Cardiac sympathetic neurons: victims and culprits in arrhythmogenic cardiomyopathy

Background Arrhythmogenic Cardiomyopathy (ACM) is a genetic disorder leading to stress-induced arrhythmic sudden death, mainly in young and athletic individuals. While ACM has been traditionally attributed to cardiomyocyte desmosomal defects, the frequent link between sympathetic activation and arrhythmias suggests a broader multicellular pathogenesis. Methods We investigated cardiac sympathetic neuron (SN) involvement in ACM using two murine models (Dsg2mut/mut and DspS311A knock-in) and human autoptic hearts. Cardiac innervation was analyzed through immunofluorescence, molecular assays, and multiphoton 3D imaging of optically cleared hearts. Morphological and transcriptomic analyses were performed on SN isolated from neonatal ACM hearts. Pharmacological sympathetic denervation was used to assess causality. Results Both murine and human SN expressed desmosomal proteins and displayed profound, mutation-specific remodeling. Altered sympathetic architecture was evident before myocardial damage. ACM-derived SN exhibited intrinsic defects in axonal growth and varicosity organization even prior to target innervation. In vivo denervation markedly attenuated myocardial remodeling and disease severity. Discussion: Our data identify SN as both victims and contributors in ACM, unveiling early neuro-cardiac alterations as a hallmark of disease. Targeting sympathetic signaling emerges as a promising therapeutic avenue to mitigate structural and electrical remodeling in ACM.