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ATHEROSCLEROSIS—A PRIMARY HEPATIC OR VASCULAR DISORDER? ROBERT E. OLSON, Ph.D., M.D.* Although the increasing incidence ofcoronary artery disease in the wellnourished peoples ofthe world has suggested to many that atherosclerosis isa "modern" disease, this is an illusion. Although recognition ofcoronary heart disease as a clinical entity is recent, the lesions ofarteriosclerosis have been found in the mummies ofancient Egyptians and Greeks, and recognition ofthe disease as a.pathologic entity dates from the earliest dissections of Vesalius and his contemporaries. Despite this ancient lineage, the precise cause ofatherosclerosis is still unknown. Search for the solution to this biologic enigma now preoccupies hundreds of investigators all over the world. Atherosclerosis is a vascular disease characterized by focal intimai thickening , intimai and subintimai lipoid deposition, deformation and fragmentation ofthe internal elastic membrane with elastic tissue regeneration, and eventually calcification and/or fibrosis. The lesions are discrete and patchy and have a predilection for areas oftortuosity and turbulence of blood flow. The lesions are found earliest and most frequendy in the aorta and rarely, ifever, in the internal mammary artery. Coronary, cerebral, and peripheral arteries (particularly those of the lower extremities) are frequendy affected. Ulceration of the plaque or subintimai hemorrhage with thrombosis or perforation are usually the immediate causes of the catastrophic manifestations of the disease widi which all clinicians are familiar. * Department ofBiochemistry and Nutrition, Graduate School ofPublic Health, University of Pittsburgh. Original work cited in this paper was carried out with the aid ofgrants from the Nutrition Foundation, New York, the National Vitamin Foundation, New York, the Department of Health, Commonwealth of Pennsylvania, Harrisburg, Pennsylvania, and the U.S. Public Health Service (C-1724) and (A-020), Bethesda, Maryland. 84 Robert E. Olson · Atherosclerosis Perspectives in Biology and Medicine · Autumn 1938 I. An Ecological View ofAtherosclerosis Although numerous hypotheses regarding the etiology of atherosclerosis have been proposed, no unitary concept of a single "cause" has stood the test oftime or experiment. It seems reasonably clear that atherosclerosis is a disease of multiple causation, and current research is not focused on the identification of a cause but rather on the assignment of values to numerous possible causes which may operate additively or synergistically to produce die final lesion. Ecologically, atherosclerosis is a disease which results from a complex interaction between organism and environment. The "agent" for the disease appears to arise within the host as a result of this interaction. The "agent" of atherosclerosis, instead of being an independent variable—as in diseases ofinfection, allergy, poisoning , drug addiction, or vitamin deficiency— is a dependent variable developing from many possible host-environment adjustments. Aldiough this "agent" has not as yet been defined and may never be characterized as precisely as the tuberculous baccillus, etbanol, ragweed, lead, or thiaminelack have been identified as agents of disease in man, there is reason to believe that a pattern of biologic circumstances leads to atherosclerosis in which one variable may be considered to be "active" while the others are "passive." The former might properly be termed the "agent" ofthe disease. The fact that this "agent" is endogenous complicates the usual distinguishing ofagent, host, and environment, one from another, within a classic ecologie framework, since what may be selected as the "agent" by one analyst may be designated a "host response" by another. Nevertheless , a theoretical attempt to identify the "agents" and the host responses which lead to the formation ofatheroma in animals and man should provide a better framework than now exists to formulate a concept of pathogenesis. Numerous causal agents have been proposed in atherosclerosis. The experimental production (i) ofatherosclerosis in rabbitsbyfeeding cholesterol led to the belief, still held by some, diat cholesterol is the agent of the disease. Cholesterol itselfis not present in blood serum as a pure lipid but is bound to both protein and fat in all its forms in serum, including the chylomicron. Further, cholesterol is a ubiquitous constituent not only ofthe serum but ofall animal cells. As further knowledge ofthe physicochemical state ofdie lipids in the blood serum evolved, the idea that die lipoproteins were the agents ofatherosclerosis became popular. Gofrnan 85 and co-workers (2) claimed at one time that the Sji2-20 group of/3-lipoproteins...


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