title: Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Preclinical Studies and Clinical Trials.
abstract: BACKGROUND
  Accumulating data support a therapeutic role for mesenchymal stem cell (MSC) therapy; however, there is no consensus on the optimal route of delivery.
  
  
  OBJECTIVE
  We tested the hypothesis that the route of MSC delivery influences the reduction in infarct size and improvement in left ventricular ejection fraction (LVEF).
  
  
  RESULTS
  We performed a meta-analysis investigating the effect of MSC therapy in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy preclinical studies (58 studies; n=1165 mouse, rat, swine) which revealed a reduction in infarct size and improvement of LVEF in all animal models. Route of delivery was analyzed in AMI swine studies and clinical trials (6 clinical trials; n=334 patients). In AMI swine studies, transendocardial stem cell injection reduced infarct size (n=49, 9.4% reduction; 95% confidence interval, -15.9 to -3.0), whereas direct intramyocardial injection, intravenous infusion, and intracoronary infusion indicated no improvement. Similarly, transendocardial stem cell injection improved LVEF (n=65, 9.1% increase; 95% confidence interval, 3.7 to 14.5), as did direct intramyocardial injection and intravenous infusion, whereas intracoronary infusion demonstrated no improvement. In humans, changes of LVEF paralleled these results, with transendocardial stem cell injection improving LVEF (n=46, 7.0% increase; 95% confidence interval, 2.7 to 11.3), as did intravenous infusion, but again intracoronary infusion demonstrating no improvement.
  
  
  CONCLUSIONS
  MSC therapy improves cardiac function in animal models of both AMI and chronic ischemic cardiomyopathy. The route of delivery seems to play a role in modulating the efficacy of MSC therapy in AMI swine studies and clinical trials, suggesting the superiority of transendocardial stem cell injection because of its reduction in infarct size and improvement of LVEF, which has important implications for the design of future studies.
authors.affiliation: From the Interdisciplinary Stem Cell Institute (A.J.K., C.P., W.B., J.M.H.), Department of Molecular and Cellular Pharmacology (C.P.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; and Florida International University Herbert Wertheim College of Medicine, Miami (J.L.).
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kanelidis
authors.affiliation: From the Interdisciplinary Stem Cell Institute (A.J.K., C.P., W.B., J.M.H.), Department of Molecular and Cellular Pharmacology (C.P.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; and Florida International University Herbert Wertheim College of Medicine, Miami (J.L.).
authors.forename: Courtney
authors.initials: C
authors.lastname: Premer
authors.affiliation: From the Interdisciplinary Stem Cell Institute (A.J.K., C.P., W.B., J.M.H.), Department of Molecular and Cellular Pharmacology (C.P.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; and Florida International University Herbert Wertheim College of Medicine, Miami (J.L.).
authors.forename: Juan
authors.initials: J
authors.lastname: Lopez
authors.affiliation: From the Interdisciplinary Stem Cell Institute (A.J.K., C.P., W.B., J.M.H.), Department of Molecular and Cellular Pharmacology (C.P.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; and Florida International University Herbert Wertheim College of Medicine, Miami (J.L.).
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.affiliation: From the Interdisciplinary Stem Cell Institute (A.J.K., C.P., W.B., J.M.H.), Department of Molecular and Cellular Pharmacology (C.P.), and Department of Medicine (W.B., J.M.H.), University of Miami Miller School of Medicine, FL; and Florida International University Herbert Wertheim College of Medicine, Miami (J.L.). jhare@med.miami.edu.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D007267:Injections / Q000009:adverse effects / Q000379:methods; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D051379:Mice; D009203:Myocardial Infarction / Q000628:therapy*; D051381:Rats; D013552:Swine
keywords: cell- and tissue-based therapy; heart failure; mesenchymal stem cell transplantation; meta-analysis; myocardial infarction