A NOVEL MECHANISM FOR CYCLOSPORINE - INHIBITION OF MYOCARDIAL-ISCHEMIA AND REPERFUSION INJURY IN A HETEROTOPIC RABBIT HEART-TRANSPLANT MODEL

Background: Advances in myocardial preservation techniques and immunos uppressive drug therapy have resulted in heart transplantation as an a cceptable treatment for end-stage heart failure. However, excessive pe riods of global myocardial ischemia followed by reperfusion can progre ss to irreversible graft injury. It has been reported that cyclosporin e A (in addition to its well-characterized immunosuppressive actions) can blunt certain features oi ischemia and reperfusion injury. This st udy was performed to examine the ability of cyclosporine A to attenuat e such injury in a model of heart transplantation. Methods: Twenty rab bit heterotopic transplants were divided into Pour study groups: (1) 3 0-minute ischemic control hearts; (2) 30-minute ischemic cyclosporine A-treated hearts: (3) 4-hour ischemic control hearts; and (4) 4-hour i schemic cyclosporine A-treated hearts. A single dose of cyclosporine A (10 mg/kg intravenously) or vehicle was administered to both thr dono r and recipient rabbits 45 minutes before heart explantation and heart transplantation, respectively. Results: After transplantation and 30 minutes of reperfusion, the 4-hour ischemic control hearts showed a si gnificant (p < 0.01) leftward shift in the left ventricular end-diasto lic pressure versus left ventricular volume curve compared with the 30 -minuie ischemic control hearts. This finding represents higher end-di astolic pressures and incomplete diastolic relaxation caused by ischem ia and reperfusion. Cyclosporine A administration to the donor and rec ipient rabbits resulted in a significant improvement (p < 0.01) in dia stolic relaxation (shift in the left ventricular end-diastolic pressur e versus left ventricular volume curve back tu the right) compared wit h 4-hour ischemic control hearts. Cyclosporine A-treated hearts also s howed significant improvements in the rate of diastolic pressure fall (p < 0.05) rind tau (the isovolumetric pressure decay constant) (p < 0 .01) compared with ischemic control hearts. Conclusions: These results indicate that single doses of cyclosporine A to both the donor and re cipient inhibit the dysfunction in extent and rate of left ventricular relaxation caused by prolonged global ischemia and reperfusion. Possi ble mechanisms for cyclosporine A's myocardial protective actions are presented in the discussion.