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Gastrointestinal bleeding is the most frequent major complication of antiplatelet therapy. In patients at low bleeding risk, however, clinically overt gastrointestinal bleeding is relatively uncommon.The authors sought to assess the effects of different antiplatelet regimens on gastrointestinal mucosal injury by means of a novel magnetically controlled capsule endoscopy system in patients at low bleeding risk.Patients (n = 505) undergoing percutaneous coronary intervention in whom capsule endoscopy demonstrated no ulcerations or bleeding (although erosions were permitted) after 6 months of dual antiplatelet therapy (DAPT) were randomly assigned to aspirin plus placebo (n = 168), clopidogrel plus placebo (n = 169), or aspirin plus clopidogrel (n = 168) for an additional 6 months. The primary endpoint was the incidence of gastrointestinal mucosal injury (erosions, ulceration, or bleeding) at 6-month or 12-month capsule endoscopy.Gastrointestinal mucosal injury through 12 months was less with single antiplatelet therapy (SAPT) than with DAPT (94.3% vs 99.2%; P = 0.02). Aspirin and clopidogrel monotherapy had similar effects. Among 68 patients without any gastrointestinal injury at randomization (including no erosions), SAPT compared with DAPT caused less gastrointestinal injury (68.1% vs 95.2%; P = 0.006), including fewer new ulcers (8.5% vs 38.1%; P = 0.009). Clinical gastrointestinal bleeding from 6 to 12 months was less with SAPT than with DAPT (0.6% vs 5.4%; P = 0.001).Despite being at low risk of bleeding, nearly all patients receiving antiplatelet therapy developed gastrointestinal injury, although overt bleeding was infrequent. DAPT for 6 months followed by SAPT with aspirin or clopidogrel from 6 to 12 months resulted in less gastrointestinal mucosal injury and clinical bleeding compared with DAPT through 12 months. (OPT-PEACE [Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by Ankon Magnetically Controlled Capsule Endoscopy]; NCT03198741).

Background and aims Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis and plaque vulnerability. The macrophage apoptosis mediated by endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of HHcy-aggravated atherosclerosis. Endoplasmic reticulum oxidoreductase 1α (Ero1α) is critical for ER stress-induced apoptosis. We hypothesize that Ero1α may contribute to ER-stress induced macrophage apoptosis and plaque stability in advanced atherosclerotic lesions by HHcy. Methods Apoe−/− mice were maintained on drinking water containing homocysteine (Hcy, 1.8 g/L) to establish HHcy atherosclerotic models. The role of Ero1α in the atherosclerotic plaque stability, macrophage apoptosis and ER stress were monitored in the plaque of aortic roots in HHcy Apoe−/− mice with or without silence or overexpression of Ero1α through lentivirus. Mouse peritoneal macrophages were used to confirm the regulation of Ero1α on ER stress dependent apoptosis in the presence of HHcy. Results The atherosclerotic plaque vulnerability and macrophage apoptosis were promoted in Apoe−/− mice by high Hcy diet, accompanied by the upregulation of Ero1α expression and ER stress. Inhibition of Ero1α prevented macrophage apoptosis and atherosclerotic plaque vulnerability, and vice versa. Consistently, in mouse peritoneal macrophages, ER stress and apoptosis were attenuated by Ero1α deficiency, but enhanced by Ero1α overexpression. Conclusions Hcy via upregulating Ero1α expression activates ER stress-dependent macrophage apoptosis, so as to promote vulnerable plaque formation in atherosclerosis. Ero1α may be a potential therapeutic target for atherosclerosis induced by Hcy.

Objectives The aim of the present study was to evaluate the safety and efficacy of thinner strut Firesorb (100/125 μm) sirolimus-eluting bioresorbable scaffolds (BRS) versus cobalt-chromium everolimus-eluting stents (CoCr-EES) in patients with coronary artery disease. Background First-generation thicker strut BRS were associated with unexpected device-related adverse outcomes at long-term follow-up. Methods Eligible patients with 1 or 2 de novo noncomplex coronary lesions were randomized to the Firesorb BRS group or CoCr-EES group in a 1:1 ratio. The primary endpoint was 1-year angiographic in-segment late loss (LL), powered for noninferiority testing. The key secondary endpoint was the 1-year proportion of covered struts assessed on optical coherence tomography, powered for noninferiority and subsequent superiority testing. Results A total of 433 participants from 28 Chinese centers were randomized to the Firesorb BRS group (n = 215) or CoCr-EES group (n = 218). Patient-level 1-year in-segment LL was 0.17 ± 0.27 mm in the Firesorb BRS group and 0.18 ± 0.37 mm in the CoCr-EES group (difference −0.01 mm; 95% confidence interval [CI]: −0.07 to 0.06; pnoninferiority Conclusions The thinner strut Firesorb BRS was noninferior to the CoCr-EES for the primary endpoint of 1-year angiographic in-segment LL and the key secondary endpoint of 1-year proportion of covered struts by optical coherence tomography. (A Trial of Firesorb in Patients With Coronary Artery Disease: FUTURE-II [FUTURE-II]; NCT02890160 )

