Acidosis: A Possible Trigger for Brugada Syndrome Associated Arrhythmia

Abstract

Brugada Syndrome (BrS) is an inherited cardiac arrhythmia implicated in SIDS and sudden death in young men. BrS is caused by loss-of-function mutations in the cardiac voltage-gated sodium channel NaV1.5. The decrease in sodium current can lead to electrical abnormalities in the ventricular action potential that can degenerate into ventricular tachycardia. The ECG phenotype and electrical abnormalities associated with BrS are not always present and are often unmasked clinically with sodium channel blockers. Paradoxically, BrS associated arrhythmias manifest during and after exercise as well as in sleeping infants. We hypothesize that one trigger for arrhythmias in BrS may be extracellular acidosis, which can occur during both exercise and sleep apnea. We used whole-cell patch clamp to characterize 3 BrS mutants, R376H, R1193Q, and E1784K, at pH 7.4 and pH 6.0. At pH 7.4 all mutants have reduced current compared to WT channels and there are changes in channel activation and fast inactivation. At pH 6.0, E1784K showed the largest proton-dependent effect with a 20 mV depolarizing shift in the midpoint voltage of activation compared to the 12 mV shift in WT. All 3 mutants showed decreased function at pH 6.0 although the magnitude of the shifts was not always different from WT. Overall, extracellular acidosis would be expected to challenge already decreased sodium currents, particularly in the E1784K mutant. Therefore, acidosis may be one of the triggers for arrhythmia in BrS patients.