© 1999 American Heart Association, Inc.
Cellular Biology |
Ionic Mechanisms Responsible for the Electrocardiographic Phenotype of the Brugada Syndrome Are Temperature Dependent
From the Departments of Molecular Biology and Experimental Cardiology (R.D., D.M.V., V.V.N., C.A.), Masonic Medical Research Laboratory, Utica, NY; Departments of Pediatrics (J.A.T., M.V.) and Medicine (R.B.), Baylor College of Medicine, Houston, Texas; Cardiovascular Center (P.B.), OLV Hospital, Aalst, Belgium; and Cardiovascular Institute (J.B.), Hospital Clinic, University of Barcelona, Barcelona, Spain.
Correspondence to Dr Robert Dumaine, Department Molecular Biology, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail rdumaine{at}mmrl.edu
Abstract—The Brugada syndrome is
a major cause of sudden death, particularly among young men of
Southeast Asian and Japanese origin. The syndrome is characterized
electrocardiographically by an ST-segment elevation in V1 through V3
and a rapid polymorphic ventricular
tachycardia that can degenerate into
ventricular fibrillation. Our group recently linked the
disease to mutations in SCN5A, the gene encoding
for the 
subunit of the cardiac sodium channel. When heterologously
expressed in frog oocytes,
electrophysiological data recorded from
the Thr1620Met missense mutant failed to adequately explain the
electrocardiographic phenotype. Therefore, we sought to further
characterize the electrophysiology of this mutant. We hypothesized that
at more physiological temperatures, the missense
mutation may change the gating of the sodium channel such that the net
outward current is dramatically augmented during the early phases of
the right ventricular action potential. In the present
study, we test this hypothesis by expressing Thr1620Met in a mammalian
cell line, using the patch-clamp technique to study the currents at
32°C. Our results indicate that Thr1620Met current decay kinetics are
faster when compared with the wild type at 32°C. Recovery from
inactivation was slower for Thr1620Met at 32°C, and steady-state
activation was significantly shifted. Our findings explain the features
of the ECG of Brugada patients, illustrate for the first time a cardiac
sodium channel mutation of which the arrhythmogenicity is revealed only
at temperatures approaching the physiological
range, and suggest that some patients may be more at risk during
febrile states.
Key Words: Brugada syndrome • Na+ channel • temperature
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A. A.M. Wilde and M. W. Veldkamp What we can learn from individual resuscitated patients Cardiovasc Res, April 1, 2000; 46(1): 14 - 16. [Full Text] [PDF]
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I. Deschenes, G. Baroudi, M. Berthet, I. Barde, T. Chalvidan, I. Denjoy, P. Guicheney, and M. Chahine Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes Cardiovasc Res, April 1, 2000; 46(1): 55 - 65. [Abstract] [Full Text] [PDF]
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J. R. Balser Sodium "Channelopathies" and Sudden Death : Must You Be So Sensitive? Circ. Res., October 29, 1999; 85(9): 872 - 874. [Full Text] [PDF]
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 I. Rivolta, H. Abriel, M. Tateyama, H. Liu, M. Memmi, P. Vardas, C. Napolitano, S. G. Priori, and R. S. Kass Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes J. Biol. Chem., August 10, 2001; 276(33): 30623 - 30630. [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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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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K. Gima and Y. Rudy Ionic Current Basis of Electrocardiographic Waveforms: A Model Study Circ. Res., May 3, 2002; 90(8): 889 - 896. [Abstract] [Full Text] [PDF]
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