Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia
Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia
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DOI：
10.1016/j.thromres.2008.06.022
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发表时间：
2009-01-01
影响因子：
7.5
通讯作者：
Luescher, Thomas F.
中科院分区：
文献类型：
--
作者：
Hermann, Frank;Enseleit, Frank;Luescher, Thomas F.
简介：虽然血浆HDL水平升高，但与心血管事件呈负相关，然而，在ILLUMINATE试验中，CETP抑制剂torcetrapib升高HDL与心血管发病率和死亡率增加相关。torcetrapib的有害临床作用是否代表分子特异性脱靶效应、CETP抑制剂的类效应或两者都是持续争论的问题。因此，本研究的目的是研究JTT 705（一种与torcetrapib明显不同的分子）对CETP的抑制是否影响血管功能，这是动脉粥样硬化血管疾病的公认替代物，以及II型高脂血症患者的炎症和氧化应激标志物。18例患者随机接受JTT-705 600 mg/d或匹配安慰剂治疗4周。使用肱动脉超声检查测量血流介导的扩张（FMD）。在JTT 705组中，HDL-C从1.14 mmol/l升高26%至1.44 mmol/l（p=0.01），而甘油三酯从2.52 mmol/l降低至1.97 mmol/l（p=0.03）。然而，用JTT 705抑制CETP没有改变FMD（3.1 +/- 0.6%至3.6 +/- 0.4%; p=0.48）。有趣的是，在低于中位HDL-C（1.19 mmol/l; p=0.01）的患者亚组分析中。血管炎症标志物（CRP，ICAM-1，IL-6，TNF α），以及血浆内皮素-1水平在整个study.Conclusion：在II型高脂血症患者中，CETP抑制与JTT 705增加HDL-C和降低甘油三酯，但改善内皮功能的患者亚组低基线HDL-C水平。(C)2008爱思唯尔有限公司版权所有
Introduction: While elevated, plasma HDL levels are inversely correlated with cardiovascular events, raising HDL with the CETP inhibitor torcetrapib, however, was associated with increased cardiovascular morbidity and mortality in the ILLUMINATE trial. Whether the deleterious clinical effects of torcetrapib represent a molecule specific off-target effect, a class effect of CETP inhibitors or both is matter of ongoing debate. As such, the aim of the present study was to investigate whether CETP-inhibition with JTT 705, a molecule distinctly different from torcetrapib, impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with type II hyperlipidemia.Methods and Results: Eighteen patients were randomized to receive JTT-705 600 mg/d or matching placebo for 4 weeks. Flow-mediated dilation (FMD) was measured using ultrasonography of the brachial artery. HDL-C increased by 26% from 1.14 mmol/l to 1.44 mmol/l (p=0.01) in the JTT 705 group, while triglycerides decreased from 2.52 mmol/l to 1.97 mmol/l (p=0.03). CETP-inhibition with JTT 705, however, did not change FMD (3.1 +/- 0.6% to 3.6 +/- 0.4%; p=0.48). Interestingly, in a sub group analysis of patients with lower than median HDL-C (1.19 mmol/l; p=0.01). Markers of vascular inflammation (CRP, ICAM-1, IL-6, TNF alpha), as well as plasma endothelin-1 levels all remained unchanged throughout the study.Conclusion: In patients with type II hyperlipidemia, CETP inhibition with JTT 705 increased HDL-C and lowered triglycerides but improved endothelial function in the subgroup of patients with low baseline HDL-C levels only. (C) 2008 Elsevier Ltd. All rights reserved