The long QT syndrome: ion channel diseases of the heart

Abstract

Once limited to discussions of the Jervell and Lange-Nielsen syndrome and Romano-Ward syndrome, the long QT syndrome (LQTS) is now understood to be a collection of genetically distinct arrhythmogenic cardiovascular disorders resulting from mutations in fundamental cardiac ion channels that orchestrate the action potential of the human heart. Our understanding of this genetic "channelopathy" has increased dramatically from electrocardiographic depictions of marked QT interval prolongation and torsades de pointes and clinical descriptions of people experiencing syncope and sudden death to molecular revelations in the 1990s of perturbed ion channel genes. More than 35 mutations in four cardiac ion channel genes--KVLQT1 (voltage-gated K channel gene causing one of the autosomal dominant forms of LQTS) (LQT1), HERG (human ether-a-go-go related gene.) (LQT2), SCN5A (LQT3), and KCNE1 (minK, LQT5)--have been identified in LQTS. These genes encode ion channels responsible for three of the fundamental ionic currents in the cardiac action potential. These exciting molecular break-throughs have provided new opportunities for translational research with investigations into genotype-phenotype correlations and gene-targeted therapies.