Congenital Long QT Syndrome: From Conventional Management to Emerging Biological Therapies

Congenital long QT syndrome (LQTS), the first identified cardiac ion channelopathy, is characterized by delayed ventricular repolarization and a prolonged heart rate-corrected QT interval (QTc), conferring an increased risk of malignant ventricular arrhythmias and sudden cardiac death. Current standard-of-care management for LQTS, including beta-blockers, sodium channel blockers, left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillators (ICDs), reduces adverse events and improves survival but primarily mitigates downstream electrophysiological consequences rather than correcting the underlying genetic defects. Rapid advances in molecular biology have driven the development of mechanism-directed strategies such as gene editing, RNA interference (RNAi), and experimental antibody-based interventions, which aim to restore channel function or modulate channel regulation at the source. This review synthesizes current knowledge on LQTS classification and pathogenesis and evaluates both guideline-directed therapies and emerging molecular interventions. We emphasize subtype-specific approaches, highlight the rationale and preclinical progress for gene- and RNA-based therapies, and outline practical considerations for translation, including delivery, durability, and safety. Therefore, this review provides a comprehensive, mechanism-based framework to inform future precision medicine approaches for LQTS.