Substrate Modification By Focal Exosome Injection As A Novel Strategy To Prevent Ventricular Tachyarrhythmias: Proof Of Concept In A Porcine Model Of Chronic Myocardial Infarction

Introduction: Myocardial infarction (MI) survivors are at increased risk of ventricular arrhythmias (VA) and sudden death. Current therapies for VA include ablation to “destroy” re-entry circuits. Isolated late potentials (ILP), which arise from viable myocardial bundles within scar, are targets for ablation in patients with recurrent VA. Cardiosphere-derived cell exosomes (CDC EXO ) have been shown to reduce scar and improve ventricular function, due to their regenerative, anti-fibrotic and anti-inflammatory properties. Here we sought to determine if substrate modification with CDC EXO could reduce ILP and the incidence of scar-related VA in a pre-clinical model. Methods: A balloon catheter was inflated in the LAD for 90 minutes, then reperfused for 8 weeks in 10 minipigs. MRI, programmed electrical stimulation (PES), and electroanatomic mapping (EAM; Rhythmia, Boston Scientific) were performed to evaluate arrhythmia inducibility and define sites of ILP. At 6-9 such sites, human CDC EXO (7.5mg/2ml, n=5) or vehicle only (2ml, n=5) was injected using a NOGA MYOSTAR catheter (Biosense Webster). Two weeks later, EAM and PES were repeated with continuous 12 lead ECG recordings. Final infarct size (scar mass divided by total LV mass) was quantified by MRI. Results: In CDC EXO -injected pigs vs. controls, infarct size was reduced (-3.4±1.2% vs. 0.6±0.9%, p=0.025) and ejection fraction improved (2.6±2.2% vs. -5.8±2.1% p=0.02). The CDC EXO group exhibited fewer ILP (CDC EXO baseline 18.6±5.9; 2 weeks 3.6±2.9 p EXO -injected pigs (-23.4±5.8 ms vs. 9.4±6.2 ms P=0.007). VA was induced in 5 of 5 CDC EXO animals at baseline, but only 1 of 5 remained inducible 2 weeks later. All control animals had inducible VA during the 2 week follow up (p=0.04 vs CDC EXO ). Conclusions: CDC EXO delivered by endocardial catheter injection can diminish ILP associated with slow conduction, and decrease the inducibility of VA. Substrate modification was evidenced by decreased infarct size and reduced ILP in CDC EXO but not in control animals. Exosome injection may represent a viable nondestructive alternative to conventional VA ablation.