ROS in diabetic atria regulate SK2 degradation by Atrogin-1 through the NF-κB signaling pathway.

One of the independent risk factors for atrial fibrillation is diabetes mellitus (DM); however, the underlying mechanisms causing atrial fibrillation in DM are unknown. The underlying mechanism of Atrogin-1-mediated SK2 degradation and associated signaling pathways are unclear. The aim of this study was to elucidate the relationship among reactive oxygen species (ROS), the NF-κB signaling pathway, and Atrogin-1 protein expression in the atrial myocardia of DM mice. We found that SK2 expression was downregulated comitant with increased ROS generation and enhanced NF-κB signaling activation in the atrial cardiomyocytes of DM mice. These observations were mimicked by exogenously applicating H2O2 and by high glucose culture conditions in HL-1 cells. Inhibition of ROS production by diphenyleneiodonium chloride or silencing of NF-κB by siRNA decreased the protein expression of NF-κB and Atrogin-1 and increased that of SK2 in HL-1 cells with high glucose culture. Moreover, chromatin immunoprecipitation assay demonstrated that NF-κB/p65 directly binds to the promoter of the FBXO32 gene (encoding Atrogin-1), regulating the FBXO32 transcription. Finally, we evaluated the therapeutic effects of curcumin, known as a NF-κB inhibitor, on Atrogin-1 and SK2 expression in DM mice and confirmed that oral administration of curcumin for 4 weeks significantly suppressed Atrogin-1 expression and protected SK2 expression against hyperglycemia. In summary, the results from this study indicated that the ROS/NF-κB signaling pathway participates in Atrogin-1-mediated SK2 regulation in the atria of streptozotocin-induced DM mice.

Diabetes Promotes Myocardial Fibrosis via AMPK/EZH2/PPAR-γ Signaling Pathway.

Background: Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. Methods: In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. Results: In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. Conclusion: Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Post translational modifications of connexin 43 in ventricular arrhythmias after myocardial infarction.

Ventricular arrhythmias are the leading cause of sudden cardiac death in patients after myocardial infarction (MI). Connexin43 (Cx43) is the most important gap junction channel-forming protein in cardiomyocytes. Dysfunction of Cx43 contributes to impaired myocardial conduction and the development of ventricular arrhythmias. Following an MI, Cx43 undergoes structural remodeling, including expression abnormalities, and redistribution. These alterations detrimentally affect intercellular communication and electrical conduction within the myocardium, thereby increasing the susceptibility to post-infarction ventricular arrhythmias. Emerging evidence suggests that post-translational modifications play essential roles in Cx43 regulation after MI. Therefore, Cx43-targeted management has the potential to be a promising protective strategy for the prevention and treatment of post infarction ventricular arrhythmias. In this article, we primarily reviewed the regulatory mechanisms of Cx43 mediated post-translational modifications on post-infarction ventricular arrhythmias. Furthermore, Cx43-targeted therapy have also been discussed, providing insights into an innovative treatment strategy for ventricular arrhythmias after MI.

Efficacy and safety of olmesartan medoxomil­amlodipine besylate tablets (Sevikar®) in older patients with essential hypertension: Subgroup analysis from the Sevikar study.

Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.

Empagliflozin Induces Vascular Relaxation in Rat Coronary Artery Due to Activation of BK Channels.

