Abstract
BACKGROUND: Explanted hearts from recipients undergoing cardiac transplantation may be utilized as a human model of cardiomyopathy. Ex-situ perfusion of hearts allows control of the physiological and biochemical conditions of perfusion. AZD8601 is a novel modRNA for VEGF-A that was shown to be safe in a Phase IIa clinical trial - the EPICCURE trial. This proof-of-concept study aimed to demonstrate the potential utility of testing novel therapies on explanted recipient hearts using ex situ machine perfusion. METHODS: In order to ascertain the expression of VEGF-A in a human model of cardiomyopathy, AZD8601 was injected at high- and low-dose into the mid-myocardium of the left ventricle of human hearts explanted at the time of cardiac transplantation and perfused on the m0rgan, a novel, normothermic organ perfusion machine. Hearts were perfused ex situ for 6 h. After which, injection sites were biopsied and divided into subendocardium, mid-myocardium and sub-epicardial myocardium. Immuno-analysis was performed to assess levels of VEGF-A protein. RESULTS: There were elevated levels of VEGF-A protein in the subendocardium and mid-myocardium of injection sites which received AZD8601. Low-dose and high-dose AZD8601 resulted in a significantly higher concentration of VEGF-A protein in the myocardium. CONCLUSIONS: This study builds on the EPICCURE study, a phase IIa clinical trial which demonstrated safety of this mRNA in patients undergoing coronary artery bypass grafting. This study provides a novel model of diseased human heart for experimental studies utilizing ex situ heart perfusion.