Journal article
Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis
American journal of physiology. Heart and circulatory physiology, Vol.304(9), pp.H1253-H1266
02/22/2013
DOI: 10.1152/ajpheart.00734.2012
PMCID: PMC3652094
PMID: 23436330
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 Ca
v
1.3 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 Ca
v
1.3 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.
Details
- Title: Subtitle
- Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis
- Creators
- Roseanne M Wolf - The Ohio State UniversityPatric Glynn - The Ohio State UniversitySeyed Hashemi - University of IowaKeyan Zarei - University of IowaColleen C Mitchell - University of IowaMark E Anderson - University of IowaPeter J Mohler - The Ohio State UniversityThomas J Hund - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.304(9), pp.H1253-H1266
- DOI
- 10.1152/ajpheart.00734.2012
- PMID
- 23436330
- PMCID
- PMC3652094
- NLM abbreviation
- Am J Physiol Heart Circ Physiol
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Publisher
- American Physiological Society
- Language
- English
- Date published
- 02/22/2013
- Academic Unit
- Mathematics
- Record Identifier
- 9984240863902771
Metrics
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