Endothelium, fibrinolysis, cardiac risk factors, and prostaglandins: a unified model of atherogenesis.

A model of atherogenesis is described in which it is proposed that a state of relative impairment of intravascular fibrinolytic function is the primary defect which makes possible both the initiation and the continued progression of arterial plaques. The key mechanism by which impaired fibrinolysis is atherogenic centers on the unique disruptive effect which fibrin has on the contiguous endothelium of the vascular intimal surface. From this perspective, in areas of spontaneous endothelial injury, impaired fibrinolysis maintains and promotes the gradual enlargement of the area of injury by causing persistently increased intimal permeability and by allowing enhanced fibrin and platelet deposition. This hypothesis thus represents a modification of the response-to-injury hypothesis in which the emphasis has been shifted from the initial endothelial injury to a state of interference with the normal process of healing endothelial injuries. Consistent with this viewpoint, it is noted that all positive risk factors for vascular disease are associated with impairment of fibrinolytic function and, conversely, negative cardiac risk factors enhance fibrinolysis. It is further proposed that one or more prostaglandins, or closely related metabolites, represent the mediators of primary physiologic importance with regard to in vivo regulation of fibrinolysis. By this hypothesis, adequate dietary intake of essential fatty acids, as well as maintenance of unimpaired eicosanoid metabolism, become centrally important in both preventing and reversing arteriosclerosis. This two-tiered model can be used to organize and potentially explain the interrelationship between diverse and apparently divergent sets of epidemiological data which previous models have been unable to accommodate.