Correlation of serum N-Acetylneuraminic acid with the risk and prognosis of acute coronary syndrome: a prospective cohort study.

BACKGROUND: N-acetylneuraminic acid (Neu5Ac) is a functional metabolite involved in coronary artery disease (CAD). We aimed to evaluate the relationship between serum Neu5Ac and the risk and prognosis of acute coronary syndrome (ACS) in a real-world prospective study. METHODS: Patients with suspected ACS who underwent coronary angiography were included. Serum Neu5Ac was measured at admission. Coronary lesion severity was evaluated by Gensini Score. GRACE risk stratification was performed at admission. Major adverse cardiac events (MACEs) were recorded during follow-up. RESULTS: A total of 766 patients, including 537 with unstable angina (UAP), 100 with myocardial infarction (MI), and 129 without CAD were included. The circulating Neu5Ac level was significantly higher in patients with MI (median [1QR]: 297[220, 374] ng/ml) than in those with UAP (227 [114, 312] ng/ml) or without CAD (207 [114, 276] ng/ml; both p < 0.001). Serum level of Neu5Ac was positively correlated with age, hypertension, serum uric acid, creatinine, MB isoform of creatine kinase (CK-MB), and Gensini score (all p < 0.05). Receiver operating characteristic curve analysis showed that a higher serum Neu5Ac was potentially associated with MI and high-risk GRACE stratification in ACS patients. Logistic analysis identified only elevated serum Neu5Ac as an independent predictor of MACEs in these patients (odds ratio [OR]: 1.003, 95% confidence interval [CI]: 1.002-1.005, p < 0.001). CONCLUSIONS: Serum Neu5Ac is associated with myocardial injury, GRACE risk category, and prognosis in ACS patients.

[Correlation of plasma N-acetyl-neuraminic acid level with TIMI risk stratification and clinical outcomes in patients with acute coronary syndrome].

OBJECTIVE: To explore the correlation of plasma N-acetyl-neuraminic acid level with Thrombolysis In Myocardial Infarction (TIMI) risk score and clinical outcomes of patients with acute coronary syndrome (ACS). METHODS: We consecutively enrolled 708 consecutive patients (401 male and 307 female, mean age 63.6±10.6 years) undergoing coronary angiography in our hospital between October, 2018 and July, 2019, including 597 patients with ACS and 111 without ACS (control group). The patients with ACS group were divided into high (n=104), moderate (n=425) and low (n=68) risk groups according to their TIMI risk scores. All the participants were examined for plasma Neu5Ac level using liquid chromatography-tandem mass spectrometry and underwent coronary angiography with their Gensini scores calculated. The patients with ACS were followed up after discharge for a mean of 15 months for the occurrence of major adverse cardiac events (Mace). Binary logistic regression analysis was performed to identify the risk factors of Mace in these patients. RESULTS: Plasma Neu5Ac levels were significantly higher in ACS group than in the control group (P < 0.05). ROC curve analysis showed that plasma Neu5Ac level could assist in the diagnosis of ACS (0.648 [0.597-0.699]) with a sensitivity of 39.2% and a specificity of 86.5% at the cutoff value of 288.50 ng/mL. In the ACS patients, plasma Neu5Ac level was significantly higher in the high-risk group than in the moderate-risk and low-risk groups (P < 0.05) and could assist in the diagnosis of a high risk (0.645 [0.588-0.703]) with a sensitivity of 42.3% and a specificity of 80.1% at the cutoff value of 327.50 ng/ mL. Plasma Neu5Ac was positively correlated with age, serum uric acid, creatinine, lipoprotein a, Ddimer, C-reactive protein, MB isoform of creatine kinase and Gensini score and negatively correlated with high-density lipoprotein level. During the followup, 80 ACS patients experienced Mace, who had significantly higher plasma Neu5Ac level than those without Mace (n=517). Logistic regression analysis showed that plasma Neu5Ac level and a history of previous stroke were independent risk factors for the occurrence of Mace. CONCLUSIONS: Plasma Neu5Ac level can provide assistance in the diagnosis and risk stratification of ACS and is an independent risk factor for prognosis of ACS patients.

