European Heart Journal Advance Access published online on July 8, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp265
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Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy
1 Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
2 Cardiovascular Division, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA
3 Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, 1501 NW 10th Avenue, 8th Floor, Miami, FL, USA
4 Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
5 Division of Hematology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
6 Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
Received 30 January 2009; revised 29 April 2009; accepted 8 June 2009 * Corresponding author. Tel: +1 305 243 1999, Fax: +1 433 287 7945, Email: jhare{at}med.miami.edu
Aims: The ability of mesenchymal stem cells (MSCs) to heal the chronically injured heart remains controversial. Here we tested the hypothesis that autologous MSCs can be safely injected into a chronic myocardial infarct scar, reduce its size, and improve ventricular function.
Methods and results: Female adult Göttingen swine (n = 15) underwent left anterior descending coronary artery balloon occlusion to create reproducible ischaemia–reperfusion infarctions. Bone-marrow-derived MSCs were isolated and expanded from each animal. Twelve weeks post-myocardial infarction (MI), animals were randomized to receive surgical injection of either phosphate buffered saline (placebo, n = 6), 20 million (low dose, n = 3), or 200 million (high dose, n = 6) autologous MSCs in the infarct and border zone. Injections were administered to the beating heart via left anterior thoracotomy. Serial cardiac magnetic resonance imaging was performed to evaluate infarct size, myocardial blood flow (MBF), and left ventricular (LV) function. There was no difference in mortality, post-injection arrhythmias, cardiac enzyme release, or systemic inflammatory markers between groups. Whereas MI size remained constant in placebo and exhibited a trend towards reduction in low dose, high-dose MSC therapy reduced infarct size from 18.2 ± 0.9 to 14.4 ± 1.0% (P = 0.02) of LV mass. In addition, both low and high-dose treatments increased regional contractility and MBF in both infarct and border zones. Ectopic tissue formation was not observed with MSCs.
Conclusion: Together these data demonstrate that autologous MSCs can be safely delivered in an adult heart failure model, producing substantial structural and functional reverse remodelling. These findings demonstrate the safety and efficacy of autologous MSC therapy and support clinical trials of MSC therapy in patients with chronic ischaemic cardiomyopathy.
Key Words: Magnetic resonance imaging • Myocardial infarction • Remodelling • Mesenchymal stem cells