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

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, histological 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 hypercholesteremia, showing sympathetic hyperinnervation, using positron emission tomography (PET). Methods A high-cholesterol rabbit model was induced (HC, n=8) and compared with healthy controls (Cont, n=8). After 14 weeks, four rabbits per group received 15 Gy carbon ion irradiation targeting the left ventricular wall. Six weeks later, mitochondrial function and nerve function were assessed using 18 F-FEDAC-PET and 18 F-FMeNER-d2-PET, respectively, in addition to tissue staining. Results PET analysis showed that 15 Gy carbon ion irradiation slightly restored physiological dispersion in 18 F-FEDAC uptake in HC rabbits, suggesting partial mitochondrial recovery. 18 F-FMeNER-PET revealed restored sympathetic nerve activity, and tyrosine hydroxylase staining confirmed the reinnervation of pathological nerves. In healthy hearts, nerve fibers remained intact, but the PET data suggested suppressed norepinephrine transporter function. Conclusion PET showed that carbon ion irradiation promoted reverse remodeling in diseased hearts but also affected healthy hearts. PET can be used evaluate therapeutic benefits and potential risks, supporting its clinical use for treatment optimization.