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Mechanisms of Disease: current understanding and future challenges in Brugada syndrome

Nature Clinical Practice Cardiovascular Medicine volume 2, pages 408–414 (2005)Cite this article

Abstract

Brugada syndrome is a clinical entity characterized by ST-segment elevation in the right precordial leads (V1–V3) and an episode of ventricular fibrillation in the absence of structural heart disease. Data regarding genotype–phenotype relationships are limited, since SCN5A, the gene encoding the α subunit of the sodium channel, is as yet the only gene linked to Brugada syndrome. Studies of SCN5A mutations responsible for the Brugada phenotype have shown the presence of functional defects in the sodium-channel current. Experimental studies employing arterially perfused right-ventricular wedge preparations have elucidated cellular mechanisms for this phenotype. Data indicate that an accentuated action-potential notch, mediated by a prominent transient outward current and loss of the action-potential dome in the epicardium (but not in the endocardium) of the right ventricle give rise to a transmural voltage gradient, resulting in ST-segment elevation and the induction of ventricular fibrillation. On the basis of cellular mechanisms, it might be possible to normalize the Brugada phenotype by use of therapeutic agents or interventions that decrease net outward currents by decreasing the transient outward current or outward potassium currents, or increasing the L-type inward calcium current or fast sodium current. Interventions that increase net outward currents through raising the transient outward current or outward potassium currents or decreasing the L-type inward calcium current or fast sodium current might aggravate or unmask the Brugada phenotype, resulting in an acquired form of this syndrome. In this review, we discuss future challenges relating to risk stratification, genetic heterogeneity, sex and ethnic differences in Brugada syndrome.

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Figure 1: Coved-type ST-segment elevation and subsequent nonsustained polymorphic ventricular tachycardia caused by premature beats induced by phase 2 re-entry in a Brugada model, employing an arterially perfused canine right-ventricular wedge preparation.
Figure 2: Snapshots of a color isopotential optical movie of the epicardial surface at the beginning of polymorphic ventricular tachycardia, and a repolarization map of the epicardial surface just before ventricular fibrillation.

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Acknowledgements

We thank Ichiro Hidaka, Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, Japan, for expert technical assistance. W Shimizu was supported by the Hoansha Research foundation, the Mitsubishi Pharma Research Foundation, the Vehicle Racing Commemorative Foundation, and health sciences research grants from the Ministry of Health, Labour and Welfare, and a research grant for cardiovascular diseases (15C-6) from the Ministry of Health, Labour and Welfare, Japan.

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine,

    Wataru Shimizu, Takeshi Aiba & Shiro Kamakura

  2. Department of Cardiovascular Dynamics, Research Institute, of the National Cardiovascular Center, Osaka, Japan

    Wataru Shimizu, Takeshi Aiba & Shiro Kamakura

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  1. Wataru Shimizu
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Correspondence to Wataru Shimizu.

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Glossary

ITO

A transient outward potassium current that activates rapidly and underlies the early (phase 1) action-potential repolarization

IK

An outward potassium current that determines the late phase (phase 3) of action-potential repolarization

FAST INA

An inward sodium current that mainly contributes to the upstroke of action-potential depolarization (phase 0)

L-TYPE ICA

An inward calcium current that is activated by membrane depolarization and contributes to the plateau phase of action potential

AUTOSOMAL DOMINANT

A pattern of Mendelian inheritance whereby an affected individual possesses one copy of a mutant allele and one normal allele

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Shimizu, W., Aiba, T. & Kamakura, S. Mechanisms of Disease: current understanding and future challenges in Brugada syndrome. Nat Rev Cardiol 2, 408–414 (2005). https://doi.org/10.1038/ncpcardio0268

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