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

BACKGROUND

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

OBJECTIVES

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

METHODS

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

RESULTS

In the presence of I sufficient to generate robust P2R, reducing sodium current (I) peak amplitude alone only slightly potentiated P2R. When I 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. 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-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients.

CONCLUSIONS

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