Mechanisms underlying age-associated manifestation of cardiac sodium channel gain-of-function.

Cardiac action potentials are initiated by sodium ion (Na) influx through voltage-gated Na channels. Na channel gain-of-function (GOF) can arise in inherited conditions due to mutations in the gene encoding the cardiac Na channel, such as Long QT syndrome type 3 (LQT3). LQT3 can be a "concealed" disease, as patients with LQT3-associated mutations can remain asymptomatic until later in life; however, arrhythmias can also arise early in life in LQT3 patients, demonstrating a complex age-associated manifestation. We and others recently demonstrated that cardiac Na channels preferentially localize at the intercalated disc (ID) in adult cardiac tissue, which facilitates ephaptic coupling and formation of intercellular Na nanodomains that regulate pro-arrhythmic early afterdepolarization (EAD) formation in tissue with Na channel GOF. Several properties related to ephaptic coupling vary with age, such as cell size and Na channel and gap junction (GJ) expression and distribution: neonatal cells have immature IDs, with Na channels and GJs primarily diffusively distributed, while adult myocytes have mature IDs with preferentially localized Na channels and GJs. Here, we perform an in silico study varying critical age-dependent parameters to investigate mechanisms underlying age-associated manifestation of Na channel GOF in a model of guinea pig cardiac tissue. Simulations predict that total Na current conductance is a critical factor in action potential duration (APD) prolongation. We find a complex cell size/ Na channel expression relationship: increases in cell size (without concurrent increases in Na channel expression) suppress EAD formation, while increases in Na channel expression (without concurrent increases in cell size) promotes EAD formation. Finally, simulations with neonatal and early age-associated parameters predict normal APD with minimal dependence on intercellular cleft width; however, variability in cellular properties can lead to EADs presenting in early developmental stages. In contrast, for adult-associated parameters, EAD formation is highly dependent on cleft width, consistent with a mechanism underlying the age-associated manifestation of the Na channel GOF.