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. 2025 Dec 17:S2405-500X(25)00923-5.
doi: 10.1016/j.jacep.2025.10.034. Online ahead of print.

Low-Dose Cardiac Radiation Improves Electrical Function and Reduces Ventricular Arrhythmogenesis in Mice With Nonischemic Cardiomyopathy

Devaki A Abhyankar  1 , Marissa R Pennino  2 , Lauren N Pedersen  3 , Felicia Grogan  3 , Amanda Klass  3 , Carla Valenzuela Ripoll  4 , Sherwin Ng  4 , Zhen Guo  5 , Hamidreza Hajirezaei  4 , Stacey L Rentschler  6 , Clifford G Robinson  3 , Phillip S Cuculich  7 , Joel D Schilling  8 , Carmen Bergom  3 , Ali Javaheri  9 , Olujimi A Ajijola  10
Affiliations

Low-Dose Cardiac Radiation Improves Electrical Function and Reduces Ventricular Arrhythmogenesis in Mice With Nonischemic Cardiomyopathy

Devaki A Abhyankar et al. JACC Clin Electrophysiol. .

Abstract

Background: Clinical cardiac radiation therapy (RT-25 Gy) decreases ventricular tachycardia (VT). Nonischemic cardiomyopathy (NICM) murine studies showed improved left ventricular (LV) ejection fraction (LVEF) with low-dose RT (LDRT-5 Gy), attributed to a decrease in macrophages. However, whether LDRT reduces VT remains unknown.

Objectives: The goal of this study was to investigate the effects of LDRT on VT in NICM mice.

Methods: NICM was modeled by using long-chain acyl-CoA synthetase-1 (ACSL1TG) mice. Post LDRT or sham treatment, ACSL1TG mice underwent echocardiography, epicardial mapping to assess electrical properties, and norepinephrine injection to examine ventricular arrhythmias (VA). Heart tissue was collected to assess LV sympathetic innervation. To investigate the role of macrophages, macrophages in ACSL1TG mice were depleted with anti-colony stimulating factor-1 receptor (CSF1R) antibody or vehicle treatment. LVEF, electrical properties, VA, and sympathetic innervation were measured in terminal studies as previously described.

Results: NICM mice treated with LDRT exhibited higher LVEF and lower VA. LDRT resulted in faster conduction velocity and lower activation time. LDRT mice exhibited greater sympathetic nerve density and reduced innervation heterogeneity. CSF1R mice exhibited greater LVEF. No differences were observed in VA, conduction velocity, or activation time in CSF1R mice vs vehicle-treated mice. CSF1R mice had greater nerve density, although they presented no differences in innervation heterogeneity.

Conclusions: In NICM mice, LDRT improved LV function and reduced spontaneous VA correlated with improved sympathetic nerve distribution, a known risk factor for VT. Decreasing macrophage abundance did not recapitulate the effects of LDRT on VA. Further studies are needed to validate these findings and explore antiarrhythmic mechanisms of LDRT.

Keywords: cardiac radiation therapy; cardiac sympathetic innervation; heart failure; ventricular tachycardia.

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Conflict of interest statement

Funding Support and Author Disclosures This work was supported by the National Institutes of Health (NIH) (R01HL162717), a Chan Zuckerberg Science Leadership Award, and a Fondacion Leducq Transatlantic Network Grant (23CVD04) to Dr Ajijola. Ms Abhyankar was supported by a National Science Foundation Graduate Research Fellowship (award DGE-2034835 and DGE-2444110). Dr Javaheri was supported by the National Heart, Lung, and Blood Institute (K08HL138262 and 1R01HL155344), the Children’s Discovery Institute of Washington University (MC-FR-2020-919), and St. Louis Children's Hospital, as well as the Diabetes Research Center at Washington University in St. Louis of the National Institutes of Health under award number P30DK020579 and NIH grant P30DK056341 (Nutrition Obesity Research Center). Dr Bergom was supported by R01HL147884. Drs Robinson and Cuculich were supported by the American Heart Association Collaborative Sciences Award (19CSLOI34630021). The authors acknowledge support from the Department of Radiation Oncology (S10 OD020136-01) at Washington University School of Medicine. Dr Ajijola has received honoraria from Medtronic, J&J Medtech/Biosense Webster, Abbott, and Boston Scientific. Dr Ajijola reports stock in Anumana and nFerence. Dr. Ajijola is a co-founder of Neufera. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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