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 In addition, we relied heavily on our own published and unpublished papers.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.
SeminarThe QT syndromes: long and short
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
References (93)
- et al.
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome
Cell
(1995) - et al.
SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome
Cell
(1995) - et al.
Gene-specific therapy for inherited arrhythmogenic diseases
Pharmacol Ther
(2006) - et al.
Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome
Cell
(2001) - et al.
Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism
Cell
(2004) - et al.
Anti-KCNH2 antibody-induced long QT syndrome: novel acquired form of LQT syndrome
J Am Coll Cardiol
(2007) - et al.
Postmortem long QT syndrome genetic testing for sudden unexplained death in the young
J Am Coll Cardiol
(2007) - et al.
Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations
J Am Coll Cardiol
(2004) - et al.
Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects
J Am Coll Cardiol
(1999) - et al.
Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1
J Am Coll Cardiol
(1998)
Significance of QT dispersion in the long QT syndrome
Prog Cardiovasc Dis
T wave alternans in idiopathic long QT syndrome
J Am Coll Cardiol
Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome
Heart Rhythm
Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome
J Am Coll Cardiol
KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes
Am J Hum Genet
Long QT syndrome and pregnancy
J Am Coll Cardiol
Mode of onset of torsade de pointes in congenital long QT syndrome
J Am Coll Cardiol
Influence of the autonomic nervous system on the Q-T interval in man
Am J Cardiol
Long QT syndrome in children in the era of implantable defibrillators
J Am Coll Cardiol
Corrected QT variability in serial electrocardiograms in long QT syndrome: the importance of the maximum corrected QT for risk stratification
J Am Coll Cardiol
Long QT syndrome in adults
J Am Coll Cardiol
Modulating effects of age and gender on the clinical course of long QT syndrome by genotype
J Am Coll Cardiol
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long Qt syndrome genetic testing
Heart Rhythm
Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects
Heart Rhythm
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia
Cell
Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3
Heart Rhythm
Comparison of QT intervals of patients with idiopathic ventricular fibrillation and healthy controls
Heart Rhythm
The long QT syndrome
The long QT interval syndrome. A rosetta stone for sympathetic related ventricular tachyarrhythmias
Circulation
Long QT syndrome presenting as epileptic seizures in an adult
Emerg Med J
Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias
Nat Genet
Mutation in the KCNQ1 gene leading to the short QT-interval syndrome
Circulation
Sudden death associated with short-QT syndrome linked to mutations in HERG
Circulation
A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene
Circ Res
Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death
Circulation
Association of long QT syndrome loci and cardiac events among patients treated with β-blockers
JAMA
Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice
JAMA
KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome
Circulation
Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients
J Mol Med
Prolongation of the QT interval and the sudden infant death syndrome
N Engl J Med
Prevalence of long-QT syndrome gene variants in sudden infant death syndrome
Circulation
Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias
Circulation
Risk stratification in the long-QT syndrome
N Engl J Med
Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system?
Eur Heart J
Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel
Circulation
Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene
Circulation
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