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

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Molecular Cardiology

Background:

• Ankyrin-B is crucial for stabilizing ion channels and transporters in excitable cells like cardiomyocytes.
• Ankyrin-B dysfunction is linked to sinoatrial node (SAN) dysfunction and atrial fibrillation, but mechanisms remain unclear.
• Previous research focused on ventricular arrhythmias, leaving atrial arrhythmias and SAN dysfunction poorly understood in ankyrin-B syndrome.

Purpose of the Study:

• To computationally model ankyrin-B dysfunction in atrial and SAN cells and tissue.
• To elucidate the molecular mechanisms underlying increased susceptibility to atrial fibrillation and SAN dysfunction in human patients.
• To investigate the combined effects of cellular and tissue-level changes in ankyrin-B deficiency.

Main Methods:

• Development of a computational model simulating ankyrin-B dysfunction in atrial and SAN cellular and tissue environments.
• Analysis of the impact of altered ion channel and transporter function on cellular electrophysiology.
• Simulation of tissue-level electrical propagation and pacemaker activity in the sinoatrial node.

Main Results:

• Defective targeting of Cav1.3 channels shortens action potentials, reducing the atrial tissue mass required for reentrant activation.
• Increased fibrosis leads to conduction slowing, further promoting sustained reentry.
• In SAN cells, Cav1.3 loss slows pacemaking; Na+/Ca2+ exchanger and Na+/K+ ATPase defects increase firing variability, leading to pacemaker shifts, exit block, and failure in simulated SAN tissue.

Conclusions:

• Ankyrin-B dysfunction mechanistically predisposes individuals to atrial fibrillation and SAN dysfunction through combined cellular and tissue-level alterations.
• Computational modeling successfully identified key molecular contributors to these cardiac arrhythmias and conduction defects.
• The findings provide a mechanistic basis for the observed clinical manifestations of ankyrin-B syndrome.