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Reassessment of mitochondrial cyclophilin D as a target for improving cardiac arrest outcomes in the era of therapeutic hypothermia

      Uncertainty exists regarding whether cyclophilin D (CypD), a mitochondrial matrix protein that plays a key role in ischemia-reperfusion injury, can be a pharmacological target for improving outcomes after cardiac arrest (CA), especially when therapeutic hypothermia is used. Using CypD knockout mice (CypD−/−), we investigated the effects of loss of CypD on short-term and medium-term outcomes after CA. CypD−/− mice or their wild-type (WT) littermates underwent either 5 minute CA followed by resuscitation with and/or without hypothermia at 33°C–34°C (targeted temperature reached within minutes after resuscitation), or a sham procedure. Brain and cardiac injury were assessed using echocardiography, neurological scores, MRI and biomarkers. Seven day survival was compared using Kaplan-Meier estimates. The rate of restoration of spontaneous circulation was significantly higher in CypD−/− mice (with shorter cardiac massage duration) than in WT mice (P < 0.05). Loss of CypD significantly attenuated CA-induced release of troponin and S100ß protein, and limited myocardial dysfunction at 150 minutes after CA. Loss of CypD combined with hypothermia led to the best neurological and MRI scores at 24 hours and highest survival rates at 7 days compared to other groups (P < 0.05). In animals successfully resuscitated, loss of CypD had no benefits on day 7 survival while hypothermia was highly protective. Pharmacological inhibition of CypD with cyclosporine A combined with hypothermia provided similar day 7 survival than loss of CypD combined with hypothermia. CypD is a viable target to improve success of cardiopulmonary resuscitation but its inhibition is unlikely to improve long-term outcomes, unless therapeutic hypothermia is associated.

      Abbreviations:

      ADC (Apparent diffusion coefficient), CI (Confidence intervals), CPR (Cardio-pulmonary resuscitation), CsA (Cyclosporine A), CypD (Cyclophilin D), DWI (Diffusion-weighted images), EtCO2 (End-tidal carbon dioxide concentration), FiO2 (Inspired fraction of oxygen), HR (Hazard ratio), LV (Left ventricle), MRI (Brain magnetic resonance imaging), PTP (Permeability transition pore), ROSC (Restoration of spontaneous circulation), SSF (Surface shortening fraction), WT (Wild-type)
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