The authors have withdrawn their manuscript because the article needs to supplement the data of cell culture to clarify the mechanism. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Wanrui Ma, 1–3 Shan He, 4 Huiyan Ma, 4 Haifeng Jiang, 5 Ning Yan, 6 Lili Zhu, 6 John J Bang, 3 P Andy Li, 2 Shaobin Jia 6 1Department of General Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technological Enterprise (BRITE), North Carolina Central University, Durham, NC, USA; 3Department of Environmental, Earth and Geospatial Sciences, North Carolina Central University, Durham, NC, USA; 4School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of hina; 5Department of Pathology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 6Heart Centre, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of ChinaCorrespondence: P Andy LiDepartment of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technological Enterprise (BRITE), North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707, USATel +1 919 530 6872Fax +1 919 530 6600Email pli@nccu.eduShaobin JiaHeart Centre, General Hospital of Ningxia Medical University, 804 Shengli South Street, Xingqing District, Yinchuan 750004, People’s Republic of ChinaTel +86 139 9507 8969Email jsbxn@163.comBackground: With the increased application of Silver nanoparticles (AgNP), its potential concerns to the health of human beings remain to be defined. This study aims to explore the harmful effects of AgNP on lung tissue in animals and to examine the mechanisms of protection achieved by sodium selenite.Methods: Sprague-Dawley(SD) rats were exposed to AgNP (200 μL,1mg/mL) through a single intratracheal instillation. Sodium selenite (0.2mg/kg) was i.p. injected. Malondialdehyde (MDA) and glutathione (GSH) were measured using a spectrophotometer. Histological outcomes and ultrastructural changes were assessed by hematoxylin and eosin (HE) staining and electronic microscopy. Caspases and mitochondrial fission and fusion markers were measured by Western blotting.Results: The histopathologic findings showed that AgNP significantly increased the thickness of alveolar septa, accumulation of macrophage, and the formation of pulmonary bullae and pulmonary consolidation. Ultrastructural studies showed localization of AgNP inside the mitochondria, hyperplasia and vacuolation of type I and type II alveolar cells, lysis of osmiophilic lamellar bodies, and swollen of the mitochondria. AgNP elevated MDA and reduced GSH levels. AgNP activated caspases-3, increased mitochondrial fission markers Dynamin-related protein 1 (Drp1) and phospho-Drp1(p-Drp1), and decreased fusion proteins optic atrophy 1 (Opa1) and mitofusins 2 (Mfn2). Treatment with sodium selenite for 7 days corrected the AgNP-caused alterations in morphological, ultrastructural, oxidative stress, caspase-3 activation and mitochondrial dynamic imbalance.Conclusion: We conclude that the exposure of AgNP causes lung tissue damage by enhances oxidative stress, activates caspases-3, and triggers mitochondrial dynamic imbalance towards fission. Sodium selenite effectively detoxifies the AgNP-induced damage to the lung tissue by preventing the above alterations.Keywords: silver nanoparticle, selenium, pulmonary, mitochondrial dynamics, mitochondrial morphology

Background: Acute coronary syndromes (ACS) is closely associated with chronic low-grade inflammation and gut microbiome composition. However, the composition and functional capacity of the gut microbiome in relation to ACS have not been systematically examined. Results: we perform a metagenome-wide association study on stools and plasma from 66 individuals with ACS and 46 healthy controls (HC). We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. We reported that the altered composition of gut microbiota was associated with ACS and exacerbated inflammatory status. Moreover, parameters in ACS including body weights (BWs), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), C-reactive protein (CRP) and high homocysteine (HCY) were elevated; whereas high-density lipoprotein (HDL) was decreased. pro-inflammatory interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1(MCP-1) and lipopolysaccaride (LPS) in ACS were increased respectively. The results of 16S rRNA sequencing and analysis displayed that the overall community of gut microbiota in ACS was notably changed mainly through increasing the abundance of Bacteroidetes, Verrucomicrobia, Proteobacteria Parabacteroide, Unidentified_Enterobacteriaceae, Subdoligranulum, Akkermansia, Alistipes, Streptococcus, Paraprevotella as well as decreasing Subdoligranulum, Roseburia, Faecalibacterium, Blautia, Agathobacter, Anaerostipes, Bifidobacterium. Further analysis showed that there was a significant correlation between the above differences in gut microbiota and inflammatory factors. Conclusions: Our data represent a comprehensive resource for further investigations on the role of the gut microbiome in promoting or preventing ACS.

Atherosclerosis (AS) is closely associated with abnormally chronic low-grade inflammation and gut dysbiosis. Flaxseed oil (FO) rich in omega-3 polyunsaturated fatty acids (PUFAs), which are mainly composed of alpha-linolenic acid (ALA, 18:3 omega-3), has been demonstrated to exhibit pleiotropic benefits in chronic metabolic diseases. However, the impact of dietary ALA-rich FO on AS and its associated underlying mechanisms remain poorly understood. Thus, the present study was designed as two phases to investigate the effects in atherosclerotic

Background Myocardial infarction (MI) represents a severe cardiovascular disease with limited therapeutic agents. This study was aimed to elucidate the role of the exosomes derived from human placental mesenchymal stem cells (PMSCs-Exos) in MI. Methods PMSCs were isolated and cultured in vitro, with identification by both transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). To further investigate the effects of PMSC-Exos on MI, C57BL/6 mice were randomly divided into Sham group, MI group, and PMSC-Exos group. After 4 weeks of the intervention, cardiac function was assessed by cardiac echocardiography, electrocardiogram and masson trichrome staining; lipid indicators were determined by automatic biochemical instrument; inflammatory cytokines were measured by cytometric bead array (CBA); gut microbiota, microbial metabolites short chain fatty acids (SCFAs) as well as lipopolysaccharide (LPS) were separately investigated by 16S rRNA high throughput sequencing, gas chromatography mass spectrometry (GC–MS) and tachypleus amebocyte lysate kit; transcriptome analysis was used to test the transcriptional components (mRNA\miRNA\cirRNA\lncRNA) of PMSC-Exos. Results We found that human PMSC-Exos were obtained and identified with high purity and uniformity. MI model was successfully established. Compared to MI group, PMSC-Exos treatment ameliorated myocardial fibrosis and left ventricular (LV) remodeling (P P Bacteroidetes, Proteobacteria, Verrucomicrobia, Actinobacteria, Akkermansia, Bacteroides, Bifidobacterium, Thauera and Ruminiclostridium, as well as decreasing Firmicutes (all P P Conclusions Our study highlighted that PMSC-Exos intervention alleviated MI via modulating gut microbiota and suppressing inflammation.

Background: Homocysteine (Hcy) has been established as an independent risk factor for atherosclerosis, and the involvement of hyperhomocysteinemia (HHcy) in atherosclerotic lesions is complex. Proprotein convertase subtilisin kexin 9 (PCSK9) has vital importance in lipid metabolism, and its inhibitors have intense lipid-lowering and anti-atherosclerotic effects. However, the underlying effect of PCSK9 on HHcy-accelerated dyslipidemia of macrophages is still uncertain. The purpose of this study was to investigate the potential role of PCSK9 in Hcy-induced lipid accumulation and atherosclerotic lesions.Methods:In vitro, gene and protein expressions were assessed by real-time quantitative PCR and western blot in THP-1 macrophages with Hcy incubation. Lipid accumulation and cholesterol efflux were evaluated with Hcy treatment. SBC-115076 was used to examine the role of PCSK9 in ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1)-dependent cholesterol efflux. In vivo, lesion area, lipid deposition and collagen contents were determined in aortas of ApoE−/− mice under a methionine diet. SBC-115076 was subcutaneously injected to explore the potential effects of PCSK9 inhibition on alleviating the severity of HHcy-related atherosclerotic lesions.Results: In THP-1 macrophages, Hcy dose- and time-dependently promoted PCSK9 gene and protein levels without regulating the translation of Low-density lipoprotein receptor (LDLR). SBC-115076 used to inhibit PCSK9 largely alleviated lipid accumulation and reversed the cholesterol efflux to apolipoprotein-I(apoA-I) and high-density lipoprotein (HDL) mediated by ABCA1 and ABCG1. In ApoE−/− mice, methionine diet induced HHcy caused larger lesion area and more lipid accumulation in aortic roots. SBC-115076 reduced atherosclerotic severity by reducing the lesion area and lipid accumulation and increasing expressions of ABCA1 and ABCG1 in macrophages from atherosclerotic plaque. In addition, SBC-115076 decreased plasma Hcy level and lipid profiles significantly.Conclusion: PCSK9 promoted lipid accumulation via inhibiting cholesterol efflux mediated by ABCA1 and ABCG1 from macrophages and accelerated atherosclerotic lesions under HHcy treatment. Inhibiting PCSK9 may have anti-atherogenic properties in HHcy-accelerated atherosclerosis.

The aim of the present study was to evaluate the safety and efficacy of thinner strut Firesorb (100/125 μm) sirolimus-eluting bioresorbable scaffolds (BRS) versus cobalt-chromium everolimus-eluting stents (CoCr-EES) in patients with coronary artery disease.First-generation thicker strut BRS were associated with unexpected device-related adverse outcomes at long-term follow-up.Eligible patients with 1 or 2 de novo noncomplex coronary lesions were randomized to the Firesorb BRS group or CoCr-EES group in a 1:1 ratio. The primary endpoint was 1-year angiographic in-segment late loss (LL), powered for noninferiority testing. The key secondary endpoint was the 1-year proportion of covered struts assessed on optical coherence tomography, powered for noninferiority and subsequent superiority testing.A total of 433 participants from 28 Chinese centers were randomized to the Firesorb BRS group (n = 215) or CoCr-EES group (n = 218). Patient-level 1-year in-segment LL was 0.17 ± 0.27 mm in the Firesorb BRS group and 0.18 ± 0.37 mm in the CoCr-EES group (difference -0.01 mm; 95% confidence interval [CI]: -0.07 to 0.06; pThe thinner strut Firesorb BRS was noninferior to the CoCr-EES for the primary endpoint of 1-year angiographic in-segment LL and the key secondary endpoint of 1-year proportion of covered struts by optical coherence tomography. (A Trial of Firesorb in Patients With Coronary Artery Disease: FUTURE-II [FUTURE-II]; NCT02890160).

