Circulation. 2002;105:794-799
Published online before print January 28, 2002, doi: 10.1161/hc0702.105124
Published online before print January 28, 2002, doi: 10.1161/hc0702.105124
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;105:794.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
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
From the Cardiology Unit (A.J.M., E.G., W.Z., J.L.R., M.L.A.) of the Department of Medicine and the Department of Biostatistics (D.R.P., W.J.H., C.F.), University of Rochester Medical Center, Rochester, NY; The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio (E.S.K.); Department of Cardiology, Bikur Cholim Hospital, Jerusalem, Israel (J.B., A.M.); Department of Pediatric Cardiology, Baylor College of Medicine, Houston, Tex (J.A.T., Z.W.); Department of Cell Biology, Children’s Hospital, Boston, Mass (M.T.K.); Molecular Cardiology, Fondazione S. Maugeri-University of Pavia (S.G.P.), and the Department of Cardiology, Policlinico S. Matteo IRCCS and University of Pavia (P.J.S.), Pavia, Italy (S.G.P.); and the Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah (G.M.V., L.Z.).
Correspondence to Arthur J. Moss, MD, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center, Rochester, NY 14642. E-mail heartajm{at}heart.rochester.edu
Background— The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go–related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (IKr). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder.
Methods and Results— A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (P<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc.
Conclusion— Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.
Key Words: long-QT syndrome • genes • arrhythmia
This article has been cited by other articles:
 |
|
 |
|
  W. Shimizu, A. J. Moss, A. A.M. Wilde, J. A. Towbin, M. J. Ackerman, C. T. January, D. J. Tester, W. Zareba, J. L. Robinson, M. Qi, et al. Genotype-Phenotype Aspects of Type 2 Long QT Syndrome. J. Am. Coll. Cardiol., November 24, 2009; 54(22): 2052 - 2062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nademanee Genotype-Phenotype Relationship in the Long QT Syndrome Brimming With Knowledge but Thirsting for a Therapeutic Solution. J. Am. Coll. Cardiol., November 24, 2009; 54(22): 2063 - 2064. [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Schwartz, M. Stramba-Badiale, L. Crotti, M. Pedrazzini, A. Besana, G. Bosi, F. Gabbarini, K. Goulene, R. Insolia, S. Mannarino, et al. Prevalence of the Congenital Long-QT Syndrome Circulation, November 3, 2009; 120(18): 1761 - 1767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Hardy, J. E. M. Fox, P. R. Giglou, N. Wijesekara, A. Bhattacharjee, S. Sultan, A. V. Gyulkhandanyan, H. Y. Gaisano, P. E. MacDonald, and M. B. Wheeler Characterization of Erg K+ Channels in {alpha}- and {beta}-Cells of Mouse and Human Islets J. Biol. Chem., October 30, 2009; 284(44): 30441 - 30452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Moss and I. Goldenberg Importance of Knowing the Genotype and the Specific Mutation When Managing Patients With Long-QT Syndrome Circ Arrhythm Electrophysiol, August 1, 2008; 1(3): 219 - 226. [Full Text] [PDF]
|
|
|
|
|
|
G. M. Vincent Genotyping Has a Minor Role in Selecting Therapy for Congenital Long-QT Syndromes at Present Circ Arrhythm Electrophysiol, August 1, 2008; 1(3): 227 - 233. [Full Text] [PDF]
|
|
|
|
|
|
I. Goldenberg and A. J. Moss Long QT syndrome. J. Am. Coll. Cardiol., June 17, 2008; 51(24): 2291 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Scheinman and E. Keung The Year in Review of Clinical Cardiac Electrophysiology J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2075 - 2081. [Full Text] [PDF]
|
|
|
|
|
|
