In selected patients, placement of an intracoronary stent, as compared with balloon angioplasty, results in an improved rate of procedural success, a lower rate of angiographically detected restenosis, a similar rate of clinical events after six months, and a less frequent need for revascularization of the original coronary lesion.

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

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

We studied the vasomotion of epicardial coronary arteries during exercise and tested the hypotheses that abnormal vasoconstriction is related to

In vascular smooth muscle, phorbol esters cause a slowly developing contraction and an associated transmembrane calcium flux, both of which are inhibited by dihydropyridine calcium channel antagonists. In the A7r5 cultured vascular cell line, we used the whole-cell voltage-clamp technique to identify voltage-dependent calcium conductances and investigate the effect of phorbol esters on that conductance having characteristic dihydropyridine sensitivity (slowly inactivating, high-threshold, "L-type"). With barium as the charge carrier, large-amplitude (100-800 pA) inward currents of two types were characterized by their kinetics and voltage dependence. With holding potential--80 mV, a rapidly inactivating, low-threshold current ("T-type") was activated by depolarizations above-40 mV and was maximal at -10 mV. With holding potential -30 mV, this component was inactivated, and a second slowly inactivating, high-threshold current was activated above -10 mV and was maximal at +10 to +20 mV. These currents are similar to the T-type and L-type currents previously described in vascular smooth muscle cells. When added to the bath, the active phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (100 nM) increased the slowly inactivating (L-type) current by 32 +/- 20% (n = 8, +/- SD). Phorbol-12,13-dibutyrate (100 nM) caused a similar effect, but the inactive phorbol, 4-alpha-phorbol (100 nM), did not. We conclude that at least two distinct calcium conductances are expressed in A7r5 vascular smooth muscle cells, and that the dihydropyridine-sensitive calcium conductance is acutely modulated by phorbol esters, presumably acting through stimulation of protein kinase C. Such modulation may play a role in increasing transmembrane calcium influx mediated by agonist-receptor interactions that lead to activation of protein kinase C and may help to sustain or amplify calcium-dependent cell responses.

Accelerated coronary atherosclerosis is a major cause of graft failure after heart transplantation. Graft atherosclerosis is typically diffuse and difficult to detect even with coronary arteriography. Recently, acetylcholine was shown to dilate blood vessels by releasing a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). We have demonstrated paradoxical vasoconstriction induced by acetylcholine both early and late in the course of coronary atherosclerosis in patients, suggesting an association of endothelial dysfunction and atherosclerosis. In this report, we tested the hypothesis that coronary arteries of heart transplant patients can show endothelial dysfunction before or in the early stages of angiographically evident coronary atherosclerosis. Acetylcholine was infused into the left anterior descending artery of 13 heart transplant patients at 12 (n = 9) and 24 (n = 4) mo after transplantation. Vascular responses were evaluated by quantitative angiography. Among patients with angiographically smooth coronary arteries, relatively few (6/25) arterial segments had preserved vasodilator responses, while the majority failed to dilate (10/25) or paradoxically constricted (9/25). Angiographically irregular coronary arteries were present in three patients, in whom 8/10 segments showed marked paradoxical constriction and the remaining 2/10 failed to dilate. Only 1 of 13 patients retained appropriate dilation to acetylcholine in all segments. Nitroglycerin, which acts directly on vascular smooth muscle, dilated nearly all segments.No clinical features of the patients, including myocardial rejection appeared to correlate with the impaired functional response of vessels. Thus impaired response to acetylcholine is a common early finding in heart transplant patients and emphasizes the potential importance of endothelial dysfunction in the development of atherosclerosis.

These results suggest that the endothelial dysfunction that characterizes early and late atherosclerosis is associated with a marked increase in sensitivity to the constrictor effects of catecholamines. This finding may explain the constrictor responses of atherosclerotic coronary arteries to exercise and the cold pressor test. In stenotic coronary arteries this mechanism may play a role in the production of myocardial ischemia.