Progression of coronary endothelial dysfunction in man and its potential clinical significance

Endothelial injury represents an important factor in the initiation of atherosclerosis and is associated with abnormal vasomotor responses (= dysfunctional endothelium) to a variety of stimuli. Therefore, the evaluation of endothelial function may provide a means to detect early vascular alteration preceding overt atherosclerotic lesions. To test this clinically important hypothesis, we studied the coronary vasomotor responses to three different endothelium-dependent stimuli in patients with different early stages of coronary artery disease: first, increasing doses of intracoronary infusion of acetylcholine (ACH) (10(-8), 10(-7), 10(-6) M); second, transient increases in coronary flow causing flow-dependent dilation by injection of papaverine into the midportion of the left descending artery (exposing the proximal segment of this vessel to increased flow, but not to papaverine); and third, sympathetic stimulation by cold pressor test. Coronary diameters were assessed by repeated coronary angiography and quantitative angiography, blood flow velocity (and subsequent calculation of blood flow) was obtained by intracoronary Doppler. In normal individuals, all three stimuli elicited epicardial artery dilation. In patients with smooth coronary arteries, but hypercholesterolemia, a substantial vasoconstriction was observed in response to ACH, whereas the response to cold pressor test and increases in flow was normal, that is, vasodilation occurred. In patients with angiographically visible atherosclerosis, acetylcholine and cold pressor test exerted coronary vasoconstriction. Moreover, flow-dependent, endothelium-mediated dilation was attenuated in those patients demonstrating visible luminal irregularities in the vessel under study. In patients with hypercholesterolemia, substantial endothelial dysfunction (as assessed by attenuated blood-flow increase in response to acetylcholine) was demonstrated in the coronary microcirculation. Thus, progression of endothelial dysfunction occurs during the early course of development of coronary atherosclerosis. Utilizing quantitative coronary angiography and the intracoronary Doppler technique, these early functional alterations can be identified safely at a stage when atherosclerotic lesions are not detectable by angiography. This may be useful in designing early effective interventions which restore endothelial function and prevent the occurrence of overt atherosclerosis.