Why Is Only Type 1 Electrocardiogram Diagnostic of Brugada Syndrome? Mechanistic Insights From Computer Modeling

Three types of characteristic ST-segment elevation are associated with Brugada syndrome but only type 1 is diagnostic. Why only type 1 ECG is diagnostic remains unanswered.

Computer simulations were performed in single cells, 1-dimensional cables, and 2-dimensional tissues to investigate the effects of the peak and late components of the transient outward potassium current (I_to), sodium current, and L-type calcium current (I_Ca,L) as well as other potassium currents on the genesis of ECG morphologies and phase 2 reentry (P2R).

Although a sufficiently large peak I_to was required to result in the type 1 ECG pattern and P2R, increasing the late component of I_to converted type 1 ECG to type 2 ECG and suppressed P2R. Increasing the peak I_to promoted spiral wave breakup, potentiating the transition from tachycardia to fibrillation, but increasing the late I_to prevented spiral wave breakup by flattening the action potential duration restitution and preventing P2R. A sufficiently large I_Ca,L conductance was needed for P2R to occur, but once above the critical conductance, blocking I_Ca,L promoted P2R. However, selectively blocking the window and late components of I_Ca,L suppressed P2R, countering the effect of the late I_to. Blocking either the peak or late components of sodium current promoted P2R, with the late sodium current blockade having the larger effect. As expected, increasing other potassium currents potentiated P2R, with ATP-sensitive potassium current exhibiting a larger effect than rapid and slow component of the delayed rectifier potassium current.

The peak I_to promotes type 1 ECG and P2R, whereas the late I_to converts type 1 ECG to type 2 ECG and suppresses P2R. Blocking the peak I_Ca,L and either the peak or the late sodium current promotes P2R, whereas blocking the window and late I_Ca,L suppresses P2R. These results provide important insights into the mechanisms of arrhythmogenesis and potential therapeutic targets for treatment of Brugada syndrome. Graphic Abstract: A graphic abstract is available for this article.