Landmesser Ulf, Bahlmann Ferdinand, Mueller Maja, Spiekermann Stephan, Kirchhoff Nina, Schulz Svenja, Manes Costantina, Fischer Dieter, de Groot Kirsten, Fliser Danilo, Fauler Günter, März Winfried, Drexler Helmut
Abteilung Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Circulation. 2005 May 10;111(18):2356-63. doi: 10.1161/01.CIR.0000164260.82417.3F. Epub 2005 May 2.
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.
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 (DeltaFDD-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 (Deltamevalonate-simvastatin, -1.04+/-0.62 versus Deltamevalonate-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). DeltaFDD-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.
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.
他汀类药物可能发挥重要的多效性作用，即改善内皮功能，这与其对低密度脂蛋白胆固醇（LDL胆固醇）的影响无关。然而，在人类中，他汀类药物的多效性作用从未得到明确证实，因为长期使用他汀类药物治疗总会导致LDL胆固醇水平降低。因此，我们检验了以下假设：辛伐他汀和新型胆固醇吸收抑制剂依折麦布使LDL胆固醇水平产生相似程度的降低，但对内皮功能的影响不同。
20例慢性心力衰竭患者被随机分为两组，分别接受4周的辛伐他汀（10mg/天）或依折麦布（10mg/天）治疗。通过高分辨率超声在动脉内注射维生素C前后测定桡动脉的血流介导的舒张功能（FDD），以确定被自由基抑制的FDD部分（ΔFDD-VC）。通过静脉注射肝素从内皮释放后，测定主要血管抗氧化酶系统细胞外超氧化物歧化酶的活性。采用体外试验分析内皮祖细胞。辛伐他汀和依折麦布治疗使LDL胆固醇降低的程度相似（分别为15.6%和15.4%；P=无显著性差异），而两组间3-羟基-3-甲基戊二酰辅酶A还原酶的产物甲羟戊酸的变化不同（辛伐他汀组甲羟戊酸变化量为-1.04±0.62，依折麦布组为1.79±0.94ng/mL；两组间P<0.05）。重要的是，辛伐他汀治疗后FDD显著改善（从5.1±0.7%提高到10.5±0.6%；P<0.01），而依折麦布治疗后无改善（从5.8±0.6%变为5.6±0.5%；P=无显著性差异）。辛伐他汀治疗后ΔFDD-VC显著降低，而依折麦布治疗后未降低。辛伐他汀治疗后细胞外超氧化物歧化酶活性增加>100%（P<0.05），而依折麦布治疗后无变化。辛伐他汀治疗增加了功能活跃的内皮祖细胞数量，而依折麦布无此作用。
至少部分通过降低氧化应激，4周的辛伐他汀治疗可独立于LDL胆固醇降低而改善内皮功能。辛伐他汀可能因此在人类中发挥重要的多效性作用。