A. E. Epstein, J. P. DiMarco, K. A. Ellenbogen, N.A. M. Estes III, R. A. Freedman, L. S. Gettes, A. M. Gillinov, G. Gregoratos, S. C. Hammill, D. L. Hayes, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons J. Am. Coll. Cardiol., May 27, 2008; 51(21): e1 - e62. [Full Text] [PDF]
|
|
|
|
|
|
Writing Committee Members, A. E. Epstein, J. P. DiMarco, K. A. Ellenbogen, N.A. M. Estes III, R. A. Freedman, L. S. Gettes, A. M. Gillinov, G. Gregoratos, S. C. Hammill, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons Circulation, May 27, 2008; 117(21): e350 - e408. [Full Text] [PDF]
|
|
|
|
|
|
R. Lazzara The congenital long QT syndrome: a mask for many faces. J. Am. Coll. Cardiol., March 4, 2008; 51(9): 930 - 932. [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Roden Long-QT Syndrome N. Engl. J. Med., January 10, 2008; 358(2): 169 - 176. [Full Text] [PDF]
|
|
|
|
|
|
L. Crotti, C. Spazzolini, P. J. Schwartz, W. Shimizu, I. Denjoy, E. Schulze-Bahr, E. V. Zaklyazminskaya, H. Swan, M. J. Ackerman, A. J. Moss, et al. The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds: Toward a Mutation-Specific Risk Stratification Circulation, November 20, 2007; 116(21): 2366 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. H. Robin, P. B. Tabereaux, R. Benza, and B. R. Korf Genetic Testing in Cardiovascular Disease J. Am. Coll. Cardiol., August 21, 2007; 50(8): 727 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Gong, L. Zhang, G. M. Vincent, B. D. Horne, and Z. Zhou Nonsense Mutations in hERG Cause a Decrease in Mutant mRNA Transcripts by Nonsense-Mediated mRNA Decay in Human Long-QT Syndrome Circulation, July 3, 2007; 116(1): 17 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Mohler, S. Le Scouarnec, I. Denjoy, J. S. Lowe, P. Guicheney, L. Caron, I. M. Driskell, J.-J. Schott, K. Norris, A. Leenhardt, et al. Defining the Cellular Phenotype of "Ankyrin-B Syndrome" Variants: Human ANK2 Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes Circulation, January 30, 2007; 115(4): 432 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Vandenberg, A. Varghese, Y. Lu, J. A. Bursill, M. P. Mahaut-Smith, and C. L.-H. Huang Temperature dependence of human ether-a-go-go-related gene K+ currents Am J Physiol Cell Physiol, July 1, 2006; 291(1): C165 - C175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Roberts Genomics and Cardiac Arrhythmias J. Am. Coll. Cardiol., January 3, 2006; 47(1): 9 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Napolitano, S. G. Priori, P. J. Schwartz, R. Bloise, E. Ronchetti, J. Nastoli, G. Bottelli, M. Cerrone, and S. Leonardi Genetic Testing in the Long QT Syndrome: Development and Validation of an Efficient Approach to Genotyping in Clinical Practice JAMA, December 21, 2005; 294(23): 2975 - 2980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Ginsburg, R. P. Konstance, J. S. Allsbrook, and K. A. Schulman Implications of Pharmacogenomics for Drug Development and Clinical Practice Arch Intern Med, November 14, 2005; 165(20): 2331 - 2336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Brink, L. Crotti, V. Corfield, A. Goosen, G. Durrheim, P. Hedley, M. Heradien, G. Geldenhuys, E. Vanoli, S. Bacchini, et al. Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population Circulation, October 25, 2005; 112(17): 2602 - 2610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Crotti, A. L. Lundquist, R. Insolia, M. Pedrazzini, C. Ferrandi, G. M. De Ferrari, A. Vicentini, P. Yang, D. M. Roden, A. L. George Jr, et al. KCNH2-K897T Is a Genetic Modifier of Latent Congenital Long-QT Syndrome Circulation, August 30, 2005; 112(9): 1251 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Shimizu The long QT syndrome: Therapeutic implications of a genetic diagnosis Cardiovasc Res, August 15, 2005; 67(3): 347 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Moss and P. J. Schwartz 25th Anniversary of the International Long-QT Syndrome Registry: An Ongoing Quest to Uncover the Secrets of Long-QT Syndrome Circulation, March 8, 2005; 111(9): 1199 - 1201. [Full Text] [PDF]
