The relationship between serum manganese concentration with all-cause and cause-specific mortality: a retrospective and population-based cross-sectional study.

BACKGROUND: The study aimed to explore the association between manganese concentration and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality in the general population of the United States. METHODS: We integrated the data from the National Health and Nutrition Examination Survey from 2011 to 2018. A total of 9,207 subjects were selected based on the inclusion and exclusion criteria. The relationship between manganese concentration and all-cause, CVD-related, and cancer-related mortality was analyzed by constructing a Cox proportional hazard regression model and a restricted cubic spline (RCS) plot. Additionally, subgroup analyses stratified by age, sex, race/ethnicity, hypertension, diabetes mellitus (DM), chronic heart disease, chronic heart failure, angina pectoris, heart attack, stroke, and BMI were further performed. RESULTS: In the full adjusted model, compared with the lowest quartile, the adjusted hazard ratios with 95% confidence intervals (CIs) for all-cause, CVD-related, and cancer-related mortality across manganese quartiles were (1.11 (0.87,1.41), 0.96 (0.74, 1.23), and 1.23 (0.96, 1.59); P-value for trend =0.041), (0.86 (0.54, 1.37), 0.87 (0.55, 1.40), and 1.07 (0.67, 1.72); P-value for trend =0.906), and (1.45 (0.92, 2.29), 1.14 (0.70, 1.88), and 1.26 (0.75, 2.11); P-value for trend =0.526), respectively. The RCS curve shown a U-shaped association between manganese concentration and all-cause mortality and CVD-related mortality (P-value for nonlinear <0.05). However, there was an increase and then a decrease in the link between manganese concentration and cancer-related mortality (P-value for nonlinear <0.05). Manganese exposure was positively correlated with sex (correlation coefficient, r =0.19, P-value <0.001) and negatively correlated with age (correlation coefficient, r =-0.11, P-value <0.001) and serum creatinine (correlation coefficient, r =-0.12, P-value <0.001), respectively. CONCLUSIONS: Our findings suggest that elevated serum manganese concentrations are associated with all-cause and CVD-related mortality in the U.S. population and that maintenance of serum manganese between 8.67-9.23 µg/L may promote public health.

Drug-coated balloon for the treatment of small vessel disease: 9 months of angiographic results and 12 months of clinical outcomes of the PEPCAD China SVD study.

BACKGROUND: Whether the drug-coated balloons (DCBs)-alone strategy was superior to plain old balloon angioplasty (POBA) in treating SVD remains unknown. AIMS: We aimed to evaluate the efficacy and safety of DCBs for the treatment of coronary de novo small vessel disease (SVD) and provide further evidence for extending the clinical indications of DCBs. (ChiCTR1800014966). METHODS: Eligible patients were randomized at a 2:1 ratio to receive DCB treatment or POBA in this prospective, multicenter clinical trial. The reference vessel diameter of lesions was visually assessed to be 2.0 to 2.75 mm. The primary endpoint of the study was angiographic in-segment late luminal loss (LLL) at the 9-month follow-up to demonstrate the superiority of DCB treatment to POBA in SVD. The composite clinical endpoints included clinically driven target lesion revascularization (CD-TLR), target lesion failure (TLF), major adverse cardiac events (MACEs), and thrombosis at the 12-month follow-up. RESULTS: A total of 270 patients were enrolled (181 for DCB, 89 for POBA) at 18 centers in China. The primary endpoint of 9-month in-segment LLL in the intention-to-treat population was 0.10 ± 0.33 mm with DCB and 0.25 ± 0.38 mm with POBA (p = 0.0027). This difference indicated significant superiority of DCB treatment (95% CI: -0.22, -0.04, psuperiority = 0.0068). The rates of the clinical endpoints-CD-TLR, TLF, and MACEs-were comparable between groups. No thrombosis events were reported. CONCLUSIONS: DCB treatment of de novo SVD was superior to POBA with lower 9-month in-segment LLL. The rates of clinical events were comparable between the two devices.

The Differences of Quantitative Flow Ratio in Coronary Artery Stenosis with or without Atrial Fibrillation.

