Electrical interaction between cardiomyocytes and non-myocytes in the metabolic heart contributes to the induction of short QT interval

Abstract

Abstract Metabolic syndrome (MetS) has impact on arrhythmia pathogenesis includes changes in QT-interval, reflecting time-course of ventricular myocyte action potentials (APs), while long or short QT-interval is associated with ventricular arrhythmias, further leading to sudden-cardiac-arrest. Cardiac conduction-system consists of distinct components besides cardiomyocytes such as non-myocytes and Cx43 via an electrotonic-conduction-coupling. Although there are well-coordination among them under physiological condition, there are important contributions of their changes in remodeling of the heart. To identify molecular mechanisms of SQT development under MetS, we investigated the involvement of non-myocyte-associated passive electrical-contribution in the cardiac remodeling by Cx43 contribution and macrophage coupling with cardiomyocytes. We used an early-state MetS rat model (with high-sucrose for 12–14 weeks), and we evaluated heart samples and freshly isolated ventricular cardiomyocytes by using both electrophysiological and histological investigations. There were significantly high heart rates and SQT in ECGs with a high ventricular contractile response to sympathetic stimulation in the MetS rats. The positive stained α-SMA and CD68 cell numbers were significantly prominent in interfibrillar spaces of hearts, together with prominent increases in expression and longitudinal cell membrane localization of phospho-Cx43. Moreover, there was a significantly shortened AP duration in the papillary muscles, at most, via increases of NaV1.5 density and decreases in L-type Ca2+-channel currents. Considering the electrotonic contribution by non-myocytes to intercellular propagation of APs with changes in phosphorylation and localization of Cx43 in the heart, we, for the first time, demonstrated that electrical-remodeling in early-stage MetS heart may be characterized by a short QT-interval with contributions of electrotonic coupling of excitable cells and non-myocytes, leading to activation of ephaptic-coupling, to be a preconditioning stimulus for development of long QT-interval in chronic MetS.