Aims Heart failure (HF) is a progressive disease with recurrent hospitalizations and high mortality. However, the mechanisms underlying HF remain unclear. The present study aimed to explore the regulatory mechanism of histone deacetylase 3 (HDAC3) and DNA methyltransferase 1 (DNMT1)/Src homology domain 2-containing tyrosine phosphatase-1 (SHP-1) axis in HF. Methods The HF rat models and hypertrophy cell models were established. The characteristic parameters of the heart were detected by echocardiography. A multichannel physiological signal acquisition system was used to detect the hemodynamic parameters. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of HDAC3, DNMT1, and SHP-1 mRNAs, while Western blot was applied to analyze the expression of proteins. Masson staining was used to analyze the degree of collagen fiber infiltration. TdT-mediated DUTP nick end labeling (TUNEL) staining was performed to analyze the apoptosis of myocardial tissue cells. Co-immunoprecipitation (co-IP) was conducted to study the interaction between HDAC3 and DNMT1. Flow cytometry was used to analyze the apoptosis. Key findings HDAC3 and DNMT1 were highly expressed in HF rat and hypertrophy cell models. HDAC3 modified DNMT1 through deacetylation to inhibit ubiquitination-mediated degradation, which promoted the expression of DNMT1. DNMT1 inhibited SHP-1 expression via methylation in the promoter region. In summary, HDAC3 modified DNMT1 by deacetylation to suppress SHP-1 expression, which in turn led to the development of cardiomyocyte hypertrophy-induced HF. Significance This study provided potential therapeutic targets for HF treatment.

Background Atrial fibrillation (AF) is known to be the most common arrhythmia, and the successful rate of long‐term ablation can vary comparatively. Therefore, a clinical scoring system to predict rhythm outcome remains a critical unmet need. The electrocardiographic (ECG) risk score which is named Morphology‐Voltage‐P‐wave duration (MVP) score was reported to be useful for predicting new‐onset AF. The goal of the current study was to investigate whether the MVP score was a useful scheme in the prediction of rhythm outcome following pulmonary vein isolation (PVI) in paroxysmal atrial fibrillation (PAF). Methods We retrospectively analyzed baseline characteristics, risk scores, and rates of AF recurrence 12 months postablation in the medical records of 207 consecutive patients with PAF undergoing PVI in General Hospital of Ningxia medical University from 2010 to 2018. Results Two hundred and seven patients (71 females, median age 58.7 years) with symptomatic PAF underwent PVI. From the cohort, 32.3% (67) had a recurrence of AF within 1 year of the PVI. The area of the MVP score under the curve in the receiver operating characteristics (ROC) analysis was 0.789 (95% CI 0.730–0.840, p 3 showed the best predictive ability for AF recurrence within 1 year after PVI, with sensitivity (53.03%) and specificity (89.87%). Conclusions The results of our study suggest that the easy‐to‐measure ECG MVP score can be used to predict recurrence of PAF after PVI.

The SARS-CoV-2 epidemic starting in Wuhan in December, 2019 has spread rapidly throughout the nation. The control measures to contain the epidemic also produced influences on the transport and treatment process of patients with acute myocardial infarction (AMI), and adjustments in the management of the patients need to be made at this particular time. AMI is characterized by an acute onset with potentially fatal consequence, a short optimal treatment window, and frequent complications including respiratory infections and respiratory and circulatory failure, for which active on-site treatment is essential. To standardize the management and facilitate the diagnosis and treatment, we formulated the guidelines for the procedures and strategies for the diagnosis and treatment of AMI, which highlight 5 Key Principles, namely Nearby treatment, Safety protection, Priority of thrombolysis, Transport to designated hospitals, and Remote consultation. For AMI patients, different treatment strategies are selected based on the screening results of SARS-CoV-2, the time window of STEMI onset, and the vital signs of the patients. During this special period, the cardiologists, including the interventional physicians, should be fully aware of the indications and contraindications of thrombolysis. In the transport and treatment of AMI patients, the physicians should strictly observe the indications for patient transport with appropriate protective measurements of the medical staff.

