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(Circulation. 1996;94:1996-2012.)
© 1996 American Heart Association, Inc.

Articles

Multiple Mechanisms in the Long-QT Syndrome

Current Knowledge, Gaps, and Future Directions

Dan M. Roden, MD; Ralph Lazzara, MD; Michael Rosen, MD; Peter J. Schwartz, MD; Jeffry Towbin, MD; G. Michael Vincent, MD; for the SADS Foundation Task Force on LQTS*

the Sudden Arrhythmic Death Syndromes (SADS) Foundation (*see "Appendix" for participants).

Correspondence to Dan M. Roden, MD, Director, Division of Clinical Pharmacology, 532 Medical Research Bldg I, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.

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.

Key Words: genes • arrhythmia • long-QT syndrome

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				K. Petrecca, R. Atanasiu, A. Akhavan, and A. Shrier N-linked glycosylation sites determine HERG channel surface membrane expression J. Physiol., February 15, 1999; 515(1): 41 - 48. [Abstract] [Full Text] [PDF]

				M. Alings and A. Wilde "Brugada" Syndrome : Clinical Data and Suggested Pathophysiological Mechanism Circulation, February 9, 1999; 99(5): 666 - 673. [Full Text] [PDF]

				S. Kupershmidt, T. Yang, M. E. Anderson, A. Wessels, K. D. Niswender, M. A. Magnuson, and D. M. Roden Replacement by Homologous Recombination of the minK Gene With lacZ Reveals Restriction of minK Expression to the Mouse Cardiac Conduction System Circ. Res., February 5, 1999; 84(2): 146 - 152. [Abstract] [Full Text] [PDF]

				A. A. M. Wilde, R. J. E. Jongbloed, P. A. Doevendans, D. R. Duren, R. N. W. Hauer, I. M. van Langen, J. P. van Tintelen, H. J. M. Smeets, H. Meyer, and J. L. M. C. Geelen Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1) J. Am. Coll. Cardiol., February 1, 1999; 33(2): 327 - 332. [Abstract] [Full Text] [PDF]

				F. C. Basilico Cardiovascular Disease in Athletes Am. J. Sports Med., January 1, 1999; 27(1): 108 - 121. [Abstract] [Full Text] [PDF]

				M. E. Anderson, A. P. Braun, Y. Wu, T. Lu, Y. Wu, H. Schulman, and R. J. Sung KN-93, an Inhibitor of Multifunctional Ca++/Calmodulin-Dependent Protein Kinase, Decreases Early Afterdepolarizations in Rabbit Heart J. Pharmacol. Exp. Ther., December 1, 1998; 287(3): 996 - 1006. [Abstract] [Full Text]

				F. Sesti and S. A.N. Goldstein Single-Channel Characteristics of Wild-Type IKs Channels and Channels formed with Two MinK Mutants that Cause Long QT Syndrome J. Gen. Physiol., December 1, 1998; 112(6): 651 - 663. [Abstract] [Full Text] [PDF]

				W. Shimizu and C. Antzelevitch Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome : Effects of ß-Adrenergic Agonists and Antagonists and Sodium Channel Blockers on Transmural Dispersion of Repolarization and Torsade de Pointes Circulation, November 24, 1998; 98(21): 2314 - 2322. [Abstract] [Full Text] [PDF]

				S. Kupershmidt, D. J. Snyders, A. Raes, and D. M. Roden A K+ Channel Splice Variant Common in Human Heart Lacks a C-terminal Domain Required for Expression of Rapidly Activating Delayed Rectifier Current J. Biol. Chem., October 16, 1998; 273(42): 27231 - 27235. [Abstract] [Full Text] [PDF]

				B. J. Maron, J. H. Moller, C. E. Seidman, G. M. Vincent, H. C. Dietz, A. J. Moss, J. A. Towbin, H. M. Sondheimer, R. E. Pyeritz, G. McGee, et al. Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome : A Statement for Healthcare Professionals From the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association Circulation, October 6, 1998; 98(14): 1460 - 1471. [Full Text] [PDF]

				C. Chouabe, M.-D. Drici, G. Romey, J. Barhanin, and M. Lazdunski HERG and KvLQT1/IsK, the Cardiac K+ Channels Involved in Long QT Syndromes, Are Targets for Calcium Channel Blockers Mol. Pharmacol., October 1, 1998; 54(4): 695 - 703. [Abstract] [Full Text]

				J. Kiehn, C. Karle, D. Thomas, X. Yao, J. Brachmann, and W. Kubler HERG Potassium Channel Activation Is Shifted by Phorbol Esters via Protein Kinase A-dependent Pathways J. Biol. Chem., September 25, 1998; 273(39): 25285 - 25291. [Abstract] [Full Text] [PDF]

				P. Babij, G. R. Askew, B. Nieuwenhuijsen, C.-M. Su, T. R. Bridal, B. Jow, T. M. Argentieri, J. Kulik, L. J. DeGennaro, W. Spinelli, et al. Inhibition of Cardiac Delayed Rectifier K+ Current by Overexpression of the Long-QT Syndrome HERG G628S Mutation in Transgenic Mice Circ. Res., September 21, 1998; 83(6): 668 - 678. [Abstract] [Full Text] [PDF]

				H L Tan and A A M Wilde T wave alternans after sotalol: evidence for increased sensitivity to sotalol after conversion from atrial fibrillation to sinus rhythm Heart, September 1, 1998; 80(3): 303 - 306. [Abstract] [Full Text]

				M.-D. Drici, I. Arrighi, C. Chouabe, J. R. Mann, M. Lazdunski, G. Romey, and J. Barhanin Involvement of IsK-Associated K+ Channel in Heart Rate Control of Repolarization in a Murine Engineered Model of Jervell and Lange-Nielsen Syndrome Circ. Res., July 13, 1998; 83(1): 95 - 102. [Abstract] [Full Text] [PDF]

				S. G. Priori, P. J. Schwartz, C. Napolitano, L. Bianchi, A. Dennis, M. D. Fusco, A. M. Brown, and G. Casari A Recessive Variant of the Romano-Ward Long-QT Syndrome? Circulation, June 23, 1998; 97(24): 2420 - 2425. [Abstract] [Full Text] [PDF]

				E. H. Locati, W. Zareba, A. J. Moss, P. J. Schwartz, G. M. Vincent, M. H. Lehmann, J. A. Towbin, S. G. Priori, C. Napolitano, J. L. Robinson, et al. Age- and Sex-Related Differences in Clinical Manifestations in Patients With Congenital Long-QT Syndrome : Findings From the International LQTS Registry Circulation, June 9, 1998; 97(22): 2237 - 2244. [Abstract] [Full Text] [PDF]

				A. Zou, Q. P Xu, and M. C Sanguinetti A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes reduces rectification by shifting the voltage dependence of inactivation J. Physiol., May 15, 1998; 509(1): 129 - 137. [Abstract] [Full Text] [PDF]

				E. Marban, T. Yamagishi, and G. F Tomaselli Structure and function of voltage-gated sodium channels J. Physiol., May 1, 1998; 508(3): 647 - 657. [Abstract] [Full Text] [PDF]