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

生物底物修饰抑制慢性缺血性心肌病猪模型中的室性心律失常

• 批准号: 10504866
• 负责人: James F. Dawkins
• 金额: $ 73.06万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504866
• 关键词: 3-Dimensional; Ablation; Animal Model; Antiinflammatory Effect; Area; Arrhythmia; Biological; Biological Assay; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiomyopathies; Catheters; Cell Cycle; Cells; Chronic; Cicatrix; Clinic; Clinical; Coculture Techniques; Data; Electric Stimulation; Evaluation; Fibroblasts; Fibrosis; Fostering; Frequencies; Gadolinium; Genetic Transcription; Goals; Heart; Heart failure; Histologic; Human; Implant; In Vitro; Infarction; Injections; Ion Channel; Longterm Follow-up; Magnetic Resonance Imaging; Malignant - descriptor; Maps; Measurement; Methods; Modeling; Modification; Myocardial; Myocardium; Parents; Pathway interactions; Patients; Perfusion; Peripheral; Physiologic Monitoring; Pirfenidone; Prevention; Procedures; Property; Protein Analysis; Radiofrequency Interstitial Ablation; Recurrence; Rodent; Route; Safety; Stromal Cells; Sudden Death; Tachyarrhythmias; Techniques; Telemetry; Testing; Tissue Viability; Tissues; Transforming Growth Factor beta; Translating; Validation; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; base; cardiac magnetic resonance imaging; cell type; clinically translatable; comparative efficacy; coronary vasculature; exosome; extracellular vesicles; first-in-human; heart function; hemodynamics; improved; in silico; in vivo; inhibitor; ischemic cardiomyopathy; myocardial injury; nanovesicle; porcine model; pre-clinical; prevent; reconstruction; recruit; regenerative; stromal progenitor; sudden cardiac death; systemic inflammatory response; transcriptome sequencing

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.

项目概要/摘要 心肌病患者容易出现室性心律失常（VA）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，从而 支持重新进入。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 慢传导可能会消除慢传导并抑制 VA。我们寻求通过本地注入来做到这一点 绘制了由心源性细胞（CDC）分泌的外泌体的慢传导区域， 来自人类心脏的基质/祖细胞类型。外泌体是充满生物活性的细胞外囊泡 货物。 CDC（CDCEXO）分泌的那些可减少心肌内分娩后的疤痕并改善心脏功能。 在易患 VA 的缺血性心肌病猪模型中，我们提供了注射的初步数据 CDCEXO 或车辆进入电解剖图定义的延迟传导区域。最多一个月后 注射，CDCEXO，但不是载体，减少心肌疤痕，抑制缓慢传导电 途径，并通过程序刺激抑制 VA 诱导。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 诱导性的抑制。这里 我们将探索更容易临床转化的替代冠状动脉内输送方法 与心肌内注射方法相比，后者需要未经批准的导管。我们还将探索 通过组织学和 RNA 测序以及共培养测定来研究抗 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泌体与传统 RF 的功效 消融。总之，我们寻求通过外泌体注射建立生物底物修饰作为 传统消融的非破坏性替代方案，用于预防复发性室性快速心律失常。