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Background: Premature ventricular complexes (PVCs) exhibit circadian fluctuation. We determine if PVCs of different origin exhibit specific circadian patterns.Methods: We analyzed Holter recordings from patients with monomorphic PVCs who underwent catheter ablation. PVC circadian patterns were classified as fast-heart rate- (HR-) dependent (F-PVC), slow-HR-dependent (S-PVC), or HR-independent (I-PVC). PVC origins were determined intraprocedurally.Results: In a retrospective cohort of 407 patients, F-PVC and S-PVC typically exhibited diurnal and nocturnal predominance, respectively. Despite decreased circadian fluctuation, I-PVC generally had heavier nocturnal than diurnal burden. PVCs of left anterior fascicle origin were predominantly S-PVC, while those of posterior hemibranch origin were mostly F-PVC. PVCs originating from the aortic sinus of Valsalva (ASV) were predominantly I-PVC, while most PVCs arising from the left ventricular outflow tract (LVOT) were F-PVC. Using a diurnal/nocturnal PVC burden ratio of 0.92 as the cutoff value to distinguish LVOT from ASV origin achieved 97% sensitivity and, as further verification, an accuracy of 89% (16/18) in a prospective cohort of patients with PVCs originating from either ASV or LVOT. In contrast, PVCs originating from right ventricles, such as right ventricular outflow tract, did not show distinct circadian patterns.Conclusions: The circadian patterns exhibit origin specificity for PVCs arising from left ventricles. An analysis of Holter monitoring provides useful information on PVC localization in ablation procedure planning. [ABSTRACT FROM AUTHOR]

Background: Primary angiosarcomas of the right atrium are extremely rare, often resulted in missed diagnosis or misdiagnosis with routine examination tools. These malignant cardiac tumors are highly aggressive with generally poor prognosis. Surgical excision is the mainstay of treatment as it is essentially not responsive to current regimens of chemoradiotherapy.Case Presentation: Herein, we describe a patient who initially presented with paroxysmal atrial fibrillation and was subsequently treated with radiofrequency catheter ablation (RFCA). Prior to RFCA, an initial transesophageal echocardiography revealed a local thickening of the intratrial septum. Three months later, she was hospitalized with progressive dyspnea and massive pericardial effusion. A large immobile, non-pedunculated mass, occupying almost half of the right atrium was detected by transthoracic and transesophageal echocardiogram. Multimodality cardiac imaging was useful in further characterizing this mass, which was ultimately diagnosed as an angiosarcoma based upon biopsy results. The growth rate was extremely rapid following RFCA, and patient underwent surgical excision. After discharge, the angiosarcoma recurred and patient survived for 7 months from the first episode of tamponade.Conclusions: Primary cardiac angiosarcoma of the right atrium can easily be mistaken for structural anomalies in its early stages, losing the opportunity for initiating earlier treatments to improve potential patient outcomes. The correct diagnosis of this rare case relied on the comprehensive utilization of multimodal imaging techniques including biopsy. [ABSTRACT FROM AUTHOR]

Objective:The objective was to determine whether obesity is associated with depressive symptoms among older Chinese. Methods:Data from the cross-sectional Rugao Longevity and Ageing Study were used including anthropometric measurements (body mass index (BMI), waist circumference (WC) and waist–hip ratio (WHR)), socio-demographic characteristics, living habits, physical health and cognitive impairment. Depressive symptoms were assessed by the 15-item Geriatric Depression Scale (GDS-15). Chi-square tests and multivariate logistic regression analyses were performed to investigate the association between obesity and depressive symptoms. Results:Among 1732 elderly Chinese aged 70–84 years, the prevalence of depressive symptoms was 6.7% (5.0%–8.5%) in men and 12.5% (10.4%–14.6%) in women. A negative linear trend was found between depressive symptoms and BMI in women (Pfor trend< 0.05). Women with BMI ≥ 28.0 kg/m2had lower chances (OR = 0.41 (0.20–0.84),p= 0.01) to have elevated depressive symptoms compared with their normal weight counterparts. Furthermore, consistent trends were observed with lower depression prevalence rates in higher WC and WHR categories in women. However, no such associations were apparent in men. Conclusion:Higher BMI, WC and WHR categories were all associated with a lower risk of depressive symptoms in older women. [ABSTRACT FROM AUTHOR]