|
|
|
|
|
|
T. Rossenbacker, K. Mubagwa, R. J. Jongbloed, J. Vereecke, K. Devriendt, M. Gewillig, E. Carmeliet, D. Collen, H. Heidbuchel, and P. Carmeliet Novel Mutation in the Per-Arnt-Sim Domain of KCNH2 Causes a Malignant Form of Long-QT Syndrome Circulation, March 1, 2005; 111(8): 961 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shimizu, M. Horie, S. Ohno, K. Takenaka, M. Yamaguchi, M. Shimizu, T. Washizuka, Y. Aizawa, K. Nakamura, T. Ohe, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: Multicenter study in Japan J. Am. Coll. Cardiol., July 7, 2004; 44(1): 117 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. P. Delisle, B. D. Anson, S. Rajamani, and C. T. January Biology of Cardiac Arrhythmias: Ion Channel Protein Trafficking Circ. Res., June 11, 2004; 94(11): 1418 - 1428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Priori Inherited Arrhythmogenic Diseases: The Complexity Beyond Monogenic Disorders Circ. Res., February 6, 2004; 94(2): 140 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S L Van Driest, B J Maron, and M J Ackerman From malignant mutations to malignant domains: the continuing search for prognostic significance in the mutant genes causing hypertrophic cardiomyopathy Heart, January 1, 2004; 90(1): 7 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Akhavan, R. Atanasiu, and A. Shrier Identification of a COOH-terminal Segment Involved in Maturation and Stability of Human Ether-a-go-go-related Gene Potassium Channels J. Biol. Chem., October 10, 2003; 278(41): 40105 - 40112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Mazzadi, X. Andre-Fouet, J. Duisit, V. Gebuhrer, N. Costes, P. Chevalier, C. Rodriguez, J.-J. Schott, H. Le Marec, P. Guicheney, et al. Cardiac retention of [11C]HED in genotyped long QT patients: a potential amplifier role for severity of the disease Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1286 - H1293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Priori, P. J. Schwartz, C. Napolitano, R. Bloise, E. Ronchetti, M. Grillo, A. Vicentini, C. Spazzolini, J. Nastoli, G. Bottelli, et al. Risk Stratification in the Long-QT Syndrome N. Engl. J. Med., May 8, 2003; 348(19): 1866 - 1874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Al-Khatib, N. M. A. LaPointe, J. M. Kramer, and R. M. Califf What Clinicians Should Know About the QT Interval JAMA, April 23, 2003; 289(16): 2120 - 2127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D. Booker, S. D. Whyte, and E. J. Ladusans Long QT syndrome and anaesthesia Br. J. Anaesth., March 1, 2003; 90(3): 349 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. V. Korolkova, E. V. Bocharov, K. Angelo, I. V. Maslennikov, O. V. Grinenko, A. V. Lipkin, E. D. Nosyreva, K. A. Pluzhnikov, S.-P. Olesen, A. S. Arseniev, et al. New Binding Site on Common Molecular Scaffold Provides HERG Channel Specificity of Scorpion Toxin BeKm-1 J. Biol. Chem., November 1, 2002; 277(45): 43104 - 43109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Roden The problem, challenge and opportunity of genetic heterogeneity in monogenic diseases predisposing to sudden death J. Am. Coll. Cardiol., July 17, 2002; 40(2): 357 - 359. [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Perry Inferring Long QT1 Genotype Based on a Simple Epinephrine Infusion Protocol: From the Bedside to the Bench and Back Mayo Clin. Proc., May 1, 2002; 77(5): 405 - 406. [PDF]
|
|