Purpose: The aim of this study was to investigate the effects and mechanisms of SGLT2 inhibitor empagliflozin on diabetic coronary function. Methods: A rat diabetic model was established by injection of streptozotocin. Rats in the treated group were administered empagliflozin by gavage and rat coronary vascular tensions were measured after eight weeks. Large conductance calcium activated K+ channel currents were recorded using a patch clamp technique, while human coronary artery smooth muscle cells were used to explore the underlying mechanisms. Results: After incubation with empagliflozin (10, 30, 100, 300, 1000 µmol/L), the Δ relaxation % of rat coronary arteries were 2.459 ± 1.304, 3.251 ± 1.119, 6.946 ± 3.407, 28.36 ± 11.47, 86.90 ± 3.868, respectively. Without and with empagliflozin in the bath solution, BK channel opening probabilities at a membrane potential of +60 mV were 0.0458 ± 0.0517 and 0.3413 ± 0.2047, respectively (p < 0.05, n = 4 cells). After incubation with iberiotoxin, the Δ tensions of rat coronary arteries in the control (Ctrl), untreated (DM), low empagliflozin (10 mg/kg/d)-treated (DM+L-EMPA) and high empagliflozin (30mg/kg/d)-treated (DM+H-EMPA) group were 103.20 ± 5.85, 40.37 ± 22.12, 99.47 ± 28.51, 78.06 ± 40.98, respectively (p < 0.01 vs Ctrl, n = 3-7; p < 0.001 vs DM+L-EMPA, n = 5-7). Empagliflozin restored high glucose-induced downregulation of Sirt1, Nrf2, and BK-ß1, while the effect of empagliflozin disappeared in the presence of EX-527, a Sirt1 selective inhibitor. Conclusion: Empagliflozin has a vasodilation effect on the coronary arteries in a concentration-dependent manner and can activate BK channels via the Sirt1-Nrf2 mechanism.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Glucose fluctuations aggravated the late sodium current induced ventricular arrhythmias via the activation of ROS/CaMKII pathway.

BACKGROUND: Recent evidence revealed that glucose fluctuation might be more likely to cause arrhythmia than persistent hyperglycemia, whereas its mechanisms were elusive. We aimed to investigate the effect of glucose fluctuation on the occurrence of ventricular arrhythmia and its mechanism. METHODS: Streptozotocin (STZ) induced diabetic rats were randomized to five groups: the controlled blood glucose (C-STZ) group, uncontrolled blood glucose (U-STZ) group, fluctuated blood glucose (GF-STZ) group, and GF-STZ rats with 100 mg/kg Tempol (GF-STZ + Tempol) group or with 5 mg/kg KN93 (GF-STZ + KN93) group. Six weeks later, the susceptibility of ventricular arrhythmias and the electrophysiological dysfunctions of ventricular myocytes were evaluated using electrocardiogram and patch-clamp technique, respectively. The levels of reactive oxygen species (ROS) and oxidized CaMKII (ox-CaMKII) were determined by fluorescence assay and Western blot, respectively. Neonatal rat cardiomyocytes and H9C2 cells in vitro were used to explore the underlying mechanisms. RESULTS: The induction rate of ventricular arrhythmias was 10%, 55%, and 90% in C-STZ group, U-STZ group, and GF-STZ group, respectively (P < 0.05). The electrophysiological dysfunctions of ventricular myocytes, including action potential duration at repolarization of 90% (APD90), APD90 short-term variability (APD90-STV), late sodium current (INa-L), early after depolarization (EAD) and delayed after depolarizations (DAD), as well as the levels of ROS and ox-CaMKII, were significantly increased in GF-STZ group. In vivo and ex vivo, inhibition of ROS or ox-CaMKII reversed these effects. Inhibition of INa-L also significantly alleviated the electrophysiological dysfunctions. In vitro, inhibition of ROS increase could significantly decrease the ox-CaMKII activation induced by glucose fluctuations. CONCLUSIONS: Glucose fluctuations aggravated the INa-L induced ventricular arrhythmias though the activation of ROS/CaMKII pathway.

Continuous positive airway pressure therapy might be an effective strategy on reduction of atrial fibrillation recurrence after ablation in patients with obstructive sleep apnea: insights from the pooled studies.

Background: Obstructive sleep apnea (OSA) is an independent and modifiable risk factor in the initiation and maintenance of atrial fibrillation (AF). However, the effective of the continuous positive airway pressure (CPAP) on AF patients with OSA after ablation is elusive. Methods: Cochrane Library, PubMed, Embase, and Web of Science were systematically searched up to February 1, 2023. Studies comprising the AF recurrence rate between the CPAP therapy group and non-CPAP therapy group for the AF patients with OSA were included. Meanwhile, trial sequential analysis (TSA) was conducted to adjust the lower statistical power and random error in this study. Subgroup analysis identified the potential determinants for the AF recurrence rate with CPAP therapy. Results: A total of eight studies including 1,231 AF patients with OSA were eligible. Compared with non-CPAP treatment group, CPAP treatment group was statistically associated with a lower AF recurrence rate (risk ratio [RR], 0.58; p = 0.000). TSA indicated the firm evidence favoring CPAP group for AF recurrence risk. Three significant intervention-covariate interactions for AF recurrence was identified, including study design, non-paroxysmal AF (PAF) proportion, and CPAP treatment strategy. Conclusion: Our study suggests that CPAP therapy might be an effective strategy on reducing AF recurrence post-ablation for AF patients with OSA. The CPAP treatment strategy and the non-PAF proportion might be the possible determinants on AF recurrence for AF patients with OSA after ablation. Clinical trial registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023398588, identifier (CRD42023398588).

