A Multiscale In Silico Study to Characterize the Atrial Electrical Activity of Patients With Atrial Fibrillation : A Translational Study to Guide Ablation Therapy

Atrial fibrillation is the most common cardiac arrhythmia. During atrial fibrillation, the atrial substrate undergoes a series of electrical and structural remodeling processes. The electrical remodeling is characterized by the alteration of specific ionic channels, which changes the morphology of the transmembrane voltage known as action potential. Structural remodeling is a complex process involving the interaction of several signalling pathways, cellular interaction, and changes in the extracellular matrix. During structural remodeling, fibroblasts, abundant in the cardiac tissue, start to differentiate into myofibroblasts, which are responsible for maintaining the extracellular matrix structure by depositing collagen. Additionally, myofibroblasts paracrine signalling with surrounding myocytes will also affect ionic channels.

Highly detailed computational models at different scales were used to study the effect of structural remodeling induced at the cellular and tissue levels. At the cellular level, a human fibroblast model was adapted to reproduce the myofibroblast electrophsyiology during atrial fibrillation. Additionally, the calcium handling in myofibroblast electrophysiology was assessed by fitting a calcium ion channel to experimental data. ... mehrAt the tissue level, myofibroblast infiltration was studied to quantify the increase of vulnerability to cardiac arrhythmia. Myofibroblasts alter the dynamics of reentry. A low density of myofibroblasts allows the propagation through the fibrotic area and creates focal activity exit points and wave breaks inside this area. Moreover, fibrosis composition plays a key role in the alteration of the propagation pattern. The alteration of the propagation pattern affects the electrograms computed at the surface of the tissue. Electrogram morphology was altered depending on the arrangement and composition of the fibrotic tissue.

Detailed cardiac tissue models were combined with realistic models of the commercially available mapping catheters to understand the clinically recorded signals. A noise model from clinical signals was generated to reproduce the signal artifacts in the model. Electrograms from highly detailed bidomain models were used to train a machine learning algorithm to characterize the atrial fibrotic substrate. Features that quantify the complexity of the signals were extracted to identify fibrotic density and fibrotic transmurality. Subsequently, fibrosis maps were generated using patient recordings as a proof of concept. A fibrosis map provides information about the fibrotic substrate without using a single cut-off voltage value of 0.5 mV. Furthermore, in this study, using information theory measurements such as transfer entropy combined with directed graphs, the wave propagation direction was tracked. Transfer entropy with directed graphs provides crucial information during electrophysiology to understand wave propagation dynamics during atrial fibrillation.

In conclusion, this thesis presents a multiscale in silico study of atrial fibrillation mechanisms providing insight into the cellular mediators responsible for the extracellular matrix remodeling and its electrophysiology. Additionally, it provides a realistic setup to create in silico data that can be translated to clinical applications that could support ablation treatment.