Neurocardiac crosstalk in inherited cardiac arrhythmias and cardiomyopathy

Inherited cardiac conditions are a leading cause of sudden cardiac death in young and otherwise healthy patients. They result from mutations in genes that encode proteins with various physiological functions. Despite knowledge of the underlying genetic basis, the disorders remain incompletely understood. There is significant interindividual variability in disease expression amongst patients, and incomplete penetrance amongst mutation carriers, indicating a more complex basis to these disorders. This review first discusses the well-established role of the autonomic nervous system (ANS) in acquired cardiac conditions, and subsequently focuses on several classically considered 'cardiac' conditions in which the ANS is known to play an important role: the inherited channelopathies catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS) and long QT syndrome type 3 (LQT3), as well as an inherited arrhythmogenic cardiomyopathy (ACM). Despite each condition being caused by different genetic mutations, they share a fundamental commonality in that cardiac-modulating neurons (e.g. those of the stellate and intracardiac ganglia) have recently been shown to be affected in addition to cardiomyocytes. Through closer examination of the pathophysiological contribution of a dysfunctional ANS to these conditions, novel avenues for both risk stratification and treatment design are likely to emerge.