Xiliang Zhao

Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients

A novel influenza A (H7N9) virus of avian origin emerged in eastern China in the spring of 2013. This virus causes severe disease in humans, including acute and often lethal respiratory failure. As of January 2014, 275 cases of H7N9-infected patients had been reported, highlighting the urgency of identifying biomarkers for predicting disease severity and fatal outcomes. Here, we show that plasma levels of angiotensin II, a major regulatory peptide of the renin–angiotensin system, are markedly elevated in H7N9 patients and are associated with disease progression. Moreover, the sustained high levels of angiotensin II in these patients are strongly correlated with mortality. The predictive value of angiotensin II is higher than that of C-reactive protein and some clinical parameters such as the PaO2/FiO2 ratio (partial pressure of arterial oxygen to the fraction of inspired oxygen). Our findings indicate that angiotensin II is a biomarker for lethality in flu infections. Supplementary information The online version of this article (doi:10.1038/ncomms4595) contains supplementary material, which is available to authorized users.

The oral glucose tolerance test for the diagnosis of diabetes mellitus in patients during acute coronary syndrome hospitalization: a meta-analysis of diagnostic test accuracy.

BackgroundThe appropriateness of the routine performance of an oral glucose tolerance test (OGTT) to screen for diabetes mellitus (DM) during acute coronary syndrome hospitalization is still under debate.MethodsA systematic search of databases (MEDLINE [1985 to March 2012], EMBASE [1985 to March 2012]) was conducted. All prospective cohort studies assessing the accuracy or reproducibility of an OGTT in ACS or non-ACS individuals were included. A bivariate model was used to calculate the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). Heterogeneity was explored using subgroup analysis and meta-regression.ResultsFifteen studies with 8,027 participants were included (10 ACS and 5 non-ACS studies). The pooled results on SEN, SPE, PLR, NLR, and DOR were 0.70 (95% CI, 0.60-0.78), 0.91 (95% CI, 0.86-0.94), 7.6 (95% CI, 4.9-11.7), 0.33 (95% CI, 0.25-0.45), and 23 (95% CI, 12–41), respectively. The OGTT has a slightly lower SPE in diagnosing DM in ACS than in non-ACS patients (0.86 [95% CI 0.81-0.92] versus 0.95 [95% CI 0.93-0.98], p<0.01), while the SEN values are comparable (0.71 [95% CI 0.60-0.82] versus 0.67 [95% CI 0.54-0.81], p=0.43). After adjusting the interval between repeated tests and age, the meta-regression did not show a difference in DOR between ACS and non-ACS studies.ConclusionsDespite the discrepancy in the interval between the two OGTTs, performing an OGTT in patients with ACS provides accuracy that is similar to that in in non-ACS patients. It is reasonable to screen patients hospitalized for ACS for previously undiagnosed DM using an OGTT.

Effect of high-dose statin versus low-dose statin plus ezetimibe on endothelial function: a meta-analysis of randomized trials.

Background: Combining low-dose statin and ezetimibe reduces the low-density lipoprotein cholesterol (LDL-C) similar to high-dose statin. However, whether there is a difference in the effect of these 2 lipid-lowering regimes on endothelial function is still controversial. Methods: We performed a systematic search of databases (MEDLINE [1950 to September 2011], EMBASE [1966 to September 2011]) and references of identified studies. Completely published randomized controlled trials comparing the effect of high-dose statin with low-dose stain plus ezetimibe on endothelial function (flow-mediated dilation [FMD] method) were included in this study. Results: Six trials with a total of 213 participants were included in the meta-analysis. The pooled weighted mean difference of FMD did not differ between the 2 lipid-lowering regimes (0.22%; 95% confidence interval [CI]: −0.85%-1.29%, P = .68). Furthermore, no significant reduction in LDL-C and C-reactive protein (CRP) occurred with high-dose statin versus low-dose statin plus ezetimibe (pooled weighted mean differences of LDL-C and CRP were −4.12 mg/dL, 95% CI: −9.54-1.12 mg/dL, P = .12, and −0.02 mg/L, 95% CI: −0.31-0.27 mg/L, P = .89, respectively). Conclusions: Based on the currently available evidence, combining a low-dose statin with ezetimibe may provide similar beneficial effects on endothelial function as high-dose statin.

