Gardner McMillan on 40 years of NIH Researches in Atherosclerosis
Gardner McMillan, Canadian trained pathologist, supervised the National Heart, Lung, and Blood Institutes research program on mechanisms in atherosclerosis for many years. His deep experience, intellectual rigor, and broad view gave weight to his work and his opinions of others work. He made a tough yet supportive program evaluator-administrator and here summarizes years of his program for the 40th anniversary conference of NHLBI.
“The years of the second World War were a period of relative inactivity in research on atherosclerosis … The field became active again in the late 1940s, and progress was rapid. The uncertainty about the association of lipids and development of atherosclerosis in humans was quickly resolved … and has been remarkably productive” (McMillan 1987, 9).
McMillan attributes to the Framingham Heart Study important information about this association and describes its initiation and findings of the first years of follow-up, showing that age, male sex, blood cholesterol level, high blood pressure, cigarette smoking, and diabetes are risk characteristics for coronary disease and stroke. He gives priority for these associations to the report of the Technical Group of the Committee on Lipoproteins in Atherosclerosis of the National Advisory Heart Council, in other words, the Gofman Study, in 1956. The 1957 AJPH report from Framingham, Los Angeles, and Albany, provided, however, the main evidence base for mounting clinical trials in hypertension and cholesterol lowering, and for the ensuing National High Blood Pressure Education Program and the National Cholesterol Education Program.
Dietary cholesterol experiments in this period resolved the outstanding inconsistencies of fatty acid effects on blood lipids with the Keys and Hegsted and other studies finding precise and predictable serum lipid changes from qualitative and quantitative changes in fat composition of diet, which “had become important to us for public health and medical practice application as well as for research purposes” (Ibid., 11). Cultural comparisons such as the Seventh Day Adventists Study and the Seven Countries Study add a major dimension elaborating the population-wide effects of diet differences, population correlations between cholesterol level and saturated fat intake and heart attack rate and these findings led to greater interest in other natural experiments such as migration studies.
By 1961, the American Heart Association began to give advice to the public and profession on controlling fats in the diet to reduce heart attack risk and this was followed by a more emphatic diet statement in 1964. All the risk factor information was gathered in the powerful Inter-Society Commission Report in 1970 leading to the beginning effort of controlled trials. The 1960s Coronary Drug Project had been the earliest U.S. undertaking. “This report was more important for its seminal influence on the design of . . . clinical trials and for findings on drug toxicity than for the demonstration of major therapeutic benefits” (Ibid., 13).
The Dayton-Pierce VA Domiciliary Study in Los Angeles and other dietary modification trials create a drive in the early 1960s for a well-designed diet-heart clinical trial in free-living men, and the National Diet-Heart Pilot Study got underway in 1962 in five U.S. Centers. McMillan’s summary of the pilot is weighty and succinct: “The final result of the (pilot) study in 1968 showed logistic feasibility, indicated that diet could lower blood lipids, and paved the way for the conduct of a definitive diet-heart trial. The results of the study, however, led to the conclusion that such a trial would be very large and very costly in terms of both money and effort. Its impracticality led a task force to recommend in 1971 that smaller scale, well-controlled trials of lipid-lowering by diet or by drugs be conducted in high-risk populations” (Ibid.). It concluded that these would best be carried out within the already initiated Lipid Research Clinics (LRC) program directed by Bethesda Central.
The LRC Prevalence Study gave the first population-based distribution data in youth and adults for serum lipids and other risk characteristics. The LRC Coronary Primary Prevention Trial was planned in 1971, recruited in 1973, and completed in 1983. All subjects received prudent dietary advice and half those received cholestyramine, a bile sequestering agent that lowered serum cholesterol moderately. The trial result was internally consistent and showed a decreased heart attack and death rate from first heart attack. It greatly strengthened causal inference about lowering LDL cholesterol and diet in human atherosclerosis, the conclusion limited by its population solely of men in a relatively homogeneous industrial society. And it was a drug rather than a diet trial yet led to considerable consensus about where lipid levels should be for intervention recommended for both medical and public health prevention strategies.
A series of pathological studies and prospective risk factor observational studies showed that severity of plaques was related to levels of risk factors, and in more than 300,000 Multiple Risk Factor Intervention Trial recruits, a smoothly graded risk of heart attack was found by serum cholesterol level; thus no biologic threshold of risk was required.
“It is clear in these investigations that the concern voiced in the 1940s that we lack substantial evidence to associate hypercholesterolemia and atherosclerotic disease in man has been laid to rest. Not only do we have detailed quantitative information that they are associated, but the influence of the quantity and type of dietary fats on blood lipids and heart attack rates has been documented in humans. Moreover, the circle of argument had been closed by the demonstration that lowering plasma cholesterol levels in high risk men, the lower the risk of atherosclerotic heart disease in a proportionate manner” (Ibid., 14).
Forty-year advances are documented in lipoprotein analysis and structure, cellular mechanisms, lipoprotein function, the role of apolipoproteins in development of plaque and the phenomenon of plaque regression that occurs slowly, with poorly understood mechanisms, when the dietary stimulus is withdrawn.
McMillan opines that the decades of the ‘50s and the ‘70s were the richest in research production leading to understanding of lipid metabolism and transport and the ‘70s for understanding the functional role of lipoproteins. In 1987, he concludes, “From the practical point of view, the risk factors for atherosclerotic disease have been characterized, treatments are in hand, and prevention through public and physician education has been initiated; and we can now add, 20 years later, . . is yet far from being accomplished” (Ibid., 31). (Henry Blackburn)
McMillan, Gardner C. 1987. Atherosclerosis research: Decades of progress. In Forty years of achievement in heart, lung and blood research: A collection of essays in selected areas of biomedical research accomplishment, 9-31. Bethesda: U.S. Dept. of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute.