title: Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  Random-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, 6.2-8.9%; 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 (≥10(7)), chronic occlusion models, and late injections (>1 week). After follow-up of 8 weeks, the effect of cell therapy decreased to 6%.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Rm E03.511, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. tspoel@umcutrecht.nl
authors.forename: Tycho I G
authors.initials: TI
authors.lastname: van der Spoel
authors.forename: Sanne J
authors.initials: SJ
authors.lastname: Jansen of Lorkeers
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Agostoni
authors.forename: Eric
authors.initials: E
authors.lastname: van Belle
authors.forename: Mariann
authors.initials: M
authors.lastname: Gyöngyösi
authors.forename: Joost P G
authors.initials: JP
authors.lastname: Sluijter
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Cramer
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Steven A J
authors.initials: SA
authors.lastname: Chamuleau
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000628:therapy*; D012107:Research Design; D012756:Sheep; D033581:Stem Cell Transplantation / Q000009:adverse effects; D013318:Stroke Volume; D013552:Swine; D016277:Ventricular Function, Left