The World Was Their Laboratory: How Two Pioneer Scientist-Administrators,James Watt and Zdenek Fejfar, Advanced Methods and International Collaboration in Cardiovascular Disease Epidemiology During the Cold War.

In 1952, James Watt, a young U.S. Public Health Service (USPHS) infectious disease epidemiologist, was appointed--amid wide surprise--director of the U.S. National Heart Institute (NHI) where he served until 1961. He skillfully advanced epidemiological research methods and study conduct nationally while also establishing epidemiology in the administrative heirarchy of the institute. Watt soon turned to development of an effective program in international cardiovascular disease (CVD) epidemiology under auspices of the World Health Organization (WHO) at the United Nations (UN) in Geneva. That effort resulted in the 1959 appointment of Zdenek Fejfar, a young Czech clinical investigator, as director of the WHO CVD Unit. The coming together of Watt and Fejfar, with a joint focus on improved methods and population comparisons, helped establish a vigorous international community of CVD epidemiology. Their collaboration and friendship remained active and close throughout their career assignments and thereafter, as documented in this story.

Early Contributions to the Design and Conduct of Clinical Trials From a Largely Unknown 1960s Pilot Trial of Physical Activity and a Well-Known Diet-Heart Feasibility Study for the Primary Prevention of Coronary Heart Disease.

This historical note focuses on contributions to the concepts, design, methods, and conduct of clinical trials from the 1960s planning and findings of a feasibility study that was little reported and largely unrecognized: the Pilot Study of Prescribed Physical Activity for the Primary Prevention of Ischemic Heart Disease (1963-1968). In contrast, complementary findings from the 1960s National Diet-Heart Feasibility Study (1962-1968) were fully reported, widely recognized, and well-analyzed by historians in context of the rapid evolution in chronic disease epidemiology and clinical trials following World War II. The experience of these thoughtfully planned and rigorously conducted pilot studies changed the career paths of their planners and investigators and shaped the form and direction of subsequent research on the causes, treatment, and prevention of heart attack. The 2 studies were both fruit and seed of a consortium of experts that evolved in reaction to new questions and findings about the midcentury coronary disease epidemic. The contributions of each study, and of this broader academy of pioneer thinkers, are essential elements in the history of cardiovascular disease epidemiology, prevention research, and health policy.

John 'Jack' Gofman. Researcher and Social Activist.: 'Fair-haired Boy' and 'Enemy Within'.

John "Jack" Gofman's research career was characterized by skills across disciplines that gave him unique insights and opportunities. He was able to choose the research strategy-laboratory, clinical, or epidemiological-most suited to the state of the problem. But Gofman's curiosity and intensity, his integrity and courage, led to dual reputations-one as a "fair-haired boy," another as a "troublesome crank"-first in atomic science, then in cardiovascular medicine, and finally in radiation energy and health policy. Gofman's earliest success was in the 1940s as a University of California-Berkeley graduate student in physical chemistry with Glenn Seaborg. Using simple laboratory methods he innovated the isolation of radioactive elements ultracentrifugally and determined their fission rates. In 1943 he produced the single milligram of plutonium needed urgently by J. Robert Oppenheimer to confirm its candidacy to power the atomic device that would implode over Nagasaki. As a young medical researcher in the 1950s, Gofman was the first to successfully isolate blood lipoprotein (LP) fractions by simply adding saline solution to serum. This increased its density such that all the LP present would float, then separate into discrete fractions on ultracentrifugation. In pioneer serial studies, Gofman and colleagues explored serum LP distributions in healthy and patient populations, LP responses to contrasting diets, and LP power to predict coronary heart disease risk (CHD). Their findings formed the platform for Brown and Goldstein's Nobel Prize discovery of hepatic low-density lipoprotein (LDL) receptors, and thus, the mechanism of lipid transport between blood and tissues. Together these provided fuller understanding of the pathogenesis and possible prevention of atherosclerosis. From the 1960s, Gofman reengaged with nuclear science in mutidisciplined studies that found cell damage and health effects of ionizing radiation were proportionate to the dosage. His conclusion that there was "no safe level" of exposure conflicted with "safe levels" recommended by the U.S. Atomic Energy Commission (AEC). Eventually, his findings, persistent questioning of policy, and effective advocacy against U.S. atomic energy programs resulted in the loss of both his AEC research funding and his leading national position in radiation and public health. He came to be viewed as "the enemy within." Gofman's research and activism were central to subsequent systemic reviews and constraints to what he called "U.S. adventurism:" in atom bomb testing, with "land engineering" using hydrogen bombs, and in the rapid build-up of nuclear energy for the U.S. electrical grid. Eventually, his body of evidence and recommendations about radiation effects on health were largely corroborated by the National Academy of Sciences and other authorities. They still influence planning for "clean energy" in today's global climate crisis.

