Chronic intermittent hypoxia (CIH) is the predominant pathophysiological disorder of obstructive sleep apnea (OSA), known to be an important risk factor for atrial fibrillation (AF). MicroRNA-10b-5p levels are significantly reduced under hypoxic conditions. Nevertheless, the role and underlying mechanism of miR-10b-5p in CIH-induced AF remain elusive. In this study, we found that miR-10b-5p expression was downregulated in the atrial tissues of patients and rats with AF. Functionally, miR-10b-5p exerts protective roles in CIH induced atrial fibroblasts activation and AF development by inhibiting the expression of Smad ubiquitin regulatory factor 1 (SMURF1) and TGFβ/Smads signaling activation. RNA sequencing and bioinformatics identified that circ_Mkrn2, as possessing multiple putative binding sites for miR-10b-5p, was increased in patients and rats with AF. Circ_Mkrn2 overexpression promoted SMURF1 expression and atrial fibroblast activation, which were effectively reversed by miR-10b-5p overexpression. Circ_Mkrn2 silencing alleviated the expression of SMURF1 and TGFβ/Smads signaling activation, atrial fibroblasts activation and AF induced by CIH. Our findings showed that circ_Mkrn2 serves as an miR-10b-5p sponge，promotes Smurf1 expression, regulates atrial fibroblast activation, cardiac fibrosis and the development of AF, revealing a potential new target for the prevention of CIH-induced AF.

Background:Coronary artery ectasia (CAE) is characterized by abnormal coronary dilation and slow flow, predisposing patients to thrombotic complications. Optimal long-term antithrombotic strategies for CAE remain undefined. This study aimed to evaluate the efficacy and safety of low-dose rivaroxaban combined with single antiplatelet therapy in patients with CAE. Methods:In this single-center retrospective cohort study, 312 patients with CAE were enrolled and followed for 36 months. Patients received either single antiplatelet therapy alone or in combination with low-dose rivaroxaban. Propensity score matching (1:1) was performed to balance baseline characteristics. The primary endpoint was major adverse cardiovascular events (MACE). Secondary analyses included changes in thrombotic, inflammatory, and myocardial injury biomarkers. Cox proportional hazards models, inverse probability weighting, competing risk models, and sensitivity analyses were conducted to assess robustness. Results:After propensity score matching (124 vs. 124), combination therapy was associated with a significantly lower risk of 36-month MACE compared with antiplatelet therapy alone (8.1% vs. 21.8%; HR = 0.34, 95% CI: 0.19-0.62; P < 0.001), corresponding to an absolute risk reduction of 13.7% and a number needed to treat of 7.3. The benefit was more pronounced in patients with diffuse ectasia (Markis I/II: HR = 0.21, 95% CI: 0.09-0.49; interaction P = 0.02) and elevated baseline D-dimer (≥0.8 mg/L: HR = 0.18, 95% CI: 0.08-0.41; interaction P = 0.01). Improvements in D-dimer, inflammatory markers, and myocardial injury biomarkers were greater in the combination group. Total bleeding rates were not significantly different between groups, and no fatal bleeding occurred. Net clinical benefit favored combination therapy. Results remained consistent across multiple sensitivity analyses. A simple risk prediction model based on D-dimer, Markis classification, and treatment regimen was developed in the same cohort (C-index 0.78) but has not been externally validated. Conclusions:In patients with CAE, low-dose rivaroxaban combined with single antiplatelet therapy was associated with lower long-term MACE risk without a significant increase in major bleeding. The benefit appeared particularly pronounced in patients with diffuse ectasia and higher thrombotic burden. The simple predictive model based on D-dimer, Markis classification, and treatment regimen may aid in individualized antithrombotic decision-making, but requires external validation.

