Noninvasive imaging reveals cardiac sympathetic reinnervation in pathologic hearts and suppressed norepinephrine transporter function in healthy hearts after carbon ion irradiation in rabbits.

Abstract

BACKGROUND: Cardiac stereotactic radiation therapy is a potential treatment for refractory ventricular tachycardia. We previously reported that carbon ion irradiation, with a higher dose concentration than x-rays, restored gap junction proteins and denervated excess sympathetic nerves in a rabbit heart model. However, histologic analysis is limited to endpoint evaluations, requiring in vivo functional assessments. OBJECTIVE: This study aimed to evaluate the effects of heavy ion therapy on mitochondrial and sympathetic nerve function in a rabbit model of hypercholesterolemia (HC), showing sympathetic hyperinnervation, using positron emission tomography (PET). METHODS: A high-cholesterol rabbit model was induced (HC, n = 8) and compared with healthy controls (n = 8). After 14 weeks, 4 rabbits per group received 15-Gy carbon ion irradiation targeting the left ventricular wall. Six weeks later, mitochondrial function and nerve function were assessed usingF-FEDAC-PET andF-FMeNER-d2-PET, respectively, in addition to tissue staining. RESULTS: PET analysis showed that 15-Gy carbon ion irradiation slightly restored physiological dispersion inF-FEDAC uptake in HC rabbits, suggesting partial mitochondrial recovery.F-FMeNER-PET revealed restored sympathetic nerve activity, and tyrosine hydroxylase staining confirmed the reinnervation of pathologic nerves. In healthy hearts, nerve fibers remained intact, but the PET data suggested suppressed norepinephrine transporter function. CONCLUSION: PET showed that carbon ion irradiation effectively promoted reverse remodeling in diseased hearts but also affected healthy hearts. This modality can be used to evaluate therapeutic benefits and potential risks, supporting its clinical use for treatment optimization.