Control of Cardiovascular Disease in the 20th Century: Meeting the Challenge of Chronic Degenerative Disease

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550-559 (Article) Published by Johns Hopkins University Press DOI: https://doi.org/10.1353/pbm.2018.

1 Control of Cardiovascular Disease in the 20th Century: Meeting the Challenge of Chronic Degenerative Disease Perspectives in Biology and Medicine, Volume 61, Number 4, Autumn 2018, pp (Article) Published by Johns Hopkins University Press DOI: For additional information about this article Access provided by Michigan State University (25 Jan :41 GMT)

2 Control of Cardiovascular Disease in the 20th Century meeting the challenge of chronic degenerative disease ABSTRACT After World War II, industrialized countries found themselves faced with a new epidemic of chronic disease. Stroke had long been a common cause of death, however a much more virulent form of vascular disease involving the coronary arteries was now recognized as a major public health challenge. By the late 1950s, cardiovascular diseases (CVD) accounted for almost two-thirds of deaths in the US. Within 10 years, the key causal factors underlying CVD had been fully defined, and by the mid-1960s, prevention trials, policy changes, and subsequent population-wide risk factor improvement and targeted high-risk medical therapy led to a rapid and sustained decline in both coronary heart disease (CHD) and stroke. By the turn of the century, CVD had declined over 80%, transforming health for adults and providing the main driver of lengthening life expectancy. This transformative process has now reached every country in the world. Epidemiologic, nutritional and clinical research, along with changes in social norms, public health education, smoke-free indoor air regulations, drug development, and clinical trials have led to the astounding success of the CVD control movement. The broad pattern pursued in the control of CVD provides a template for similar control efforts aimed at cancer, diabetes, renal disease, and other common chronic diseases. Department of Public Health Sciences, Loyola University Medical School, 2160 S. First Avenue, Maywood, IL rcooper@luc.edu. Perspectives in Biology and Medicine, volume 61, number 4 (autumn 2018): by Johns Hopkins University Press 550

3 Control of Cardiovascular Disease in the 20th Century he scientific understanding of common chronic disease began in the Tmid-19th century, driven in large part by the development of the modern autopsy. For cardiovascular disease (CVD), the recognition that rigid plaques were obstructing muscular arteries, especially in the coronary arteries, provided a mechanism to explain what had been a mysterious chest pain sudden collapse syndrome. The origin of these plaques was totally obscure, however, and they were given the descriptive name of atherosclerosis, or hardened porridge in Greek. Not until 50 years later, when animal experimental models serendipitously revealed the hyper-lipidemic consequences of a diet high in animal fat, followed by accretion of lipid material in the arterial wall, was the pathogenesis understood (Stamler 1967). Later experiments demonstrated the role of hypercholesterolemia in human coronary syndromes and, perhaps most convincing, the importance of nutrition as the driver of the striking cross-cultural variation in CVD in societies like China compared to Europe (Epstein 1992). CVD therefore came to be seen as a mass disease on a scale similar to tuberculosis and smallpox and was recognized as a social phenomenon of a similar character. The formulation put forward by the pioneers of the 19th-century sanitary movement rested on the foundational idea that mass disease means society is out of joint (Stamler 1967). This framework assumed that, in aggregate, the human species is naturally protected from common environmental threats as a result of our long history of evolutionary selection. Only with major social disruption would large segments of the population be put a risk of exposure to noxious forces that result in either high levels of infection or chronic degenerative disease. This general principle was originally developed to explain outbreaks of typhus in the setting of under-nutrition, crowded living conditions, and poor sanitation, but it came to be seen as equally illuminating for diseases resulting from modern health threats, such as air pollution, high-fat diets, and tobacco use. This framework continues to be at the core idea of chronic disease prevention science and has guided the course of the public health movement to control CVD. Age of Discovery of the Causes of CVD The golden age of CVD epidemiology began in the late 1940s, with the initiation of the Seven Countries Study by Ancel Keys and collaborators, and of the Framingham Heart Study, sponsored by the National Institutes of Health (NIH) (Mensah et al. 2017). Keys and colleagues set out to document the tenfold variation in CHD observed between countries like Finland (highest) and Japan and several Greek islands (lowest). Now a classic in nutrition research, this project performed chemical analyses of duplicate meals, collected blood samples for cholesterol and other biochemical traits, and followed cohorts of middle-aged men in multiple communities in Europe and Japan to assess CVD event rates (Keys 1980). Serum cholesterol, driven by the level of intake of saturated fat and to autumn 2018 volume 61, number 4 551

