title: Cardiac Stem Cell Treatment in Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Studies.
abstract: BACKGROUND
  Cardiac stem cells (CSC) therapy has been clinically introduced for cardiac repair after myocardial infarction (MI). To date, there has been no systematic overview and meta-analysis of studies using CSC therapy for MI.
  
  
  OBJECTIVE
  Here, we used meta-analysis to establish the overall effect of CSCs in preclinical studies and assessed translational differences between and within large and small animals in the CSC therapy field. In addition, we explored the effect of CSC type and other clinically relevant parameters on functional outcome to better predict and design future (pre)clinical studies using CSCs for MI.
  
  
  RESULTS
  A systematic search was performed, yielding 80 studies. We determined the overall effect of CSC therapy on left ventricular ejection fraction and performed meta-regression to investigate clinically relevant parameters. We also assessed the quality of included studies and possible bias. The overall effect observed in CSC-treated animals was 10.7% (95% confidence interval 9.4-12.1; P<0.001) improvement in ejection fraction compared with placebo controls. Interestingly, CSC therapy had a greater effect in small animals compared with large animals (P<0.001). Meta-regression indicated that cell type was a significant predictor for ejection fraction improvement in small animals. Minor publication bias was observed in small animal studies.
  
  
  CONCLUSIONS
  CSC treatment resulted in significant improvement of ejection fraction in preclinical animal models of MI compared with placebo. There was a reduction in the magnitude of effect in large compared with small animal models. Although different CSC types have overlapping culture characteristics, we observed a significant difference in their effect in post-MI animal studies.
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Peter Paul
authors.initials: PP
authors.lastname: Zwetsloot
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Anna Maria Dorothea
authors.initials: AM
authors.lastname: Végh
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Sanne Johanna
authors.initials: SJ
authors.lastname: Jansen of Lorkeers
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Gerardus P J
authors.initials: GP
authors.lastname: van Hout
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Currie
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Emily S
authors.initials: ES
authors.lastname: Sena
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Hendrik
authors.initials: H
authors.lastname: Gremmels
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Buikema
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Marie-Jose
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Macleod
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.).
authors.forename: Steven A J
authors.initials: SA
authors.lastname: Chamuleau
authors.affiliation: From the Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, The Netherlands (P.P.Z., A.M.D.V., S.J.J.o.L., G.P.J.v.H., J.W.B., P.A.D., S.A.J.C., J.P.G.S.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands (A.M.D.V., M.-J.G.); Department of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom (G.L.C., E.S.S., M.R.M.); Department of Nephrology & Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (H.G.); ICIN, Netherlands Heart Institute, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.); and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands (P.A.D., S.A.J.C., J.P.G.S.). J.Sluijter@umcutrecht.nl.
authors.forename: Joost P G
authors.initials: JP
authors.lastname: Sluijter
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000502:physiology / Q000637:transplantation*; D033581:Stem Cell Transplantation / Q000379:methods*; D016896:Treatment Outcome
keywords: adult stem cells; animal models; cardiac progenitor cells; cell transplantation; ischemic cardiomyopathy; meta-analysis; myocardial infarction