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.