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

Abstract

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.

The great and wonderful success story—not to say—saga—of CVD epidemiology—is rooted in the accumulated knowledge gained over a remarkably short space of time in a number of countries from an even larger number of studies. The wonder and fascination lies in having been able to build a solid, coherent, and powerful theory of causation as a starting point for preventive action.

—Frederick Epstein (1)

In a pioneering period of chronic disease epidemiologic research—from Gertler and White’s (2) 1946 Harvard study of risk characteristics among 100 young coronary patients versus controls to cohort studies of varied groups in the United States, Britain, the European Continent, and Japan—a wave of cardiovascular disease (CVD) preventive research swept the world. These studies among populations, along with prevention research conducted in clinics and laboratories, were an enthusiastic and rapid response of the scientific community—mainly nonepidemiologists—to the epidemic of heart attacks that was recognized soon after World War II.

Absent an authoritative academic text on the history of CVD epidemiology, some documentation of the origins and early evolution of this new science, as well as of the community of investigators and institutions that nurtured it, may be found in modern literature (3–6). That history is also accessible from a dedicated archive and website of the University of Minnesota School of Public Health (7).

The tabular presentation herein is not, in itself, a history of CVD epidemiology; rather, it is a ready reference to the early literature that comprises that history. The tables ignore less formal but nonetheless influential historical elements upon which formal CVD epidemiology was built. The sources tabulated here exclude the following:

• Accounts of informal observations by medical “Marco Polos,” that is, astute travelers who encountered people having apparently few CVD events in one place and populations with an apparently great CVD burden in another. Voyagers returned from foreign lands with new and researchable ideas about possible causes of the apparent cultural differences. A critical few among these travelers recognized that such widely contrasting “natural experiments” indicated powerful environmental and behavioral influences on CVD and thus the potential for prevention (8).

• Salient clinical studies, such as a large case-series of coronary disease in the US armed forces by Yater et al. (9), and systematic comparisons of arterial pathology across cultures, such as the International Geopathological Study by Strong et al. (10) from New Orleans.

• Cross-sectional surveys of CVD risk factors and prevalence, either single or serial, in which individuals were not subsequently followed (and thus were not cohort studies).

This tabulation of articles from CVD epidemiologic studies initiated between 1946 and 1976 includes the following:

• Formal prospective studies among varied cohorts (Table 1) and experiments as prevention trials (Table 2). Case-control comparisons, so fruitful in cancer epidemiology, were uniquely uncommon in early CVD epidemiology and played no role in construction of the popular CVD risk profile. Here, for the sake of completeness and consistency, the entirety of early case-control literature for CVD is included in Table 3, comprising 3 articles, 2 of which were analyses from the Framingham Study. (Nested case-control comparisons have since come into substantial use in post hoc analyses, often of newer ideas about risk, carried out in long-term data bases of large cohort studies.)

Table 1.

