Atherosclerosis: A process determined primarily by the physical state of plasma lipid that has entered the arterial wall

Abstract

(i) A consideration of the factors determining the localisation of atherosclerotic lesions, particularly the role of endothelial injury, suggests that this must occur to a similar degree in all human populations and thus cannot be the primary determinant of clinically significant disease. It does however have a permissive role in atherogenesis which becomes relevant when plasma low density lipoproteins (LDL) are elevated. (ii) LDL gain access to the subendothelial space of arteries in significant amounts at sites where the endothelial barrier is defective at a rate which varies directly with their concentration in plasma. At this site LDL are precipitated by mucopolysaccharides when the concentration of LDL exceeds a critical level. Disruption of the LDL complexes leaves free lipid in the subendothelial space and it is this free lipid which evokes the tissue reaction that has relevance to atherogenesis in man. (iii) Since the inner arterial wall lacks an adequate scavenging system, the extent of the tissue reaction to free lipid, particularly cholesterol, depends on the efficacy with which this lipid is phagocytosed by smooth muscle cells that appear in evolving lesions during their proliferative phase. Effective phagocytosis requires that the neutral lipids are adequately dispersed by phospholipids. The capacity of phospholipids to do so is limited and markedly inhibited by glucose and sorbitol. Thus suboptimal glucose homoeostasis promotes atherogenesis. (iv) The sites of evolving lesions have decreased compliance, increasing their liability to injury and this accelerates the above processes. The proliferative phase continues until the deeper layers of lesions are deprived of nutrients and necrose. Further trapping of lipid can no longer evoke a tissue response but coagulation products continue to accrete to these sites leading ultimately to development of fibrous plaques. (v) The fact that LDL cholesterol does not gain access to cells of subjects with familial hypercholesterolaemia, whereas cholesterol free of apolipoprotein does, lends support to the above concepts. The turnover of LDL in tendon xanthomas of these subjects is not analogous to that in arteries since extravasated LDL in tendons can be cleared by lymphatics and these are absent in the inner arterial wall. (vi) Veins and the pulmonary artery are free of atheroma because they are not liable to recurrent endothelial injury at the same sites and because LDL reaching the subendothelial space could be cleared by lymphatics which are present at this site in these vessels. The development of pulmonary hypertension would obliterate low pressure vessels near the artery luman and this, together with increased endothelial injury, makes it liable to the atherosclerotic process.