4 Figure 1 Serum cholesterol and CVD risk a lesser extent of cholesterol, was proven to be the sine qua non, the original initiating cause, underlying CHD, with a contributing effect from smoking and hypertension. As is also well known, the cohort study from Framingham, Massachusetts, likewise confirmed these results in 5,209 men and women, ages 28 to 62, who were followed prospectively from 1948 (Dawber 1980). It is worth noting that the powerful impact of smoking had not been anticipated ahead of time. Further, the clarity of the message that emerged with cohorts in both the Seven Countries Study and Framingham that would be considered woefully under-powered by current standards, further reinforces the elegance of the original hypothesis. The strong exponential relationship between serum cholesterol and CVD risk, in conjunction with a similarly strong across-country relationship between dietary patterns and national mortality rates from CHD, has now been well summarized in the second generation of studies (Figure 1). Harvesting the Fruit from the Tree: Control of CVD In the 1960s, the complementary strategy of population-wide prevention by altering dietary patterns, reducing tobacco use, and improving other secondary risk factors (like the sedentary lifestyle) was adopted (Rose 1992). It was recognized that the strongest possible scientific basis for public policy interventions to improve eating patterns would be a randomized trial to use nutritional means to reduce cholesterol, and consequently CHD. However, a trial of that design requires long-term adherence to prescribed diets in free-living people, and feasibility was an obvious concern. To gather necessary preliminary data, the Diet Heart 552 Perspectives in Biology and Medicine

5 Control of Cardiovascular Disease in the 20th Century Study was mounted (Walker 1969). Volunteers were randomized to receive food items either fat-modified (such as margarine) or full-fat (butter) from neighborhood dispensaries, without knowing which group they had been assigned to. While the intervention resulted in a modest decline in serum cholesterol, it was clear that adherence was a significant problem: further calculations demonstrated that a definitive trial would require an enormous sample size with many years of follow-up. A direct nutrition trial therefore was abandoned, and in fact has never been conducted, other than through use of the Mediterranean Diet as an intervention (Kris-Etherton 2001). Nonetheless, the evidence in favor of the diet-heart theory was overwhelming, and the ongoing epidemic demanded action, so public health messages aimed at the most important sources of saturated fat began to appear. In short order there were important reductions in whole-fat dairy products and a new market for skim milk developed. The concurrent campaign against smoking aimed at reducing lung disease was also crucial. In 1977 the first hint of a downturn in mortality was recognized. Given the delay in availability of death records, it was not until 1978 that formal statistical analyses demonstrated that indeed a sharp downturn in CHD mortality had started in 1968, and was proceeding in a monotonic fashion at a rate of 2 3% year after year (Cooper et al 1978; Higgins and Thorn 1989). (See Figure 2.) A historic conference at the NIH in 1978 examined the trends in risk factors, mortality rates, and treatment of risk factors and concluded that the observed pattern was not temporary variation and most likely a causal outcome of improvement in risk factors (NHLBI 1979). A Senate Select Committee on Nutrition further reviewed the evidence and made forceful recommendations in regard to changes in food manufacture and marketing and dietary habits (Stamler 1992). At the same time better agents to treat hypertension were becoming available, and randomized trials demonstrated a universal benefit of blood pressure reduction. By 1980 most of the key elements for a coordinated, comprehensive public health program to reduce CVD were in place (Epstein 1992; Stamler 1992). The single missing element was safe, tolerable, and effective drugs to lower cholesterol. Making It Happen: CVD as a Public Health Priority A coalition of professional organizations, most prominently the American Heart Association, and federal agencies, with the NHLBI in the lead, launched a vigorous public education campaign aimed at the general public, patients, and physicians (Mensah et al. 2017; Stamler 1992). The NHLIB played a key role through the National High Blood Pressure Education Program (NCEP), which promoted screening, detection, and control with pharmacologic agents, and the National Cholesterol Education Program, which initially created awareness of the importance of high cholesterol, disseminated information on beneficial dietary patterns, and subsequently set guidelines for drug treatment (Mensah 2017; NCEP 2002). autumn 2018 volume 61, number 4 553

6 Figure 2 Trends in mortality from CVD, National survey data from the National Health and Nutrition Examination Survey (NHANES) documented the decline in mean serum cholesterol from 220 mg/dl in the 1980s to less than 200 mg/dl at the present time, and the increase in treatment and control of hypertension to greater than 50% in the population. The advent of statins in the 1990s led to a major improvement in cholesterol control in high-risk individuals. Over this entire period, of course, advances in hospital methods led to higher survival rates with myocardial infarction and continuous improvement in surgical and catheter-based methods to re-vascularize diseased coronary and carotid vessels. A well-developed strategy now exists to intervene on every stage of the etiologic sequence from dietary intake to rehabilitation and secondary prevention (Table 1). Of course, all of these efforts were met with staunch resistance. The food industry, particularly the egg and beef interests, fought tooth and nail to delay public health action. Scientific evidence was criticized, the reputations of individual scientists were impugned, data were subpoenaed for re-analysis, and a small cohort of academics allowed themselves to be used as responsible critics. These efforts certainly sowed confusion in the media and created a legacy of hucksters and quacks who to this day promote a panoply of theories and diets that 554 Perspectives in Biology and Medicine