Cohort Studies Initiated From 1946 to 1976

Defining Publication of the Studya	Common Name of the Study	Principal Investigator	Start Date
Gertler and White, 1954 (2)b	Coronary Heart Disease in Young Adults	P. D. White	1946
Keys et al., 1963 (16)	Minnesota Business and Professional Men Study	A. Keys	1947
Dawber et al., 1957 (17)	Framingham Heart Study	T. R. Dawber	1948
Thomas, 1951 (18)	Johns Hopkins Precursors Study	C. B. Thomas	1948
Chapman et al.,1957 (19)	Los Angeles Civil Servants Study	J. Chapman	1949
Morris et al.,1953 (20)	London Transport and Postal Workers Studies	J. Morris	1949
Paffenbarger et al., 1970 (21)	California Longshoremen Study	R. Paffenbarger	1951
Doll and Hill, 1954 (22)	British Doctors Study	R. Doll and B. Hill	1951
Cooperative Lipoprotein Study Group, 1956 (23)	Cooperative Lipoprotein Study	Cooperative Lipoprotein Study Group	1952
Doyle et al., 1957 (24)	Albany Civil Servants Study	J. Doyle	1953
Pell and D’Alonzo, 1961 (25)	Dupont Company Study	S. Pell and C. A. D’Alonzo	1956
Keys, 1980 (26)	Seven Countries Study	A. Keys	1957
Paul et al., 1963 (27)	Chicago Western Electric Study	O. Paul	1957
Taylor et al., 1970 (28)	US Railway Study	H. L. Taylor	1957
Stamler et al., 1960 (29)	Chicago Peoples Gas Company Study	J. Stamler	1958
Epstein et al., 1965 (30)	Tecumseh Community Health Study	T. Francis, Jr.	1959
Keil et al., 1977 (31)	Charleston Heart Study	E. Boyle	1960
Rosenman et al., 1966 (32)	Western Collaborative Group Study	R. H. Rosenman	1960
Hames, 1971 (33)	Evans County Heart Study	C. Hames	1960
Carlson and Lindstedt, 1968 (34)	Stockholm Study	L. A. Carlson	1961
Sadoshima et al., 1980 (35)	Hisayama Study	S. Sadoshima	1961
Paffenbarger et al., 1978 (36)	Harvard Alumni Study	R. Paffenbarger	1962
Komachi et al., 1971 (37)	Osaka Study	Y. Komachi	1963
Medalie et al., 1973 (38)	Israel Ischemic Heart Disease Study	J. H. Medalie	1963
Tibblin et al., 1975 (39)	Göteborg Study of Men Born in 1913	G. Tibblin	1963
Marmot et al., 1975 (40)	Ni-Hon-San Study	Ni-Hon-San Study Group	1963
Breslow and Breslow, 1993 (41)	Alameda County Study	L. Breslow	1964
Cutler, 1967 (42)	Seal Beach Study	R. A. Stallones	1964
Hagerup, 1974 (43)	Glostrup Study	L. M. Hagerup	1964
Trombold et al., 1966 (44)	Honolulu Heart Study	A. Kagan	1964
Kornitzer et al., 1993 (45)	Belgian Bank Study	M. Kornitzer	1964
Kozarevic et al., 1981 (46)	Yugoslavia Cardiovascular Disease Study	D. Kozarevic	1964
Connolly et al., 1981 (47)	Olmsted County Study	D. C. Connolly	1965
García-Palmieri et al., 1978 (48)	Puerto Rico Cardiovascular Disease Study	R. Garcia-Palmieri	1965
Reunanen et al, 1983. (49)	Finnish Social Insurance Institution Study	A. Aromaa	1966
Pyörälä et al., 1979 (50)	Helsinki Policemen Study	K. Pyörälä	1966
Welborn et al., 1969 (51)	Busselton Health Study	T. A. Welborn	1966
Marmot et al., 1984 (52)	Whitehall I Study	M. Marmot	1967
Stamler et al., 1975 (53)	Chicago Heart Association Detection Project in Industry	J. Stamler	1967
Jouven et al., 1998 (54)	Paris Prospective Study	J. Richard	1967
Bengtsson, 1973 (55)	Prospective Study of Swedish Women	C. Bengtsson	1968
Lannerstad et al., 1977 (56)	Malmö Study of Men Born in 1914	O. Lannerstad	1970
The Lipid Research Clinics Program Epidemiology Committee, 1979 (57)	Lipid Research Clinics Population Study	The Lipid Research Clinics Program Epidemiology Committee	1971
Lauer et al., 1975 (58)	Muscatine Iowa Study	R. M. Lauer	1971
Berenson et al., 1978 (59)	Bogalusa Heart Study	G. Berenson	1972
Hawthorne et al., 1995 (60)	Paisley-Renfrew Study	V. M. Hawthorne	1972
Holme et al., 1980 (61)	Oslo Study (Cohort)	P. Leren	1972
Schnohr et al., 1977 (62)	Copenhagen City Heart Study	P. Schnohr	1976

Abbeviation: Ni-Hon-San, Nippon, Honolulu, San Francisco.

^a The references are those that either defined the particular study and called international attention to it or presented the first substantive results. They are usually neither the very first nor the summative or final study reports.

^b This study in young coronary patients began in 1946 as a case-control study and is included here because it was later converted into a prospective study of the cohort that was followed for 25 years with pair-matched and unmatched controls.

Table 2.

