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1 School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States; Division of Cardiology, and Institue of Cell Engineering (ICE), United States
2 Division of Cardiology, and Institute for Cell Engineering (ICE), Baltimore, Maryland, United States; The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
3 University of California San Francisco, San Francisco, California, United States
4 The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; Division of Cardiology, and Institute for Cell Engineering (ICE), Baltimore, Maryland, United States
5 Medicine, Division of Cardiology, University of Miami, Miami, Florida, United States
6 The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; Cardiology, University of Miami, Miller School of Medicine, Miami, Florida, United States; Interdisciplinary Stem Cell Institute, United States
7 Osiris Therapeutics, Inc., Baltimore, Maryland, United States
8 The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; Miami, Florida, United States; Division of Cardiology, and Institute for Cell Engineering (ICE), Baltimore, Maryland, United States; Cardiology, University of Miami, Miller School of Medicine, Miami, Florida, United States
9 The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; Division of Cardiology, and Institute for Cell Engineering (ICE), Baltimore, Maryland, United States; Cardiology, University of Miami, Miller School of Medicine, Miami, Florida, United States
* To whom correspondence should be addressed. E-mail: jhare{at}med.miami.edu.
The underlying mechanism(s) of improved left ventricular function (LV) due to MSC administration after myocardial infarction (MI) remains highly controversial. Myocardial regeneration and neovascularization, which leads to increased tissue perfusion, are proposed mechanisms. Here we demonstrate that delivery of MSC 3 days post MI increased tissue perfusion preceded improved LV-function in a porcine model. MI was induced in pigs by 60 minute occlusion of the left anterior descending coronary artery, followed by reperfusion. Pigs were assigned to receive intra-myocardial injection of allogeneic MSCs (200 million, ~15 injections) (n=10) or placebo (n=6) or to no intervention (n=8). Resting myocardial blood flow (MBF) was serially assessed by first-pass perfusion magnetic resonance imaging (MRI) over an 8 week period. Over the first week, resting MBF in the infarct area of MSC treated pigs increased compared to placebo injected and untreated animals (1.12±0.11, 0.43±0.05 and 0.65±0.12 respectively, signal intensity ratio of MI to remote myocardial territories; p<0.001 vs. placebo, and p<0.01 vs. non-treated). In contrast, the signal intensity ratios of the three groups were indistinguishable at weeks 4 and 8. However, MSC treated animals showed larger, more mature vessels and less apoptosis in the infarct zones evaluated for MBF, and improved regional and global function at week 8. Together these findings suggest that an early increase in tissue perfusion precedes improvements in left ventricular function and a reduction in apoptosis in MSC treated hearts. Cardiac MRI-based measures of blood flow may be a useful tool to predict successful myocardial regenerative process after MSC treatment.
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