Commentary: Reciprocal Modulation of IK1–INa Extends Excitability in Cardiac Ventricular Cells

We read with great interest the excellent paper by Varghese (2016) who describes an in silico approach to study the consequences of reciprocal regulation of expression of the sodium current (INa) and the inward rectifier potassium current (IK1) in the ventricle for cardiac excitability and conduction. The in silico approach follows the experimental results obtained by Milstein et al. (2012) who demonstrated functional co-regulation of the sodium and inward rectifier currents, and their underlying channel proteins Nav1.5 and KIR2.1 respectively, and electrophysiological consequences upon overexpression in rodent cardiomyocytes with respect to action potential duration and re-entry based arrhythmia propensity. Varghese adapted the guinea pig ventricular cardiomyocyte model, developed by Noble et al. (1998), that is extrapolated to simulations for one dimensional cardiac fibers, in which the fiber is represented as a linear cable model. Varghese changed either the conductance for INa and IK1 individually or in tandem, to assess their influence on the excitability of mammalian ventricular cardiomyocytes. One of the most interesting findings in this paper is the dominance of IK1 over INa in regulation of cardiac excitability, which yields important questions about the significance of the inward rectifier in this process (Varghese, 2016). This commentary will put these results in a broader context in order to provide a framework for future research questions.