7 Control of Cardiovascular Disease in the 20th Century Table 1 The Development Process of CVD Yields a Clear Strategy for Prevention and Treatment lack scientific support. These disruptive voices have no doubt limited progress, at the cost of many needless deaths and lives of long-term disability. But this level of dissension, if so it can be called, is inevitable in a pluralistic society. In truth it must be said that the CVD prevention message has demonstrated remarkable durability and success. The positive outcomes must be taken as a tribute to the elegance and validity of the theory and the dedication and skill of those who have fought to make a heart healthy lifestyle the norm, and as proof most of all that in the long-term success breeds ever greater success. Where Do We Stand Today? Both CVD and stroke have declined 80% since Each year there are approximately 600,000 deaths that are averted, and over the entire period of the decline, 20 million early deaths have been avoided. A fatal CVD event, especially from sudden cardiac arrest, occurring in persons under 55 years of age is now almost rare. A very close correspondence between trends in risk factors and other preventive treatments and trends in CVD rates has been documented in most countries in the world (Koopman et al 2016). Ford and colleagues (2007) have provided a detailed analysis of this question for the US: about 60% of the decline could be ascribed to improvements in risk factors, including some secondary prevention. The massive improvement in CV health observed in the US has become a worldwide phenomenon, even among middle- and low-income countries with weaker public health and medical infrastructures and less regulation of tobacco and food. autumn 2018 volume 61, number 4 555

8 Nonetheless, very substantial racial/ethnic and geographic disparities in the burden of CVD persist. CVD remains the most common cause of death, and the rate of decline appears to have stalled in the last three years (Cooper et al. 2000). As patients with CVD survive longer heart failure, particularly among persons in their 80s, is a major problem and a huge source of health-care cost. The diabetes epidemic, a major risk factor for CVD, threatens to erode some of the gains in CVD prevention with the frequent occurrence of diabetes in young adults of grave concern. The CVD prevention movement s goal remains the elimination of all forms of nutritional vascular disease at least as common causes of death and disability. Epidemiologists and public health scientists have struggled to define what should be considered a reasonable quantifiable target. The simplest metric is the proportion of all deaths, and the figure of 3 5% has been mooted. However, CVD is a disease of aging, and as life expectancy extends into the late 80s, the risk of a vascular event rises exponentially. The human vascular system is comprised of a very fragile tissue in the endothelium, and it is intensely exposed to blood-borne toxins. Likewise, continuous stress and strain of pulsating blood flow takes a toll on the integrity of the vessel wall matrix. At the same time, we are nowhere near the limits of the preventive potential. Only in the last few years has the optimal state of clinical risk been defined. While observational studies suggested as early as the 1950s the minimal-risk profile for the major risk factors, only in last two years, as a result of trials of intensive therapy for lipids and blood pressure, has this formulation met growing acceptance. We now know that a lifelong LDL cholesterol less than 50 mg/dl is associated with extremely low risk of CVD, while a blood pressure of 120 mmhg or less markedly reduces CVD risk and also leads to very substantial reduction in stroke and heart failure. Of course, an absence of smoking, diabetes, obesity, and other risk factors should be included. The profile outlined here gained initial support from the observations that it is the norm in pre-industrial societies, where to the extent it can be determined CV health is extremely good; nonhuman primates in the wild have a similar profile and are also not observed to share our propensity for vascular disease. A life lived at the optimal risk profile would yield another quantum leap of improvement in CV health. That is the challenge now facing the next generation of cardiovascular and prevention scientists. Lessons Learned The CVD prevention movement has much to teach us about the meeting the challenges of modern public health. The first principle that is now foundational to chronic disease research is the understanding that the breakdown of society s capacity to provide healthful living conditions is also the original cause of mass disease, and that only by addressing those social determinants will signifi- 556 Perspectives in Biology and Medicine

