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.

Ca ²⁺ -activated K ⁺ channels are critical to cellular Ca ²⁺ homeostasis and excitability; they couple intracellular Ca ²⁺ and membrane voltage change. Of these, the small, 4–14 pS, conductance SK channels include three, KCNN1-3 encoded, SK1/KCa2.1, SK2/KCa2.2 and SK3/KCa2.3, channel subtypes with characteristic, EC ₅₀ ∼ 10 nM, 40 pM, 1 nM, apamin sensitivities. All SK channels, particularly SK2 channels, are expressed in atrial, ventricular and conducting system cardiomyocytes. Pharmacological and genetic modification results have suggested that SK channel block or knockout prolonged action potential durations (APDs) and effective refractory periods (ERPs) particularly in atrial, but also in ventricular, and sinoatrial, atrioventricular node and Purkinje myocytes, correspondingly affect arrhythmic tendency. Additionally, mitochondrial SK channels may decrease mitochondrial Ca ²⁺ overload and reactive oxygen species generation. SK channels show low voltage but marked Ca ²⁺ dependences (EC ₅₀ ∼ 300–500 nM) reflecting their α-subunit calmodulin (CaM) binding domains, through which they may be activated by voltage-gated or ryanodine-receptor Ca ²⁺ channel activity. SK function also depends upon complex trafficking and expression processes and associations with other ion channels or subunits from different SK subtypes. Atrial and ventricular clinical arrhythmogenesis may follow both increased or decreased SK expression through decreased or increased APD correspondingly accelerating and stabilizing re-entrant rotors or increasing incidences of triggered activity. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.

Diabetes mellitus (DM) eventually leads to chronic vascular complications, resulting in cardiovascular diseases. DM-associated endothelial dysfunction (ED) plays an important role in the development of chronic vascular complications. Low endothelial nitric oxide synthase (eNOS) activity, inflammation, and oxidative stress all contribute to ED. The G protein–coupled receptor Takeda G protein–coupled receptor 5 (TGR5) is a membrane receptor for bile acids that plays an important role in the regulation of glucose metabolism. Recent studies have shown that TGR5 is involved in the regulation of various mediators of ED, which suggests that TGR5 may represent a target for the treatment of DM-associated ED. In this review, we summarize the principal mechanisms of DM-associated ED, then propose TGR5 as a novel therapeutic target on the basis of its mechanistic involvement, and suggest potential directions for future research.

Heart failure (HF) is a prevalent cardiovascular disease with significant morbidity and mortality rates worldwide. Due to the intricate structure of the heart, diverse cell types, and the complex pathogenesis of HF, further in‐depth investigation into the underlying mechanisms is required. The elucidation of the heterogeneity of cardiomyocytes and the intercellular communication network is particularly important. Traditional high‐throughput sequencing methods provide an average measure of gene expression, failing to capture the “heterogeneity” between cells and impacting the accuracy of gene function knowledge. In contrast, single‐cell sequencing techniques allow for the amplification of the entire genome or transcriptome at the individual cell level, facilitating the examination of gene structure and expression with unparalleled precision. This approach offers valuable insights into disease mechanisms, enabling the identification of changes in cellular components and gene expressions during hypertrophy associated with HF. Moreover, it reveals distinct cell populations and their unique roles in the HF microenvironment, providing a comprehensive understanding of the cellular landscape that underpins HF pathogenesis. This review focuses on the insights provided by single‐cell sequencing techniques into the mechanisms underlying HF and discusses the challenges encountered in current cardiovascular research.