Glucose fluctuations aggravate myocardial fibrosis via activating the CaMKII/Stat3 signaling in type 2 diabtetes.

BACKGROUND: Glucose fluctuations (GF) are a risk factor for cardiovascular complications associated with type 2 diabetes. However, there is a lack of adequate research on the effect of GF on myocardial fibrosis and the underlying mechanisms in type 2 diabetes. This study aimed to investigate the impact of glucose fluctuations on myocardial fibrosis and explore the potential mechanisms in type 2 diabetes. METHODS: Sprague Dawley (SD) rats were randomly divided into three groups: the control (Con) group, the type 2 diabetic (DM) group and the glucose fluctuations (GF) group. The type 2 diabetic rat model was established using a high-fat diet combined with low-dose streptozotocin injection and the GF model was induced by using staggered glucose and insulin injections daily. After eight weeks, echocardiography was used to assess the cardiac function of the three groups. Hematoxylin-eosin and Masson staining were utilized to evaluate the degree of pathological damage and fibrosis. Meanwhile, a neonatal rat cardiac fibroblast model with GF was established. Western and immunofluorescence were used to find the specific mechanism of myocardial fibrosis caused by GF. RESULTS: Compared with rats in the Con and the DM group, cardiac function in the GF group showed significant impairments. Additionally, the results showed that GF aggravated myocardial fibrosis in vitro and in vivo. Moreover, Ca2+/calmodulin­dependent protein kinase II (CaMKII) was activated by phosphorylation, prompting an increase in phosphorylation of signal transducer and activator of transcription 3 (Stat3) and induced nuclear translocation. Pretreatment with KN-93 (a CaMKII inhibitor) blocked GF-induced Stat3 activation and significantly suppressed myocardial fibrosis. CONCLUSIONS: Glucose fluctuations exacerbate myocardial fibrosis by triggering the CaMKII/Stat3 pathway in type 2 diabetes.

Advanced Glycation End Products Downregulate Connexin 43 and Connexin 40 in Diabetic Atrial Myocytes via the AMPK Pathway.

Purpose: Diabetes mellitus is an independent risk factor for atrial fibrillation (AF), which may be related to accumulation of advanced glycation end products (AGEs). However, the mechanisms involved are not completely clear. Abnormality of gap junction proteins, especially connexin 43 (Cx43) and connexin 40 (Cx40) in atrial myocytes, is an important cause of increased susceptibility of AF. The aim of our work is to investigate the mechanism of dysregulated Cx43 and Cx40 in atrial myocytes of diabetic rats. Methods: We established a type 1 diabetic rat model by intraperitoneal injection of streptozotocin. HL-1 cells and primary rat atrial myocytes were treated with AGEs in vitro. Using Western blotting, immunofluorescence staining, immunohistochemistry, and lucifer yellow diffusion measurements, we investigated dysregulation of Cx43 and Cx40 and its mechanism in atrial myocytes of diabetic rats. Results: Accumulation of AGEs was found in diabetic rats. The expression of Cx43 and Cx40 was reduced in the atrium of diabetic rats, accompanied by the decrease of phosphorylated Adenosine 5'-monophosphate-activated protein kinase (p-AMPK). Similar results were found in cultured HL-1 cells and primary rat atrial myocytes, suggesting a role of AGEs on gap junction proteins. An AMPK agonist, 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), reversed the down-regulated Cx43 expression induced by AGEs stimulation. More importantly, lucifer yellow diffusion assay showed that AGEs significantly affected gap junctional function, and these changes were reversed by AICAR. Conclusion: Thus, we conclude that AGEs cause dysregulation of Cx43 and Cx40 in diabetic atria via the AMPK pathway, thereby leading to gap junction dysfunction, which may contribute to the increased AF susceptibility in diabetes.

