Human relevance of pre-clinical studies in stem cell therapy: Systematic review and meta-analysis of large animal models of ischaemic heart disease

Aims Stem cell therapy is a treatment strategy for ischaemic heart disease patients. Meta-analysis of randomized human trials showed <5 improvement in left ventricular ejection fraction (LVEF). Meta-analysis of available pre-clinical data of ischaemic heart disease could provide important clues to design human clinical trials. Methods and resultsRandom-effects meta-analysis was performed on pig, dog, or sheep studies investigating the effect of cardiac stem cell therapy in ischaemic cardiomyopathy (52 studies; n 888 animals). Endpoints were LVEF and death. Ischaemia/reperfusion infarction was performed in 23 studies and chronic occlusion in 29 studies. Pooled analysis showed a LVEF difference of 7.5 at follow-up after cell therapy vs. control (95 confidence interval, 6.28.9; P < 0.001). By exploratory multivariable meta-regression, significant predictors of LVEF improvement were: cell type [bone marrow mononuclear cells (BM-MNC) showed less effect than other cell types, e.g. mesenchymal stem cells; P 0.040] and type of infarction (left anterior descending artery 8.0 vs. left circumflex artery 5.8; P 0.045). Cell therapy was not associated with increased mortality (P 0.68). Sensitivity analysis showed trends towards more improvement with higher cell number (<107), chronic occlusion models, and late injections (>1 week). After follow-up of 8 weeks, the effect of cell therapy decreased to 6. ConclusionThis meta-analysis showed that large animal models are valid to predict the outcome of clinical trials. Our results showed that cell therapy is safe and leads to a preserved LVEF. Future trials should focus on cell types other than BM-MNC, large infarction, and strategies to obtain sustained effects. © 2011 The Author.