Inhibition of mitochondrial remodeling by cyclosporine A preserves myocardial performance in a neonatal rabbit model of cardioplegic arrest

ObjectiveMitochondrial permeability transition pore opening is associated with apoptotic signaling and alterations in mitochondrial structure and function. We tested whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A preserved mitochondrial structure and function after cardioplegic arrest and whether this preservation is associated with improved myocardial performance.MethodsLangendorff-perfused neonatal rabbit hearts were perfused for 30 minutes with Krebs–Henseleit buffer (CCP; n = 6) or Krebs–Henseleit buffer containing 2 μmol/L of cyclosporine A (CCP+CsA; n = 6) followed by 60 minutes of normothermic crystalloid cardioplegia (CCP) and 60 minutes of reperfusion. Control hearts (non-CCP; n = 6) were constantly perfused for 150 minutes without cardioplegic arrest.ResultsIn comparison with non-CCP, CCP was associated with Bax translocation to the mitochondria, cytochrome c release, and greater frequency of terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling–positive myocytes These changes were also associated with deficits in isolated mitochondrial oxygen consumption at complex I. CsA pretreatment minimized or prevented all these findings. Myocardial performance (systolic pressure, maximum positive and negative dP/dt, and elevated left ventricular end-diastolic pressure) at 5, 15, 30, and 60 minutes after reperfusion was diminished in CCP hearts when compared with non-CPB, and these deficits could be minimized with cyclosporine A pretreatment. (P < .05 all comparisons)ConclusionsCyclosporine A prevents apoptosis-related mitochondrial permeabilization and dysfunction after cardioplegic arrest. This protection is associated with improved myocardial performance. Prevention of mitochondrial permeability transition pore opening is a valuable target for mitochondrial (and myocardial) preservation after neonatal cardioplegic arrest.