Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models.

Recent experimental studies have shown that fibroblasts can electrotonically couple to myocytes via gap junctions. In this study, we investigated how this coupling affects action potential and intracellular calcium (Ca(i)) cycling dynamics in simulated fibroblast-myocyte pairs and in two-dimensional tissue with random fibroblast insertions. We show that a fibroblast coupled with a myocyte generates a gap junction current flowing to the myocyte with two main components: an early pulse of transient outward current, similar to the fast transient outward current, and a later background current during the repolarizing phase. Depending on the relative prominence of the two components, fibroblast-myoycte coupling can 1) prolong or shorten action potential duration (APD), 2) promote or suppress APD alternans due to steep APD restitution (voltage driven) and also result in a novel mechanism of APD alternans at slow heart rates, 3) promote Ca(i)-driven alternans and electromechanically discordant alternans, and 4) promote spatially discordant alternans by two mechanisms: by altering conduction velocity restitution and by heterogeneous fibroblast distribution causing electromechanically concordant and discordant alternans in different regions of the tissue. Thus, through their coupling with myocytes, fibroblasts alter repolarization and Ca(i) cycling alternans at both the cellular and tissue scales, which may play important roles in arrhythmogenesis in diseased cardiac tissue with fibrosis.