The National Cooperative Trial on Multifactorial Prevention of First Heart Attacks and Coronary Mortality in Free-Living, High-Risk, Middle-Aged American Men, Also Known as JUMBO: A Short Story.

The concept of a multiple risk-factor intervention trial (MRFIT) originated in mid-20th century efforts to determine whether modifying the "risk factors" established by cardiovascular disease epidemiology would prevent heart attacks. The term "MRFIT" probably first appeared in the 1968 report to the National Heart Institute from investigators of the National Diet-Heart Feasibility Study. Based on their pilot experience, they recommended a trial of diet alone. Aware, however, that authorities might agree with the rationale but not the implementation of such a massive and risky undertaking, they also proposed an alternative: whether coronary heart disease was preventable at all by simultaneous intervention on several risk factors; that is, a multiple risk-factor intervention trial. After some years agonizing by serial expert committees, the National Heart Institute opted against an explanatory diet trial and for a pragmatic multiple risk-factor intervention, one designed by Institute staff and operated under contract. Meanwhile, an impatient community of investigators met together in the Makarska Conference, outlined a broad cardiovascular disease prevention policy, and submitted their idealized version of a multiple risk-factor trial, called JUMBO. But the National Heart Institute, because of the plan for its own trial, had no funds left for an investigator-initiated proposal. Hence, this background and story of the MRFIT that wasn't.

The Origins and Early Evolution of Epidemiologic Research in Cardiovascular Diseases: A Tabular Record of Cohort and Case-Control Studies and Preventive Trials Initiated From 1946 to 1976.

This article serves as a ready reference guide to the pioneering formal studies in cardiovascular disease (CVD) epidemiology initiated during 3 decades of the subject's evolution into an established academic field that contributed to the public health. The article is not intended to be a history of CVD epidemiology or an editorial about its significance. The appended tables include the titles and starting dates of the early studies, the names of their principal investigators, and references to a single defining article from each. The early observational studies of CVD epidemiology provided a widely useful CVD risk-factor paradigm. The early clinical trials justified the more definitive preventive trials of the 1980s and beyond. This early research in populations, along with others in clinics and laboratories, led to greater understanding of the causes of CVD, to a vigorous practice of preventive cardiology, and to national policy and programs of health promotion, all of which were coincident with a 50-year decline in CVD mortality rates.

Invited Commentary: 30-Year Perspective on the Seven Countries Study.

In a 1986 article (Am J Epidemiol. 1986;124(6):903-915), Keys et al. described and discussed 15-year findings from 15 cohorts of the Seven Countries Study (SCS), the first systematic study of diet, risk characteristics, disease-specific death rates, and their ecologic and individual associations both among and within whole populations of working men in regions with contrasting traditional diets. The SCS findings included 30-fold cohort differences in rates of death from coronary heart disease and 3-fold differences in rates of death from all causes, along with strong ecologic associations among diet, risk factors, and disease rates. These results have motivated a generation of causal research conducted using bench, clinical, and population strategies. The study has contributed to survey methods, preventive practice, nutrition science, and policy on health, food and agriculture, and diet. The article is a succinct and accessible account by Ancel Keys, near the end of his long career, of the SCS design, conduct, and findings, with his discussion and interpretation of their importance. My commentary deals with the extent, validity, and historical meaning of SCS findings, as well as their influence and the influence of the 1986 article itself on epidemiologic thought and on public health. Students of epidemiology and of history should read this rich original source.

Ten-year blood pressure trajectories, cardiovascular mortality, and life years lost in 2 extinction cohorts: the Minnesota Business and Professional Men Study and the Zutphen Study.

