title: Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis.
abstract: Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction.
authors: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.
authors: Roseanne M
authors: RM
authors: Wolf
authors: Patric
authors: P
authors: Glynn
authors: Seyed
authors: S
authors: Hashemi
authors: Keyan
authors: K
authors: Zarei
authors: Colleen C
authors: CC
authors: Mitchell
authors: Mark E
authors: ME
authors: Anderson
authors: Peter J
authors: PJ
authors: Mohler
authors: Thomas J
authors: TJ
authors: Hund
mesh_terms: D000200:Action Potentials; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001281:Atrial Fibrillation / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003198:Computer Simulation; D005355:Fibrosis / Q000503:physiopathology; D006325:Heart Atria / Q000473:pathology; D006801:Humans; D051379:Mice; D008955:Models, Cardiovascular; D012849:Sinoatrial Node / Q000473:pathology / Q000503:physiopathology*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: C498995:Ank2 protein, mouse; D017487:Ankyrins; C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ankyrin-B; arrhythmia (mechanisms), atrial fibrillation; sinus node disease