Cardiac α4β2 nicotinic receptors as a therapeutic target for fatal ventricular arrhythmias.

Abstract (English)

BACKGROUND AND AIMS: Fatal ventricular tachyarrhythmias (FVTs) are a major cause of sudden cardiac death globally. Despite their clinical importance, current antiarrhythmic therapies remain constrained by limited efficacy and proarrhythmic risks. Although endogenous cardiac cholinergic signalling contributes to electrophysiological regulation, the therapeutic potential of targeting ventricular α4β2 nicotinic acetylcholine receptors (nAChRs), a pivotal component of this system, for FVT treatment remains to be elucidated. METHODS: A pharmacological screen identified positive allosteric modulators (PAMs) of α4β2 nAChRs as possessing antiarrhythmic properties. Through structure-based design, salvage-1 was developed and its efficacy and safety profile were evaluated in rodent, porcine, and human ex vivo heart models of FVTs. The underlying mechanism was investigated using patch-clamp electrophysiology, high-resolution optical mapping, and molecular dynamics simulations. RESULTS: Pharmacological screening validated the potentiation of α4β2 nAChRs as a promising antiarrhythmic strategy. Structure-guided development yielded salvage-1, a PAM that selectively engages Phe312 and Phe316 on the α4 subunit to stabilize the receptor in an open-channel state. Across rodent, porcine, and human ex vivo heart models of FVTs, salvage-1 consistently prevented arrhythmogenesis and rapidly restored sinus rhythm. Mechanistically, salvage-1 enhanced acetylcholine-gated currents, selectively improved conduction velocity in injured myocardium, and suppressed re-entry, without compromising electrophysiology in healthy tissue. CONCLUSIONS: This study identifies ventricular α4β2 nAChRs as a druggable target for FVTs and introduces salvage-1 as a first-in-class therapeutic candidate, thereby establishing a new direction for the pharmacological therapy of cardiac arrhythmias.