Quantitative flow ratio (QFR) is a new method for the assessment of the extent of coronary artery stenosis. But it may be obscured by the cardiac remodeling and abnormal blood flow of the coronary artery when encountering atrial fibrillation (AF). The present study aimed to examine the impact of these changed structures and blood flow of coronary arteries on QFR results in AF patients. Methods and Results. We evaluated QFR in 223 patients (112 patients with AF; 111 non-AF patients served as controls) who had undergone percutaneous coronary intervention (PCI) due to severe stenoses in coronary arteries. QFR of the target coronary was determined according to the flow rate of the contrast agent. Results showed that AF patients had significantly higher QFR values than control (0.792 ± 0.118 vs. 0.685 ± 0.167, p < 0.001). We further analyzed local QFR around the stenoses (0.858 ± 0.304 vs. 0.756 ± 0.146, p=0.002), residual QFR (0.958 ± 0.055 vs. 0.929 ± 0.093, p=0.005), and index QFR (0.807 ± 0.108 vs. 0.713 ± 0.152, p < 0.001) in these two groups of patients with and without AF. Further analysis revealed that QFR in AF patients was negatively correlated with coronary flow velocity (R = -0.22, p=0.02) and area of stenosis (R = -0.70, p < 0.001) but positively correlated with the minimum lumen area (MLA) (R = 0.47, p < 0.001). Conclusion. AF patients with coronary artery stenosis have higher QFR values, which are associated with decreased blood flow velocity, smaller stenosis, and larger MLA in AF patients upon cardiac remodeling.

Inhibition of myocardial remodeling through miR-150/TET3 axis after AMI.

BACKGROUND: Current studies have suggested that miRNA is beneficial in inhibiting myocardial remodeling after myocardial infarction (AMI), however, its underlying mechanism is unclear. OBJECTIVES: We aimed to investigate whether miR-150 can inhibit myocardial remodeling after myocardial infarction and whether this process is regulated by the miR-150/TET3 pathway. METHODS: On the first day, C57BL/6 AMI mice(n = 15) were administrated with miR-150, and another 15 AMI mice were administrated with the same volume of control Agomir. Left ventricular ejection fraction (LVEF%) and myocardial remodeling were compared after one week; TET3 (ten-eleven translocation 3) and VEGF-α (vascular endothelial growth factor-α) were also determined in the infracted heart simultaneously. The neovascularization in the infarcted area at day 21 was compared through CD31 using fluorescence microscopy; Activated monocytes stimulated with LPS were transfected with miR-150. Laser scanning confocal microscopy was used to detect the intracytoplasmic imaging of miR-150 in Ly6Chigh monocytes. Expression of the miR-150 in the monocytes was measured using Q-PCR. After 48 h, the proportion of Ly6Chigh/low monocytes was determined using flow cytometry. Expression of TET3 in Ly6Chigh/low monocytes was measured using Q-PCR and Western blot. After the downregulation of TET3 specifically, the levels of Ly6Chigh/low monocytes were further determined. RESULTS: We first observed an increased trend of mice survival rate in the miR-150 injection group, but it didn't reach a statistical difference (66.7% vs. 40.0%, p = 0.272). However, AMI mice administrated with miR-150 displayed better LVEF% (51.78%±2.90% vs. 40.28%±4.20%, p<0.001) and decreased infarct size% (25.47 ± 7.75 vs. 50.39 ± 16.91, p = 0.002). After miR-150 was transfected into monocytes, the percentage of Ly6Clow monocytes increased significantly after 48 h (48.5%±10.1% vs. 42.5%±8.3%, p < 0.001). Finally, Western blot analysis (0.56 ± 0.10/ß-actin vs. 0.99 ± 0.12/ß-actin, p < 0.001) and real-time PCR (1.09 ± 0.09/GAPDH vs. 2.53 ± 0.15/GAPDH, p < 0.001, p < 0.001) both confirmed decreased expression of TET3 in monocytes after transfection with miR-150. After the downregulation of TET3 specifically, Ly6Clow monocytes showed a significant increase (16.73%±6.45% vs. 6.94%±2.99%, p<0.001, p < 0.001). CONCLUSIONS: miR-150 alleviated myocardial remodeling after AMI. Possible mechanisms are ascribed to the regulating of TET3 and VEGF-α in inflammatory monocytes.

Macrophage-driven cardiac inflammation and healing: insights from homeostasis and myocardial infarction.