Hypertension-induced tunica media thickening (TMT) is the most important fundamental for the subsequent complications like stroke and cardiovascular diseases. Pathogenically, TMT originates from both vascular smooth muscle cells (VSMCs) hypertrophy due to synthesizing more amount of intracellular contractile proteins and excess secretion of extracellular matrix. However, what key molecules are involved in the pathogenesis of TMT is unknown. We hypothesize that formin homology 2 domain-containing protein 1 (FHOD1), an amply expressed mediator for assembly of thin actin filament in VSMCs, is a key regulator for the pathogenesis of TMT. In this study, we found that FHOD1 expression and its phosphorylation/activation were both upregulated in the arteries of three kinds of hypertensive rats. Ang-II induced actin filament formation and hypertrophy through activation and upregulation of FHOD1 in VSMCs. Active FHOD1-mediated actin filament assembly and secretions of collagen-1α/collagen-3α played crucial roles in Ang-II-induced VSMCs hypertrophy in vitro and hypertensive TMT in vivo. Proteomics demonstrated that activated FL-FHOD1 or its C-terminal diaphanous-autoregulatory domain significantly upregulated RNF213 (ring finger protein 213), a 591-kDa cytosolic E3 ubiquitin ligase with its loss-of-functional mutations being a susceptibility gene for Moyamoya disease which has prominent tunica media thinning in both intracranial and systemic arteries. Mechanistically, activated FHOD1 upregulated its downstream effector RNF213 independently of its classical pathway of decreasing G-actin/F-actin ratio, transcription, and translation, but dependently on its C-terminus-mediated stabilization of RNF213 protein. FHOD1-RNF213 signaling dramatically promoted collagen-1α/collagen-3α syntheses in VSMCs. Our results discovered a novel signaling axis of FHOD1-RNF213-collagen-1α/collagen-3α and its key role in the pathogenesis of hypertensive TMT. [Display omitted] • FHOD1 was activated in hypertensive rats and angiotensin-II-stimulated VSMCs. • Inactivated FHOD1 alleviated angiotensin-II-induced hypertension and TMT. • Activated FHOD1 promoted the hypertrophy, migration and fibrosis of VSMCs. • Activated FHOD1 upregulated RNF213 through a novel mechanism. • This study deepens our understanding of the pathogenesis of hypertensive TMT. [ABSTRACT FROM AUTHOR]

Heart failure is a serious and life-threatening disease worldwide. Cadherin-11 (Cad-11) is highly expressed in the heart and closely associated with inflammation. There is currently limited understanding on how Cad-11 contributes to cardiac remodeling and its underline molecular mechanism. We found an increased expression of Cad-11 in biopsy heart samples from heart failure patients, suggesting a link between Cad-11 and heart failure. To determine the role of Cad-11 in cardiac remodeling, Cad-11-deficient mice were used in a well-established mouse transverse aortic constriction (TAC) model. Loss of Cad11 greatly improved pressure overload-induced LV structural and electrical remodeling. IL (interleukin)-6 production was increased following TAC in WT mice and this increase was inhibited in cadherin-11−/− mice. We further tested the effect of IL-6 on myocyte hypertrophy and fibrosis in a primary culture system. The addition of hCad-11-Fc to cultured cardiac fibroblasts increased IL-6 production and fibroblast cell activation, whereas neutralizing IL-6 with an IL-6 antibody resulted in alleviating the fibroblast activation induced by hCad-11-Fc. On the other hand, cardiomyocytes were promoted to cardiomyocyte hypertrophy when cultured in condition media collected from cardiac fibroblasts stimulated by hCad-11-Fc.Similarly, neutralizing IL-6 prevented cardiomyocyte hypertrophy. Finally, we found that MAPKs and CaMKII–STAT3 pathways were activated in both hCad-11-Fc stimulated fibroblasts and cardiomyocytes treated with hCad-11-Fc stimulated fibroblast condition medium. IL-6 neutralization inhibited such MAPK and CaMKII-STAT3 signaling activation. These data demonstrate that Cad-11 functions in pressure overload-induced ventricular remodeling through inducing IL-6 secretion from cardiac fibroblasts to modulate the pathophysiology of neighboring cardiomyocytes. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is an important pathological process in many diseases. Wdr5 catalyzes the trimethylation of lysine K4 on histone H3. The effects of Wdr5 on the cardiac fibrosis phenotype and the activation or transformation of cardiac fibroblasts were investigated by Ang-II-infused mice by osmotic mini-pump and isolated primary neonatal rat cardiac fibroblasts. We found that the Wdr5 expression and histone H3K4me3 modification were significantly increased in Ang-II-infused mice. By stimulating primary neonatal rat cardiac fibroblasts with Ang II, we detected that the expression of Wdr5 and H3K4me3 modification were also significantly increased. Two Wdr5-specific inhibitors, and the lentivirus that transfected