Low Expression Levels of Sodium Channels in the Right Ventricular Outflow Tract Underly the Genesis of the Characteristic Electrocardiogram Waveform in Brugada Syndrome

BACKGROUND: Despite active research into the pathophysiology of Brugada syndrome (BrS), the mechanisms of the genesis of changes in the characteristic electrocardiogram (ECG) are still controversial. METHODS AND RESULTS: Using multiscale computer simulation of ECGs, we compared 3 hypotheses to identify the mechanisms of the BrS-type ECG caused by a mutation in cardiac sodium channels. In addition to the dominant repolarization disorder and depolarization disorder hypotheses, we tested a new hypothesis assuming the combination of a slow conduction property, upregulation of transient outward potassium current channels, and reduced expression levels of sodium channels in the right ventricular outflow tract (embryonic phenotype model). We found that only the embryonic phenotype model reproduced the clinically observed BrS-type ECG by strongly inhibiting sodium current selectively in the right ventricular outflow tract. We also simulated a ventricular wedge experiment and confirmed that strong inhibition of the sodium current was the prerequisite for a change in the ECG. CONCLUSIONS: Strong selective inhibition of the sodium current in the right ventricular outflow tract generates the characteristic BrS-type ECG in the precordial leads without affecting the waveforms in other lead positions. This change can only be achieved using the embryonic phenotype model in which reduced expression levels of sodium channels play an essential role.