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

• Published in: Journal of molecular and cellular cardiology 2021-04, Vol.153, p.60-71
• Main Authors: Nowak, Madison B., Poelzing, Steven, Weinberg, Seth H.
• Format: Article
• Language: English
• Subjects: Action Potentials; Adult; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - pathology; Cardiac Conduction System Disease - genetics; Cardiac Conduction System Disease - metabolism; Cardiac electrophysiology; Computational models; Gain of Function Mutation; Gap Junctions - physiology; Humans; Infant, Newborn; Intercalated disc; Long QT syndrome; Long QT Syndrome - genetics; Long QT Syndrome - metabolism; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Sodium - metabolism; Sodium channels
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.12.008

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. [Display omitted] •Long QT syndrome type 3 can present early in life or be concealed to adulthood.•Age-dependent properties regulate LQT3-associated Na + channel gain-of-function.•Cell size and Na + channel density increases promote arrhythmias in neonatal tissue.•Intercel