Sh-Wdr5, were used to treat primary mouse cardiac fibroblasts, which not only inhibited the histone methylation by Wdr5 but also significantly reduced the activation and migration ability of Ang-II-treated fibroblasts. To explore its mechanism, we found that the inhibition of Wdr5 increased the expression of P53, P21. Cut&Tag-qPCR showed that the inhibition of Wdr5 significantly reduced the enrichment of H3K4me3 in the Mdm2 promoter region. For in vivo experiments, we finally proved that the Wdr5 inhibitor OICR9429 significantly reduced Ang-II-induced cardiac fibrosis and increased the expression of P21 in cardiac fibroblasts. Inhibition of Wdr5 may mediate cardiac fibroblast cycle arrest through the Mdm2/P53/P21 pathway and alleviate cardiac fibrosis. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the molecular mechanisms by which BRD4 play a role in atrial fibrillation (AF). We used a discovery-driven approach to detect BRD4 expression in the atria of patients with AF and in various murine models of atrial fibrosis. We used a BRD4 inhibitor (JQ1) and atrial fibroblast (aFB)-specific BRD4-knockout mice to elucidate the role of BRD4 in AF. We further examined the underlying mechanisms using RNA-seq and ChIP-seq analyses in vitro, to identify key downstream targets of BRD4. We found that BRD4 expression is significantly increased in patients with AF, with accompanying atrial fibrosis and aFB differentiation. We showed that JQ1 treatment and shRNA-based molecular silencing of BRD4 blocked ANG–II–induced extracellular matrix production and cell-cycle progression in aFBs. BRD4-related RNA-seq and ChIP-seq analyses in aFBs demonstrated enrichment of a subset of promoters related to the expression of profibrotic and proliferation-related genes. The pharmacological inhibition of BRD4 in vivo or in aFB-specific BRD4-knockout in mice limited ANG–II–induced atrial fibrosis, atrial enlargement, and AF susceptibility. Our findings suggest that BRD4 plays a key role in pathological AF, at least partially by activating aFB proliferation and ECM synthesis. This study provides mechanistic insights into the development of BRD4 inhibitors as targeted antiarrhythmic therapies. [Display omitted] [ABSTRACT FROM AUTHOR]

Vascular injury-induced endothelium-denudation and profound vascular smooth muscle cells (VSMCs) proliferation and dis-regulated apoptosis lead to post-angioplasty restenosis. Coptisine (CTS), an isoquinoline alkaloid, has multiple beneficial effects on the cardiovascular system. Recent studies identified it selectively inhibits VSMCs proliferation. However, its effects on neointimal hyperplasia, re-endothelialization, and the underlying mechanisms are still unclear. Cell viability was assayed by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and cell counting kit-8 (CCK-8). Cell proliferation and apoptosis were measured by flow cytometry and immunofluorescence of Ki67 and TUNEL. Quantitative phosphoproteomics (QPP) was employed to screen CTS-responsive phosphor-sites in the key regulators of cell proliferation and apoptosis. Neointimal hyperplasia was induced by balloon injury of rat left carotid artery (LCA). Adenoviral gene transfer was conducted in both cultured cells and LCA. Re-endothelialization was evaluated by Evan's blue staining of LCA. 1) CTS had strong anti-proliferative and pro-apoptotic effects in cultured rat VSMCs, with the EC 50 4∼10-folds lower than that in endothelial cells (ECs). 2) Rats administered with CTS, either locally to LCA's periadventitial space or orally, demonstrated a potently inhibited balloon injury-induced neointimal hyperplasia, but had no delaying effect on re-endothelialization. 3) The QPP results revealed that the phosphorylation levels of Pak1S144/S203, Pak2S20/S197, Erk1T202/Y204, Erk2T185/Y187, and BadS136 were significantly decreased in VSMCs by CTS. 4) Adenoviral expression of phosphomimetic mutants Pak1D144/D203/Pak2D20/D197 enhanced Pak1/2 activities, stimulated the downstream pErk1T202/Y204/pErk2T185/Y187/pErk3S189/pBadS136, attenuated CTS-mediated inhibition of VSMCs proliferation and promotion of apoptosis in vitro , and potentiated neointimal hyperplasia in vivo. 5) Adenoviral expression of phosphoresistant mutants Pak1A144/A203/Pak2A20/A197 inactivated Pak1/2 and totally simulated the inhibitory effects of CTS on platelet-derived growth factor (PDGF)-stimulated VSMCs proliferation and PDGF-inhibited apoptosis in vitro and neointimal hyperplasia in vivo. 6) LCA injury significantly enhanced the endogenous phosphorylation levels of all but pBadS136. CTS markedly attenuated all the enhanced levels. These results indicate that CTS is a promising medicine for prevention of post-angioplasty restenosis without adverse impact on re-endothelialization. CTS-directed suppression of pPak1S144/S203/pPak2S20/S197 and the subsequent effects on downstream pErk1T202/Y204/pErk2T185/Y187/pErk3S189 and pBadS136 underline its mechanisms of inhibition of VSMCs proliferation and stimulation of apoptosis. Therefore, the phosphor-sites of Pak1S144/S203/Pak2S20/S197 constitute a potential drug-screening target for fighting neointimal hyperplasia restenosis. [Display omitted] • Coptisine effectively suppresses neointimal hyperplasia without impeding re-endothelialization post-injury. • Coptisine inhibits phosphorylation of P21-Activated Kinase 1 (Pak1) at S144/S203 and Pak2 at S20/S197 in VSMCs. • Transfer of the mutants (S>D and A) into injured artery respectively promotes and attenuates the neointima formation in vivo. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common cardiac arrhythmia nowadays. The occurrence of AF is closely associated with obesity. Cadherin‐11 (Cad‐11), as a member of the cadherin family, can make a contribution to diet‐induced obesity and it will be informative to know whether Cad‐11 exerts its effects on atrial remodeling and AF vulnerability in a diet‐induced obesity model. In this study, we demonstrated that the expression of Cad‐11 was significantly upregulated in the left atrium of AF patients with obesity and mice following 16 weeks of high‐fat diet (HFD) feeding. Further confirmed that Cad‐11 could regulate the activity of atrial fibroblasts by participating in inducing proinflammatory cytokines production. At animal levels, we found that although there was a lack of statistical difference in body weight, Cad‐11−/− mice could markedly improve impaired glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, inflammation, and fibrosis provoked by HFD feeding were mitigated in Cad‐11−/− mice. Mechanistically, Cad‐11 activated mitogen‐activated protein kinases and nuclear factor‐κB for interleukin‐6 production in atrial fibroblasts that may contribute to the atrial fibrosis process in obesity‐related AF, suggesting Cad‐11 might be a new therapeutic target for obesity‐related AF. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang-II)-induced fibroblast differentiation plays an important role in the development of atrial fibrosis and atrial fibrillation (AF). Here, we show that the expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is increased in atrial muscle and atrial fibroblasts in patients with AF, accompanied by significant atrial fibrosis and atrial fibroblast differentiation. In addition, EZH2 is induced in murine models of atrial fibrosis. Furthermore, either pharmacological GSK126 inhibition or molecular silencing of EZH2 can inhibit the differentiation of atrial fibroblasts and the ability to produce ECM induced by Ang-II. Simultaneously, inhibition of EZH2 can block the Ang-II-induced migration of atrial fibroblasts. We found that EZH2 promotes fibroblast differentiation mainly through the Smad signaling pathway and can form a transcription complex with Smad2 to bind to the promoter region of the ACTA2 gene. Finally, our in vivo experiments demonstrated that the EZH2 inhibitor GSK126 significantly inhibited Ang-II-induced atrial enlargement and fibrosis and reduced AF vulnerability. Our results demonstrate that targeting EZH2 or EZH2-regulated genes might present therapeutic potential in AF. • EZH2 expression was significantly elevated in atrial muscle specimens of patients with atrial fibrillation. • EZH2 regulates the transformation and migration of atrial fibroblasts. • EZH2 regulates fibroblasts transformation mainly through Ang-II-TGF-β-Smads signaling pathway. • EZH2 inhibitor GSK126 significantly inhibits Ang-II-induced atrial enlargement, fibrosis, and reduced AF vulnerability. [ABSTRACT FROM AUTHOR]

Endothelial‐to‐mesenchymal transition (EndMT) was first reported in heart development. Recent studies have shown that EndMT also occurs in the progression of cardiac fibrosis. Herein, we demonstrated a critical role of the Forkhead Box M1 (Foxm1) transcription factor in transforming growth factor beta (TGF‐β)‐induced EndMT in endothelial cells (ECs) and a possible underlying molecular mechanism. Foxm1 was induced in ECs following TGF‐β stimulation. Using both pharmacological and molecular approaches to inhibit Foxm1 function can attenuate the TGF‐β‐induced EndMT and cell migration. In contrast, lentivirus‐mediated overexpression of Foxm1 allowed EndMT to proceed despite the absence of TGF‐β in ECs. Moreover, we found that the activation of the Smad2/3 signaling pathway and EndMT‐related transcription factors played important roles in the pathogenesis of Foxm1‐mediated EndMT. Further analysis revealed that Foxm1 bound to and increased the promoter activity of the Snail gene encoding a critical transcriptional regulator of EndMT. In conclusion, our results identify FOXM1 as a driver of TGF‐β‐induced EndMT and underscore the therapeutic potential of targeting