Abstract 13205: Mitochondrial Inhibitor of Division 1 (Mdivi-1) Improves Myocardial Hemodynamics and Return of Spontaneous Circulation in a Murine Model of Cardiac Arrest
Introduction: Mitochondrial fission following ischemia/reperfusion injury (IR) is an important determinant of reactive oxygen species (ROS) generation and cellular apoptosis but its role in cardiac arrest is unknown. The cytosolic protein, Dynamin Related Protein-1 (DRP1) initiates fission within minutes of IR via its altered phosphorylation and translocation to the mitochondria. Previous work by our lab has demonstrated that DRP1 inhibition using the small molecule Mdivi-1 (mitochondrial inhibitor of division 1) inhibits fission, decreases ROS, and reduces diastolic pressure following IR in a langendorff model of cardiac arrest. We hypothesized that Mdivi-1 would improve survival and cardiac hemodynamics in an in vivo model of cardiac arrest.
Methods: Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-min KCL- induced cardiac arrest. After 90 seconds of cardiopulmonary resuscitation (CPR) mice were blindly randomized to a single intravenous injection of 5uM Mdivi-1 or DMSO vehicle. CPR was continued until the spontaneous return of circulation (ROSC). Following ROSC, mice underwent continued ventilation and hemodynamic monitoring for 2 hours. Survival was assessed for up to 72 hours following cardiac arrest. Immunoblotting was performed on cardiac tissue obtained 2 hours post ROSC from a cohort of 5 mice. DRP1 expression in the mitochondrial fraction was measured.
Results: Mdivi-1 reduced the time to ROSC 111±4 vs. 143±9 sec (N=10, p<. 01) and the rate of ROSC increased (94% vs. 79%). Mdivi-1 improved myocardial hemodynamics at 2 hours post-ROSC vs. control (cardiac output 7.2±0.8 vs. 3.3±0.6 ml/ min, systolic pressure 73.6±4.9 vs. 54.1±3.7 mmHg, and diastolic pressure 3.6±0.8 vs. 7.1±1.5 mmHg, n=10 p<. 05). DRP1 decreased in mitochondrial fractions from Mdivi-1 treated hearts 2 hours post ROSC compared to controls. Long-term survival rates suggested a non-significant trend towards Mdivi-1 protection vs. control (55% vs. 31% respectively, p = 0.09).
Conclusions: Mdivi-1 inhibits DRP1 translocation to the mitochondria while improving resuscitation and post ROSC hemodynamics following cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.
- © 2013 by American Heart Association, Inc.