Elsevier

The Lancet

Volume 372, Issue 9640, 30 August–5 September 2008, Pages 750-763
The Lancet

Seminar
The QT syndromes: long and short

https://doi.org/10.1016/S0140-6736(08)61307-0Get rights and content

Summary

This Seminar presents the most recent information about the congenital long and short QT syndromes, emphasising the varied genotype-phenotype association in the ten different long QT syndromes and the five different short QT syndromes. Although uncommon, these syndromes serve as a Rosetta stone for the understanding of inherited ion-channel disorders leading to life-threatening cardiac arrhythmias. Ionic abnormal changes mainly affecting K+, Na+, or Ca2+ currents, which either prolong or shorten ventricular repolarisation, can create a substrate of electrophysiological heterogeneity that predisposes to the development of ventricular tachyarrhythmias and sudden death. The understanding of the genetic basis of the syndromes is hoped to lead to genetic therapy that can restore repolarisation. Presently, symptomatic individuals are generally best treated with an implantable cardioverter defibrillator. Clinicians should be aware of these syndromes and realise that drugs, ischaemia, exercise, and emotions can precipitate sudden death in susceptible individuals.

Introduction

Inherited long QT syndrome (LQTS) is characterised by a prolonged QT interval in the electrocardiogram (ECG), syncope, and sudden cardiac death due to ventricular tachyarrhythmias, typically torsades de pointes.1 Although LQTS was initially described as a rare inherited disease, many patients have been identified since then and the mechanisms responsible for tachyarrhythmias are common to other sudden death syndromes.1, 2 Because torsades de pointes can cause seizures due to cerebral anoxia, LQTS is important to consider in patients with apparent drug-resistant seizure disorders.3

The QT interval indicates the duration of ventricular depolarisation and repolarisation, which is caused by transmembrane flow of ions (eg, inward depolarising currents mainly through Na+ and Ca2+ channels, and outward repolarising currents mainly through K+ channels). Such cellular activity is called an action potential (figure 1). Until the early 1990s, dominant activity in the left cardiac sympathetic nerve was thought to be responsible for LQTS. However, abnormal cardiac repolarisation induced by K+ channel blockers have caused acquired LQTS with QT interval prolongation, early afterdepolarisations, and frequent torsades de pointes,1, 2 indicating that a reduced net repolarising current could be a possible mechanism for congenital LQTS.

The genetic causes of the LQTS were established when mutations in proteins forming Na+ and K+ channels were shown to delay repolarisation and cause LQTS (table 1).4, 5, 6 Since then, many mutations in cardiac ion channels and membrane proteins have been reported, classifying LQTS into at least ten subtypes. Importantly, phenotype does not always follow genotype. Mutations in these same cardiac ion channels also cause other disease phenotypes: Na+ channel mutations in type 3 LQTS (LQT3) have a role in idiopathic ventricular fibrillation, Brugada syndrome, and progressive cardiac conduction disease.5, 7 K+ channel mutations can delay repolarisation (LQTS),4, 6 lead to Andersen-Tawil syndrome (ATS1 or LQT7),8 speed up repolarisation (short QT syndrome [SQTS]),9, 10, 11 or trigger atrial fibrillation.7 Abnormal changes in intracellular Ca2+ handling can cause LQT8,12 Brugada syndrome, SQTS,13 catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy.7 Some patients carrying LQTS-related gene mutations—eg, in the slow component of delayed rectifier K+ channels—can actually have a normal QT, but can also have reduced repolarisation reserve and raised risks of tachyarrhythmia and sudden cardiac death.7, 14, 15 Other patients with LQTS phenotypes may have no identifiable LQTS-related gene mutation, but can have acquired LQTS resulting from similar abnormal changes in ion currents.16, 17, 18

