Heart failure with reduced ejection fraction (HFrEF) remains a significant cause of morbidity and mortality worldwide, particularly in patients who remain symptomatic despite guideline-directed medical therapy (GDMT). Preliminary data suggest that a single fraction low-dose whole-heart external beam radiotherapy (EBRT) may improve cardiac function by modulating inflammatory and fibrotic processes. This trial aims to evaluate the preliminary efficacy of a single fraction 5 Gy whole-heart EBRT to improve left ventricular ejection fraction (LVEF) in patients with HFrEF on GDMT. Secondary objectives will assess safety, cardiac biomarkers and patient-reported outcomes.

Single-centre, single-arm, prospective interventional trial aiming to enrol 40 patients with HFrEF (LVEF≤35%) on maximal GDMT, New York Heart Association (NYHA) classes II–IV, and stable for ≥6 months prior to enrolment, without recent heart failure admissions or GDMT changes. All participants are required to have cardiac implantable electronic devices. Recruitment will be balanced with 20 patients with ischaemic and 20 with non-ischaemic aetiology. Eligible patients will receive a single fraction of 5 Gy whole-heart EBRT guided by a non-contrast enhanced primary planning CT. Follow-up assessments will be conducted at baseline, 6 weeks, 12 weeks and 6 months. The primary outcome is an improvement in LVEF of ≥5% at 6 months, assessed by transthoracic echocardiography. This is an open-label trial with blinded ascertainment of the primary outcome. Secondary outcomes include acute and late toxicity, overall survival, hospital admission for heart failure, patient-reported quality of life, cardiac biomarkers and device-reported arrhythmia burden.

The trial has been approved by the Ethics Committee Research UZ/KU Leuven, Belgium (S69569). The study results will be shared through peer-reviewed journals and presentations at academic conferences.

NCT06661876.