Sharp Willard W, Beiser David G, Fang Yong Hu, Han Mei, Piao Lin, Varughese Justin, Archer Stephen L
1Section of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, IL. 2Department of Medicine, Queen's University at Kingston, ON, Canada.
Crit Care Med. 2015 Feb;43(2):e38-47. doi: 10.1097/CCM.0000000000000817.
Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation and the use of therapeutic hypothermia. Dynamin-related protein 1, a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that dynamin-related protein 1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest.
Laboratory investigation.
University laboratory.
Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-minute KCl-induced cardiac arrest followed by 90 seconds of cardiopulmonary resuscitation. Mice were then blindly randomized to a single IV injection of Mdivi-1 (0.24 mg/kg), a small molecule dynamin-related protein 1 inhibitor or vehicle (dimethyl sulfoxide).
Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by dynamin-related protein 1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during cardiopulmonary resuscitation inhibited dynamin-related protein 1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (116 ± 4 vs 143 ± 7 s; p < 0.001) during cardiopulmonary resuscitation and enhanced myocardial performance post-return of spontaneous circulation. These improvements were associated with significant increases in survival (65% vs 33%) and improved neurological scores up to 72 hours post cardiac arrest.
Post-cardiac arrest inhibition of dynamin-related protein 1 improves time to return of spontaneous circulation and myocardial hemodynamics, resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.
尽管心肺复苏和治疗性低温技术有所进步，但心脏骤停后的生存率仍然很低。动力相关蛋白1是线粒体分裂的调节因子，是缺血/再灌注损伤后活性氧生成、心肌坏死和左心室功能的重要决定因素，但其在心脏骤停中的作用尚不清楚。我们假设抑制动力相关蛋白1可提高心脏骤停体内模型的生存率、心脏血流动力学和线粒体功能。
实验室研究。
大学实验室。
对麻醉并通气的成年雌性C57BL/6野生型小鼠进行8分钟氯化钾诱导的心脏骤停，随后进行90秒的心肺复苏。然后将小鼠随机分为单次静脉注射Mdivi-1（0.24mg/kg）、小分子动力相关蛋白1抑制剂或载体（二甲基亚砜）。
心脏骤停复苏后，动力相关蛋白1转位至线粒体膜以及线粒体大小减小证明了线粒体分裂。线粒体分裂与乳酸增加和氧化损伤证据相关。心肺复苏期间给予Mdivi-1可抑制动力相关蛋白1激活，保留线粒体形态并减少氧化损伤。Mdivi-1还缩短了心肺复苏期间自主循环恢复的时间（116±4秒对143±7秒；p<0.001），并改善了自主循环恢复后的心肌性能。这些改善与生存率显著提高（65%对33%）以及心脏骤停后72小时内神经学评分改善相关。
心脏骤停后抑制动力相关蛋白1可改善自主循环恢复时间和心肌血流动力学，从而提高心脏骤停小鼠模型的生存率和神经学结局。线粒体分裂的药物靶向治疗可能是一种有前景的心脏骤停治疗方法。