Efficacy and safety of biodegradable polymer biolimus-eluting stents versus durable polymer drug-eluting stents: a meta-analysis.

Backgrounds Drug-eluting stents (DES) with biodegradable polymers have been developed to address the risk of thrombosis associated with first-generation DES. We aimed to determine the efficacy and safety of biodegradable polymer biolimus-eluting stents (BES) versus durable polymer DES. Methods Systematic database searches of MEDLINE (1950 to June 2013), EMBASE (1966 to June 2013), the Cochrane Central Register of Controlled Trials (Issue 6 of 12, June 2013), and a review of related literature were conducted. All randomized controlled trials comparing biodegradable polymer BES versus durable polymer DES were included. Results Eight randomized controlled trials investigating 11,015 patients undergoing percutaneous coronary interventions were included in the meta-analysis. The risk of major adverse cardiac events did not differ significantly between the patients treated with the biodegradable polymer BES and the durable polymer DES (Relative risk [RR], 0.970; 95% CI, 0.848–1.111; p = 0.662). However, biodegradable polymer BES was associated with reduced risk of very late ST compared with the durable polymer DES, while the risk of early or late ST was similar (RR for early or late ST, 1.167; 95% CI 0.755–1.802; p = 0.487; RR 0.273; 95% CI 0.115–0.652; p = 0.003; p for interaction = 0.003). Conclusions In this meta-analysis of randomized controlled trials, treatments with biodegradable polymer BES did not significantly reduce the risk of major adverse cardiac events, but demonstrated a significantly lower risk of very late ST when compared to durable polymer DES. This conclusion requires confirmation by further studies with long-term follow-up. PROSPERO register number http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42013004364#.UnM2lfmsj6J

Association Between Subclinical Hypothyroidism and Blood Pressure - A Meta-Analysis of Observational Studies

OBJECTIVE This meta-analysis aimed to examine the relationship between subclinical hypothyroidism (SCH) and blood pressure (BP). METHODS A systematic search of MEDLINE and EMBASE databases was performed to identify all related cross-sectional studies and baseline data in prospective cohort studies in the general population. Weighted mean differences (WMDs) of systolic blood pressure (SBP) and diastolic blood pressure (DBP) between SCH and euthyroid groups were calculated. Subgroup analyses and meta-regression were used to explore potential heterogeneities among studies. RESULTS Twenty studies with 50,147 individuals were included. The WMDs of SBP and DBP were 1.47 mm Hg (95% confidence interval [CI] 0.54-2.39 mm Hg, P = .002) and 0.44 mm Hg [95% CI: -0.15-1.02 mm Hg, P = .142] between SCH and euthyroid groups, respectively. Significant heterogeneity was indentified among the included studies. Subgroup analysis showed that differences in study design, gender, and thyroid-stimulating hormone (TSH) cutoff level were not associated with the WMD of SBP, except for age difference between SCH and euthyroid groups. Meta-regression revealed a significant association between WMDs of SBP and age difference between the 2 groups (P = .015). CONCLUSION In this meta-analysis, SCH was associated with slightly higher SBP, which could be attributed to the age difference between SCH and euthyroid groups in the general population. However, this study could not exclude an association between SCH and BP. Prospective studies are needed to confirm these findings.

Use of atorvastatin in lipid disorders and cardiovascular disease in Chinese patients.

Objective: Statins are still underused for the prevention of cardiovascular disease (CVD) in China. Hence, we conducted a systemic review on the pharmacology, clinical efficacy, and adverse events of atorvastatin, as well as on patient adherence. Data Sources: We conducted a systemic search in PubMed with the following keywords: “atorvastatin” (Supplementary concept) or “atorvastatin” (All field) and (“China” [AD] or “China” [all field] or “Chinese” [All field]). Study Selection: Clinical or basic research articles on atorvastatin were included. Results: Atorvastatin is a reversible and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, decreasing the de novo cholesterol synthesis. The pharmacokinetics of atorvastatin among Chinese is similar to those in Caucasians, and several gene polymorphisms have proved to be associated with the metabolism of atorvastatin in the Chinese population. Several international multiple-center randomized control trials have demonstrated the benefit of atorvastatin for primary and secondary prevention of CVD. None of them, however, included the Chinese, and current evidence in the population is still inadequate, due to the small sample size, low study quality, short study duration, and the use of surrogate endpoints instead of clinical endpoints. The overall incidence of adverse events observed with atorvastatin did not increase in the 10–80 mg dose range, and was similar to that observed with placebo and in patients treated with other statins, which makes atorvastatin well-tolerated in the Chinese population. Moreover, high patient adherence was observed in clinical studies. Conclusions: Based on the current available evidence, there is no significant difference between Chinese and non-Chinese population in term of pharmacology and clinical efficacy/safety. High-quality evidence is still needed to support the use of atorvastatin in high-risk Chinese population.

