Long QT Syndromes and Torsades de Pointes

Definition and Causes

Long QT syndrome (LQTS) is a cardiac conduction disorder characterized by prolongation of the QT interval and an association with a specific polymorphic VT termed torsades de pointes (TdP). The unifying mechanism of this heterogenous disease is prolongation of repolarization with early after depolarizations (EADs), which, on reaching a threshold, trigger events such as ventricular arrhythmias. These can be self-terminating or progress to ventricular fibrillation (VF) and sudden cardiac death (SCD).

LQTS may be congenital (c-LQTS) or acquired (a-LQTS). A proportion of a-LQTS cases are patients with latent genetic mutations that reduce the “repolarization reserve,” without meeting the diagnostic criteria for c-LQTS. The autosomal recessive Jervell Lange-Nielsen syndrome, associated with sensorineural hearing loss, was the first c-LQTS to be described followed by the autosomal dominant Romano-Ward syndrome. A multitude of mutations have since been identified, producing 13 subtypes of c-LQTS. LQT 1, LQT2, and LQT3 account for more than 92% of genetically confirmed cases.

The putative mechanism of drug-induced LQTS is inhibition of the potassium channel encoded by the KCNH2/HERG gene. Flow through this ion channel produces the rapidly acting outward-rectifying potassium current (IKr), responsible for phase 3 of the cardiac action potential. Dysfunction results in prolongation of repolarization, manifesting as prolonged QTc. Genetic mutations of KCNH2 cause LQT2 and may share causative mechanisms. It is worth noting that many drugs block IKr and do not produce TdP.

LQT1 is caused by a genetic mutation in KVLQT1, which encodes a protein component of the slow delayed rectifier potassium current (IKs). These patients comprise 30% to 35% of c-LQTS and are sensitive to sympathetic stimulation, on which they will display prolongation of QTc. This can be used for diagnostic purposes. Beta-blockade and sympathectomy in this group is particularly beneficial.

Prolonged repolarization can also be caused by inappropriate inward sodium current, as is the case in LQT3, where genetic mutations of SCN5A cause impaired inactivation of sodium channels.

The triggers for TdP in LQT1 are catecholamine mediated, whereas in LQT3 and a-LQTS slow heart rates, bradyarrhythmias, and pauses that follow premature extrasystoles can trigger TdP (“pause dependent”). Indeed, TdP and SCD occur mostly during sleep in LQT3. In such circumstances, increasing the heart rate will reduce the QTc (reverse use-dependence) and can be exploited for therapeutic effect (see Management).

Recognition

Prolonged QT interval on the surface ECG ( Fig. 155.1 ) signifies prolongation of repolarization of the cardiac myocyte. Although it is the hallmark of LQTS, it may be absent at rest. Heterogeneity of repolarization across the ventricles is thought to provide the necessary milieu for EADs and reentrant circuits, causing and sustaining TdP. ECG features of this heterogeneity include increased QT dispersion (QT _max -QT _min ), abnormal T-wave morphology, and T-wave alternans ( Fig. 155.2 ).

The normal QT interval range, corrected for heart rate by Bazett’s formula (QTc = QT interval/ interval), is less than 430 ms for men and 450 ms for women (sex hormone effect), with prolonged accepted as 450 ms and 470 ms, respectively. QTc varies with autonomic state, drugs, and diurnal variation.

The ECG features of TdP are as follows ( Fig. 155.3 ):

• QRS complexes that vary in amplitude and appear to twist around the isoelectric baseline

• Rate between 200 and 250 beats per minute

• Associated with bradycardia and heart block (especially a-LQTS)

These may be brief and well tolerated, or sustained with hemodynamic collapse and degrade to VF.

Risk Assessment