Mechanism of Sinus Node Dysfunction in Carriers of the E161K Mutation in the SCN5A Gene

Abstract

Heterozygous carriers of the E161K mutation in the SCN5A gene, which encodes the Na V 1.5 pore-forming αsubunit of the ion channel carrying the cardiac fast sodium current (I Na), show sinus node dysfunction. We assessed the mechanism by which the E161K mutation causes sinus bradycardia and reduces atrial excitability, as well as the potential role of the common H558R polymorphism. To this end, we incorporated reported mutation-induced changes in I Na into the recently developed Fabbri-Severi model of a single human sinoatrial node (SAN) cell. The threshold current of the Courtemanche-Ramirez-Nattel human right atrial cell model was used as a measure of atrial excitability. The E161K/H558 mutation significantly increased the cycle length of the SAN cell, in particular under vagal tone. The mutant component of I Na was effectively zero, thus slowing diastolic depolarization. Highly similar results were obtained with the E161K/R558 mutation. The E161K mutation increased the threshold stimulus current of the atrial cell by a factor of ≈2.2, virtually independent of the H558 or R558 background. We conclude that the E161K mutation underlies the clinically observed sinus node dysfunction. Furthermore, we conclude that the common H558R polymorphism does not significantly alter the effects of the E161K mutation.