SCN10A as a Key Modulator of Cardiac Autonomic Dysfunction in POTS

Postural Orthostatic Tachycardia Syndrome (POTS) is a complex disorder characterized by an
exaggerated heart rate increase upon standing, often accompanied by arrhythmias, suggesting broad
cardiac conduction and autonomic dysfunction. While POTS is linked to sympathetic nervous system
hyperactivity, emerging evidence highlights parasympathetic nervous system involvement, pointing
to a breakdown in autonomic balance. Our research focuses on Nav1.8, a voltage-gated Na+ channel
encoded by SCN10A, which is increasingly recognized as a key player in cardiac and autonomic
excitability. We hypothesize that the Nav1.8p.R14L gain-of-function mutation found in patients
disrupts cardiac conduction and alters the interplay between sympathetic and parasympathetic
regulation. To investigate this, we will employ new animal models to map Nav1.8 expression, assess
excitability in cardiomyocytes and autonomic neurons, and evaluate whole-heart function via
electrophysiology, optical mapping, telemetry, and vagus nerve stimulation. Furthermore, we will
examine whether immune activation triggers or exacerbates POTS-like symptoms. While
Nav1.8p.R14L serves as an exemplar, other Nav channel variants and excitability-related proteins
may converge on a shared mechanism in POTS pathology. By elucidating the role of Nav1.8 in
autonomic dysregulation, this study will provide crucial mechanistic insights into POTS
pathophysiology, laying the groundwork for future diagnostic and therapeutic advancements