Mutations of ion channels that induce LQTS also cause sudden infant death syndrome.19, 20 In 201 cases of sudden infant death syndrome, 26 had the same ion-channel mutations as in LQTS: SCN5A (50%), KCNH2 (19%), KCNQ1 (15%), CAV3 (11%), and KCNE2 (4%).20 Thus, a molecular autopsy can be useful to help explain some sudden deaths in very young patients.21 Although dysfunctional ion channels are regarded as the primary cause of LQTS, sympathetic nerve function is an important modulator of the disorder and can further delay repolarisation, induce early afterdepolarisations, and trigger sudden arrhythmic death in patients with LQTS.2, 22

Section snippets

QT interval

Although the current classifications of LQTS are genetically based, the most important clinical characteristic is still QT-interval prolongation,1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 which may establish the prognosis of patients with LQTS, especially those with LQT1 and LQT2.14, 15, 22 Both the severity of ion-channel dysfunction and sites of mutation affect the QT interval.25, 26 Transmembrane mutations of ion channels, especially at the pore region, and mutations that cause

Arrhythmia triggers in LQTS

Both exercise (especially swimming) and emotional stress (sudden loud noise, anger) can trigger syncope in patients with LQTS, possibly via an increase in catecholamine concentrations.1, 2, 22 In healthy individuals, acute sympathetic stimulation increases inward Ca2+ currents, shortens the RR interval, and initially prolongs and then shortens the QT interval by activating the delayed rectifier K+ current (slow component, IKs).42, 47 In LQT1, IKs dysfunction prevents QT abbreviation after

Torsades de pointes and polymorphic ventricular tachycardia in LQTS

Torsades de pointes is a form of polymorphic ventricular tachycardia with characteristic beat-by-beat changes (twisting around the baseline) in the QRS complex and occurs frequently in LQTS (figure 6).53 Although torsades de pointes usually terminates within seconds, it can recur repeatedly, cause faintness or syncope, and degenerate into ventricular fibrillation, resulting in sudden death. Torsades de pointes is often preceded by frequent premature ventricular complexes as a bigeminal rhythm.

Clinical diagnosis of LQTS

Criteria to diagnose long QT syndrome consist of ECG findings, clinical histories, and family histories (table 2).56 Sex-based QTc interval prolongation and other ECG events such as specific T-wave configurations and torsades de pointes help detect typical patients, but not those with latent forms (ie, who have gene mutations but with a normal QT interval). Therefore, new QT-interval criteria have been proposed to screen relatives of patients with LQTS (male relatives QTc≥430 ms, female

Risk stratification of LQTS

High-risk patients with LQTS usually have QTc intervals of at least 500 ms, and can also show T-wave alternans and torsades de pointes. Cardiac arrest survivors and patients with recurrent syncope despite β-blocker treatment usually receive implantation of cardioverter defibrillators.59, 60

Risk stratification can change with age; children younger than 10 years, with 2:1 atrioventricular block, and of male sex (especially in LQT1) are recognised to have high-risk signs.61, 62 Severe channel

Ion currents, clinical manifestations, genetic factors, and specific treatment in genotypes associated with LQTS

Current therapeutic options for patients with LQTS are β-adrenergic blockers, implantable cardioverter defibrillators, and left cardiac sympathetic denervation.14, 60 Gene-specific treatments have been investigated in small numbers of patients7 and could lead to future clinical applications because three-quarters of these patients with LQTS phenotype have been carriers of a specific gene mutation.70, 71

Conclusions

The early hypothesis of sympathetic imbalance as a cause of LQTS has been replaced by several complex genetic and clinical variations of prolonged (or shortened) ventricular repolarisation, all with a common clinical endpoint. Understanding of the syndromes will continue to reveal a wide range of genotype-phenotype relations. The ultimate goal—genetic treatment—seems frustratingly distant, but the exercise has enabled us to begin to understand basic cell machinery that can cause or prevent

Search strategy and selection criteria

Literature review was completed by use of the National Library of Medicine database (from 1965 to current). In addition, we relied heavily on our own published and unpublished papers. We searched mostly publications in English language.

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