Engraftment, Differentiation, and Functional Benefits of Autologous Cardiosphere-Derived Cells in Porcine Ischemic Cardiomyopathy

Abstract

Cardiosphere-derived cells (CDCs) isolated from human endomyocardial biopsies reduce infarct size and improve cardiac function in mice. Safety and efficacy testing in large animals is necessary for clinical translation. Mesenchymal stem cells, which resemble CDCs in size and thrombogenicity, have been associated with infarction after intracoronary infusion. To maximize CDC engraftment while avoiding infarction, we optimized the infusion protocol in 19 healthy pigs. A modified cocktail of CDCs in calcium-free PBS, 100 U/mL of heparin, and 250 microg/mL of nitroglycerin eliminated infusion-related infarction. Subsequent infusion experiments in 17 pigs with postinfarct left ventricular dysfunction showed CDC doses > or =10(7) but <2.5 x 10(7) result in new myocardial tissue formation without infarction. In a pivotal randomized study, 7 infarcted pigs received 300,000 CDCs/kg (approximately 10(7) total) and 7 received placebo (vehicle alone). Cardiac magnetic resonance imaging 8 weeks later showed CDC treatment decreased relative infarct size (19.2% to 14.2% of left ventricle infarcted, P=0.01), whereas placebo did not (17.7% to 15.3%, P=0.22). End-diastolic volume increased in placebo, but not in CDC-treated animals. Hemodynamically, the rate of pressure change (dP/dt) maximum and dP/dt minimum were significantly better with CDC infusion. There was no difference between groups in the ability to induce ventricular tachycardia, nor was there any tumor or ectopic tissue formation. Intracoronary delivery of CDCs in a preclinical model of postinfarct left ventricular dysfunction results in formation of new cardiac tissue, reduces relative infarct size, attenuates adverse remodeling, and improves hemodynamics. The evidence of efficacy without obvious safety concerns at 8 weeks of follow-up motivates human studies in patients after myocardial infarction and in chronic ischemic cardiomyopathy.