Early evidence of endothelial vasodilator dysfunction at coronary branch points.

Abstract

Intracoronary acetylcholine produces endothelium-dependent dilation of normal coronary arteries and paradoxical constriction of atherosclerotic vessels. Regional differences in endothelium-dependent vasomotion, however, have not been studied in relation to the nonuniform development of atherosclerosis. We compared the vasomotor response to increasing doses of acetylcholine of angiographically smooth coronary artery segments prone to atherosclerosis (coronary branch points) with segments remote from branch points (straight segments). In patients with entirely smooth coronary arteries and a dilator response to acetylcholine (group 1, n=7), branch points and straight segments demonstrated equal and significant dosedependent dilation to acetylcholine (14.7±8.9%o and 12.3±12.7%, respectively; p_NS). In patients with early atherosclerosis as manifest by luminal coronary irregularities, the lowest dose of acetylcholine (10-8 M) produced constriction at branch points and slight dilation at straight segments (-6.3 ±7.4% vs. +2.2+7.3%, p <0.05). At higher doses of acetylcholine, both branch point and straight segments constricted, but constriction remained more pronounced at branch points. Both branch point and straight segments, however, retained the ability to dilate to the non-endothelium-dependent agent, nitroglycerin. In a third group of patients with angiographically entirely smooth coronary arteries but without dilation to acetylcholine, constriction to acetylcholine again occurred first at branch points. Thus, coronary branch points demonstrate increased sensitivity to acetylcholine-induced constriction in patients with angiographic evidence of early coronary atherosclerosis and in middle-aged patients with smooth coronary arteries. These segments, however, retain the ability to dilate to nitroglycerin.Whether this early evidence of defective endothelium-dependent vasodilation predicts the later development of occlusive atherosclerosis is not yet known. (Circulation 1990;82:1169-1173 C oronary atherosclerosis has a long asymptomatic phase of development,1'2 and only the later phases, particularly segmental narrowing and stenosis, can be assessed by coronary arteriography. Furthermore, atherosclerosis is a focal disease with specific sites of predilection that include branch points and other regions of disturbed flow.3 Experimental studies suggest that alterations in local arterial wall shear stress produce morphological changes in the vascular endothelium that may play a central role in atherogenesis.4-6

The endothelial cell in health and disease: its function, dysfunction, measurement and therapy

“…When acetylcholine was infused intravenously, normal controls showed a vasodilatory response, but responses were reduced or vasoconstrictive in patients with hypertension, 13 diabetes, 15 hypercholesterolemia, 14 congestive heart failure 28 or atherosclerosis. 5,21,[23][24][25] Similarly, increases in flow subject the endothelium to increased shear stress, which stimulates the NO-cGMP pathway, so that FMD is also dependent on endothelial cells. Abnormal FMD has been shown in patients with cardiac risk factors and in atherosclerosis.…”

“…3,5,[16][17][18][19][20]22,29 Importantly, many of these studies also showed that vasodilation to nitrates, which act directly on smooth muscle in an endothelial-independent manner, was preserved. [13][14][15][16]18,21,23,24 Moreover, N G -monomethyl L-arginine (L-NMMA), a NO synthase inhibitor, blunted the vasodilatory response to acetylcholine and FMD, but did not affect nitroprusside-induced vasodilation. 30,31 Endothelial dysfunction contributes to atherosclerosis The NO-cGMP pathway becomes impaired before the development of atherosclerosis and its impairment likely contributes to the pathogenesis of atherosclerosis.…”

“…4,[6][7][8][9][10][11] Cardiac risk factors are prevalent in patients with ED 12 and correlate with endothelial dysfunction, including hypertension, 13 hypercholesterolemia, 3,14,15 diabetes, 6,15 smoking 3, [16][17][18] and age, 18 as well as with atherosclerosis. 3,[19][20][21][22][23][24][25] This study reviews normal endothelial function, as well as endothelial dysfunction in general and related specifically to ED. A variety of methods to measure endothelial function and therapies that improve endothelial function are reviewed.…”

Endothelial dysfunction and coronary artery disease

“…Like atherosclerosis, endothelial dysfunction is evidenced earlier in the bifurcations of human coronary arteries 19 . In the presence of coronary atherosclerosis, the intensity of endothelial dysfunction is directly related to the atherosclerotic damage 5 .…”

“…In contrast, endothelial dysfunction appears to play a pathogenic role in the initial development of atherosclerosis [7][8][9] and of unstable coronary syndromes 10 , being associated with atherosclerotic disease risk factors [11][12][13][14][15][16][17][18] , and being present even before vascular involvement becomes evident 6,[19][20][21] .…”