Effect of myocyte-fibroblast coupling on the onset of pathological dynamics in a model of ventricular tissue

Area of Science:

• Cardiology
• Computational Biology
• Biophysics

Background:

• Managing lethal cardiac arrhythmias remains a significant challenge in cardiology.
• Early afterdepolarizations (EADs) are known cellular mechanisms contributing to arrhythmias.
• Cardiac fibrosis, associated with aging and heart disease, is another arrhythmogenic factor, but its role in tissue-level arrhythmias is not fully understood.

Purpose of the Study:

• To investigate the effects of diffuse cardiac fibrosis on arrhythmias originating from cellular EADs.
• To explore the influence of fibroblast-cardiac myocyte (M-F) coupling on EADs and arrhythmia occurrence.
• To determine if specific fibrotic patterns promote ectopic activity.

Main Methods:

• Utilized an in-silico systematic study approach.
• Employed the TNNP model for human cardiac cells and the MacCannell model for (myo)fibroblasts.
• Simulated the effects of diffuse fibrosis on EADs and arrhythmia generation.

Main Results:

• The resting potential of fibroblasts (VFR) influences M-F coupling, which can either expand or contract the parameter space leading to EADs.
• Cardiac fibrosis increases the likelihood of arrhythmias following a single focal stimulation.
• The pro-arrhythmic effect of fibrosis intensifies with stronger M-F coupling.
• Arrhythmias in simulations arose from fibrosis-induced ectopic activity, irrespective of specific fibrotic patterns.

Conclusions:

• Fibroblast-cardiac myocyte coupling plays a complex role in modulating EADs and arrhythmia susceptibility.
• Diffuse cardiac fibrosis, particularly with strong M-F coupling, enhances the risk of arrhythmias through ectopic beats.
• The study highlights the importance of M-F interactions in fibrosis-related arrhythmogenesis, independent of specific fibrotic architectures.