Elsevier

Cardiology Clinics

Volume 18, Issue 2, 1 May 2000, Pages 309-325
Cardiology Clinics

LONG QT SYNDROME

https://doi.org/10.1016/S0733-8651(05)70143-0Get rights and content

The long QT syndrome (LQTS) is a disorder of cardiac ion channels that affect repolarization. The characteristic manifestations are prolongation of the QT interval and T-wave abnormalities on the ECG and exercise or emotion precipitation of syncope and sudden death, resulting from the ventricular tachyarrhythmia torsade de pointes (TDP) (Fig. 1). The ion-channel dysfunction may be acquired or inherited. The acquired form is more common, usually caused by administration of QT-prolonging drugs Table 1, Table 2, which for the most part impair the function of the IKr delayed rectifier channel. The inherited form is caused by mutations of genes that encode for cardiac ion channels, principally the IKr and IKs delayed rectifier potassium channels, with a minority of cases caused by mutations of the gene that encodes for the cardiac sodium channel.

Inherited LQTS has become a particularly important entity for several reasons. It is estimated to be present in 1 in 7000 persons in the United States and thus is not a rare disorder. It may cause as many as 3000 unexpected deaths in children and young adults per year. Further, recent discoveries concerning the molecular genetics and pathophysiology of LQTS have provided important insights into the mechanisms of arrhythmias, not only in LQTS but in general. These findings may provide molecular strategies for arrhythmia prevention in some of the estimated 300,000 to 400,000 sudden cardiac deaths100 that occur annually in the United States, including an estimated 7000 to 8000 in young persons.

Section snippets

MOLECULAR GENETICS OF LQTS

Inherited LQTS is an autosomal dominant genetic disorder caused by mutations of genes that encode for cardiac ion channels. Five genes have been discovered as of this time. Four encode for potassium ion channels and one for the cardiac sodium channel. An additional locus has been discovered on chromosome 4, but the gene has not yet been identified. The currently known genes are listed in Table 3.

Over 180 different mutations of the five known genes have been described. LQTS, therefore, shows a

RELATIVE FREQUENCY OF THE LQTS GENOTYPES

In genotyped patients, the KvLQT1 gene is the most common, being found in about 50% of patients. HERG accounts for about 45% of cases. Thus, mutations of the potassium genes KvLQT1 and HERG together cause about 95% of cases. The SCN5A gene accounts for about 3% to 5% of the cases. The MinK and MiRP1 genes each account for 1% or less. The LQT4 genotype is very rare. As noted previously, approximately 50% of families who appear to have LQTS by clinical criteria cannot be genotyped to one of these

CLINICAL GENETICS

Historically, two forms of LQTS have been recognized. Jervell and Lange–Nielsen syndrome is characterized by severe LQTS with a high incidence of sudden death, severe congenital deafness, and autosomal recessive inheritance.26, 27 Romano–Ward syndrome shows autosomal dominant inheritance and normal hearing. The molecular findings have clarified the genetics of Jervell and Lange–Nielsen syndrome and have demonstrated all LQTS to be autosomal dominant, but with reduced penetrance and variable

CLINICAL MANIFESTATIONS

LQTS occurs in all races and ethnic groups, although the relative frequency in each group is as yet unknown, because no systematic screening of different groups has been attempted. The principal symptoms are syncope and sudden death, from TDP (Fig. 1). Most often, TDP is self-terminating and causes a syncopal episode from which the patient quickly recovers. Cardiac arrest occurs if the TDP is more persistent, and sudden death results if the rhythm does not return to normal spontaneously and the

ECG MANIFESTATIONS

The predominant feature is, of course, QT prolongation. The QTc averages 0.49 seconds82, 83, 98 in both LQT1 and LQT2 genotypes. In the modest number of LQT3 patients available for study, the values appear to be somewhat longer, with a mean value around 0.51 seconds.98 The range of QTc intervals extends from about 0.41 seconds to more than 0.60 seconds. Although QT-interval prolongation is the characteristic feature of LQTS, it is not always present. We first demonstrated this finding in 1992

PATHOPHYSIOLOGY

Although the physiologic defects in the different LQTS genotypes are diverse, all cause prolongation of the APD. The APD prolongation renders the myocytes vulnerable to early afterdepolarizations (EADs), which are the initiating mechanism for the TDP arrhythmia. APD prolongation produces a baseline propensity to EADs by activation of L-type Ca++ channels,25 providing the inward depolarizing current necessary for generating the EAD. It would appear, though, that additional physiologic

MANAGEMENT OF LQTS

The gold-standard therapy for LQTS remains β-blocker administration, which is effective in the large majority of patients. Like virtually all treatments, there are treatment failures and partial responders, but it is estimated that β-blocker treatment is effective in 80% to 90% of patients with a significant reduction in rate of sudden death.10, 19, 33, 52, 74, 80, 97 Our long-term follow-up of a number of LQT1 patients suggest that β-blockers are particularly effective in this genotype.77, 79

SUMMARY

In conclusion, much has been learned in the past several years regarding the molecular biology of LQTS, and this information has been directly applicable to the clinical care of patients with this syndrome. The knowledge also has been of considerable importance for understanding the molecular basis of arrhythmias in general and is providing insights into potential molecular-based therapies for arrhythmias.

