Efficacy of Stem Cell Therapy in Large Animal Models of Ischemic Cardiomyopathies: A Systematic Review and Meta-Analysis

Simple Summary The present work focuses on stem-cell assessment as a therapeutic approach on cardiovascular diseases, both in terms of safety and efficacy. In particular, this is a systematic review of the relevant literature about the use of stem-cell treatment against acute or chronic ischemic cardiomyopathies in large animal models and a meta-analysis on collected data with regard to the left ventricular ejection fraction (LVEF) as functional parameter. This approach is compliant with the "3Rs" (replacement, reduction and refinement) principle about the use of animal experimentation in preclinical trials to predict evidences and perform the future translational researches. Stem-cell therapy provides a promising strategy for patients with ischemic heart disease. In recent years, numerous studies related to this therapeutic approach were performed; however, the results were often heterogeneous and contradictory. For this reason, we conducted a systematic review and meta-analysis of trials, reporting the use of stem-cell treatment against acute or chronic ischemic cardiomyopathies in large animal models with regard to Left Ventricular Ejection Fraction (LVEF). The defined research strategy was applied to the PubMed database to identify relevant studies published from January 2011 to July 2021. A random-effect meta-analysis was performed on LVEF mean data at follow-up between control and stem-cell-treated animals. In order to improve the definition of the effect measure and to analyze the factors that could influence the outcomes, a subgroup comparison was conducted. Sixty-six studies (n = 1183 animals) satisfied our inclusion criteria. Ischemia/reperfusion infarction was performed in 37 studies, and chronic occlusion in 29 studies; moreover, 58 studies were on a pig animal model. The meta-analysis showed that cell therapy increased LVEF by 7.41% (95% Confidence Interval 6.23-8.59%; p < 0.001) at follow-up, with significative heterogeneity and high inconsistency (I-2 = 82%, p < 0.001). By subgroup comparison, the follow-up after 31-60 days (p = 0.025), the late cell injection (>7 days, p = 0.005) and the route of cellular delivery by surgical treatment (p < 0.001) were significant predictors of LVEF improvement. This meta-analysis showed that stem-cell therapy may improve heart function in large animal models and that the swine specie is confirmed as a relevant animal model in the cardiovascular field. Due to the significative heterogeneity and high inconsistency, future translational studies should be designed to take into account the evidenced predictors to allow for the reduction of the number of animals used.