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Sodium-hydrogen exchange inhibitors, such as cariporide, are potent cardioprotective agents, however, safety concerns have been raised about intravenously (i.v.) administered cariporide in humans. The aim of this study was to develop a preservation strategy that maintained cariporide's cardioprotective efficacy during heart transplantation while minimizing recipient exposure. We utilized a porcine model of orthotopic heart transplantation that incorporated donor brain death and 14 h static heart storage. Five groups were studied: control (CON), hearts stored in Celsior; CAR1, hearts stored in Celsior with donors and recipients receiving cariporide (2 mg/kg i.v.) prior to explantation and reperfusion, respectively; CAR2, hearts stored in Celsior supplemented with cariporide (10 mumol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 mumol/L) plus GTN (100 mg/L). A total of 5/5 CAR1 and 5/6 COMB recipients were weaned from cardiopulmonary bypass compared with 1/5 CON, 1/5 CAR2 and 0/5 GTN animals (p = 0.001). Hearts from the CAR1 and COMB groups demonstrated similar cardiac function and troponin release after transplantation. Supplementation of Celsior with cariporide plus GTN provided superior donor heart preservation to supplementation with either agent alone and equivalent preservation to that observed with systemic administration of cariporide to the donor and recipient.

Background: The aim of this study was to determine the efficacy of cariporide (a sodium-hydrogen exchanger inhibitor), BMS180448 (a pharmacologic ischemic preconditioning agent), and the combination thereof, as adjuvant therapies for extended cardiac allograft preservation., Methods: A porcine model of donor brain death and orthotopic heart transplantation was used. All hearts were arrested and stored for 14 hr in an extracellular preservation solution. Control hearts (CON; n=3) did not receive any additional treatment. Treated hearts received BMS180448 alone (BMS; n=3), cariporide alone (CAR; n=6), or both BMS180448 and cariporide (B+C; n=6). Donors of BMS180448-treated hearts received 2 mg/kg, 15 min before explantation. Donors and recipients of cariporide-treated hearts received 2 mg/kg, 15 min before explantation and reperfusion, respectively., Results: The CON and BMS arms of the study were terminated after three transplantations because initial results in these groups were poor. Significantly, none of the control hearts could be weaned successfully from bypass, whereas all of the treated hearts were weaned successfully (CAR vs. CON and B+C vs. CON: P=0.012). The rate of troponin I release during the first 3 hr after reperfusion was significantly lower in CAR (P=0.0180) and B+C (P=0.0154) recipients than in CON recipients. Mean plasma troponin I levels (microg/mL) 3 hr after reperfusion were as follows: CON 633+/-177, BMS 576+/-110, CAR 346+/-93, and B+C 296+/-97., Conclusion: In this porcine model of extended cardiac allograft preservation, cariporide was more effective than BMS180448 as an adjuvant to our usual preservation solution. There was no additional benefit from the combination of the two therapies.

Background: Acute graft dysfunction caused by ischemia-reperfusion injury is recognized as a major source of morbidity and mortality following adult heart transplantation. The aim of this study was to determine whether treating the donor and recipient with cariporide, an inhibitor of the sodium-hydrogen exchanger, could reduce ischemia-reperfusion injury., Methods: A porcine model of donor brain death, hypothermic ischemic preservation, and orthotopic cardiac transplantation was used. Allografts in both the control group (CON, n=6) and treatment group (CAR, n=6) were arrested and stored for 4 hours in the extracellular crystalloid cardioplegia currently used in the clinical transplantation program at our institution. In addition, both the donor and recipient animals in the CAR group received a single intravenous dose of cariporide (2 mg/kg) 15 minutes before harvesting and reperfusion, respectively., Results: The initial rate of troponin I release was significantly lower in recipients of CAR hearts than in recipients of CON hearts (P =0.020). All hearts were weaned successfully from bypass. More CAR hearts were weaned successfully at the first attempt, at 1 hour post-reperfusion, than CON hearts (6 of 6 vs 3 of 6), but this did not achieve statistical significance. Left ventricular contractility (preload recruitable stroke-work relationship) and left ventricular compliance (end-diastolic pressure-volume relationship) were significantly better preserved in CAR hearts than CON hearts (both P <0.0001)., Conclusions: Myocardial injury was reduced, and contractile function was better preserved in allografts that received cariporide, compared with allografts that received conventional preservation alone.