Prevention Trials Initiated From 1946 to 1976

Defining Publication of the Triala	Common Name of the Trial	Diet, Drug, or Lifestyle Advice	Principal Investigator	Start Date
Diet
Morrison, 1951b (63)	Morrison Diet-Heart Study	Dietc	L. M. Morrison	1946
Christakis et al., 1966b (64)	Anti-Coronary Club Trial	Dietd	G. Christakis	1957
Leren, 1966 (65)	Oslo Diet-Heart Study	Dietc	P. Leren	1957
Turpeinen et al., 1968 (66)	Finnish Mental Hospital Study	Dietd	O. Turpeinen	1958
Dayton et al., 1968 (67)	Wadsworth Veterans Administration Domiciliary Hospital Study	Dietd	S. Dayton	1959
Bierenbaum et al., 1967b (68)	Bierenbaum-St. Vincent’s Hospital Study	Dietc	M. L. Bierenbaum	1959
British Medical Research Council, 1968 (69)	British MRC Soya-Bean Oil Trial	Dietc	British Medical Research Council	1960
National Diet-Heart Research Group, 1968 (70)	National Diet Heart Pilot Trial	Dietd (pilot)	National Diet-Heart Research Group	1962
Drugs: Cholesterol Lowering
Committee of Principal Investigators, 1984 (71)	WHO Cooperative (Clofibrate) Trial	Drugsd	Committee of Principal Investigators (M. Oliver, chairman)	1962
Research Committee of the Scottish Society of Physicians, 1971 (72)	Scottish Society of Physicians Clofibrate Trial	Drugc	Research Committee of the Scottish Society of Physicians	1964
Krasno and Kidera, 1972 (73)	United Airlines Study	Drugc and drugd	L. R. Krasno	1966
Coronary Drug Project Research Group, 1977 (74)	Coronary Drug Project	Dietc	Coronary Drug Project Research Group (J. Stamler, chairman)	1966
Carlson and Rosenhamer, 1988 (75)	Stockholm Prevention Trial with Clofibrate and Niacin	Drugc	L. A. Carlson	1972
The Lipid Research Clinics Program Group, 1984 (76)	Lipid Research Clinics Coronary Primary Prevention Trial	Drugd	Lipid Research Clinics Program Group	1973
Hypertension
VA Cooperative Study on Hypertension, 1967 (77)	VA Cooperative Study on Hypertension	Drugd	E. D. Freis (chair)	1962
VA Cooperative Study on Hypertension, 1970 (78)	VA Cooperative Study on Hypertension	Drugd	E. D. Freis (chair)	1962
Smith, 1977 (79)	US Public Health Service Hospitals Cooperative Study	Drugd	W. McFate Smith	1966
Hypertension Detection and Follow-up Program Cooperative Group, 1979 (80)	Hypertension Detection and Follow-up Program	Diet and drugd	Hypertension Detection and Follow-up Program Cooperative Group	1971
Helgeland (81)	The Oslo Study on Mild Hypertension l	Drugd	A. Helgeland	1972
Amery et al., 1985 (82)	European Working Party on High Blood Pressure in the Elderly	Drugd	A. Amery	1972
Parry, 1980 (83)	Australian National Blood Pressure Study	Drugd	Management Committee	1973
Smoking
Rose et al., 1982 (84)	Whitehall Anti-Smoking Trial	Lifestyle and antismoking adviced	G. Rose	1972
Multifactoral
University Group Diabetes Program Group, 1970 (85)	University Group Diabetes Program	Drug and dietd	University Group Diabetes Program Group	1960
Wilhelmsen et al., 1986 (86)	Göteborg Multifactorial Primary Prevention Trial	Diet and drugd	L. Wilhelmsen	1970
Rose et al., 1983 (87)	WHO European Collaborative Trial of Multifactorial Prevention of Coronary Heart Disease	Lifestyle adviceand treatment of hypertensiond	WHO Collaborative Group (G. Rose, chair)	1971
Multiple Risk Factor Intervention Trial Group, 1976 (88)	Multiple Risk Factor Intervention Trial	Diet and drugd	Multiple Risk Factor Intervention Trial Group	1971
Hjermann, 1980 (89)	Oslo Study of Diet and Anti-Smoking Advice	Diet and antismoking adviced	I. Hjermann	1972
Miettinen et al., 1985 (90)	Multifactorial Cardiovascular Disease Prevention Trial in Helsinki Businessmen	Diet, antismoking advice, and drugsd	T. A. Miettinen	1974

^a The references are those that either defined the particular study and called international attention to it or presented the first substantive results. They are usually neither the very first nor the summative or final study reports.

^b Nonrandomized controls.

^c Secondary prevention.

^d Primary prevention.

Table 3.