Type 2 diabetes mellitus (T2DM) complicated by white matter hyperintensities (WMH) represents a high-risk population for cognitive decline. However, the association between continuous glucose monitoring (CGM) metrics and mild cognitive impairment (MCI) in this specific population remains inadequately explored. This study aimed to evaluate the associations between hemoglobin A1c (HbA1c), CGM metrics and MCI in patients with T2DM and WMH, and to identify potential threshold effects and subgroup differences. This single-center cross-sectional study enrolled 1068 hospitalized patients with T2DM and WMH from January 2020 to December 2025. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), with MCI defined as a score of 18–25. Glycemic metrics included HbA1c and CGM-derived parameters, namely mean amplitude of glycemic excursions (MAGE), coefficient of variation (CV), time in range (TIR), time above range (TAR), time below range (TBR), and mean of daily differences (MODD). Multivariable logistic regression, restricted cubic splines, threshold effects analysis, ROC curves, and subgroup interaction tests were performed. Among 1068 patients (396 MCI, 672 non-MCI), MCI patients were older, had fewer years of education, more severe WMH, longer diabetes duration, and higher HbA1c (all P < 0.05). After multivariable adjustment, higher HbA1c (OR = 1.48), MAGE (OR = 3.1), CV (OR = 1.013), TBR (OR = 1.26), and lower TIR (OR = 0.92) were independently associated with MCI (all P < 0.05). MAGE showed the best discriminatory performance (AUC = 0.713). Nonlinear associations and significant threshold effects were identified: MCI risk increased significantly when MAGE ≥ 3.95 mmol/L (OR = 6.23) or HbA1c ≥ 7.86

Efficient removal of Pb(II) and Cu(II) from wastewater is crucial for safeguarding environmental safety and public health. Biomass-based adsorbents with surface-specific functionality hold great promise for selective adsorption of metal cations. In this study, a novel phosphorylated chitosan-lignin (PCSL) composite is successfully synthesized via Mannich reaction. The PCSL exhibits remarkable selectivity in the adsorption of Pb(II) and Cu(II), as evidenced by Density Functional Theory (DFT) calculations. Furthermore, DFT analysis reveals that the incorporation of phosphate groups significantly enhances the chelation capacity of the adsorbent towards heavy metals. The PCSL demonstrates ultrafast adsorption capabilities for Pb(II) and Cu(II). Specifically, the adsorption processes reach equilibrium within 7 min and 5 min, respectively, with maximum adsorption capacities of 207.9 mg·g-1 for Pb(II) and 100.0 mg·g-1 for Cu(II). X-ray photoelectron spectroscopy analysis indicates that the adsorption mechanisms involve both chemical complexation and electrostatic attraction. Notably, the adsorbent can be recycled many times, and the spent Cu-PCSL, upon pyrolysis treatment, demonstrate remarkable catalytic activity in nitrate reduction reactions, with Faradaic efficiencies as high as 98.3 % and NH3 yield of 4.3 mg·h-1·mgcat.-1. This work not only advances the progression of biomass adsorbents but also demonstrates considerable industrial potential in mitigating water pollution and promoting sustainable development.

BackgroundAtrial fibrosis serves as a key pathological basis for atrial fibrillation, significantly elevating the risk of cardiovascular events. However, its molecular mechanisms remain incompletely understood. N⁶-methyladenosine (m6A) modifications have been proven to involve in the pathological processes of cardiovascular diseases, yet its role in atrial fibrosis remains unclear. m6A plays an important role in disease pathogenesis via mRNA modification. This study aimed to define the role of m6A modifications in the fibrotic atria of rats with chronic intermittent hypoxia (CIH).MethodsA CIH model was established using rats living in an intermittent hypoxia simulation chamber filled with oxygen and nitrogen. Myocardial function and atrial fibrosis were examined by echocardiography, electrophysiology, and histopathology. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and mRNA sequencing (mRNA-Seq) were performed on atria from control and CIH rats to identify differential m6A methylated genes and transcripts and further analyze their coexistence. Functional enrichment of the conjoint genes was analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes assays. m6A distribution of the conjoint gene ANGPTL4 (angiopoietin like 4) was also observed. ANGPTL4 and m6A-related gene expression levels were determined by quantitative real-time polymerase chain reaction.ResultsCIH led to electrical conduction dysfunction and abnormal expression of fibrosis-associated proteins, indicating successful atrial fibrosis. Conjoint analysis identified 10 genes with upregulated m6A peaks and transcripts and 24 genes with downregulated m6A peaks and transcripts. These genes were functionally enriched in the calcium ion transport-related and fibrosis pathways (extracellular matrix receptor interaction). The m6A modification level of ANGPTL4 mRNA and the expression of four m6A regulatory enzymes were significantly different between control and CIH rats.ConclusionOur results revealed that m6A modification plays a crucial role in atrial fibrosis and may provide new therapeutic strategies for this disease.

