Hardin B. Jones

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.

Lipoproteins and atherosclerosis.

Author(s): Gofman, John W.; Lindgren, Frank T.; Jones, Hardin B.; Lyon, Thomas P.; Strisower, Beverly.

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.

A low-protein diet restricts albumin synthesis in nephrotic rats.

High-protein diets increase albumin synthesis in rats with Heymann nephritis but albuminuria increases also, causing serum albumin concentration to be suppressed further than in nephrotic animals eating a low-protein diet. Experiments were designed to determine whether dietary protein augmentation directly stimulates albumin synthesis, or whether instead increased albumin synthesis is triggered by the decrease in serum albumin concentration. Evidence is presented that dietary protein augmentation directly stimulates albumin synthesis, accompanied by a proportional increase in steady-state hepatic albumin mRNA concentration (AlbmRNA) and by an increase in AlbmRNA transcription. When the increased albuminuria resulting from dietary protein augmentation is blunted with enalapril, serum albumin concentration is shown to increase in nephrotic rats. Both albumin synthesis and AlbmRNA increase in these animals despite the greater serum albumin concentration. Albumin synthesis correlates inversely with both serum albumin and serum oncotic pressure in nephrotic rats fed 40% protein, but does not correlate with serum albumin concentration in nephrotic rats fed 8.5% protein (LP), even when serum albumin concentration is reduced. Albumin masses are preserved in LP primarily because of reduced albuminuria. Reduced serum oncotic pressure and dietary protein augmentation combine to stimulate albumin synthesis in nephrotic rats at the level of gene transcription.

Environmental factors in the origin of cancer and estimation of the possible hazard to man

Summary The stages in the development of cancer are described as: (1) alteration of cellular function by the carcinogen; (2) reinforcing interaction by proximal altered cells-a microscopic control force; (3) failure of the restraining factors against tumorous proliferation within an organ-a macroscopic control; (4) failure of restraining forces against tumorous growth in the body as a whole. All four stages are important in human cancers. Urethane-induced lung cancer is a single-stage process atypical of cancer induction except as an example of the first stage. The relationship of dose to time of appearance of cancers is shown to have general validity as a law relating latent time to the inverse cube-root of the dose. The law is explained as the consequence of the second carcinogenesis stage, in which there is interaction of cells altered by carcinogens. Several examples of the estimation of cancer risk are presented as they apply to current problems of exposure of man to low levels of diethylstilboestrol, nitrosamines and radiation. If the cube-root of the dose applies to the estimation of the time of appearance of cancers, low-dosage exposure at some levels is virtually without risk because the expected lifespan of those exposed is exceeded by the time necessary for low concentrations of altered cells to develop into cancers.

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.

The distribution of radioactivity in the mouse following administration of dibenzanthracene labeled in the 9 and 10 positions with carbon 14.

Dibenzanthracene, labeled in the 9 and 10 positions with carbon fourteen has been administered to mice intravenously and by stomach tube as an aqueous colloid, and intraperitoneally, subcutaneously, and by stomach tube in tricaprylin solution. The distribution of radioactivity in the mice at various time intervals after administration of the carcinogen has been determined. The radioactivity is rapidly eliminated, largely through the feces, and ordinarily very little is absorbed. The distribution and rate of elimination depends upon the mode of administration. There is an appreciable quantity of radioactivity in tumors produced several months after a single subcutaneous injection of dibenzanthracene. There appear to be no detectable effects from the radiation of the labeled carcinogen.

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..