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Coronary heart disease (CHD) is one of the leading causes of deaths globally. Identification of serum metabolic biomarkers for its early diagnosis is thus much desirable. Serum samples were collected from healthy controls (n = 86) and patients with CHD (n = 166) and subjected to untargeted and targeted metabolomics analyses. Subsequently, potential biomarkers were detected and screened, and a clinical model was developed for diagnosing CHD. Four dysregulated metabolites, namely PC(17:0/0:0), oxyneurine, acetylcarnitine, and isoundecylic acid, were identified. Isoundecylic acid was not found in Human Metabolome Database, so we could not validate differences in its relative abundance levels. Further, the clinical model combining serum oxyneurine, triglyceride, and weight was found to be more robust than that based on PC(17:0/0:0), oxyneurine, and acetylcarnitine (AUC = 0.731 vs. 0.579, sensitivity = 83.0 vs. 75.5%, and specificity = 64.0 vs. 46.5%). Our findings indicated that serum metabolomics is an effective method to identify differential metabolites and that serum oxyneurine, triglyceride, and weight appear to be promising biomarkers for the early diagnosis of CHD.

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Despite advances in the treatment of coronary diseases, acute coronary syndrome (ACS) remains the leading cause of death worldwide. ACS is associated with metabolic abnormalities of lipid oxidation stress. In this study, based on liquid chromatograph mass spectrometry technique, we conducted the metabolic profiling analysis of serum samples from stable plaques (SPs) and vulnerable plaques (VPs) in ACS patients for exploring the potential biomarkers of plaque stability. The results showed that four differential metabolites were identified between the SPs and VPs, including betaine, acetylcarnitine, 1-heptadecanoyl-sn-glycero-3-phosphocholine, and isoundecylic acid. Meanwhile, the diagnostic model was identified using stepwise logistic regression and internally validated with 10-fold cross-validation. We analyzed the correlations between serum metabolic perturbations and plaque stability, and the serum betaine and ejection fraction-based model was established with a good diagnostic efficacy [area under the curve (AUC) = 0.808, sensitivity = 70.6%, and specificity = 80.0%]. In summary, we firstly illustrate the comprehensive serum metabolic profiles in ACS patients, suggesting that the combined model of serum betaine and ejection fraction seems to be used as the potential diagnostic biomarker for the vulnerability of plaque stability.

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BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) has contributed to an increasing number of deaths and readmissions over the past few decades. Despite the appearance of standard treatments, including diuretics, ß-receptor blockers and angiotensin-converting enzyme inhibitor (ACEI), there are still a large number of patients who have progressive deterioration of heart function and, inevitably, end-stage heart failure. In recent years, new medications for treating chronic heart failure have been clinically applied, but there is controversy surrounding drug selection and whether patients with HFrEF benefit from these medications. Therefore, we aimed to compare and rank different new pharmacological treatments in patients with HFrEF. METHODS: We performed a network meta-analysis to identify both direct and indirect evidence from relevant studies. We searched MEDLINE, EMBASE, and PsycINFO through the OVID database and CENTRAL through the Cochrane Library for clinical randomized controlled trials investigating new pharmacological treatments in patients with HFrEF published up to September 30, 2018. We included trials of ivabradine, levosimendan, omega-3, tolvaptan, recombinant human B-type natriuretic peptide (rhBNP), isosorbide dinitrate and hydralazine (ISDN/HYD) and angiotensin-neprilysin inhibition (LCZ696). We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool. Based on these items, more than half of the entries were judged as having an overall low to moderate risk of bias; the remaining studies had a high or unclear risk of bias. The outcomes investigated were left ventricle ejection fraction (LVEF %), heart rate (HR) and serum level of B-type natriuretic peptide (BNP). We performed a random-effects network meta-analysis within a Bayesian framework. RESULTS: We deemed 32 trials to be eligible that included 3810 patients and 32 treatments. Overall, 32 (94.1%) trials had a low to moderate risk of bias, while 2 (5.9%) trials had a high risk of bias. The quality of the included studies was rated as low in regard to allocation concealment and blinding and high in regard to other domains according to the Cochrane tools. As for increasing LVEF%, levosimendan was better than placebo (-3.77 (-4.96, -2.43)) and was the best intervention for improving ventricle contraction. As for controlling HR, n3-PUFA was better than placebo (4.01 (-0.44, 8.48)) and was the best choice for regulating HR. As for decreasing BNP, omega-3 was better than placebo (941.99 (-47.48, 1952.89) and was the best therapy for improving ventricle wall tension. CONCLUSIONS: Our study confirmed the effectiveness of the included new pharmacological treatments for optimizing the structural performance and improving the cardiac function in the management of patients with HFrEF and recommended several interventions for clinical practice.

