Author:

Keywords:

Adenosine Triphosphate, Animals, Cell Differentiation, Cell Lineage, Cyclosporine, Energy Metabolism, Female, Immunosuppressive Agents, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Models, Animal, Multipotent Stem Cells, Myocardial Contraction, Myocardial Infarction, Myocardium, Myocytes, Cardiac, Neovascularization, Physiologic, Phosphocreatine, Random Allocation, Regeneration, Sus scrofa, Swine, Ventricular Remodeling, Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Peripheral Vascular Disease, Cardiovascular System & Cardiology, cells, heart failure, hypertrophy, magnetic resonance imaging, metabolism, myocardial contraction, myocardial infarction, REGENERATE INFARCTED MYOCARDIUM, MESENCHYMAL STEM-CELLS, ISCHEMIC MYOCARDIUM, CARDIAC-FUNCTION, FAILING HEARTS, PORCINE MODEL, BORDER ZONE, REPAIR, ABNORMALITIES, HYPERTROPHY, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1117 Public Health and Health Services, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences, 4207 Sports science and exercise

Abstract:

BACKGROUND: The present study examined whether transplantation of adherent bone marrow-derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion. METHODS AND RESULTS: Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55+/-5.6% to 30+/-5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP (31P magnetic resonance spectroscopy; 1.06+/-0.30 in infarcted hearts [n=9] versus 1.90+/-0.15 in normal hearts [n=8; P<0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34+/-0.29; n=7; P<0.05). The BZ protein expression of creatine kinase-mt and creatine kinase-m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7+/-9.8%, P<0.01), whereas the left ventricular ejection fraction improved to 42.0+/-6.5% (P<0.05 versus myocardial infarction). Only 0.35+/-0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, n=6; no cyclosporine A, n=7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and approximately 2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (P<0.05). CONCLUSIONS: Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.