Long non-coding RNAs (LncRNAs) are essential regulators in the occurrence and development of AS. Here we aim to explore the underlying molecular mechanism of LncRNA SNHG16 in regulating ox-LDL-induced VSMC proliferation, migration and invasion. After constructing AS in vivo and in vitro models, the expressions of SNHG16, miR-22–3p, HMBG2, proliferation- and metastasis-related proteins were determined by qRT-PCR and Western blot assays. Detection of serological lipids, H&E and Masson staining analysis were conducted to evaluate the AS injury in mice. The effects of ox-LDL treatment on VSMCs were examined by CCK-8, wound scratch and Transwell Chamber assays. The targeted relationship was measured by luciferase reporter and RIP assays. The results showed that SNHG16 and high-mobility group box 2 (HMGB2) expressions were increased while miRNA-22–3p expression was decreased in AS mice and ox-LDL-stimulated VSMCs. Functionally, sh-SNHG16 restrained ox-LDL-induced VSMC growth and migration. SNHG16 suppressed miRNA-22–3p expression by direct binding. Furthermore, in ox-LDL-treated VSMCs, miRNA-22–3p mimic prevented proliferation, migration, and invasion. Further explorations showed that HMGB2 was a target of miRNA-22–3p, SNHG16 upregulated HMGB2 levels by acting as a competing endogenous RNA (ceRNA) of miRNA-22–3p. More importantly, sh-HMGB2 partially reversed the effects of sh-SNHG16 together with miR-22–2p inhibitor on ox-LDL-induced VSMC proliferation, migration and invasion. Collectively, SNHG16 accelerated atherosclerotic plaque (AP) formation and enhanced ox-LDL-activated VSMCs proliferation and migration by miRNA-22–3p/HMGB2 axis.

Atherosclerosis (AS) is closely associated with chronic low-grade inflammation and gut dysbiosis. Metformin (MET) presents pleiotropic benefits in the control of chronic metabolic diseases, but the impacts of MET intervention on gut microbiota and inflammation in AS remain largely unclear. In this study, ApoE-/- mice with a high-fat diet (HFD) were adopted to assess the MET treatment. After 12 weeks of MET intervention (100mg·kg-1·d-1), relevant indications were investigated. As indicated by the pathological measurements, the atherosclerotic lesion was alleviated with MET intervention. Moreover, parameters in AS including body weights (BWs), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC) and malondialdehyde (MDA) were elevated; whereas high-density lipoprotein (HDL) and total superoxide dismutase (T-SOD) levels were decreased, which could be reversed by MET intervention. Elevated pro-inflammatory interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and lipopolysaccaride (LPS) in AS were decreased after MET administration. However, anti-inflammatory IL-10 showed no significant difference between AS group and AS+MET group. Consistently, accumulated macrophages in the aorta of AS were conversely lowered with MET treatment. The results of 16S rRNA sequencing and analysis displayed that the overall community of gut microbiota in AS was notably changed with MET treatment mainly through decreasing Firmicutes, Proteobacteria, Romboutsia, Firmicutes/Bacteroidetes, as well as increasing Akkermansia, Bacteroidetes, Bifidobacterium. Additionally, we found that microbiota-derived short-chain fatty acids (SCFAs) including acetic acid, propionic acid, butyric acid and valeric acid in AS were decreased, which were significantly up-regulated with MET intervention. Consistent with the attenuation of MET on gut dysbiosis, decreased intestinal tight junction protein zonula occludens-1 (ZO)-1 in AS was restored after MET supplementation. Correlation analysis showed close relationships among gut bacteria, microbial metabolites SCFAs and inflammation. Collectively, MET intervention ameliorates AS in ApoE-/- mice through restoring gut dysbiosis and anti-inflammation, thus can potentially serve as an inexpensive and effective intervention for the control of the atherosclerotic cardiovascular disease.

Aims Hyperhomocysteinemia (Hhcy) is an independent risk factor of atherosclerosis and promotes unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism is still undefined. Lesional apoptotic cells and necrotic core formation contribute greatly to the progression of plaque. The present study sought to determine whether modification of histone methylation is involved in macrophage apoptosis and unstable plaque formation in the condition of Hhcy. Materials and methods The unstable plaque formation, lesional apoptotic cells and status of histone methylation were monitored in the aortas of Hhcy ApoE −/− mice induced by a high-methionine (HM) diet for 20 weeks. Involvement of histone methylation in macrophage apoptosis and foam cell formation were assessed in macrophage Raw 264.7 cells after being challenged with homocysteine alone or in combination with the histone methylation inhibitor BIX 01294. Key findings The unstable plaque formation and lesion apoptotic cells are increased in ApoE −/ − mice supplemented with high-methionine (HM), accompanied with a decreased expression of histone H3 lysine 9 dimethylation. Hhcy increases the apoptosis of macrophages and inhibits the histone H3 lysine 9 dimethylation, as well as the expression of histone methyltransferase G9a in vitro. Inhibition of histone methylation by BIX01294 enhances macrophage apoptosis and foam cell formation in vitro. Significance Our data suggest that Hhcy promotes the progression of atherosclerosis via macrophage apoptosis. Histone methylation might be involved in macrophage apoptosis and unstable plaque formation in methionine induced hyperhomocysteinemic ApoE −/− mice.

