THE VIEW that coronary heart disease, or arteriosclerosis, is a multifactorial disease has always disturbed me -not because it isn't important to uncover the conditions that aggravate this disease, but because as a basis for scientific inquiry I feel that it may be a very long time before we can formulate a model that will be both scientifically sound as well as aesthetically pleasing.In some way nearly every process around us is mul tifactorial. Even a simple discussion about the weight of a gas can be conducted in multifactorial terms. The weight depends, of course, on its volume, pressure, temperature, molecular weight and the gravitational force. Even in this simple analysis at least flve factors determine the outcome of the inquiry. If we analyzed the question in terms of molecular, atomic or subatomic physics the number of factors involved in answering the inquiry would probably be increased manifold.Therefore, we should not be discouraged by the multitude of possible etiological and risk factors that compete for priority status. It is highly unlikely that we shall have to control each and every one of them to prevent the clinical manifestations of arteriosclerosis.However, it is still not possible to present a unitary view of the atherogenic process. Consequently, this presentation deals only with selected early manifestations of arterial pathology, i.e., lipid accumulation, and leans more heavily on my own work than is warranted by its importance. I shall, however, synthesize our findings with those of others in support of the view that arterial lipid accumulates as the result not only of abnormally high concentrations of low- density lipoproteins (LDL) in the blood plasma, but also as a consequence of the normal process of lipid absorption and transport. This normal process may be innocuous in persons who ingest low-fat diets, but is probably pathogenic in those who consume a diet rich in fat and cholesterol. Lipid and AtherosclerosisCholesterol and AtherosclerosisMost scientists working in the atherosclerosis area see cholesterol as a pivotal element in the etiology of cardiovascular disease. At least five areas of research contribute to this view. In 1910, Windaus' described the presence of cholesterol in the lesions of diseased arteries. Since then, many studies have confirmed that free and esterified cholesterol accumulate in the aorta, coronary arteries, cerebral vessels and other large arteries at different rates in different persons or in different population groups.2 In persons with premature, genetically determined hypercholesterolemia, arterial cholesterol accumulates more rapidly and clinical manifestations of cardiovascular disease appear earlier in life.3 Epidemiological studies have repeatedly shown high degrees of correlation between the intake of cholesterol and other lipids with the prevalence of coronary heart disease in various populations.2 Animal studies show, almost without exception, that experimentally induced hypercholesterolemia is followed by the accumulation of cholesterol in...

Although labeling agents have been widely used to characterize the course of reactions in the animal body, their application to quantitative aspects of the turnover of a substance has been slow to develop.I r a certain fraction of the administered isotopic substance a is incorporated into a compound, at least the same fraction of the total administered labeled substancO must have been converted into that compound. Such a calculation gives a minimum value for the conversion of a labeled substance into a compound. Fishier (1) showed that the fraction of the administered pn recovered in the phospholipid of liver, muscle, or blood of rats after a 12 hour interval was the same even though the amounts of labeled phosphate injected varied from 6 to 48 rag. This demonstrates that the administered labeled phosphate was negligible in comparison with the phosphate available for incorporation into phospholipids in the animal body. It must therefore be obvious that such minimum values have little significance, for when the amount of injected labded substance was ~aried eightfold the minimum value was altered to the same extent.For the above type of calculation to yield a correct measure of the amount of labeled atoms ~ incorporated into a substance, the amount of labeled molecules injected should be large enough to render negligible the amount of those molecules already present in the organism. Such a procedure, however--namely one in which the amount of injected substance is large enough to yield a correct measure of the amount of newly formed compound--would probably disturb the normal metabolism of the organism.Artom et al. made an interesting contribution to this field, well realizing the difficulties involved in simplifying the complex system in which most of the biological reactions occur (2).By means of repeated injections of Pn Heresy and Hahn (3) maintained a constant specific activity of inorganic phosphate in the plasma. They assumed 1 Isotopic molecules (-substance) --all the molecules (substance) containing the particular isotopic atom.Labeled atoms (-molecules, -substance) = all the atoms (molecules, substance) mixed with, and chemically indistinguishable from, the isotopic atoms (-molecules, -substance).

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The mechanism of release of alkaline phosphatase from membranes by phosphatidylinositol-specific phospholipase C from Staphylococcus aureus was studied. Alkaline phosphatase was readily released from pig kidney microsomes by phospholipase C but not by a variety of other treatments, e.g., high ionic strength, extremes of pH, divalent cations, chelating agents, or analogues of the polar head group of phosphatidylinositol. Alkaline phosphatase released from microsomes by phospholipase C did not bind to phospholipid vesicles containing phosphatidylinositol. Alkaline phosphatase solubilized from microsomes by butanol extraction, however, was able to bind phospholipid vesicles even when they contained no phosphatidylinositol. The ability of butanol-extracted alkaline phosphatase to bind to phospholipid vesicles was destroyed by added phosphatidylinositol-specific phospholipase C. Hydrolysis of added phosphatidylinositol by endogenous phospholipase activity in butanol extracts was also accompanied by loss of binding ability. Loss of binding ability was paralleled by a decrease in the apparent molecular weight of alkaline phosphatase. These results indicate that alkaline phosphatase is attached to membranes by a strong interaction with phosphatidylinositol.