Ventricular Repolarization – The Brugada Syndrome

Masayasu Hiraoka and Yuji Hirano

Department of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University,
Tokyo, Japan

Correspondence: M Hiraoka, Deaprtment of Cardiovascular Diseases, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Munkyo-ku, Tokyo 113-8510, Japan.
E-mail: hiraoka.card@mri.tmd.ac.jp, phone +81-3-5803-5829, fax +81-3-5684-6295

1.    Introduction

The Brugada syndrome is characterized by a unique ECG waveform of ST elevation in the right precordial leads (V1-V3) and development of ventricular fibrillation in subjects with apparently normal heart. The mechanism of ST elevation in the Brugada syndrome is implicated by different action potential repolarization between epicardial and endocardial cells in the right ventricular outflow tract. A notch caused by a prominent I_to at early phase of repolarization in epicardial but not in endocardial action potentials is exacerbated by decreased inward Na⁺ current, which forms the basis of ST elevation [Yan and Antzelevitch 1999]. Several lines of evidence support the involvement the Na⁺ channel dysfunction in the genesis of ST elevation; Mutations in Na⁺ channel gene, SCN5A, have been found in familiar and some sporadic cases of the Brugada syndrome. Expressed currents of the mutated genes exhibit either a loss of current expression or decreased channel functions (Chen et al 1998). The latter defects mostly show abnormalities in inactivation properties of the Na⁺ channels. Cardiac Na⁺ channels exhibit multiple steps of inactivation, such as a rapid, intermediate and slow. It is not known which step of the inactivation play an essential role for the repolarization abnormality seen in the Brugada syndrome.

2.    Material and Methods

Computer simulations were conducted using the models of cardiac action potentials reported by Luo & Rudy (1994), and by our new model equipped with Ca²⁺-entry dependent inactivation property of L-type Ca channels (Hirano & Hiraoka, 2003). Formulation of I_to described by Dumaine et al (1999) was introduced to these models with several re-scaling of current systems, to keep appropriate action potential shapes and durations for different cell types (ventricular epicardial, endocardial and M cells, etc.).

 We employed classical Hodgkin-Huxley type (H-H) formulations to describe the Na⁺ current (I_Na ), based on the Ebihara-Johnson formulation as described in the paper by Luo & Rudy (1994). In this study, we introduced additional inactivation parameters describing intermediate (t~70msec) and slow (t>5sec) inactivation processes based on experimental data, including those reported by Veldkamp et al (2000).

3.    Results

The introduction of I_to produced a "notch" in action potentials as typically seen in ventricular epicardial cells. For epicardial cells, changes in I_Na amplitudes produced by the modification of inactivation properties (either fast, intermediate or slow inactivation) contributed to elicit early repolarization changes or "loss of dome" of action potentials.

Acceleration of "fast inactivation" (reduced time constants for h and j) decreased peak I_Na and caused an early repolarization with increased notch or action potentials without producing the "dome". During rapid stimulation, "intermediate inactivation" parameters cycled between partial inactivation and recovery. The decrease in I_Na by this parameter, however, was largest at the second action potential with little changes thereafter in successive beats. On the other hand, "slow inactivation" parameters continued to decline during stimulations. Changes in these inactivation parameters produced variable morphology of action potentials in beat-by-beat basis, which were rate-dependent.

4.    Discussion

With the introduction of parameters of I_to, decreased I_Na easily reproduced increased notch in the early repolarization or “loss of dome” of abortive action potential repolarization in our computer simulation model. Impairments of the inactivation properties in the Na⁺ channels either with faster kinetics in the fast inactivation or slowed kinetics for both the intermediate and the slow inactivation elicited changes in action potential repolarization compatible to epicardial action potentials presumed to be the basis for ST elevation seen in the Brugada syndrome. In addition, changes in the parameters of the fast and slow inactivation processes contributed to action potential alterations in beat-by-beat basis, which may provide a substrate for reentry.

5.    Conclusions

Impairments in inactivation properties of Na⁺ channel cause repolarization changes and provide a substrate for reentry in the Brugada syndrome.

Acknowledgements

Supported by the Research Grant for Cardiovascular Diseases (13-A) from the Ministry of Health, Labor and Welfare of Japan.

References

Yan G-X, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999;100:1660-1666.

Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature.1998; 392: 293-296.

Luo CH, Rudy Y. A dynamic model of cardiac ventricular action potential. I. simulations of ionic currents and concentration changes. Circ.Res. 74:1071-1096, 1994

Hirano Y, Hiraoka M. Ca²⁺ entry-dependent inactivation of L-type Ca current: A novel formulation for cardiac action potential models. Biophys.J. 84:696-708, 2003

Veldkamp MW, Viswanathan PC, Bezzina C, Baartscheer A, Wilde AAM, Balser JR. Two distinct congenital arrhythmias evoked by a multidysfunctional Na channel. Circ.Res. 86:e91-e97, 2000

Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ.Res. 85:803-809, 1999