One of the main characteristics of atherosclerosis is vascular calcification, which is linked to adverse cardiovascular events. Increased homocysteine (Hcy), a feature of hyperhomocysteinemia, is correlated with advanced vascular calcification and phenotypic switching of vascular smooth muscle cells (VSMCs). Oxidative stress and high phosphate levels also induce VSMC calcification, suggesting that the Krüppel-like factor 4 (KLF4) signaling pathway may also contribute to vascular calcification. In this study, we investigated this possibility and the role and mechanisms of Hcy in vascular calcification. We found that in atherosclerotic apolipoprotein E–deficient (ApoE(−/−)) mice, Hcy significantly increases vascular calcification in vivo, as well as VSMC calcification in vitro. Of note, the Hcy-induced VSMC calcification was correlated with elevated KLF4 levels. Hcy promoted KLF4 expression in calcified atherosclerotic lesions in vivo and in calcified VSMCs in vitro. shRNA-mediated KLF4 knockdown blocked the Hcy-induced up-regulation of runt-related transcription factor 2 (RUNX2) and VSMC calcification. RUNX2 inhibition abolished Hcy-induced VSMC calcification. Using ChIP analysis, we demonstrate that KLF4 interacts with RUNX2, an interaction promoted by Hcy stimulation. Our experiments also revealed that the KLF4 knockdown attenuates Hcy-induced RUNX2 transactivity, indicating that KLF4 is important in modulating RUNX2 transactivity. These findings support a role for Hcy in regulating vascular calcification through a KLF4–RUNX2 interaction and indicate that Hcy-induced, enhanced RUNX2 transactivity increases VSMC calcification. These insights reveal possible opportunities for developing interventions that prevent or manage vascular calcification.

To explore the efficiency and safety of bivalirudin in patients undergoing emergency percutaneous coronary intervention via radial access.Bivalirudin reduces bleeding risks over heparin in patients undergoing PCI. However, bleeding advantages of bivalirudin in patients undergoing transradial intervention is uncertain.In the BRIGHT trial, 1,723 patients underwent emergency PCI via radial access, with 576 patients in the bivalirudin arm, 576 in the heparin arm and 571 in the heparin plus tirofiban arm. The primary outcome was 30-day net adverse clinical event (NACE), defined as a composite of major cardiac and cerebral events or any bleeding.30-day NACE occurred in 5.7% with bivalirudin, 7.8% with heparin alone (vs. bivalirudin, P = 0.159), and 10.3% with heparin plus tifofiban (vs. bivalirudin, P = 0.004). The 30-day bleeding rate was 0.9% for bivalirudin, 2.3% for heparin (vs. bivalirudin, P = 0.057), and 5.8% for heparin plus tirofiban (vs. bivalirudin, P 0.001). Major cardiac and cerebral events (4.9 vs. 5.7 vs. 4.6%, P = 0.899), stent thrombosis (0.5 vs. 0.5 vs. 0.7%, P = 0.899) and acquired thrombocytopenia (0.2 vs. 0.5 vs. 0.9%, P = 0.257) at 30 days were similar among three arms. The interaction test for PCI access and randomized treatment showed no significance on all bleeding (P 0.05).The bleeding benefit of bivalirudin was independent of artery access. Bivalirudin lead to statistical reduction on bleeding risks in comparison to heparin plus tirofiban, and only small numerical difference in comparison to heparin, with comparable risks of ischemic events and stent thrombosis in patients with acute myocardial infarction (AMI) undergoing emergency transradial PCI. © 2016 Wiley Periodicals, Inc.

Aims Macrophage-derived foam-cell formation plays a crucial role in the development of atherosclerosis, and liver X receptor alpha (LXRα) is a key regulator of lipid metabolism in macrophages. Homocysteine (Hcy) is an independent risk factor of atherosclerosis; however, the regulation of lipid metabolism and role of LXRα induced by Hcy in macrophages is still unknown. The present study aimed to investigate the potential role of Hcy in disordered lipid metabolism and atherosclerotic lesions, especially the effects of Hcy on cholesterol efflux in macrophages and the possible mechanisms. Main methods In vitro, lipid accumulation and cholesterol efflux were evaluated in THP-1 macrophages with Hcy intervention. Real-time quantitative PCR and western blot analyses were used to assess mRNA and protein levels. In vivo, atherosclerotic lesions and lipid profiles were evaluated by methionine diet-induced hyperhomocysteinemia (HHcy) in ApoE−/− mice. The LXRα agonist T0901317 was used to verify the role of LXRα in HHcy-accelerated atherosclerosis. Key findings Hcy promoted lipid accumulation and inhibited cholesterol efflux in THP-1 macrophages. HHcy mice showed increased lesion area and lipid accumulation in plaque. Both studies in vitro and in vivo showed decreased expression of ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1). T0901317 treatment increased ABCA1 and ABCG1 levels; reversed macrophage-derived foam-cell formation in THP-1 macrophages and reduced atherosclerotic lesions in ApoE−/− mice. Significance Inhibition of LXRα-mediated ABCA1/ABCG1-dependent cholesterol efflux from macrophages is a novel mechanism in Hcy-accelerated atherosclerosis.

