Background: Inherited arrhythmia syndromes are a leading cause of sudden cardiac death in young and otherwise healthy patients. These are often caused by mutations in genes that encode ion channels or transporters, leading to conditions such as Brugada Syndrome (BrS), Long QT Type 3 (LQT3), and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).
BrS and LQT3 are associated with mutations in SCN5A (encoding sodium channel, Nav1.5), whilst CPVT is caused by mutations in RYR2 (encoding ryanodine receptor 2, RyR2). Investigation into the effects of these mutations have exclusively been performed in cardiac cells. However, these ion channels are also present in neuronal tissue, including intracardiac neurons1 (which modulate cardiac function). Moreover, patients often present with clinical signs of dysfunction of the autonomic nervous system.
Aim: Our novel research line aims to investigate the neuronal phenotype induced by these ion channel mutations, using arrhythmia mouse models to assess functional alterations as well as broader autonomic remodelling. Ultimately, we will assess the contribution of this to arrhythmogenesis.
Results: Using immunohistochemistry approaches, we reveal for the first time that both Nav1.5 and RyR2 are also expressed in mouse stellate ganglia (a crucial autonomic modulator of cardiac function). Current functional investigations, including patch clamp analysis, are aimed at assessing the functional consequences of Scn5a and RyR2 mutations in stellate and intracardiac ganglia in mouse models of BrS, LQT3 and CPVT. These experiments also allow for investigation of the modulatory effects of pharmacological interventions. In addition, autonomic remodelling in stellate/intracardiac ganglia and (ventricular) myocardium is currently being assessed through RNA sequencing, immunohistochemistry in mouse heart cryosections, and whole-heart neuronal imaging. Findings from these investigations will be presented.
Conclusions: All neurons that modulate heart function (stellate ganglion and intracardiac neurons) express Nav1.5 and RYR2. Mouse models of BrS/LQTS/CPVT are employed to investigate the consequences of Scn5a/RyR2 mutations on neuronal (dys)function and their potential role in arrhythmogenesis.