The George E. Brown Memorial Lecture

Abstract

In this lecture a partial and tentative examination has been made of chemical factors possibly important in the pathogenesis of atherosclerosis. The discussion has centered about four observations concerning the incidence and extent of the disease. The first is that man appears to be unique among mammals in his predisposition; the second, that the condition is seldom if ever seen in the human infant at birth; the third, that healthy women are not likely to develop its complications before the time of the menopause; the fourth, that in man certain maladies and particularly diabetes, familial xanthomatosis, and nephrosis favor early and extensive atheromatous deposits. An attempt has been made to relate present knowledge of lipid composition of the blood to known variations in the degree of predisposition to the disease. This has included scrutiny of observations on concentration of cholesterol and the S f 10-20 bodies of Gofman, on cholesterol-phospholipid ratios and on the distribution of cholesterol between the lipoproteins of plasma. It has been shown that in mammals which never develop spontaneous atherosclerosis the values of all the criteria of concentration and distribution of lipids differ from those of man. Among human beings only the infant at birth has plasma which in its lipid composition closely resembles that of immune mammals. In young women the deviation is less than in other human adults. In groups of patients that display the greatest tendency to the development of atherosclerosis, the plasma lipid patterns differ most widely from those of other mammals. Among survivors of myocardial infarction many but not all display striking abnormalities in every one of the criteria of lipid concentration and distribution. Comparison of the different methods indicates that in survivors of infarction the distribution of cholesterol between the lipoproteins is more constantly disturbed than the other chemical factors. No test however deviates with sufficient constancy to permit its use in the clinical diagnosis either of the presence of atherosclerosis or of a tendency to its development. It has been shown that the lipid patterns in man are not immutable but can be manipulated to a considerable degree. Specifically, it has been demonstrated that the administration of estrogen can convert the highly pathologic patterns of survivors of myocardial infarction to normal adult human values, and that the use of methyl testosterone exaggerates the chemical pathology of myocardial infarction and may even produce deviant patterns in those who have been previously normal. Although the observations which have been reviewed offer strong evidence that predisposition to atherosclerosis is related to deviations in the lipid composition of the blood, they do not establish the chemical hypothesis of pathogenesis. Although at present they lead to no practical applications in therapy, they are regarded as worthy of further investigation with a justifiable hope that greater knowledge may offer new clues to prevention and control.