Genomics of the Drug-Induced Long-QT syndrome

The QT interval is a readily measured parameter on the surface electrocardiogram (ECG). It represents the time from the onset of ventricular depolarization to the end of ventricular repolarization, and is therefore a rough indicator of the duration of action potentials in individual ventricular cells (Figure 13.1). Marked prolongation of the QT interval on the surface ECG necessarily indicates prolongation of at least some action potentials within the ventricle (Figure 13.1). While there is some evidence that QT-interval prolongation can be antiarrhythmic, the change may also signal susceptibility to a mechanistically and morphologically distinct polymorphic ventricular tachycardia, torsades de pointes (TdP) (Figure 13.2, left). A History of Torsades de Pointes In 1957, Jervell and Lange-Nielsen described a kindred with a high incidence of sudden death in childhood (4 of 6 children) with marked prolongation of the QT interval and congenital deafness in affected subjects. The parents were unaffected, so the assumption, which proved correct, was that the Jervell-Lange-Nielsen syndrome represented an autosomal recessive disorder. In the early 1960s, two groups independently reported autosomal dominant transmission of a syndrome of QT prolongation, normal hearing, and episodes of syncope and sudden death (the Romano-Ward syndrome). Interestingly, the initial descriptions of these syndromes did not identify ventricular arrhythmia as the mechanism of death.