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Maintenance of normal cardiac rhythm requires coordinated activity of ion channels and transporters that allow well-ordered propagation of electrical impulses across the myocardium. Disruptions in this orderly process provoke cardiac arrhythmias that may be lethal in some patients. Risk of common acquired arrhythmias is increased markedly when structural heart disease caused by myocardial infarction (due to fibrotic scar formation) or left ventricular dysfunction is present. Genetic polymorphisms influence structure or excitability of the myocardial substrate, which increases vulnerability or risk of arrhythmias in patients. Similarly, genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups within the population that affect specific drug biotransformation reactions. Nonetheless, identification of triggers involved in initiation or maintenance of cardiac arrhythmias remains a major challenge. Herein, we provide an overview of knowledge regarding physiopathology of inherited and acquired cardiac arrhythmias along with a summary of treatments (pharmacologic or non-pharmacologic) used to limit their effect on morbidity and potential mortality. Improved understanding of molecular and cellular aspects of arrhythmogenesis and more epidemiologic studies (for a more accurate portrait of incidence and prevalence) are crucial for development of novel treatments and for management of cardiac arrhythmias and their consequences in patients, as their incidence is increasing worldwide.

Necroptosis, a novel programmed cell death, plays a critical role in the development of fibrosis, yet its role in atrial fibrillation (AF) remains elusive. Mounting evidence demonstrates that aerobic exercise improves AF‐related symptoms and quality of life. Therefore, we explored the role of necroptosis in AF pathogenesis and exercise‐conferred cardioprotection. A mouse AF model was established either by calcium chloride and acetylcholine (CaCl2‐Ach) administration for 3 weeks or high‐fat diet (HFD) feeding for 12 weeks, whereas swim training was conducted 60 min/day, for 3‐week duration. AF susceptibility, heart morphology and function and atrial fibrosis were assessed by electrophysiological examinations, echocardiography and Masson's trichrome staining, respectively. Both CaCl2‐Ach administration and HFD feeding significantly enhanced AF susceptibility (including frequency and duration of episodes), left atrial enlargement and fibrosis. Moreover, protein levels of necroptotic signaling (receptor‐interacting protein kinase 1, receptor‐interacting protein kinase 3, mixed lineage kinase domain‐like protein and calcium/calmodulin‐dependent protein kinase II or their phosphorylated forms) were markedly elevated in the atria of AF mice. However, inhibiting necroptosis with necrostatin‐1 partly attenuated CaCl2‐Ach (or HFD)‐induced fibrosis and AF susceptibility, implicating necroptosis as contributing to AF pathogenesis. Finally, we found 3‐week swim training inhibited necroptotic signaling, consequently decreasing CaCl2‐Ach‐induced AF susceptibility and atrial structural remodeling. Our findings identify necroptosis as a novel mechanism in AF pathogenesis and highlight that aerobic exercise may confer benefits on AF via inhibiting cardiac necroptosis.

Atrial fibrillation (AF) causes a heavy socio-economic burden on healthcare systems around the globe. Identification of new preventive, diagnostic, and treatment methods is imperative. In recent years, special attention has been paid to microRNAs (miRNAs) as potential regulators of AF pathogenesis. Through post-transcriptional regulation of genes, miRNAs have been shown to play crucial roles in AF-related structural and electrical atrial remodeling. Altered expression of different miRNAs has been related to proarrhythmic changes in the duration of action potentials and atrial fibrosis. In clinical studies, miRNA changes have been associated with AF, whereas in experimental studies miRNA manipulation has emerged as a potential therapeutic approach. It would appear that, with the advent of miRNAs, we may have found the Holy Grail, and that efficient and personalized AF therapy may be one step away. Yet, the clinical relevance of miRNA evaluation and manipulation remains questionable. Studies have identified numerous miRNAs associated with AF, but none of them have shown sufficient specificity for AF. MicroRNAs are not gene-specific but regulate the expression of a myriad of genes. Cardiac and non-cardiac off-target effects may thus occur following miRNA manipulation. A Pandora’s box might thus have opened with the advent of these sophisticated molecules. In this paper, we provide a critical analysis of the clinical and experimental, epidemiological and mechanistic data linking miRNAs to AF, we discuss the most promising miRNA therapeutic approaches, we emphasize a number of questions that remain to be answered, and we identify hotspots for future research.