Although several studies have suggested that intensive statin pretreatment could reduce the incidence of procedure-related myocardial infarction in western population, the data on the effect in Asian patients have been still limited. The aim of the study was to investigate the efficacy and safety of intensive atorvastatin load in Chinese patients undergoing elective PCI. A total of 1202 patients with stable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS) scheduled to undergo PCI received either intensive statin treatment (80 mg atorvastatin daily × 2 days before PCI and 40 mg daily × 30 days after PCI) or usual care. The primary endpoint was incidence of major adverse cardiac events (cardiac death, myocardial infarction, or unexpected target vessel revascularization) within 30 days after PCI. Safety endpoints include the incidence of contrast induced nephropathy (CIN), ALT/AST >3 upper limit of normal (ULN), CK >5 ULN. The incidence of 30-day MACE did not significantly differ between the intensive group and control group (19.4 vs 18.3%, P = 0.63). Multivariate analysis revealed age (OR = 1.024, 95% CI 1.003–1.045, P = 0.023) and total stent length as an independent predictor of 30-day MACE (OR = 1.012, 95% CI 1.007–1.018, P < 0.0001). The incidence of CIN was comparable between intensive group and control group (4.09 vs 4.39%, P = 0.795). No significant differences were observed in other safety profile at all follow-ups between treatment groups. The ISCAP trial demonstrated that serial intensive atorvastatin therapy did not improve the clinical outcome with similar safety profile comparing with usual care among Chinese patients undergoing elective PCI.

BACKGROUND AND PURPOSE Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (INa,L) could modulate the drug-induced reverse use-dependence in QT and Tp-e (an index of dispersion of repolarization), and therefore the liability for TdP.

Hyperhomocystinemia(Hhcy) is an independent risk factor of atherosclerosis and promotes the unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism still undefined. The present study sought to

Background: Homocysteine is an independent risk factor of atheroslceorsis, characterized by the formation of macrophage-derived foam cells. Liver X receptor alpha (LXRα) can keep cholesterol homeostasis, while proprotein convertase subtilisin/kexin 9(PCSK9), a lipid metabolism regulatory protein

Objectives This study sought to evaluate the safety and efficacy of rosuvastatin in preventing contrast-induced acute kidney injury (CI-AKI) in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). Background CI-AKI is an important complication after contrast medium injection. While small studies have shown positive results with statin therapy, the role of statin therapy in prevention of CI-AKI remains unknown. Methods We randomized 2,998 patients with type 2 DM and concomitant CKD who were undergoing coronary/peripheral arterial angiography with or without percutaneous intervention to receive rosuvastatin, 10 mg/day (n = 1,498), for 5 days (2 days before, and 3 days after procedure) or standard-of-care (n = 1,500). Patients' renal function was assessed at baseline, 48 h, and 72 h after exposure to contrast medium. The primary endpoint of the study was the development of CI-AKI, which was defined as an increase in serum creatinine concentration ≥0.5 mg/dl (44.2 μmol/l) or 0.25% above baseline at 72 h after exposure to contrast medium. Results Patients randomized to the rosuvastatin group had a significantly lower incidence of CI-AKI than controls (2.3% vs. 3.9%, respectively; p = 0.01). During 30 days' follow-up, the rate of worsening heart failure was significantly lower in the patients treated with rosuvastatin than that in the control group (2.6% vs. 4.3%, respectively; p = 0.02). Conclusions Rosuvastatin significantly reduced the risk of CI-AKI in patients with DM and CKD undergoing arterial contrast medium injection. (Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes [TRACK-D]; NCT00786136 )

Hyperhomocysteinemia(Hhcy) promotes unstable atherosclerotic plaque formation. Macrophage apoptosis and plaque necrosis are the two hallmarks of advanced plaque. Endoplasmic reticulum stress plays a critical role in macrophage apoptosis and plaque instability induced by homocysteine. The present

