Mechanistic Basis of Cardiac Irradiation as a Therapy for Ventricular Tachycardia

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SBRT- treated patients suggests that fibrosis alone cannot account for the magnitude of the observed clinical effect (unpublished).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