Article
Role of Endothelial Dysfunction in Coronary Artery Disease and Implications for Therapy

https://doi.org/10.1016/S0002-9149(97)00793-5Get rights and content

Abstract

Atherosclerosis is a complex process that is characterized by the accumulation of modified low-density lipoprotein (LDL), local inflammatory and immune responses, and reduced nitric oxide bioavailability within the arterial wall. These cellular changes lead to endothelial vasomotor dysfunction, plaque instability, and the development of clinical events such as stable angina and the acute coronary syndromes. The vascular endothelium plays a critical role in modulating both the inflammatory response and vasomotor abnormalities that occur in those with coronary artery disease or risk factors for disease. In these conditions, endothelial cells are activated by cytokines to express cellular adhesion molecules that facilitate the adhesion of leukocytes to the endothelium, and their migration into the subintimal space. Cytokines stimulate inflammatory and smooth muscle cells in the intima to produce degradative enzymes, including metalloproteinases that can weaken the fibrous cap of atherosclerotic lesions and make them vulnerable to rupture. Endothelial cells also regulate vascular tone by the synthesis of nitric oxide. Atherosclerosis and other conventional risk factors for coronary artery disease are associated with endothelial vasodilator dysfunction in the coronary epicardial and resistance vessels, which likely contributes to myocardial ischemia. Several studies have demonstrated that lowering serum total and LDL cholesterol reverses endothelial vasomotor dysfunction, reduces myocardial ischemia, and lowers the risk of the acute coronary syndromes or need for revascularization. Improving endothelial function, for example, by lowering blood cholesterol should now be regarded as a goal of therapy in the treatment of coronary artery disease.

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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