Cellular consequences of non-ablative radiotherapy: A novel approach to ventricular tachycardias
Abstract
Aims: Radiotherapy (RT) with a single application of ionizing radiation [Stereotactic Arrhythmia Radioablation (STAR)] has been suggested as a non-invasive alternative to radiofrequency in ablating ventricular tachycardia (VT). Emerging data reveal that STAR may suppress VT without substrate destruction by enhancing impulse conduction instead, through increased expression of NaV1.5 channels and connexin 43. The study aims to investigate electrophysiology and intracellular Ca2+ dynamics in cardiomyocytes from mice subjected to in vivo RT. The emerging data led us to evaluate biochemical changes potentially linking electrophysiological response to ionizing irradiation.
Methods and results: Cardiomyocytes isolated 2 weeks after RT with low-dose (15 Gy) or high-dose (25 Gy) were compared to those of sham-treated mice (CTRL). We evaluated: (i) the properties of the transient (INaT) and sustained (INasus) components of INa; (ii) action potential (AP) parameters, including the prevalence of early afterdepolarizations (EADs); (iii) intracellular Ca2+ dynamics; (iv) CaMKII phosphorylation, and (v) reactive oxygen species (ROS) content. 25 Gy RT (i) increased INaT and, to a larger extent, INasus (increased INasus/INaT ratio); (ii) increased AP amplitude, +dV/dtMAX and duration (APD) and facilitated EADs; (iii) depressed intracellular Ca2+ dynamics. 15 Gy RT had similar but smaller effects (dose-dependency). 25 Gy RT reduced CaMKII phosphorylation but increased cell ROS content, thus providing a mechanism for the late component of INa (INaL) enhancement.
Conclusion: The results support the view that STAR may suppress VT by increasing conduction velocity, with APD prolongation providing an additional mechanism. On the other hand, INasus enhancement and Ca2+ handling depression may impair electrical stability and contractility in the irradiated region.
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BibTeX
@article{maniezzi2026cellular,
title = {{Cellular consequences of non-ablative radiotherapy: A novel approach to ventricular tachycardias}},
author = {Claudia Maniezzi and Stefano Busti and Angela S Maione and Elena Sommariva and Chiara Florindi and Francesca Misitano and Ilenia Anzaldi and Francesco P Cammarata and Giusi I Forte and Roberto Catalano and Gaetano M De Ferrari and Francesco Lodola and Antonio Zaza},
journal = {Europace},
year = {2026},
month = oct,
doi = {10.1093/europace/euag282},
url = {https://doi.org/10.1093/europace/euag282},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cellular consequences of non-ablative radiotherapy: A novel approach to ventricular tachycardias
AU - Claudia Maniezzi
AU - Stefano Busti
AU - Angela S Maione
AU - Elena Sommariva
AU - Chiara Florindi
AU - Francesca Misitano
AU - Ilenia Anzaldi
AU - Francesco P Cammarata
AU - Giusi I Forte
AU - Roberto Catalano
AU - Gaetano M De Ferrari
AU - Francesco Lodola
AU - Antonio Zaza
PY - 2026
DA - 2026/10/17
JO - Europace
DO - 10.1093/europace/euag282
UR - https://doi.org/10.1093/europace/euag282
AB - Aims: Radiotherapy (RT) with a single application of ionizing radiation [Stereotactic Arrhythmia Radioablation (STAR)] has been suggested as a non-invasive alternative to radiofrequency in ablating ventricular tachycardia (VT). Emerging data reveal that STAR may suppress VT without substrate destruction by enhancing impulse conduction instead, through increased expression of NaV1.5 channels and connexin 43. The study aims to investigate electrophysiology and intracellular Ca2+ dynamics in cardiomyocytes from mice subjected to in vivo RT. The emerging data led us to evaluate biochemical changes potentially linking electrophysiological response to ionizing irradiation. Methods and results: Cardiomyocytes isolated 2 weeks after RT with low-dose (15 Gy) or high-dose (25 Gy) were compared to those of sham-treated mice (CTRL). We evaluated: (i) the properties of the transient (INaT) and sustained (INasus) components of INa; (ii) action potential (AP) parameters, including the prevalence of early afterdepolarizations (EADs); (iii) intracellular Ca2+ dynamics; (iv) CaMKII phosphorylation, and (v) reactive oxygen species (ROS) content. 25 Gy RT (i) increased INaT and, to a larger extent, INasus (increased INasus/INaT ratio); (ii) increased AP amplitude, +dV/dtMAX and duration (APD) and facilitated EADs; (iii) depressed intracellular Ca2+ dynamics. 15 Gy RT had similar but smaller effects (dose-dependency). 25 Gy RT reduced CaMKII phosphorylation but increased cell ROS content, thus providing a mechanism for the late component of INa (INaL) enhancement. Conclusion: The results support the view that STAR may suppress VT by increasing conduction velocity, with APD prolongation providing an additional mechanism. On the other hand, INasus enhancement and Ca2+ handling depression may impair electrical stability and contractility in the irradiated region.
SN - 1099-5129
SN - 1532-2092
ER -