FOXM1 for cardiac fibrosis. We found that the activation of the Smad2/3 signaling pathway and endothelial‐to‐mesenchymal transition (EndMT)‐related transcription factors played important roles in the pathogenesis of Forkhead Box M1 (Foxm1)‐mediated EndMT. Our results identify FOXM1 as a driver of TGF‐β‐induced EndMT and underscore the therapeutic potential of targeting FOXM1 for cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Cardiac fibrosis (CF), a process characterized by potentiated proliferation of cardiac fibroblasts and excessive secretion and deposition of extracellular matrix (ECM) from the cells, contributes strongly to the pathogenesis of a series of cardiovascular (CV) diseases, including AMI, heart failure and atrial fibrillation. Endothelial-mesenchymal transition (EndMT), one of the sources of transformed cardiac fibroblasts, has been reported as a key factor involved in CF. However, the molecular basis of EndMT has not been thoroughly elucidated to date. At the posttranscriptional level, of the three epigenetic regulators, writer and eraser are reported to be involved in EndMT, but the role of reader in the process is still unknown. In this study, we aimed to explore the role of Bromodomain-containing protein 4 (BRD4), an acetyl-lysine reader protein, in EndMT-induced CF and related mechanisms. We found that BRD4 was upregulated in endothelial cells (ECs) in the pressure-overload mouse heart and that its functional inhibitor JQ1 potently attenuated the TAC-induced CF and preserved cardiac function. In umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs), bothJQ1 and shRNA-mediated silencing of BRD4 blocked TGF-β-induced EC migration, EndMT and ECM synthesis and preserved the EC sprouting behavior, possibly through the downregulation of a group of transcription factors specific for EndMT (Snail, Twist and Slug), the Smads pathway and TGF-β receptor I. In the absence of TGF-β stimulation, ectopic expression of BRD4 alone could facilitate EndMT, accelerate migration and increase the synthesis of ECM. In vivo, JQ1 also attenuated TAC-induced EndMT and CF, which was consistent with JQ1's intracellular mechanisms of action. Our results showed that BRD4 plays a critical role in EndMT-induced CF and that targeting BRD4 might be a novel therapeutic option for CF. [ABSTRACT FROM AUTHOR]

• The correlation between PM2.5 and different arrhythmias was found in this study. • The impact mode of PM2.5 for each type of arrhythmia was addressed in this study. • This study was performed in Shanghai, a city with serious air pollution problem. • The study was performed based on large-scale population data of over 200,000 ECGs. Recently, the impact of fine particulate matter pollution on cardiovascular system is drawing considerable concern worldwide. The association between ambient fine particulate and the cardiac arrhythmias is not clear now. To study associations of ambient fine particulate with incidence of arrhythmias in outpatients. Data was collected from the remote electrocardiogram (ECG) system covering 282 community hospitals in Shanghai from June 24th, 2014 to June 23rd, 2016. ECG was performed for patients admitted to above hospitals with complaining of chest discomfort or palpitation, or for regular check-ups. Air quality data during this time period was obtained from China National Environment Monitoring Center. A generalized additive quasi-Poisson model was established to examine the associations between PM2.5 and cardiac arrhythmias. Cardiac arrhythmias were detected in 202,661 out of 1,016,579 outpatients (19.9%) and fine particulate matter ranged from 6 to 219 μg/m3 during this period. Positive associations were evidenced between fine particulate matter level and prevalence of cardiac arrhythmia by different lag models. Per 10 μg/m3 increase in fine particulate matter was associated with a 0.584%(95%CI:0.346-0.689%, p < 0.001) increase of cardiac arrhythmia detected in these patient cohort at lag0-2. For different types of cardiac arrhythmias, an immediate arrhythmogenic effect of fine particulate matter (increase of the estimates of cardiac arrhythmia prevalence detected in daily outpatient visits) was found with paroxysmal supraventricular tachycardia; a lag effect was found with atrial fibrillation; and both immediate and lag effect was found with premature atrial contractions or atrial tachycardia, atrioventricular block. Moreover, the impact of fine particulate matter on cardiac arrhythmias was significantly greater in women (lag3 and lag0-4), and in people aged <65 years (lag0). Ambient exposure to fine particulate matter is linked with increased risk of arrhythmias in outpatients visiting Shanghai community hospitals, with an immediate or lag effect. The arrhythmogenic effect varies among different types of cardiac arrhythmias. [ABSTRACT FROM AUTHOR]