Abstract 17356: Anti-arrhythmic Effect of Exosomes Secreted by Cardiosphere-derived Cells: Reduction in Inducible Ventricular Arrhythmias in a Porcine Model of Chronic Myocardial Infarction

Abstract

Introduction: Myocardial infarction (MI) survivors are at increased risk for ventricular arrhythmias and sudden death; risk directly correlates with infarct size and scar heterogeneity. The regenerative effects of cardiosphere-derived cells (CDCs),which are now in phase 2 clinical trials, are mediated by exosomes (CDC exo ).Like CDCs, CDC exo reduce scar size and increase viable mass in chronic MI. These naturally secreted nanoparticles mediate cell-cell signaling by transfer of bioactive payloads including microRNAs. Hypothesis: We hypothesized that post-MI hearts treated with CDC exo exhibit reduced inducibility of ventricular tachycardia (VT). Methods: An angioplasty balloon was inflated in the left anterior descending coronary artery for 150 minutes followed by one month of reperfusion in 7 female Yucatán minipigs. Electroanatomical mapping (EAM) was then performed to define the MI border zone (4.1-7mV NOGA tip potentials), after which we injected either CDC exo (7.5mg/1 ml n=4) or phosphate-buffered saline(PBS, 1ml, n=3), in 12-15 border zone sites via MYOSTAR catheter. Four weeks later, EAM was repeated and arrhythmia susceptibility was probed using both programmed ventricular stimulation and burst pacing (train of 8 beats from 400 to 200ms in 10 ms decrements) at the infarct border zone, and in healthy tissue near the posterolateral wall (>10mv). Arrhythmia morphology was characterized by 12 lead ECG. Final infarct size was quantified by histology (TTC). Results: In CDC exo -injected pigs, infarct size was lower (11.4% vs 7.8%, p=0.05) and viable mass was higher (69.3g vs 79.3g, p=0.03) than in PBS controls. No sustained VT was induced by programmed ventricular stimulation. Burst pacing elicited VT which rapidly degenerated into ventricular fibrillation in all control animals (n=3), but in only 1 of 4 CDC exo -treated animals (p=0.04),when paced at both the infarct border and healthy myocardium. Conclusions: Exosomes from CDCs regenerate myocardium post-MI. Pigs treated with CDC exo exhibit reduced inducibility of sustained ventricular arrhythmias by burst pacing. This first demonstration of an anti-arrhythmic effect of exosomes motivates more extensive investigation of the effects of these nanoparticles on rhythm disorders.