Kv1.5 Inhibition in Atrial Fibrillation: Molecular Mechanisms, Translational Challenges, and Implications for Equitable Rhythm Control

ABSTRACT: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a growing source of cardiovascular morbidity, stroke, heart failure, and death. Current pharmacologic rhythm-control strategies rely predominantly on antiarrhythmic agents with significant ventricular proarrhythmia risk and systemic toxicity, limiting their use in medically complex and underserved patient populations. The Kv1.5 channel, encoded by KCNA5, generates the atrial-selective ultrarapid delayed rectifier current (I_Kur) and has long been considered a promising target for safer rhythm control. This review focuses on the molecular biology of Kv1.5, including its regulation by auxiliary Kvβ1.2 subunits, redox signaling, oxidative stress, and extra-atrial vascular roles, and examines the preclinical and clinical evidence for Kv1.5-targeted therapy. We analyzed why selective I_Kur inhibitors, including XEN-D0103 and MK-0448, have failed to translate into effective antiarrhythmic therapy, with particular attention to the role of atrial electrical remodeling and reduced I_Kur density in established AF. We also review the limitations of existing class III and class Ic antiarrhythmic agents and discuss how genetic variation in KCNA5 across ethnic populations may inform more precise and equitable approaches to rhythm control. Together, these findings highlight the promise of Kv1.5 as an atrial-selective target and the major barriers limiting its clinical translation in AF.