9 Control of Cardiovascular Disease in the 20th Century cant change be possible. The second lesson is the value of high-quality scientific research to explore the exposure-outcome process at the individual level (high intake of dietary fat leads to elevated serum cholesterol) and the capacity to embed that observation in social reality (societies that consume high-fat diets have high CVD risk). The reinforcing and complementary information derived from those two classes of observations offer a solid basis for a theory of pathogenesis. (A similar paradigm emerged, it should be noted, in the history of research on smoking and cancer.) Third, hypothesis-driven observational studies, whether cohorts or case-control, can elevate the knowledge base to a level of great sophistication. Clinical trials add further invaluable information, especially about effect size and limits of benefit. At the same time, it must be reiterated that the oft-cited canard that only trials can define causal relationships does not and never has successfully been applied to common chronic disease. One cannot intentionally expose people long-term to a putative harmful agent, and the timeframe of the etiologic phase eliminates the usefulness of the study design if one could. The proof of the diet-heart theory was a synthesis of knowledge from multiple reinforcing disciplines. Finally, the ultimate stage in establishing of the validity of a theory of disease lies in long-term outcome after interventions of sufficient magnitude have been implemented. It is from reference to that standard with its record of an 80% decline in burden and a saving of 20 million early deaths that the diet-heart theory, and the CVD prevention movement, rise above challenge. The experiment has been conducted, and the experiment was a success. Quod est demonstrandum. It will not escape the notice of the reader of this issue of the journal that genomics and precision medicine have, to date, made no contribution whatsoever to control of CVD as a mass disease. The remaining challenges of common disease most prominently diabetes, cancer, lung disease, and renal disease will yield only through a campaign that builds on the basic principles of discovery, validation, and implementation observed for CVD. In sum, for 40 years the CVD prevention movement that created a storehouse of knowledge that is grounded in clinical and epidemiologic science and shown to able to solve enormous public health challenges. This science and subsequent experience in implementation stands in contrast to much of the precision medicine and omics approach. Claude Lenfant, the long-time director of the NHLBI during much of the period described above, ended his career with the motto Use what we know. This call for action has been marginalized by precision medicine, while elaborate procedures to overcome probabilistic variation in risk estimation and treatment response have taken center stage. As we attempt to take on the challenges of contemporary unsolved mass causes of ill-health, such as obesity and diabetes, much is at stake. As a cautionary tale, for example, one might reflect on the 30-year history of genetic research among groups at high risk for diabetes, such as the Pima Indians in Arizona, and worry autumn 2018 volume 61, number 4 557

10 that the continued worsening of their health status while they serve as intense subjects for genetic research suggests other paths would be more fruitful. While the origins and solutions to the obesity/diabetes epidemic will of course be different from what was accomplished for CVD, the fundamental principles of the discovery science and the implementation will remain the same. References Cooper, R., et al The Decline in Mortality from Coronary Heart Disease, USA, J Chron Dis 31: Cooper, R., et al Trends and Disparities in Coronary Heart Disease, Stroke and Other Cardiovascular Diseases in the United States: Findings of the National Conference on CVD Prevention. Circulation 102: Epstein, F. H Contribution of Epidemiology to Understanding Coronary Heart Disease. In Coronary Heart Disease Epidemiology: from Aetiology to Public Health, ed. M. Marmot and P. Elliot, New York: Oxford University Press. Dawber, T. R The Framingham Study: The Epidemiology of Atherosclerotic Disease. Cambridge: Harvard University Press. Ford, E. S., et al Explaining the Decrease in US Deaths from Coronary Disease, N Engl J Med 356 (23): Higgins, M., and T. Trends In CHD in the United States. Int J Epidemiol 18: S58 S66. Keys, A Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. Cambridge: Harvard University Press. Koopman, C., et al. Explaining the Decline in Coronary Heart Disease Mortality in the Netherlands between 1997 and PLoS One 11 (12): e Kris-Etherton, P., et al Lyon Diet Heart Study: Benefits of a Mediterranean-Style. National Cholesterol Education Program/American Heart Association Step I Dietary Pattern on Cardiovascular Disease. Circ 103: Mensah, GA, et al Decline in Cardiovascular Mortality: Possible Causes and Implications. Circ Res 120 (2): National Cholesterol Education Program (NCEP) Third Report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. NIH publication no Bethesda, MD: NHLBI, NIH. National Heart, Lung and Blood Institute (NHLBI) Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. NIH publication no Bethesda, MD: NHLBI, NIH. National Heart, Lung and Blood Institute (NHLBI) Report of the Task Force on Research in Epidemiology and Prevention of Cardiovascular Diseases. Rockville, MD: NIH. National Institutes of Health (NIH) The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH publication no Rockville, MD: NIH. Rose, G The Strategy of Preventive Medicine. New York: Oxford University Press. Stamler, J Lectures on Preventive Cardiology. New York: Grune and Stratton. 558 Perspectives in Biology and Medicine

11 Control of Cardiovascular Disease in the 20th Century Stamler, J Established Major Coronary Risk Factors. In Coronary Heart Disease Epidemiology: From Aetiology to Public Health, ed. M. Marmot and P. Elliott, New York: Oxford University Press. Walker, W. J The National Diet-Heart Study: Final Report. Arch Intern Med 123 (4): autumn 2018 volume 61, number 4 559

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Page down (pdf converstion error) 1 of 6 2/10/2005 7:57 PM Weekly August6, 1999 / 48(30);649-656 2 of 6 2/10/2005 7:57 PM Achievements in Public Health, 1900-1999: Decline in Deaths from Heart Disease and Stroke -- United States, 1900-1999