (that actually were not very long) than in “short” trials with only a 9% reduction. Projections from observational epidemiology, however, suggest that life-long reduction of cholesterol level would lead to an even more marked reduction in CHD incidence. Thus, there is good scientific basis for a combined population and high-risk strategy for cholesterol-lowering. Now, when new potent cholesterol-lowering drugs, in particular so-called HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin), have become available, there is an inherent danger that drug treatment of elevated cholesterol levels may reach very wide dimensions and lead to a neglect of dietary therapy and the control of other risk factors that always should be the first-line individual treatment. In many populations, like the Finnish and most European populations but also the U.S. population, the majority of people have elevated serum TC levels, often combined with other risk factors. Therefore, implementation of a population strategy, improvement of eating habits in the whole population, has a key role in attempts to shift the population cholesterol distribution to a lower position. High-risk strategy alone would have a relatively small impact, but a high-risk strategy combined in a sensible way with a population strategy could, potentially, achieve the desired result. Progress in the Nonpharmacological

Control of Elevated Blood Pressure

The role of nonpharmacological measures in hypertension control has been another area attracting growing interest during the last 4 years. The results of large

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controlled trials of drug treatment of hypertension have been disappointing in one respect, namely that blood pressure-lowering by drugs has produced only about one-half of the reduction in CHD incidence predicted on the basis of epidemiological studies, whereas the reduction in stroke incidence achieved in these trials corresponds well to epidemiological predictions (80). One possible explanation for the smaller than expected effect on CHD incidence could be that adverse metabolic effects of antihypertensive drugs dissipate the beneficial effect of blood pressure-lowering. Another alternative explanation is that due to the multifactorial etiology of CHD, blood pressure-lowering alone without control of other risk factors, in particular smoking and elevated serum lipids, does not produce the maximum benefit in CHD prevention. Thus, nonpharmacological measures for blood pressure-lowering, including reduction in salt intake, excess calories and the resultant overweight, and excessive alcohol use, as well as regular physical activity, have come into the focus of research, and this research has addressed both population strategy and individual treatment aspects of BP control. The INTERSALT study results focused attention on the potential for the prevention of the age-related increase of BP in populations by modification of daily sodium intake (48). With an average population intake of sodium decreased by 100 mmole, the increase in systolic pressure from age 25 to 55 in a population would be less by 9 mm Hg. In addition, the predicted reduction in the population mean systolic blood pressure (SBP) from a reduction of sodium intake from the median level for INTERSALT populations-about 170 mmole-to 70 mmole, would be 2 mm Hg (81). Some increase in potassium intake with a reduction of sodium/potassium intake ratio from 3 + to 1, would produce some further effect and if, in addition, the average degree of obesity would become reduced from body mass index of 25 to 23, the reduction in population mean SBP would be 5 mm Hg. High alcohol intake has a clear effect on BP, and the combined effect of all these nutritional measures would be particularly strong in heavy drinkers, if alcohol use was also reduced. Although these reductions in population mean SBP levels do not sound very impressive, epidemiological predictions suggest, however, that these downward shifts in blood pressure would lead to substantial reductions in both CHD and stroke mortality. Thus, a reduction of population mean SBP by 5 mm Hg could reduce CHD mortality by %, stroke mortality by 14%, and all causes of mortality by 7%. As to the application of nutritional measures in a clinical treatment setting, very encouraging results were reported from a 4-year randomized controlled trial carried out in Chicago and Minneapolis (82). This trial assessed whether less severe hypertensive patients who had been well controlled by antihypertensive drugs could discontinue drug therapy, substituting nutritional means to control BP. Subjects were randomized into three groups: group 1 discontinued drug treatment and was given nutritional therapy (reduction of overweight and excess salt, as well as recommendation to reduce alcohol consumption); group 2 discontinued drug therapy without any nutritional program; and group 3 continued drug therapy without nutritional program. In the group receiving nutritional therapy reductions in body weight and salt use were quite successful and well maintained over the Cyear trial period, but results with regard to the reduction in high alcohol intake