The uptake of modified lipoproteins by macrophages to form foam cells is a crucial step in atherosclerosis (AS) development. N7-methylguanosine (m7G) is frequently methylated internally in eukaryotic RNA transcripts and plays a crucial role in various processes. This study aimed to investigate the m7G RNA methylation profile in AS. We employed high-throughput sequencing to analyze the m7G methylome in foam cells induced by ox-LDL, using an in vitro AS model. Then, m7G-seq, RNA-seq, bioinformatic analysis, cell biological analyses, followed by qRT-PCR were performed. Additionally, the roles of SCARB2 and RASSF8 were investigated in an in vivo AS mouse model, and cells with SCARB2/RASSF8 overexpression/knockdown. In vitro and in vivo oil red O staining confirmed the successful establishment of the atherosclerotic foam cell and mouse models. We identified 1197 m7G peaks and 430 differentially expressed mRNAs during foam cell formation. Bioinformatics analyses revealed different m7G peaks associated with the gonadotropin-releasing hormone (GnRH) signaling pathway, cytoskeleton-dependent intracellular transport, and mitochondrial organization, regulating the processes of macrophage foaminess. Moreover, 28 key differentially expressed methylated genes were identified. m7G methyltransferases (WDR4, METTL1, WBSCR22) were upregulated in the AS cell model, and m7G modification genes (SCARB2 and RASSF8) associated with pathological processes were confirmed. Immunofluorescence staining showed that RASSF8 and SCARB2 were both expressed in AS mice plaque tissues. Finally, RASSF8/SCARB2 overexpression could promote apoptosis and lipid accumulation of ox-LDL-induced RAW264.7 cells. An m7G transcriptome-wide map of AS in vitro was created, and the differentially m7G methylated genes SCARB2 and RASSF8 may be crucial in macrophage foaminess. Our findings offer novel insights into the underlying mechanisms and potential treatments for AS.

Obesity and osteoporosis (OP) are becoming more prevalent and endangering people’s health. As the most commonly used indicator for assessing obesity, body mass index (BMI) has its limitations. The health issues caused by central obesity in the non-overweight state need to be addressed. The relationship between waist circumference (WC), a traditional indicator of central obesity, and bone health is controversial. To date, the association between WC and OP in non-overweight populations has been unclear. Our study therefore aimed to assess the association between WC and risk of OP in non-overweight U.S. adults. This cross-sectional study included subjects aged 18 years or older with a BMI ≤ 25 kg/m2 from National Health and Nutrition Examination Survey 1999–2018. A multivariable logistic regression model was used to assess the association between WC and risk of OP. Restricted cubic spline curves were used to evaluate the potential non-linear association. Subgroup and sensitivity analysis were conducted to assess the robustness of the results. 3606 participants were included. A higher WC was associated with a reduced risk of OP, regardless of traditional confounders. Each 1 cm increase in WC was associated with a 4

