Mechanistic Basis of Cardiac Irradiation as a Therapy for Ventricular Tachycardia

项目摘要 室性心动过速（VT）是一种危险的心律失常，如果不及时治疗会导致心脏骤停。VT 通常涉及心脏的结构和/或电不均匀的区域， 重返大气层的基质目前可用的抗心律失常和导管消融治疗在安全性和安全性方面都有限。 和功效。在常规治疗难治性室性心动过速患者中，立体定向体部放射治疗 (RT)已经成为一种很有前途的新疗法最初的临床试验表明，25戈伊的单次剂量 对心脏的电离辐射与VT负荷减少99.9%以上相关， 减少持续了至少12个月。重要的是，在几个独立的学术医院的研究， 现在证明了RT治疗室性心动过速的有效性。尽管取得了这些令人鼓舞的成果， 高剂量辐射降低VT的精确机制尚不清楚。据推测，25 对心脏致瘤区域的灰色辐射导致晚期纤维化，从而防止再进入， 类似于由热导管消融产生的疤痕。然而，来自SBRT患者心脏移植的组织学数据- 治疗的患者表明，纤维化本身不能解释所观察到的临床效应的大小 （未发表）。相反，我们的初步数据表明，对心脏的辐射会导致心脏功能的变化。 电子衬底，可以防止再入和减少VT。我们假设对心脏的电离辐射 导致心脏基因表达和电生理学的变化。拟议的研究将描述关键的 电离辐射影响心脏传导的分子和细胞信号机制。的 以下具体目标将（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，以及（3）将生物学转化为 从动物模型到人类的见解，通过分析来自RT治疗的血清衍生生物标志物， 患者确定辐射对电基底的急性效应有望促进临床 这一有前途的新的抗心律失常治疗的实施和推进心脏放射生物学领域。

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SBRT- treated patients suggests that fibrosis alone cannot account for the magnitude of the observed clinical effect (unpublished).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.