Abstract 107: Mitochondrial Dysfunction Mediated Myocardial Stunning Following Resuscitation From Cardiac Arrest

Rationale: Severe myocardial contractile dysfunction following resuscitation from cardiac arrest (CA) is a major contributor to CA mortality. The pathophysiology and etiology of this dysfunction is not known and there are no pharmacological therapies known to improve outcomes. Previously, we demonstrated that Dynamin related protein 1 (Drp1) is activated and recruited to the mitochondria during CA and that the Drp1 inhibitor Mdivi-1 improves post CA survival. Objective: To determine the effects of CA length on myocardial and mitochondrial function. We also sought to determine the effects of Mdivi-1 on post CA outcomes. Methods and Results: Asystolic cardiac arrest (CA) was induced in mice by IV injection of 0.08 mg/g KCL. CPR begun at 4, 8, 12, and 16 minutes post-cardiac arrest had rates of return of spontaneous circulation (ROSC) of 100%(12/12), 93%(14/15), 71%(10/14), and 44% (4/9) and 2-hour survival of 100%(12/12), 67%(10/15), 50%(7/14), and 11%(1/9). Transthoracic echocardiography 15 min post-resuscitation demonstrated percent fractional shortening of 36±4% (Sham,n=6), 30±4% (4 minCA,n=11), 24±5% (8minCA,n=10), 15±2% (12minCA,n=12). In surviving animals, myocardial dysfunction persisted for 2 hours post-resuscitation, but slowly recovered to baseline by 72 hours. No evidence of myocardial necrosis, inflammation, or apoptosis was noted following resuscitation. Progressive increases in mitochondrial derived reactive oxygen species (ROS) during CA was observed by MitoSOX red myocardial tissue staining. Mitochondria isolated from 12 min CA hearts demonstrated decreased substrate coupled and uncoupled respiration. Mdivi-1, a mitochondrial inhibitor of division (fission), improved survival and neurological scores in mice following an 8 min cardiac arrest compared to controls. Conclusions: Severe, time dependent myocardial stunning (contractile dysfunction in the absence of irreversible injury) was observed following asystolic cardiac arrest. This myocardial stunning was associated with mitochondrial injury and improved by an inhibitor of Drp1. Strategies targeting ischemia/reperfusion-induced changes in mitochondrial dynamics hold promise for improving myocardial function and survival following cardiac arrest.