Na(+) current expression in human atrial myofibroblasts: identity and functional roles

In the mammalian heart fibroblasts have important functional roles in both healthy conditions and diseased states. During pathophysiological challenges, a closely related myofibroblast cell population emerges, and can have distinct, significant roles. Recently, it has been reported that human atrial myofibroblasts can express a Na(+) current, I(Na). Some of the biophysical properties and molecular features suggest that this I(Na) is due to expression of Na(v) 1.5, the same Na(+) channel α subunit that generates the predominant I(Na) in myocytes from adult mammalian heart. In principle, expression of Na(v) 1.5 could give rise to regenerative action potentials in the fibroblasts/myofibroblasts. This would suggest an active as opposed to passive role for fibroblasts/myofibroblasts in both the “trigger” and the “substrate” components of cardiac rhythm disturbances. Our goals in this preliminary study were: (i) to confirm and extend the electrophysiological characterization of I(Na) in a human atrial fibroblast/myofibroblast cell population maintained in conventional 2-D tissue culture; (ii) to identify key molecular properties of the α and β subunits of these Na(+) channel(s); (iii) to define the biophysical and pharmacological properties of this I(Na); (iv) to integrate the available multi-disciplinary data, and attempt to illustrate its functional consequences, using a mathematical model in which the human atrial myocyte is coupled via connexins to fixed numbers of fibroblasts/myofibroblasts in a syncytial arrangement. Our experimental findings confirm that a significant fraction (approximately 40–50%) of these human atrial myofibroblasts can express I(Na). However, our data suggest that I(Na) may be generated by a combination of Na(v) 1.9, Na(v) 1.2, and Na(v) 1.5. Our results, when complemented with mathematical modeling, provide a background for re-evaluating pharmacological management of supraventricular rhythm disorders, e.g., persistent atrial fibrillation.