Review
The Long QT Syndrome: Ion Channel Diseases of the Heart

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Once limited to discussions of the Jervell and Lange-Nielsen syndrome and Romano-Ward syndrome, the long QT syndrome (LQTS) is now understood to be a collection of genetically distinct arrhy thmogenic cardiovascular disorders resulting from mutations in fundamental cardiac ion channels that orchestrate the action potential of the human heart. Our understanding of this genetic “channelopathy” has increased dramatically from electro-cardiographic depictions of marked QT interval prolongation and torsades de pointes and clinical descriptions of people experiencing syncope and sudden death to molecular revelations in the 1990s of perturbed ion channel genes. More than 35 mutations in four cardiac ion channel genes—KVLQT1 (voltage-gated K channel gene causing one of the autosomal dominant forms of LQT5) (LQT1), HERG (human ether-a-go-go related gene) (LQT2), SCN5A (LQT3), and KCNE1 (minK, LQT5)—have been identified in LQTS. These genes encode ion channels responsible for three of the fundamental ionic currents in the cardiac action potential. These exciting molecular breakthroughs have provided new opportunities for translationsl research with investigations into genotype-phenotype correlations and gene-targeted therapies.

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CLINICAL FACE OF LQTS

The numerous causes of LQTS are listed in Table 1.7 Although this review focuses particularly on the adrenergic-dependent inherited forms of LQTS, the acquired (secondary) forms are numerous and should be remembered. In fact, many of the exogenous factors causing acquired LQTS exert their deleterious effects on the same ion channels implicated in inherited LQTS. Numerous drugs can cause QT prolongation and torsades de pointes. Most notably, quinidine, a class IA antiarrhythmic, causes acquired

ION CHANNELS, CARDIAC ACTION POTENTIAL, AND LQTS

Understanding the cardiac action potential with its ion channel-based framework is essential to appreciating the clinical consequences that occur when these ion channels are disturbed. Ion channels are the fundamental class of proteins responsible for generating and orchestrating the electrical signals passing through the cells of the beating heart. The filling and subsequent contraction of atria and ventricles are timed with great precision to facilitate the pumping of blood most efficiently.

MOLECULAR BASIS OF LQTS

Today, five distinct molecular genotypes for autosomal dominant LQTS (four involving cardiac ion channel defects) and two molecular genotypes for the JLN syndrome have been characterized (Table 1) (Fig. 5).6, 26, 51, 52, 53, 54

LQT6?

Gene discovery for LQTS is still unfinished, inasmuch as only 50 to 75% of families with autosomal dominant LQTS are believed to be of the LQT1 through LQT5 genotypes. Another distinct LQTS phenotype with possible X-linked or autosomal recessive inheritance has been reported.82 Four male children from four different families had markedly prolonged QTc (greater than 0.60 second1, 2), bradycardia with 2:1 atrioventricular block, fetal decelerations, and bilateral cutaneous syndactyly (webbed

FROM BENCH TO BEDSIDE: EVALUATION, TREATMENT, AND THE FUTURE OF LQTS

By grasping the basics of ion channel structure and function, appreciating the exquisitely choreographed cardiac action potential, and realizing the molecular basis for inherited LQTS, new insights into the clinical care of the patient with LQTS are possible.

CONCLUSION

LQTS encompasses a fascinating collection of ion channel diseases of the heart. The field of LQTS research has shown the fruits and excitement provided by effective bedside to bench to bedside translational research. This review article has taken the same course: from the clinical manifestation of LQTS to the cellular cardiac action potential orchestrated by ion channels, to the molecular architecture and inner workings of these critical proteins, to the elucidation of defective ion channels as

ACKNOWLEDGMENT

I thank Drs. David J, Driscoll, Co-burn J. Porter, and Amy M. Kelly for their helpful comments during the preparation of the submitted manuscript.

REFERENCES (106)

  • G Romey et al.

    Molecular mechanism and functional significance of the MinK control of the KvLQTl channel activity

    J Biol Chem

    (1997)
  • ML Marks et al.

    A new form of long QT syndrome associated with syndactyly

    J Am Coll Cardiol

    (1995)
  • ML Marks et al.

    syndrome associated with syndactyly identified in females

    Am J Cardiol

    (1995)
  • M Eldar et al.

    Combined use of beta-adrenergic blocking agents and long-term cardiac pacing for patients with the long QT syndrome

    J Am Coll Cardiol

    (1992)
  • 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 Colt Cardiol

    (1995)
  • E Dausse et al.