Early and prompt reperfusion therapy has markedly improved the survival rates among patients enduring myocardial infarction (MI). Nonetheless, the resulting adverse remodeling and the subsequent onset of heart failure remain formidable clinical management challenges and represent a primary cause of disability in MI patients worldwide. Macrophages play a crucial role in immune system regulation and wield a profound influence over the inflammatory repair process following MI, thereby dictating the degree of myocardial injury and the subsequent pathological remodeling. Despite numerous previous biological studies that established the classical polarization model for macrophages, classifying them as either M1 pro-inflammatory or M2 pro-reparative macrophages, this simplistic categorization falls short of meeting the precision medicine standards, hindering the translational advancement of clinical research. Recently, advances in single-cell sequencing technology have facilitated a more profound exploration of macrophage heterogeneity and plasticity, opening avenues for the development of targeted interventions to address macrophage-related factors in the aftermath of MI. In this review, we provide a summary of macrophage origins, tissue distribution, classification, and surface markers. Furthermore, we delve into the multifaceted roles of macrophages in maintaining cardiac homeostasis and regulating inflammation during the post-MI period.

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Vaccination for Negative Conversion Time of Nucleic Acid in Nonsevere COVID-19 Patients Infected by SARS-CoV-2 Omicron Variant.

SARS-CoV-2 Omicron variant is significantly different from all the previous variants and has rapidly replaced other variants as the dominant variant across the globe. An easily obtained, inexpensive, and rapid marker is needed to predict the negative conversion time (NCT) of nucleic acid in nonsevere COVID-19 patients infected by the Omicron variant. This retrospective study enrolled 226 patients infected by the Omicron variant between April 23, 2022, and May 16, 2022. The median age of the patients was 61 (interquartile range (IQR), 48-70) years, and 56.2% were male. 84 patients (37.2%) had at least one comorbidity, and 49 patients (21.7%) were classified into the moderate illness group. 145 patients (64.2%) received at least one dose of vaccine, in which 67 patients (29.6%) received a booster dose of vaccine. The median duration of NCT was 8 (IQR, 7-11) days. Univariate Cox analyses found that high NLR (>2.22), aged ≥65 years, vaccination, and moderate illness were significantly related to the NCT of nucleic acid. Multivariate Cox regression analysis showed that high NLR (NLR > 2.22, hazard ratio (HR):0.718, 95% CI: 0.534-0.964, p = 0.028) and vaccination (vaccinated ≥1 dose, HR: 1.536, 95% CI: 1.147-2.058, p = 0.004) were independently associated with NCT of nucleic acid. NLR is a rapid, simple, and useful prognostic factor for predicting NCT of nucleic acid in nonsevere COVID-19 patients with the Omicron variant. In addition, vaccination may also play a valuable role in predicting the NCT of nucleic acid.

Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity.

Doxorubicin is one of the most common antitumor drugs. However, cardiotoxicity's side effect limits its clinical applicability. In the present study, Gene Expression Omnibus (GEO) datasets were applied to reanalyze differentially expressed genes (DEGs) and construct weighted correlation network analysis (WGCNA) modules of doxorubicin-induced cardiotoxicity in wild-type mice. Several other bioinformatics analyses were performed to pick out the hub gene, and then the correlation between the hub gene and immune infiltration was evaluated. In total, 120 DEGs were discovered in a mouse model of doxorubicin-induced cardiotoxicity, and PF-04217903, propranolol, azithromycin, etc. were found to be potential drugs against this pathological condition. Among all the DEGs, 14 were further screened out by WGCNA modules, of which Limd1 was upregulated and finally regarded as the hub gene after being validated in other GEO datasets. Limd1 was upregulated in the peripheral blood mononuclear cell (PBMC) of the rat model, and the area under curve (AUC) of the receiver operating characteristic curve (ROC) in diagnosing cardiotoxicity was 0.847. The GSEA and PPI networks revealed a potential immunocyte regulatory role of Limd1 in cardiotoxicity. The proportion of "dendritic cells activated" in the heart was significantly elevated, while "macrophage M1" and "monocytes" declined after in vivo doxorubicin application. Finally, Limd1 expression was significantly positively correlated with "dendritic cells activation' and negatively correlated with "monocytes" and "macrophages M1'. In summary, our results suggested that limd1 is a valuable biomarker and a potential inflammation regulator in doxorubicin-induced cardiotoxicity.

Upregulation of key genes Eln and Tgfb3 were associated with the severity of cardiac hypertrophy.

