Background: Oxidatively modified LDL has been shown to markedly impair endothelium-dependent dilation in experimental studies. The aim of the present study was to determine the relationship between the coronary vasomotor response to the endothelium-dependent agonist acetylcholine and the in vitro susceptibility of LDL to oxidation in patients.
Methods and results: Endothelium-dependent coronary vasomotion in response to acetylcholine (10(-8) to 10(-6) mol/L) was assessed in 23 patients with hypercholesterolemia (mean age, 56 +/- 9 years) after 1 year of therapy with either an American Heart Association Step 1 diet (seven patients), lovastatin and cholestyramine (seven patients), or lovastatin and probucol (nine patients). The susceptibility of LDL to oxidation was determined by measuring the lag phase of conjugated diene formation induced by Cu2+. Patients treated with lovastatin and probucol had prolongation of the lag phase (263 +/- 64 minutes) compared with diet- (91 +/- 22 minutes) or lovastatin and cholestyramine-(118 +/- 57 minutes) treated patients (P<.0001). By univariate analysis, the coronary vasomotor response to acetylcholine was significantly related to the lag phase of conjugated diene formation (P=.002), cholesterol-lowering therapy (P=.002), and serum cholesterol (P=.02). By multivariate analysis, the lag phase remained a significant predictor of the acetylcholine vasomotor response, independent of the effect of cholesterol-lowering treatment.
Conclusions: In patients treated with lipid-lowering agents, the vasodilator response to acetylcholine is related to the susceptibility of LDL to oxidation. These findings suggest that oxidative stress is an important determinant of the coronary endothelial dysfunction observed in patients with atherosclerosis and hypercholesterolemia.