ACKNOWLEDGMENTS

Sincere appreciation is expressed to Don Atkinson in Dr Mark Keating's laboratory at the University of Utah, who kindly provided the graphic representations of the LQTS gene morphologies, Figs. 3 through 6. Also, great appreciation to Raymond Woosley, MD, PhD, of Georgetown University, who compiled the list of drugs to avoid, shown in Table 1, for the sudden arrhythmia death syndromes (SADS Foundation, Salt Lake City, UT), and to the SADS Foundation for permission to reproduce the list for this

References (100)

  • P.J. Schwartz

    Cardiac sympathetic innervation and the sudden infant death syndrome: A possible pathogenetic link [review]

    Am J Med

    (1976)
  • W. Shimizu et al.

    Effects of verapamil and propranolol on early afterdepolarizations and ventricular arrhythmias induced by epinephrine in congenital long QT syndrome

    J Am Coll Cardiol

    (1995)
  • I. Splawski et al.

    Genomic structure of three long QT syndrome genes: KVLQT1, HERG and KCNE1

    Genomics

    (1998)
  • D.E. Vetter et al.

    Inner ear defects induced by null mutation of the IsK gene

    Neuron

    (1996)
  • G.M. Vincent et al.

    Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome

    Am J Cardiol

    (1991)
  • S. Viskin et al.

    Mode of onset of torsades de pointes in congenital long QT syndrome

    J Am Coll Cardiol

    (1996)
  • Q. Wang et al.

    Genomic organization of the human SCN5A gene encoding the cardiac sodium channel

    Genomics

    (1996)
  • Q. Wang et al.

    SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome

    Cell

    (1995)
  • R.G. Weintraub et al.

    The congenital long QT syndromes in childhood

    J Am Coll Cardiol

    (1990)
  • A.A. Wilde et al.

    Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1)

    J Am Coll Cardiol

    (1999)
  • J.A. Abildskov et al.

    Mechanisms in adrenergic dependent onset of torsades de pointes

    Journal of Chinese Cardiac Pacing and Electrophysiology

    (1997)
  • J.A. Abildskov et al.

    The autonomic nervous system in relation to electrocardiographic waveform and cardiac rhythm

  • C. Antzelevitch et al.

    Regional differences in the electrophysiology of ventricular cells: Physiological and clinical implications

  • J. Barhanin et al.

    KvLQT1 and IsK (minK) proteins associate to form the IKs cardiac potassium current

    Nature

    (1996)
  • P.B. Bennett et al.

    Molecular mechanism for an inherited cardiac arrhythmia

    Nature

    (1996)
  • A.K. Bhandari et al.

    Efficacy of left cardiac sympathectomy in the treatment of patients with the long QT syndrome

    Circulation

    (1984)
  • M. Chinushi et al.

    Nicorandil suppresses a hump on the monophasic action potential and torsades de pointes in a patient with idiopathic long QT syndrome

    Jpn Heart J

    (1995)
  • S.J. Compton et al.

    Genetically defined therapy of inherited long-QT syndrome: Correction of abnormal repolarization by potassium

    Circulation

    (1996)
  • C. Donger et al.

    KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome

    Circulation

    (1997)
  • N. El-Sherif et al.

    The long QT syndrome and torsades de pointes [review]

    Pacing Clin Electrophysiol

    (1999)
  • N. El-Sherif et al.

    Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome: Detailed analysis of ventricular tridimensional activation patterns

    Circulation

    (1997)
  • D.J. Ewing

    Diabetic autonomic neuropathy and the heart

    Diabetes Res Clin Pract

    (1996)
  • GarsonA. et al.

    The long QT syndrome in children: An international study of 287 patients

    Circulation

    (1993)
  • GeorgeA.L. et al.

    Assignment of the human heart tetrodotoxin-resistant voltage-gated Na+ channel alpha-subunit gene SCN5A to band 3p21

    Cytogenet Cell Genet

    (1995)
  • M.A. Grossman

    Cardiac arrhythmias in acute central nervous system disease

    Arch Intern Med

    (1976)
  • L.C. Guili et al.

    Long QT genotype can be identified by ECG phenotype

    J Am Coll Cardiol

    (1998)
  • M. Guthlin et al.

    Form fruste of long QT syndrome

    Z Kardiol

    (1996)
  • C.T. January et al.

    Early afterdepolarizations: Mechanism of induction and block: A role for L-type Ca2+ current

    Circ Res

    (1989)
  • N.K. Jurkiewicz et al.

    Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent: Specific block of IKr by dofetilide

    Circ Res

    (1993)
  • J.K. Kahn et al.

    QT interval prolongation and sudden cardiac death in diabetic autonomic neuropathy

    J Clin Endocrinol Metab

    (1987)
  • M. Katagiri-Kawade et al.

    Abnormal response to exercise, face immersion, and isoproterenol in children with the long QT syndrome

    Pacing Clin Electrophysiol

    (1995)
  • M.T. Keating et al.

    Consistent linkage of the long QT syndrome to the Harvey ras-1 locus on chromosome 11

    Circulation

    (1991)
  • R. Lazzara

    Mechanisms and management of congenital and acquired long QT syndromes

    Arch Mal Coeur Vaiss

    (1996)
  • A.J. Moss et al.

    The long QT syndrome: A prospective international study

    Circulation

    (1985)
  • A.J. Moss et al.

    ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome

    Circulation

    (1995)
  • N. Neyroud et al.

    Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome

    Eur J Hum Genet

    (1998)
  • N. Neyroud et al.

    A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome

    Nat Genet

    (1997)
  • T. Ohe et al.

    Electrocardiographic and electrophysiologic studies in patients with torsades de pointes: Role of monophasic action potentials

    Jpn Circ J

    (1990)
  • S.G. Priori et al.

    Low penetrance in the long QT syndrome: Clinical impact

    Circulation

    (1999)
  • S.G. Priori et al.

    Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management: Parts I and II

    Circulation

    (1999)
  • Cited by (0)

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