BACKGROUND: Hypertension-induced cardiac hypertrophy is one of the most common pre-conditions that accompanies heart failure. This study aimed to identify the key pathogenic genes in the disease process. METHODS: GSE18224 was re-analyzed and differentially expressed genes (DEGs) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. Networks of transcription factor (TF)-mRNA, microRNA (miRNA)-mRNA and Protein-Protein interaction (PPI) were constructed, and a key module was further screened out from PPI network. GSE36074 dataset and our transverse aortic constriction (TAC) mouse model were used to validate gene expression in the module. Finally, the correlation between the genes and biomarkers of cardiac hypertrophy were evaluated. RESULTS: Totally, there were 348 DEGs in GSE18224, which were mainly enriched in biological processes including collagen fibril organization, cellular response to transforming growth factor-beta stimulus and were involved in ECM-receptor interaction and Oxytocin signaling pathway. There were 387 miRNAs targeted by 257 DEGs, while 177 TFs targeted 71 DEGs. The PPI network contained 222 nodes and 770 edges, with 18 genes screened out into the module. After validation, 8 genes, which were also significantly upregulated in the GSE36074 dataset, were selected from the 18 DEGs. 2 of the 8 DEGs, including Eln and Tgfb3 were significantly upregulated in our mouse model of myocardial hypertrophy. Finally, the expression of Eln and Tgfb3 were found to be positively correlated with the level of the disease biomarkers. CONCLUSIONS: Upregulated key genes Eln and Tgfb3 were positively correlated with the severity of cardiac hypertrophy, which may provide potential therapeutic targets for the disease.

Effects of PCSK9 Inhibition on Coronary Atherosclerosis Regression of Nontarget Lesions after Primary Percutaneous Coronary Intervention in Acute Coronary Syndrome Patients.

Aims: To evaluate the regression of coronary atherosclerosis with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in acute coronary syndrome (ACS) patients following primary percutaneous coronary intervention (PPCI). Methods and Result. We examined 40 nontarget lesions in 17 ACS patients who underwent PPCI and were treated with PCSK9 inhibitors. At 1 year, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and atherogenic index (AI) decreased significantly by 2.5 mmol/L, 2.01 mmol/L, and 1.86, respectively. On quantitative coronary angiography, treatment with PCSK9 inhibitors reduced significantly the atherosclerotic area stenosis in nontarget lesions (61.18 ± 14.55 at baseline vs. 52.85 ± 15.51 at 1 year, P < 0.001). Conclusions: After 1 year of PCSK9 inhibition treatment for ACS patients, the area stenosis of non-TLR was considerably reduced.

Vaspin Ameliorates Cardiac Remodeling by Suppressing Phosphoinositide 3-Kinase/Protein Kinase B Pathway to Improve Oxidative Stress in Heart Failure Rats.

ABSTRACT: This study aimed to explore whether vaspin could alleviate cardiac remodeling through attenuating oxidative stress in heart failure rats and to determine the associated signaling pathway. Cardiac remodeling was induced by myocardial infarction, transverse aortic constriction, or angiotensin (Ang) II infusion in vivo, and the neonatal rat cardiomyocytes (NRCMs) and neonatal rat cardiac fibroblasts (NRCFs) were treated with Ang II. Vaspin treatment alleviated fibrosis in myocardial infarction, transverse aortic constriction, and Ang II-treated rats. The Ang II-induced increases of atrial natriuretic peptide and brain natriuretic peptide in NRCMs and Ang II-induced increases of collagen I and collagen III in NRCFs were reduced after vaspin treatment. Vaspin administration inhibited the Ang II-induced increases of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, superoxide anions, malondialdehyde, and NADPH oxidases activity in NRCMs and NRCFs. The overexpression of PI3K, Akt, or NADPH oxidases 1 reversed the attenuating effects of vaspin on Ang II-induced elevation of atrial natriuretic peptide and brain natriuretic peptide in NRCMs, as well as Ang II-induced increases of collagen I and collagen III in NRCFs. The administration of wortmannin (PI3K inhibitor) or MK2206 (Akt inhibitor) inhibited the oxidative stress induced by Ang II in NRCMs and NRCFs. The above results suggest that vaspin can alleviate cardiac dysfunction and remodeling in heart failure rats. Vaspin attenuates Ang II-induced hypertrophy of NRCMs and fibrosis of NRCFs through suppressing PI3K/Akt pathway to alleviate oxidative stress.

