Molecular aspects of the congenital and acquired Long QT Syndrome: clinical implications

The Long QT Syndrome (LQTS) is a complex and multi-factorial disorder that predisposes to life-threatening ventricular arrhythmias. Both hereditary and acquired subforms have been identified over the years. Recently, it has become clear that the interaction of multiple acquired and genetic aetiologic factors (e.g. disease modifiers) play an important role in differentiating genotype into a continuous spectrum of clinical or subclinical phenotypes. The genotype-phenotype correlation thereby remains very unpredictable in asymptomatic patients, raising important concerns for clinical practice and also for drug development. Therefore, this review aims at providing a comprehensive overview on LQTS highlighting the molecular mechanisms of arrhythmogenesis involved in both the hereditary and the acquired subtypes of the disorder. From this perspective this manuscript then focuses on how the genotype translates into phenotype. A logical overview is provided with the multitude of hereditary and acquired factors that are involved and of the complexity of the interactions that ultimately result in the heterogeneous expressivity and the unpredictability of the phenotype. Based on recent basic and clinical data this review further aims at providing an update on the clinical properties and management of LQT patients including diagnostic work-up and therapy.