To investigate the effects of folic acid on Bcl-2 gene methylation status in rats with hyperhomocystinemia induced by ingestion of excess methionine.36 healthy 6-week-old wistar male rats, weighing (160 +/- 10) g, after being fed adaptable for one week, were randomly divided into control group (n = 12), hyperhomocysteinemia group (n = 12), folic acid treatment group (n = 12). The control group was fed with AIN-93G diet. The hyperhomocysteinemia group was fed with high-methionion diet, consisting of AIN-93G diet plus 1.7% methionion. The folic acid treatment group was fed with high-methionion plus folic acid-rich diet, consisting of AIN-93G diet plus 1.7% methionion and 0.008% folic acid. After be maintained for 18 weeks on the previously described diets, the concentrations in the plasma Hcy and folic acid and Vit B12 were measured with the IMX assays. The thoracic aorta was harvested for immunohist Chemical analysis. The methylation status of Bcl-2 gene was determined by nest touch-down PCR combined MSP(methylation specific PCR). Real-time RT PCR was used to detect mRNA expression of arotic Bcl-2.The study showed the following: (a) A high methionine diet for 18 weeks is sufficient to induce hyperhom degree Cystinemia; Folic acid supplementation to the rats fed the high-methionine diet prevented an elevation homocysteine (Hcy) levels in the plasma (P0.01 ). (b) Compared with the control group, the Hhcy group had a elevating Bcl-2 expression by immunohistochemical analysis in aorta, along with Bcl-2 hypomethylation (P0.05) and increased Bcl-2 mRNA expression (P0.05 ). (c) Most important, after folic acid supplementation, the lowering of Hcy levels was accompanied by a marked decreased Bcl-2 expression by immunohistochemical analysis and Bcl-2 hypermethylation (P0.05) and reduced Bcl-2 mRNA expression (P0.05).Folic acid supplementation can prevents Bcl-2 hypomethylation in rats with hyperhomocysteinemia, resulting in a decreased Bcl-2 expression.

Objective Th1 activation and regulatory T (Treg) cell suppression have been observed in acute coronary syndrome (ACS), including unstable angina (UA) and acute myocardial infarction (AMI). However, the role of Th17 cell or IL-17A remains controversial in ACS patients, and little is known about the role of recently discovered Th17/Th1 cells, a subset of Th17 cells, in coronary artery disease (CAD). The purpose of this study is to investigate functional changes of Th17/Th1, Th17, Th1, Th2 and Treg cells in ACS patients. Methods The contents of Th17/Th1, Th17, Th1, Th2 and Treg cells, related gene expression, and plasma cytokines from CAD and control patients with normal coronary arteries (NCA) were measured by flow cytometry, real-time quantitative PCR and ELISA. Results Th17/Th1 and Th1 cell contents and related gene expression (T-bet, IFN-γ, STAT4, RORγt, STAT3 and IL-17) were significantly increased in ACS patients, whereas plasma IFN-γ only increased in CAD patients. In contrast, Treg cell population, Foxp3 levels, and plasma TGF-β1 were decreased in ACS patients compared with stable angina (SA) and NCA patients. Conclusion The study showed activation of Th17/Th1 and Th1 cell in ACS patients, which may provide insight into the mechanisms underlying culprit plaque relevant T-cell activation in ACS patients.

Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I(Na,L) ) could modulate the drug-induced reverse use-dependence in QT and T(p-e) (an index of dispersion of repolarization), and therefore the liability for TdP.Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I(Na,L) enhancer), d,l-sotalol, clarithromycin and ranolazine (an I(Na,L) blocker) on rate-dependent changes in QT, T(p-e) and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T(p-e) slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion.ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and T(p-e) intervals, steeper QT-basic cycle length (BCL) and T(p-e) -BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, T(p-e) -BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and T(p-e) without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T(p-e) -BCL slopes and further increased TdP score.Modulation of I(Na,L) altered drug-induced reverse use-dependence related to QT as well as T(p-e) , indicating that inhibition of I(Na,L) can markedly reduce the TdP liability of agents that prolong QT intervals.

To investigate the characteristics for activated coagulation factor VII(F VIIa) and the R353Q, -323 0/10 bp, HVR4 polymorphisms in the gene in patients with coronary heart disease (CHD) and myocardial infarction from Ningxia Hui and Han populations.Four hundred and twenty angiographically proven CHD patients in the Hui population, and 508 healthy blood donors were tested for their plasma levels of coagulation factor VII using recombinant tissue factor method. The coagulation factor VII gene R353Q, -323 0/10 bp and HVR4 genotypes were identified by polymerase chain reaction. In addition, 600 Han patients with CHD and 604 healthy Han control subjects were also investigated.(1) The plasma F VIIa levels was significantly higher in patients with CHD and myocardial infarction than that in healthy control subjects and angor pectoris (P0.01) in both Hui and Han populations. (2) There were significant differences in the distribution of genotypes and allelic frequencies of the R353Q between myocardial infarction and angor pectoris disease in the Hui population (P0.05). So was the -323 0/10 bp locus in both the Hui and Han population. (3) The F VIIa level was significantly higher in individuals with RR genotype than those of Q allele carriers in the Hui population.There are polymorphisms of the F VII gene R353Q, -323 0/10 bp and HVR4 in the Hui and Han populations. The Q allele might be a protective factor against myocardial infarction in the Hui, and the plasma F VIIa level may be influenced by the R353Q polymorphism of the F VII gene. The 10 allele may be a protective factor against myocardial infarction in both the Hui and Han populations.