Calcineurin/NFATc3 pathway mediates myocardial fibrosis in diabetes by impairing enhancer of zeste homolog 2 of cardiac fibroblasts.

BACKGROUND: Diabetes is associated with myocardial fibrosis, while the underlying mechanisms remain elusive. The aim of this study is to investigate the underlying role of calcineurin/nuclear factor of activated T cell 3 (CaN/NFATc3) pathway and the Enhancer of zeste homolog 2 (EZH2) in diabetes-related myocardial fibrosis. METHODS: Streptozotocin (STZ)-injected diabetic rats were randomized to two groups: the controlled glucose (Con) group and the diabetes mellitus (DM) group. Eight weeks later, transthoracic echocardiography was used for cardiac function evaluation, and myocardial fibrosis was visualized by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with high-glucose medium with or without cyclosporine A or GSK126. The expression of proteins involved in the pathway was examined by western blotting. The nuclear translocation of target proteins was assessed by immunofluorescence. RESULTS: The results indicated that high glucose treatment increased the expression of CaN, NFATc3, EZH2 and trimethylates lysine 27 on histone 3 (H3K27me3) in vitro and in vivo. The inhibition of the CaN/NFATc3 pathway alleviated myocardial fibrosis. Notably, inhibition of CaN can inhibit the nuclear translocation of NFATc3, and the expression of EZH2 and H3K27me3 protein induced by high glucose. Moreover, treatment with GSK126 also ameliorated myocardial fibrosis. CONCLUSION: Diabetes can possibly promote myocardial fibrosis by activating of CaN/NFATc3/EZH2 pathway.

Advanced glycation end products impair coronary artery BK channels via AMPK/Akt/FBXO32 signaling pathway.

Background: Advanced glycation end products (AGEs) impair vascular physiology in Diabetes mellitus (DM). However, the underlying mechanisms remain unclear. Vascular large conductance calcium-activated potassium (BK) channels play important roles in coronary arterial function.Purpose: Our study aimed to investigate the regulatory role of AGEs in BK channels.Research Design: Using gavage of vehicle (V, normal saline) or aminoguanidine (A) for 8 weeks, normal and diabetic rats were divided into four groups: C+V group, DM+V group, C+A group, and DM+A group.Study Sample: Coronary arteries from different groups of rats and human coronary smooth muscle cells were used in this study.Data Collection and Analysis: Data were presented as mean ± SEM (standard error of mean). Student's t-test was used to compare data between two groups. One-way ANOVA with post-hoc LSD analysis was used to compare data between multiple groups.Results: Compared to the C+V group, vascular contraction induced by iberiotoxin (IBTX), a BK channel inhibitor, was impaired, and BK channel densities decreased in the DM+V group. However, aminoguanidine administration reduced the impairment. Protein expression of BK-ß1, phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), and protein kinase B (PKB or Akt) were down-regulated, while F-box protein 32 (FBXO32) expression increased in the DM+V group and in high glucose (HG) cultured human coronary smooth muscle cells. Treatment with aminoguanidine in vitro and in vivo could reverse the above protein expression. The effect of aminoguanidine on the improvement of BK channel function by inhibiting the generation of AGEs was reversed by adding MK2206 (Akt inhibitor) or Compound C (AMPK inhibitor) in HG conditions in vitro.Conclusions: AGEs aggravate BK channel dysfunction via the AMPK/Akt/FBXO32 signaling pathway.

Deep learning-mediated prediction of concealed accessory pathway based on sinus rhythmic electrocardiograms.

