title: Early improvement in cardiac tissue perfusion due to mesenchymal stem cells.
abstract: The underlying mechanism(s) of improved left ventricular function (LV) due to mesenchymal stem cell (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 MSCs 3 days after MI increased tissue perfusion in a manner that preceded improved LV function in a porcine model. MI was induced in pigs by 60-min occlusion of the left anterior descending coronary artery, followed by reperfusion. Pigs were assigned to receive intramyocardial injection of allogeneic MSCs (200 million, approximately 15 injections) (n = 10), placebo (n = 6), or no intervention (n = 8). Resting myocardial blood flow (MBF) was serially assessed by first-pass perfusion magnetic resonance imaging (MRI) over an 8-wk period. Over the first week, resting MBF in the infarct area of MSC-treated pigs increased compared with placebo-injected and untreated animals [0.17 +/- 0.03, 0.09 +/- 0.01, and 0.08 +/- 0.01, respectively, signal intensity ratio of MI to left ventricular blood pool (LVBP); P < 0.01 vs. placebo, P < 0.01 vs. nontreated]. 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 and improved regional and global LV function at week 8. Together these findings suggest that an early increase in tissue perfusion precedes improvements in LV function and a reduction in apoptosis in MSC-treated hearts. Cardiac MRI-based measures of blood flow may be a useful tool to predict a successful myocardial regenerative process after MSC treatment.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Schuleri
authors.forename: Luciano C
authors.initials: LC
authors.lastname: Amado
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Boyle
authors.forename: Marco
authors.initials: M
authors.lastname: Centola
authors.forename: Anastasios P
authors.initials: AP
authors.lastname: Saliaris
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gutman
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Hatzistergos
authors.forename: Behzad N
authors.initials: BN
authors.lastname: Oskouei
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Zimmet
authors.forename: Randell G
authors.initials: RG
authors.lastname: Young
authors.forename: Alan W
authors.initials: AW
authors.lastname: Heldman
authors.forename: Albert C
authors.initials: AC
authors.lastname: Lardo
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D017209:Apoptosis; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000473:pathology*; D020127:Recovery of Function; D012038:Regeneration; D012039:Regional Blood Flow; D013552:Swine; D013997:Time Factors; D014184:Transplantation, Homologous; D016277:Ventricular Function, Left