Spontaneous left main coronary artery dissection occurred in a young male: a case report and review of literature.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is now recognized as an important cause of acute coronary syndrome (ACS), which is thought to be more prevalent in women. However, the male patients, on the other hand, cannot be easily ignored. CASE PRESENTATION: A 26-year-old male suffered from SCAD that occurred in the left main coronary artery (LMCA) and a secondary acute myocardial infraction (AMI). Coronary CT angiography and coronary angiography (CAG) revealed aneurysms in the LMCA and right coronary artery (RCA), as well as a total occlusion in the proximal branch of the left anterior descending artery (LAD). Along with drug therapy, coronary artery bypass graft (CABG) surgery was recommended, and the patient has been symptom-free for one year. CONCLUSION: We report a case of spontaneous left main coronary artery dissection that occurred in a young male. The necessity of identifying typical imaging features and following up patients with SCAD for life to reduce the risk of fatal cardiac complications cannot be overstated.

METTL3 mediates Ang-II-induced cardiac hypertrophy through accelerating pri-miR-221/222 maturation in an m6A-dependent manner.

BACKGROUND: METTL3 is the core catalytic enzyme in m6A and is involved in a variety of cardiovascular diseases. However, whether and how METTL3 plays a role during angiotensin II (Ang-II)-induced myocardial hypertrophy is still unknown. METHODS: Neonatal rat cardiomyocytes (NRCMs) and C57BL/6J mice were treated with Ang-II to induce myocardial hypertrophy. qRT-PCR and western blots were used to detect the expression of RNAs and proteins. Gene function was verified by knockdown and/or overexpression, respectively. Luciferase and RNA immunoprecipitation (RIP) assays were used to verify interactions among multiple genes. Wheat germ agglutinin (WGA), hematoxylin and eosin (H&E), and immunofluorescence were used to examine myocardial size. m6A methylation was detected by a colorimetric kit. RESULTS: METTL3 and miR-221/222 expression and m6A levels were significantly increased in response to Ang-II stimulation. Knockdown of METTL3 or miR-221/222 could completely abolish the ability of NRCMs to undergo hypertrophy. The expression of miR-221/222 was positively regulated by METTL3, and the levels of pri-miR-221/222 that bind to DGCR8 or form m6A methylation were promoted by METTL3 in NRCMs. The effect of METTL3 knockdown on hypertrophy was antagonized by miR-221/222 overexpression. Mechanically, Wnt/ß-catenin signaling was activated during hypertrophy and restrained by METTL3 or miR-221/222 inhibition. The Wnt/ß-catenin antagonist DKK2 was directly targeted by miR-221/222, and the effect of miR-221/222 inhibitor on Wnt/ß-catenin was abolished after inhibition of DKK2. Finally, AAV9-mediated cardiac METTL3 knockdown was able to attenuate Ang-II-induced cardiac hypertrophy in mouse model. CONCLUSIONS: Our findings suggest that METTL3 positively modulates the pri-miR221/222 maturation process in an m6A-dependent manner and subsequently activates Wnt/ß-catenin signaling by inhibiting DKK2, thus promoting Ang-II-induced cardiac hypertrophy. AAV9-mediated cardiac METTL3 knockdown could be a therapeutic for pathological myocardial hypertrophy.

Maintained P2Y12 inhibitor monotherapy after shorter-duration of dual antiplatelet therapy in patients undergoing coronary drug-eluting stents implantation: An updated meta-analysis of randomized trials.

WHAT IS KNOWN AND OBJECTIVE: It is well known that high in-stent thrombotic risk due to the superimposition of a platelet-rich thrombus was considered as the main origin of major adverse cardiac events after stent implantation. The clinical management of antiplatelet therapy strategy after percutaneous coronary intervention (PCI) remains controversial. This study is sought to explore the efficacy and safety of a maintained P2Y12 inhibitor monotherapy after shorter-duration of dual antiplatelet therapy (DAPT) in these patients. METHODS: Medline, Google Scholar, Web of Science, and the Cochrane Controlled Trials Registry were searched online for retrieving eligible citations. A composite of all-cause death, myocardial infarction (MI) and stroke was defined as major adverse cardio- and cerebro-vascular events (MACCE), which is analysed as the primary efficacy endpoint. The risk of bleeding events was chosen as safety endpoint. RESULTS: Five randomized clinical trials (RCT) with 32,143 patients were finally analysed. A maintained P2Y12 inhibitor monotherapy after shorter-duration of DAPT cloud not only reduce the incidence of MACCE [odds ratios (OR): 0.89, 95% confidence intervals (CI): 0.79-0.99, p = 0.037], but also the bleeding risk (OR 0.61, 95% CI: 0.44-0.85, p = 0.003). No higher incidence of any ischaemic events, including MI, stroke or definite stent thrombosis (ST) was observed with respect to this new antiplatelet therapy option. CONCLUSIONS: A maintained P2Y12 inhibitor monotherapy after shorter-duration of DAPT was suggested as a more preferable antiplatelet therapy option in patients undergoing coronary drug-eluting stents (DES) placement. Larger and more powerful randomized trials with precise sub-analyses are still necessary for further confirming these relevant benefits.

