Abstract 282: Mitochondrial Complex I Induced Myocardial Stunning Following Cardiopulmonary Resuscitation

Abstract

Background: Cardiogenic shock following cardiopulmonary resuscitation (CPR) for sudden cardiac arrest is common, occurring even in the absence of acute coronary artery occlusion, and contributes to high rates of post-CPR mortality. The pathophysiology of this shock is unclear and effective therapies for improving clinical outcomes are lacking. Methods and Results: Using a murine model of asystolic cardiac arrest, we investigated the pathophysiology of post-CPR cardiogenic shock and discovered that duration of cardiac arrest (4, 8, 12 or 16-minute) prior to CPR determined post-resuscitation success rates, degree of neurological injury, and severity of myocardial dysfunction. Post-CPR cardiac dysfunction was not associated with myocardial necrosis, apoptosis, inflammation, or mitochondrial permeability transition pore opening and recovered within several days, indicative of myocardial stunning. Post-CPR myocardial stunning was associated with increases in ventricular and mitochondrial reactive oxygen species (ROS, P <0.001 vs Sham, respectively). Seahorse micropolarimetry of isolated post-CPR cardiac mitochondria revealed decreased rates of maximal oxygen consumption rates (OCR) for both Complex I and Complex II vs controls ( P <0.01 vs Sham, respectively), indicating inhibition of mitochondrial oxidative phosphorylation. Paradoxically, in the presence of ADP stimulated coupled respiration, post-CRP mitochondria demonstrated increased OCR ( P <0.05 vs Sham) and increased rates of proton leak ( P <0.05 vs Sham), suggesting Complex I as the site of ROS generation. These findings were not observed at complex II. S1QEL, a complex I-specific superoxide inhibitor, administered during CPR, decreased myocardial ROS generation while improving post-CPR myocardial function ( P <0.01 vs CPR control), neurological injury ( P <0.01 vs CPR control), and survival ( P <0.01 vs CPR control). Conclusions: Our results demonstrate that cardiogenic shock following resuscitation from cardiac arrest is consistent with myocardial stunning mediated by mitochondrial complex I injury and ROS generation. Targeting this mechanism represents a novel and practical therapy for improving sudden cardiac arrest resuscitation outcomes.