Septic cardiomyopathy is a secondary myocardial injury caused by sepsis. N6-methyl-adenosine (m6A) modification is involved in the pathological progression of septic cardiomyopathy; however, the pathological mechanism remains unclear. In this study, we identified the overall m6A modification pattern in septic myocardial injury and determined its potential interactions with differentially expressed genes (DEGs). A sepsis mouse model exhibiting septic symptoms and myocardial tissue damage was induced by lipopolysaccharide (LPS). LPS-induced septic myocardial tissues and control myocardial tissues were subjected to methylated RNA immunoprecipitation sequencing and RNA sequencing to screen for differentially expressed m6A peaks and DEGs. We identified 859 significantly m6A-modified genes in septic myocardial tissues, including 432 upregulated and 427 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore the biological importance of differentially expressed m6A methylated genes and DEGs. Differentially expressed m6A methylated genes were enriched in immune- and inflammation-related pathways. Conjoint analysis revealed co-expression of differentially expressed m6A genes and DEGs, including genes that were upregulated or downregulated and those showing opposite trends. High expression of m6A-related genes (WTAP and IGF2BP2), interleukin-17, and interleukin-17 pathway-related genes (MAPK11 and TRAF3IP2) was verified using reverse transcription-quantitative PCR. We confirmed the presence of m6A modification of the transcriptome and m6A-mediated gene expression in septic myocardial tissues.

PURPOSE:Obesity and osteoporosis (OP) are receiving increasing attention. Waist circumference (WC) is an effective indicator for assessing central obesity. Currently, there is controversy regarding the relationship between WC and bone mineral density (BMD), as well as OP. Therefore, our study aims to utilize data from the National Health and Nutrition Examination Survey (NHANES) to evaluate the relationship between WC and BMD, as well as OP, in US adults. METHODS:This cross-sectional study included subjects aged ≥18 years from the NHANES 1999-2018. Multivariate linear regression models were performed to investigate the association between WC and BMD. Multivariate logistic regression models were employed to assess the relationship between WC and OP. Restricted cubic spline curves were used to assess potential nonlinear association between WC and BMD, OP. Subgroup analysis and sensitivity analysis were performed to assess the robustness of the results. RESULTS:Finally, 11,165 participants (non-OP, n = 10,465; OP, n = 700) were included in the final analysis. The results showed that WC was positively associated with total femur (TF), femoral neck (FN), and lumbar spine (LS) BMD, and might be a protective factor for OP, independent of traditional confounding factors. For each 1 cm increased in WC, TF BMD, FN BMD and LS BMD increased by 0.004 g/cm2, 0.003 g/cm2 and 0.003 g/cm2, respectively, and the risk of OP decreased by 3.1 %. Furthermore, there was a non-linear relationship between WC and BMD, OP. The association remained robust in sensitivity and subgroup analyses. CONCLUSION:In US adults, there is a positive association between WC and BMD, and WC may be a protective factor for the risk of OP. The association between WC and BMD as well as OP exhibits a non-linear relationship.

Aims: This study aimed to characterize circular RNA (circRNA) profiles associated with atrial fibrosis-related atrial fibrillation (AF) and reveal critical circRNAs for AF. Methods: Sprague Dawley rats were randomly divided into control and atrial fibrosis-related AF groups (n = 15 in each group). The rats in the atrial fibrosis-related AF group were induced by chronic intermittent hypoxia (CIH), and then confirmed by electrocardiograms, echocardiography, hematoxylin-eosin staining, Masson staining, immunohistochemistry assays and western blotting. After that, the atrial tissues were sent for circRNA sequencing, and the differentially expressed circRNAs were identified and validated by quantitative real-time polymerase chain reaction (qRT-PCR). Finally, a series of cell experiments were performed to explore the roles of two crucial circRNAs in rat atrial fibroblasts. Results: A CIH-induced AF model was successfully established in the rats. After sequencing, five upregulated and 11 downregulated circRNAs were identified in the CIH-induced AF group. These dysregulated circRNAs were primarily associated with "carbohydrate metabolism" and "cardiovascular diseases". Two circRNAs (circRNA_0263 and circRNA_1507) were predicted to regulate target gene expression by interacting with corresponding miRNAs, including rno-miR-29b-5p, rno-miR-29b-3p, rno-miR-496-5p, rno-miR-136-5p, and novel123-mature. Additionally, circRNA_0263 knockdown and circRNA_1507 overexpression inhibited the cell viability of fibroblasts, and downregulated the expression of fibrosis-related proteins. Conclusion: A series of circRNAs were identified as dysregulated in an AF rat model, and circRNA_0263 and circRNA_1507 might be crucial for atrial fibrosis-related AF development by competing with several miRNAs.

