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Inhibition of the Mitochondrial Fission Protein Dynamin-Related Protein 1 Improves Survival in a Murine Cardiac Arrest Model

Sharp, Willard W. MD, PhD1; Beiser, David G. MD1; Fang, Yong Hu MD1; Han, Mei MD1; Piao, Lin PhD1; Varughese, Justin BS1; Archer, Stephen L. MD2

doi: 10.1097/CCM.0000000000000817
Online Laboratory Investigation
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Objectives: 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.

Design: Laboratory investigation.

Setting: University laboratory.

Interventions: 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).

Measurements and Main Results: 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.

Conclusions: 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.

Supplemental Digital Content is available in the text.

1Section of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, IL.

2Department of Medicine, Queen’s University at Kingston, ON, Canada.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Sharp received support for article research from the National Institutes of Health (NIH) (K08 HL103901-01A1 and R03 HL110826-01A1). His institution received grant support from the NIH. Dr. Beiser received support for article research from the NIH (K08HL091184). His institution received grant support from the NIH/National Heart, Lung, and Blood Institute. Dr. Piao’s institution received grant support from the NIH. Dr. Archer received support for article research from NIH-RO1-HL071115 and 1RC1HL099462. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: wsharp@medicine.bsd.uchicago.edu

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