John W. Gofman

Blood Lipids and Human Atherosclerosis

The transport of cholesterol and other lipids of serum is almost wholly in the form of very large molecular complexes of these lipids with variable amounts of protein. The exact components present in the blood of a particular individual may be quantitatively described both as to character and concentration by ultracentrifugal flotation of these components in the analytic ultracentrifuge. With this technic it is possible to demonstrate the presence of certain lipid and lipoprotein components which are related to coronary atherosclerosis, to hypertension and to other diseases associated with atherosclerosis, such as diabetes mellitus, the nephrotic syndrome and hypothyroidism. The blood level of these components may be influenced by dietary means. The blood level of these components is poorly correlated with the analytic serum cholestrol determined by the Schoenheimer-Sperry method.

Lipoproteins in atherosclerosis

Abstract 1.1. Serum lipoprotein patterns as studied ultracentrifugally in the human indicate lipoprotein transport may be interpreted as reflecting varying degrees of a lipid metabolic error. 2.2. The nature of several lipid transport disturbances have been described for a variety of experimental procedures in the rabbit. In all disturbances there is a strong positive correlation between elevation of the S f 10–30 class of lipoproteins and the rate of development of atherosclerosis. Lipoproteins of the classes of S f 10 and less and S f 40–50 and higher do not show this correlation. Total serum cholesterol is positively related to the development of atherosclerosis only in those experimental procedures which allow for the increased serum cholesterol to be largely in the S f 10–30 class. 3.3. A critical comparison has been made, in which the analysis of total cholesterol and S f 12–20 lipoproteins was done on aliquots of the same serum sample, of both levels in normals vs. atherosclerotics, using myocardial infarctions as the test group. The over-all correlation of S f 12–20 lipoprotein levels with atherosclerosis is two to four times as great as that for serum cholesterol levels with atherosclerosis. 4.4. The S f 12–20 lipoprotein levels are associated with atherosclerosis, independently of their relationship with serum cholesterol. The S f 12–20 levels account for the bulk of the over-all predictive segregation of atherosclerotics from normals. 5.5. The serum cholesterol level is very much less, if at all, associated with atherosclerosis, when considered independently of its association with the S f 12–20 levels. 6.6. One-year follow-up studies of patients with coronary artery disease indicate that early recurrence of myocardial infarction is significantly associated with elevated S f 12–20 lipoprotein levels. An approximate estimate of recurrence rate as a function of S f 12–20 level may be made from the data on thirty-nine recurrences in the follow-up study. At 50 mg. per cent S f 12–20 the chance of recurrence is ~6 per cent in one year; at 110 mg. per cent the chance is ~18 per cent. 7.7. In acute myocardial infarction the prognosis for survival is worsened with highly elevated S f 12–20 lipoprotein levels, as determined during the acute phase. 8.8. Follow-up studies show that the reduction of S f 12–20 lipoprotein levels by dietary restriction of fats and cholesterol gives a significant degree of protection against recurrent myocardial infarction in patients with coronary artery disease whose levels before dietary restriction ranged above 80 mg. per cent. 9.9. The only pharmacologic agent which rapidly shifts the lipoprotein pattern in humans in the direction of normality is parenteral heparin. The possibility is considered that a deficiency of heparin or a heparin-like substance may be involved in causing the basic lipid metabolic defect in humans.

BLOOD LIPIDS AND HUMAN ATHEROSCLEROSIS II. THE INFLUENCE OF HEPARIN UPON LIPOPROTEIN METABOLISM

Heparin administered to humans and rabbits causes profound reorientation in the distribution of low density lipoproteins, characterized by a shift of lipoproteins of high Sf rates to those of successively lower Sf rates. The observations appear to indicate that this agent has actually caused a transformation of the former group into the latter. Heparin administered to the rabbit prevents the usual buildup of high concentration of the Sf 10-50 lipoproteins during cholesterol feeding and retards the development of atherosclerosis. In man, accompanying the redistribution of lipoproteins, there was observed a marked reduction in angina pectoris in 55 of 59 patients studied who presented this symptom. The relation between the heparin effect upon lipoproteins and its effect upon angina cannot be assessed at present.