BACKGROUND: Blood pressure (BP) trajectories derived from measurements repeated over years have low measurement error and may improve cardiovascular disease prediction compared to single, average, and usual BP (single BP adjusted for regression dilution). We characterized 10-year BP trajectories and examined their association with cardiovascular mortality, all-cause mortality, and life years lost. METHODS AND RESULTS: Data from 2 prospective and nearly extinct cohorts of middle-aged men­the Minnesota Business and Professional Men Study (n=261) and the Zutphen Study (n=632)­were used. BP was measured annually during 1947-1957 in Minnesota and 1960-1970 in Zutphen. BP trajectories were identified by latent mixture modeling. Cox proportional hazards and linear regression models examined BP trajectories with cardiovascular mortality, all-cause mortality, and life years lost. Associations were adjusted for age, serum cholesterol, smoking, and diabetes mellitus. Mean initial age was about 50 years in both cohorts. After 10 years of BP measurements, men were followed until death on average 20 years later. All Minnesota men and 98% of Zutphen men died. Four BP trajectories were identified, in which mean systolic BP increased by 5 to 49 mm Hg in Minnesota and 5 to 20 mm Hg in Zutphen between age 50 and 60. The third systolic BP trajectories were associated with 2 to 4 times higher cardiovascular mortality risk, 2 times higher all-cause mortality risk, and 4 to 8 life years lost, compared to the first trajectory. CONCLUSIONS: Ten-year BP trajectories were the strongest predictors, among different BP measures, of cardiovascular mortality, all-cause mortality, and life years lost in Minnesota. However, average BP was the strongest predictor in Zutphen.

Stories from the evolution of guidelines for causal inference in epidemiologic associations: 1953-1965.

Guidelines for causal inference in epidemiologic associations were a major contribution to modern epidemiologic analysis in the 1960s. This story recounts dramatic elements in a series of exchanges leading to their formulation and effective use in the 1964 Report of the Advisory Committee to the US Surgeon General on Smoking and Health, the landmark report which concluded that cigarette smoking caused lung cancer. The opening salvo was precipitated by Ancel Keys' presentation of an ecologic correlation between diet and cardiac death, which was vigorously criticized in an article by Jacob Yerushalmy calling for "proper handling" of bias and confounding in observational evidence. The dispute demonstrated a need for guidelines for causal inference and set off their serial refinement among US thinkers. Less well documented parallel efforts went on in the United Kingdom, leading to the criteria that Bradford Hill presented in his 1965 President's Address to the Royal Society of Medicine. Here the authors recount experiences with some of the principals involved in development of these criteria and note the omission from both classic reports of proper attribution to those who helped create the guidelines. They also present direct, if unsatisfying, evidence about those particular lapses.

Trends in blood pressure and hypertension detection, treatment, and control 1980 to 2009: the Minnesota Heart Survey.

BACKGROUND: Hypertension is common and treatable, but detection and control remain a major health challenge. This study sought to determine population trends in blood pressure and in the control of hypertension in the Minneapolis/St. Paul area (2010 population, 2.85 million) from 1980 to 2009. METHODS AND RESULTS: Surveys of risk factors were performed every 5 years among randomly selected adults aged 25 to 74 years. Data on hypertension knowledge and use of medications were collected by interview. Blood pressure was measured by standardized methods, with hypertension defined as blood pressure ≥140 mm Hg systolic and/or 90 mm Hg diastolic or controlled at <140 and/or 90 mm Hg with medications. Six surveys included 11 192 men and 12 795 women. Mean systolic blood pressure fell from 124.9 mm Hg in 1980 to 1982 to 121.1 mm Hg in 2007 to 2009 for men (P<0.0001) and from 120.1 to 114.7 mm Hg for women (P<0.0001). Similar trends for diastolic blood pressure were observed. The percentage of adults with uncontrolled blood pressure (≥140 and/or 90 mm Hg) with or without medication use fell from 20.3% to 5.8% (P<0.001) for men and from 13.1% to 2.7% (P<0.0001) for women. Antihypertensive medication use rose to >50% among all adults aged 55 to 74 years. Sixty-six percent of men and 72% of women with hypertension had their hypertension treated or controlled by 2007 to 2009. A majority of the decline in mean population blood pressure was the result of control with aggressive use of antihypertensive drugs. Stroke mortality in this population fell in parallel. CONCLUSIONS: The rate of hypertension detection and control in this community is among the highest observed in a US population and already exceeds Healthy People 2020 goals.

Isolated negative T waves as independent predictors of short-term and long-term coronary heart disease mortality in men free of manifest heart disease in the Seven Countries Study.

Isolated T-wave findings are generally considered of little importance in clinical electrocardiogram (ECG) interpretation, although a few studies have associated them with excess mortality risk. We used Cox regression models to evaluate coronary heart disease (CHD) mortality risk for isolated inverted T waves in 8713 men in the Seven Countries Study with no manifest cardiac diseases at baseline. The study population was stratified into 3 mutually exclusive groups: (1) isolated inverted T waves in the absence of other codable ECG findings according to the Minnesota Code; (2) other ECG findings with or without negative T waves; and (3) no codable ECG findings, used as the reference group. Mortality follow-up of the entire cohort was performed at 5, 10, 20, 30, and 40 years. The prevalence of isolated negative T waves at baseline was low, 1.6%, in these men from working populations. The hazard ratio (HR) for CHD mortality risk after 5 years in the isolated T-wave inversion group was more than 3 times greater than that in the reference group after adjusting for age, body mass index, cigarette smoking, systolic blood pressure, serum cholesterol and cohort (HR 3.68, 95% confidence interval [1.44-9.37]). Hazard ratio declined gradually with the length of follow-up but was still at 50% excess risk at 40-year follow-up (HR 1.51, 95% confidence interval [1.12-2.05]). T waves in the isolated T-wave inversion group were "flat" or less negative than 1mm (-100 µV) in the majority (86%) of inverted T waves. We conclude that inverted T waves with even a minor degree of negativity as an isolated ECG finding in men with no evidence of heart disease predict an excess short-term and long-term risk of CHD death.

