Objective. Ageing is one of the risk factors associated with cardiovascular diseases including cardiac arrhythmias and heart failure. Ageing‐related cardiac dysfunction involves a complicated pathophysiological progress. Abnormal membrane voltage and Ca²⁺ dynamics in aged cardiomyocytes contribute to ageing‐related arrhythmias. However, its underlying mechanisms have not been well clarified. Methods. Young and old rats or mice were included in this study. Cardiac electrophysiological properties and functions were assessed by ECG, echocardiography, and ex vivo heart voltage and Ca²⁺ optical mapping. Proteomics, phosphor‐proteomics, Western blotting, Masson staining, and ROS measurement were used to investigate the underlying mechanisms. Results. Ageing increased the incidence of cardiac hypertrophy and fibrosis in rats. Moreover, ageing increased the occurrence of ventricular tachycardia or ventricular fibrillation induced by rapid pacing and during isoprenaline (ISO) (1 mg/kg i.p.) challenge in mice in vivo. Optical mapping with dual dyes (membrane voltage (V_m) dye and intracellular Ca²⁺ dye) simultaneously recording revealed that ageing increased the action potential duration (APD) and Ca²⁺ transient duration (CaTD) and slowed the ventricular conduction with the Langendorff‐perfused mouse heart. More importantly, ageing increased the ISO‐induced (1 μM) changes of APD (ΔAPD80) and CaTD (ΔCaTD50). Ageing also delayed the decay of Ca²⁺ transient by extending the decay time constant from 30% to 90% (τ₃₀₋₉₀). In addition, ageing decreased the V_m/Ca²⁺ latency which represented the coupling of V_m/Ca²⁺ including between the midpoint of AP depolarization and Ca²⁺ upstroke, peak transmembrane voltage and peak cytosolic calcium, and time to 50% voltage repolarization and extrusion of cytosolic calcium. Optical mapping also revealed that ageing increased the ISO‐induced arrhythmia incidence and occurrence of the excitation rotor. Proteomics and phosphor‐proteomics assays from rat hearts demonstrated ageing‐induced protein and phosphor‐protein changes, suggesting that CaMKII was involved in ageing‐induced change. Ageing increased the level of ROS and the expression of NOX4, oxidative CaMKII (ox‐CaMKII), phosphorated CaMKII (p‐CaMKII), and periostin. Conclusion. Ageing accelerates cardiac remodelling and increases the susceptibility to ventricular arrhythmias through NOX4/ROS/CaMKII pathway‐mediated abnormal membrane voltage and intracellular Ca²⁺ handling and V_m/Ca²⁺ coupling.

Recanalization therapy can significantly improve the prognosis of patients with acute myocardial infarction (AMI). However, infarction or reperfusion-induced cardiomyocyte death, immune cell infiltration, fibroblast proliferation, and scarring formation lead to cardiac remodeling and gradually progress to heart failure or arrhythmia, resulting in a high mortality rate. Due to the inability of cardiomyocytes to regenerate, the healing of infarcted myocardium mainly relies on the formation of scars. Cardiac fibroblasts, as the main effector cells involved in repair and scar formation, play a crucial role in maintaining the structural integrity of the heart after MI. Recent studies have revealed that exosome-mediated intercellular communication plays a huge role in myocardial repair and signaling transduction after myocardial infarction (MI). Exosomes can regulate the biological behavior of fibroblasts by activating or inhibiting the intracellular signaling pathways through their contents, which are derived from cardiomyocytes, immune cells, endothelial cells, mesenchymal cells, and others. Understanding the interactions between fibroblasts and other cell types during cardiac remodeling will be the key to breakthrough therapies. This review examines the role of exosomes from different sources in the repair process after MI injury, especially the impacts on fibroblasts during myocardial remodeling, and explores the use of exosomes in the treatment of myocardial remodeling after MI.

