Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis

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Abstract
Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT. Clinically, RT was associated with increased NaV1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (T32 HL134635, R01 HL130212, UH3 HL141800)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (T32 GM07200)
  • U.S. Department of Health & Human Services | NIH | NIH Office of the Director (S10 OD020136)
  • Dr. Schwarz holds a Female Investigator Award from the AACR-Bristol Meyers Squibb and funding from the Radiological Society of North America.
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
  • U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
  • Dr. Rentschler holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and funding from The Foundation for Barnes-Jewish Hospital that directly supported this work.

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