20th-Century "medical Marco Polos" in the origins of preventive cardiology and cardiovascular disease epidemiology.

In mid-20th century, several streams of knowledge converged to create the new academic discipline of cardiovascular disease epidemiology and the new practice of preventive cardiology. One stream was modern cardiology, with the ability to diagnose myocardial infarction, to characterize and count its victims, and to report vital statistics on cardiovascular causes of death. Another stream came from burgeoning clinical and laboratory research and greater understanding of the underlying processes of atherosclerosis and hypertension. A third stream came from the observations of intellectually curious "medical Marco Polos," who brought back from travels their tales of unusual population frequencies of heart attacks, along with ideas about sociocultural causes. This led to more formal research about cardiovascular disease risk and causes among populations and about mechanisms in the clinic and laboratory. The broad river of investigation thus formed produced a risk paradigm of the multiple biologic, behavioral, and societal factors in causal pathways to the common cardiovascular diseases. An evidence base was built for sound clinical and public health approaches to prevention. Here, the author tells brief stories about 5 early and particularly observant world travelers and their influence on knowledge and thinking about prevention.

Trends in smoking among adults from 1980 to 2009: the Minnesota heart survey.

OBJECTIVES: We examined population-based smoking trends in Minnesota between 1980 and 2009. METHODS: The Minnesota Heart Survey (MHS) is a population-based, serial, cross-sectional study of cardiovascular risk factor trends among Minneapolis-Saint Paul metropolitan residents. The MHS recently completed its sixth survey (1980-1982 [n = 3799], 1985-1987 [n = 4641], 1990-1992 [n = 5159], 1995-1997 [n = 6690], 2000-2002 [n = 3281], and 2007-2009 [n = 3179]). We used MHS data to examine smoking trends among adults aged 25 to 74 years by means of age-adjusted generalized linear mixed models. RESULTS: Between 1980 and 2009, the prevalence of current smoking decreased from 32.8% to 15.5% for men and from 32.7% to 12.2% for women (P < .001 for each). Greater decreases occurred among those with higher income and those with more education. Among currently smoking men, the number of cigarettes smoked per day decreased from 26.0 in the 1980-1982 survey to 16.0 in the 2007-2009 survey (P < .001). Similar trends were observed among women. CONCLUSIONS: Although the prevalence of smoking and cigarette consumption decreased from the 1980-1982 period to the 2007-2009 period, interventions specifically designed for those of lower socioeconomic status are needed.

Trends in cardiovascular risk factor levels in the Minnesota Heart Survey (1980-2002) as compared with the National Health and Nutrition Examination Survey (1976-2002): A partial explanation for Minnesota's low cardiovascular disease mortality?

The authors compared trends in and levels of coronary heart disease (CHD) risk factors between the Minneapolis-St. Paul, Minnesota, metropolitan area (Twin Cities) and the entire US population to help explain the ongoing decline in US CHD mortality rates. The study populations for risk factors were adults aged 25-74 years enrolled in 2 population-based surveillance studies: the Minnesota Heart Survey (MHS) in 1980-1982, 1985-1987, 1990-1992, 1995-1997, and 2000-2002 and the National Health and Nutrition Examination Survey (NHANES) in 1976-1980, 1988-1994, 1999-2000, and 2001-2002. The authors found a continuous decline in CHD mortality rates in the Twin Cities and nationally between 1980 and 2000. Similar decreasing rates of change in risk factors across survey years, parallel to the CHD mortality rate decline, were observed in MHS and in NHANES. Adults in MHS had generally lower levels of CHD risk factors than NHANES adults, consistent with the CHD mortality rate difference. Approximately 47% of women and 44% of men in MHS had no elevated CHD risk factors, including smoking, hypertension, high cholesterol, and obesity, versus 36% of women and 34% of men in NHANES. The better CHD risk factor profile in the Twin Cities may partly explain the lower CHD death rate there.