Congenital Long QT syndrome and torsade de pointes

Abstract

Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD. This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT. This review will discuss the genetic, molecular, and phenotype characteristics of congenital LQTS as well as current management strategies and future directions in the field.

Keywords: cellular electrophysiology; electrophsiology long QT syndrome; genetics; ion channels and membrane transporters; ventricular tachycardia.

Figure 1

Tachycardia‐dependent QT alternans from a newborn baby with the Romano–Ward long QT syndrome (LQTS). The figure illustrates the development of TWA alternans with gradual acceleration of the heart rate. At a cardiac cycle length (CL) of 610 ms (a), the QTU interval was 440–480 ms and TWA alternans was not discernible. Gradual shortening of the CL to 540 ms resulted in TWA alternans that became more prominent at shorter CLs (b and c). In (d), on further shortening of the CL to 420 ms, TWA alternans was markedly exaggerated and was associated with the onset of nonsustained polymorphic ventricular tachycardia (VT) with a twisting QRS morphology characteristic of torsade de pointes (TdP). Panel (e) was recorded at reduced paper speed to illustrate the onset and termination of a longer run of TdP that was also associated with marked TWA alternans at a sinus CL of 420‐440 ms. Reproduced with permission from Habbab MA, El‐Sherif N, Pace 1992;15:916–931

Figure 2

Genotype‐specific T‐wave morphology of the common genotypes: LQT1 is characterized by broad‐based T waves, LQT2 by low amplitude T waves, and LQT3 by late peaking T waves. Reproduced with permission from Moss et al., Circulation 1995;92:2929–2934

Figure 3

Composite figure that illustrates the correlation between the specific molecular changes of the Na channel that result in LQT3, the electrophysiological consequence, and the final phenotype presentation of LQTS. (a) Cell‐attached patch clamp recordings of the Na channel during control and following superfusion with ATXII. This neurotoxin faithfully reproduces the molecular changes associated with the clinical mutations of the Na channel in patients with LQT3. It illustrates sequential recordings of single Na channel current responses during depolarizing steps from −120 to −20 mV from rabbit cardiomyocytes. The left panel shows control recordings and the right panel shows recordings from a patch exposed to 100 nm of ATXII that resulted in long‐lasting bursts consisting of repetitive long opening interrupted by brief closures. The ensemble current from this patch shows markedly slowed relaxation. (b) Action potential recordings from a Purkinje fiber (PF) and a midmyocardial (M) cell, both isolated from a 10‐week‐old puppy and placed in the same chamber perfused with 50 mg/l AP‐A and stimulated at 3000 ms. The PF shows a series of early afterdepolarizations (EADs) that increased gradually in amplitude before final repolarization. (c) Simultaneous recordings from a subepicardial cell (EPI), M cell, and a subendocardial cell (END) from a transmural strip isolated from the left ventricle of a 12‐week‐old puppy and transfused with 50 mg/l AP‐A and stimulated at 4000 ms. AP‐A resulted in marked differential prolongation of the action potential of the M cell resulting in asynchronous activation in the preparation which is a substrate of reentrant excitation. (d) Illustration of cardiac tridimensional activation maps of a 12‐beat run of TdP VT from the in vivo canine surrogate AP‐A model of LQT3; it helps to summarize the final electrophysiological mechanism of the characteristic twisting QRS configuration of the TdP electrocardiogram in the LQTS

Figure 4

Genotype‐ and phenotype‐guided risk classification of long QT syndrome patients: Risk groups have been defined based on the previously published probability of suffering a first or recurrent cardiac event (syncope, seizure, sudden cardiac arrest, or sudden cardiac death) before 40 years of age without appropriate therapeutic interventions. A probability of suffering a first cardiac event >80% defines the extremely high‐risk group, >50% the high‐risk group, between 30% and 49% as the intermediate‐risk group, and below 30% as the low‐risk group. Genotype‐guided recommendations are indicated by purple text, phenotype‐guided recommendations are indicated by orange text, and a combination of genotype‐ and phenotype‐guided recommendations is indicated by black text within the figure. Reprinted from Giudicessi JR, Ackerman MJ, Curr Probl Cardiol, 2013;38:417–455, with permission