BACKGROUND: Concealed accessory pathway (AP) may cause atrial ventricular reentrant tachycardia impacting the health of patients. However, it is asymptomatic and undetectable during sinus rhythm. METHODS: To detect concealed AP with electrocardiography (ECG) images, we collected normal sinus rhythmic ECG images of concealed AP patients and healthy subjects. All ECG images were randomly allocated to the training and testing datasets, and were used to train and test six popular convolutional neural networks from ImageNet pre-training and random initialization, respectively. RESULTS: We screened 152 ECG recordings in concealed AP group and 600 ECG recordings in control group. There were no statistically significant differences in ECG characteristics between control group and concealed AP group in terms of PR interval and QRS interval. However, the QT interval and QTc were slightly higher in control group than in concealed AP group. In the testing set, ResNet26, SE-ResNet50, MobileNetV3_large_100, and DenseNet169 achieved a sensitivity rate more than 87.0% with a specificity rate above 98.0%. And models trained from random initialization showed similar performance and convergence with models trained from ImageNet pre-training. CONCLUSION: Our study suggests that deep learning could be an effective way to predict concealed AP with normal sinus rhythmic ECG images. And our results might encourage people to rethink the possibility of training from random initialization on ECG image tasks.

A comparable efficacy and safety between intracardiac echocardiography and transesophageal echocardiography for percutaneous left atrial appendage occlusion.

Background: Accumulated clinical studies utilized intracardiac echocardiography (ICE) to guide percutaneous left atrial appendage occlusion (LAAO). However, its procedural success and safety compared to traditional transesophageal echocardiography (TEE) remained elusive. Therefore, we performed a meta-analysis to compare efficacy and safety of ICE and TEE for LAAO. Methods: We screened studies from four online databases (including the Cochrane Library, Embase, PubMed, and Web of Science) from their inception to 1 December 2022. We used a random or fixed-effect model to synthesize the clinical outcomes and conducted a subgroup analysis to identify the potential confounding factors. Results: A total of twenty eligible studies with 3,610 atrial fibrillation (AF) patients (1,564 patients for ICE and 2,046 patients for TEE) were enrolled. Compared with TEE group, there was no significant difference in procedural success rate [risk ratio (RR) = 1.01; P = 0.171], total procedural time [weighted mean difference (WMD) = -5.58; P = 0.292], contrast volume (WMD = -2.61; P = 0.595), fluoroscopic time (WMD = -0.34; P = 0.705; I2 = 82.80%), procedural complications (RR = 0.82; P = 0.261), and long-term adverse events (RR = 0.86; P = 0.329) in the ICE group. Subgroup analysis revealed that ICE group might be associated with the reduction of contrast use and fluoroscopic time in the hypertension proportion <90 subgroup, with lower total procedure time, contrast volume, and the fluoroscopic time in device type subgroup with multi-seal mechanism, and with the lower contrast use in paroxysmal AF (PAF) proportion ≤50 subgroup. Whereas, ICE group might increase the total procedure time in PAF proportion >50 subgroup and contrast use in multi-center subgroup, respectively. Conclusion: Our study suggests that ICE may have comparable efficacy and safety compared to TEE for LAAO.

Identification of TNFα-mediated inflammation as potential pathological marker and therapeutic target for calcification progress of congenital bicuspid aortic valve.

BACKGROUD: Congenital bicuspid aortic valve (cBAV) develops calcification and stenotic obstruction early compared with degenerative tricuspid aortic valve (dTAV), which requires surgical intervention. Here we report a comparative study of patients with cBAV or dTAV to identify risk factors associated with the rapid development of calcified bicuspid valves. METHODS: A total of 69 aortic valves (24 dTAV and 45 cBAV) were collected at the time of surgical aortic valve replacement for comparative clinical characteristics. Ten samples were randomly selected from each group for histology, pathology, and inflammatory factors expression and comparison analyses. OM-induced calcification in porcine aortic valve interstitial cell cultures were prepared for illustrating the underlying molecular mechanisms about calcification progress of cBAV and dTAV. RESULTS: We found that cBAV patients have increased cases of aortic valve stenosis compared with dTAV patients. Histopathological examinations revealed increased collagens deposition, neovascularization and infiltrations by inflammatory cells, especially T-lymphocytes and macrophages. We identified that tumor necrosis factor α (TNFα) and its regulated inflammatory cytokines are upregulated in cBAV. Further in vitro study indicated that TNFα-NFκB and TNFα-GSK3ß pathway accelerate aortic valve interstitial cells calcification, while inhibition of TNFα significantly delays this process. CONCLUSION: The finding of intensified TNFα-mediated inflammation in the pathological cBAV advocates the inhibition of TNFα as a potential treatment for patients with cBAV by alleviating the progress of inflammation-induced valve damage and calcification.