The impairment of the angiopoietin-1 (Ang-1)/Tie-2 signaling pathway has been thought to play a critical role in diabetic complications. However, the underlying mechanisms remain unclear. The present study aims to investigate the effects of Tie-2 glycation on Ang-1 signaling activation and Ang-1-induced angiogenesis. We identified that Tie-2 was modified by advanced glycation end products (AGEs) in aortae derived from high fat diet (HFD)-fed mice and in methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). MGO-induced Tie-2 glycation significantly inhibited Ang-1-evoked Tie-2 and Akt phosphorylation and Ang-1-regulated endothelial cell migration and tube formation, whereas the blockade of AGE formation by aminoguanidine remarkably rescued Ang-1 signaling activation and Ang-1-induced angiogenesis in vitro. Furthermore, MGO treatment markedly increased AGE cross-linking of Tie-2 in cultured aortae ex vivo and MGO-induced Tie-2 glycation also significantly decreased Ang-1-induced vessel outgrow from aortic rings. Collectively, these data suggest that Tie-2 may be modified by AGEs in diabetes mellitus and that Tie-2 glycation inhibits Ang-1 signaling activation and Ang-1-induced angiogenesis. This may provide a novel mechanism for Ang-1/Tie-2 signal dysfunction and angiogenesis failure in diabetic ischaemic diseases.

Background: Dexmedetomidine (DEX), a highly selective alpha 2-adrenoceptor agonist, can decrease the incidence of arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the underlying mechanisms by which DEX affects cardiac electrophysiological function remain unclear. Methods: Ryanodine receptor (RyR2) heterozygous R2474S mice were used as a model for CPVT. WT and RyR2 R2474S/ + mice were treated with isoproterenol (ISO) and DEX, and electrocardiograms were continuously monitored during both in vivo and ex vivo experiments. Dual-dye optical mapping was used to explore the antiarrhythmic mechanism of DEX. Results: DEX significantly reduced the occurrence and duration of ISO-induced of VT/VF in RyR2 R2474S/ + mice in vivo and ex vivo . DEX remarkably prolonged action potential duration (APD 80 ) and calcium transient duration (CaTD 80 ) in both RyR2 R2474S/ + and WT hearts, whereas it reduced APD heterogeneity and CaT alternans in RyR2 R2474S/ + hearts. DEX inhibited ectopy and reentry formation, and stabilized voltage-calcium latency. Conclusion: DEX exhibited an antiarrhythmic effect through stabilizing membrane voltage and intracellular Ca 2 + . DEX can be used as a beneficial perioperative anesthetic for patients with CPVT or other tachy-arrhythmias.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a novel class of glucose-lowering agents that offer benefits beyond glycemic control and weight loss and are increasingly recognized for their cardioprotective benefits, including protective effects against hypertension, heart failure, myocardial infarction, and arrhythmias. Notably, GLP-1RAs have demonstrated a significant capacity to reduce arrhythmia risk not only in animal models but also in large-scale clinical trials. However, the antiarrhythmic mechanisms of GLP-1RAs remain incompletely understood. This mechanistic review synthesizes current preclinical and clinical evidence to delineate the key pathways through which GLP-1RAs may exert their antiarrhythmic effects. The primary mechanisms discussed include the attenuation of cardiomyocyte death, improvement of myocardial metabolism, and inhibition of the inflammatory response. Additional mechanisms, such as the promotion of autophagy, maintenance of ion homeostasis in cardiomyocytes, and modulation of the autonomic nervous system, are also examined. By clarifying these mechanisms, this review aims to offer novel therapeutic strategies for arrhythmia prevention, especially in the high-risk population with cardiometabolic diseases.

The post-natal development and maturation of the mammalian heart involve highly intricate processes that remain incompletely understood, particularly concerning the molecular signature and roles of the diverse cell types involved. In this study, we present a comprehensive dataset generated from murine hearts at three key post-natal developmental stages using Spatio-Temporal Enhanced Resolution Omics-Sequencing (Stereo-seq), an advanced spatially resolved transcriptomic technology. This dataset encompasses spatial transcriptomes of approximately 0.186 million individual cells within intact sections of murine hearts at post-natal developmental stages. Our dataset serves as a valuable resource for investigating the mechanisms underlying mammalian heart development and maturation. Through initial analyses, we identified distinct cell types and their spatial distributions, including 93,826 cardiomyocytes within a single heart section. This extensive dataset provides researchers with opportunities for data mining and facilitates diverse analyses, including studies on transcriptional regulation, cell-to-cell communication, and the functional activities of genes and signalling molecules during critical phases of heart development.