TY - JOUR
T1 - Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome
T2 - A computational analysis
AU - Wolf, Roseanne M.
AU - Glynn, Patric
AU - Hashemi, Seyed
AU - Zarei, Keyan
AU - Mitchell, Colleen C.
AU - Anderson, Mark E.
AU - Mohler, Peter J.
AU - Hund, Thomas J.
N1 - Funding Information:
This study was supported by the National Institutes of Health (NIH) (U01HL89709, U01HL089786, U01HL089907, and U01HL089645), St. Jude Medical Drug Foundation and Corporation , Biosense Webster, Medtronic, and Boston Scientific Corporation. The content of this article does not necessarily represent the views of the National Heart, Lung, and Blood Institute (NHLBI) or the Department of Health and Human Services. Dr. Poole has received research funding from ATriCure, Biotronik, Medtronic, and Kestra, Inc. outside of the submitted work; has served on the Advisory Board with compensation for Boston Scientific; has served as a speaker with honoraria from Boston Scientific, Medtronic, and MediaSphere Medical; and has served on a Data and Safety Monitoring Board on a study funded by EBR Systems. Dr. Bahnson has received grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study; has received grants from St. Jude Medical, Abbott Medical, Medtronic, Biosense Webster, Johnson & Johnson, NIH, and Boston Scientific; has received consulting fees from Cardiofocus and Ventrix outside of the submitted work; and has patents pending for a catheter for intracardiac imaging and intracardiac electrogram signal analysis. Dr. Monahan has received grants from the NIH/NHLBI, St. Jude Foundation and Corporation, Biosense Webster, Medtronic, and Boston Scientific during the conduct of the study; has served as a consultant without compensation for Biosense Webster; and has received personal fees from Thermedical outside of the submitted work. Dr. Al-Khalidi has received grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study. Dr. Mark has received grants from the NIH/NHLBI and Mayo Clinic during the conduct of the study; has received grants from Merck, Oxygen Therapeutics, Bristol-Myers Squibb, AstraZeneca, the University of Calgary, Eli Lilly & Company, AGA Medical, St. Jude Medical, and Tufts University; and has received personal fees from CeleCor outside of the submitted work. Dr. Lee has received grants from the NIH/NHLBI, Mayo Clinic, St. Jude Medical Foundation and Corporation, Biosense Webster, Medtronic, and Boston Scientific; and has served on Data and Safety Monitoring Boards on studies funded by AstraZeneca, Medtronic, Merck, Amgen, and the Cardiovascular Research Foundation during the conduct of the study. Dr. Packer has received grants from the NIH/NHLBI, St. Jude Medical Corporation and Foundation, Biosense Webster, Medtronic, and Boston Scientific during the conduct of the study; has received grants from Abbott, Biosense Webster, Boston Scientific, CardioFocus, Medtronic, St. Jude Medical, CardioInsight, NIH, Siemens, Thermedical, Endosense, Robertson Foundation, and Hansen Medical; has served on the Advisory Board without compensation for Abbott, Biosense Webster, Boston Scientific, CardioFocus, Medtronic, St. Jude Medical, Spectrum Dynamics, Siemens, Thermedical, Johnson & Johnson, and SigNum Preemptive Healthcare Inc.; has served as a speaker with honorarium from Biotronik and MediaSphere Medical LLC; has received royalties from Wiley & Sons, Oxford, and St. Jude Medical; has equity jointly with Mayo Clinic in a privately held company, External Beam Ablation Medical Devices, outside of the submitted work; and has mapping technologies with royalties paid. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
PY - 2013
Y1 - 2013
N2 - 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 Ca2+ 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+/Ca2+ 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.
AB - 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 Ca2+ 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+/Ca2+ 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.
KW - Ankyrin-B
KW - Arrhythmia (mechanisms)
KW - Atrial fibrillation
KW - Sinus node disease
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U2 - 10.1152/ajpheart.00734.2012
DO - 10.1152/ajpheart.00734.2012
M3 - Article
C2 - 23436330
AN - SCOPUS:84878618708
SN - 0363-6135
VL - 304
SP - H1253-H1266
JO - American Journal of Physiology
JF - American Journal of Physiology
IS - 9
ER -