(Circulation. 1995;92:3381-3386.)
© 1995 American Heart Association, Inc.
Articles |
Long QT Syndrome Patients With Mutations of the SCN5A and HERG Genes Have Differential Responses to Na+ Channel Blockade and to Increases in Heart Rate
Implications for Gene-Specific Therapy
From the Cattedra di Cardiologia, Università degli Studi di Pavia, and IRCCS Policlinico S Matteo, Pavia, Italy (P.J.S.); Centro di Fisiologia Clinica e Ipertensione/Istituto di Clinica Medica Generale e Terapia Medica, Università degli Studi di Milano, Italy (P.J.S., S.G.P., E.H.L., C.N., F.C.); Phoebe Willingham Muzzy Pediatric Molecular Cardiology Laboratory, Baylor College of Medicine, Texas Children's Hospital, Houston (J.A.T.); Eccles Institute of Human Genetics and Howard Hughes Medical Institute, University of Utah, Salt Lake City (M.T.K.); Centre Hospitalier de Sainte-Ode, Belgium (H.H.); Case Western Reserve University, Rammelkamp Center, MetroHealth Campus, Cleveland, Ohio (A.M.B.); and Division of Cardiovascular and Metabolic Diseases, Wyeth-Ayerst Research, Princeton, NJ (L-S.K.C., T.J.C.).
Correspondence to Peter J. Schwartz, MD, Cattidra di Cardiologia, Università degli Studi di Pavia, Divisione di Cardiologia, Policlinico S. Matteo IRCCS, Piazzale Golgi, 2-27100 Pavia, Italy.
Background The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate.
Methods and Results Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QTc were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QTc from 535±32 to 445±31 ms, P<.005) but not among LQT2 patients (QTc from 530±79 to 503±60 ms, P=NS). LQT3 patients (n=7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n=4) and also more than 18 healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33, P<.05; data expressed as percent reduction in QT per 100-ms shortening in RR). Among these patients, there is also a trend for LQT2 patients to have syncope or cardiac arrest under emotional or physical stress and for LQT3 patients to have cardiac events either at rest or during sleep.
Conclusions This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefit from Na+ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates. Conversely, LQT2 patients may be at higher risk to develop syncope under stressful conditions because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval when heart rate increases.
Key Words: genes • mexiletine • long QT syndrome • death, sudden
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C. Bezzina, M. W. Veldkamp, M. P. van den Berg, A. V. Postma, M. B. Rook, J.-W. Viersma, I. M. van Langen, G. Tan-Sindhunata, M. Th. E. Bink-Boelkens, A. H. van der Hout, et al. A Single Na+ Channel Mutation Causing Both Long-QT and Brugada Syndromes Circ. Res., December 3, 1999; 85(12): 1206 - 1213. [Abstract] [Full Text] [PDF]
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J. Merot, F. Charpentier, J.-M. Poirier, G. Coutris, and J. Weissenburger Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol Cardiovasc Res, November 1, 1999; 44(2): 303 - 314. [Abstract] [Full Text] [PDF]
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H. Swan, M. Viitasalo, K. Piippo, P.a. Laitinen, K. Kontula, and L. Toivonen Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects J. Am. Coll. Cardiol., September 1, 1999; 34(3): 823 - 829. [Abstract] [Full Text] [PDF]
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Gene-specific lethality of arrhythmic events in the long QT syndrome? A message from the International Registry Eur. Heart J., August 2, 1999; 20(16): 1137 - 1139. [PDF]
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R. A. Li, R. G. Tsushima, K. Himmeldirk, D. S. Dime, and P. H. Backx Local Anesthetic Anchoring to Cardiac Sodium Channels : Implications Into Tissue-Selective Drug Targeting Circ. Res., July 9, 1999; 85(1): 88 - 98. [Abstract] [Full Text] [PDF]
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J. Wei, D. W. Wang, M. Alings, F. Fish, M. Wathen, D. M. Roden, and A. L. George Jr Congenital Long-QT Syndrome Caused by a Novel Mutation in a Conserved Acidic Domain of the Cardiac Na+ Channel Circulation, June 22, 1999; 99(24): 3165 - 3171. [Abstract] [Full Text] [PDF]
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R. Chandra, V. S. Chauhan, C.F. Starmer, and A. O. Grant {beta}-adrenergic action on wild-type and KPQ mutant human cardiac Na+ channels: shift in gating but no change in Ca2+: Na+ selectivity Cardiovasc Res, May 1, 1999; 42(2): 490 - 502. [Abstract] [Full Text] [PDF]
