Publications by authors named "Irene M Lang"

218 Publications

The impact of comorbidities on selexipag treatment effect in patients with pulmonary arterial hypertension: insights from the GRIPHON study.

Eur J Heart Fail 2021 Nov 21. Epub 2021 Nov 21.

Division of Cardiology, Medical University of Vienna, Vienna, Austria.

Aims: The number of pulmonary arterial hypertension (PAH) patients with comorbidities is increasing and there are limited data on response to PAH-targeted therapies in this population. These post hoc analyses explored the effect of selexipag in PAH patients with cardiovascular comorbidities in the GRIPHON study.

Methods And Results: Randomized patients (n = 1156) were classified using three methods: (i) by subgroups defined according to previously published comorbidity count and restrictive haemodynamic criteria: Subgroup A (<3 comorbidities and haemodynamic criteria met; n = 962) and Subgroup B (≥3 comorbidities and/or haemodynamic criteria not met; n = 144); comorbidities included body mass index ≥30 kg/m , essential hypertension, diabetes, history of coronary artery disease; (ii) by number of comorbidities, with addition of atrial fibrillation (0, 1, 2, 3, 4, or 5); (iii) by presence of individual comorbidities. Selexipag to placebo hazard ratios (HR) and 95% confidence intervals (CI) for morbidity/mortality (primary composite endpoint) were estimated using Cox regression adjusting selexipag effect for baseline covariates. Approximately half of the patients in GRIPHON (n = 584; 50.5%) had comorbidities. Selexipag reduced the risk of a morbidity/mortality event compared with placebo in both Subgroup A (HR 0.66, 95% CI 0.53, 0.82) and Subgroup B (HR 0.50, 95% CI 0.26, 0.96), with no evidence of an inconsistent treatment effect between subgroups (interaction p = 0.432). Consistent results were observed in analyses by number and by specific type of comorbidity.

Conclusion: Selexipag reduces the risk of a morbidity/mortality event vs. placebo irrespective of patient comorbidity status, suggesting that comorbidity status does not influence the treatment effect of selexipag.
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http://dx.doi.org/10.1002/ejhf.2369DOI Listing
November 2021

Plasma Trimethylamine-N-Oxide Is an Independent Predictor of Long-Term Cardiovascular Mortality in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome.

Front Cardiovasc Med 2021 29;8:728724. Epub 2021 Oct 29.

Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CEPT), Medical University of Warsaw, Warsaw, Poland.

To investigate the association of liver metabolite trimethylamine N-oxide (TMAO) with cardiovascular disease (CV)-related and all-cause mortality in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention. Our prospective observational study enrolled 292 patients with ACS. Plasma concentrations of TMAO were measured during the hospitalization for ACS. Observation period lasted seven yr in median. Adjusted Cox-regression analysis was used for prediction of mortality. ROC curve analysis revealed that increasing concentrations of TMAO levels assessed at the time point of ACS significantly predicted the risk of CV mortality (c-index=0.78, < 0.001). The cut-off value of >4 μmol/L, labeled as high TMAO level (23% of study population), provided the greatest sum of sensitivity (85%) and specificity (80%) for the prediction of CV mortality and was associated with a positive predictive value of 16% and a negative predictive value of 99%. A multivariate Cox regression model revealed that high TMAO level was a strong and independent predictor of CV death (HR = 11.62, 95% CI: 2.26-59.67; = 0.003). High TMAO levels as compared with low TMAO levels were associated with the highest risk of CV death in a subpopulation of patients with diabetes mellitus (27.3 vs. 2.6%; = 0.004). Although increasing TMAO levels were also significantly associated with all-cause mortality, their estimates for diagnostic accuracy were low. High TMAO level is a strong and independent predictor of long-term CV mortality among patients presenting with ACS.
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http://dx.doi.org/10.3389/fcvm.2021.728724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585769PMC
October 2021

Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry: Pulmonary Endarterectomy First!

Authors:
Irene M Lang

Chest 2021 Nov;160(5):1599-1601

Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2021.07.004DOI Listing
November 2021

Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension.

Adv Ther 2021 Oct 30. Epub 2021 Oct 30.

University of Texas Southwestern Medical Center, Dallas, USA.

Introduction: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag.

Methods: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019.

Results: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively.

Conclusions: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen.

Trial Registration: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.
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http://dx.doi.org/10.1007/s12325-021-01898-1DOI Listing
October 2021

Dyspnea after pulmonary embolism: a nation-wide population-based case-control study.

Pulm Circ 2021 Oct-Dec;11(4):20458940211046831. Epub 2021 Sep 30.

Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden.

Dyspnea is common after a pulmonary embolism. Often, but not always, the dyspnea can be explained by pre-existing comorbidities, and only rarely by chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is probably the extreme manifestation of a far more common condition, called the post-pulmonary embolism syndrome. The purpose of this retrospective study was to investigate the prevalence and predictors of dyspnea among Swedish patients that survived a pulmonary embolism, compared to the general population. All Swedish patients diagnosed with an acute pulmonary embolism in 2005 (n = 5793) were identified via the Swedish National Patient Registry. Patients that lived until 2007 (n = 3510) were invited to participate. Of these, 2105 patients responded to a questionnaire about dyspnea and comorbidities. Data from the general population (n = 1905) were acquired from the multinational MONItoring of trends and determinants in CArdiovascular disease health survey, conducted in 2004. Patients with pulmonary embolism had substantially higher prevalences of both exertional dyspnea (53.0% vs. 17.3%, odds ratio (OR): 5.40, 95% confidence intervals (CI): 4.61-6.32) and wake-up dyspnea (12.0% vs. 1.7%, OR: 7.7, 95% CI: 5.28-11.23) compared to control subjects. These differences remained after adjustments and were most pronounced among younger patients. The increased risk for exertional dyspnea and wake-up dyspnea remained after propensity score matching (OR (95% CI): 4.11 (3.14-5.38) and 3.44 (1.95-6.06), respectively). This population-based, nation-wide study demonstrated that self-reported dyspnea was common among patients with previous pulmonary embolism. This finding suggested that a post-pulmonary embolism syndrome might be present, which merits further investigation.
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http://dx.doi.org/10.1177/20458940211046831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488523PMC
September 2021

Evaluation and management of patients with chronic thromboembolic pulmonary hypertension - consensus statement from the ISHLT.

J Heart Lung Transplant 2021 Nov 3;40(11):1301-1326. Epub 2021 Aug 3.

Pulmonary Hypertension and CTEPH Research Program, Temple Heart and Vascular Institute, Temple University, Lewis Katz School of Medicine, Philadelphia, Pennsylvania.

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence.
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http://dx.doi.org/10.1016/j.healun.2021.07.020DOI Listing
November 2021

Computer modeling to predict balloon pulmonary angioplasty success.

Am J Physiol Heart Circ Physiol 2021 09 20;321(3):H567-H568. Epub 2021 Aug 20.

Department of Internal Medicine II, Cardiology, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1152/ajpheart.00356.2021DOI Listing
September 2021

Current strategies for managing chronic thromboembolic pulmonary hypertension: results of the worldwide prospective CTEPH Registry.

ERJ Open Res 2021 Jul 16;7(3). Epub 2021 Aug 16.

Royal Papworth Hospital, Cambridge, UK.

Background: Pulmonary endarterectomy (PEA), pulmonary arterial hypertension (PAH) therapy and balloon pulmonary angioplasty (BPA) are currently accepted therapies for chronic thromboembolic pulmonary hypertension (CTEPH). This international CTEPH Registry identifies clinical characteristics of patients, diagnostic algorithms and treatment decisions in a global context.

Methods: 1010 newly diagnosed consecutive patients were included in the registry between February 2015 and September 2016. Diagnosis was confirmed by right heart catheterisation, ventilation-perfusion lung scan, computerised pulmonary angiography and/or invasive pulmonary angiography after at least 3 months on anticoagulation.

Results: Overall, 649 patients (64.3%) were considered for PEA, 193 (19.1%) for BPA, 20 (2.0%) for both PEA and BPA, and 148 (14.7%) for PAH therapy only. Reasons for PEA inoperability were technical inaccessibility (n=235), comorbidities (n=63) and patient refusal (n=44). In Europe and America and other countries (AAO), 72% of patients were deemed suitable for PEA, whereas in Japan, 70% of patients were offered BPA as first choice. Sex was evenly balanced, except in Japan where 75% of patients were female. A history of acute pulmonary embolism was reported for 65.6% of patients. At least one PAH therapy was initiated in 35.8% of patients (26.2% of PEA candidates, 54.5% of BPA candidates and 54.1% of those not eligible for either PEA or BPA). At the time of analysis, 39 patients (3.9%) had died of pulmonary hypertension-related causes (3.5% after PEA and 1.8% after BPA).

Conclusions: The registry revealed noticeable differences in patient characteristics (rates of pulmonary embolism and sex) and therapeutic approaches in Japan compared with Europe and AAO.
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http://dx.doi.org/10.1183/23120541.00850-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365143PMC
July 2021

Clinical Impact of Pre-Procedural Percutaneous Coronary Intervention in Low- and Intermediate-Risk Transcatheter Aortic Valve Replacement Recipients.

J Pers Med 2021 Jul 3;11(7). Epub 2021 Jul 3.

Department of Cardiology, Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.

The clinical relevance of as well as the optimal treatment strategy for coronary artery disease (CAD) in patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS) are unclear. Current data are conflicting, and mainly derived from high-risk patients. We aimed to investigate the feasibility and safety of complete revascularization prior to TAVR for severe AS in low- and intermediate-risk patients. We enrolled 449 patients at low (STS score < 4%) and intermediate risk (STS score 4-8%) undergoing TAVR for severe AS and investigated the influence of recent (<3 months) and prior (>3 months) complete revascularization on clinical outcome. Primary study endpoint was all-cause mortality. Overall, 58% of patients had no or non-significant CAD; 18% had a history of complete revascularization prior to TAVR and 24% had complete revascularization shortly before TAVR. Two-year all-cause mortality was not different between patients with recent revascularization prior to TAVR and patients with no or non-significant CAD (13.7% vs. 14.2%, = 0.905). Cox regression did not reveal an effect on all-cause mortality for recent revascularization. The present analysis reassures that percutaneous complete revascularization prior to TAVR procedures is neutral in terms of all-cause mortality in patients at low and intermediate surgical risk.
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http://dx.doi.org/10.3390/jpm11070633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304453PMC
July 2021

Mild Therapeutic Hypothermia Alters Hemostasis in ST Elevation Myocardial Infarction Patients.

Front Cardiovasc Med 2021 6;8:707367. Epub 2021 Jul 6.

Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.

Mild therapeutic hypothermia (MTH) is a concept to reduce infarct size and improve outcome after ST-segment elevation myocardial infarction (STEMI). In the STATIM trial, we investigated MTH as an additional therapy for STEMI patients. In the intention-to-treat set, 101 patients were included. No difference in primary and secondary endpoints measured by cardiac magnetic resonance imaging was found. Platelet activation and plasmatic coagulation are key in the pathophysiology of STEMI. In the present study, we investigated the effect of MTH on primary and secondary hemostasis in STEMI patients. Platelet function and morphology were assessed by routine blood count, aggregometry testing, and flow cytometry. Soluble platelet markers were determined by enzyme-linked immunosorbent assay (ELISA) testing. Plasmatic coagulation was measured throughout the study. Platelet count remained unchanged, irrespective of treatment, whereas platelet size decreased in both patient groups. Platelet aggregometry indicated increased platelet reactivity in the MTH group. Furthermore, higher adenosine diphosphate (ADP) plasma levels were found in MTH patients. Expression of glycoprotein IIb/IIIa was increased on platelets of STEMI patients treated with MTH. Lower patient temperatures correlated with longer clotting times and resulted in reduced pH. Lower pH values were positively correlated with longer clotting times. Present data indicate longer clotting times and higher platelet reactivity in STEMI patients treated with MTH. These changes did not correspond to clinical bleeding events or larger infarct size.
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http://dx.doi.org/10.3389/fcvm.2021.707367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290912PMC
July 2021

Efficacy and Safety of Percutaneous Pulmonary Artery Subtotal Occlusion and Chronic Total Occlusion Intervention in Chronic Thromboembolic Pulmonary Hypertension.

Circ Cardiovasc Interv 2021 08 16;14(8):e010243. Epub 2021 Jul 16.

Department of Internal Medicine II, Division of Cardiology (C.G., M.G., I.S., R.S.-K., N.S.-S., I.M.L.), Medical University of Vienna, Austria.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.010243DOI Listing
August 2021

Culprit site extracellular DNA and microvascular obstruction in ST-elevation myocardial infarction.

Cardiovasc Res 2021 Jun 26. Epub 2021 Jun 26.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Austria.

Aims: Extracellular chromatin and deoxyribonuclease (DNase) have been identified as important players of thrombosis, inflammation and homeostasis in a murine model. We previously demonstrated that activated neutrophils release neutrophil extracellular traps (NETs) at the culprit site in ST elevation myocardial infarction (STEMI), which significantly contribute to extracellular chromatin burden, and are associated with larger infarcts. To understand the correlation between neutrophil activation, extracellular chromatin and infarct size (IS), we investigated these parameters in a porcine myocardial infarction model, and at different time points and sites in a prospective STEMI trial with cardiac magnetic resonance (CMR) endpoints.

Methods And Results: In a prospective STEMI trial (NCT01777750), 101 STEMI patients were included and blood samples were obtained from first medical contact until 6 months after primary percutaneous coronary intervention (pPCI) including direct sampling from the culprit site. CMR was performed 4 ± 2 days and 6 months after pPCI. Neutrophil counts, markers of extracellular chromatin and inflammation were measured. Double-stranded DNA (dsDNA), citrullinated histone 3, nucleosomes, myeloperoxidase, neutrophil elastase and interleukin (IL)-6 were significantly increased, while DNase activity was significantly decreased at the culprit site in STEMI patients. High neutrophil counts and dsDNA levels at the culprit site correlated with high microvascular obstruction (MVO) and low ejection fraction (EF). High DNase activity at the culprit site correlated with low MVO and high EF.In correspondence, dsDNA correlated with IS in the porcine myocardial infarction model. In porcine infarcts, neutrophils and extracellular chromatin were detected in congested small arteries corresponding with MVO. Markers of neutrophil activation, extracellular chromatin, DNase activity and CMR measurements correlated with markers of systemic inflammation C-reactive protein and IL-6 in patients.

Conclusions: NETs and extracellular chromatin are important determinants of MVO in STEMI. Rapid degradation of extracellular chromatin by DNases appears to be crucial for microvascular patency and outcome.

Translational Perspective: We show that NETs and extracellular DNA obstruct microvessels in the porcine myocardial infarction model and is connected to increased infarct size. We are able to prove this observation in human STEMI patients. DNase is capable to counteract these effects. Extracellular DNA could be a new treatment target in STEMI.
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http://dx.doi.org/10.1093/cvr/cvab217DOI Listing
June 2021

Deoxyribonuclease is prognostic in patients undergoing transcatheter aortic valve replacement.

Eur J Clin Invest 2021 Nov 8;51(11):e13595. Epub 2021 Jun 8.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.

Degenerative aortic valve stenosis is an inflammatory process that resembles atherosclerosis. Neutrophils release their DNA upon activation and form neutrophil extracellular traps (NETs), which are present on degenerated aortic valves. NETs correlate with pressure gradients in severe aortic stenosis. Transcatheter aortic valve replacement (TAVR) is an established treatment option for aortic valve stenosis. Bioprosthetic valve deterioration promoted by inflammatory, fibrotic and thrombotic processes limits outcome. Deoxyribonuclease is a natural counter mechanism to degrade DNA in circulation. In the present observational study, we investigated plasma levels of double-stranded DNA, deoxyribonuclease activity and outcome after TAVR. 345 consecutive patients undergoing TAVR and 100 healthy reference controls were studied. Double-stranded DNA was measured by fluorescence assays in plasma obtained at baseline and after TAVR. Deoxyribonuclease activity was measured at baseline using single radial enzyme diffusion assays. Follow-up was performed at 12 months, and mean aortic pressure gradient and survival were evaluated. Receiver operating characteristic, Kaplan-Meier curves and Cox regression models were calculated. Baseline double-stranded DNA in plasma was significantly higher compared to healthy controls, was increased at 3 and 7 days after TAVR, and declined thereafter. Baseline deoxyribonuclease activity was decreased compared to healthy controls. Interestingly, low deoxyribonuclease activity correlated with higher C-reactive protein and higher mean transaortic gradient after 12 months. Finally, deoxyribonuclease activity was a strong independent predictor of outcome 12 months after TAVR. Deoxyribonuclease activity is a potential biomarker for risk stratification after TAVR. Pathomechanisms of bioprosthetic valve deterioration involving extracellular DNA and deoxyribonuclease merit investigation.
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http://dx.doi.org/10.1111/eci.13595DOI Listing
November 2021

Synthetic Fibrin-Derived Bβ Peptide Delays Thrombus Resolution in a Mouse Model.

Arterioscler Thromb Vasc Biol 2021 07 3;41(7):2168-2180. Epub 2021 Jun 3.

Division of Cardiology, Department of Internal Medicine II (S.C., S.S., I.M.L.), Medical University of Vienna, Austria.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316404DOI Listing
July 2021

Neutrophil Extracellular Traps as Prognostic Markers in COVID-19: A Welcome Piece to the Puzzle.

Arterioscler Thromb Vasc Biol 2021 02 27;41(2):995-998. Epub 2021 Jan 27.

Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Austria.

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http://dx.doi.org/10.1161/ATVBAHA.120.315633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837687PMC
February 2021

Deoxyribonuclease 1 Q222R single nucleotide polymorphism and long-term mortality after acute myocardial infarction.

Basic Res Cardiol 2021 04 23;116(1):29. Epub 2021 Apr 23.

Department of Cardiology, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Upon activation, neutrophils release neutrophil extracellular traps (NETs), which contribute to circulating DNA burden and thrombosis, including ST-segment elevation myocardial infarction (STEMI). Deoxyribonuclease (DNase) 1 degrades circulating DNA and NETs. Lower DNase activity correlates with NET burden and infarct size. The DNase 1 Q222R single nucleotide polymorphism (SNP), impairing DNase 1 function, is linked with myocardial infarction. We assessed whether the Q222R SNP is connected to increased NET burden in STEMI and influences long-term outcomes. We enrolled 711 STEMI patients undergoing primary percutaneous coronary intervention (pPCI), and 1422 controls. Genotyping was performed for DNase 1 Q222R SNP. DNase activity, double-stranded (ds)DNA and citrullinated histone H3 were determined in culprit site and peripheral plasma during pPCI. The association of the Q222R variant on cardiovascular and all-cause mortality was assessed by multivariable Cox regression adjusted for cardiovascular risk factors. Homozygous Q222R DNase 1 variant was present in 64 (9.0%) STEMI patients, at the same frequency as in controls. Patients homozygous for Q222R displayed less DNase activity and increased circulating DNA burden. In overall patients, median survival was 60 months. Homozygous Q222R variant was independently associated with cardiovascular and all-cause mortality after STEMI. dsDNA/DNase ratio independently predicted cardiovascular and all-cause mortality. These findings highlight that the Q222R DNase 1 SNP is associated with increased NET burden and decreased compensatory DNase activity, and may serve as an independent risk factor for poor outcome after STEMI.
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http://dx.doi.org/10.1007/s00395-021-00864-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064981PMC
April 2021

ELISA detection of MPO-DNA complexes in human plasma is error-prone and yields limited information on neutrophil extracellular traps formed in vivo.

PLoS One 2021 22;16(4):e0250265. Epub 2021 Apr 22.

Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.

Over the past years, neutrophil extracellular traps (NETs) were shown to contribute to states of acute and chronic inflammatory disease. They are composed of expelled chromatin and decorated by neutrophil-derived proteins. Therefore, the analysis of DNA complexes with myeloperoxidase (MPO) by ELISA has become an attractive tool to measure NET formation in in vitro and in vivo samples. When we used a published MPO-DNA ELISA protocol and included an isotype control for the anti-MPO coating antibody, we observed high assay specificity for in vitro prepared NET samples, whereas the specificity for in vivo plasma samples was low. In addition, the assay failed to detect in vitro generated MPO-DNA complexes when spiked into plasma. Therefore, we set out to improve the specificity of the MPO-DNA ELISA for plasma samples. We found that the use of Fab fragments or immunoglobulins from different species or reversal of the antibody pair led to either a high background or a low dynamic range of detection that did not improve the specificity for plasma samples. Also, the use of higher plasma dilutions or pre-clearing of plasma immunoglobulins were ineffective. Finally, we found that a commercial reagent designed to block human anti-mouse antibodies and multivalent substances increased the detection window between the MPO antibody and isotype control for highly diluted plasma. We applied this modified ELISA protocol to analyze MPO-DNA complexes in human blood samples of acute and chronic inflammatory conditions. While markers of neutrophil activation and NET formation such as MPO, elastase and citrullinated histone H3 correlated significantly, we observed no correlation with the levels of MPO-DNA complexes. Therefore, we conclude that ELISA measurements of MPO-DNA complexes in human plasma are highly questionable regarding specificity of NET detection. In general, plasma analyses by ELISA should more frequently include isotype controls for antibodies to demonstrate target specificity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250265PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062102PMC
October 2021

Relative risk of arterial and venous thromboembolism in persons with cancer vs. persons without cancer-a nationwide analysis.

Eur Heart J 2021 06;42(23):2299-2307

Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria.

Aims: An interrelation between cancer and thrombosis is known, but population-based studies on the risk of both arterial thromboembolism (ATE) and venous thromboembolism (VTE) have not been performed.

Methods And Results: International Classification of Disease 10th Revision (ICD-10) diagnosis codes of all publicly insured persons in Austria (0-90 years) were extracted from the Austrian Association of Social Security Providers dataset covering the years 2006-07 (n = 8 306 244). Patients with a history of cancer or active cancer were defined as having at least one ICD-10 'C' diagnosis code, and patients with ATE and/or VTE as having at least one of I21/I24 (myocardial infarction), I63/I64 (stroke), I74 (arterial embolism), and I26/I80/I82 (venous thromboembolism) diagnosis code. Among 158 675 people with cancer, 8559 (5.4%) had an ATE diagnosis code and 7244 (4.6%) a VTE diagnosis code. In contrast, among 8 147 569 people without cancer, 69 381 (0.9%) had an ATE diagnosis code and 29 307 (0.4%) a VTE diagnosis code. This corresponds to age-stratified random-effects relative risks (RR) of 6.88 [95% confidence interval (CI) 4.81-9.84] for ATE and 14.91 (95% CI 8.90-24.95) for VTE. ATE proportion was highest in patients with urinary tract malignancies (RR: 7.16 [6.74-7.61]) and lowest in patients with endocrine cancer (RR: 2.49 [2.00-3.10]). The corresponding VTE proportion was highest in cancer of the mesothelium/soft tissue (RR: 19.35 [17.44-21.47]) and lowest in oropharyngeal cancer (RR: 6.62 [5.61-7.81]).

Conclusion: The RR of both ATE and VTE are significantly higher in persons with cancer. Our population-level meta-data indicate a strong association between cancer, ATE and VTE, and support the concept of shared risk factors and pathobiology between these diseases.Relative risk of ATE and VTE in persons with a cancer diagnosis code versus persons without a cancer diagnosis code.
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http://dx.doi.org/10.1093/eurheartj/ehab171DOI Listing
June 2021

Chronic Thromboembolic Disease and Chronic Thromboembolic Pulmonary Hypertension.

Clin Chest Med 2021 03 12;42(1):81-90. Epub 2021 Jan 12.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria.

Chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic pulmonary vascular disease (CTED) are rare manifestations of venous thromboembolism. Presumably, CTEPH and CTED are variants of the same pathophysiological mechanism. CTEPH and CTED can be near-cured by pulmonary endarterectomy, balloon pulmonary angioplasty, and medical treatment with Riociguat or subcutaneous treprostinil, which are the approved drugs.
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http://dx.doi.org/10.1016/j.ccm.2020.11.014DOI Listing
March 2021

Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis.

Blood 2021 02;137(8):1104-1116

Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.

Acute pulmonary embolism generally resolves within 6 months. However, if the thrombus is infected, venous thrombi transform into fibrotic vascular obstructions leading to chronic deep vein thrombosis and/or chronic thromboembolic pulmonary hypertension (CTEPH), but precise mechanisms remain unclear. Neutrophils are crucial in sequestering pathogens; therefore, we investigated the role of neutrophil extracellular traps (NETs) in chronic thrombosis. Because chronic pulmonary thrombotic obstructions are biologically identical to chronic deep venous thrombi, the murine inferior vena cava ligation model was used to study the transformation of acute to chronic thrombus. Mice with staphylococcal infection presented with larger thrombi containing more neutrophils and NETs but less resolution. Targeting NETs with DNase1 diminished fibrosis and promoted thrombus resolution. For translational studies in humans, we focused on patients with CTEPH, a severe type of deep venous and pulmonary artery fibrotic obstruction after thrombosis. Neutrophils, markers of neutrophil activation, and NET formation were increased in CTEPH patients. NETs promoted the differentiation of monocytes to activated fibroblasts with the same cellular phenotype as fibroblasts from CTEPH vascular occlusions. RNA sequencing of fibroblasts isolated from thrombo-endarterectomy specimens and pulmonary artery biopsies revealed transforming growth factor-β (TGF-β) as the central regulator, a phenotype which was replicated in mice with fibroblast-specific TGF-β overactivity. Our findings uncover a role of neutrophil-mediated inflammation to enhance TGF-β signaling, which leads to fibrotic thrombus remodeling. Targeting thrombus NETs with DNases may serve as a new therapeutic concept to treat thrombosis and prevent its sequelae.
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http://dx.doi.org/10.1182/blood.2020005861DOI Listing
February 2021

Neutrophil Extracellular Traps in Atherosclerosis and Thrombosis.

Handb Exp Pharmacol 2020 Dec 1. Epub 2020 Dec 1.

Department of Cardiology, Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Despite effective therapeutic and preventive strategies, atherosclerosis and its complications still represent a substantial health burden. Leukocytes and inflammatory mechanisms are increasingly recognized as drivers of atherosclerosis. Neutrophil granulocytes within the circulation were recently shown to undergo neutrophil extracellular trap (NET) formation, linking innate immunity with acute complications of atherosclerosis. In this chapter, we summarize mechanisms of NET formation, evidence for their involvement in atherosclerosis and thrombosis, and potential therapeutic regimens specifically targeting NET components.
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http://dx.doi.org/10.1007/164_2020_409DOI Listing
December 2020

Balloon Pulmonary Angioplasty for Inoperable Chronic Thromboembolic Pulmonary Hypertension: First Experience at the Israeli National CTEPH Referral Center.

Isr Med Assoc J 2020 Dec;22(12):752-756

Department of Interventional Cardiology, Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, distinct pulmonary vascular disease caused by chronic obstruction of major pulmonary arteries, which can be cured by pulmonary endarterectomy. However, many CTEPH patients are not surgical candidates. Balloon pulmonary angioplasty (BPA) is an emerging technique used to treat inoperable CTEPH.

Objectives: To describe the first Israeli experience with BPA for inoperable CTEPH.

Methods: In 2017 we established a BPA program at our institution. We reviewed the outcomes to date of BPA in our center.

