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

项目摘要/摘要 心肌病患者容易发生室性心律失常(VA)和猝死。目前的治疗方法是 预防VA包括射频消融以破坏存活心肌的缓慢传导通路 支持重返大气层。在这里，我们建议测试相反的概念，即在区域中提高局部组织的活力 慢传导可消除慢传导，抑制VA。我们寻求通过局部注入、向 心球源细胞(CDCs)分泌的外切体的慢传导区域，a 来自人类心脏的基质/祖细胞类型。胞外体是一种充满生物活性的胞外小泡。 货物。CDC(CDCEXO)分泌的CDCEXO心肌内给药后可减少瘢痕，改善心功能。 在易患VA的猪缺血性心肌病模型中，我们提供了初步数据，在其中我们注射了 CDCEXO或载体进入由电解剖标测定义的延迟传导区域。最多一个月后- 注射CDCEXO，但不注射赋形剂，减少心肌瘢痕，抑制慢传导电 并抑制程控刺激诱导的VA诱导。在电活动的计算机重建中 基于磁共振图像，准确再现了CDCEXO对VA诱导性的抑制作用。这里 我们将探索更容易在临床上翻译的替代冠状动脉内给药方法 而不是心肌内注射的方法，后者需要未经批准的导管。我们还将探索 通过组织学和RNA测序以及细胞共培养实验研究抗VA作用的机制 心肌细胞和成纤维细胞。我们还将直接比较外切体与传统射频的疗效。 消融。总之，我们试图通过外切体注射来建立生物底物修饰作为一种 非破坏性替代常规消融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.