Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction.
OBJECTIVE
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.
Cedars-Sinai Heart Institute, Los Angeles, California 90048, USA.
Shuo-Tsan
ST
Lee
Anthony J
AJ
White
Satoshi
S
Matsushita
Konstantinos
K
Malliaras
Charles
C
Steenbergen
Yiqiang
Y
Zhang
Tao-Sheng
TS
Li
John
J
Terrovitis
Kristine
K
Yee
Sinan
S
Simsir
Raj
R
Makkar
Eduardo
E
Marbán
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000401:mortality / Q000601:surgery*; D015552:Injections, Intralesional; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D009203:Myocardial Infarction / Q000150:complications*; D032383:Myocytes, Cardiac / Q000637:transplantation*; D011897:Random Allocation; D012016:Reference Values; D012307:Risk Factors; D013318:Stroke Volume; D015996:Survival Rate; D013552:Swine; D013556:Swine, Miniature; D013907:Thoracostomy / Q000379:methods; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology*