TASK FORCES Task Force 1. Pathogenesis of Coronary Disease: The Biologic Role of Risk Factors

Our understanding of the pathophysiology of coronary atherosclerosis has dramatically changed in the last few years. The mechanisms of progression of coronary atherosclerosis and of plaque instability and rupture in acute coronary syndromes are now much better understood (1,2). Therapeutic strategies leading to coronary atherosclerosis stabilization and even regression (as well as improvement in vascular function) are being pursued by many investigators. Conceptually, approaches toward retardation or even reversal of atherosclerotic lesions in humans for prevention of acute coronary events include the better control of risk factors, such as by reducing plasma cholesterol levels. Thus, it might be possible to modify the lipid-rich atherosclerotic plaques that are more prone to rupture, thereby preventing progression and even inducing regression by removal of lipid. In published trials that compared a more aggressive versus a more conservative treatment of lipid abnormalities in patients with coronary disease identified at arteriography, four important observations were made (3,4). 1) Progression of the disease was significantly decreased by the more aggressive approaches, but overall, only minimal regression of atherosclerosis has been shown (1% to 2% decrease in degree of stenosis). 2) Despite the marginal impact on arteriographic regression, there was a substantial reduction (over 50%) in the incidence of acute cardiac events in most trials. The recent Scandinavian 4S study in a well identified large group of patients with coronary disease and dyslipoproteinemia plus the West of Scotland Coronary Prevention Study in a large group of men with hypercholesterolemia showed a decrease in mortality and coronary events with the use of simvastatin and pravastatin, respectively (5,6). These landmark studies, with the use of an aggressive pharmacologic approach , support and go beyond the data of the regression and stabilization studies (5). 3) Preliminarily, it appears that the impact on coronary disease progression and coronary events was also observed by modification of risk factors other than lipids. 4) Also on a preliminary basis, it appears that there was substantial reduction in angina in several of the studies, despite minimal or no regression of atherosclerosis. Based on these four observations, the following interpretation of the data is evolving (2,3). 1) The lack of significant regression observed in atherosclerotic lesions seen on arteriography is probably because such lesions tend to be already advanced, fibrotic and less lipid-rich; therefore, they are less prone to reabsorption or to favorable remodeling. 2) The substantial reduction in coronary events is probably related to favorable dynamics of influx and efllux of lipoproteins in the smaller lipid-rich plaques--those not necessarily visualized at arteriography, but prone to disruption and to acute events. Specifically, when high low density lipoprotein (LDL) cholesterol is substantially reduced therapeutically, etttux from the plaques of the liquid or esterified cholesterol and also deposition in the vessel wall as cholesterol crystals predominate over the influx of LDL cholesterol. Consequently, there is a decrease in the softness of the plaque and so, presumably in the "passive" phenomenon of plaque disruption previously described. Whether there is also a partial decrease in the number and activity of the macrophages and in the "active" phenomenon of plaque disruption is under investigation. Other effects of lipid-modifying strategies on endothelial function and in thrombogenicity (whether related to the plasma levels of LDL cholesterol or to the specific agents used) are also under investigation. 3) As discussed in the second part of this section, the beneficial effects exerted by modification of risk factors other than LDL or high density lipoprotein (HDL) cholesterol are probably because of their influence on the entry of LDL cholesterol into the vessel wall as well as their influence on the thrombogenic complication of plaque disruption. 4) The reduction in clinical coronary events reported in some of the studies, despite minimal or no regression of atherosclerotic lesions on arteriography, may relate to the correction of the detrimental effect of dyslipoproteinemia and other risk factors on endothelial function and microvascular flow, which cannot be assessed by arteriography. Diseases of the coronary arteries have generally been considered from the vantage point of the epicardial coronary vessels, which is a reflection of the widespread use of coronary angiography as the reference standard for the diagnosis of coronary artery disease. In the past decade, advances in our ability to assess the coronary microcirculation have led to a better understanding of the manifestations of coronary artery disease (7-9). 1) Recent work has revealed that the cardiovas-