Background:Atrial fibrosis caused by long-term atrial fibrillation influences the outcomes of clinical treatment. An improved understanding of the mechanisms underlying atrial fibrillation may reveal new therapeutic targets. This study was conducted to analyze the changes in protein levels in the atrial tissue of a rat model of atrial fibrillation based on proteome sequencing. Methods:Sprague-Dawley rats were used to develop a model of atrial fibrillation induced by chronic intermittent hypoxia (CIH). Histopathological changes were detected using hematoxylin and eosin staining and Masson's staining, and immunohistochemistry and western blotting for the levels of fibrosis biomarkers. Atrial fibrosis tissue samples were also evaluated by proteome sequencing. Differentially expressed proteins (DEPs) between the CIH and control groups were evaluated in functional assay. The expression levels of several key proteins were validated using western blotting. Results:CIH resulted in atrial fibrosis and induced atrial fibrillation. We identified 145 DEPs between the CIH and control groups. These included Myh7, Myl2, Myl3, and Atpla3, which are involved in signaling pathways related to hypertrophic cardiomyopathy, glycerolipid metabolism, and cardiac muscle contraction. Western blotting revealed the upregulation of Myh7, Myl2, and Myl3 and the downregulation of Atpla3 in the CIH group compared with the control group. These results were consistent with the sequencing results. Conclusions:Myh7, Myl2, Myl3, and Atpla3 may play key roles in the progression of atrial fibrillation through their involvement in cardiovascular-disease-related signaling pathways.

BACKGROUND:Prediabetes is an intermediate metabolic state between euglycaemia and diabetes, including three different definitions: impaired fasting glucose, impaired glucose tolerance, and mildly elevated glycated haemoglobin (HbA1c) (range 5.7%-6.4%). The effect of prediabetes on bone mineral density (BMD) has not been established. Therefore, we performed a meta-analysis to evaluate the association between prediabetes and BMD. METHODS:We retrieved studies related to prediabetes and BMD from PubMed, Web of Science, and Embase databases from January 1990 to December 2022. All data were analysed using the random effects model. Statistical heterogeneity was tested by I2 . Subgroup analysis was performed after each study-level variable was pre-defined by meta-regression. RESULTS:A total of 17 studies were included involving 45,788 patients. We detected a significant overall association of prediabetes with increased spine BMD (weighted mean difference [WMD] = 0.01, 95% CI [0.00, 0.02], p = 0.005; I2  = 62%), femur neck (FN) BMD (WMD = 0.01, 95% CI [0.00, 0.01], p < 0.001; I2  = 19%), and femur total (FT) BMD (WMD = 0.02, 95% CI [0.01, 0.03], p < 0.001; I2  = 51%). Several variables leading to heterogeneity were defined by meta-regression, including age, sex, region, study type, dual-energy X-ray absorptiometry scanner manufacturer, and prediabetes definition. Subgroup analyses indicated that the association of prediabetes with increased BMD was stronger in men, Asians, and older adults over 60 years of age. CONCLUSIONS:Current evidence shows that prediabetes is strongly associated with increased BMD of the spine, FN, and FT. The association was stronger among males, Asians, and older adults over 60 years of age.

