Investigations of pharmacological pre- and posttreatments with Omegaven and ATP in a four-chamber isolated working swine heart model : implications for cardiac interventions, cardiac transplantation and ex vivo perfusion systems

Abstract

Myocardial ischemia and reperfusion injury (RI) both negatively affect the outcome of cardiac interventions and transplantation. Therefore, investigations have been attempted to discover drugs for administration prior to organ procurement or for ex vivo cardiac perfusion, aiming to maintain and recover functional performance of the organ clinically. Ischemic preconditioning has been utilized to protect the heart from an ischemic event, whereas postconditioning is employed to minimize the consequences of ischemia at the onset of reperfusion. The underlying mechanisms and pathways of ischemic pre- and postconditioning continue to be investigated as therapeutic targets. We evaluated the effects after administration of Omegaven and adenosine triphosphate (ATP) on various parameters associated with RI upon and after reperfusion of isolated porcine hearts. An ex vivo four-chamber working swine heart model was utilized to monitor hemodynamic and metabolic measurements. In total, 45 trials were included in the final data analyses. Three major strategies were studied. In the first protocol, pharmacological preconditioning was performed using Omegaven, which was administered in situ into the pericardial cradle before the onset of ischemia. In the second and third protocol, ATP was administered either as a postconditioning agent to the perfusion buffer solution in various concentrations immediately before and/or during reperfusion, or was provided as a supplement administered incrementally to the buffer solution shortly following reperfusion ex vivo. For the latter, ATP was proposed to function as an inotropic and cardiosupportive drug, due to its various receptor interactions. In general, it was observed that the administration of these agents relative to a transplant scenario could improve organ recovery and functional outcomes. Preconditioning with Omegaven enhanced hemodynamic functions of the reanimated swine hearts. Furthermore, the addition of ATP as a supplement in our experimental studies also elicited beneficial effects.