Optimal Oral Antithrombotic Regimes for Patients with Acute Coronary Syndrome: A Network Meta-Analysis

Objective We performed a network meta-analysis to investigate the optimal antithrombotic regime by indirectly comparing new antithrombotic regimes (new P2Y12 inhibitors plus aspirin or novel oral anticoagulants on top of traditional dual antiplatelet therapy [DAPT]) in patients with acute coronary syndrome (ACS). Methods A systematic search of MEDLINE, EMBASE, and the Cochrane databases was performed to identify all phase 3 randomized controlled trials (RCTs) involving novel oral anticoagulants or oral P2Y12 inhibitors in patients with ACS. Major adverse cardiac events (MACE) were regarded as the efficacy endpoint, and thrombolysis in myocardial infarction (TIMI) major bleeding events were used as the safety endpoint. The net clinical benefit was calculated as the sum of MACE and TIMI major bleeding events. Results Five phase 3 RCTs with 64,476 ACS patients were included. Although there were no significant differences among new antithrombotic regimes, rivaroxaban 5 mg twice daily plus traditional DAPT might be the most effective in reducing the incidence of MACE, accompanying the highest risk of TIMI major bleeding. Ticagrelor plus aspirin presented slight advantage on the net clinical benefit over other new antithrombotic regimes, with the highest probability of being the best regimes for net clinical benefit (35.0%), followed by prasugrel plus aspirin (28.0%), and rivaroxaban 2.5 mg twice daily plus traditional DAPT (19.5%). Conclusion Novel antithrombotic regime with ticagrelor plus aspirin brings a larger clinical benefit in comparison with other regimes, suggesting that it may be the optimal antithrombotic regime for patients with ACS.

Association between serum chemokine CC-motif ligand 17 and coronary artery disease

Chemokines, a family of small chemotactic cytokines, have been recognized as important contributors to the pathogenesis of atherosclerosis and related cardiovascular disease [1]. Chemokine CC ligand 17 (CCL 17), also known as thymus activation and regulated chemokine (TARC), is a member of the chemokine family. Recently, Weber et al. found that dendritic cell-derived CCL17 accumulated in advanced human and mouse atherosclerotic lesions. Furthermore, deficiency or blockade of dendritic cell-derived CCL17 reduced atherosclerosis by expanding regulatory T cells (Tregs), whereas CCL17 expression in dendritic cells limited Treg retention to promote atherosclerosis, suggesting CCL17 as an important regulator of atherosclerosis [2]. To date, however, there has been no report exploring the relationship between serum CCL 17 levels and CAD. In the current study, we measured the serum CCL17 levels in patients with andwithout CAD and tried to determine the association between serum CCL17 levels and different forms of CAD or severity of CAD. The study population consisted of a cohort of 119 patients who underwent coronary angiography from January 2012 to December 2012 in a single academic center. Patients were divided into 4 groups according to diagnosis: 30 consecutive patients with angiographically normal coronary arteries (b20% stenosis), 30 consecutive patients with stable angina pectoris (SAP) and N50% stenosis in at least one major coronary artery branch, 29 consecutive patients with nonST elevation myocardial infarction (NSTEMI) and 30 consecutive patients with ST elevation myocardial infarction (STEMI). Exclusion criteria included dermatitis, current infection, malignancy, auto-immune disease, vasculitis, asthma, cirrhosis, severe renal failure (eGFR b 30 ml/min) and shock. This study has been approved by the local Ethics Committees and all participants have given their informed consent. Coronary angiography (CA) was performed with a conventional angiography unit (Integris H; Philips Medical Systems). The severity of atherosclerosis was determined using the Gensini score (GSS) [6]. Blood for determining serum levels of CCL 17 and high sensitive-C reactive protein (hs-CRP) was collected from the radial or femoral artery after the insertion of sheathe prior to any anticoagulation and coronary angiography. Serum CCL 17 concentrations weremeasured with the Quantikine ELISA development kit for human CCL17/TARC (RD NSTEMI 316.17 ± 162.26 pg/ml; STEMI 339.54 ± 130.26 pg/ml; p for ANOVA= 0.682). There was a linear relationship between serum CCL 17 levels and the Gensini Scores (R = 0.24, p = 0.024). No associationwas found between serum CCL 17 levels and age, BMI, lipid profile, creatinine or Hs-CRP levels.