Conduction system pacing is superior to biventricular pacing in patients with heart failure: Insights from the pooled clinical studies.

Background: The effects of conduction system pacing (CSP) compared with conventional biventricular pacing (BVP) on heart function in patients with heart failure remain elusive. Methods: PubMed, Embase, Cochrane's Library and Web of science databases were searched up to 1 October 2022 for pertinent controlled studies. Random or fixed-effect model were used to synthesize the clinical outcomes. Subgroup analysis was performed to screen the potential confounding factors. Results: Fifteen studies including 1,347 patients were enrolled. Compared with BVP, CSP was significantly associated with shortened QRS duration [WMD -22.51 ms; p = 0.000], improved left ventricular ejection fraction [WMD 5.53%; p = 0.000], improved NYHA grade [WMD -0.42; p = 0.000], higher response rate and lower heart failure rehospitalization rate. CSP resulted in better clinical outcomes in higher male proportion group than lower one compared with BVP. No significant differences of clinical outcomes were observed between left bundle branch area pacing (LBBaP) and his bundle pacing (HBP) except the pacing threshold. The pacing threshold of LBBaP was significantly lower than those in BVP and HBP. Conclusion: This study suggests that CSP might be superior to conventional BVP for HF patients. In a higher male proportion group, CSP may be associated with more benefits than BVP. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022355991; Identifier: CRD42022355991.

Protein arginine methyltransferase 5-mediated arginine methylation stabilizes Kruppel-like factor 4 to accelerate neointimal formation.

AIMS: Accumulating evidence supports the indispensable role of protein arginine methyltransferase 5 (PRMT5) in the pathological progression of several human cancers. As an important enzyme-regulating protein methylation, how PRMT5 participates in vascular remodelling remains unknown. The aim of this study was to investigate the role and underlying mechanism of PRMT5 in neointimal formation and to evaluate its potential as an effective therapeutic target for the condition. METHODS AND RESULTS: Aberrant PRMT5 overexpression was positively correlated with clinical carotid arterial stenosis. Vascular smooth muscle cell (SMC)-specific PRMT5 knockout inhibited intimal hyperplasia with an enhanced expression of contractile markers in mice. Conversely, PRMT5 overexpression inhibited SMC contractile markers and promoted intimal hyperplasia. Furthermore, we showed that PRMT5 promoted SMC phenotypic switching by stabilizing Kruppel-like factor 4 (KLF4). Mechanistically, PRMT5-mediated KLF4 methylation inhibited ubiquitin-dependent proteolysis of KLF4, leading to a disruption of myocardin (MYOCD)-serum response factor (SRF) interaction and MYOCD-SRF-mediated the transcription of SMC contractile markers. CONCLUSION: Our data demonstrated that PRMT5 critically mediated vascular remodelling by promoting KLF4-mediated SMC phenotypic conversion and consequently the progression of intimal hyperplasia. Therefore, PRMT5 may represent a potential therapeutic target for intimal hyperplasia-associated vascular diseases.

Higher glucose fluctuation is associated with a higher risk of cardiovascular disease: Insights from pooled results among patients with diabetes.

BACKGROUND: The relationship between glucose fluctuation and the risk of cardiovascular disease (CVD) in patients with diabetes remains elusive. Glycated hemoglobin (HbA1c) variability is a key parameter of glucose fluctuation. METHODS: PubMed, Cochrane Library, Web of Science, and Embase were searched up to 1 July 2022. Studies reporting associations of HbA1c variability (HbA1c-SD), coefficient of variation of HbA1c (HbA1c-CV), and HbA1c variability score [HVS] with the risk of CVD among patients with diabetes were included. We used three different insights (a high-low value meta-analysis, a study-specific meta-analysis, and a non-linear dose-response meta-analysis) to explore the relationship between HbA1c variability and CVD risk. A subgroup analysis was also performed to screen the potential confounding factors. RESULTS: A total of 14 studies with 254 017 patients with diabetes were eligible. The highest HbA1c variability was significantly associated with increased risks of CVD (HbA1c-SD, risk ratio [RR] 1.45; HbA1c-CV, RR 1.74; HVS, RR 2.46; all p < .001) compared to the lowest HbA1c variability. The RRs of CVD for per HbA1c variability were significantly >1 (all p < .001). The subgroup analysis for per HbA1c-SD found a significant exposure-covariate interaction in the types of diabetes (p = .003 for interaction). The dose-response analysis showed a positive association between HbA1c-CV and CVD risk (P for nonlinearity <.001). CONCLUSIONS: Our study suggests that the higher glucose fluctuation is significantly associated with the higher CVD risk in diabetes patients based on HbA1c variability. The CVD risk associated with per HbA1c-SD might be higher among patients type 1 diabetes than patients with type 2 diabetes.

