Coronary Artery Spasm as a Cause of Angina

Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (greater than 50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (less than 20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94 +/- 0.16 mm to 2.16 +/- 0.15 mm with the maximal acetylcholine dose (P less than 0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05 +/- 0.05 to 0.32 +/- 0.16 mm at the highest concentration of acetylcholine (P less than 0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm.

This study aimed at determining the prevalence of epicardial and microvascular coronary spasm in patients with anginal symptoms, despite angiographically normal coronary arteries. Despite a typical clinical presentation with exercise-related anginal symptoms (chest pain or dyspnea) with or without occasional attacks of resting chest pain suggestive of coronary artery disease, 40% of patients undergoing diagnostic angiography have normal or "near" normal coronary arteriograms. Many of these patients are given a diagnosis of noncardiac chest pain, and some are considered to have microvascular angina. However, we speculate that abnormal coronary vasomotion (reduced vasodilatation with exercise = reduced coronary flow reserve and/or vasospasm at rest) might also represent a plausible explanation for the symptoms of the patient. This was a prospective study in 304 consecutive patients (50% men, mean age 66 ± 10 years) with exertional anginal symptoms undergoing diagnostic angiography. A total of 139 patients (46%) had ≥50% coronary artery disease in at least 1 coronary artery, 21 patients (7%) had luminal narrowings ranging from >20% to 49%, and 144 patients (47%) had normal coronary arteries or only minimal irregularities (<20% diameter reduction). One hundred twenty-four patients of the latter (86%) underwent intracoronary acetylcholine (ACH) testing, which elicited coronary spasm in 77 patients (62%), 35 patients (45%) with epicardial spasm (≥75% diameter reduction with reproduction of the symptoms of the patient) and 42 patients (55%) with microvascular spasm (reproduction of symptoms, ischemic electrocardiographic changes, and no epicardial spasm). Nearly 50% of patients undergoing diagnostic angiography for assessment of stable angina had angiographically normal or near normal coronary arteriograms. The ACH test triggered epicardial or microvascular coronary spasm in nearly two-thirds of these patients. Our results suggest that abnormal coronary vasomotion plays a pathogenic role in this setting and that the ACH test might be useful to identify patients with cardiac symptoms, despite normal coronaries. (Abnormal Coronary Vasomotion in Patients With Suspected CAD But Normal Coronary Arteries; NCT00921856). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.