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

David M. Zhang, Rachita Navara, Tiankai Yin, Jeffrey Szymanski, Uri Goldsztejn, Camryn Kenkel, Adam Lang, Cedric Mpoy, Catherine E. Lipovsky, Yun Qiao, Stephanie Hicks, Gang Li, Kaitlin M. S. Moore, Carmen Bergom, Buck E. Rogers, Clifford G. Robinson, Phillip S. Cuculich, Julie K. Schwarz and Stacey L. Rentschler ()
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David M. Zhang: Washington University in St. Louis, School of Medicine
Rachita Navara: Washington University in St. Louis, School of Medicine
Tiankai Yin: Washington University in St. Louis, School of Medicine
Jeffrey Szymanski: Washington University in St. Louis, School of Medicine
Uri Goldsztejn: Washington University in St. Louis, School of Medicine
Camryn Kenkel: Washington University in St. Louis, School of Medicine
Adam Lang: Washington University in St. Louis, School of Medicine
Cedric Mpoy: Washington University in St. Louis, School of Medicine
Catherine E. Lipovsky: Washington University in St. Louis, School of Medicine
Yun Qiao: Washington University in St. Louis, School of Medicine
Stephanie Hicks: Washington University in St. Louis, School of Medicine
Gang Li: Washington University in St. Louis, School of Medicine
Kaitlin M. S. Moore: Washington University in St. Louis, School of Medicine
Carmen Bergom: Washington University in St. Louis, School of Medicine
Buck E. Rogers: Washington University in St. Louis, School of Medicine
Clifford G. Robinson: Washington University in St. Louis, School of Medicine
Phillip S. Cuculich: Washington University in St. Louis, School of Medicine
Julie K. Schwarz: Washington University in St. Louis, School of Medicine
Stacey L. Rentschler: Washington University in St. Louis, School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25730-0

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