Biological substrate modification suppresses ventricular arrhythmias in a porcine model of chronic ischaemic cardiomyopathy. (9th March 2022)

• Record Type: Journal Article
• Authors: Dawkins, James F.; Ehdaie, Ashkan; Rogers, Russell; Soetkamp, Daniel; Valle, Jackelyn; Holm, Kevin; Sanchez, Lizbeth; Tremmel, Ileana; Nawaz, Asma; Shehata, Michael; Wang, Xunzhang; Prakosa, Adityo; Yu, Joseph; Van Eyk, Jennifer E; Trayanova, Natalia; Marbán, Eduardo; Cingolani, Eugenio
• Is Part Of: European heart journal. Volume 43:Number 22(2022)
• Page Start: 2139
• Page End: 2156
• Publication Date: 2022-03-09
• Subjects: Arrhythmia -- Ventricular tachycardia -- Cardiac stem cells -- Cardiosphere-derived cells -- Exosomes -- Heart failure -- Myocardial infarction -- Ischaemic cardiomyopathy; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac042
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Aims: Cardiomyopathy patients are prone to ventricular arrhythmias (VA) and sudden cardiac death. Current therapies to prevent VA include radiofrequency ablation to destroy slowly conducting pathways of viable myocardium which support re-entry. Here, we tested the reverse concept, namely that boosting local tissue viability in zones of slow conduction might eliminate slow conduction and suppress VA in ischaemic cardiomyopathy. Methods and results: Exosomes are extracellular vesicles laden with bioactive cargo. Exosomes secreted by cardiosphere-derived cells (CDCEXO ) reduce scar and improve heart function after intramyocardial delivery. In a VA-prone porcine model of ischaemic cardiomyopathy, we injected CDCEXO or vehicle into zones of delayed conduction defined by electroanatomic mapping. Up to 1-month post-injection, CDCEXO, but not the vehicle, decreased myocardial scar, suppressed slowly conducting electrical pathways, and inhibited VA induction by programmed electrical stimulation. In silico reconstruction of electrical activity based on magnetic resonance images accurately reproduced the suppression of VA inducibility by CDCEXO . Strong anti-fibrotic effects of CDCEXO, evident histologically and by proteomic analysis from pig hearts, were confirmed in a co-culture assay of cardiomyocytes and fibroblasts. Conclusion: Biological substrate modification by exosome injection may be worth developing as a non-destructive alternative to conventional ablation for the prevention of recurrent ventricular tachyarrhythmias. Structured Graphical Abstract: