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Absolute treatment effects-i.e. numbers needed to treat (NNTs)-of novel antidiabetic drugs for cardiovascular outcomes have not been comprehensively evaluated. We aimed to perform a meta-analysis of digitalized individual patient outcomes to display and compare absolute treatment effects.Individual patient time-to-event information from Kaplan-Meier plots of cardiovascular mortality (CM) and/or hospitalization for heart failure (HHF) endpoints from cardiovascular outcome trials (CVOTs) evaluating dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium glucose transporter 2 (SGLT2) inhibitors vs. placebo were digitalized using WebPlotDigitizer 4.2 and the R code of Guyot et al.; Weibull regression models were generated, validated, and used to estimate NNT for individual trials; random-effects meta-analysis generated Meta-NNT with 95% confidence intervals. Sixteen CVOTs reported time-to-event information (14 in primary diabetes and 2 in primary heart failure populations). Thirteen studies including 96 860 patients were meta-analysed for CM: At the median follow-up of 30 months, Meta-NNTs were 178 (64 to ∞ to -223) for DPP-4 inhibitors, 261 (158 to 745) for GLP-1 receptor agonists, and 118 (68 to 435) for SGLT2 inhibitors. Ten studies including 96 128 patients were meta-analysed for HHF: At the median follow-up of 29 months, estimated Meta-NNTs were -644 (229 to ∞ to -134) for DPP-4 inhibitors, 441 (184 to ∞ to -1100) for GLP-1 receptor agonists, and 126 (91 to 208) for SGLT2 inhibitors. SGLT2 inhibitors were especially effective for HHF in primary heart failure populations [Meta-NNT 25 (19 to 39)] vs. primary diabetes populations [Meta-NNT 233 (167 to 385)] at 16 months of follow-up.We found only modest treatment benefits of GLP-1 receptor agonists and SGLT2 inhibitors for CM and HHF in primary type 2 diabetes mellitus populations. In primary heart failure populations, SGLT2 inhibitor benefits were substantial and comparable in efficacy to established heart failure medication.

Risk factor control of diabetes mellitus (DM) and especially dyslipidemia remains unsatisfactory in patients with atherosclerotic cardiovascular disease (ASCVD). We aimed to analyze the knowledge of low-density lipoprotein cholesterol (LDL-C) and glycated hemoglobin (HbA1c) treatment goals, subjective level of information, and information needs in very high-risk patients with ASCVD.ASCVD patients (n = 210; 75 ± 9 years; 71.4% male; 89.5% coronary disease) with DM (96.7% type 2) completed a questionnaire assessing knowledge of HbA1c and LDL-C treatment goals and subjective level of information and information needs on disease-related topics of DM and ASCVD. Serum LDL-C and HbA1c were measured.HbA1c goal (7.0% in 60.6%) was attained more frequently than LDL-C goal (70 mg/dl in 39.9%; p .01). Significantly more participants named the correct goal for HbA1c compared to LDL-C (52.9% vs. 2.4%; p .01). Subjective levels of information were higher and information needs were lower for DM than for ASCVD (p .01 for all topics). No associations of knowledge of treatment goals and level of information with the attainment of treatment goals for HbA1c and LDL-C were found. However, in multivariate regression, higher levels of education were associated with knowledge of treatment goals (HbA1c: odds ratio [OR] 1.32, 95% confidence interval [CI] 1.01-1.72, p = .04; LDL-C: OR 2.32, 95% CI 1.07-5.03; p = .03).In very high-risk patients with ASCVD, a deficit of knowledge of treatment goals to control dyslipidemia exists when compared to DM, patients felt significantly better informed for topics of DM than for ASCVD and display higher information needs for topics of ASCVD.

Background and purpose Risk prediction with the Global Registry of Acute Coronary Events (GRACE) risk model is guideline-recommended in acute coronary syndrome (ACS) patients. However, the performance of more contemporary scores derived from ACTION (Acute Coronary Treatment and Intervention Outcomes Network) and National Cardiovascular Data (NCDR) registries remains incompletely understood. We aimed to compare these models in German ACS patients. Methods and results A total of 1567 patients with (Non-)ST-segment elevation myocardial infarction (NSTEMI: 1002 patients, STEMI: 565 patients) undergoing invasive management at University Hospital Dusseldorf (Germany) from 2014 to 2018 were included. Overall in-hospital mortality was 7.5% (NSTEMI 3.7%, STEMI 14.5%). Parameters for calculation of GRACE 1.0, GRACE 2.0, ACTION and NCDR risk models and in-hospital mortality were assessed and risk model performance was compared. The GRACE 1.0 risk model for prediction of in-hospital mortality discriminated risk superior (c-index 0.84) to its successor GRACE 2.0 (c-index 0.79, pGRACE1.0vsGRACE2.0 = 0.0008). The NCDR model performed best in discrimination of risk in ACS overall (c-index 0.89; pACTIONvsNCDR Conclusions In a contemporary German patient population with ACS, modern NCDR and ACTION risk models showed superior performance in prediction of in-hospital mortality compared to the gold-standard GRACE model.

Expressions and clinical implications of cancer-testis antigen (CTA) lactate dehydrogenase (LDH)-C4 in hepatocellular carcinoma (HCC) have not been fully elucidated. Herein, expressions of LDHC mRNA in the serum and serum-derived exosomes of early-stage HCC patients were determined using qRT-PCR, and the expression of LDH-C4 protein in HCC tissues was detected using high-throughput tissue microarray analysis. It was found that positive rates of LDHC mRNA expressions in the serum and serum exosomes of HCC patients were 68% and 60%, respectively. The AUCs of serum and exosomal LDHC in differentiating HCC patients from healthy controls were 0.8382 and 0.9451, respectively. The serum and exosomal LDHC levels in HCC patients in the treatment group were higher than the levels in the preliminary diagnosis group, but lower than those in the recurrence group. Survival analysis showed that the expression of LDH-C4 was negatively correlated with the prognosis of HCC. The Cox regression analysis showed that an LDH-C4 level was an independent risk factor for the prognosis of HCC patients. Therefore, serum and exosomal LDHC can be used as a biomarker for early diagnosis, efficacy evaluation and recurrence prediction of HCC. Moreover, LDH-C4 can be used as an important reference indicator for monitoring the prognosis of HCC.

Lactate dehydrogenase C4 (LDH-C4) as a cancer/testis antigen (CTA) is abnormally expressed in some malignant tumors. However, the expression and clinical significance of LDH-C4 in breast cancer (BC) has not been characterized.We determined LDHC mRNA expression in serum and serum-derived exosomes of BC patients by quantitative RT-PCR. We also evaluated the protein expression of LDH-C4 in BC tissues using high-throughput tissue microarray analysis and immunohistochemistry.Our results showed high mRNA expression level of LDHC in serum and serum-derived exosomes of BC patients. The LDHC level in serum and exosomes could distinguish BC cases from healthy individuals based on their AUCs of 0.9587 and 0.9464, respectively. Besides, the LDHC level in exosomes of BC patients associated with tumor size, and positively correlated with HER2 and Ki-67 expressions (all with P 0.05). Serum and exosomal level of LDHC negatively correlated with medical treatment and positively with the recurrence of BC. Survival analysis showed that LDH-C4 expression negatively correlated with BC prognosis.Serum and exosomal LDHC may be an effective indicator for the diagnosis, efficacy evaluation, and monitoring the recurrence of BC. LDH-C4 may act as a biomarker that predicts BC prognosis.

Guidelines recommend adjunct glycoprotein IIb/IIIa inhibitors (GPIs) only in selected patients with acute ST-segment elevation myocardial infarction (STEMI). This study aimed to evaluate routine GPI use in STEMI treated with primary percutaneous coronary intervention.Online databases were searched for randomized controlled trials of routine GPI vs control therapy in STEMI. Data from retrieved studies were abstracted and evaluated in a comprehensive meta-analysis. Twenty-one randomized controlled trials with 8585 patients were included: 10 trials randomized tirofiban, 9 abciximab, 1 trial eptifibatide, and 1 trial used abciximab+tirofiban; only 1 trial used dual antiplatelet therapy with prasugrel/ticagrelor.Routine GPI use was associated with a significant reduction in all-cause mortality at 30 days (2.4% [GPI] vs 3.2%; risk ratio [RR], 0.72; P = 0.01) and 6 months (3.7% vs 4.8%; RR, 0.76; P = 0.02), and a reduction in recurrent myocardial infarction (1.1% vs 2.1%; RR, 0.55; P = 0.0006), repeat revascularization (2.5% vs 4.1%; RR, 0.63; P = 0.0001), thrombolysis in myocardial infarction flow3 after percutaneous coronary intervention (5.4% vs 8.2%; RR, 0.61; P0.0001), and ischemic stroke (RR, 0.42; P = 0.04). Major (4.7% vs 3.4%; RR, 1.35; P = 0.005) and minor bleedings (7.2% vs 5.1%; RR, 1.39; P = 0.006) but not intracranial bleedings (0.1% vs 0%; RR, 2.7; P = 0.37) were significantly increased under routine GPI.Routine GPI administration in STEMI resulted in a reduction in mortality, driven by reductions in recurrent ischemic events-however predominantly in pre-prasugrel/ticagrelor trials. Trials with contemporary STEMI management are needed to confirm these findings.

Background: Patients with chronic kidney disease (CKD) and atrial fibrillation have increased risks for stroke and bleeding under oral anticoagulation (OAC). We investigated an alternative therapy of percutaneous left atrial appendage occlusion (LAAO) in CKD patients in this study.Methods: Consecutive patients undergoing LAAO were included in a retrospective analysis and stratified for kidney function into CKD/Non-CKD groups (cutoff eGFR 60 ml/min). Procedural characteristics, in-hospital and follow-up events were analysed and compared between groups.Results: LAAO was performed in 146 patients (81 CKD; 65 Non-CKD), mean follow-up was 391 days. Groups differed in eGFR (40.1 (CKD) vs. 75.1 (Non-CKD) ml/min) and CHA2DS2VASc scores (4.65 ± 1.3 (CKD) vs. 4.06 ± 1.4 (Non-CKD)). Procedural success was 98.6%, contrast-induced acute kidney injury was significantly more frequent in CKD patients (11.1% vs. 0%; p = .004). Follow-up mortality was higher in CKD (10.5/100 PY vs. 4.2/100 PY; p = .156). Follow-up stroke rates were 2.3/100 (CKD) patient-years (PY) and 1.4/100 PY (Non-CKD) (p = 1.000), corresponding to a relative risk reduction (RRR) of 60% (all), 68% (CKD) and 71% (Non-CKD) compared to expected stroke rates. Follow-up major bleeding rates were 3.5/100 PY (CKD) and 4.2/100 PY (Non-CKD), corresponding to RRR of 57% (all), 61% (CKD) and 53% (Non-CKD) compared to OAC.Conclusions: Left atrial appendage occlusion shows comparable efficacy for stroke and bleeding prevention in CKD and Non-CKD patients. CKD patients experience more adverse events during follow-up and a significantly increased risk for periprocedural contrast-induced acute kidney injury.

Background Contrast-induced nephropathy (CIN) is a major adverse event in patients undergoing coronary angiography. The Mehran risk model is the gold-standard for CIN risk prediction. However, its performance in comparison to more contemporary National Cardiovascular Data Registry-Acute Kidney Injury (NCDR-AKI) risk models remains unknown. We aimed to compare both in this study. Methods and results Predictions of Mehran and NCDR-AKI risk models and clinical events of CIN and need for dialysis were assessed in a total of 2067 patients undergoing coronary angiography with or without percutaneous coronary intervention. Risk models were compared regarding discrimination (receiver operating characteristic analysis), net reclassification improvement (NRI) and calibration (graphical and statistical analysis). The NCDR risk model showed superior risk discrimination for predicting CIN (NCDR c-index 0.75, 95% CI 0.72–0.78; vs. Mehran c-index 0.69, 95% CI 0.66–0.72, p NCDRvsMehran Conclusion In German patients undergoing coronary angiography, the modern NCDR risk model for predicting contrast-induced nephropathy showed superior discrimination compared to the Mehran model while showing less accurate calibration. Results for the outcome ‘need for dialysis’ were equivocal. Graphic abstract

Introduction and purpose Patient risk in non-ST-segment elevation myocardial infarction (NSTEMI) depends on clinical setting, individual patient variables and procedural characteristics. Standardized risk-adjusted periprocedural management for catheterization procedures using a Standard Operating Procedure (SOP) was investigated to evaluate associations with in-hospital clinical outcomes. Methods In 01/2018, our heart center established an SOP for coronary catheterization procedures in NSTEMI, targeting 1) standardized pre-procedural risk assessment using National Cardiovascular Data Registry (NCDR) risk models, and 2) standardized post-procedural risk-adjusted safety measures, including advanced patient monitoring (intermediate/intensive care) and use of vascular closure devices. All patients presenting with invasively-managed NSTEMI in 2018 were retrospectively evaluated for SOP-based pre-procedural risk scoring, SOP-based post-procedural management and in-hospital clinical outcomes of mortality, major bleeding (MB, according to BARC ≥3) and acute kidney injury (AKI, according to KDIGO). Results A total of 430 patients (age 72±12 years, 71% male, BMI 27±5) presenting with NSTEMI from 01 to 12/2018 were included, 9.8% presented in cardiogenic shock and 4.7% had suffered a preclinical cardiac arrest. Overall in-hospital mortality was 3.7%, MB occurred in 6.5%. 207 patients (48.1%, SOP+ group) had received both 1) pre-procedural risk assessment and 2) post-procedural risk-adjusted safety measures; the other 223 patients (51.9%, SOP- group) had not received either 1) or 2). There were no significant differences in baseline characteristics and prior-existing medical conditions between groups, however, significantly more patients in SOP- group were treated in emergency settings (39.9% vs. 21.7%, p=0.004). However, significantly more patients in SOP- were treated in emergency settings at higher risk (39.9% (SOP-) vs. 21.7% (SOP+); p Conclusion Standardized risk management in invasively managed NSTEMI was associated with significantly lower rates of in-hospital major bleedings. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Junior Clinician Scientist Track, Medical faculty, Heinrich-Heine-University Düsseldorf, Germany

Background Iron is essential to the mitochondrial energy production in cardiomyocytes and its depletion is negatively associated with symptoms, functional capacity, quality of life and outcomes in patients with heart failure – independent of anemia. The relevance of iron deficiency in adults with congenital heart disease however has not been evaluated to date, and we thus aimed to evaluate it in an all-comer cohort of patients with congenital heart disease in correlation with symptoms and functional capacity. Methods and results 527 patient cases from one referral center over 2 years were evaluated concerning their iron status, anemia, functional capacity and ejection fraction of their systemic ventricle. 264 were female, 94 had a shunt lesion, 96 had left-sided obstructive lesions, 181 right-sided lesions, while 108 were considered to have complex lesions and 28 were cyanotic. The median age was 34 years, the mean BMI was 25.2±5 kg/m2, 429 patients had a normal ejection fraction and 34 moderately and severely depressed. 35 patients were classified as NYHA III, and 56 as NYHA II, while their functional capacity was evaluated via cardiopulmonary testing with a mean VO2max/kg of 22.6±6.5 and mean 69±17% of the expected. The mean serum iron concentration was 99.4±42.3 mcg/dL, their mean transferrin saturation was 27.36±13%, the mean ferritin concentration was 130.8±185 ng/mL, the mean soluble transfer factor was 1.3±0.66 mg/l and their mean Hemoglobin 14.8±2 mg/dL, while the mean MCV was 88±5.3 and the mean MCHC 33.7±1.4. 40 patients were anemic according to the WHO definition for anemia, in 28 of those patients that was already known. Iron deficiency according to stratified according to ferritin was present in 53 patients. However, when stratified according to the heart failure guidelines definition for iron deficiency 299 patients were found affected. Using the soluble transferrin receptor (sTfR) and sTfR-ferritin index iron deficiency was suspected in 10 additional individuals. Iron deficiency was associated with the ejection fraction (p=0.0001) - patients with moderately or severely depressed systemic ventricular function more often were diagnosed with iron deficiency (p=0.007)-, while it did not correlate with functional NYHA classification (p=0.622) or functional capacity (p=0.1 and 0.057). Iron deficiency was also not found significantly different amongst congenital defects but did correlate with all laboratory iron studies. Conclusions In this ambulatory population of adults with congenital heart disease we found an association of ejection fraction with iron deficiency, however no association of iron deficiency with functional capacity. The question arising is if a new definition of iron deficiency anemia in congenital heart disease similar to heart failure would be of clinical value. Funding Acknowledgement Type of funding source: None

Background Uninterrupted anticoagulation during catheter ablation of atrial fibrillation (CAAF) became standard of care after positive results of trials investigating vitamin K antagonists (VKA). Previous studies and meta-analyses of uninterrupted direct oral anticoagulants (DOAC) vs. VKA have given controversial results. We thus aimed to elucidate the risks and benefits of uninterrupted DOAC vs. VKA during CAAF in an updated meta-analysis of randomized controlled trials (RCTs). Methods Online databases were searched for RCTs comparing uninterrupted DOAC to VKA in patients undergoing CAAF until September 2019. Data from retrieved studies were analysed in a comprehensive meta-analysis. Primary safety outcome was major bleeding; primary efficacy outcome was stroke or transient ischemic attack (TIA). Secondary outcomes included a composite of major bleeding and stroke or TIA, minor bleeding, acute cerebral lesions on magnetic resonance imaging (ACL) and mortality. Results Six eligible RCTs comprising 2,369 patients were included. Pooled meta-analysis showed no significant differences in DOAC vs. VKA concerning the rates of major bleeding (2.2% vs. 3.8%; odds ratio (OR) 0.69, 95% confidence interval (CI) 0.30–1.56; p=0.37) and stroke or TIA (0.2% vs. 0.2%; OR 0.97, CI 0.20–4.72; p=0.97). There were no significant differences found in secondary outcomes (OR 0.73, p=0.49 for composite of major bleeding and stroke or TIA; OR 1.08, p=0.52 for minor bleeding; OR 1.12, p=0.59 for ACL; and OR=0.60, p=0.64 for all-cause mortality). Conclusion Our meta-analysis suggests that uninterrupted periprocedural anticoagulation with DOAC or VKA is characterized by a similar risk/benefit ratio in patients undergoing CAAF with comparable rates of major bleeding and stroke. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Medical faculty of the Heinrich-Heine-University Düsseldorf, Germany

Aims Virtual reality (VR) has been used successfully in different clinical settings to treat anxiety. This prospective, randomised pilot study aimed to investigate the feasibility and safety of VR in patients undergoing conscious sedation during transfemoral transcatheter aortic valve implantation (TAVI). Methods and results Thirty-two patients were included and randomised to VR intervention (n=16) or control (n=16). In the intervention group, patient-selected relaxing 3D videos were projected during the TAVI procedure; pain and anxiety before and after TAVI were measured using visual analogue scales (VAS; 0-10). The median age was 83 years (IQR 78.25-87). Patients' baseline characteristics did not differ significantly between the groups. During TAVI under conscious sedation, the median duration of VR intervention was 30.5 minutes (IQR 23.5-46); 81.3% of the patients watched the videos until device implantation, 37.5% during the whole procedure. The VR intervention group reported significantly less anxiety after the procedure (VAS 2 [IQR 0-3.75] vs 5 [IQR 2-8], p=0.04) than patients randomised to control. In the intervention group, 93.8% would use VR during TAVI again. Nausea and vomiting did not occur more frequently compared to control. Conclusions VR interventions during TAVI to assist conscious sedation are safe and feasible, even in very old and frail patients. In this small cohort, there was a significant reduction in periprocedural anxiety.

Background: Periprocedural uninterrupted anticoagulation for catheter ablation of atrial fibrillation (AF) became standard after positive results of vitamin K antagonist (VKA) trials. Previous studies of uninterrupted direct oral anticoagulants (DOACs) vs. VKA have given controversial results. We thus aimed to elucidate the risk/benefit ratio of uninterrupted DOAC vs. VKA during catheter ablation of AF in an updated meta-analysis of randomised controlled trials (RCTs). Methods: Online databases were searched for RCTs comparing uninterrupted DOAC to VKA in patients undergoing catheter ablation of AF. Data from retrieved studies were analysed in a comprehensive meta-analysis. Primary safety outcome was major bleeding; primary efficacy outcome was stroke or transient ischaemic attack (TIA). Secondary outcomes included a composite of major bleeding and stroke or TIA, minor bleeding, acute cerebral lesions on magnetic resonance imaging (MRI), and mortality. Results: Six eligible RCTs comprising 2,369 patients were included. There were no significant differences in DOAC vs. VKA concerning the rates of major bleeding (2.2% vs. 3.8%; odds ratio (OR) 0.69, 95% confidence interval (CI) 0.30–1.56; p = .37) and stroke or TIA (0.2% vs. 0.2%; OR 0.97, CI 0.20–4.72; p = .97). Pooled meta-analysis of secondary outcomes revealed no significant differences (OR 0.73, p = .49 for composite of major bleeding and stroke or TIA; OR 1.08, p = .52 for minor bleeding; OR 1.12, p = .59 for acute cerebral lesions on MRI; and OR 0.60, p = .64 for all-cause mortality). Conclusion: Our meta-analysis suggests that uninterrupted DOAC is not superior to VKA in patients undergoing catheter ablation of AF with comparable rates of major bleeding and stroke.

Background Bempedoic acid (BA) is a novel oral low-density lipoprotein cholestrol (LDL-C) lowering drug. Its efficacy and safety for clinical outcomes in high cardiovascular risk patients remains unknown. Objectives and methods A systematic review was performed and randomized controlled trials (RCTs) of BA vs. placebo in high cardiovascular risk patients reporting clinical efficacy and safety outcomes were included in a meta-analysis. Cumulative odds ratios (OR) and mean differences with 95% confidence intervals (CI) were reported as summary statistics. Results Six RCTs with a total of 3,956 patients and follow-ups of four to 52 weeks were identified. There was no difference in MACE (OR 0.84; CI 0.61, 1.15), all-cause mortality (OR 2.37; CI 0.80, 6.99) and cardiovascular mortality (OR 1.66; CI 0.45, 6.04) for BA vs. placebo. BA showed beneficial trends for nonfatal myocardial infarction (OR 0.57; CI 0.32, 1.00) and was associated with a lower risk of new-onset or worsening of diabetes mellitus (OR 0.68; CI 0.49, 0.94) and non-coronary revascularization (OR 0.41; CI 0.18, 0.95), but higher risk of gout (OR 3.29; CI 1.28, 8.46) and a trend for worsening of renal function (OR 4.24; CI 0.98, 18.39) and muscular disorders (OR 2.60; CI 1.15, 5.91). Conclusion Bempedoic acid in high cardiovascular risk patients showed no significant effects on major cardiovascular outcomes in short-term follow-up. Unfavourable effects on muscular disorders, renal function and the incidence of gout sound a note of caution. Hence, further studies with longer-term follow-up are needed to clarify the risk/benefit ratio of this novel therapy. Funding Acknowledgement Type of funding sources: None.

Background Aspirin is a key element in prevention of cardiovascular and thromboembolic events. During non-cardiac surgery however, its balance of bleeding risks and benefits remains unclear. Methods A systematic review and meta-analysis of randomized controlled trials was performed. Online databases were screened for clinical trials randomizing aspirin to no aspirin therapy in non-cardiac surgery. Clinical outcomes of all-cause mortality and cardiovascular mortality, arterial ischemic events, venous thromboembolic events and bleeding events were separately evaluated. Results Seven RCTs comprising 28,302 patients were included. All-cause mortality (3.7% vs. 3.8%; odds ratio (OR) 0.97, CI 0.86–1.10) and cardiovascular mortality (2.0% vs. 2.1%, OR 0.92; CI 0.78–1.09) were not different in aspirin vs. no aspirin groups. Arterial ischemic events showed no differences, including myocardial infarction (2.5% (aspirin) vs. 2.5% (no aspirin)), cerebrovascular events (0.6% (aspirin) vs. 0.6% (no aspirin)) and peripheral arterial events (0.2% (aspirin) vs. 0.3% (no aspirin)). Aspirin significantly reduced the risk for venous thromboembolic events (VTE; 1.5% (aspirin) vs. 2.0% (no aspirin); OR 0.74, CI 0.59–0.94, p =0.02). Perioperative major bleeding was significantly more frequent in aspirin groups (4.4% vs. 3.7%; OR 1.18, CI 1.05 to 1.33, p =0.007). Conclusion Aspirin remained neutral with respect to overall survival, cardiovascular mortality and arterial ischemic events. It reduced venous thromboembolic events at the expense of perioperative major bleedings. Thus, this analysis supports recommendations against perioperative aspirin continuation/initiation in cardiovascular disease patients at intermediate risk, as well as recommendations of aspirin for VTE prophylaxis in orthopedic patients only.

Sudden cardiac death (SCD) is frequent in patients with heart failure due to dilated cardiomyopathy (DCM). Implantable cardioverter/defibrillator (ICD) device therapy is currently used for primary prevention. However, publication of the DANISH trial has recently given reason for doubt, showing no significant improvement in all-cause mortality in comparison to contemporary medical therapy. We performed a meta-analysis of all randomized controlled trials comparing ICD therapy to medical therapy (MT) for primary prevention in DCM. The primary outcome was all-cause mortality; secondary analyses were performed on sudden cardiac death, cardiovascular death and non-cardiac death. Five trials including a total of 2992 patients were included in the pooled analysis. Compared to contemporary medical treatment there was a significant mortality reduction with ICD device therapy [odds ratio (OR) 0.77, 95% confidence interval (CI) 0.64–0.93; p = 0.006]. SCD was decreased significantly (OR 0.43, CI 0.27–0.69; p = 0.0004), while cardiovascular death and non-cardiac death showed no differences. Sensitivity analyses showed no influence of amiodarone therapy on overall results. Analysis of MT details revealed the DANISH population to adhere the most to current guideline recommendations. In addition, it was the only study including a substantial amount of CRT devices (58%). Our meta-analysis of all available randomized evidence shows a survival benefit of ICD therapy for primary prevention in DCM. DANISH results suggest an attenuation of this ICD advantage when compared to contemporary medical and cardiac resynchronization therapy. Until larger trials have confirmed this finding, ICD therapy should remain the recommendation for primary prevention of SCD in DCM.

Background Breast cancer is a common malignant tumor with increasing incidence worldwide. This study aimed to investigate the molecular mechanisms of the adriamycin (ADR) resistance in breast cancer. Methods The GSE76540 dataset downloaded from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database was adopted for analysis. Differentially expressed genes (DEGs) in chemo-sensitive cases and chemo-resistant cases were identified using the GEO2R online tool respectively. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of DEGs were carried out by using the DAVID online tool. The protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) and visualized with Cytoscape software. The impact of key tumor genes on the survival and prognosis were described. Results A total of 1,481 DEGs were excavated, including 549 up-regulated genes and 932 down-regulated genes. According to the GO analysis, the DEGs were significantly enriched in: extracellular matrix organization, positive regulation of transcription from RNA polymerase II promoter, lung development, positive regulation of gene expression, axon guidance and so on. The results of KEGG pathway enrichment analysis showed that the most enriched DEGs can be detected in: pathways in cancer, PI3K/AKT signaling pathway, focal adhesion, Ras signaling pathway and so on. In the PPI network analysis, hub genes of CDH1, ESR1, SOX2, AR, GATA3, FOXA1, KRT19, CLDN7, AGR2, ESRP1, RAB25, CLDN4, IGF1R, CLDN3 and IRS1 were detected. Finally, there is a correlation filter out these hub genes in resistance of ADR. Conclusions Hub genes associated with ADR resistance were identified using bioinformatic techniques. The results of this study may contribute to the development of targeted therapy for breast cancer.

Background and purpose Previous studies and meta-analyses of perioperative levosimendan to improve the outcomes of patients with low cardiac output syndrome (LCOS) undergoing cardiac surgery have given controversial results and the optimal time of infusion of levosimendan remains uncertain. We thus aimed to elucidate the risk/benefit ratio of preoperative levosimendan in a meta-analysis of randomized controlled trials (RCTs). Methods Online databases were searched for RCTs comparing preoperative levosimendan to placebo in patients with LCOS undergoing cardiac surgery until February 2019. Data from retrieved studies were abstracted and analyzed in a comprehensive meta-analysis. Primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction, renal failure/replacement therapy, need for inotropic therapy, need for left ventricular assist devices, ventricular arrhythmia and arterial hypotension. Results As a result of the online database search, six eligible RCTs with 1,326 patients were included in the meta-analysis. Preoperative levosimendan showed a significant reduction in all-cause mortality (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.29–0.83; p Conclusions Preoperative administration of levosimendan may improve survival in patients with low cardiac output syndrome undergoing cardiac surgery. It reduces need for inotropic medical support and renal failure/replace-ment therapy compared to placebo.

Background and purpose EuroSCORE (ES) and Society of Thoracic Surgeons (STS) risk prediction models are routinely used to guide decision-making for transcatheter aortic valve replacement (TAVR), however their accuracy remains limited, especially in very old and high-risk patients. New and updated scoring models have thus been developed to improve risk stratification. We performed a comparative evaluation of classical and new risk scoring models for prediction of 30d mortality in transcatheter aortic valve interventions. Methods and results A total of 1,569 patients undergoing transfemoral (TF, n=1.235) or transapical (TA, n=334) TAVR from 2009 to 2018 were included in a single-center all-comer analysis. Six risk scoring models (logES_I, ES_II, STS-PROM, FRANCE-2, OBSERVANT, GAV-2) were calculated for all patients and evaluated for prediction of 30d mortality in their model discrimination (c-indices with 95% confidence intervals (CI)) and calibration (graphical evaluation). Mean classical risk scores confirmed an intermediate-to-high-risk patient collective (logES_I 27.0±16.9%; STS-PROM 7.0±6.4%), mean 30-day mortality was 3.4% (TF 2.3%; TA 7.8%). Overall discrimination performance was best in FRANCE-2 (c-index 0.73, 95% CI 0.67–0.80), followed by STS-PROM (c-index 0.68, 95% CI 0.62–0.75), OBSERVANT (c-index 0.68, 95% CI 0.61–0.76), ES_II (c-index 0.64) and logES_I and GAV-2 (both c-indices 0.63). FRANCE-2 discriminated best in TF TAVR (c-index 0.72; range of c-indices 0.63 to 0.72), while OBSERVANT performed best in TA TAVR (c-index 0.70; range of c-indices 0.61 to 0.70). All risk scoring models – with the exception of lowest-risk deciles of STS-PROM and ES_II – showed an overestimation of mortality probability in all risk strata. Conclusion FRANCE-2 and OBSERVANT risk models showed superior discrimination performance to classical risk scoring models in TF and TA TAVR, however all models tended to overestimate mortality probability.

Background and purpose The risk of major cardiovascular events (MACE) is increased in patients with diabetes mellitus. Recently published clinical trials of three different pharmacological classes (DPP4 inhibitors (DPP4i), SGLT2-inhibitors (SGLT2i), GLP-1-receptor-antagonists (GLP1RA)) of new anti-diabetic agents (ADA) showed potential benefits for cardiovascular (CV) outcomes. We thus aimed to perform a meta-analysis of randomized controlled trials (RCTs) of these ADA to elucidate benefits on CV outcomes in diabetic patients. Methods Following a systematic online database search, all RCTs reporting CV outcomes of DPP4i, SGLT2i or GLP1RA vs. Placebo in diabetic patients up until December 2018 were eligible for inclusion in the meta-analysis. Studies including patients with acute coronary syndrome (ACS) were excluded. Data were abstracted and analyzed with the inverse-variance method and a random-effects model, hazard ratios (HR) with 95% confidence intervals (CI) were used as summary statistics. CV outcomes of MACE, myocardial infarction (MI), stroke, heart failure (HF), CV death and all-cause mortality were analyzed. Results Eleven RCTs (DPP4i: SAVOR, TECOS, CARMELINA; GLP1RA: LEADER, SUSTAIN-6, EXSCEL, Harmony; SGLT2i: EMPA-REG OUTCOME, CANVAS Program, DECLARE) with 109,316 patients were selected for inclusion. ELIXA and EXAMINE were excluded due to their inclusion of patients with ACS, CAROLINA was excluded for lack of placebo-control. In the pooled meta-analysis of all trials, ADA significantly reduced the risk for MACE (Hazard ratio (HR) 0.91, CI 0.86–0.96, p=0.0004), MI (HR 0.91, CI 0.85–0.96, p=0.02), CV death (HR 0.9, CI 0.82–0.99, P=0.02) and all-cause mortality (HR 0.92, CI 0.85–0.99, p=0.03). There was no difference in the risk for stroke (HR 0.94, CI 0.87–1.02, p=0.16) and HF (HR 0.88, CI 0.76–1.02, p=0.08). In agent-specific subgroup analyses, GLP1RA and SGLT2i showed significant reductions in MACE (GLP1RA: HR 0.85, CI 0.78–0.92, p Conclusions This meta-analysis lends evidence to GLP1RA and SGLT2i benefits for MACE, MI and all-cause mortality, while DPP4i failed to show superiority in cardiovascular outcomes. Individualized medication for diabetic patients depending on CV disease status should be considered.

Background and purpose Although endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) is guideline-recommended to improve functional recovery, thus far there are only inconclusive data from underpowered singular trials of EVT vs. medical therapy (MT) on mortality. We here aimed to perform a meta-analysis on short-term mortality in guideline-relevant EVT vs. MT randomized controlled trials (RCTs). Methods All randomized controlled trials (RCT) reporting EVT vs. MT in the latest 2018 American Stroke Association/American Heart Association (ASA/AHA) Guidelines were eligible for inclusion. Data were abstracted by two independent investigators and double-checked by four others. Study data were integrated using the Cochran-Mantel-Haenszel method and a random-effects model to compute summary statistics of risk ratios (RR) with 95% confidence intervals (CI). Ninety-day mortality and intracranial hemorrhage (ICH) were analyzed. Results Ten of the twelve guideline-relevant EVT vs. MT RCTs (DAWN, DEFUSE 3, ESCAPE, EXTEND-IA, MR CLEAN, MR RESCUE, REVASCAT, SWIFT PRIME, THERAPY, THRACE) with 2,313 patients were selected for inclusion. Studies IMS III and SYNTHESIS were excluded due to their very infrequent use of EVT. Stent retrievers (Trevo, Solitaire, Merci) were most frequently applied, followed by thrombus aspiration (Penumbra). Intravenous thrombolysis was administered in addition to EVT in the majority of patients. In the pooled meta-analysis of all eligible RCTs, EVT significantly reduced the risk for 90-day mortality by 3.7% compared to MT (15.0% vs. 18.7%; RR 0.81 with CI 0.68 to 0.98; p=0.03), accounting for a number-needed-to-treat of 27 to prevent one all-cause death. Trends were similar in early-window (RR 0.83) and late-window trials only (RR 0.76). There was no difference in the risk for ICH in EVT vs. MT (4.2% vs. 4.0%; RR 1.11 with CI 0.71 to 1.72; p=0.65). All included trials were published in high-quality journals and risk of bias was judged low. Conclusions This meta-analysis lends evidence to EVT benefits for survival already during the first 90 days after acute ischemic stroke. These results further highlight the evolution of interventional techniques in this setting.

Background Circular RNAs (circRNAs) are potential, novel biomarkers for the early diagnosis of gastric carcinoma. Herein, a meta-analysis was conducted to assess the diagnostic potential for circRNAs in gastric carcinoma. Methods Online databases were searched for eligible studies. Study quality was judged using the Quality Assessment for Studies of Diagnostic Accuracy (QUADAS) checklist-II tool. STATA 12.0 and Meta-Disc 1.4 software were used for statistical analysis. Results Twelve studies consisting of 1,278 patients and 1,250 paired controls were considered for meta-analysis. The pooled sensitivity and specificity of circRNAs for gastric carcinoma were compared to normal controls and found to be 0.68 (95% CI: 0.66 - 0.71) and 0.70 (95% CI: 0.68 - 0.73), respectively. A corresponding area under the receiver operating characteristic curve of 0.78 was identified. Moreover, stratified analysis demonstrated an improved diagnostic value for circRNAs when tissue and plasma specimens were combined. Conclusions This meta-analysis demonstrates that circRNAs are promising biomarkers for gastric carcinoma.

The National Cardiovascular Data Registry (NCDR) risk scores for mortality, bleeding and acute kidney injury (AKI) are accurate outcome predictors of coronary catheterization procedures in North American populations. However, their application in German clinical practice remained elusive and we thus aimed to verify their use. NCDR scores for mortality, bleeding and AKI and corresponding clinical outcomes were retrospectively assessed in patients undergoing catheterization for ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) or for elective coronary procedures at a German Heart Center from 2014 to 2017. Risk model performance was assessed using receiver-operating-characteristic curves (discrimination) and graphical analysis/logistic regression (calibration). A total of 1637 patients were included, procedures were performed for STEMI (565 patients, 34.5%), NSTEMI (572 patients, 34.9%) and elective purposes (500 patients, 30.5%); 6% (13% of STEMI and 5% of NSTEMI patients) presented in cardiogenic shock and 3% with resuscitated cardiac arrest. Radial access was used in 38% of procedures and cross-over was necessary in 5%; PCI was performed in 60% of procedures. In-hospital mortality was 6.3% (STEMI 14.5%; NSTEMI 3.7%; elective 0%) and major bleedings occurred in 5.6% (STEMI 10.6%; NSTEMI 5.4%; elective 0.2%); AKI was detected in 18.1% of patients (STEMI 23.7%; NSTEMI 27.3%; elective 1.4%), amounting to KDIGO stage I/II/III in 11.5%/3.5%/3.2%. NCDR risk models discriminated very well for mortality [AUC 0.93 with 95% confidence interval (CI) 0.91–0.95] and well for major bleeding (AUC 0.82, CI 0.78–0.86) and any AKI (AUC 0.83, CI 0.81–0.86). Discrimination in the subgroup of patients with PCI was comparable (mortality: AUC 0.90; major bleeding: AUC 0.78; any AKI: AUC 0.79). However, calibration showed considerable underestimation of mortality and AKI in high-risk patients, while major bleeding was consistently overestimated (Hosmer–Lemeshow p

Previous randomized controlled trials (RCT) failed to demonstrate benefits of patent foramen ovale (PFO) closure (PFO-C) over medical therapy (MT) for secondary prevention of cryptogenic ischemic stroke. Three recently published RCTs, however, turned out positive for PFO-C and warrant an updated meta-analysis. Data from all available RCTs on PFO-C vs. MT for secondary prevention of cryptogenic ischemic stroke up until October 2017 were abstracted and analyzed in a comprehensive meta-analysis. Clinical efficacy outcomes were recurrent stroke, recurrent TIA, and their combination; safety outcomes were mortality, major bleeding, venous thromboembolism (VTE), and new-onset atrial fibrillation/flutter (NOAF). Five trials including a total of 3440 patients were included in the meta-analysis. PFO-C significantly reduced recurrent stroke [odds ratio (OR) 0.41, 95% confidence interval (CI) 0.19–0.90; p = 0.03] and the combination of recurrent stroke + TIA (OR 0.53, CI 0.36–0.80; p = 0.002) compared to MT; recurrent TIA alone showed no differences (OR 0.77; CI 0.51–1.14; p = 0.19). NOAF was significantly more frequent after PFO-C (OR 5.75, CI 3.09–10.70; p

Importance Although endovascular thrombectomy (EVT) in acute ischemic stroke is recommended by guidelines to improve functional recovery, thus far there are insufficient data on its association with mortality. Objective To identify guideline-relevant trials of EVT vs medical therapy reporting 90-day mortality and perform a meta-analysis. Data Sources All randomized clinical trials cited for recommendations on EVT vs medical therapy in the latest 2018 American Stroke Association/American Heart Association guidelines. Study Selection Ten American Stroke Association/American Heart Association guideline–relevant randomized clinical trials of EVT vs medical therapy were selected for inclusion. Two EVT trials were excluded owing to infrequent use of EVT. Data Extraction and Synthesis Data were abstracted by 2 independent investigators and double-checked by 4 others. Singular study data were integrated using the Cochran-Mantel-Haenszel method and a random-effects model to compute summary statistics of risk ratios (RR) with 95% CIs. Main Outcomes and Measures Risk of 90-day mortality and 90-day intracranial hemorrhage was analyzed; sensitivity analyses were performed in early-window EVT trials (which included patients from the onset of symptoms onward) vs late-window EVT trials (which included patients from 6 hours after onset of symptoms onward). Results In 10 trials with 2313 patients, EVT significantly reduced the risk for 90-day mortality by 3.7% compared with medical therapy (15.0% vs 18.7%; RR, 0.81; 95% CI, 0.68-0.98;P = .03). Trends were similar in early-window (RR, 0.83; 95% CI, 0.67-1.01;P = .06) and late-window trials only (RR, 0.76; 95% CI, 0.41-1.40;P = .38). There was no difference in the risk for intracranial hemorrhage in EVT vs medical therapy (4.2% vs 4.0%; RR, 1.11; 95% CI, 0.71-1.72;P = .65). Limitations of the studies include trial protocol heterogeneity and bias originating from prematurely terminated trials. Conclusions and Relevance This meta-analysis of all evidence on EVT cited in the 2018 American Stroke Association/American Heart Association guidelines shows significant benefits for survival during the first 90 days after acute ischemic stroke compared with medical therapy alone.

Introduction: There are two different therapeutic concepts of endothelin receptor antagonism: blocking receptor subtype A (ET A R; selective antagonism) and blocking subtypes A and B (ET B R) (dual antagonism). Anti-inflammatory effects of endothelin receptor antagonists (ERA) have been shown, but little is known about the differences of selective versus dual antagonism. We used ambrisentan (selective ERA) and bosentan (dual ERA) as both are used in therapy. Aims: To assess the anti-inflammatory potential of ERA and to find out whether one concept is superior to the other. We studied the influence of ERA on pro-inflammatory cytokines in human airway smooth muscle cells (HASMCs). Methods: HASMC culture, ELISA, qRT-PCR. Results: TNFα induced transcription and expression of CXCL2, CXCL3, GM-CSF and MMP12 in HASMCs. In concentration-response experiments, bosentan led to a significantly greater reduction of GM-CSF and MMP12 protein release than ambrisentan while there was no significant difference in their effect on GM-CSF and MMP12 mRNA; they had no influence on CXCL2 and equally reduced CXCL3. Blocking MAP kinases with specific inhibitors revealed that both ET A R and ET B R signal through p38 MAPK , but only ET B R also signals through ERK-1/-2 to induce GM-CSF expression. After stopping transcription with actinomycin D, bosentan but not ambrisentan reduced GM-CSF but not MMP12 and CXCL3 mRNA. Conclusions: Both ERA hold anti-inflammatory potential which should be investigated in clinical trials. Bosentan led to a significantly stronger reduction of GM-CSF and MMP12 expression. ET B R protects GM-CSF mRNA from degradation via ERK-1/-2; this explains the greater reduction of GM-CSF expression by bosentan.

BACKGROUND Guidelines recommend statins as first-line therapy for dyslipidemia. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new lipid-lowering approach. PURPOSE To assess the efficacy and safety of PCSK9 antibodies in adults with hypercholesterolemia. DATA SOURCES MEDLINE, PubMed Central, and Google Scholar; conference proceedings; and the ClinicalTrials.gov registry through 4 April 2015. STUDY SELECTION Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia. DATA EXTRACTION Two investigators independently extracted data on study characteristics and lipid and clinical outcomes, and rated risk of bias of trials. Prespecified primary end points were all-cause and cardiovascular mortality. DATA SYNTHESIS Twenty-four RCTs comprising 10 159 patients were included. Compared with no antibody, treatment with PCSK9 antibodies led to marked reductions in low-density lipoprotein cholesterol levels (mean difference, -47.49% [95% CI, -69.64% to -25.35%]; P < 0.001] and other atherogenic lipid fractions, and it reduced all-cause mortality (odds ratio [OR], 0.45 [CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I2 = 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I2 = 0%). The rate of myocardial infarction was significantly reduced with use of PCSK9 antibodies (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.45; I2 = 0%), and increases in the serum creatine kinase level were reduced (OR, 0.72 [CI, 0.54 to 0.96]; P = 0.026; heterogeneity P = 0.65; I2 = 0%). Serious adverse events did not increase with administration of PCSK9 antibodies. LIMITATION Results were derived from study-level data rather than patient-level data, and clinical outcome data are rare. CONCLUSION PCSK9 antibodies seem to be safe and effective for adults with dyslipidemia. PRIMARY FUNDING SOURCE CRC 1116 Masterswitches in Myocardial Ischemia, German Research Council DFG.

