Copyright © 2005, European Society of Cardiology
Brugada syndrome and fever: Genetic and molecular characterization of patients carrying SCN5A mutations
aService of Cardiology, CHUV, Lausanne, Switzerland
bDepartment of Pharmacology and Toxicology, University of Lausanne, Switzerland
cDepartment of Cardiology, University Hospital, Basel, Switzerland
dDepartment of Physiology, University of Bern, Switzerland
eINSERM U582, Institut de Myologie, IFR14, Pitié-Salpêtrière Hospital, Paris, France
fService of Biochemistry B, IFR 14, Pitié-Salpêtrière Hospital, Paris, France
gSecond Department of Medicine, University Hospital, 30599 Pilzen, Czech Republic
* Corresponding authors. H. Abriel is to be contacted at Service of Cardiology, and Department of Pharmacology and Toxicology, University of Lausanne, Bugnon, 27, 1005 Lausanne, Switzerland. Tel.: +41 21 6925364; fax: +41 21 6935355. J. Schläpfer, Service of Cardiology, CHUV and University of Lausanne, 1011 Lausanne, Switzerland. Tel.: +41 21 3140052; fax: +41 21 3140013. Email address: Jurg.Schlaepfer{at}chuv.hospvd.ch Hugues.Abriel{at}unil.ch
Objective: Brugada syndrome (BrS) is characterized by ventricular tachyarrhythmias leading to sudden cardiac death and is caused, in part, by mutations in the SCN5A gene encoding the sodium channel Nav1.5. Fever can trigger or exacerbate the clinical manifestations of BrS. The aim of this work was to characterize the genetic and molecular determinants of fever-dependent BrS.
Methods: Four male patients with typical BrS ST-segment elevation in V1–V3 or ventricular arrhythmias during fever were screened for mutations in the SCN5A gene. Wild-type (WT) and mutant Nav1.5 channels were expressed in HEK293 cells. The sodium currents (INa) were analysed using the whole-cell patch clamp technique at various temperatures. Protein expression of WT and mutant channels was studied by Western blot experiments.
Results: Two mutations in SCN5A, L325R and R535X, were identified. Expression of the two mutant Nav1.5 channels in HEK293 cells revealed in each case a severe loss-of-function. Upon the increase of temperature up to 42 °C, we observed a pronounced acceleration of Nav1.5 activation and fast inactivation kinetics. Cardiac action potential modelling experiments suggest that in patients with reduced INa, fever could prematurely shorten the action potential by virtue of its effect on WT channels. Further experiments revealed that L325R channels are likely misfolded, since their function could be partially rescued by mexiletine or curcumin. In co-expression experiments, L325R channels interfered with the proper function of WT channels, suggesting that a dominant negative phenomenon may underlie BrS triggered by fever.
Conclusions: The genetic background of BrS patients sensitive to fever is heterogeneous. Our experimental data suggest that the clinical manifestations of fever-exacerbated BrS may not be mutation specific.
KEYWORDS Arrhythmia (mechanism); Na-channel; Sudden death
1 Both authors contributed equally to this study.
Time for primary review 23 days
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