The Herb-Drug Interaction of Clopidogrel and Xuesaitong Dispersible Tablet by Modulation of the Pharmacodynamics and Liver Carboxylesterase 1A Metabolism.

OBJECTIVE: Clopidogrel and Xuesaitong dispersible tablet (XST) have been clinically proven to be effective for treating cardiocerebrovascular disease. The present study was to investigate the herb-drug interaction of Clopidogrel and XST by modulation of the pharmacodynamics and liver Carboxylesterase 1A(CES1A) metabolism. METHODS: 30 male SD rats were randomly divided into a control group (equal volumes of saline, 6 rats for mRNA analysis), a clopidogrel group (clopidogrel with dose 30 mg/kg), and a combination group (clopidogrel and XST, with dose 30 and 50 mg/kg respectively, each group continuous administration once daily for 30 days). The clopidogrel and combination group comprised 12 rats, with 6 designated for mRNA analysis and 6 for the pharmacokinetic study. The 2-bromo-3'-methoxyacetophenone- (MPB-) derivatized clopidogrel active thiol metabolite (CAMD) was measured by UHPLC-MS/MS for pharmacokinetics (n=6). The expression of CES1A mRNA was examined with real-time RT-PCR (n=6). Molecular simulation was used to investigate the inhibition effect of XST on the CES1A protein. The CAMD pharmacodynamics and CES1A metabolism were investigated to evaluated the herb-drug interaction. RESULTS: Clopidogrel and XST coadministration appreciably increased the Cmax, AUC, and MRT of CAMD. However, the expression of CES1A mRNA was decreased accordingly. It also indicated that the bioactive components in XST had good interaction with the CES1A metabolism target by molecular simulation. The animal study indicated that clopidogrel and XST coadministration produced significant herb-drug interactions at active CAMD pharmacokinetic and CES1A metabolic enzyme aspect. CONCLUSION: 30-days dose of coadministration altered hepatic CES1A protein and resulted in reduced plasma levels of active CAMD. both the decreased CES1A mRNA expression and the inhibition on the protein were due to the combination of XST, which accordingly upregulated the pharmacokinetics of plasma active CAMD.

MicroRNA­138 promotes proliferation and suppresses mitochondrial depolarization in human pulmonary artery smooth muscle cells through targeting TASK­1.

MicroRNA (miR)­138 serves an important role in the proliferation, differentiation and apoptosis of human pulmonary artery smooth muscle cells (HPASMCs), indi-cating the involvement of miR­138 in the development and progression of pulmonary artery hypertension (PAH). Potassium channel subfamily K member 3 (TASK­1), a two­pore domain K+ channel, is expressed in HPASMCs and is associated with hypoxic PAH. However, whether miR­138 mediates PAH through targeting TASK­1 is not known. In the present study, HPASMCs were transfected with miR­138 mimic to establish a PAH model in vitro, and the effects of a miR­138 inhibitor and a TASK­1 inhibitor (A293) were examined. Cell proliferation and mitochondrial membrane potential (MMP) were measured by CCK­8 assay and flow cytometry, respectively. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to examine the expression of miR­138, TASK­1, Bcl­2, caspase­3 and activation of extracellular signal­regulated kinase 1/2 (ERK1/2). A dual­luciferase reporter assay was also used to analyse the expression level of TASK­1 in HPASMCs. The results of the present study demonstrated that the miR­138 mimic promoted proliferation and MMP level, which was similar to the effect of A293 treatment on HPASMCs. However, the miR­138 inhibitor inhibited the effects induced by miR­138 mimic or A293 treatment, as demonstrated by a decrease in proliferation and MMP level in HPASMCs, accompanied by a decrease of Bcl­2 and an increase of caspase­3 expression levels, as well as ERK1/2 activation. The dual­luciferase reporter assay indicated that TASK­1 expression was negatively regulated by miR­138. The results of the present study suggested that miR­138 promoted proliferation and suppressed mitochondrial depolarization of HPASMCs by targeting TASK­1.