Abstract Background Oxidative stress leads to adverse atrial remodeling in diabetes mellitus. AMP-activated protein kinase (AMPK) agonists have been shown to prevent cardiomyocytes from oxidative stress by improving mitochondrial function, but their underlying mechanisms are not completely understood. This study investigated the molecular changes and their underlying regulatory mechanisms by the AMPK agonists, metformin and AICA ribonucleotide (AICAR). Methods Mouse atrial cardiomyocytes (HL-1 cells) and rats with type 2 diabetes mellitus (DM) were used as study models. A total of 40 rats were randomly divided into control, DM alone, DM treated with metformin, AICAR, or metformin with the AMPK inhibitor Compound C. Echocardiographic, hemodynamic, and electrophysiological measurements were made in vivo. Reactive oxygen species (ROS) production rate and mitochondrial membrane potential (MMP) levels were performed in vitro. Protein expression of SOD, COX43 and mitochondrial biogenesis related proteins were measured using Western blotting. Results Compared with controls, the diabetes group demonstrated larger left atrial diameter and fibrosis area associated with a higher incidence of inducible atrial fibrillation (AF). Lower Mn-SOD, COX42, and mitochondrial biogenesis (PGC-1α, NRF1 and TFAM)-related proteins were observed, accompanied by mitochondrial swelling. Metformin treatment led to reversal of structural remodeling and lower inducible AF incidence, which were associated with higher Mn-SOD, COX42, and biogenesis-related proteins as well as improvement in the structure and function of mitochondria. Similar protective changes were observed following AICAR or metformin with Compound C treatment. In HL-1 cell line, compared with controls, the DM group demonstrated higher mitochondrial ROS production rat and lower MMP levels. Mn-SOD, COX42, and mitochondrial biogenesis (PGC-1α, NRF1 and TFAM)-related proteins expression were consistent with animal levels. Conclusions Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Metformin prevented these abnormalities through activation of the AMPK signaling pathway.

OBJECTIVES A novel temperature-controlled intravascular radiofrequency balloon angioplasty (RFBA) technique was designed and developed for atherosclerosis (AS) management. METHODS After establishing an AS model based on a balloon denudation injury of the abdominal aorta and a high cholesterol diet in rabbits, 46 animals were randomly assigned to the RFBA group (n = 28) or the plain balloon angioplasty (PBA) group (n = 28). The groups were further subdivided based on post-treatment euthanasia times (1 hour, 7 days, 14 days, and 28 days). Histopathological changes were observed by hematoxylin and eosin and Masson's staining. Immunohistochemistry, western blotting, and real-time quantitative polymerase chain reaction were used to detect changes in pro-inflammatory, anti-inflammatory, and apoptotic factors; TGF-β/Smad-2 pathway protein Immune levels; and mRNA levels in tissues, respectively. RESULTS The vascular lumen area in the RFBA group was larger than that in the PBA group at the same time points, although the change in the vascular lumen area was not different between groups. The expression of Bax, TGF-β, Smad-2, and Caspase-3 in the RFBA group was significantly higher than that in the PBA group. The expression levels of Bcl-2 in the RFBA group were significantly lower than those in the PBA group. CONCLUSIONS At 28 days, RFBA dilated the atherosclerotic blood vessels and thickened the fibrous cap of atherosclerotic plaques to promote plaque stability. RFBA was also found to activate apoptotic factors and the TGF-/Smad-2 inflammatory pathway.

心血管疾病(cardiovascular disease,CVD)是全世界死亡的主要原因.研究表明表观遗传修饰在CVD的进展中起着重要作用.在几种已知的RNA修饰中,N6-甲基腺苷(N6-methyladenosine,m6A)RNA甲基化修饰是研究最多的RNA表观转录组修饰,该过程是动态的、可逆的,在mRNA代谢和各种生物活动中起着至关重要的作用.在这篇综述中,我们描述了 m6A甲基化的作用机制,总结了 m6A甲基化在CVD中的作用,包括动脉粥样硬化、心肌梗死、心力衰竭和糖尿病相关CVD等.m6A甲基化及其调控因子有望成为CVD的治疗靶点.