Case-Control Studies Initiated From 1946 to 1976

Defining Publication of the Studya	Common Name of the Study	Principal Investigator	Dates of the Study
Gertler and White, 1954 (2)b	Coronary Heart Disease in Young Adults	P.D. White	1946–1954
Friedman et al., 1966 (91)	Case-control versus cohort analysis in the Framingham Study	G. D. Friedman	1964
Friedman et al., 1974 (92)	Case-Control Study of Standard Risk Factors	G. D. Friedman	1972–1973

^a The references are those that either defined the particular study and called international attention to it or presented the first substantive results. They are usually neither the very first nor the summative or final study reports.

^b This study was converted to a prospective study of the cohort with both pair-matched and unmatched controls, then followed for 25 years.

THE TABULATIONS

Publications from early population studies and trials of CVD prevention initiated between 1946 and 1976 are catalogued here to facilitate pursuit of the historic beginnings of CVD epidemiology. “Initiation” refers to the approximate start of data collection in each study, which usually followed extensive planning, collaboration, and pilot studies. The tables are intended for use by students and scholars of CVD, public health, and the history of science. The publications chosen (1 per study) are those that either defined the particular study and called international attention to it or that presented the first substantive results. Therefore, the articles are often neither the very first nor the summative or final report from a given study.

A few of the earliest diet trials are labeled with a note indicating the studies were inadequately controlled, and thus their conclusions about diet effects were questionable. Those articles are included in this collection because of their impact at the time: They were led by noted investigators, they were published after review by prestigious journals, and their conclusions were widely, if erroneously, accepted.

CONTEXT

A remarkable element of this array of historical observational studies (Tables 1 and 3) is the overwhelming early adoption of cohort design, that is, a baseline survey to establish personal characteristics and CVD prevalence at entry, with follow-up observations of varied duration for rates of CVD events and deaths. This more expensive and “patient” cohort strategy was chosen over case-control design because of its strength and for its simplicity: It was a straightforward design readily understood by CVD investigators who had insufficient training or understanding of the complexities of case-control comparisons.

An additional strong feature of these early epidemiologic studies was the prominent use of whole or healthy population cohorts, thus providing greatest relevance to primary prevention. Another was the great variety of populations recruited. Study initiators used whatever population was at hand: an accessible organization, industry, school, or community. This variety of samples had positive implications for the generalizability of the several CVD risk characteristics that were consistently found.

EVOLUTION

Despite stumbling performance—frequently by the pioneering CVD experts who were untrained in epidemiology or trial design—the magnitude, sophistication, and fruits of research on population rates and on risk of CVD advanced rapidly after World War II. The curiosity of the early investigators and the intense postwar period of prospective studies, particularly among healthy cohorts, established by the mid-1970s a risk-factor paradigm for CVD that proved universally useful in the research, practice, and policy of prevention. During 3 decades of combined, focused clinical, laboratory, and epidemiologic research from the mid-1940s to the mid-‘70s, sufficient evidence was brought forward to provoke the greater systemic efforts required to better understand and modify the underlying disease processes of atherosclerosis and hypertension.

The combined enterprise of this early period led to greater acceptance, support, and research volume in CVD epidemiology, a prime stimulus for which was the advent of new policy at the US National Institutes of Health that soon followed by measures from the World Health Organization and various national heart foundations. Under pressure from and the guidance of expert recommendations from the science community (11–13), Theodore Cooper, Director of the National Heart and Lung Institute (now the National Heart, Lung, and Blood Institute), announced a broad US policy and program of CVD prevention at the 1971 Annual Scientific Sessions of the American Heart Association (14). This was promptly translated into new prospective studies, trials, and community education programs (on tobacco use, hypertension control, and diet and blood lipids), as well as a proliferation in teaching and practice of CVD epidemiology and preventive cardiology. The ultimate mission was to prevent CVD in the individual and among the population at large.

Beginning in the late 1960s and continuing today, CVD death rates have declined in many industrial countries; there have also been favorable trends in health knowledge and behavior and in cardiac care (3). The average decline in age-adjusted CVD mortality rate from its US peak in 1968 was 3% per year for the decades 1968–1997 and 5% per year from 1998 to 2008 (15). Similar rates of decline occurred in other industrial countries, with wide variations among the regions and ethnic groups of those countries.

Nevertheless, today much of the world is experiencing rapid socioeconomic development, with new exposures and behaviors accompanied by a scourge of mass obesity and metabolic diseases. Concerned scholars of this new epidemic should profit from the lessons of history reflected in these early reports, as well as from today’s improved epidemiologic skills.

Abbreviation

CVD

cardiovascular disease.