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were rather parallel in the three groups. At 4 years, 39% of the patients receiving nutritional therapy remained normotensive without drugs, compared with only 5% of the patients without nutritional therapy. This study and some other studies indicate that nutritional therapy alone is able to maintain normotension in a substantial proportion of patients with mild hypertension. A recent elegantly designed and performed Australian study (83) randomized a group of about 100 mildly hypertensive subjects with an average initial blood pressure of 155 mm Hg systolic and 95 mm Hg diastolic after a run-in period of 6 weeks into one group with a moderately reduced sodium intake with the goal of 80 mmole sodium/day, and another with usual sodium intake, for an g-week period. Average differences of about 70 mmole sodium/day between the groups could be maintained over the trial. Mean SBP became reduced in the low-sodium group by 5 mm Hg and mean DBP by 3 mm Hg. Since the results of previous studies on the effectiveness of reduced sodium intake as the first-line treatment of mild hypertension have been to some extent controversial, the results of this study add important confirmatory evidence to support the concept that reduced salt use should be an integral part of that treatment. As to the effectiveness of nutritional-hygienic intervention (reduction of overweight, reduction in the use of salt and alcohol, and increased physical activity) in the prevention of the development of hypertension, a recently completed randomized, controlled study has assessed this question in middle-aged men and women whose initial BPSwere at the upper end of the normal range (84). There was a 50% reduction in the S-year incidence of hypertension in the intervention group compared with that observed in the control group (8.8% vs 19.2%). Thus, important new information has been added to both population strategy and clinical treatment aspects of hypertension control by nutritional-hygienic measures, but much further research and demonstrations centered on practical aspects in the application of these measures will be needed. Non-Progress

in Smoking Control

As to the third major cardiovascular risk factor, smoking, it is unfortunate that this habit still remains a great public health problem. Even in countries like Norway and Finland, taking many measures to reduce and abolish smoking, including legislative measures, there has been relatively little progress during the past few years. In many countries the smoking problem is largely neglected, as reflected by the smoking habits of physicians and other health professionals. Because physicians, nurses, and other health personnel influence the behavior of their societies by their example, there is urgent need for the initiation of a movement toward a worldwide non-smoking community of health personnel. I am sure that if we physicians, in our everyday work, spent as much time trying to persuade our patients to stop smoking as we now do in measuring and treating their cholesterol and BP levels, this would have a positive impact on the smoking problem. CONCLUDING REMARKS I will end this opening lecture by showing two figures illustrating the huge

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differences existing between the countries in CHD mortality and their current trends based on a recent summary of these data by Uemura and Pisa (85). Northem Ireland, Scotland, and Finland, the three leading countries in CHD mortality statistics for men, have CHD mortality rates 4 to 5 times higher than some southern European countries, like Portugal and France, and almost 10 times higher CHD mortality rates than Japan (Fig. 1). Data for women are by and large similar as to magnitude of differences between countries. Figure 2, showing the percentage change in CHD mortality among men in different countries during a 15year period (1970-1985), is even more impressive. At the positive end of the wide spectrum is the United States with an impressive reduction of almost 50% in CHD mortality, accompanied by Australia, Israel, and Canada. Also, in many European countries CHD mortality has declined substantially, whereas in some countries there has been very little change and at the other end of the spectrum some MEN 400

300

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N. IRELAND SCOTLAND FINLAND EsSOVIET UNlON ( 1966) [-] CZECHOSLOVAKIA IRELAND NUNGARY ENGLAND 6 WALES NEW ZEALAND NORWAY DENMARK ICELAND AUSTRALIA SWEMN UNITED STATES POLAND CANADA NETHERLANDS LUXEMBOURG BULGARIA MALTA GERMANY, F.R. AUSTRIA ISRAEL GERMANY, D.R. RUMANIA ( 1984) BELGIUM ( 1984) YUGOSLAVIA ( 1 QB SWITZERLAND ITALY ( 1984) GREECE SPAIN ( 1983) PORTUGAL FRANCE JAPAN

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FIG. 1. Age-standardized mortality from coronary heart disease for men and women (ages 30-69 years) in 35 countries in 1985 (85).

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UNllED STATES AUSTRALIA ISRAEL CANADA JAPAN IKLGKIM NEW ZEALAND LUXEMBOlBlG ICELAND NETHERLANDS FlM.AND PORTUGAL NDNWAY ITALY SCOTLAND ENGLAND & WALES SWITZERLAND AUSTRIA N. IRELAND (KRMAI’JY, F.R. FRANCE DENMARK MALTA SWEDEN IRELAND CZECHOSLOVAKIA GERMANY, D.R. HLMGARY GREECE BULGARIA SPAIN YUGOSLAVIA POLAND RUMANIA

FIG. 2. Percentage change in age-standardized coronary heart disease mortality in men (ages 30-69 years) in 34 countries during the period 1970-1985(85).

southern and eastern European countries are showing alarming increases in CHD mortality. These differing trends in CHD mortality in different countries have become a subject of great interest during the last two decades (86, 87) and their possible explanations will also be discussed at this conference. I would like to note in this context that favorable trends in CHD mortality and incidence have, in many countries, been preceded and paralleled by increasing attention to nutrition, with concomitant reductions in population mean TC levels, by reduction in smoking, and by improvement of hypertension control. Improved treatment of symptomatic CHD may also have contributed to the declining trends. At the same time, adverse changes in lifestyles and risk factors have been occurring in many of those countries showing increasing CHD mortality trends. Thus, there is much room for further progress, including the need for further research, but first of all, there is the need for the application of already existing knowledge to the practice of preventive cardiology.

