Pro-arrhythmic Effects Of Fibroblast-myocyte Coupling In Simulated Cardiac Tissue

Abstract

Fibroblasts comprise the majority of non-cardiac cells in normal heart and mediate the structural remodeling underlying progressive fibrosis in cardiac diseases. Recent experimental studies have shown that fibroblasts can electronically couple to myocytes via gap junctions and alter myocyte electrophysiology. However, the implications for cardiac arrhythmias are incompletely understood. In this study, we used mathematical modeling and computer simulation to investigate how fibroblast-myocyte coupling affects the dynamics of action potential duration (APD), excitation-contraction coupling, and alternans. Our major findings are: 1) Fibroblast-myocyte coupling shortens APD when fibroblast membrane conductance is high and resting membrane potential is low, but prolongs APD for other choices of conductance and resting potential. 2) Depending on the membrane conductance and resting potential of fibroblasts, fibroblast-myocyte coupling can either promote or suppress APD alternans by steepening or flattening APD restitution. 3) When alternans is calcium-driven, fibroblast-myocyte coupling always promotes alternans, and can result in electromechanically discordant alternans. 4) In cardiac tissue, fibroblast-myocyte coupling slows conduction velocity and broadens its restitution, promoting spatially discordant alternans. Spatially discordant alternans can also arise from electromechanically concordant alternans and electromechanically discordant alternans in different regions of the tissue. In conclusion, fibroblast-myocyte coupling has multiple pro-arrhythmic effects on electrophysiological properties in cardiac tissue.