Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase

Abstract 

Aim of study

Significant myocardial dysfunction and high mortality occur after whole-body ischaemia-eperfusion injuries in the post-cardiac arrest status. The inhibition of mitochondrial permeability transition pore (mPTP) opening during ischaemia-reperfusion can ameliorate injuries in the specific organs. We investigated the effect and therapeutic window of pharmacological inhibition of mPTP opening in cardiac arrest.

Methods

Forty male Wistar rats were resuscitated after cardiac arrest induced by 8.5 min of asphyxia. Cyclosporine (10 mg/kg) was administered intravenously at onset of resuscitation in protocol 1 study and administered 3 min after ROSC in protocol 2 with placebo control in both.

Results

Left ventricular systolic (dP/dt40), diastolic (maximal negative dP/dt) functions and cardiac output were improved in the group with cyclosporine treatment at onset of resuscitation compared to control group (p < 0.01, respectively). Seventy-two hour survival was better in the group with cyclosporine treatment at onset of resuscitation compared to control (p = 0.046). Left ventricular systolic and diastolic function, cardiac output and 72 h survival were not improved in the group with cyclosporine treatment 3 min after ROSC. The severity of mitochondrial damage under electronic microscopy, mPTP opening, mitochondrial respiratory control ratio and ADP:O ratio were ameliorated in the group with cyclosporine treatment at onset of resuscitation (p< 0.05, respectively) but not in the group with cyclosporine treatment at 3 min after ROSC.

Conclusions

Post-cardiac arrest myocardial dysfunction and survival can be improved by cyclosporine treatment at onset of resuscitation, but not by the cyclosporine treatment at 3 min after ROSC.

Key Words:  Cardioprotection , Cardiopulmonary resuscitation , Cyclosporine , Mitochondria , Myocardial dysfunction , Post-cardiac arrest syndrome , Rat , Therapeutic window

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