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41. Inter-Society Commission on Heart Disease Resources. Atherosclerosis Study Group. Optimal resources for primary prevention of atherosclerotic diseases. Circulation 1984; 70: 153A-205A. 42. Lowering blood cholesterol to prevent heart disease, Consensus Conference. JAMA 1985; 253:208&2090. 43. U.S. Department of Health and Human Services. The Surgeon General’s Report on Nutrition and Health. DHHS (PHS) Publication No. 88-50210. Washington, DC: U.S. Government Printing Offke, 1988. 44. National Cholesterol Education Program. Highlights of the Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Bethesda, MD: National Institutes of Health, NIH Publication No. 88-2926, 1987. 45. National Research Council. Diet and Health: Implications for Reducing Chronic Disease Risk. National Academy Press, Washington, DC, 1989. 46. Stamler R, Stamler J, Eds. Asymptomatic hyperglycaemia and coronary heart disease. A series of papers by the International Collaborative Group, based on studies in fifteen populations. J Chron Dis 1979; 32:638-837. 47. International Collaborative Group. Circulating cholesterol and risk of death from cancer in men aged 40 to 69 years. Experience of an International Collaborative Group. JAMA 1982;248:28532859. 48. Intersalt Cooperative Research Group. Intersah: An international study on electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. JJr Med J 1988; 297:319-328. 49. Rheumatic Diseases. First Report of the Expert Committee. WHO Technical Report Series 78. Geneva: World Health Organization, 1954. 50. Prevention of Rheumatic Fever. Second Report of the Expert Committee on Rheumatic Diseases. WHO Technical Report Series 126. Geneva: World Health Organization, 1957. 51. Arterial Hypertension and Ischaemic Heart Disease. Report of a WHO Expert Committee. WHO Technical Report Series 231. Geneva: World Health Organization, 1957. 52. Prevention of Rheumatic Fever. Report of a WHO Expert Committee. WHO Technical Report Series 342. Geneva: World Health Organization, 1966. 53. WHO Regional Office for Europe. Methodology of multifactorial trials in ischaemic heart disease. Report on a Working Group, Rome, 1970. Copenhagen: WHO/EURO 5011(3), 1971. 54. WHO Regional Office for Europe. Methodology of multifactorial trials in ischaemic heart disease. Report on a Working Group, Innsbruck, 1973. Copenhagen: WHO/EURO 8202(6), 1973. 55. WHO Regional Office for Europe. The prevention and control of major cardiovascular diseases. Report on a Conference, Brussels, 1973. Copenhagen: WHO/EURO 8214, 1974. 56. WHO Regional Offtce for Europe. The prevention of coronary heart disease. Report on a Working Group, Berlin, GDR, 1976. Copenhagen: WHO/EURO ICP/CVD 002(10), 1974. 57. Smoking Control. Report of a WHO Expert Committee. WHO Technical Report Series 636. Geneva: World Health Organization, 1979. 58. Prevention of Coronary Heart Disease. Report of a WHO Expert Committee. WHO Technical Report Series 678. Geneva: World Health Organization, 1982. 59. Smoking Control Strategies in Developing Countries. Report of a WHO Expert Committee. WHO Technical Report Series 695. Geneva: World Health Organization, 1983. 60. Primary Prevention of Essential Hypertension. Report of a WHO Scientific Group. WHO Technical Report Series 686. Geneva: World Health Organization, 1983. 61. WHO Regional Office for Europe. Primary prevention of coronary heart disease. Report on a WHO Meeting, Capri, 1984. EURO Reports and Studies 98. Copenhagen: WHO/EURO, 1985. 62. Community Prevention and Control of Cardiovascular Diseases. Report of a WHO Expert Committee. WHO Technical Report Series 732. Geneva: World Health Organization, 1986. 63. Prevention of Cardiovascular Diseases among the Elderly. Report of a WHO Meeting, Geneva, 1987. Geneva: World Health Organization, Document WHO/CVD/87.2, 1987. 64. Development of Methodology for Prevention and Control of Hypertension in &v&ping Countries. Report of a Meeting of Investigators, Geneva, 1987.Geneva: World Health Organization, Document CVD/88.5, 1988.

