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(Circulation. 1999;100:1660-1666.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Cellular Basis for the Brugada Syndrome and Other Mechanisms of Arrhythmogenesis Associated With ST-Segment Elevation
From the Masonic Medical Research Laboratory, Utica, NY.
Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail ca{at}mmrl.edu
Background—The Brugada syndrome is characterized by marked ST-segment elevation in the right precordial ECG leads and is associated with a high incidence of sudden and unexpected arrhythmic death. Our study examines the cellular basis for this syndrome.
Methods and Results—Using arterially perfused wedges of canine right ventricle (RV), we simultaneously recorded transmembrane action potentials from 2 epicardial and 1 endocardial sites, together with unipolar electrograms and a transmural ECG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 µmol/L), a K+ channel opener, or the combination of a Na+ channel blocker (flecainide, 7 µmol/L) and acetylcholine (ACh, 2 to 3 µmol/L) resulted in an abbreviation of epicardial response and a transmural dispersion of repolarization, which caused an ST-segment elevation in the ECG. ACh facilitated loss of the action potential dome, whereas isoproterenol (0.1 to 1 µmol/L) restored the epicardial dome, thus reducing or eliminating the ST-segment elevation. Heterogeneous loss of the dome caused a marked dispersion of repolarization within the epicardium and transmurally, thus giving rise to phase 2 reentrant extrasystole, which precipitated ventricular tachycardia (VT) and ventricular fibrillation (VF). Transient outward current (Ito) block with 4-aminopyridine (1 to 2 mmol/L) or quinidine (5 µmol/L) restored the dome, normalized the ST segment, and prevented VT/VF.
Conclusions—Depression or loss of the action potential dome in RV epicardium creates a transmural voltage gradient that may be responsible for the ST-segment elevation observed in the Brugada syndrome and other syndromes exhibiting similar ECG manifestations. Our results also demonstrate that extrasystolic activity due to phase 2 reentry can arise in the intact wall of the canine RV and serve as the trigger for VT/VF. Our data point to Ito block (4-aminopyridine, quinidine) as an effective pharmacological treatment.
Key Words: electrophysiology • ventricles • electrocardiography • J wave • fibrillation • tachycardia
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T. Kurita, W. Shimizu, M. Inagaki, K. Suyama, A. Taguchi, K. Satomi, N. Aihara, S. Kamakura, J. Kobayashi, and Y. Kosakai The electrophysiologic mechanism of ST-segment elevation in Brugada syndrome J. Am. Coll. Cardiol., July 17, 2002; 40(2): 330 - 334. [Abstract] [Full Text] [PDF]
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S. Nagase, K. F. Kusano, H. Morita, Y. Fujimoto, M. Kakishita, K. Nakamura, T. Emori, H. Matsubara, and T. Ohe Epicardial electrogram of the right ventricular outflow tract in patients with the brugada syndrome: Using the epicardial lead J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1992 - 1995. [Abstract] [Full Text] [PDF]
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C. Antzelevitch Late potentials and the Brugada syndrome J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1996 - 1999. [Full Text] [PDF]
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M. Kanda, W. Shimizu, K. Matsuo, N. Nagaya, A. Taguchi, K. Suyama, T. Kurita, N. Aihara, and S. Kamakura Electrophysiologic characteristics andimplications of induced ventricular fibrillationin symptomatic patients with brugada syndrome J. Am. Coll. Cardiol., June 5, 2002; 39(11): 1799 - 1805. [Abstract] [Full Text] [PDF]
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A.A.M. Wilde, C.A. Remme, R. Derksen, E.F.D. Wever, and R.N.W. Hauer Brugada syndrome Eur. Heart J., April 2, 2002; 23(8): 675 - 676. [Full Text] [PDF]
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J. Brugada, R. Brugada, C. Antzelevitch, J. Towbin, K. Nademanee, and P. Brugada Long-Term Follow-Up of Individuals With the Electrocardiographic Pattern of Right Bundle-Branch Block and ST-Segment Elevation in Precordial Leads V1 to V3 Circulation, January 1, 2002; 105(1): 73 - 78. [Abstract] [Full Text] [PDF]
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P. C. Viswanathan, C. R. Bezzina, A. L. George Jr., D. M. Roden, A. A.M. Wilde, and J. R. Balser Gating-Dependent Mechanisms for Flecainide Action in SCN5A-Linked Arrhythmia Syndromes Circulation, September 4, 2001; 104(10): 1200 - 1205. [Abstract] [Full Text] [PDF]
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A. C. Zygmunt, G. T. Eddlestone, G. P. Thomas, V. V. Nesterenko, and C. Antzelevitch Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H689 - H697. [Abstract] [Full Text] [PDF]
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C. Antzelevitch Transmural dispersion of repolarization and the T wave Cardiovasc Res, June 1, 2001; 50(3): 426 - 431. [Full Text] [PDF]
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T. Ikeda, H. Sakurada, K. Sakabe, T. Sakata, M. Takami, N. Tezuka, T. Nakae, M. Noro, Y. Enjoji, T. Tejima, et al. Assessment of noninvasive markers in identifying patients at risk in the brugada syndrome: insight into risk stratification J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1628 - 1634. [Abstract] [Full Text] [PDF]
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C Antzelevitch The Brugada syndrome: diagnostic criteria and cellular mechanisms Eur. Heart J., March 1, 2001; 22(5): 356 - 363. [PDF]
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D. Corrado, C. Basso, G. Buja, A. Nava, L. Rossi, and G. Thiene Right Bundle Branch Block, Right Precordial ST-Segment Elevation, and Sudden Death in Young People Circulation, February 6, 2001; 103(5): 710 - 717. [Abstract] [Full Text] [PDF]
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C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
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X. Wan, S. Chen, A. Sadeghpour, Q. Wang, and G. E. Kirsch Accelerated inactivation in a mutant Na+ channel associated with idiopathic ventricular fibrillation Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H354 - H360. [Abstract] [Full Text] [PDF]
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C. Antzelevitch Electrical Heterogeneity, Cardiac Arrhythmias, and the Sodium Channel Circ. Res., November 24, 2000; 87(11): 964 - 965. [Full Text] [PDF]
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D. W. Wang, N. Makita, A. Kitabatake, J. R. Balser, and A. L. George Jr Enhanced Na+ Channel Intermediate Inactivation in Brugada Syndrome Circ. Res., October 13, 2000; 87 (8): e37 - e43. [Abstract] [Full Text] [PDF]
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X. H. T. Wehrens, H. Abriel, C. Cabo, J. Benhorin, and R. S. Kass Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na+ Channel {alpha}-Subunit : A Computational Analysis Circulation, August 1, 2000; 102(5): 584 - 590. [Abstract] [Full Text] [PDF]
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G. Baroudi, S. Acharfi, C. Larouche, and M. Chahine Expression and Intracellular Localization of an SCN5A Double Mutant R1232W/T1620M Implicated in Brugada Syndrome Circ. Res., January 11, 2002; 90 (1): e11 - e16. [Abstract] [Full Text] [PDF]
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R. Weiss, M. M. Barmada, T. Nguyen, J. S. Seibel, D. Cavlovich, C. A. Kornblit, A. Angelilli, F. Villanueva, D. M. McNamara, and B. London Clinical and Molecular Heterogeneity in the Brugada Syndrome: A Novel Gene Locus on Chromosome 3 Circulation, February 12, 2002; 105(6): 707 - 713. [Abstract] [Full Text] [PDF]
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C. E. Clancy and Y. Rudy Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism Circulation, March 12, 2002; 105(10): 1208 - 1213. [Abstract] [Full Text] [PDF]
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