Abnormal vascular reactivity represents a fundamental disturbance in vascular biology with the development of atherosclerosis. Because endothelial vasodilator function plays a pivotal role in controlling vasomotor tone, we hypothesized that atherosclerotic wall thickening might directly interfere with deficient endothelium-mediated dilation and thereby contribute to the abnormal reactivity of atherosclerotic arteries in vivo.

In 26 patients without focal stenoses in the left anterior descending coronary artery, acetylcholine (0.036 to 3.6 micrograms/mL) was infused into the artery to evaluate endothelium-mediated vasodilation. Segmental vasomotor responses to acetylcholine were correlated with the local extent of atherosclerotic wall thickening quantitated by intracoronary ultrasound examination. Seventeen of the patients also underwent cold pressor testing to assess the vasoreactivity to sympathetic activation. The response of coronary artery segments to acetylcholine varied from 35% dilation to 52% constriction and demonstrated a segmental pattern, with dilation and constriction observed in different segments of the same artery. The vasomotor response to acetylcholine was closely correlated with the extent of local atherosclerotic wall thickening (r = -.82, P < .0001). Over the entire range of atherosclerotic wall thickening, segments from patients with elevated high-density lipoprotein (HDL) cholesterol serum levels (> 75th percentile) demonstrated a significantly blunted constrictor response to acetylcholine (P < .01 at the maximal acetylcholine concentration) compared with segments from patients with HDL cholesterol < 75th percentile. The degree of constriction or dilation in response to the acetylcholine infusion correlated with the response to cold pressor testing (r = .75, P < .0001). Again, the cold pressor test-induced constrictor response was significantly (P < .05) blunted in segments from patients with elevated HDL cholesterol serum levels compared with those from patients with HDL cholesterol < 75th percentile despite equal degrees of atherosclerotic wall thickening.

Coronary vasomotor responses to the endothelium-dependent dilator acetylcholine and to sympathetic stimulation by cold pressor test correlate with local atherosclerotic wall thickening. Thus, the degree of abnormal local vascular reactivity is closely related to the extent of atherosclerotic "plaque load" in human epicardial arteries in vivo. Elevated HDL cholesterol serum levels ameliorate abnormal vasoconstriction at any given extent of atherosclerotic wall thickening, suggesting that HDL cholesterol exerts a beneficial effect on abnormal vascular reactivity, a fundamental functional disturbance associated with coronary atherosclerosis.