During angiogenesis, endothelial cells (ECs) from intact blood vessels quickly infiltrate avascular regions via vascular sprouting. This process is fundamental to many normal and pathological processes such as wound healing and tumor growth, but its initiation and control are poorly understood. Vascular endothelial cell growth factor (VEGF) can promote vessel dilation and angiogenic sprouting, but given the complex nature of vascular morphogenesis, additional signals are likely necessary to determine, for example, which vessel segments sprout, which dilate, and which remain quiescent. Fluid forces exerted by blood and plasma are prime candidates that might codirect these processes, but it is not known whether VEGF cooperates with mechanical fluid forces to mediate angiogenesis. Using a microfluidic tissue analog of angiogenic sprouting, we found that fluid shear stress, such as exerted by flowing blood, attenuates EC sprouting in a nitric oxide-dependent manner and that interstitial flow, such as produced by extravasating plasma, directs endothelial morphogenesis and sprout formation. Furthermore, positive VEGF gradients initiated sprouting but negative gradients inhibited sprouting, promoting instead sheet-like migration analogous to vessel dilation. These results suggest that ECs integrate signals from fluid forces and local VEGF gradients to achieve such varied goals as vessel dilation and sprouting.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and its prevalence increases with age. The irregular and rapid contraction of the atria can lead to ineffective blood pumping, local blood stasis, blood clots, ischemic stroke, and heart failure. NADPH oxidases (NOX) and mitochondria are the main sources of reactive oxygen species in the heart, and dysregulated activation of NOX and mitochondrial dysfunction are associated with AF pathogenesis. NOX- and mitochondria-derived oxidative stress contribute to the onset of paroxysmal AF by inducing electrophysiological changes in atrial myocytes and structural remodeling in the atria. Because high atrial activity causes cardiac myocytes to expend extremely high energy to maintain excitation-contraction coupling during persistent AF, mitochondria, the primary energy source, undergo metabolic stress, affecting their morphology, Ca2+ handling, and ATP generation. In this review, we discuss the role of oxidative stress in activating AF-triggered activities, regulating intracellular Ca2+ handling, and functional and anatomical reentry mechanisms, all of which are associated with AF initiation, perpetuation, and progression. Changes in the extracellular matrix, inflammation, ion channel expression and function, myofibril structure, and mitochondrial function occur during the early transitional stages of AF, opening a window of opportunity to target NOX and mitochondria-derived oxidative stress using isoform-specific NOX inhibitors and mitochondrial ROS scavengers, as well as drugs that improve mitochondrial dynamics and metabolism to treat persistent AF and its transition to permanent AF.

Macrophage migration inhibitory factor (MIF) is a multifunctional upstream cytokine that has attracted increasing attention for its role in the initiation and perpetuation of atrial fibrillation (AF). This review systematically discusses the dual regulatory roles of MIF in AF and its potential as both a biomarker and a therapeutic target. Mechanistically, MIF drives atrial electrical remodeling by promoting the release of pro-inflammatory cytokines, modulating ion channels, disrupting calcium homeostasis, and downregulating connexin 43. Concurrently, MIF promotes atrial structural remodeling and fibrosis through the activation of fibroblasts, enhancement of collagen deposition, and modulation of the TGF-β/Smad signaling pathway. Clinical studies have demonstrated that circulating MIF levels are independently associated with AF type, disease burden, the extent of atrial fibrosis, and long-term adverse outcomes, including heart failure, stroke, and myocardial infarction. MIF possesses an N-terminal tautomerase activity and a thiol-protein oxidoreductase (TPOR) activity mediated by its Cys57-Ala-Leu-Cys60 (CALC) motif, the latter serving as the structural basis for its antioxidant functions. Reflecting this property, the dynamic perioperative changes in MIF exhibit a biphasic predictive value for postoperative AF (POAF). Therapeutically, direct MIF inhibition (e.g., with 4-IPP) or blockade of downstream signaling (e.g., with CXCR2 antagonists) has shown antiarrhythmic potential in animal models; however, non-selective pan-inhibition may inadvertently ablate the endogenous antioxidant and cardioprotective signals of MIF. Future research should focus on elucidating the molecular switch that governs the functional transition of MIF, developing highly selective drugs targeting the disease-related conformational isoform oxMIF to precisely block pathogenic signaling, validating the existence of a MIF-TGF-β positive feedback loop in atrial fibroblasts, implementing time-window-based intervention strategies, and incorporating MIF promoter polymorphisms into personalized patient stratification. Addressing these priorities will be essential to advance the clinical translation of MIF-targeted therapies for atrial fibrillation.

Left atrial structural remodeling is closely linked with the prognosis of patients with hypertrophic cardiomyopathy (HCM). This study aimed to evaluate the clinical characteristics and risk factors associated with left atrial remodeling in HCM and to develop an early prediction model. HCM patients who underwent echocardiography during hospitalized enrolled. Patients with a left atrial diastolic anteroposterior diameter ≥ 40 mm were classified as the remodeling group, while others were assigned to the control group. Logistic regression analysis was employed to identify independent predictors, and a nomogram was constructed for prediction. A total of 1554 patients were enrolled, including 442 patients in the remodeling group. Significant differences in clinical and echocardiographic characteristics were observed between the two groups. Multivariate logistic regression analysis identified the following as independent predictors of left atrial remodeling: prothrombin time ( P  < 0.001; OR 0.863; 95% CI 0.813–0.915), main pulmonary artery diameter ( P  < 0.001; OR 0.881; 95% CI 0.852–0.911), left ventricular ejection fraction ( P  < 0.001; OR 1.057; 95% CI 1.043–1.071), and interventricular septal thickness ( P  < 0.001; OR 0.937; 95% CI 0.916–0.959). A nomogram prediction model based on these factors demonstrated good discriminatory power, with a receiver operating characteristic curve area of 0.7328 (95% CI 0.7052—0.7603). The model’s calibration showed high accuracy and consistency with actual outcomes, particularly in intermediate probability ranges. Prothrombin time, main pulmonary artery diameter, left ventricular ejection fraction, and interventricular septal thickness were identified as risk factors for left atrial remodeling in HCM patients. The developed nomogram provides a valuable tool for early risk assessment, aiding in the early detection of left atrial remodeling and facilitating optimized treatment strategies to improve patient prognosis.

