Departments of Histology-Embryology, Faculty of Medicine, Ankara University, Ankara, Türkiye.
Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Türkiye.
Cell Biochem Funct. 2023 Dec;41(8):1526-1542. doi: 10.1002/cbf.3893. Epub 2023 Nov 28.
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 Ca -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.
心脏传导异常是代谢综合征（MetS）中的一种紊乱，但其机制尚不清楚。尽管室性心律失常反映了与心肌细胞动作电位时程（APD）变化相关的心电图 QT 间期变化，但最近的研究强调了心肌细胞和非心肌细胞之间通过被动（电）传导的细胞间串扰作用。因此，考虑到非心肌细胞与心肌细胞之间的细胞间相互作用可能增加，我们假设在早期 MetS 心脏中，通过非心肌细胞对心室 APs 的变化的贡献和调节，存在以短 QT 间期为特征的早期心脏重塑。在给 8 周龄大鼠喂食高蔗糖饮食（32%；MetS 大鼠）并验证胰岛素抵抗后，心率显著增加，心脏电特性发生变化，特别是乳头肌动作电位（AP）持续时间缩短。心室肌细胞的膜片钳分析显示，钠通道电流增加，而 L 型钙通道（LTCC）电流减少，而钾通道电流不变。连接蛋白 43 的磷酸化形式（pCx43）增加，主要位于细胞膜的侧向定位，而其非磷酸化形式（Cx43）在闰盘内高度定位。高水平的阳性染色 α-SMA 和 CD68 细胞主要定位于和分布在心脏的纤维间空间，这意味着成纤维细胞和巨噬细胞可能对 MetS 心脏的 APD 缩短和异常电传导都有贡献。我们的数据提出了一种以前未被认识的心脏 SQT 诱导途径。该途径不仅包括通过离子机制贡献的短心室 APD，还包括通过增加的细胞间相互作用和心肌细胞和非心肌细胞之间的重新定位，增加电兴奋心肌去极化和心脏内自发性电活动相关的快速异质冲动传导，这可能是 SQT 在早期心脏重塑中发展的一种解释。