BACKGROUND Cardiac fibrosis has gradually gained significance in the field of cardiovascular disease; however, its specific pathogenesis remains unclear. This study aims to establish the regulatory networks based on whole-transcriptome RNA sequencing analyses and reveal the underlying mechanisms of cardiac fibrosis. METHODS An experimental model of myocardial fibrosis was induced using the chronic intermittent hypoxia (CIH) method. Expression profiles of long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) were acquired from right atrial tissue samples of rats. Differentially expressed RNAs (DERs) were identified, and functional enrichment analysis was performed. Moreover, a protein-protein interaction (PPI) network and competitive endogenous RNA (ceRNA) regulatory network that are related to cardiac fibrosis were constructed, and the relevant regulatory factors and functional pathways were identified. Finally, the crucial regulators were validated using qRT-PCR. RESULTS DERs, including 268 lncRNAs, 20 miRNAs, and 436 mRNAs, were screened. Further, 18 relevant biological processes, such as "chromosome segregation, " and 6 KEGG signaling pathways, such as "cell cycle, " were significantly enriched. The regulatory relationship of miRNA-mRNA-KEGG pathways showed eight overlapping disease pathways, including "pathways in cancer." In addition, crucial regulatory factors, such as Arnt2, WNT2B, GNG7, LOC100909750, Cyp1a1, E2F1, BIRC5, and LPAR4, were identified and verified to be closely related to cardiac fibrosis. CONCLUSION This study identified the crucial regulators and related functional pathways in cardiac fibrosis by integrating the whole transcriptome analysis in rats, which might provide novel insights into the pathogenesis of cardiac fibrosis.

Background and aims:The role of circular RNAs (circRNAs) in the pathophysiology of cardiovascular disease is gradually being elucidated; however, their roles in atrial fibrillation (AF)-related fibrosis are largely unknown. This study aimed to characterize the different circRNA profiles in the rapid-pacing atria of dogs and explore the mechanisms involved in atrial fibrosis. Methods:A rapid right atrial-pacing model was established using electrical stimulation from a pacemaker. After 14 days, atrial tissue was collected for circRNA sequencing analysis. In vitro fibrosis was established by stimulating canine atrial fibroblasts with angiotensin II (Ang II). The fibroblasts were transfected with siRNA and overexpressing plasmids to explore the effects of cfa-circ002203 on fibroblast proliferation, migration, differentiation, and the expression of fibrosis-related proteins. Results:In total, 146 differentially expressed circRNAs were screened, of which 106 were upregulated and 40 were downregulated. qRT-PCR analysis showed that cfa-circ002203 was upregulated in both in vivo and in vitro fibroblast fibrosis models. The upregulation of cfa-circ002203 enhanced proliferation and migration while weakening the apoptosis of fibroblasts. Western blotting showed that cfa-circ002203 overexpression increased the protein expression levels of fibrosis-related indicators (Col I, Col III, MMP2, MMP9, and α-SMA) and decreased the protein expression levels of pro-apoptotic factors (Bax and Caspase 3) in Ang II-induced fibroblast fibrosis. Conclusion:Cfa-circ002203 might serve as an active promoter of the proliferation, migration, and fibrosis of atrial fibroblasts and is involved in AF-induced fibroblast fibrosis.

