Gene

Electrical conduction system of the heart

QRS complex

Internal medicine

Downregulation and upregulation

Refractory (planetary science)

Cell

Cardiology

Ventricular tachycardia

Cardiac fibrosis

Heart failure

Atrial fibrillation

Electrocardiography

Tachycardia

Fibrosis

Cardiac arrhythmia

Radiation therapy

Genetics

Biochemistry

Refractory period

Medicine

Reprogramming

Biology

Astrobiology

Nature Communications

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 V 1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to Na V 1.5 upregulation after RT. Clinically, RT was associated with increased Na V 1.5 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.

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