In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunc- (Circulation 1990;81:491-497) In animals, acetylcholine produces endotheliumdependent dilation of normal arteries and vasoconstriction in pathologic states such as hypersee p 697 cholesterolemia, hypertension, or atherosclerosis.1-9 Clinical studies have shown that intracoronary acetylcholine infusion constricts atherosclerotic coronary arteries.9-11 Smooth segments may also constrict in patients with coronary artery disease evident in
Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).
Endothelium-dependent vasodilation is markedly impaired in the coronary microvessels of patients with hypertension and ventricular hypertrophy. Loss of this vasodilator mechanism may contribute to disordered coronary flow regulation and the ischemic manifestations of hypertensive heart disease.
Dilator reserve of the coronary microvasculature is diminished in patients with dilated cardiomyopathy. Although increased extravascular compressive forces, tachycardia, and increased myocardial mass can explain some impairment, recent evidence suggests the possibility of intrinsic microvascular disease. We tested the hypothesis that impairment of endothelium-dependent dilation of the microvasculature could be a contributing mechanism. We infused the endothelium-dependent dilator acetylcholine (Ach) (10-8 to 10-6 M) and the smooth muscle vasodilator adenosine (AD) (10-6 to 10`-M) into the left anterior descending coronary artery in eight patients with dilated cardiomyopathy (mean ejection fraction, 28%) and seven controls (atypical chest pain). Small In seven control patients receiving both Ach and AD, 56±9%o of the maximal AD flow response was attained with the endothelium-dependent vasodilator Ach, whereas in seven cardiomyopathy patients receiving both Ach and AD, only 23±14% of the maximal AD response was attained (p<0.01). Thus, endothelium-dependent vasodilator function is impaired in the coronary microvasculature of patients with dilated cardiomyopathy. There might be pathogenetic links between dysfunction of the endothelium and myocardial failure. (Circulation 1990;81:772-779) C oronary flow reserve is diminished in patients with dilated cardiomyopathy (DC).1-5 Elevated filling pressures, increased heart rate, decreased coronary perfusion pressure, and increasing left ventricular mass out of proportion to micro-
Studies in animals have suggested that increases in blood flow result in dilation of large arteries by an endothelium-dependent mechanism. Atherosclerosis can impair endothelium-dependent vasodilation to vasoactive agents. The purpose of this study was to determine whether or not large coronary arteries in humans exhibit dilation with increases in blood flow and to test the hypothesis that this response is impaired in the presence of atherosclerosis. Graded concentrations of adenosine were infused into the distal left anterior descending (LAD) coronary artery to test the dilator response of the proximal LAD to increases in blood flow. The proximal LAD was thereby exposed to changes in blood flow, but not directly to adenosine. Ten patients with angiographically smooth proximal LAD segments (group 1) and seven patients with irregularities in the proximal LAD consistent with mild atherosclerosis (group 2) were studied. Infusions of adenosine throughout the range of 0.022 to 2.2 mg/min into the LAD produced a dose-dependent increase in estimated coronary blood flow and a mean increase of 305 ±27% at 2.2 mg/min adenosine. At 2.2 mg/min adenosine, a striking dilference (p<0.001) occurred between the significant flow-mediated dilation of the proximal LAD observed in group 1 (+13.2±1.3% from 2.63±0.16 mm,p<0.001), and the lack of dilation in group 2 (+1.8±1.5% from 3.20±0.17 mm, p=NS), despite a greater increase in coronary blood flow in group 2 (+387±29%) than in group 1 (+230±36%). When adjacent segments of the same arteries in these patients were directly exposed to an infusion of the endothelium-independent vasodilator nitroglycerin (16.6 ug/min), angiographically smooth and irregular segments dilated similarly (+31.1+4.3% and +33.6±4.2%, respectively). Thus, in humans, flow-mediated dilation was observed in angiographically normal proximal LAD segments but was markedly impaired in atherosclerotic vessels. Because the normal and mildly atherosclerotic vessels were capable of equal dilation to the endothelium-independent vasodilator nitroglycerin, the absence of flow-mediated dilation in atherosclerosis may reflect impaired endothelial vasodilator function. (Circulation 1989;80:458-465
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