Coronary Thrombosis: Pathogenesis and Prevention

Summary

Acute myocardial infarction is most commonly initiated by fissuring of an atheromatous plaque. Through such fissures the blood is exposed to thrombogenic constituents of the intima, causing thrombotic obstruction of the coronary artery. Why plaque fissuring occurs is not known. Our investigation is to establish which types of plaque undergo fissuring by relating their mechanical with their cellular and biochemical properties; and to quantify the distribution of fissures. Results so far indicate that fissures occur predominantly in plaques with lipid pools in one segment of intima, and that the commonest single site of fissuring is that of maximal stress concentration as predicted by computer modelling. The results also suggest that arterial spasm at the immediate site of fissuring is not involved, as more than half the fissures occur at sites where there is no residual medial smooth muscle. Obstructive coronary thrombosis is initiated in most cases by plaque fissure with local haemorrhage which induces intravascular platelet aggregation. Recent observations with novel techniques have provided evidence that platelet aggregation in vivo is initiated by ADP and potentiated by thromboxane A₂ and thrombin, with actual contribution of exposed collagen still undetermined. These observations provide an explanation for the limited effectiveness of any simple platelet-inhibiting drug, including Aspirin, by itself whenever arterial, eg. coronary or cerebral thrombosis is initiated by haemorrhages into atheromatous plaques. On the other hand, Aspirin is significantly effective when myocardial infarction follows unstable angina and when strokes follow transient episodes of cerebral ischaemia. This partial effectiveness can be explained through an action of Aspirin on platelets by assuming that, in such cases, their thrombo-embolic aggregation is initiated by haemodynamic effects of atheromatous lesions. Recently we discovered that the uptake of atherogenic low-density lipoprotein is accelerated by noradrenaline at its physiological blood concentrations (Shafi, Cusack & Born, 1989: Proc. Roy. Soc. B., 235, 289). This may help to explain the increased incidence of coronary thrombosis in conditions associated with elevated blood noradrenaline, including cigarette smoking and stress; and it may open new therapeutic approaches.