Biological substrate modification to suppress ventricular arrhythmias in a porcine model of chronic ischemic cardiomyopathy

项目总结/摘要 心肌病患者易发生室性心律失常和猝死。目前的治疗方法， 预防VA包括射频消融，以破坏存活心肌的缓慢传导通路， 支持重返。在这里，我们建议测试相反的概念，即提高区域中的局部组织活力 慢传导抑制剂可消除慢传导，抑制VA。我们寻求通过本地注入， 心脏球源性细胞（CDC）分泌的外泌体的慢传导区域， 来源于人类心脏的基质/祖细胞类型。外泌体是一种细胞外囊泡， 货物.由CDC分泌的那些（CDCEXO）在心肌内递送后减少瘢痕并改善心脏功能。 在VA倾向的缺血性心肌病猪模型中，我们提供了初步数据， CDCEXO或溶剂进入电解剖标测定义的延迟传导区。一个月后， 注射CDCEXO，而不是媒介物，减少心肌瘢痕，抑制缓慢传导的电 途径，并抑制VA诱导程序化刺激。电活动的计算机重建 基于磁共振图像准确地再现了CDCEXO对VA诱导的抑制。这里 我们将探索更易于临床转化的替代冠状动脉内给药方法 而心肌内注射方法需要未经批准的导管。我们还将探索 抗VA作用的机制在组织学上和通过RNA测序，以及在共培养试验中 心肌细胞和成纤维细胞。我们还将直接比较外泌体与传统RF的疗效， 消融术总之，我们试图建立通过外泌体注射的生物基质修饰作为一种生物学方法。 非破坏性替代传统消融，用于预防复发性室性快速性心律失常。

PROJECT SUMMARY/ABSTRACT Cardiomyopathy patients are prone to ventricular arrhythmias (VA) and sudden death. Current therapies to prevent VA include radiofrequency ablation to destroy slowly conducting pathways of viable myocardium which support re-entry. Here we propose to test the reverse concept, namely that boosting local tissue viability in zones of slow conduction might eliminate slow conduction and suppress VA. We seek to do so by local injection, into mapped areas of slow conduction, of exosomes secreted by cardiosphere-derived cells (CDCs), a stromal/progenitor cell type from the human heart. Exosomes are extracellular vesicles laden with bioactive cargo. Those secreted by CDCs (CDCEXO) reduce scar and improve heart function after intramyocardial delivery. In a VA-prone porcine model of ischemic cardiomyopathy, we present preliminary data in which we injected CDCEXO or vehicle into zones of delayed conduction defined by electroanatomic mapping. Up to one month post- injection, CDCEXO, but not vehicle, decreased myocardial scar, suppressed slowly conducting electrical pathways, and inhibited VA induction by programmed stimulation. In silico reconstruction of electrical activity based on magnetic resonance images accurately reproduced the suppression of VA inducibility by CDCEXO. Here we will explore alternative intracoronary delivery methods which would be more readily translatable clinically than the intramyocardial injection approach, which requires non-approved catheters. We will also explore mechanism of the anti-VA effects histologically and by RNA sequencing, as well as in a co-culture assay of cardiomyocytes and fibroblasts. We will also compare directly the efficacy of exosomes versus conventional RF ablation. In conclusion, we seek to establish biological substrate modification by exosome injection as a nondestructive alternative to conventional ablation for the prevention of recurrent ventricular tachyarrhythmias.