Bradycardia in LQT3 patients: insights from 0D models

Abstract

Type 3 of the long-QT syndrome (LQT3) is caused by mutations in the human cardiac sodium channel gene (SCN5A). LQT3 carriers regularly present with bradycardia and sinus pauses. This has been reported for carriers of the /spl Delta/K1500, /spl Delta/KPQ, E1784K, D1790G, and 1795insD mutations, which all show a persistent inward sodium current and/or a negative shift in voltage dependence of inactivation. The 1795insD channel had previously been characterized by a -10 mV. We hypothesized that the relative bradycardia that has been reported for carriers of the 1795insD mutation is, at least in part, due to intrinsic slowing of the sinus node. Therefore, we carried out computer simulations to test the effects of the 1795insD mutation on the intrinsic pacemaker activity of sinus node cells. We found that the negative shift in inactivation reduces sinus rate by slowing diastolic depolarization, whereas the persistent inward current reduces sinus rate by an increase in action potential duration, and that these effects are almost additive. Also, sinus node cells may fail to repolarize. We conclude that sodium channel mutations may account for the relative bradycardia and sinus node dysfunction seen in LQT3 patients.