An increase in intercellular crosstalk and electrotonic coupling between cardiomyocytes and nonmyocytes reshapes the electrical conduction in the metabolic heart characterized by short QT intervals in ECGs

Abstract

Cardiac conduction abnormalities are disorders in metabolic syndrome (MetS), however, their mechanisms are unknown. Although ventricular arrhythmia reflects the changes in QT-interval of electrocardiograms associated with the changes in cardiomyocyte action potential durations (APDs), recent studies emphasize role of intercellular crosstalk between cardiomyocytes and nonmyocytes via passive (electrotonic)-conduction. Therefore, considering the possible increase in intercellular interactions of nonmyocytes with cardiomyocytes, we hypothesized an early-cardiac-remodeling characterized by short QT-interval via contributions and modulations of changes by nonmyocytes to the ventricular APs in an early-stage MetS hearts. Following the feeding of 8-week-old rats with a high-sucrose diet (32%; MetS rats) and validation of insulin resistance, there was a significant increase in heart rate and changes in the electrical characteristics of the hearts, especially a shortening in action potential (AP) duration of the papillary muscles. The patch-clamp analysis of ventricular cardiomyocytes showed an increase in the Na⁺ -channel currents while there were decreases in l-type Ca²⁺ -channel (LTCC) currents with unchanged K⁺ -channel currents. There was an increase in the phosphorylated form of connexin 43 (pCx43), mostly with lateral localization on sarcolemma, while its unphosphorylated form (Cx43) exhibited a high degree of localization within intercalated discs. A high-level positively-stained α-SMA and CD68 cells were prominently localized and distributed in interfibrillar spaces of the heart, implying the possible contributions of myofibroblasts and macrophages to both shortened APDs and abnormal electrical conduction in MetS hearts. Our data propose a previously unrecognized pathway for SQT induction in the heart. This pathway includes not only the contribution of short ventricular-APDs via ionic mechanisms but also increasing contributions of the electrotonic-cardiomyocyte depolarization, spontaneous electrical activity-associated fast heterogeneous impulse conduction in the heart via increased interactions and relocations between cardiomyocytes and nonmyocytes, which may be an explanation for the development of an SQT in early-cardiac-remodeling.

Keywords: ECG; arrhythmia; connexin phosphorylation; electrical activity; heart function; insulin resistance; metabolic syndrome.