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From the Atherosclerosis Research Group, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, Bethesda, Md.
The cardiovascular medicine community lost a leading light with the death, in April 2004, of Gardner C. McMillan. He recognized, early on, the complexity of human and experimental atherosclerosis. Dr McMillan’s observations, thoughts, and articulate advocacy were always at the forefront of a major shift in how we conceptualize atherogenesis. He led the way in transforming contemporary atherosclerosis and vascular biology research.
Gardner McMillan began his career in medicine by earning a medical degree from McGill University in Montreal, Canada in 1944, taking prize-winning honors in anatomy (the John Munro Elder Prize). He developed a keen interest in pathology during his early postgraduate days, which was solidified with a Masters degree in 1946 and a PhD degree in 1948 under the sponsorship of another pioneering leader of atherosclerosis research, George Lyman Duff. He remained in Dr Duff’s department as a Markel Scholar in Medical Science and began his research career with investigations of human and experimental atherosclerosis. Gardner’s keen interest in comparative pathology enabled him to grasp the magnitude of the contribution that animal models could make toward better-understanding atherosclerosis in humans. His research markedly influenced ensuing research directions in arteriosclerosis. Among his early work was the paradoxical observation that experimental diabetes (induced by alloxan) inhibited the atherosclerosis resulting from feeding cholesterol to the rabbit.1 As a result of this fundamental research, we came to recognize that some lipoprotein particles are atherogenic whereas others are not, and it likely fuelled Dr McMillan’s lifelong suspicion that the cause of atherosclerosis was far more complicated than being solely caused by too much cholesterol in the blood.
During the 1950s and much of the 1960s, the literature on arteriosclerosis was confusing and complex regarding how atherosclerotic lesions at various stages in the natural history of human atherosclerosis were described. Dr McMillan (joined by Dr Duff and, later on, by Dr Henry McGill) described the variety of atherosclerotic lesions in 2 classic publications.2,3 That work remains a standard reference to this day and its lesion illustrations can be seen hanging on the walls of autopsy rooms in most academic medical centers. Between 1955 and 1971, Dr McMillan served as a member of the Lesions Committee of the Council on Arteriosclerosis of the American Heart Association (AHA). He participated in the pioneering efforts of that group to develop standardized methods for grading human atherosclerosis.4 These reports stimulated a number of efforts to quantify atherosclerotic lesions for epidemiological studies of human atherosclerosis.
Gardner also studied the effects of undernutrition and of cortisone on cholesterol-induced atherosclerosis. He demonstrated that the endothelium directly overlying experimentally caused lesions had increased permeability and showed that the amount of cholesterol in lesions was only moderately correlated with their severity. 5 As recognition of his scientific contributions and insight, Gardner delivered the prestigious Duff Memorial Lecture at the 1957 annual scientific meeting of the AHA and received the AHA Citation for Distinguished Service to Research in 1965.
Dr McMillan, who served as Strathcona Professor of Pathology, succeeded Dr Duff as Chairman of the Department of Pathology at McGill University. He was also chief of Pathology at the Royal Victoria Hospital in 1957, and a consulting pathologist, through 1966, to the Royal Edward Laurentian Hospital, the Montreal Neurological Institute, the Montreal Children’s Hospital, the Montreal General Hospital, and the Jewish Hospital of Hope. He became a fellow of the Royal College of Physicians and Surgeons of Canada (Pathology) in 1964. He continued to study human and experimental atherosclerosis, reporting on the effects of saturated, unsaturated, and trans-fatty acids in cholesterol-fed rabbits and on amino acid deficiencies. Early in his career, Gardner had noted the presence of mitotic activity in experimental atherosclerotic lesions,6 which later on stimulated Dr Herbert Stary to demonstrate this more dramatically when tritiated thymidine techniques became available.7 These studies were key in focusing attention on the role of the artery wall in atherogenesis. Two years later, he and Stary published a definitive article describing the use of radioautography to characterize the kinetics of cellular proliferation in experimental atherosclerosis. These seminal observations presaged our current interest in the dynamic nature of the early atherosclerotic lesion.
In 1966, Dr McMillan joined the National Institutes of Health (NIH), first as a consultant and then as special assistant to the Director of the Heart Institute (1968), as Chief of the Arteriosclerosis Diseases Branch, and (between 1972 and 1991) as Director of the Arteriosclerosis, Hypertension, and Lipid Metabolism Program at the National Heart, Lung, and Blood Institute. For these 2 decades, until his retirement in 1991, Gardner was a staunch advocate of atherosclerosis research and a counselor and catalyst for stimulating young investigators and attracting new research talent to the field. He had that special ability to be both a specialist and a generalist in clarifying and identifying areas of opportunity and advancement in atherosclerosis and cardiovascular research. In a very prescient way, he contributed to the overall expansion and progress in atherosclerosis research by supporting new and established investigators at the country’s leading granting agency.
