Effects of Na+ Current and Mechanogated Channels in Myofibroblasts on Myocyte Excitability and Repolarization

Fibrotic remodeling, characterized by fibroblast phenotype switching, is often associated with atrial fibrillation and heart failure. This study aimed to investigate the effects on electrotonic myofibroblast-myocyte (Mfb-M) coupling on cardiac myocytes excitability and repolarization of the voltage-gated sodium channels (VGSCs) and single mechanogated channels (MGCs) in human atrial Mfbs. Mathematical modeling was developed from a combination of (1) models of the human atrial myocyte (including the stretch activated ion channel current, 𝐼SAC) and Mfb and (2) our formulation of currents through VGSCs (𝐼Na Mfb) and MGCs (𝐼MGC Mfb) based upon experimental findings. The effects of changes in the intercellular coupling conductance, the number of coupled Mfbs, and the basic cycle length on the myocyte action potential were simulated. The results demonstrated that the integration of 𝐼SAC, 𝐼Na Mfb, and 𝐼MGC Mfb reduced the amplitude of the myocyte membrane potential (𝑉max) and the action potential duration (APD), increased the depolarization of the resting myocyte membrane potential (𝑉rest), and made it easy to trigger spontaneous excitement in myocytes. For Mfbs, significant electrotonic depolarizations were exhibited with the addition of 𝐼Na Mfb and 𝐼MGC Mfb. Our results indicated that 𝐼SAC, 𝐼Na Mfb, and 𝐼MGC Mfb significantly influenced myocytes and Mfbs properties and should be considered in future cardiac pathological mathematical modeling.