Associations between P2RY12 gene polymorphisms and risks of clopidogrel resistance and adverse cardiovascular events after PCI in patients with acute coronary syndrome.

Clopidogrel resistance in patients with acute coronary syndrome (ACS) is one of the key causes of recurrent cardiovascular disease (CVD) events after percutaneous coronary intervention (PCI). Clopidogrel targets the platelet membrane receptor P2RY12 to inhibit platelet aggregation via adenosine diphosphate (ADP). This study aimed to investigate the relationships between P2RY12 polymorphisms and the risk of clopidogrel resistance and adverse CVD events after PCI. From January 2015 to December 2014, patients who had been diagnosed with ACS undergoing PCI and treated with clopidogrel were recruited for this prospective cohort study (N = 498). Data regarding demographics, medication intake, and ACS lesion were recorded, and whole blood samples were collected for biochemical tests, ADP-induced platelet aggregation ratio detection, and P2RY12 genotyping. P2RY12 genotyping was performed by polymerase chain reaction. The left ventricular ejection fraction was calculated by echocardiography. After 3 to 12 months of follow-up, data regarding any adverse CVD event or death were recorded. The allele frequencies for the T variation alleles in C34T and G52T of P2RY12 were 20.3% and 11.6%, respectively. Patients with T variations at C34T or G52T of P2RY12 had a significantly higher risk of clopidogrel resistance (C34T: P < 0.001; G52T: P = 0.003) and total cardiovascular events (C34T: P = 0.013; G52T: P = 0.018) compared to those with the wild-type genotype. Moreover, multivariable logistic regression showed that patients with the T variations in C34T (odds ratio [OR]: 2.89 (95% confidence interval [CI]: 1.48-5.64), P = 0.002) and G52T (OR: 3.68 [95% CI: 1.71-7.92], P = 0.001) also had a significantly higher risk of clopidogrel resistance. Also, the T variations in C34T (OR: 2.68 [95% CI: 1.07-6.73], P = 0.035) and G52T (OR: 5.64 [95% CI: 1.52-20.88], P = 0.010) significantly increased the risk of post-PCI CVD events after accounting for confounding factors. The P2RY12 gene polymorphisms C34T and G52T were significantly associated with a higher risk of clopidogrel resistance and sequential cardiovascular events in Chinese ACS patients after PCI.

MTHFR C677T gene polymorphism and the severity of coronary lesions in acute coronary syndrome.

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, circulating levels of homocysteine (Hcy), and the severity of coronary lesion in patients with acute coronary syndrome (ACS) remains unknown.Consecutive ACS patients were included. MTHFR C677T polymorphisms were determined via amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Gensini scores were used to evaluate the severity of coronary lesions.Three hundred ten ACS patients were included, and grouped according to the MTHFR C677T polymorphism variant: CC (n = 78, 25.2%), CT (n = 137, 44.2%), and TT (n = 95, 30.6%) groups. No significant differences were detected with respect to baseline characteristics. Patients in TT group had significantly higher Hcy, and significantly lower folic acid (FA) levels as compared with those in the other 2 groups (P < .05 for both). More importantly, patients with TT had more severe coronary lesions as compared with those from the other 2 groups, as evidenced by higher Gensini scores (P < .05 for both); however, no significant differences were observed with respect to the numbers of affected coronary arteries, or the number, length, and diameter of stents implanted in each group (P > .05 for all). On multivariate logistic regression analysis, presence of a T allele in MTHFR C677T was found to be independently associated with higher circulating Hcy (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01-1.12, P = .024), and higher Gensini scores (OR: 1.01, 95% CI: 1.00-1.02, P = .046).MTHFR C677T TT polymorphism was associated with higher Hcy levels and more severe coronary lesions in patients with ACS.