The Ionic Mechanisms of Triggered Atrial Activity Under a TBX5-driven Regulatory Network

Abstract

Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice, yet the pathophysiology by which genetic factors can increase the risk of AF is not well understood. Recently, a multitiered transcriptional network, driven by a T-box transcription factor gene TBX5 and a paired-like homeodomain transcription factor 2 gene PITX2 was discovered. This transcriptional network regulates gene expressions associated with ion channels in a complex fashion, and through mice knockout studies, it was found that reducing the expression of TBX5 altered the gene expressions of certain types of ion channels and generated abnormal depolarizations in the form of early afterdepolarizations, delayed afterdepolarizations, or spontaneous triggered action potentials. To systematically investigate the ionic mechanisms by which impaired TBX5 can lead to AF, we integrated the calcium dynamics of the Grandi et al. model into the Courtemanche-Ramirez-Nattel model. Our model reproduced all forms of abnormal depolarizations observed in TBX5 knockout atrial myocytes. Furthermore, we discovered that the remodeling of the inward-rectifier potassium channel (IK1) and the L- type calcium channel (ICaL), due to impaired TBX5, causes an elevation in the concentration of calcium ([Ca2+]), which reactivates the sodium-calcium exchanger (INaCa) and ICaL to generate abnormal depolarizations.