Atherosclerosis: pathology, pathogenesis, and role of risk factors.

Atherosclerosis is a complex disease that represents the end product of the interaction of many different causative agents. Those that originate external to the arterial wall usually are called primary risk factors. Many other influences, the secondary risk factors, modulate the primary factors. The penetrance of the secondary factors is variable. They can have a major effect in some people but not in others. The idea of risk factor is important because it provides the conceptual framework upon which to build an intervention program for prevention of atherosclerosis. The development of atherosclerosis can be viewed as a two-step process (Table 2). The first is injury to the arterial wall. The second is response to injury. The primary risk factors can be regarded as the injurious agents. Examples are factors causing endothelial damage, influx of plasma lipoproteins, toxic products of smoking, hemodynamic injury of hypertension, and perhaps microvascular injury from diabetes mellitus. The response to injury represents typical pathologic changes--proliferation of smooth muscle cells, mononuclear infiltration, phagocytosis of products of injury, secretion of connective tissue elements, neovascularization, and necrosis. Regulation of these latter processes is poorly understood and is a worthy subject for future research. Modulation of the primary injurious factors through alteration of secondary risk factors is currently the only significant approach to prevention of atherosclerosis. Future investigation may provide more direct ways to prevent or retard atherogenesis, either by more effective modification of primary factors or by reducing the magnitude of response to these factors.