The Blueprint of Neurocardiac Crosstalk in Arrhythmic Syndromes

Inherited arrhythmogenic syndromes encompass a spectrum of genetic cardiac disorders unified by heightened vulnerability to sympathetic stimulation and risk of sudden cardiac death. Traditionally categorized as either functional (e.g. catecholaminergic polymorphic ventricular tachycardia, CPVT) or structural (e.g. arrhythmogenic cardiomyopathy, ACM), these syndromes are increasingly recognized to share a common reliance on neuro-cardiac signalling. In this review, we examine CPVT and ACM as representative extremes of the functional–structural continuum, highlighting how sympathetic activation acts not only as an acute arrhythmic trigger but also as a chronic driver of disease progression. We dissect the roles of β-adrenergic signalling, Neuropeptide Y (NPY), and regional innervation patterns in shaping myocardial excitability, remodelling, and arrhythmogenesis. While CPVT exemplifies a trigger-dependent, Ca 2+ -driven arrhythmia in structurally normal hearts, ACM demonstrates a substrate-amplified phenotype involving maladaptive autonomic remodelling and neurogenic fibrofatty infiltration. We discuss the emerging relevance of neuro-modulatory and peptidergic therapies—including β-blockade, left cardiac sympathetic denervation, and NPY antagonism—and propose an integrated framework for arrhythmia classification and management based on autonomic mechanisms. By reframing inherited arrhythmias as disorders of integrated neural and myocardial physiology, we highlight new opportunities for mechanistic insight, biomarker development, patient stratification, and translational therapy.