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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, METHODS, METHODS, RESULTS. Meshes: Aconitate Hydratase, Animals, Disease Models, Animal, Dynamins, Female, Heart Arrest, Immunoblotting, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Mitochondrial Dynamics, Quinazolinones, Random Allocation.
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Does inhibition of the mitochondrial fission protein dynamin-related protein 1 improve survival in a murine cardiac arrest model? Context: 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.
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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. Final Decision: yes