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.

Impact of High-Dose Irradiation on Human iPSC-Derived Cardiomyocytes Using Multi-Electrode Arrays: Implications for the Antiarrhythmic Effects of Cardiac Radioablation

“…SBRT is an emerging therapeutic option for patients with refractory VA [ 5 ]. Although the mechanism of suppressing VA is not fully elucidated, recent researches have suggested possible mechanisms [ 13 , 14 , 15 ]. Radiotherapy-induced fibrotic remodeling and increased CV are presumed to prevent re-entry of cardiac impulses [ 13 , 14 , 15 ].…”

“…Although the mechanism of suppressing VA is not fully elucidated, recent researches have suggested possible mechanisms [ 13 , 14 , 15 ]. Radiotherapy-induced fibrotic remodeling and increased CV are presumed to prevent re-entry of cardiac impulses [ 13 , 14 , 15 ]. However, conducted studies have observed changes over days to months [ 13 , 14 , 15 ].…”

“…Radiotherapy-induced fibrotic remodeling and increased CV are presumed to prevent re-entry of cardiac impulses [ 13 , 14 , 15 ]. However, conducted studies have observed changes over days to months [ 13 , 14 , 15 ]. Moreover, it takes several months for fibrosis to occur, which is not enough to explain the immediate antiarrhythmic effect of radioablation.…”

“…Recently, the mechanism of cardiac radiotherapy was suggested as electrical conduction reprogramming. Ionizing radiation to the heart can increase the levels of cardiac conduction proteins, such as Cx43 and Na V 1.5, and enhance ventricular conduction [ 15 ]. Other previous studies reported lateralization and elevation of Cx43 expression after carbon radiation to the heart [ 33 , 34 , 35 ].…”

Cardiac stereotactic ablative radiotherapy for control of refractory ventricular tachycardia: initial UK multicentre experience

“…34 However, any perturbation of myocardial conduction whether increase or decrease may be sufficient to prevent re-entrant VT and most recent data again points to a 'supraphysiologic' phenotype induced by radiation. 35 The acute and late side effects of radiotherapy also need consideration, including those affecting the heart itself. We did not perform follow-up imaging apart from echo and did not document any clinically significant acute side effects, but long-term effects including pericardial fibrosis and constriction, or coronary and valve disease are well-documented in cancer survivors and are a concern.…”