Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction.
Transplantation of stem cells may improve regional perfusion and post-infarct ventricular function, but the optimal dose and efficacy of cell delivery via the intravenous route has not been determined. This study tested the hypothesis that intravenous infusion of bone marrow-derived mesenchymal stem cells (MSCs) enhances regional perfusion and improves ventricular function after myocardial infarction. In a closed-chest pig model, the LAD coronary artery was occluded for 75 min by angioplasty balloon inflation followed by 12 weeks of reperfusion. After 15 min of reperfusion, pigs randomly received 1 of 4 treatments: (1) Vehicle (Control, n = 10); (2) 1 x 10(6) MSCs/kg (1 mill, n = 7); (3) 3 x 10(6) MSCs/kg (3 mill, n = 8) and (4) 10 x 10(6) MSCs/kg (10 mill, n = 8). Angiogenesis was demonstrated by immunohistochemical staining, myocardial blood flow (steady state and vasodilator reserve) was measured using 15 microm neutron-activated microspheres, and cardiac function was determined by contrast left ventriculography (ejection fraction) and pressure-volume relationships. After 12 week of reperfusion, von Willebrand Factor-positive vessels and tissue vascular endothelial growth factor (VEGF) expression in the scar zone was significantly greater in all MSCs-treated animals relative to Control. Steady state myocardial blood flow in the scar tissue was comparable among groups. However, adenosine recruited vasodilator reserve in the scar zone induced by intracoronary adenosine was significantly higher in the MSC-treated animals compared to Control. Furthermore, preload-recruitable stroke work and systolic performance were significantly greater compared to Control. In conclusion, these data demonstrate that intravenous delivery of MSCs during early reperfusion augments vasculogenesis, enhances regional perfusion, and improves post-infarct ventricular function. The results suggest that intravenous infusion of MSCs is an effective modality for the treatment of ischemia/reperfusion induced myocardial injury.
Halkos
Michael E
ME
Cardiothoracic Research Laboratory, Division of Cardiothoracic Surgery, Emory Crawford Long Hospital, 550 Peachtree Street, NE, Atlanta, GA 30308, USA.
Zhao
Zhi-Qing
ZQ
Kerendi
Faraz
F
Wang
Ning-Ping
NP
Jiang
Rong
R
Schmarkey
L Susan
LS
Martin
Bradley J
BJ
Quyyumi
Arshed A
AA
Few
Walter L
WL
Kin
Hajime
H
Guyton
Robert A
RA
Vinten-Johansen
Jakob
J
D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D054059:Coronary Occlusion / Q000209:etiology; D003331:Coronary Vessels / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D015425:Myocardial Reperfusion; D018919:Neovascularization, Physiologic / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A