OBJECTIVE:Extracellular histone (EH) is involved in the development of septic myocardial injury (SMI). In this study, we explored whether EH could induce left ventricular diastolic dysfunction (LVDD) in sepsis, and investigated the potential mechanisms through in vivo and in vitro experiments using animal models.METHODS:The ratio between E-wave and A-wave (E/A ratio), left ventricular end diastolic volume, and isovolumic relaxation time (IVRT) were measured in cecal ligation and perforation (CLP)- and EH-treated male C57BL/6J mice using echocardiography. The protein and mRNA levels of apoptosis-related proteins (cleaved caspase-3, Bcl-2, and Bax) and cardiac troponin T (cTnT) in the left ventricular tissue/cardiomyocytes were measured using enzyme-linked immunosorbent assay, qRT-PCR, and western blotting. Cardiomyocyte apoptosis was detected by flow cytometry.RESULTS:CLP mice presented with LVDD, which was accompanied by increased circulating histones, cTnT and Bax protein levels. Circulating histones were correlated with cTnT, Bax, IVRT, and E/A ratio in CLP mice. Intraperitoneal injection of EH resulted in LVDD in mice. EH induced cardiomyocyte apoptosis, and histone neutralizing agents improved SMI and protected mice against CLP- and EH-induced death.CONCLUSION:EH is involved in septic LVDD, and this alteration might be associated with EH-induced apoptosis. EH may serve as a potential therapeutic target for SMI.

Context Paeonol (PAE) is the main phytochemical from Cortex Moutan. Its main pharmacological effects are anti-inflammatory and antioxidant, but its cardioprotective effect is unclear. Objective The study investigates the effects and underlying mechanisms of PAE on transverse aortic constriction (TAC)-induced heart failure (HF) in mice. Materials and methods C57BL/6 mice were randomly divided into five groups: sham, TAC, PAE10 (TAC + PAE 10 mg/kg), PAE20 (TAC + PAE 20 mg/kg) and PAE 50 (TAC + PAE 50 mg/kg). Paeonol was intragastrically administered to mice for 4 weeks. Mice were anaesthetized with pentobarbital sodium and underwent cardiac echocardiography using echocardiography system. Serum levels of atrial natriuretic peptide (ANP), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial apoptosis was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining. Haematoxylin-eosin (H&E) and Masson's staining were used for histopathological evaluation. Western and quantitative real-time PCR (qRT-PCR) were performed to detect levels of apoptosis and fibrosis-related proteins. Results Echocardiography showed PAE improved cardiac function (LVEF: TAC, 52.3 +/- 6.8%; PAE20, 65.8 +/- 3.6%; PAE50, 71.4 +/- 2.5%) and H&E staining showed PAE alleviated myocardial injury (TAC: 1170.3 +/- 134.6 mu m(2); PAE50: 576.0 +/- 53.5 mu m(2)). Western and qRT-PCR results showed that PAE down-regulated the levels of ANP, BNP and alpha-MHC. In addition, TUNEL and western results showed PAE significantly inhibited apoptosis. Masson and western results showed PAE inhibited cardiac hypertrophy. Western results showed the ERK1/2/JNK pathway could be inhibited by PAE. Discussion and conclusions Paeonol regulates ERK1/2/JNK to improve cardiac function, which provides theoretical support for the extensive clinical treatment of HF.

The recurrence of atrial fibrillation (AF) after cryoablation still needs to be prioritized, including discriminating predictive indicators. Eighty-seven patients aged 43–83 years who underwent cryo-balloon ablation were divided into paroxysmal atrial fibrillation (PAF) and non-paroxysmal atrial fibrillation (non-PAF) groups. Baseline data, intraoperative index, and miRNA21, IL-18, NLRP3, and visfatin levels in peripheral venous blood and left atrial blood were assessed. Follow-up was performed for 6 months to observe the recurrence of AF. A Cox risk ratio model was used to analyze indicators for predicting AF recurrence. The non-PAF and PAF group recurrence rates of AF were statistically different (p < 0.05) at 9/22 (40.9%) and 11/65 (16.9%), respectively. Biomarker levels in the left atrial blood were higher in the non-PAF group than in the PAF group (p < 0.05). The effects of non-PAF and levels of miRNA21 and IL-18 in left atrial serum on the recurrence of AF after cryoablation statistically differed (p < 0.05). The levels of miRNA21 and IL-18 were higher in left atrial blood than in peripheral blood, which may be related to the severity of AF and recurrence of AF after cryoablation.