Multiple mechanisms in the long-QT syndrome

Current knowledge, gaps, and future directions

Dan M. Roden, Ralph Lazzara, Michael Rosen, Peter J. Schwartz, Jeffrey Towbin, G. Michael Vincent

Research output: Contribution to journalReview article

545 Citations (Scopus)

Abstract

The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease. Mutations in the human ether-a- go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.

Original languageEnglish (US)
Pages (from-to)1996-2012
Number of pages17
JournalCirculation
Volume94
Issue number8
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

Fingerprint

Long QT Syndrome
Mutation
Genes
Sodium Channels
Ether
Delayed Rectifier Potassium Channels
Cardiac Electrophysiology
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 7
Direction compound
Potassium Channels
Ventricular Tachycardia
Sudden Death
Ion Channels
Adrenergic Agents
Cardiac Arrhythmias
Potassium
Electrocardiography
Incidence

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Roden, D. M., Lazzara, R., Rosen, M., Schwartz, P. J., Towbin, J., & Michael Vincent, G. (1996). Multiple mechanisms in the long-QT syndrome: Current knowledge, gaps, and future directions. Circulation, 94(8), 1996-2012. https://doi.org/10.1161/01.CIR.94.8.1996

Multiple mechanisms in the long-QT syndrome : Current knowledge, gaps, and future directions. / Roden, Dan M.; Lazzara, Ralph; Rosen, Michael; Schwartz, Peter J.; Towbin, Jeffrey; Michael Vincent, G.

In: Circulation, Vol. 94, No. 8, 01.01.1996, p. 1996-2012.

Research output: Contribution to journalReview article

Roden, DM, Lazzara, R, Rosen, M, Schwartz, PJ, Towbin, J & Michael Vincent, G 1996, 'Multiple mechanisms in the long-QT syndrome: Current knowledge, gaps, and future directions', Circulation, vol. 94, no. 8, pp. 1996-2012. https://doi.org/10.1161/01.CIR.94.8.1996
Roden, Dan M. ; Lazzara, Ralph ; Rosen, Michael ; Schwartz, Peter J. ; Towbin, Jeffrey ; Michael Vincent, G. / Multiple mechanisms in the long-QT syndrome : Current knowledge, gaps, and future directions. In: Circulation. 1996 ; Vol. 94, No. 8. pp. 1996-2012.
@article{9520fb5605604a0f91e75c26b42c0976,
title = "Multiple mechanisms in the long-QT syndrome: Current knowledge, gaps, and future directions",
abstract = "The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease. Mutations in the human ether-a- go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.",
author = "Roden, {Dan M.} and Ralph Lazzara and Michael Rosen and Schwartz, {Peter J.} and Jeffrey Towbin and {Michael Vincent}, G.",
year = "1996",
month = "1",
day = "1",
doi = "10.1161/01.CIR.94.8.1996",
language = "English (US)",
volume = "94",
pages = "1996--2012",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Multiple mechanisms in the long-QT syndrome

T2 - Current knowledge, gaps, and future directions

AU - Roden, Dan M.

AU - Lazzara, Ralph

AU - Rosen, Michael

AU - Schwartz, Peter J.

AU - Towbin, Jeffrey

AU - Michael Vincent, G.

PY - 1996/1/1

Y1 - 1996/1/1

N2 - The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease. Mutations in the human ether-a- go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.

AB - The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease. Mutations in the human ether-a- go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.

UR - http://www.scopus.com/inward/record.url?scp=0029847602&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029847602&partnerID=8YFLogxK

U2 - 10.1161/01.CIR.94.8.1996

DO - 10.1161/01.CIR.94.8.1996

M3 - Review article

VL - 94

SP - 1996

EP - 2012

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 8

ER -