Inhibition of the Mitochondrial Fission Protein Dynamin-Related Protein 1 Improves Survival in a Murine Cardiac Arrest Model. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Sharp, Willard W.; Beiser, David G.; Fang, Yong Hu; Han, Mei; Piao, Lin; Varughese, Justin; Archer, Stephen L.
• Is Part Of: Critical care medicine. Volume 43:Issue 2(2015)
• Publication Date: 2015-02
• Subjects: Critical care medicine -- Periodicals; Soins intensifs -- Périodiques; 616.028
• DOI: 10.1097/CCM.0000000000000817
• Languages: English
• ISSNs: 0090-3493

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Objectives:</title> <p>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.</p> </sec> <sec> <title>Design:</title> <p>Laboratory investigation.</p> </sec> <sec> <title>Setting:</title> <p>University laboratory.</p> </sec> <sec> <title>Interventions:</title> <p>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).</p> </sec> <sec> <title>Measurements and Main Results:</title> <p>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; <italic>p</italic> < 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.</p> </sec> <sec> <title>Conclusions:</title> <p>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.</p> </sec> </abstract>