A comparison of therapeutic hypothermia and genetic mitochondrial permeability transition pore inhibition in a murine model of cardiac arrest

Abstract

Recent evidence suggests that therapeutic hypothermia limits the severity of the post-cardiac arrest syndrome by inhibiting mitochondrial permeability transition pore (mPTP) opening through a Cyclophilin-D (CypD) dependent mechanism. We sought to compare the effects of genetic loss of CypD (CypD-KO) and therapeutic hypothermia on resuscitability and survival after cardiac arrest (CA). Adult mice underwent 5 minutes of asphyxial CA followed by resuscitation. Animals were assigned to one of the 5 following groups: Sham, Control (Ctrl): normothermic CA in wild-type mice, CypD-KO: normothermic CA in CypD-KO mice, therapeutic hypothermia (TH): CA in wild-type mice with fast hypothermia induced by external cooling at the onset of cardiac massage (33 °C for 1 hour) and CypD-KO + TH. Two hours after CA, left ventricle-shortening fraction, blood levels of S100B protein (a marker of brain injury) and troponin Ic, were assessed. Additional mice were included in the same 5 groups for survival follow-up. Baseline characteristics and characteristics of CA were similar among groups. Rate of restoration of spontaneous circulation (ROSC) was significantly higher in CypD-KO and TH groups compared to controls ( P < 0.05). Time to ROSC was significantly shorter in CypD-KO mice versus wild-type mice ( P < 0.05). Genetic loss of CypD and therapeutic hypothermia prevented to a similar extent CA-induced myocardial dysfunction, increase in S100B, troponin Ic and death within 24 hours after CA ( P < 0.05 versus Ctrl). Only therapeutic hypothermia applied to either wild-type or CypD-KO animals improved survival at day 7 ( P < 0.05 versus non-hypothermic groups). There were no additive beneficial effects in the combination of genetic loss of CypD and therapeutic hypothermia. In our CA model, genetic inhibition of CypD improved resuscitability and early cardiac dysfunction but, unlike therapeutic hypothermia, failed to improve 7-day survival.