    A mutation in HERG associated with notched T waves in long QT syndrome

    J Mot Cell Cardiol

    (1996)
  • WB Kannil et al.

    Sudden death risk in overt coronary heart diseases: the Framingham Study

    Am Heart J

    (1987)
  • C Romano et al.

    Aritmie cardiache rare dell'eta' pediatrica. 11. Accessi sincopali per fibrillazione ventricolare parossistica

    Clin Pediatr (Bologna)

    (1963)
  • OC Ward

    A new familial cardiac syndrome in children

    J Irish Med Assoc

    (1964)
  • MJ Ackerman et al.

    Ion channels-basic science and clinical disease

    NEnglJMed

    (1997)
  • LF Janeira

    Torsades de pointes and long QT syndromes

    Am Fam Physician

    (1995)
  • DM Roden

    Current status of class III antiarrhythmic drug therapy

    Am J Cardiol

    (1993)
  • H Suessbrleh et al.

    The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes

    Br J Pharmacol

    (1997)
  • M Roy et al.

    HERG. a primary human ventricular target of the nonsedating antihistamine terfenadine

    Circulation

    (1996)
  • HR Alderton

    Tricyclic medication in children and the QT interval: case report and discussion

    Can J Psychiatry

    (1995)
  • SH Thomas

    Drugs, QT interval abnormalities and ventricular arrhythmias

    Adverse Drug React Toxicol Rev

    (1994)
  • KK Koh et al.

    Torsade de pointes induced by terfenadine in a patient with long QT syndrome

    J Electrocardiol

    (1994)
  • MV Brandriss et al.

    Erythromycin-induced QT prolongation and polymorphic ventricular tachycardia (torsades de pointes): case report and review

    Clin Infect Dis

    (1994)
  • M Zimmerman et al.

    Torsades de pointes after treatment with terfenadine and ketocanazole

    Eur Heart J

    (1992)
  • JP Chvilicek et al.

    Diuretic-induced hypokalaemia inducing torsades de pointes

    Can J Anaesth

    (1995)
  • R Lazzara

    Mechanisms and management of congenital and acquired long QT syndromes

    Arch Mal Coeur vaiss

    (1996)
  • DM Roden

    Torsade de pointes

    Clin Cardioi

    (1993)
  • A Yokohama et al.

    Prolonged QT interval in alcoholic autonomie nervous dysfunction

    Alcohol Clin Exp Res

    (1992)
  • N Neyroud et al.

    A novel mutation in the potassium channel gene KVLQT1 causes the Jetvell and Länge-Nielsen cardioauditory syndrome

    Nat Genet

    (1997)
  • I Splawski et al.

    Molecular basis of the long-QT syndrome associated with deafness

    N Engl J Med

    (1997)
  • I Splawski et al.

    Mutations in the hminK gene cause long QT syndrome and suppress lKl function

    Nat Genet

    (1997)
  • E Schulze-Bahr et al.

    KCNE1 mutations cause Jervell and Lange-Nielsen syndrome

    Nat Genet

    (1997)
  • MT Keating

    The long QT syndrome: a review of recent molecular genetic and physiologic discoveries

    Medicine

    (1996)
  • HC Bazett

    An analysis of the time-relations of electrocardiograms

    Heart

    (1920)
  • GM Vincent et al.

    The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome

    N Eng J Med

    (1992)
  • PJ Schwartz et al.

    Diagnostic criteria for the long QT syndrome: an update

    Circulation

    (1993)
  • F Dessertenne

    La tachycardie ventriculaire a deux foyers opposes variables

    Arch Mal Coeur

    (1966)
  • AJ Moss et al.

    Long QT syndrome

    Heart Dis Stroke

    (1992)
  • AJ Moss et al.

    Clinical aspects of the idiopathic long QT syndrome

    Ann N Y Acad Sci

    (1992)
  • AJ Garson et al.

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

    Circulation

    (1993)
  • AJ Moss et al.

    The long QT syndrome: prospective longitudinal study of 328 families

    Circulation

    (1991)
  • MJ Ackerman et al.

    Identification of a family with Inherited long QT syndrome following a pédiatrie near drowning

    Pediatrics

    (1998)
  • Ackerman MJ, Clapham DE. Normal cardiac electrophysiology: understanding the action potential in the human heart. In:...
  • AM Katz

    Cardiac ion channels

    N Engl J Med

    (1993)
  • JH Lawrence et al.

    Ion channels: structure and function

    Heart Dis Stroke

    (1993)
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