Observations on the Fate of Ingested Cholesterol in Man

Tritium-labeled Cholesterol has been used to study several aspects of exogenous cholesterol metabolism in man. The rate and magnitude of the appearance of ingested cholesterol in the various blood compartments has been followed. Fecal excretion of the labeling material was measured. Cholesterol of dietary origin was demonstrated in a human atherosclerotic aorta.

Obesity, Fat Metabolism and Cardiovascular Disease

Lipoproteins of the Sf 12-100 class, representing only about 10 to 15 per cent of the serum cholesterol, are strongly associated with atherosclerosis. The major independent contributions to this association are from the Sf 12-20 lipoproteins and the Sf 35-100 lipoproteins. The Sf 20-35 lipoproteins are primarily associated by virtue of their intercorrelation with the other classes. Obesity is moderately associated with the Sf 35-100 and definitely, but to a lesser degree, with the Sf 12-20. The association of obesity with total serum cholesterol is so low as to obscure the stronger association with the Sf 35-100 lipoproteins. The relationship of the Sf 12-100 lipoproteins with obesity may be adequate to explain the major share, if not all, of the association of obesity with atherosclerosis. The control of obesity should therefore be a prime consideration in the management of atherosclerosis and its complications.

Effects of Total Body Irradiation upon Lipoprotein Metabolism

Author(s): Hewitt, John E.; Hayes, Thomas L.; Gofman, John W.; Jones, Hardin B.; Pierce, Frank T..

Diet in the prevention and treatment of myocardial infarction

Abstract 1. (1) The increase in risk of future myocardial infarction associated with elevation of lipoproteins of the S f o 0–12, 12–20, 20–100, and 100–400 classes provides the basis for a rational application of dietary measures in this disease. 2. (2) The prospect for dietary management of the coronary disease problem lies primarily in the ability of dietary measures to lower these lipoprotein levels. 3. (3) Animal fat contains some factor (or factors) which provokes elevation in the serum level of S f o 0–12 and S f o 12–20 lipoproteins. 4. (4) No valid evidence exists that any protective factor is present in vegetable oils which will lower S f o 0–12 or S f o 12–20 lipoprotein levels. 5. (5) Dietary carbohydrate intake is a prime factor in controlling the serum level of the S f o 20–100 and S f o 100–400 lipoprotein classes. Restriction of dietary carbohydrate can provoke marked falls in the serum level of these lipoproteins. 6. (6) The effect of caloric restriction and weight reduction can be largely explained on the basis of the alteration in animal fat intake and carbohydrate intake in such diets. 7. (7) The serum cholesterol measurement can be a dangerously misleading guide in evaluation of the effect of diet upon the serum lipids. 8. (8) Rational management of patients with coronary heart disease or of individuals attempting to avoid coronary disease depends upon knowledge of the lipoprotein distribution in the individual patient.

Macrophage Migration in Experimental Atherosclerosis

With the object of testing the importance of macrophage transport of lipid in the production of atheromas, a radioisotope was employed in labeling reticuloendothelial cells. Rabbits were injected with this isotope, and lipemia induced by cholesterol feeding. Subsequently the animals were sacrificed and the distribution of the label determined. High concentrations of the label were found in Kupffer cells, in splenic and marrow macrophages, but no significant increase was demonstrated in aortic atheromas. This finding is interpreted as evidence against the macrophage theory of genesis of atherosclerosis.

Lipoproteins, liver disease, and atherosclerosis.

The blood levels of the Sf 10-20 class of giant cholesterol-bearing lipoproteins were studied in a group of patients with cirrhosis. No significant difference was observed between the blood levels of this group and of a similar group of normal individuals of corresponding age and sex. This observation suggests that patients with cirrhosis are as susceptible to atherosclerosis as the general population.

The Effect of Carbon Tetrachloride Poisoning on Serum Lipoproteins Associated with Atherosclerosis

Carbon tetrachloride was injected into normal rabbits and the levels of Sf 3-12, 12-20, and 20-40 classes of lipoproteins were determined during the course of these injections. A marked increase in concentration of these three classes of lipoproteins occurred during the administration of carbon tetrachloride. After the cessation of this drug, the lipoproteins of largest Sf rate returned to normal first with those of lower Sf rate returning to normal levels in the order of decreasing Sf rates. Rabbits fed cholesterol were also injected with carbon tetrachloride, and their lipoproteins continued to increase after cessation of this drug.