European Heart Journal Advance Access originally published online on December 11, 2007
European Heart Journal 2008 29(2):251-259; doi:10.1093/eurheartj/ehm559
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A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction
1 Cardiovascular Division, Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, PA 19104, USA
2 Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
3 CV Path, Gaithersburg, MD, USA
4 Osiris Therapeutics Inc., Baltimore, MD, USA
Received 16 July 2007; revised 8 October 2007; accepted 31 October 2007; online publish-ahead-of-print 11 December 2007.
* Corresponding author. Tel: +1 215 615 3060, Fax: +1 215 615 3073, Email: robert.wilensky{at}uphs.upenn.edu
Aims: Although mesenchymal stem cells (MSCs) show promising signs in reducing myocardial infarct (MI) size, the safety of endomyocardial delivery and the most efficacious dose is unknown.
Methods and results: Three days after MI, female Yorkshire swine (25–32 kg, age 2 months, n = 32) were randomized to endomyocardial delivery of one of three MSC doses (2.4 x 107, 2.4 x 108, 4.4 x 108 cells) or vehicle control. Animals were sacrificed at 12 weeks. There were no safety issues related to cell delivery and all animals tolerated the procedure. By magnetic resonance imaging infarct size (g) was decreased in the experimental groups and increased in the control group; 2.4 x 107: 
–2.5 ± 2.5 g, 2.4 x 108: –0.9 ± 2.71 g, 4.4 x 108: –1.6 ± 5.8 g, and control +3.6 ± 3.4 g (P = 0.002, P = 0.016, and P = 0.055 compared with control, respectively). There was no effect on ejection fraction or left ventricular volumes. By histology there were no toxic effects of MSC delivery, however, few engrafted MSCs were observed.
Conclusion: Direct MSC delivery into infarcted myocardium was safe and produced a local but not a functional effect. There was no dose-dependent effect. The effect of MSCs on infarct reduction may result from transient residence and subsequent paracrine effects.
Key Words: Catheterization • Magnetic resonance imaging • Myocardium • Stem cells • Regeneration
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