High serum fibroblast growth factor 21 levels were related to the prognosis and ventricular remodeling of heart failure patients with mildly reduced and reduced ejection fraction.

INTRODUCTION: Previous studies have shown that fibroblast growth factor 21 (FGF21) is involved in the ventricular remodeling process in heart failure with preserved ejection fraction (HFpEF). We hypothesized that high levels of FGF21 correlated with the ventricular remodeling of heart failure patients with mildly reduced (HFmrEF) and reduced ejection fraction (HFrEF). METHODS: A total of 203 participants with HFmrEF or HFrEF were enrolled and followed up from June 2018 to June 2021. 68 subjects without heart failure (HF) underwent physical examinations during the same time were selected as the control group. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), which were defined as all-cause or cardiac mortality and rehospitalization for decompensation. Serum FGF21 levels were measured early the next morning after admission using enzyme-linked immunosorbent assay (ELISA). RESULTS: The FGF21 levels were significantly higher in patients with HFmrEF or HFrEF than that in the control group (213.57 ± 42.65 pg/mL, 222.93 ± 34.36 pg/mL vs 171.00 ± 12.86 pg/mL, p < .001). The serum levels of FGF21 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were both higher in the endpoint event group than those of non-endpoint event group regardless of the HFmrEF or HFrEF group (p < .001). Spearman's correlation revealed that FGF21 was positively correlated with left ventricular end-systolic diameter left ventricular end-diastolic diameter left ventricular mass index (p < .01). Moreover, there was a negative correlation between FGF21 and left ventricular ejection fraction in addition to relative wall thickness (p < .001). The area under the receiver operating characteristic (ROC) curve (AUC) of FGF21 was 0.874. The optimal cut-off value of FGF21 determined by ROC curve was 210.11 pg/mL. The Kaplan-Meier analysis demonstrated that the low FGF21 levels group had an increased MACE-free survival rate compared with the high FGF21 levels group. On univariate and multivariate Cox analysis, it was seen that both serum FGF21 and NT-proBNP were independent predictors of a poor prognosis in HF patients. CONCLUSION: Baseline levels of FGF21 and NT-proBNP were related to the ventricular remodeling of patients with a mildly reduced or reduced ejection fraction. FGF21 and NT-proBNP both had good prognostic value for MACEs in heart failure patients with a mildly reduced and reduced ejection fraction.

Protective role of serpina3c as a novel thrombin inhibitor against atherosclerosis in mice.

Abnormal vascular smooth muscle cell (VSMC) proliferation is a critical step in the development of atherosclerosis. Serpina3c is a serine protease inhibitor (serpin) that plays a key role in metabolic diseases. The present study aimed to investigate the role of serpina3c in atherosclerosis and regulation of VSMC proliferation and possible mechanisms. Serpina3c is down-regulated during high-fat diet (HFD)-induced atherosclerosis. An Apoe-/-/serpina3c-/--double-knockout mouse model was used to determine the role of serpina3c in atherosclerosis after HFD for 12 weeks. Compared with Apoe-/- mice, the Apoe-/-/serpina3c-/- mice developed more severe atherosclerosis, and the number of VSMCs and macrophages in aortic plaques was significantly increased. The present study revealed serpina3c as a novel thrombin inhibitor that suppressed thrombin activity. In circulating plasma, thrombin activity was high in the Apoe-/-/serpina3c-/- mice, compared with Apoe-/- mice. Immunofluorescence staining showed thrombin and serpina3c colocalization in the liver and aortic cusp. In addition, inhibition of thrombin by dabigatran in serpina3c-/- mice reduced neointima lesion formation due to partial carotid artery ligation. Moreover, an in vitro study confirmed that thrombin activity was also decreased by serpina3c protein, supernatant and cell lysate that overexpressed serpina3c. The results of experiments showed that serpina3c negatively regulated VSMC proliferation in culture. The possible mechanism may involve serpina3c inhibition of ERK1/2 and JNK signaling in thrombin/PAR-1 system-mediated VSMC proliferation. Our results highlight a protective role for serpina3c as a novel thrombin inhibitor in the development of atherosclerosis, with serpina3c conferring protection through the thrombin/PAR-1 system to negatively regulate VSMC proliferation through ERK1/2 and JNK signaling.

