Simvastatin, capillary permeability, and acetylcholine-mediated vasomotion in atherosclerotic, hypercholesterolemic men

Objectives: The aim of this study was to test the effect of high-dose simvastatin therapy on vascular permeability, a key variable in the atherogenic process, and endothelial-mediated vasodilator responses in patients with hypercholesterolemic atherosclerosis. Methods: The transcapillary albumin escape rate (TERalb, the 1-hour decline rate of intravenous I-125-albumin, a measure of macromolecular permeability of capillary endothelium) and forearm vasodilatation (venous plethysmography) to intraarterial acetylcholine and sodium nitroprusside (7.5, 15, 30 mug/min and 0.8, 1.6, and 3.2 mug/min respectively, 5 minutes at each rate) to account for endothelium-dependent and independent mechanisms, were measured at baseline and after 1-month simvastatin (40 mg once daily) in 16 hypercholesterolemic (low-density lipoprotein cholesterol >130 mg/dL), atherosclerotic men. Thirteen healthy, untreated subjects were the controls. Results: Baseline TERalb was higher and responsiveness to both acetylcholine and sodium nitroprusside was depressed in patients compared with controls. One-month high-dose simvastatin reduced low-density lipoprotein cholesterol by 39%, normalized TERalb, and improved local vasomotor responses to acetylcholine, without modifying those to sodium nitroprusside. Changes in TERalb and acetylcholine-mediated vasodilatation were dissociated and unrelated to lipid modifications. Conclusions: Low-density lipoprotein cholesterol reduction through 1 month of high-dose simvastatin normalized the exaggerated transvascular albumin leakage of patients with hypercholesterolemic atherosclerosis, perhaps by restoring an exaggerated endothelial permeability, apparently through mechanisms independent of circulating lipids. Improvements in acetylcholine-mediated vasomotion were also evident, but were dissociated from TERalb, demonstrating a heterogeneous behavior of the 2 indices of endothelial function in response to high-dose statin treatment.