ArticleRole of Endothelial Dysfunction in Coronary Artery Disease and Implications for Therapy
Section snippets
Clinical Events and the Vulnerable Plaque
Pathologic studies have found that most cases of unstable angina, myocardial infarction, and sudden coronary death (the acute coronary syndromes) are the result of rupture of an atheromatous plaque and overlying thrombus formation that occludes or partly occludes the vessel lumen.3, 4, 5, 6, 7The characteristics of plaques that are prone to rupture (i.e., the “vulnerable plaque”) have also been described by several authors.2, 4, 6Compared with stable plaques, vulnerable plaques have a large
Inflammation and Cell Adhesion Molecules
Inflammatory cells within the plaque are derived from the circulating bloodstream. Under normal circumstances, the endothelium provides a barrier to leukocytes. However, the activated endothelium plays a key role in capturing leukocytes and assisting their migration into the vessel wall. Leukocyte recruitment from the blood stream is largely controlled by a series of coordinated events that occur at the endothelium-blood interface.23, 24, 25These events include initial rolling of leukocytes on
Hypercholesterolemia and the Expression of Adhesion Molecules
Hypercholesterolemia leads to increased expression of adhesion molecules on the endothelial surface. Experimental studies have shown that endothelial cells incubated with components of oxidized LDL increase their expression of adhesion molecules.32, 33Rabbits with diet-induced hyperlipidemia show increased expression of VCAM-1 on aortic endothelial cells after 1 week.34, 35Genetically bred hyperlipidemic rabbits also have abundant expression of VCAM-1 on endothelial cells.[34]In contrast,
Endothelium and Vasomotor Function
The early experiments by Furchgott and Zawadski[36]demonstrated the important role of the normal endothelium in regulating vasodilation in isolated artery models. Normal arteries that were preconstricted with norepinephrine dilated with acetylcholine, but arteries with the endothelium removed constricted to acetylcholine. Further studies identified nitric oxide as the endothelium-dependent dilating agent that was responsible for vasodilation to acetylcholine, and counteracted the direct
Treating Endothelial Dysfunction by Reversing Hypercholesterolemia
Decreasing blood total and LDL cholesterol can improve endothelial vasomotor function over a period of weeks to months. Several studies in patients with atherosclerosis have shown that lowering blood cholesterol improves the coronary artery responses to acetylcholine.56, 57, 58, 59This includes greater vasodilation of the epicardial vessels and increases in blood flow of coronary resistance vessels with cholesterol lowering. The benefits of cholesterol lowering and improvement in vasomotor
Summary and Future Directions
The application of vascular biology to coronary artery disease has improved our understanding of the cellular events that lead to plaque rupture and acute coronary syndromes. Studies of endothelium-dependent vasomotion enable us to examine a function of nitric oxide that is an important determinant of myocardial perfusion and ischemia, angina, and the need for coronary revascularization. Therapies that improve endothelial vasomotor function may also impact vascular inflammation and the events
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