Combining Cariporide with Glyceryl Trinitrate Optimizes Cardiac Preservation During Porcine Heart Transplantation

Abstract

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 lmol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 lmol/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.

Increasing the Tolerance of DCD Hearts to Warm Ischemia by Pharmacological Postconditioning

“…Our group has previously reported that glyceryl trinitrate, erythropoietin and zoniporide, when added as single or combined supplements to C solution, activate the same intracellular kinases that mediate ischemic preconditioning and postconditioning (14)(15)(16)(17). We have further shown that supplementing C solution with these agents reduces IRI in an isolated working rat heart model (16) and in an NDD porcine transplant model (18).…”

“…The chest cavity was subsequently filled with cold saline slush. In the ''supplemented'' groups (Cs), pharmacological agents known to activate ischemic conditioning pathways (14)(15)(16) were added to the C solution. These supplements and their doses are listed in Table 1.…”

“…Similar cellular and mitochondrial protective mechanisms are activated in ischemic preconditioning and postconditioning, with actions initiated through either mechanical or biochemical stimuli and acting to minimize ischemia reperfusion injury (IRI) (11)(12)(13). Our group has previously reported that glyceryl trinitrate, erythropoietin and zoniporide, when added as single or combined supplements to Celsior (C) solution, activate the intracellular kinases which mediate ischemic preconditioning and postconditioning (14)(15)(16)(17). We have further shown that supplementing C solution with these three agents reduces IRI in an isolated working rat heart model (16) and in an NDD porcine transplant model (18).…”

Cardiac xenotransplantation

“…If this is the case then a combination of pretransplant immunoabsorption, cardiac preconditioning (49) or pharmacological treatments to improve cardiac resistance to I/R injury (50, 51) may modulate PCXD. Genetic modification to increase adenosine receptor (52) and CD39 expression (53) in the heart or to increase the number of collateral arteries (54) might also alleviate PCXD.…”

Achieving 12 Hour Normothermic Ex Situ Heart Perfusion: An Experience of 40 Porcine Hearts

“…An Australian group demonstrated that glyceryl trinitrate, erythropoietin, and zoniporide are mediators of pre and post conditioning at the enzymatic level. 21–23 They attempted to use these agents to limit the detrimental effects of warm ischemia in a porcine model of donation after circulatory death (DCD). They were able to show improvement in the tolerance to warm ischemia based on improvement in return of electromechanical function, and a decrease in biomarkers indicative of myocardial injury including lactate.…”