阿托伐他汀联合替格瑞洛预防健康年轻男性缺血再灌注诱导的血管内皮功能障碍：一项随机、安慰剂对照、双盲研究。

Atorvastatin combined with ticagrelor prevent ischemia-reperfusion induced vascular endothelial dysfunction in healthy young males - A randomized, placebo-controlled, double-blinded study.

机构信息

Department of Clinical Pharmacology, Medical University of Vienna, Austria.

出版信息

Int J Cardiol. 2018 Mar 15;255:1-7. doi: 10.1016/j.ijcard.2017.12.067. Epub 2017 Dec 24.

DOI:10.1016/j.ijcard.2017.12.067

PMID:29288055

Abstract

BACKGROUND

Atorvastatin and ticagrelor have been shown to prevent against tissue injury in animals. It is unclear if these beneficial effects are also detectable in humans. We studied the effect of high-dose atorvastatin combined with ticagrelor loading on endothelial dysfunction in a model of forearm vascular ischemia-reperfusion (IR) injury.

METHODS

32 healthy subjects (n=16 per group) were enrolled in this randomized, placebo-controlled, double-blinded trial. Forearm blood flow (FBF) measurements in response to increasing intra-arterial doses of the vasodilator acetylcholine (ACh; endothelium-dependent agonist) and glyceryltrinitrate (GTN; endothelium-independent) were performed before and after a cuff-induced 20min forearm ischemia, respectively. FBF reactivity was assessed prior to any pharmacological intervention and after 14days intake of 80mg atorvastatin once daily or placebo, followed by an oral loading dose of 180mg ticagrelor. In addition, lipoprotein parameters and platelet aggregation were evaluated.

RESULTS

Ticagrelor loading mitigated ischemia-induced endothelial dysfunction and in combination with repeated atorvastatin dosing the response to ACh during reperfusion was completely normalized (FBF ACh ratio post- vs. pre-ischemia: 0.81 [ticagrelor] vs. 1.04 [atorvastatin+ticagrelor]; P=0.001). As expected, GTN-induced vasodilation was not affected by IR injury. Atorvastatin significantly reduced total and low density lipoprotein cholesterol concentrations, while high density lipoprotein cholesterol and triglyceride levels remained unchanged.

CONCLUSION

Chronic atorvastatin treatment combined with ticagrelor loading prevents against endothelial dysfunction after acute forearm ischemia. Ticagrelor alone mitigated the impaired endothelium-dependent FBF response as compared to no pharmacological intervention.

CLINICAL TRIAL REGISTRATION

URL: https://clinicaltrials.gov. Unique identifier: NCT02910778.

摘要

背景

阿托伐他汀和替格瑞洛已被证明可预防动物的组织损伤。但这些有益作用在人类中是否也能被检测到尚不清楚。我们研究了大剂量阿托伐他汀联合替格瑞洛负荷对前臂血管缺血再灌注（IR）损伤模型中内皮功能障碍的影响。

方法

32 名健康受试者（每组 16 名）被纳入这项随机、安慰剂对照、双盲试验。分别在动脉内给予递增剂量的血管扩张剂乙酰胆碱（ACh；内皮依赖性激动剂）和硝酸甘油（GTN；内皮非依赖性）前后，测量前臂血流（FBF）。在任何药物干预之前评估 FBF 反应，然后在 14 天内每天服用 80mg 阿托伐他汀或安慰剂，然后口服 180mg 替格瑞洛负荷剂量。此外，还评估了脂蛋白参数和血小板聚集。

结果

替格瑞洛负荷减轻了缺血引起的内皮功能障碍，并且与重复阿托伐他汀给药联合使用时，再灌注期间对 ACh 的反应完全正常（缺血后 vs. 缺血前 ACh 比值：0.81 [替格瑞洛] vs. 1.04 [阿托伐他汀+替格瑞洛]；P=0.001）。如预期的那样，IR 损伤不影响 GTN 诱导的血管扩张。阿托伐他汀显著降低了总胆固醇和低密度脂蛋白胆固醇浓度，而高密度脂蛋白胆固醇和甘油三酯水平保持不变。