Phase 2 Re-Entry Without I_to: Role of Sodium Channel Kinetics in Brugada Syndrome Arrhythmias

In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (I_to) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations.

The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of I_to.

Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models.

In the presence of I_to sufficient to generate robust P2R, reducing sodium current (I_Na) peak amplitude alone only slightly potentiated P2R. When I_Na inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of I_to. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. I_Na-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients.

Altered I_Na kinetics synergize powerfully with reduced I_Na amplitude to promote P2R-induced arrhythmias in BrS in the absence of I_to, establishing a robust mechanistic link between altered I_Na kinetics and the P2R-mediated arrhythmia mechanism.