Could Cellular Therapy Rescue the Chronically Failing Heart

Purpose Myocardial infarction (MI) results in permanent cardiomyocyte loss, frequently leading to heart failure with 50% 5-year mortality. At subacute time points following MI, animal studies have shown ‘remuscularization’ of the damaged heart with human embryonic stem cell (hESC)-derived cardiomyocytes. We recently improved outcomes by co-delivering hESC-derived epicardium. Clinically, the main challenge remains chronic heart failure. However, hESC-cardiomyocytes alone, in the chronically infarcted heart show no benefit. We hypothesized that co-delivering hESC-epicardium or a species-matched therapy could regenerate the chronically infarcted heart. Methods 3 separate pilot studies on chronically infarcted rodents were conducted: I) Vehicle-control ii) P1/P2 neonatal rat cardiomyocytes (NRVM) iii) hESC-epicardium & cardiomyocytes (Epi+CM). Rats underwent temporary left anterior descending artery ligation, resulting in MI. At 28days post-MI, animals with fractional shortening (FS%) Results Overall, Vehicle-control persistently decreased in cardiac function, whilst species-matched therapy (NRVM) had sustained functional recovery. Initially, combination therapy (EPI+CM) sharply declined, with a trend towards recovery by 3months. Infarct sizes between groups were similar. At 3months, Epi+CM's cardiac graft size=1.2±1.3% of LV whilst NRVM=2.7±1.9% of LV. Both NRVM and Epi+CM grafts displayed increased sarcomeric alignment, maturation, connexin-43 organization and neovascularization, compared to previous reports. Conclusion Our serial observations of within-group trends showed functional recovery for species-matched therapy (NRVM), whereas combination cellular therapy (Epi+CM) attenuated cardiac dysfunction at 3months. hESC-combination cell therapy holds clinical promise for ‘remuscularising’ chronically infarcted hearts and needs validation in a randomized preclinical study.