SummaryInternational guidelines differ in strengths of recommendation for anticoagulation strategies in acute coronary syndromes (ACS). We performed a comprehensive network meta-analysis (NMA) of randomised controlled trials (RCTs) to investigate the comparative efficacy and safety of parenteral anticoagulants in ACS. MEDLINE, Cochrane, EM-BASE, Google Scholar, major cardiology websites, and abstracts/presentations were searched. Six treatments were identified: 1) unfractionated heparin (UFH) + glycoprotein IIb/IIIa inhibitor (GPI) [UFH+GPI], 2) UFH±GPI, 3) bivalirudin, 4) low-molecular-weight heparins (LMWHs), 5) otamixaban, and 6) fondaparinux. Prespecified outcomes (death, myocardial infarction [MI], revascularisation, major bleeding [MB], minor bleeding, and stent thrombosis [ST]) were evaluated up to 30 days. Forty-two RCTs involving 117,353 patients were included. No significant differences in mortality rates were found among strategies. Compared to UFH+GPI, bivalirudin reduced the odds of MB but increased the odds of ST and MI. LMWHs vs bivalirudin reduced MI risk at the price of MB excess. UFH±GPI significantly increased the odds of MI vs LMWHs, of ST vs UFH+GPI, and of MB vs bivalirudin. Reduced ST risk with otamixaban vs UFH±GPI and vs bivalirudin was offset by a marked 2.5- to four-fold MB excess. Fondaparinux showed an intermediate profile. Results for ST-segment elevation MI were consistent with the overall findings. Early anticoagulant strategies for ACS differ in efficacy and safety, with UFH+GPI and LMWHs reducing ischaemic but increasing bleeding risk, and bivalirudin reducing MB but increases MI and ST. The findings support individualised therapy based on patients´ bleeding and ischaemic risks.

Evidence is lacking on the differential effects of the two therapeutic concepts of endothelin receptor antagonists (ERAs): the blockade of only the endothelin receptor A (ETAR; selective antagonism) versus both ETAR and endothelin receptor B (ETBR; dual blockade). Ambrisentan, a selective ERA, and bosentan, a dual blocker, are both available for therapy. We hypothesized that there are differences in the potential of ERAs to ameliorate inflammatory processes in human airway smooth muscle cells (HASMCs) and aimed to unravel underlying mechanisms. We used HASMC culture, enzyme-linked immunosorbent assay, and quantitative reverse-transcription polymerase chain reaction. Tumor necrosis factor α (TNFα) induced transcription and expression of chemokine (C-X-C motif) ligand 2 (CXCL2), chemokine (C-X-C motif) ligand 3 (CXCL3), granulocyte macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase 12 (MMP12) in HASMCs. In concentration-response experiments, bosentan led to a significantly greater reduction of GM-CSF and MMP12 protein release than ambrisentan, whereas there was no significant difference in their effect on GM-CSF and MMP12 mRNA. Both ERAs reduced CXCL3 protein and mRNA equally but had no effect on CXCL2. Blocking mitogen-activated protein kinases revealed that both ETAR and ETBR signal through p38 mitogen-activated protein kinase, but ETBR also signals through extracellular signal-regulated kinase (ERK) 1/2 to induce GM-CSF expression. In the presence of the transcription inhibitor actinomycin D, bosentan, but not ambrisentan, reduced GM-CSF but not MMP12 or CXCL3 mRNA. In conclusion, blockade of each endothelin receptor subtype reduces GM-CSF transcription, but blocking ETBR additionally protects GM-CSF mRNA from degradation via ERK-1/2. Accordingly, blocking both ETAR and ETBR leads to a stronger reduction of TNFα-induced GM-CSF protein expression. This mechanism might be specific to GM-CSF. Our data stress the anti-inflammatory potential of ERA and warrant further investigation of their utility in chronic inflammatory airway diseases.

Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammation and tissue remodeling. We hypothesized that human airway smooth muscle cells (HASMCs) participate in linking inflammation with remodeling and that associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (nonselective/dual ETRA). Inflammatory responses of ex vivo-cultivated HASMCs to TNF-α were investigated by whole-genome microarray analyses. qRT-PCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared in HASMCs from patients with chronic obstructive pulmonary disease. TNF-α induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in severe, corticosteroid-insensitive asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and/or pulmonary hypertension. Thirteen cytokines/chemokines, MMP13, and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B receptor impact on transcriptional regulation and mRNA stabilization. Chemokine (C-C motif) ligands 2 and 5, granulocyte macrophage colony-stimulating factor, and MMP13 had increased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNF-α-activated human bronchial epithelial cells. HASMCs and human bronchial epithelial cells participate in the interaction of inflammation and tissue remodeling. This interaction is targeted differentially by selective and nonselective ETRAs, which could be used in therapies of chronic lung diseases with corticosteroid-resistant airway inflammation at early disease stages to attenuate inflammation-induced airway remodeling.

Chronic obstructive pulmonary disease (COPD) therapy is complicated by corticosteroid resistance of the interleukin 8 (IL-8)-dependent and granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent chronic airway inflammation, for whose establishment human airway smooth muscle cells (HASMCs) might be crucial. It is unclear whether the release of inflammatory mediators from HASMCs is modulated by cigarette smoking and is refractory to corticosteroids in COPD. Resveratrol, an antiaging drug with protective effects against lung cancer, might be an alternative to corticosteroids in COPD therapy. Vascular endothelial growth factor (VEGF) might offer protection from developing emphysema. We tested the following hypotheses for HASMCs: 1) smoking with or without airway obstruction modulates IL-8, GM-CSF, and VEGF release; and 2) corticosteroids, but not resveratrol, fail to inhibit cytokine release in COPD. Cytokine release from HASMCs exposed to tumor necrosis factor α (TNFα), dexamethasone, and/or resveratrol was measured via enzyme-linked immunosorbent assay and compared between nonsmokers (NS), smokers without COPD (S), and smokers with COPD (all n = 10). In response to TNFα, IL-8 release was increased, but GM-CSF and VEGF release was decreased in S and COPD compared with NS. Dexamethasone and resveratrol inhibited concentration-dependently TNFα-induced IL-8, GM-CSF, and VEGF release. For IL-8 and GM-CSF efficiency of dexamethasone was NSSCOPD. That of resveratrol was NS = S = COPD for IL-8 and NS = SCOPD for GM-CSF. For VEGF the efficiency of dexamethasone was NS = S = COPD, and that of resveratrol was NS = SCOPD. All resveratrol effects were partially based on p38 mitogen-activated protein kinase blockade. In conclusion, smoking modulates cytokine release from HASMCs. Corticosteroid refractoriness of HASMCs in COPD is cytokine-dependent. Resveratrol might be superior to corticosteroids in COPD therapy, because it more efficiently reduces the release of inflammatory mediators and has limited effects on VEGF in COPD.