In Silico Screening of the Key Electrical Remodelling Targets in Atrial Fibrillation-induced Sinoatrial Node Dysfunction

Atrial fibrillation (AF) is believed to shut down the normal function of sinoatrial node (SAN) by long-term overdrive suppression of its activity. Although AF-induced remodelling may impair SAN function, ionic mechanisms underlying sinus node dysfunction (SND) remain unclear. Here, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates SND through biophysically detailed computer modelling. The recent Fabbri et al. model of human SAN cell and our mathematical model for human atrial cell action potential were modified to incorporate various experimental data on AF-induced changes in ionic channel currents and intracellular calcium handling. In our simulations, AF-induced electrical remodelling abbreviated atrial action potential duration (APD) and lowered heart rates. APD abbreviation can be mainly attributed to reduced I CaL and increased potassium currents (I Ks and I K1 ). Down-regulation of I f prolonged cycle length and thereby influenced the function of voltage clock in human SAN cells. Altogether, our simulated results indicate that voltage clock malfunction might be one mechanism underlying AF-induced SND and our SND mathematical model can be a useful in the design of experiments and the development of drugs.