Fibroblast Growth Factor 21 Correlates with the Prognosis of Dilated Cardiomyopathy.

OBJECTIVES: The goal of this study was to evaluate whether serum fibroblast growth factor 21 (FGF21) levels can be used to predict the prognosis of dilated cardiomyopathy (DCM). METHODS: 241 patients with DCM and 80 control subjects were recruited and followed up for an average of 16.12 months. A 2-dimensional (2-D) echocardiography technique was performed to calculate the left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) percentages. The levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and creatinine were measured in routine clinical laboratory tests. Serum FGF21 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The levels of serum FGF21 were significantly higher in the DCM groups than in the control groups (225.85 ± 32.57 vs. 145.36 ± 30.57, p < 0.001). Serum FGF21 levels were positively correlated with the NYHA functional classification of heart failure (HF) (r = 0.610, p < 0.001) and NT-proBNP levels (r = 0.741, p < 0.001). Moreover, a negative correlation was observed between the serum FGF21 levels and the LVEF (r = -0.402, p < 0.001). FGF21, NT-proBNP, the LVEF and a history of atrial fibrillation (AF) correlated significantly with NYHA class IV (p < 0.05). The AUC of NT-proBNP for predicting NYHA class IV in DCM patients was greater than that of FGF21 (0.830 vs. 0.772, p < 0.001). Overall, 133 patients with DCM were recorded at the end point. Kaplan-Meier analysis results showed that the survival probability of those individuals with high levels of FGF21 and NT-proBNP was significantly lower than of those with low levels of these factors (p < 0.001). In the multivariate Cox analysis, FGF21 (HR 2.561; 95% CI 1.705-3.849) and NT-proBNP (HR 4.458; 95% CI 2.645-7.513) were independent predictors of a poor prognosis in DCM patients. CONCLUSIONS: Serum FGF21 levels were associated with the risk factors, severity, and prognosis of DCM. Therefore, FGF21 may serve as a novel biomarker for the prognosis of DCM.

Clinical Significance of Serum Kallistatin and ENOX1 Levels in Patients with Coronary Heart Disease.

BACKGROUND: Kallistatin and ENOX1 are regulators of inflammation and oxidative stress which are typical pathological reactions in atherosclerosis. However, there is limited information of kallistatin and ENOX1 in coronary heart disease (CHD). METHODS: Fifty healthy controls, 56 stable angina pectoris (SAP) patients, and 47 acute coronary syndrome (ACS) patients were included in this study. Levels of kallistatin and ENOX1 in serum were measured by ELISA. χ2 test was performed to analyze categorical data. ANOVA, Pearson correlation analysis, and multiple linear regression were performed to analyze the numerical data. Finally, receiver operating characteristic (ROC) curve was applied to assess the diagnostic value of kallistatin in CHD. RESULTS: Among the 153 participants, 59.5% were male and the average age was 63.8 ± 11.39 years. Compared with the control group, kallistatin expression was decreased in the SAP and ACS groups while expression of ENOX1 was increased in the ACS group (p < 0.05). Pearson correlation analysis showed that the kallistatin level was negatively correlated with the Gensini score (r = -0.210, p < 0.01), white blood cell (WBC) count (r = -0.283, p < 0.001), and triglyceride levels (r = -0.242, p < 0.01) and positively correlated with age (r = 0.353, p < 0.001) and high-density lipoprotein cholesterol (r = 0.310, p < 0.001). ENOX1 expression was positively correlated with WBC count (r = 0.244, p < 0.01), international normalized ratio (r = 0.177, p < 0.05), and Gensini score (r = 0.201, p < 0.05). Multiple linear regression showed that Cr, alanine transaminase, glucose, and kallistatin are independent predictors for Gensini score. The ROC curve showed that kallistatin had the highest diagnostic significance (p = 0.007) when the area under curve was 0.636, with a sensitivity of 0.735 and a specificity of 0.495. CONCLUSION: Expression of kallistatin was decreased in CHD patients and that of ENOX1 was increased in ACS patients. Kallistatin and ENOX1 were closely connected with the severity of CHD, and kallistatin may be helpful in the diagnosis of CHD.

Protease-activated receptor 2 deficiency in hematopoietic lineage protects against myocardial infarction through attenuated inflammatory response and fibrosis.