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E. A Sosunov, E. P Anyukhovsky, A. Shvilkin, Motoki Hara, S. F Steinberg, P. Danilo Jr., M. R Rosen, N Sydney Moise, J. Merot, V. Probst, et al. Abnormal cardiac repolarization and impulse initiation in German shepherd dogs with inherited ventricular arrhythmias and sudden death Cardiovasc Res, April 1, 1999; 42(1): 65 - 79. [Abstract] [Full Text] [PDF]
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S. G. Priori, J. Barhanin, R. N. W. Hauer, W. Haverkamp, H. J. Jongsma, A. G. Kleber, W. J. McKenna, D. M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Parts I and II Circulation, February 2, 1999; 99(4): 518 - 528. [Abstract] [Full Text] [PDF]
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S. G. Priori, C. Napolitano, and P. J. Schwartz Low Penetrance in the Long-QT Syndrome : Clinical Impact Circulation, February 2, 1999; 99(4): 529 - 533. [Abstract] [Full Text] [PDF]
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S.G. Priori, J. Barhanin, R.N.W. Hauer, W. Haverkamp, H.J. Jongsma, A.G. Kleber, W.J. McKenna, D.M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management Eur. Heart J., February 1, 1999; 20(3): 174 - 195. [PDF]
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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]
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T. Nagatomo, Z. Fan, B. Ye, G. S. Tonkovich, C. T. January, J. W. Kyle, and J. C. Makielski Temperature dependence of early and late currents in human cardiac wild-type and long Q-T Delta KPQ Na+ channels Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2016 - H2024. [Abstract] [Full Text] [PDF]
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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]
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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]
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W. Zareba, A. J. Moss, P. J. Schwartz, G. M. Vincent, J. L. Robinson, S. G. Priori, J. Benhorin, E. H. Locati, J. A. Towbin, M. T. Keating, et al. Influence of the Genotype on the Clinical Course of the Long-QT Syndrome N. Engl. J. Med., October 1, 1998; 339(14): 960 - 965. [Abstract] [Full Text] [PDF]
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L. Eckardt, W. Haverkamp, M. Borggrefe, and G. Breithardt Experimental models of torsade de pointes Cardiovasc Res, July 1, 1998; 39(1): 178 - 193. [Abstract] [Full Text] [PDF]
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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]
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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]
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W. Shimizu, T. Kurita, K. Matsuo, K. Suyama, N. Aihara, S. Kamakura, J. A. Towbin, and K. Shimomura Improvement of Repolarization Abnormalities by a K+ Channel Opener in the LQT1 Form of Congenital Long-QT Syndrome Circulation, April 28, 1998; 97(16): 1581 - 1588. [Abstract] [Full Text] [PDF]
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H. Li, Q. Chen, A. J. Moss, J. Robinson, V. Goytia, J. C. Perry, G. M. Vincent, S. G. Priori, M. H. Lehmann, S. W. Denfield, et al. New Mutations in the KVLQT1 Potassium Channel That Cause Long-QT Syndrome Circulation, April 7, 1998; 97(13): 1264 - 1269. [Abstract] [Full Text] [PDF]
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E. J. Rashba, W. Zareba, A. J. Moss, W. J. Hall, J. Robinson, E. H. Locati, P. J. Schwartz, and M. Andrews Influence of Pregnancy on the Risk for Cardiac Events in Patients With Hereditary Long QT Syndrome Circulation, February 10, 1998; 97(5): 451 - 456. [Abstract] [Full Text] [PDF]
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D. E Featherstone, E. Fujimoto, and P. C Ruben A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita J. Physiol., February 1, 1998; 506(3): 627 - 638. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome Circulation, September 16, 1997; 96(6): 2038 - 2047. [Abstract] [Full Text]
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A. D. Krahn, G. J. Klein, and R. Yee Hysteresis of the RT Interval With Exercise : A New Marker for the Long-QT Syndrome? Circulation, September 2, 1997; 96(5): 1551 - 1556. [Abstract] [Full Text]
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