Role of endothelial dysfunction in coronary artery disease and implications for therapy.
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.
Kinlay
S
S
Cardiac Catheterization Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Ganz
P
P
D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D003327:Coronary Disease / Q000209:etiology* / Q000628:therapy*; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology*; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy
D000924:Anticholesteremic Agents; D015815:Cell Adhesion Molecules