Since coming to the NIH, Gardner was instrumental in promoting landmark programs and studies to investigate atherosclerosis and its sequelae. He was the harbinger of multidisciplinary research to tackle complex diseases and syndromes. He promoted investigation of the relationships among hyperlipidemia, hypertension, thrombosis, diabetes, cigarette smoking, other systemic risk factors, and the cause and pathogenesis of atherosclerosis. He was a prominent member of the team that devised the Specialized Centers of Research (SCOR) program that, to this day, allows investigators to engage in interdisciplinary and collaborative research on atherosclerosis, bringing together both basic and clinical science. Through the programs he instigated long ago, Gardner’s insight has borne so much fruit—we now have far better understanding of the structure and function of lipoproteins and apolipoproteins at the systemic and cellular levels and their role in atherogenesis; the oxidative modification hypothesis for atherosclerosis; the role of cholesterol-lowering in familial hypercholesterolemia in retarding the progression and promoting the regression of human coronary atherosclerotic lesions; and pediatric and behavioral aspects of atherosclerosis. Through Gardner’s efforts, the NIH pioneered research programs on nutrition, lesion dynamics, and the relationship of hemodynamics to atherogenesis, which led to the establishment of nonhuman primate resources.
Dr McMillan was also instrumental in initiating, in 1985, the landmark nationwide study, Pathological Determinants of Atherosclerosis in Youth (PDAY). Examining the pathogenesis of atherosclerosis in young people, aged 15 to 34, has enabled us to demonstrate conclusively that risk factors for adult coronary heart disease are associated with atherosclerosis development during youth, providing strong support for early risk reduction, beginning in adolescence and probably earlier. In particular, PDAY research suggests that risk factor reduction retards the rate at which fatty streaks are converted to raised lesions, the clinically significant lesions of atherosclerosis. It is because of Gardner’s encouragement and efforts that this study has been completed and that banked specimens will continue to provide a wealth of information for generations to come.
As a scientist, clinician, administrator, and public servant, Gardner McMillan adhered to the highest standards of performance and integrity. He was an eloquent speaker and a germane and compelling writer. His quiet enduring enthusiasm for his subject inspired many whom worked with and studied under him. As a colleague, one could always rely on him to focus on the clinically and scientifically relevant questions, to offer a meticulous eye for detail, and to maintain an uncompromising desire for rigorously high standards. As a mentor, Gardner was always a willing and sympathetic listener, a source of patient and calm advice, and hugely generous and unselfish with his time, his famous insights, and his creative ideas. Modern medicine owes him a huge debt.
Gardner was as warm a human as he was an accomplished scientist and teacher. Animated conversation and spirited debates with friends and colleagues would reveal his critical capacities but never obscure his friendship. Those who knew him will miss immensely his personal warmth and good humor. He shared his appreciation for culture and beauty with his wife and children through his love of photography, music, woodworking, gardening, fine food, and wine. Dr McMillan is survived by his wife, Lois, 4 children, and 8 grandchildren. Few transform a field as decisively as did Gardner McMillan. His contributions affect the daily parlance and practice of physicians, pathologists, and research investigators worldwide. His influence will long be felt, and his passing leaves a great gap.
Acknowledgments
Discussion and material provided by Dr Henry McGill and Dr Thomas Clarkson are greatly appreciated.
References
Duff GL, McMillan GC. The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit. J Exper Med. 1949; 89: 611–630.
Duff GL, McMillan GC. Pathology of atherosclerosis. Am J Med. 1951; 11: 92–108.
McGill HC Jr., Brown BW, Gore I, McMillan GC, Paterson JC, Pollak OJ, Roberts JC Jr, Wissler RW. Grading human atherosclerotic lesions using a panel of photographs. Circulation. 1968; 37: 455–459.
Holman RL, Brown BW, Gore I, McMillan GC, Paterson JC, Pollak OJ, Roberts JC, Wissler RW. An index for the evaluation of atherosclerotic lesions in the abnormal aorta. A report by the committee on lesions of the Am Society for the study of arteriosclerosis. Circulation. 1960; 22: 1137–1143.
McMillan GC, Horlick L, Duff GL. Cholesterol content of Aorta in relation to severity of atherosclerosis. Studies during progression and retroregression of experimental lesions. Arch Path. 1955; 59: 285–290.
McMillan GC, Duff GL. Mitotic activity in the aortic lesions of experimental cholesterol atherosclerosis in rabbits. Arch Path. 1948; 46: 179–182.
McMillan GC, Stary HC. Preliminary experience with mitotic activity of cellular elements in the atherosclerotic plaques of cholesterol-fed rabbits. Studies by labeling with tritiated thymidine, atherosclerosis. Recent advances, Annals of the New York academy of Sciences. 1968; 149: 699–709.