TY - JOUR
T1 - Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction
AU - Lee, Shuo Tsan
AU - White, Anthony J.
AU - Matsushita, Satoshi
AU - Malliaras, Konstantinos
AU - Steenbergen, Charles
AU - Zhang, Yiqiang
AU - Li, Tao Sheng
AU - Terrovitis, John
AU - Yee, Kristine
AU - Simsir, Sinan
AU - Makkar, Raj
AU - Marbán, Eduardo
N1 - Funding Information:
Major funding for this work was from the National Institutes of Health Specialized Centers for Cell-based Therapy ( U01 HL081028 ). Additional funding was provided by the Donald W. Reynolds Foundation and the Lincy Foundation . Dr. White is a post-doctoral C. J. Martin Fellow of the National Health and Medical Research Council of Australia. Dr. Terrovitis is a consultant for Capricor Inc. Dr. Marbán owns equity in Capricor Inc.; however, this company provided no funding for the studies herein. All other authors have reported that they have no relationships to disclose. Drs. Lee, White, Matsushita, and Malliaras contributed equally to this work.
PY - 2011/1/25
Y1 - 2011/1/25
N2 - Objectives The purpose of this study was to test the safety and efficacy of direct injection of cardiosphere-derived cells (CDCs) and their 3-dimensional precursors, cardiospheres, for cellular cardiomyoplasty in a mini-pig model of heart failure after myocardial infarction. Background Intracoronary administration of CDCs has been demonstrated to reduce infarct size and improve hemodynamic indexes in the mini-pig model, but intramyocardial injection of CDCs or cardiospheres has not been assessed in large animals. Methods Autologous cardiospheres or CDCs grown from endomyocardial biopsies were injected through thoracotomy 4 weeks after anteroseptal myocardial infarction. Engraftment optimization with luciferase-labeled CDCs guided the choice of cell dose (0.5 million cells/site) and target tissue (20 peri-infarct sites). Pigs were randomly allocated to placebo (n = 11), cardiospheres (n = 8), or CDCs (n = 10). Functional data were acquired before injection and again 8 weeks later, after which organs were harvested for histopathology. Results Beyond the immediate perioperative period, all animals survived to protocol completion. Ejection fraction was equivalent at baseline, but at 8 weeks was higher than placebo in both of the cell-treated groups (placebo vs. CDC, p = 0.01; placebo vs. cardiospheres, p = 0.01). Echocardiographic and hemodynamic indexes of efficacy improved disproportionately with cardiospheres; likewise, adverse remodeling was more attenuated with cardiospheres than with CDCs. Provocative electrophysiologic testing showed no differences among groups, and no tumors were found. Conclusions Dosage-optimized direct injection of cardiospheres or CDCs is safe and effective in preserving ventricular function in porcine ischemic cardiomyopathy. Although CDCs and cardiospheres have equivalent effects on left ventricular ejection fraction, cardiospheres are superior in improving hemodynamics and regional function, and in attenuating ventricular remodeling.
AB - Objectives The purpose of this study was to test the safety and efficacy of direct injection of cardiosphere-derived cells (CDCs) and their 3-dimensional precursors, cardiospheres, for cellular cardiomyoplasty in a mini-pig model of heart failure after myocardial infarction. Background Intracoronary administration of CDCs has been demonstrated to reduce infarct size and improve hemodynamic indexes in the mini-pig model, but intramyocardial injection of CDCs or cardiospheres has not been assessed in large animals. Methods Autologous cardiospheres or CDCs grown from endomyocardial biopsies were injected through thoracotomy 4 weeks after anteroseptal myocardial infarction. Engraftment optimization with luciferase-labeled CDCs guided the choice of cell dose (0.5 million cells/site) and target tissue (20 peri-infarct sites). Pigs were randomly allocated to placebo (n = 11), cardiospheres (n = 8), or CDCs (n = 10). Functional data were acquired before injection and again 8 weeks later, after which organs were harvested for histopathology. Results Beyond the immediate perioperative period, all animals survived to protocol completion. Ejection fraction was equivalent at baseline, but at 8 weeks was higher than placebo in both of the cell-treated groups (placebo vs. CDC, p = 0.01; placebo vs. cardiospheres, p = 0.01). Echocardiographic and hemodynamic indexes of efficacy improved disproportionately with cardiospheres; likewise, adverse remodeling was more attenuated with cardiospheres than with CDCs. Provocative electrophysiologic testing showed no differences among groups, and no tumors were found. Conclusions Dosage-optimized direct injection of cardiospheres or CDCs is safe and effective in preserving ventricular function in porcine ischemic cardiomyopathy. Although CDCs and cardiospheres have equivalent effects on left ventricular ejection fraction, cardiospheres are superior in improving hemodynamics and regional function, and in attenuating ventricular remodeling.
KW - ANOVA
KW - CDC
KW - E
KW - IV
KW - LV
KW - LVEF
KW - MI
KW - analysis of variance
KW - cardiosphere-derived cell
KW - end-systolic elastance
KW - intravenous
KW - left ventricular
KW - left ventricular ejection fraction
KW - myocardial infarction
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U2 - 10.1016/j.jacc.2010.07.049
DO - 10.1016/j.jacc.2010.07.049
M3 - Article
C2 - 21251587
AN - SCOPUS:78751621958
SN - 0735-1097
VL - 57
SP - 455
EP - 465
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 4
ER -