Relevance of vascular biology to the ischemic syndromes of coronary atherosclerosis

The pathophysiologic basis for stable and unstable angina, as well as for myocardial infarction, has been clarified through clinical and pathologic studies. Only recently have we begun to understand these clinical syndromes in the context of biologic processes within the vessel wall. Atherosclerotic lesion formation is now characterized as an inflammatory response to both metabolic and physical injury. Oxidative modification of low-density lipoprotein (LDL) cholesterol is of central importance in the initiation of this inflammatory cascade. The endothelium, a site of LDL oxidation, regulates vessel tone, inflammatory activity within the vessel wall, and vascular smooth muscle growth. In addition, it provides a nonthrombogenic surface within the vasculature. Endothelial damage could drastically alter these functions, predisposing to vasoconstriction, thrombosis, inflammation, and smooth muscle growth, the key components of atherogenesis. All ischemic coronary syndromes (stable angina, unstable angina, and myocardial infarction) are characterized by alterations in normal endothelium-mediated relaxation. Considerable evidence suggests that free-radical mediated nitric oxide destruction accounts for these abnormalities. In the oxidative environment of the atherosclerotic vessel wall, these free-radical by-products are plentiful. In addition to vasospasm, unstable angina and myocardial infarction are associated with plaque rupture and mural thrombus formation. We currently have little understanding of this conversion from a stable plaque to a rupture-prone, “active” atherosclerotic plaque, although monocyte and lymphocyte products, oxygen-derived free radicals, and degradative enzymes probably contribute. This concept of the unstable coronary syndromes in an inflammatory context with “episodic” plaque activation alters our traditional view of atherosclerosis. The high-risk life-threatening coronary lesion is not necessarily the most severely stenotic but, rather, the lesion having the most active state of inflammation. The biologic state of the atherosclerotic plaque is therefore a more important determinant of clinical course than is the extent of stenosis. As our understanding of the pathogenesis of atherosclerosis evolves, even more effective and specific therapeutic approaches will emerge, diminishing the late and often catastrophic consequences of this disease.