Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Abstract

Reduced cardiac sodium (Na⁺) channel current (I_Na) resulting from the loss-of-function of Na⁺ channel is a major cause of lethal arrhythmias in Brugada syndrome (BrS). Inspired by previous experimental studies which showed that in heart diseases I_Na was reduced along with expression changes in Na⁺ channel within myocytes, we hypothesized that the local decrease in I_Na caused by the alteration in Na⁺ channel expression in myocytes leads to the occurrence of phase-2 reentry, the major triggering mechanism of lethal arrhythmias in BrS. We constructed in silico human ventricular myocardial strand and ring models, and examined whether the Na⁺ channel expression changes in each myocyte cause the phase-2 reentry in BrS. Reducing Na⁺ channel expression in the lateral membrane of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, the selective reduction in Na⁺ channels on the lateral membrane of each myocyte together with spatial tissue heterogeneity of Na⁺ channel expression caused the phase-2 reentry and phase-2 reentry-mediated reentrant arrhythmias. Our data suggest that the BrS phenotype is strongly influenced by expression abnormalities as well as genetic abnormalities of Na⁺ channels.