[The effects of simvastatin withdrawal on brachial artery endothelial function in healthy normocholesterolemic men]

To determine whether acute withdrawal of simvastatin treatment in healthy normocholesterolemic men impairs the brachial artery endothelial function.

The study was performed on 16 healthy, young male subjects with desirable serum levels of cholesterol. They were administered with simvastatin (20 mg/d) for 4 weeks. Endothelial dependent flow-mediated vasodilation (FMD) was assessed on the brachial artery using high-resolution ultrasound, and fasting serum lipid profiles as well as vasoactive substances [NO, endothelin (ET) and 6-keto-PGF1 alpha] were measured. The parameters mentioned above were obtained at indicated time points before and after simvastatin treatment.

Simvastatin treatment for 4 weeks significantly improved FMD and reduced low density LDL-C and total TC levels. Withdrawal of simvastatin, however, resulted in dramatic impairment of endothelium-dependent relaxation on the first day after withdrawal [(4.6 +/- 0.48)% and (10.9 +/- 0.89)%, P < 0.01], Furthermore, FMD decreased significantly as compared with baseline level [(4.6 +/- 0.48 )% vs (6.44 +/- 0.47)%, P < 0.01]. Serum NO level varied according to the change of endothelial-dependent relaxation (gamma = 0.496, P < 0.01). After discontinuing simvastatin therapy, plasma ET increased and plasma 6-keto-PGF1 alpha decreased progressively. In addition, serum TC and LDL-C were not significantly modified during the initial 2 days. No correlation was shown between FMD and serum LDL-C level (gamma = -0.172, P = 0.101).

Withdrawal of simvastatin not only abrogates the beneficial effect on endothelial function of healthy normocholesterolemic men rapidly, but also induces further endothelial deterioration as compared with pretreatment status. This adverse effect is independent of serum cholesterol. The underlying mechanism may be related to the suppression of endothelial NO production.