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65. Rheumatic Fever and Rheumatic Heart Disease. Report of a WHO Study Group. Technical Report Series 764. Geneva: World Health Organization, 1988. 66. Prevention in Childhood and Youth of Adult Cardiovascular Diseases: Time for Action. Report of a WHO Expert Committee. WHO Technical Report Series. Geneva: World Health Organization in press. 67. Diet, Nutrition, and Prevention of Noncommunicable Diseases. Report of a WHO Study Group. WHO Technical Report Series. Geneva: World Health Organization, in press. 68. Study Group, European Atherosclerosis Society. Strategies for the prevention of coronary heart disease: A policy statement of European Atherosclerosis Society. Eur Heart J 1987; 8:77-88. 69. Study Group, European Atherosclerosis Society. The recognition and management of hyperlipidaemia in adults: A policy statement of the European Atherosclerosis Society. Eur Heart J 1988;9:57lAOO.

70. Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure, and mortality: Implications from a cohort of 361,662 men. Lancet 1986; 2:933-936. 71. Stamler J, Wentworth D, Neaton J. Is the relationship between serum cholesterol and risk of death from coronary heart disease continuous and graded? Findings on the 356,222primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986; 256:2823-2828. 72. Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events. Final report of the Pooling Project. .I Chron Dis 1978; 31:210-306. 73. Stamler J, Wentworth D, Neaton JD. Prevalence and significance of hypercholesterolemia in men with hypertension. Prospective data on the primary screenees of the Multiple Risk Factor Intervention Trial. Am J Med 1986; 8O(Suppl2A):33-39. 74. Chen Z, Peto R, Collins R, MacMahon S, Li W. Continuous positive relationship between serum cholesterol and coronary heart disease in a population with low mean cholesterol. 2nd International Conference on Preventive Cardiology and the 29th Annual Meeting of the AHA Council on Epidemiology, Washington, D.C., June 18-22, 1989. Abstracts:AlOl. 75. Levy R, Brensike JF, Epstein SE, Kelsey SF, Passamani ER, Richardson JM, Loh IK, Stone NJ, Aldrich RF, Battaglini JW, Moriarty DJ, Fisher ML, Friedman L, Friedewald W, Detre KM. The infhtence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: Results of the NHLBI Type II Coronary Intervention Study. Circulation 1984;69:325-327.

76. Nikkila EA, Viikinkoski P, Valle M, Frick MH. Prevention of progression of coronary atherosclerosis by treatment of hyperlipidaemia: A seven year prospective angiographic study. Br MedJ

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77. Amtzenius AC, Kromhout D, Barth JD, Reiber JHC, Bruschke AVG, Buis B, van Gent CM, Kempen-Voogd N, Strikwerda S, van der Velde E. Diet, lipoproteins, and the progression of coronary atherosclerosis. The Leiden Intervention Trial. N Engl J Med 1985; 312:805-811. 78. Blankenhom DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hempbill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987; 257:3233-3240. 79. Peto R, Yusuf S, Collins R. Cholesterol-lowering trial results in their epidemiological context (abstract). Circulation 1985; 72:111-451. 80. MacMahon SW, Cutler JA, Neaton JD, Furberg CD, Cohen JD, Kuller LH, Stamler J, and the Multiple Risk Factor Intervention Trial Research Group. Relationship of blood pressure to coronary and stroke morbidity and mortality in clinical trials and epidemiological studies. .I Hypertension 1986; 4(Suppl6):Sl&S17. 81. Stamler J, Rose G, Stamler R, Elliott P, Dyer A, Marmot M. INTERSALT Study findings: Public health and medical care implications. CZin Exp Hypertens 1989; 11:1025-1034. 82. Stamler R, Stamler J, Grimm R, Gosch FC, Elmer P, Dyer A, Berman R, Fishman J, Van Heel N, Civmelli J, McDonald A. Nutritional therapy for high blood pressure. Final report of a four-year randomized controlled trial-The Hypertension Control Program. JAMA 1987; 257:148&1491.

83. Australian National Health and Medical Research Council Dietary Salt Study Management COm-

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KALEVI PYbR,&LA mittee. Fall in blood pressure with modest reduction in dietary salt intake in mild hypertension. Lancer 1989; 1:395)-402. Stamler R, Stamler J, Gosch FC, Civinelli J, Fishman J, McKeever P, McDonald A, Dyer AR. Primary prevention of hypertension by nutritional-hygienic means: Final report of a randomized, controlled trial. JAMA 1989; 262:1801-1807. Uemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialized countries since 1950. World Health Stat Q 1988; 41:155-178. Havlik RJ, Feinleib M, Eds. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality, October 24-25, 1978, National Institutes of Health, Bethesda, Maryland. Bethesda, MD: U.S. Department of Health, Education and Welfare. Public Health Service, National Institutes of Health, NIH Publication No. 791610, 1979. Higgins M, Luepker R, Eds. Trends and Determinants of Coronary Heart Disease Mortality: International Comparisons. Int J Epidemiol 1989; 18:Suppl l:Sl-S232.