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; Stacey L. Rentschler

doi:10.1038/s41467-021-25730-0

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, Stacey L. Rentschler

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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 Na_V1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to Na_V1.5 upregulation after RT. Clinically, RT was associated with increased Na_V1.5 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.

Original language	English
Article number	5558
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25730-0
State	Published - Dec 1 2021

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Zhang, D. M., Navara, R., Yin, T., Szymanski, J., Goldsztejn, U., Kenkel, C., Lang, A., Mpoy, C., Lipovsky, C. E., Qiao, Y., Hicks, S., Li, G., Moore, K. M. S., Bergom, C., Rogers, B. E., Robinson, C. G., Cuculich, P. S., Schwarz, J. K., & Rentschler, S. L. (2021). Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis. Nature communications, 12(1), [5558]. https://doi.org/10.1038/s41467-021-25730-0

@article{d104e0bd8430494586b1026f9be5d7bb,

title = "Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis",

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.",

author = "Zhang, {David M.} and Rachita Navara and Tiankai Yin and Jeffrey Szymanski and Uri Goldsztejn and Camryn Kenkel and Adam Lang and Cedric Mpoy and Lipovsky, {Catherine E.} and Yun Qiao and Stephanie Hicks and Gang Li and Moore, {Kaitlin M.S.} and Carmen Bergom and Rogers, {Buck E.} and Robinson, {Clifford G.} and Cuculich, {Phillip S.} and Schwarz, {Julie K.} and Rentschler, {Stacey L.}",

note = "Funding Information: This work was supported by NIH grant numbers T32 HL134635 (D.M.Z.), T32 GM07200 (D.M.Z.), R01 HL130212 (S.L.R.), UH3 HL141800 (S.L.R.), and S10 OD020136. This study received seed funding from the Department of Radiation Oncology, Cancer Biology Division, at Washington University (J.K.S. and S.L.R.). Dr. Schwarz holds a Female Investigator Award from the AACR-Bristol Meyers Squibb and funding from the Radiological Society of North America. 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. The authors would like to thank Dr. Yoram Rudy for providing valuable feedback during the study. We thank Carla Weinheimer at the Washington University Mouse Cardiovascular Phenotyping Core for performing surgical ligation procedures. We also thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for RNA sequencing and assistance in genomic analysis. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-25730-0",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

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Zhang, DM, Navara, R, Yin, T, Szymanski, J, Goldsztejn, U, Kenkel, C, Lang, A, Mpoy, C, Lipovsky, CE, Qiao, Y, Hicks, S, Li, G, Moore, KMS, Bergom, C , Rogers, BE , Robinson, CG , Cuculich, PS , Schwarz, JK & Rentschler, SL 2021, 'Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis', Nature communications, vol. 12, no. 1, 5558. https://doi.org/10.1038/s41467-021-25730-0

TY - JOUR

T1 - Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis

AU - Zhang, David M.

AU - Navara, Rachita

AU - Yin, Tiankai

AU - Szymanski, Jeffrey

AU - Goldsztejn, Uri

AU - Kenkel, Camryn

AU - Lang, Adam

AU - Mpoy, Cedric

AU - Lipovsky, Catherine E.

AU - Qiao, Yun

AU - Hicks, Stephanie

AU - Li, Gang

AU - Moore, Kaitlin M.S.

AU - Bergom, Carmen

AU - Rogers, Buck E.

AU - Robinson, Clifford G.

AU - Cuculich, Phillip S.

AU - Schwarz, Julie K.

AU - Rentschler, Stacey L.

N1 - Funding Information: This work was supported by NIH grant numbers T32 HL134635 (D.M.Z.), T32 GM07200 (D.M.Z.), R01 HL130212 (S.L.R.), UH3 HL141800 (S.L.R.), and S10 OD020136. This study received seed funding from the Department of Radiation Oncology, Cancer Biology Division, at Washington University (J.K.S. and S.L.R.). Dr. Schwarz holds a Female Investigator Award from the AACR-Bristol Meyers Squibb and funding from the Radiological Society of North America. 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. The authors would like to thank Dr. Yoram Rudy for providing valuable feedback during the study. We thank Carla Weinheimer at the Washington University Mouse Cardiovascular Phenotyping Core for performing surgical ligation procedures. We also thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for RNA sequencing and assistance in genomic analysis. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-021-25730-0

DO - 10.1038/s41467-021-25730-0

M3 - Article

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SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5558

ER -

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

Abstract

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