ROLE OF IMPAIRED ENDOTHELIUM-DEPENDENT VASODILATION IN ISCHEMIC MANIFESTATIONS OF CORONARY-ARTERY DISEASE

Abnormal constriction of the epicardial coronary arteries contributes to the pathogenesis of myocardial ischemia, not only in variant angina but also in patients with stable and unstable forms of angina. This augmented vasoconstrictor responsiveness associated with atherosclerosis can in large part be attributed to an impairment in endothelium-dependent relaxation. When the endothelium is removed experimentally or is dysfunctional (as in atherosclerosis), normal vasodilation is replaced by paradoxical vasoconstriction. Infusion of acetylcholine into normal coronary arteries of humans results in vasodilation, which is mediated by endothelium-derived relaxing factor (EDRF), presumably nitric oxide or a closely related substance. When acetylcholine is infused into coronary arteries of patients with atherosclerosis, loss of dilation and paradoxical constriction are observed. This abnormal coronary response to acetylcholine reflects impairment of EDRF due to either its diminished release and/or increased inactivation. Similar reductions in endothelium-dependent coronary dilation in patients with atherosclerosis have been observed in response to other pharmacological or physiological stimuli-serotonin, blood flow, and catecholamines-and to a lesser degree in response to substance P. Normal human epicardial coronary arteries dilate during daily activities such as exercise, mental stress, or exposure to cold. This dilation is mediated by increases in blood flow (and thereby EDRF) in response to increasing metabolic demand. In healthy vessels, this dilation overcomes the constrictor influences of catecholamines (predominantly norepinephrine) that are released locally from nerve endings during these activities. Atherosclerosis, by impairing EDRF, leaves the vasoconstrictor influence of catecholamines unopposed. The resultant abnormal coronary constriction, when superimposed on stenoses, is likely to be an important contributing mechanism of myocardial ischemia by further reducing the available coronary blood flow reserve. The setting of exertion-related coronary constriction is of greatest importance among patients with stable angina. Episodes of unstable angina may occur at rest, unrelated to physical exertion. The pathological findings in this condition include the presence of a complex, degenerated plaque; intracoronary platelet aggregates; and thrombus. Serotonin, a product released from aggregating platelets, and thrombin, formed by the coagulation cascade, have been shown to dilate normal coronary arteries by the release of EDRF. Atherosclerotic arteries, which are deficient in EDRF, are paradoxically constricted by serotonin and thrombin. Thus, although the underlying culprit in the pathogenesis of abnormal coronary vasoconstriction is an impairment of endothelium-dependent dilation, the specific triggering mechanisms that lead to the unopposed vasoconstriction may differ in various forms of angina. Abnormal responses to catecholamines and blood How are more germane in patients with stable angina, whereas responses to serotonin and possibly to thrombin are more relevant to patients with unstable forms of angina. Recent experimental and clinical studies have suggested that the abnormalities of endothelium-dependent relaxation in atherosclerosis may extend to the microvasculature even though these vessels are free of overt pathology. In patients with nonobstructive coronary atherosclerosis, the flow responses of small vessels to acetylcholine, substance P, and rapid pacing have been shown to be markedly blunted. These findings may have profound implications regarding the ability of atherosclerotic arteries to regulate their blood flow, as the small vessels are where metabolic regulation normally resides.