Ischaemic heart disease is one of the leading causes of death. Protease-activated receptor 2 (PAR2) is widely expressed within the cardiovascular system and is known to mediate inflammatory processes in various immunocytes, such as macrophages, mastocytes and neutrophils. Here, we investigated whether activating macrophage PAR2 modulates cardiac remodelling in a murine model of myocardial infarction. Myocardial infarction was produced by the permanent ligation of the left anterior descending coronary artery (LAD) in C57BL/6J background wild-type (WT) mice transplanted with bone marrow from WT or PAR2 knockout (PAR2 KO) mice. Hematopoietic deficiency of PAR2 had improvement of left ventricular systolic dysfunction and dilatation and decreased fibrosis deposition in remote zone at 1 week after LAD ligation. Inactivation of PAR2 also led to less recruitment of macrophages in myocardium, which was accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, cultured cardiac fibroblasts (CFs) were activated and showed a fibrotic phenotype after being co-cultured in medium containing PAR2-activating macrophage, which enhances interferon-beta (INF-ß) expression. The beneficial effects of macrophages with INF-ß neutralisation or PAR2-deletion ameliorates the JAK/STAT3 pathway in CFs, which might be attributed to CF activation. These data suggest that macrophage-derived IFN-ß plays a crucial role in adverse cardiac remodelling after myocardial infarction, at least in part, through a PAR2-dependent mechanism.

Three-year follow up of biodegradable polymer cobalt-chromium sirolimus-eluting stent (EXCROSSAL) in treating de novo coronary artery disease: Pooled analysis of CREDIT II and CREDIT III trials.

OBJECTIVES: To analyze the 3-year outcomes of the biodegradable polymer cobalt-chromium sirolimus-eluting stent (EXCROSSAL) in CREDIT II AND III TRIALS. BACKGROUND: Though approved by CFDA, the long-term safety and efficacy of EXCROSSAL is still unknown. METHODS: CREDIT II was a randomized trial comparing the EXCROSSAL versus EXCEL stents in patients with up to two de novo coronary lesions, and CREDIT III was a prospective, single-arm study evaluating the efficacy and safety of EXCROSSAL in broad types of de novo coronary artery lesions. We pooled the 3-year follow-up data of the EXCROSSAL arm of the CREDIT II and CREDIT III Trials. The primary outcome was 3-year target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), and clinically indicated target lesion revascularization (CI-TLR). The patient-oriented composite endpoint (PoCE) (all-cause death, all MI, or any revascularization) and stent thrombosis (ST) were also analyzed. RESULTS: A total of 833 patients were included in this study. The incidence of TLF and PoCE in the 3-year follow-up were 7.6% and 12.5%, respectively. ST occurred in 0.6% of patients. In the subgroup analyses, TLF was significantly higher in small target vessels, multi-lesion PCI, and multi-vessel disease. CONCLUSIONS: The 3-year follow-up analysis confirmed low rates of TLF and ST in EXCROSSAL, which is similar to the most widely used new generation durable polymer drug-eluting stent.

miR-142 is a Sensitive Biomarker for the Diagnosis and Prognosis of Acute Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) is myocardial necrosis caused by acute and persistent ischemia and hypoxia of coronary arteries. AMI is one of the most common diseases in European countries and over 1.5 million AMI patients die of it in the United States annually. A collection of studies proposed that certain micro-RNAs play crucial roles in the onset and development of AMI. METHODS: Ninety-four AMI patients and 83 non-AMI healthy controls were recruited from Zhongda Hospital, Southeast University between July 2015 and September 2017. Serum samples were collected at admission and the expression of miR-142 was detected using real-time quantitative polymerase chain reaction (RT-qPCR) assays. RESULTS: miR-142 expression was markedly elevated in serum samples of AMI patients compared with the 83 non-AMI healthy controls. miR-142 expression was positively correlated with creatine kinase-KB (CK-MB; r = 0.6731, p = 0.0021) and troponin (r = 0.7138, p = 0.0013). The area under the curve (AUC) of miR-142, CK-MB, and troponin for the diagnosis of AMI were 0.9185, 0.8172, and 0.8717, respectively. Overall survival analysis implied that high miR-142 expression may predict poor survival (log-rank test, p = 0.0146). CONCLUSIONS: miR-142 may be a diagnostic and prognostic indicator for AMI, and therefore, it may contribute to AMI clinicopathologic prediction.