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Leptin has been reported to be expressed in carotid atherosclerotic plaques, where it can promote lesion instability. Matrix metalloproteinases (MMPs) produced by smooth muscle cells (SMCs) are known to contribute to the weakening of atherosclerotic plaques via the degradation of extracellular matrix (ECM) proteins. The present study investigated whether leptin promotes plaque rupture by increasing the expression of MMP in SMCs in vivo and in vitro. In vivo, the neointima/media ratio and expression of MMP in the carotid artery of ob/ob mice were measured following carotid ligation and systemic administration of leptin. In vitro, the effect of leptin treatment on the expression of MMP in isolated SMCs and the underlying signaling pathways were investigated by gelatin zymography and western blot analysis. The results demonstrated that leptin treatment significantly increased the neointima/media ratio and expression of MMP-9 in the carotid artery of mice following carotid ligation. In vitro, leptin also significantly increased the expression and activity of MMP-9 in cultured SMCs in a dose-dependent manner. Leptin also increased the production of MMP-9 by activating leptin receptor and mitogen-activated protein kinases, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which in turn enhanced the binding of the transcription factor activator protein-1 (AP-1) to the MMP-9 promoter. The inhibition of leptin-activated phosphorylation of ERK and JNK suppressed the leptin-stimulated expression of AP-1 and MMP-9. Leptin treatment induced the expression of MMP-9 in SMCs, suggesting that leptin may have substantial involvement in plaque rupture by promoting the degradation of ECM.

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Coronary artery disease is a disease with high morbidity and mortality, in which vascular endothelial dysfunction plays an important role. Hypoxia leads to the inflammation and oxidative stress in endothelial cells, which results in the endothelial injury. The present study was designed to investigate the protective effect and mechanism of folic acid on hypoxia-induced injury in human umbilical vein endothelial cells (HUVEC). Cell counting Kit was used to detect cell survival rate, and apoptotic cells were detected by Hoechst 33258 staining. Intracellular reactive oxygen species (ROS) level was measured using dichloro-dihydro-fluorescein diacetate staining. Western blot was used to determine the protein expressions of extracellular signal protein kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2), NOX4 subunit of NAPDH and endothelial nitric oxide synthase (eNOS). Folic acid significantly increased the cell survival rate and decreased the apoptosis of HUVECs treated with folic acid compared with hypoxia-treated HUVEC. Folic acid also decreased ROS level, while it increased the nitrite content in HUVECs. In addition, folic acid decreased protein expressions of NOX4 and p-ERK1/2, while it increased the protein expression of eNOS in HUVECs. Furthermore, N-acetyl cysteine (NAC), the antioxidant, had similar effect on the cell survival rate and the apoptosis. In addition, DPI (NOX4 inhibitor) and U0126 (ERK1/2 inhibitor) rather than NAC decreased the protein expression of NOX4. NAC, DPI, and U0126 increased the protein expression of eNOS. Furthermore, U0126 rather than DPI and NAC decreased the protein expression of p-ERK1/2. Taken together, the results suggested that hypoxia decreased the cell survival rate and induced apoptosis via ERK1/2/NOX4/ROS pathway, which could be the target of folic acid in protecting the HUVECs from injury caused by hypoxia.

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