Extending myocardial viability during heart preservation with cyclosporine A.

Abstract

Hypothermic preservation (PRES) of donor hearts is limited to 12-14 hours for complete functional recovery after reperfusion. In a canine heterotopic heart transplant model, 50% to 60% functional recovery returned after 18 hours of PRES with University of Wisconsin (UW) solution. Concomitant with functional changes were marked increases in apoptotic cells at 2 (2.69%) and 6 (5.98%) hours of reperfusion with a concomitant decrease in lamin B1 (2% and 7.6%, respectively) with no evidence of necrotic cells. These results suggested that blockade of apoptosis may prolong myocardial viability during PRES and reperfusion. Donor hearts were subjected to 18 and 24 hours of PRES (2 degrees C to 4 degrees C) with and without cyclosporine A (CyS) treatment (apoptosis blocker). CyS was given to the donor animal (10 mg/kg), in the PRES solution (10(-5) mol/L), slowly infused during the PRES period (1 mL/min), and also to the recipient animal (2.5 mg/kg). After 18 hours of PRES with CyS, function returned to 100% within 1 hour and stayed at this level throughout a 6-hour recovery period. Apoptotic myocytes were reduced (55%) after 18 hours PRES with CyS treatment, and 6-hour reperfusion lamin B1 was reduced to only 3.7%. Twenty-four hour PRES in UW resulted in no functional recovery. However, after CyS treatment, functional recovery returned to 100% after 4 hours of reperfusion. Adenosine triphosphate (ATP) and creatine phosphate (CP) concentrations were surprisingly the same with or without CyS treatment at 18 hours and lower with 24 hours. Use of CyS in the PRES solution prolongs myocardial viability during donor heart PRES. The mechanism of action may be associated with the mitochondrial permeability transition (MPT) pore via cyclophilin D binding.