Smoking and prasugrel

Recently, clopidogrel has beenproved to be reduced or complete lack of clinical benefit in nonsmokers in post-hoc analysis of several largescale randomized controlled trials (RCTs). These observations raise concerns about the costs and potential risks incurred by treating nonsmokers with clopidogrel [1]. In acute coronary syndrome (ACS) patients with scheduled percutaneous coronary intervention, the thirdgeneration thienopyridine prasugrel was associated with significantly reduced rates of ischemic events compared to clopidogrel in TRITONTIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) [2]. Thus, we tried to determine the association between prasugrel and smoking habits in patients with ACS. Two largest RCTs comparing prasugrel with clopidogrel (TRITONTIMI 38 [2] and TRILOGY ACS [The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes] [3,4]) were included in our analysis. In TRITON-TIMI 38, 13,608 patients with moderate-to-high-risk ACS with scheduled percutaneous coronary intervention were randomized to receive prasugrel or clopidogrel for 6 to 15 months. The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio[HR] for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; pb0.001). In TRILOGYACS, 9326 patients with unstable angina or myocardial infarction without ST-segment elevation who did not undergo revascularization were randomized to receive prasugrel or clopidogrel. After a median follow-up of 17 months, prasugrel did not significantly reduce the frequency of the primary end point. Both studies were high quality RCTs, and scored 5 using JADAD scale [5]. Both studies used death from cardiovascular causes, myocardial infarction, or stroke as primary end point. Thus, we directly calculated the pooled HR of primary endpoint for both smokers and non-smokers using STATA 11.0 (STATA, TX, USA) with inverse-variance method. The authors of this manuscript have certified that they comply with the

Varinostat alters gene expression profiles in aortic tissues from ApoE-/- mice

Atherosclerosis (AS) is a complex, chronic inflammatory disease that is characterized by plaque buildup within arterial vessel walls. Preclinical trials have suggested that vorinostat, a pan-histone deacetylase inhibitor (HDACi), reduces vascular inflammation and AS, but the underlying protective mechanism has not been fully elucidated. The present study aimed to identify altered gene expression profiles in aortic tissues from ApoE-/- mice after vorinostat treatment. Male ApoE-/- mice fed a high-fat diet were treated with either vorinostat or vehicle, and the aortic plaque area was quantified 8 weeks after treatment. Aortic tissues were collected from both the vorinostat group (n = 3) and vehicle group (n = 3) for deep sequencing of the cDNA to construct sRNA libraries. Oral administration of vorinostat significantly reduced plaque size in the ApoE-/- mice (p < 0.05). In total, 1,550 differentially expressed mRNAs, 56 differentially expressed miRNAs, and 381 differentially expressed lncRNAs were identified in the vorinostat group compared to the vehicle group. Subsequently, a global lncRNA-miRNA-mRNA triple network was constructed based on the competitive endogenous RNA (ceRNA) theory. The hepatitis C signaling pathway was significantly enriched among the differentially expressed mRNAs from the ceRNA network, which suggests that vorinostat has anti-inflammatory properties. Importantly, the identified target pair of mmu-miR-3075-5p/lncRNA-A330023F24Rik/Ldlr may regulate drug response. Upregulation of low-density lipid receptor (Ldlr) and lncRNA-A330023F24Rik and downregulation of mmu-miR-3075-5p were further verified by quantitative real-time polymerase chain reaction. To conclude, vorinostat reduced AS in ApoE-/- mice. Differentially expressed mRNA, lncRNAs, and miRNAs, as well as their interactions and pathways, were identified, which partially explain vorinostats anti-atherosclerotic effects.