Remodeling Promotes Proarrhythmic Disruption of Calcium Homeostasis in Failing Atrial Myocytes

Area of Science:

• Computational Biology
• Cardiac Electrophysiology
• Biophysics

Background:

• Heart failure (HF) frequently coexists with atrial fibrillation (AF).
• The underlying mechanistic link between HF and AF remains unclear.
• Atrial myocyte structural remodeling in HF is implicated in AF pathogenesis.

Purpose of the Study:

• To establish a mechanistic link between HF-induced atrial myocyte remodeling and AF.
• To investigate the role of calcium (Ca) signaling disruption in HF-related AF.
• To model the generation and propagation of electrical waves in atrial tissue.

Main Methods:

• Utilized a multiscale computational framework.
• Employed a spatially distributed model of Ca signaling in atrial myocytes.
• Incorporated atrial cell models into 2D tissue simulations.

Main Results:

• Disruption of L-type Ca channel (LCC) and ryanodine receptor spatial relationships increases SR Ca content.
• Increased SR Ca load leads to subcellular Ca waves during the action potential (AP) in atrial myocytes.
• Subcellular Ca waves trigger electrical wave fractionation and conduction block in atrial tissue, promoting arrhythmias.

Conclusions:

• HF-induced alterations in atrial myocyte Ca handling mechanisms contribute to AF.
• Subcellular Ca waves, facilitated by atrial cell architecture, are a key mechanism for arrhythmia generation in HF.
• This study provides a mechanistic explanation for the increased propensity of atrial arrhythmias in heart failure.