Human lesion studies.

We describe recent information on the atherothrombotic processes leading to the acute coronary syndromes (ACS) in humans. Then, we outline the mechanism of action and impact of lipid-lowering therapy in stabilization and secondary prevention of such processes. We start with (1) definitions of atherosclerotic lesions. In the progression of coronary atherosclerosis, eight morphologically different lesions are defined (Type I to VI) in various phases of disease. (2) Then we discuss vulnerable lipid-rich plaques and ACS. The type IV and Va lesions tend to be relatively small in size, but soft or vulnerable to disruption (with subsequent thrombosis) because of high lipid content (cholesterol esters rather than free cholesterol monohydrate crystals). The above process represents a "passive" phenomenon of plaque disruption. In addition to this "passive" phenomenon, an "active," macrophage-dependent, phenomenon of plaque disruption is evolving. (3) We then show the role of thrombosis in ACS. Monocytes/macrophages in lipid-rich plaques may play a detrimental role after plaque disruption, promoting thrombin generation and thrombosis through the tissue factor pathway, which can be prevented by tissue factor pathway inhibitor. Such thrombotic phenomena are critical in the development of ACS. (4) Finally, we discuss the effect of lipid-modifying strategies on the vulnerable lipid-rich plaques. When high LDL-cholesterol is reduced therapeutically, efflux from the plaques of the liquid or sterified cholesterol, and also its hydrolysis into cholesterol crystals depositing in the vessel wall, 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. When low HDL-cholesterol is increased experimentally, there is a partial decrease in the number and activity of the macrophages and so, presumably in the "active" phenomenon of plaque disruption.