Abstract 3976: Direct Intramyocardial Injection of Autologous Cardiosphere-Derived Cells Yields Consistent Engraftment and Improves Cardiac Function in a Porcine Model of Ischemic Cardiomyopathy
Background: This study aimed to optimize short-term engraftment of cardiosphere-derived cells (CDCs) injected directly into myocardium, and to test the safety and functional efficacy of the optimized dosing protocol
Methods and Results: Myocardial infarction (MI) was induced in mini-pigs by 21/2 hr occlusion of the LAD, and RV biopsies obtained. CDCs expanded from the biopsies were injected directly into myocardium via sternotomy, 4 weeks post-MI. To quantify engraftment CDCs were genetically transduced with the gene encoding firefly luciferase. Varying doses were injected (0.5, 2.0 or 10M cells/site) into infarct scar, border-zone or remote non-infarcted myocardium in 7 pigs. 24 hours later, cell engraftment was estimated by luciferase assay of excised tissues. No cells survived when injected into infarct scar. In non-infarcted myocardium ~8% of cells engrafted at each dose injected. In the border-zone, engraftment was inversely proportional to the number of cells injected, being 7.9±2.4%, 1.8±0.7% and 0.1±0.02% of the 0.5, 2.0 and 10M doses respectively. In a prospective, randomized, blinded protocol, 19 pigs received injections of either placebo (n=9) or CDCs (n=10; 20 peri-infarct injections × 0.5M cells/site) and were followed 8 weeks post-injection. Functional (left ventriculography, echocardiography) and hemodynamic (LV conductance catheter) measurements were obtained just before injection and 8 weeks later. Before injection, LVEF was comparable in placebo (43±6%) and CDC groups (41±9%, p=ns); 8 weeks later, LVEF was higher in the CDC group than placebo (43±6% vs 37±6%, p<0.05). Likewise, the absolute treatment-related change in LVEF was greater (+2±6% vs −6±4%, p=0.001) in the CDC group relative to placebo. Endpoint Emax was improved in the CDC group relative to placebo (1.66±0.45 vs 1.08±0.29 mmHg/mL, p<0.05). Echo indicated improved systolic function in the apical septum (wall thickening 22.9±15.5 vs 9.2±8.2%, p<0.05) in the CDC group. There were no deaths in either group after injection, and there was no difference in ability to induce ventricular tachycardia between groups 8 weeks post-injection.
Conclusion: Dose-optimized injection of CDCs is safe and effective in improving global cardiac function in ischemic cardiomyopathy.