title: Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Laboratory investigation.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  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).
  
  
  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.
authors.affiliation: 1Section of Emergency Medicine, Department of Medicine, University of Chicago, Chicago, IL. 2Department of Medicine, Queen's University at Kingston, ON, Canada.
authors.forename: Willard W
authors.initials: WW
authors.lastname: Sharp
authors.forename: David G
authors.initials: DG
authors.lastname: Beiser
authors.forename: Yong Hu
authors.initials: YH
authors.lastname: Fang
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.forename: Lin
authors.initials: L
authors.lastname: Piao
authors.forename: Justin
authors.initials: J
authors.lastname: Varughese
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D034281:Dynamins / Q000037:antagonists & inhibitors*; D005260:Female; D006323:Heart Arrest / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000502:physiology*; D052999:Quinazolinones / Q000494:pharmacology*; D011897:Random Allocation
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D052999:Quinazolinones; D034281:Dynamins; D000154:Aconitate Hydratase