Radiofrequency ablation of premature ventricular contractions guided by robotic magnetic navigation combined with pattern matching filter.

BACKGROUND: This study's intent is to evaluate the usefulness of pattern matching filter (PMF) function combined with robotic magnetic navigation (RMN) in guiding the ablation of premature ventricular contractions (PVCs). HYPOTHESIS: Assume that PMF can improve the outcomes of PVCs ablation using RMN. METHODS: A retrospective analysis was completed consisting of 118 consecutive patients with PVCs who underwent radiofrequency ablation guided by RMN. According to the application of PMF, patients were divided into two groups: 20 patients underwent ablation without PMF (group A), and another 98 patients received ablation incorporating PMF (group B). RESULTS: Compared with group A, the procedure time (135.0 ± 28.3 min vs. 106.3 ± 37.9 min, p = 0.02) in group B was significantly decreased, while the X-ray exposure time (6.0 ± 2.6 min vs. 6.5 ± 3.6 min, p = 0.705) and dose (3.2 ± 2.4 gycm2 vs. 3.9 ± 2.7 gycm2 ，p = 0.208) had no significant difference. Group B had a more than twofold number of points acquired (66.9 ± 23.0 vs. 143.9 ± 68.3, p < 0.001) and required a shorter radiofrequency ablation time (13.2 ± 3.5 min vs. 8.1 ± 2.9 min, p < 0.001). There were no serious complications in either group. The acute success rate was similar [90.0% (18/20) vs. 87.8% (86/98), p = 1.000] in two groups, and the success rate was also similar in the long-term follow-up [83.3% (15/18) vs. 87.2% (75/86), p = 0.776]. CONCLUSIONS: The ablation of PVCs guided by RMN is safe and effective. Combined with the functional capability of PMF, both procedure time and radiofrequency ablation time were significantly decreased.

Identification of key immune-related genes in dilated cardiomyopathy using bioinformatics analysis.

Dilated cardiomyopathy (DCM) is characterized by the left ventricular dilatation and impaired myocardial systolic dysfunction with high mortality and morbidity. However, the underlying mechanisms remain elusive. We first identified the differentially expressed genes (DEGs) between the DCM and control group using two expression profiles from GSE3585 and GSE84796. Enrichment analysis was conducted to explore the potential mechanisms underlying DCM. A total of four algorithms, including key module of MCODE, degree, maximum neighborhood component (MNC), and maximal clique centrality (MCC), were used to identify the hub genes within Cytoscape. The correlation between hub genes and infiltrated immune cells was evaluated to determine potential immune-related genes. The expression analysis and diagnosis value analysis of potential immune-related genes were performed. Finally, the expression analysis with GSE57338 and relationship analysis with the comparative toxicogenomics database (CTD) were performed to identify the key immune-related genes in DCM. A total of 80 DEGs were screened for DCM. Enrichment analysis revealed that DEGs were involved in the immune-related pathological process. Immune infiltration analysis indicated a potentially abnormal immune response in DCM. Four up-regulated genes (COL1A2, COL3A1, CD53, and POSTN) were identified as potential immune-related genes. Finally, three genes (COL1A2, COL3A1, and POSTN) were determined as the key immune-related genes in DCM via expression analysis with a validation set (GSE57338) and relationship analysis with CTD. Our study suggested that the upregulated COL1A2, COL3A1, and POSTN might be the key immune-related genes for DCM. Further studies are needed to validate the underlying mechanisms.