Metabolic syndrome (MetS) drives cardiac remodeling and fibrosis, contributing to diastolic dysfunction and heart failure with preserved ejection fraction, but chamber-specific mechanisms remain poorly defined. New Zealand White rabbits were fed a high-fat/high-sucrose diet for 28 weeks to induce experimental MetS. Systemic phenotype, cardiac structure (echocardiography), myocardial fibrosis (Picrosirius red histology), myosin/collagen gene expression (qRT-PCR), and chamber-specific proteomics were assessed across left/right atria and ventricles. The model reproduced central obesity, glucose intolerance, dyslipidemia, and mild hypertension, with concentric left ventricular hypertrophy and selective ventricular fibrosis, as follows: increased collagen in left ventricle (LV) and right ventricle (RV), unchanged in atria. Ventricular α-myosin heavy-chain gene expression was upregulated, while collagen I and α-smooth muscle actin transcripts showed ventricular-specific downregulation. Proteomics revealed atrial metabolic and cytoskeletal adaptations with minimal extracellular matrix involvement; ventricles displayed early profibrotic cues (galectin-3 in LV), metabolic inefficiency (impaired glycolysis/ATP production in LV; lipid oxidation shift in RV), and diminished provisional matrix support. Conclusions: concentric LV hypertrophy and great vessel enlargement occurred without systolic/diastolic dysfunction; ventricular-selective fibrosis, α-myosin heavy-chain upregulation, type I collagen/α-smooth muscle actin downregulation, and chamber-specific proteomic changes showed atrial adaptation versus ventricular early profibrotic/metabolic inefficiency.

With a purpose of extending the application of β-cyclodextrin (β-CD) for gas adsorption, this paper aims to reveal the pore formation mechanism of a promising adsorbent for CO2 capture which was derived from the structural remodeling of β-CD by thermal activation. The pore structure and performance of the adsorbent were characterized by means of SEM, BET and CO2 adsorption. Then, the thermochemical characteristics during pore formation were systematically investigated by means of TG-DSC, in situ TG-FTIR/FTIR, in situ TG-MS/MS, EDS, XPS and DFT. The results show that the derived adsorbent exhibits an excellent porous structure for CO2 capture accompanied by an adsorption capacity of 4.2 mmol/g at 0 °C and 100 kPa. The porous structure is obtained by the structural remodeling such as dehydration polymerization with the prior locations such as hydroxyl bonded to C6 and ring-opening polymerization with the main locations (C4, C1, C5), accompanied by the release of those small molecules such as H2O, CO2 and C3H4. A large amount of new fine pores is formed at the third and fourth stage of the four-stage activation process. Particularly, more micropores are created at the fourth stage. This revealed that pore formation mechanism is beneficial to structural design of further thermal-treated graft/functionalization polymer derived from β-CD, potentially applicable for gas adsorption such as CO2 capture.

The normal ageing process affects resistance arteries, leading to various functional and structural changes. Systolic hypertension is a common occurrence in human ageing, and it is associated with large artery stiffening, heightened pulsatility, small artery remodeling, and damage to critical microvascular structures. Starting from young adulthood, a progressive elevation in the mean arterial pressure is evidenced by clinical and epidemiological data as well as findings from animal models. The myogenic response, a protective mechanism for the microcirculation, may face disruptions during ageing. The dysregulation of calcium entry channels (L-type, T-type, and TRP channels), dysfunction in intracellular calcium storage and extrusion mechanisms, altered expression of potassium channels, and a change in smooth muscle calcium sensitization may contribute to the age-related dysregulation of myogenic tone. Flow-mediated vasodilation, a hallmark of endothelial function, is compromised in ageing. This endothelial dysfunction is related to increased oxidative stress, lower nitric oxide bioavailability, and a low-grade inflammatory response, further exacerbating vascular dysfunction. Resistance artery remodeling in ageing emerges as a hypertrophic response of the vessel wall that is typically observed in conjunction with outward remodeling (in normotension), or as inward hypertrophic remodeling (in hypertension). The remodeling process involves oxidative stress, inflammation, reorganization of actin cytoskeletal components, and extracellular matrix fiber proteins. Reactive oxygen species (ROS) signaling and chronic low-grade inflammation play substantial roles in age-related vascular dysfunction. Due to its role in the regulation of vascular tone and structural proteins, the RhoA/Rho-kinase pathway is an important target in age-related vascular dysfunction and diseases. Understanding the intricate interplay of these factors is crucial for developing targeted interventions to mitigate the consequences of ageing on resistance arteries and enhance the overall vascular health.