Simvastatin versus ezetimibe -: Pleiotropic and lipid-lowering effects on endothelial function in humans
Simvastatin versus ezetimibe -: Pleiotropic and lipid-lowering effects on endothelial function in humans
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DOI：
10.1161/01.cir.0000164260.82417.3f
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发表时间：
2005-05-10
期刊：
影响因子：
37.8
通讯作者：
Drexler, H
中科院分区：
文献类型：
--
作者：
Landmesser, U;Bahlmann, F;Drexler, H
背景：他汀类药物可能发挥重要的多效作用，即改善内皮功能，而不依赖于其对低密度脂蛋白胆固醇的影响。然而，在人类中，他汀类药物的多效效应从未得到明确证明，因为长期他汀类药物治疗总是导致低密度脂蛋白胆固醇水平降低。因此，我们验证了一种假设，即辛伐他汀和依折替米贝（一种新型胆固醇吸收抑制剂）对低密度脂蛋白胆固醇的类似降低对内皮功能的影响不同。方法与结果：20例慢性心力衰竭患者随机分为辛伐他汀（10mg /d）或依折替米贝（10mg /d）治疗4周。采用高分辨率超声检测动脉内维生素C前后桡动脉血流依赖性扩张（FDD），测定自由基抑制的FDD部分（δ FDD- vc）。研究了肝素从内皮中释放后细胞外超氧化物歧化酶（一种主要的血管抗氧化酶系统）的活性。用体外实验分析内皮祖细胞。辛伐他汀和依zetimibe治疗降低LDL胆固醇的程度相似（15.6%对15.4%,P = NS），而hmg - coa还原酶产物甲羟戊酸的变化在两组之间存在差异（甲伐他汀-甲伐他汀，-1.04 +/- 0.62，甲伐他汀-甲伐他汀- 1.79 +/- 0.94 ng/mL，组间P < 0.05）。重要的是，辛伐他汀治疗后FDD明显改善（10.5 +/- 0.6% vs 5.1 +/- 0.7%; P < 0.01），但依泽替米贝治疗后无明显改善（5.6 +/- 0.5% vs 5.8 +/- 0.6%; P = NS）。辛伐他汀治疗后δ FDD-VC显著降低，依泽替米贝治疗后无显著降低。辛伐他汀组细胞外超氧化物歧化酶活性比依折麦比组提高了100% （P < 0.05）。辛伐他汀治疗增加了功能活跃的内皮祖细胞的数量，而依折麦布没有效果。结论：四周的辛伐他汀治疗可以改善内皮功能，而不依赖于降低LDL胆固醇，至少部分是通过降低氧化应激。辛伐他汀可能因此在人类中发挥重要的多效性作用。
Background-Statins may exert important pleiotropic effects, ie, improve endothelial function, independently of their impact on LDL cholesterol. In humans, however, pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels. We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe, a novel cholesterol absorption inhibitor, result in different effects on endothelial function.Methods and Results-Twenty patients with chronic heart failure were randomized to 4 weeks of simvastatin (10 mg/d) or ezetimibe (10 mg/d) treatment. Flow-dependent dilation (FDD) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals (Delta FDD-VC). Activity of extracellular superoxide dismutase, a major vascular antioxidant enzyme system, was determined after release from the endothelium by a heparin bolus injection. Endothelial progenitor cells were analyzed with an in vitro assay. Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent (15.6% versus 15.4%; P = NS), whereas changes in mevalonate, the product of HMG-CoA-reductase, differed between groups (Delta mevalonate-simvastatin, -1.04 +/- 0.62 versus Delta mevalonate-ezetimibe, 1.79 +/- 0.94 ng/mL; P < 0.05 between groups). Importantly, FDD was markedly improved after simvastatin (10.5 +/- 0.6% versus 5.1 +/- 0.7%; P < 0.01) but not after ezetimibe treatment (5.6 +/- 0.5% versus 5.8 +/- 0.6%; P = NS). Delta FDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment. Extracellular superoxide dismutase activity was increased by > 100% (P < 0.05) after simvastatin but not ezetimibe treatment. Simvastatin treatment increased the number of functionally active endothelial progenitor cells, whereas ezetimibe had no effect.Conclusions-Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering, at least in part by reducing oxidant stress. Simvastatin may thereby exert important pleiotropic effects in humans.