Fibrotic Remodeling during Persistent Atrial Fibrillation: In Silico Investigation of the Role of Calcium for Human Atrial Myofibroblast Electrophysiology

During atrial fibrillation, cardiac tissue undergoes different remodeling processes at different scales from the molecular level to the tissue level. One central player that contributes to both electrical and structural remodeling is the myofibroblast. Based on recent experimental evidence on myofibroblasts’ ability to contract, we extended a biophysical myofibroblast model with Ca$^{2+}$ handling components and studied the effect on cellular and tissue electrophysiology. Using genetic algorithms, we fitted the myofibroblast model parameters to the existing in vitro data. In silico experiments showed that Ca$^{2+}$ currents can explain the experimentally observed variability regarding the myofibroblast resting membrane potential. The presence of an L-type Ca$^{2+}$ current can trigger automaticity in the myofibroblast with a cycle length of 799.9 ms. Myocyte action potentials were prolonged when coupled to myofibroblasts with Ca$^{2+}$ handling machinery. Different spatial myofibroblast distribution patterns increased the vulnerable window to induce arrhythmia from 12 ms in non-fibrotic tissue to 22 ± 2.5 ms and altered the reentry dynamics. ... mehrOur findings suggest that Ca$^{2+}$ handling can considerably affect myofibroblast electrophysiology and alter the electrical propagation in atrial tissue composed of myocytes coupled with myofibroblasts. These findings can inform experimental validation experiments to further elucidate the role of myofibroblast Ca$^{2+}$ handling in atrial arrhythmogenesis.