The Role of the Ina-Ik1 Complex on Human Ventricular Conduction Velocity

Abstract

Conduction velocity (CV) IntroductionSeveral cardiac diseases exhibit dispersion of electrical conduction velocity (CV), including atrial fibrillation [1], Brugada Syndrome [2], hypertrophic cardiomyopathy [3] and arrhythmogenic right ventricular cardiomyopathy (ARVC) [4]. Slow and heterogeneous CV, in combination with appropriate anatomical substrates, translates into an increased risk of re-entry. Even in the absence of structural heart changes, such as in early-stage ARVC patients with ion channel remodelling but otherwise healthy hearts [4], CV abnormalities have been shown to cause sudden cardiac death in young individuals [5].Cardiac voltage-gated sodium channels (INa) are transmembrane proteins responsible for regulating the flow of sodium ions. Loss-of-function mutations in INa channels have been implicated in lethal arrhythmias [6]. The inward rectifier current (IK1) stabilises the resting membrane potential of the human action potential (AP). IK1 downregulation has been also experimentally linked to the creation of regional differences in cardiac excitability [7].Emerging experimental evidence suggests that ionic channels are not regulated independently and are organised in macromolecular complexes. The INa-IK1 ion channels form one such complex, recently shown to control cardiac excitability and arrhythmia by Milstein et al. [8]. Their inter-species study concluded that an increase in functional expression of one channel reciprocally modulates the expression of the other to maximise cardiac excitability.The This study extends to human electrophysiology the in silico study by Varghese [10], where CV modulation by the INa-IK1 complex was investigated using a mammalian model. Importantly, we focus on INa-IK1 downregulation rather than its overexpression, given the reported role of reduced function of these channels in arrhythmogenesis. We further investigate rate-dependence interactions of the INa-IK1 complex on human ventricular CV, as well as its modulation by [K + ]o plasma levels. Methods Human tissue electrophysiology modelAt the cellular level, this study was conducted using the O'Hara-Rudy (ORd) model, as state-of-the-art and most extensively validated human cardiac electrophysiology model [11], which incorporates all main ionic channels and subcellular processes involved in the human AP.