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

Nat Commun. 2021 Sep 24;12(1):5558. doi: 10.1038/s41467-021-25730-0.


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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / physiology
  • Action Potentials / radiation effects
  • Animals
  • Connexin 43 / genetics*
  • Connexin 43 / metabolism
  • Dose-Response Relationship, Radiation
  • Electrocardiography
  • Endomyocardial Fibrosis
  • Female
  • Gene Expression Regulation
  • Heart / physiopathology
  • Heart / radiation effects*
  • Heart Conduction System / physiopathology
  • Heart Conduction System / radiation effects*
  • Heart Rate / physiology
  • Heart Rate / radiation effects
  • Humans
  • Male
  • Mice
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Signal Transduction
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / physiopathology
  • Tachycardia, Ventricular / radiotherapy*


  • Connexin 43
  • GJA1 protein, human
  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human