Mechanistic Basis of Cardiac Irradiation as a Therapy for Ventricular Tachycardia

心脏照射治疗室性心动过速的机制基础

基本信息

批准号：
10626107
负责人：
STACEY Lynn RENTSCHLER
金额：
$ 78.72万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626107
关键词：
Ablation Acceleration Acute Address Animal Model Anti-Arrhythmia Agents Area Arrhythmia Biological Biological Assay Biological Markers Cancer Patient Carbon ion Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiac ablation Cardiotoxicity Chemical-Induced Change Chromatin Chromatin Remodeling Factor Cicatrix Clinical Clinical Trials Connexin 43 Coupled Dangerousness Data Disease Dose Down-Regulation Electrophysiology (science)Epigenetic Process Family suidae Fibrosis Focused Ultrasound Therapy Gap Junctions Gene Expression Genes Genetic Genetic Models Genetic Transcription Heart Heart Arrest Heart Diseases Heart failure High-Throughput Nucleotide Sequencing Histologic Hospitals Human Image Ion Channel Ionizing radiation Left Maps Measures Mediating Messenger RNA MicroRNAs Modeling Molecular Monitor Morbidity - disease rate Mus Myocardial Myocardial Infarction Myocardium Optics Output Pathway interactions Patient Representative Patients Phenotype Physiological Plasma Prospective cohort Protein Inhibition Proteins Radiation Radiation Dose Unit Radiation therapy Radiobiology Reactive Oxygen Species Refractory Safety Serum Signal Transduction Slice Sodium Channel System Techniques Testing Therapeutic Effect Therapy trial Tissues Translating Transposase Treatment Efficacy Ventricular Ventricular Arrhythmia Ventricular Tachycardia circulating biomarkers clinical effect clinical implementation cohort conventional therapy fractionated radiation innovation insight irradiation loss of function mortality mouse model notch protein participant enrollment porcine model prevent programs protein expression radiation effect response single fraction radiation sodium channel proteins specific biomarkers sudden cardiac death transcriptional reprogramming treatment effect

项目摘要

Project Summary Ventricular tachycardia (VT) is a dangerous arrhythmia that leads to sudden cardiac arrest if left untreated. VT most often involves regions of the heart that are structurally and/or electrically heterogeneous which provide a substrate for reentry. Currently available antiarrhythmic and catheter ablation therapies are limited in both safety and efficacy. In patients with VT that is refractory to conventional therapy, stereotactic body radiation therapy (RT) has emerged as a promising new treatment. An initial clinical trial showed that a single fraction of 25 Gy ionizing radiation to the heart was associated with greater than 99.9% reduction of VT burden, and this VT reduction persisted for at least 12 months. Importantly, studies at several independent academic hospitals have now demonstrated the efficacy of RT for the treatment of ventricular tachycardia. Despite these promising results, the precise mechanisms by which high-dose radiation reduces VT is unknown. It has been hypothesized that 25 Gray radiation to arrhythmogenic regions of the heart causes late-stage fibrosis thereby preventing re-entry, analogous to scar created by thermal catheter ablation. However, histologic data from explanted hearts of SBRT- treated patients suggests that fibrosis alone cannot account for the magnitude of the observed clinical effect (unpublished). Instead, our preliminary data suggest that radiation to the heart causes functional changes in the electrical substrate that may prevent reentry and reduce VT. We hypothesize that ionizing radiation to the heart leads to changes in cardiac gene expression and electrophysiology. The proposed studies will characterize key molecular and cell-signaling mechanisms by which ionizing radiation influences cardiac conduction. The following specific aims will (1) determine the cellular mechanisms by which ionizing radiation influences cardiac electrophysiology, (2) determine the minimal dose response in a porcine model, and (3) translate biological insights from animal models into humans through analysis of serum-derived biomarkers from RT-treated patients. Defining the acute effects of irradiation on the electrical substrate is expected to facilitate clinical implementation of this promising new anti-arrhythmic therapy and advance the field of cardiac radiation biology.

项目摘要心室心动过速（VT）是一种危险的心律不齐，如果不加以治疗，会导致心脏骤停。 VT 通常涉及在结构上和/或电异质上的心脏区域重新进入的底物。目前可用的抗心律失常和导管消融疗法在两种安全方面都受到限制和功效。在常规治疗的VT患者中，立体定向身体放射治疗（RT）已成为一种有希望的新待遇。最初的临床试验表明，只有25 Gy的单个部分对心脏的电离辐射与VT负担的减少大于99.9％，并且该VT 减少持续至少12个月。重要的是，几家独立学术医院的研究现在证明了RT对心室心动过速治疗的功效。尽管有这些有希望的结果高剂量辐射减少VT的确切机制尚不清楚。已经假设25 心脏心律失常区域的灰色辐射会导致后期纤维化，从而防止重新进入，类似于由热导管消融产生的疤痕。但是，来自SBRT的外植的组织学数据接受治疗的患者表明，仅纤维化无法解释观察到的临床效果的大小（未出版）。相反，我们的初步数据表明，对心脏的辐射会导致功能变化电底物，可能会阻止重新进入并减少VT。我们假设将电离辐射到心脏导致心脏基因表达和电生理学的变化。拟议的研究将表征关键电离辐射影响心脏传导的分子和细胞信号机制。这以下特定目的将（1）确定电离辐射影响心脏的细胞机制电生理学，（2）确定猪模型中的最小剂量反应，（3）翻译生物学通过分析RT处理的血清衍生的生物标志物，从动物模型到人类的见解患者。定义辐射对电底物的急性影响有望促进临床实施这种有希望的新的抗心律失常疗法并推进心脏辐射生物学领域。