Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function.
Complement factor 5 blockade reduces porcine myocardial infarction size and improves immediate cardiac function.
复制标题
DOI：
10.1007/s00395-017-0610-9
复制
发表时间：
2017-05
影响因子：
9.5
通讯作者：
Mollnes TE
中科院分区：
文献类型：
--
作者：
Pischke SE;Gustavsen A;Orrem HL;Egge KH;Courivaud F;Fontenelle H;Despont A;Bongoni AK;Rieben R;Tønnessen TI;Nunn MA;Scott H;Skulstad H;Barratt-Due A;Mollnes TE
在动物研究中，抑制补体因子5（C5）可减少心肌梗死，而在临床研究中未发现任何益处。由于临床使用的C5抗体缺乏交叉反应性，在动物和临床研究中使用了不同的抑制剂。Coversin（Ornithodoros moubata补体抑制剂，OmCI）在人类和猪中阻断C5裂解并结合白三烯B4。我们假设在猪心肌梗死模型中，在再灌注前抑制C5将减少梗死面积并改善心室功能。在猪（Sus scrofa）中，闭塞左冠状动脉前降支（40分钟）并再灌注（240分钟）。在16只盲法随机分组的猪中，在闭塞后20分钟和整个再灌注期间输注Coversin或安慰剂。Coversin显著减少了39%（p = 0.03，氯化三苯基四唑染色）和19%（p = 0.02）的风险区域的心肌梗死使用磁共振成像。方法相关性显著（R = 0.92，p < 0.01）。组织多普勒超声心动图显示coversin处理的猪的收缩期位移增加（31%，p < 0.01）和收缩期速度增加（29%，p = 0.01）。coversin治疗后，心肌微透析液中的白细胞介素-1 β显著降低（31%，p < 0.05），组织E-选择素表达显著降低（p = 0.01）。Coversin在整个再灌注期间消融血浆C5活化，并减少心肌C5 b-9沉积，而血浆和心肌LTB 4均未显著减少。Coversin通过抑制C5显著减小了该猪模型中的梗死面积，改善了心室功能，并减弱了白细胞介素-1 β和E-选择素。我们的结论是，心肌梗死抑制C5应重新考虑。本文的在线版本（doi：10.1007/s 00395 -017-0610-9）包含补充材料，可供授权用户使用。
Inhibition of complement factor 5 (C5) reduced myocardial infarction in animal studies, while no benefit was found in clinical studies. Due to lack of cross-reactivity of clinically used C5 antibodies, different inhibitors were used in animal and clinical studies. Coversin (Ornithodoros moubata complement inhibitor, OmCI) blocks C5 cleavage and binds leukotriene B4 in humans and pigs. We hypothesized that inhibition of C5 before reperfusion will decrease infarct size and improve ventricular function in a porcine model of myocardial infarction. In pigs (Sus scrofa), the left anterior descending coronary artery was occluded (40 min) and reperfused (240 min). Coversin or placebo was infused 20 min after occlusion and throughout reperfusion in 16 blindly randomized pigs. Coversin significantly reduced myocardial infarction in the area at risk by 39% (p = 0.03, triphenyl tetrazolium chloride staining) and by 19% (p = 0.02) using magnetic resonance imaging. The methods correlated significantly (R = 0.92, p < 0.01). Tissue Doppler echocardiography showed increased systolic displacement (31%, p < 0.01) and increased systolic velocity (29%, p = 0.01) in coversin treated pigs. Interleukin-1β in myocardial microdialysis fluid was significantly reduced (31%, p < 0.05) and tissue E-selectin expression was significantly reduced (p = 0.01) in the non-infarcted area at risk by coversin treatment. Coversin ablated plasma C5 activation throughout the reperfusion period and decreased myocardial C5b-9 deposition, while neither plasma nor myocardial LTB4 were significantly reduced. Coversin substantially reduced the size of infarction, improved ventricular function, and attenuated interleukin-1β and E-selectin in this porcine model by inhibiting C5. We conclude that inhibition of C5 in myocardial infarction should be reconsidered. The online version of this article (doi:10.1007/s00395-017-0610-9) contains supplementary material, which is available to authorized users.