Lipoprotein(a) selectively impairs receptor-mediated endothelial vasodilator function of the human coronary circulation

Objectives: We investigated the influence of lipoprotein(a) [Lp(a)] serum levels on different endothelium-dependent vasodilator stimuli representing different mechanisms of endothelium-dependent vasodilation. Background: Lp(a) is an independent predictor for the development and progression of coronary artery disease. Impairment of endothelium-dependent vasodilation of epicardial arteries has been shown in patients with high levels of Lp(a). Methods: In 108 patients with angiographically normal or minimally diseased coronary vessels, vasomotor responses to acetylcholine, cold pressor testing, increased blood flow and nitroglycerin were assessed. Results: Lp(a) levels ≤30 mg/dl were associated with significant dose- dependent enhancement of the vasoconstrictor response to acetylcholine [receptor-mediated vasodilation, p = 0.002; acetylcholine 10^-6 mol/liter, - 29 ± 21% vasoconstriction with Lp(a) levels ≤30 mg/dl vs. -5.6 ± 25% with Lp(a) levels ≤30 mg/dl]. In addition, vasoconstrictor response to cold pressor test (receptor-and flow-mediated vasodilation) was significantly enhanced in patients with Lp(a) levels ≤30 mg/dl (-13 ± 12% vs. 1.2 ± 16%, p = 0.005). In contrast, strictly endothelium-dependent, but non-receptor- mediated, flow-dependent dilation and endothelium-independent dilation with nitroglycerin were not compromised. Linear regression analysis revealed an inverse relation between Lp(a) and both acetylcholine-induced (r = -0.34, p = 0.0007) and cold pressor test-induced (r = -0.44, p = 0.0001) vasodilation. By multivariate analysis, Lp(a) was a strong and independent predictor of paradoxic vasoconstriction only in response to acetylcholine and cold pressor testing. Impairment of coronary blood flow increase in patients with Lp(a) levels ≤30 mg/dl did not reach statistical significance. Conclusions: High Lp(a) levels are associated with a selective impairment of vasodilator capacity of receptor-mediated endothelial stimuli. Impaired dilator capacity of the coronary circulation associated with elevated Lp(a) levels may contribute to the pathogenesis of myocardial ischemia in response to trigger mechanisms involving receptor-mediated stimulation such as sympathetic activation.