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

Cardiovasc Res. 2011 Sep 1;91(4):649-58. doi: 10.1093/cvr/cvr113. Epub 2011 Apr 14.


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 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%.

Conclusion: 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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Dogs
  • Humans
  • Myocardial Ischemia / physiopathology
  • Myocardial Ischemia / therapy*
  • Research Design
  • Sheep
  • Stem Cell Transplantation* / adverse effects
  • Stroke Volume
  • Swine
  • Ventricular Function, Left