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

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 (ACSL1) mice. Post LDRT or sham treatment, ACSL1mice 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 ACSL1mice 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.