Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome

Abstract

Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum. Ion channel dysfunction due to congenital or acquired defects has been linked to human cardiac arrhythmia. More recently, defects in ion channel-associated proteins have been associated with arrhythmia. Ankyrin-B is a multifunctional adapter protein responsible for targeting select ion channels, transporters, cytoskeletal proteins, and signaling molecules in excitable cells, including neurons, pancreatic β-cells, and cardiomyocytes. Ankyrin-B dysfunction has been linked to cardiac arrhythmia in human patients and ankyrin-B heterozygous (ankyrin-B(+/-)) mice with a phenotype characterized by sinus node dysfunction, susceptibility to ventricular arrhythmias, and sudden death ("ankyrin-B syndrome"). At the cellular level, ankyrin-B(+/-) cells have defects in the expression and membrane localization of the Na(+)/Ca(2+) exchanger and Na(+)-K(+)-ATPase, Ca(2+) overload, and frequent afterdepolarizations, which likely serve as triggers for lethal cardiac arrhythmias. Despite knowledge gathered from mouse models and human patients, the molecular mechanism responsible for cardiac arrhythmias in the setting of ankyrin-B dysfunction remains unclear. Here, we use mathematical modeling to provide new insights into the cellular pathways responsible for Ca(2+) overload and afterdepolarizations in ankyrin-B(+/-) cells. We show that the Na(+)/Ca(2+) exchanger and Na(+)-K(+)-ATPase play related, yet distinct, roles in intracellular Ca(2+) accumulation, sarcoplasmic reticulum Ca(2+) overload, and afterdepolarization generation in ankyrin-B(+/-) cells. These findings provide important insights into the molecular mechanisms underlying a human disease and are relevant for acquired human arrhythmia, where ankyrin-B dysfunction has recently been identified.

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

“…Computer code was written in C++ and compiled using Intel Composer XE 2011 for Linux. Computer simulations were performed on a Dell PowerEdge R515 server (dual 6 core, 32 GB RAM running CentOS 6.2), as described 21, 22, 27, 28, 29, 30. Regression was performed using MATLAB R2014b (MathWorks) on a MacBook Pro with a 2.5‐GHz Intel Core i7 processor (Apple Inc).…”

Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis

“…In ventricular myocytes, increased susceptibility to proarrhythmogenic calcium-dependent afterdepolarizations has been observed, likely because of, in part, the loss of membrane localization of Na ϩ /K ϩ ATPase (NKA) and Na ϩ /Ca 2ϩ exchanger (NCX) and associated imbalance in intracellular ion homeostasis (5,8,34,44). In atrial and sinoatrial node (SAN) cells, L-type Ca 2ϩ current is uniquely affected because of loss of membrane targeting of Ca v 1.3 (not expressed in ventricle) (9,27).…”

“…In previous work, we used a computational approach to analyze the substrate for stressinduced ventricular arrhythmias in ankyrin-B syndrome (44). We found that loss of NCX and NKA membrane targeting resulted in calcium overload under stress conditions, promoting inappropriate release of calcium from the sarcoplasmic reticulum and even afterdepolarizations.…”

Coordinating electrical activity of the heart: ankyrin polypeptides in human cardiac disease

“…Both the Na/K ATPase and the NCX are down-regulated in AnkB +/− hearts. This shifts the balance of fluxes in favor of Na accumulation [62;63]. Much like the effects of cardiac glycosides on contraction, this results in increased SR Ca 2+ load ([Ca] SRT ), and increased contractility [64].…”

“…This disruption of the EC coupling machinery reasonably explains why patients with ankyrin-B syndrome suffer from non-reentrant arrhythmias and CPVT, while partially explaining the high rate of AF (see section 3.3 below). While the actual mechanism for the often observed prolongation of the QT interval remains unknown, models point to the Na + accumulation arising from the loss of NCX and Na/K ATPase resulting in slowed or blocked conduction [62]. …”