Results: Forty-seven BPA procedures were performed in five patients with inoperable CTEPH (4-17 procedures/patient). Mean pulmonary artery pressure improved in all patients (median decrease 17 mmHg, range 10-26 mmHg). Pulmonary vascular resistance also improved (median decrease 11 Woods Units/m2, range 8-16 Woods Units/m2). Cardiac output increased in 4 of 5 patients and decreased in one. Functional capacity improved from New York Heart Association (NYHA) III to II in four patients; one patient was NYHA II at baseline without change after BPA. Six-minute walking distance improved by a median of 97 meters. (range 21-197 meters). Hemodynamic and functional improvements were sustained at follow-up 5-11 months after the last BPA procedure. BPA enabled 2 of 3 patients treated with parenteral prostanoids to be switched to oral therapy. There were no major complications.

Conclusions: We successfully established BPA as a treatment for inoperable CTEPH in our center. BPA resulted in hemodynamic and clinical improvements that were sustained over time.
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December 2020

Neutrophil Extracellular Traps Induce MCP-1 at the Culprit Site in ST-Segment Elevation Myocardial Infarction.

Front Cell Dev Biol 2020 9;8:564169. Epub 2020 Nov 9.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.

Background: Leukocyte-mediated inflammation is crucial in ST-segment elevation myocardial infarction (STEMI). We recently observed that neutrophil extracellular traps (NETs) are increased at the culprit site, promoting activation and differentiation of fibrocytes, cells with mesenchymal and leukocytic properties. Fibrocyte migration is mediated by monocyte chemoattractant protein (MCP)-1 and C-C chemokine receptor type 2 (CCR2). We investigated the interplay between NETs, fibrocyte function, and MCP-1 in STEMI.

Methods: Culprit site and peripheral blood samples of STEMI patients were drawn during primary percutaneous coronary intervention. MCP-1 and the NET marker citrullinated histone H3 (citH3) were measured by ELISA while double-stranded DNA was stained with a fluorescent dye. The influence of MCP-1 on NET formation was assessed using isolated healthy donor neutrophils. Human coronary artery endothelial cells (hCAECs) were stimulated with isolated NETs, and MCP-1 gene expression was measured by ELISA and qPCR. CCR2 expression of culprit site and peripheral blood fibrocytes was characterized by flow cytometry. Healthy donor fibrocyte receptor expression and chemotaxis were investigated in response to stimulation with MCP-1 and NETs

Results: NETs and concentrations of MCP-1 were increased at the culprit site of 50 consecutive STEMI patients. NET stimulation of hCAECs induced transcription of ICAM-1, IL-6, and MCP-1, and secretion of MCP-1. MCP-1 promoted NET formation of healthy donor neutrophils . An increasing MCP-1 gradient correlated with fibrocyte accumulation at the culprit site. Locally increased MCP-1 levels were negatively correlated with CCR2 expression on fibrocytes. MCP-1 and NETs induced CCR2 downregulation on fibrocytes . NETs did not function as a chemotactic stimulus for fibrocytes or monocytes and could block migration in response to MCP-1 for both cell populations.

Conclusion: NETs function as signaling scaffolds at the culprit site of STEMI. NETs assist MCP-1 and ICAM-1 release from culprit site coronary artery endothelial cells. MCP-1 facilitates further NETosis. Monocytes enter the culprit site along an MCP-1 gradient, to transdifferentiate into fibrocytes in the presence of NETs.
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http://dx.doi.org/10.3389/fcell.2020.564169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680894PMC
November 2020

Comparison of Light Transmission Aggregometry With Impedance Aggregometry in Patients on Potent P2Y12 Inhibitors.

J Cardiovasc Pharmacol Ther 2021 05 27;26(3):260-268. Epub 2020 Oct 27.

Department of Internal Medicine II, 27271Medical University of Vienna, Vienna, Austria.

Since data on the agreement between light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) in patients on the more potent P2Y inhibitors are missing so far, we investigated if the evaluation of the responsiveness to therapy by LTA can be replaced by MEA in 160 acute coronary syndrome (ACS) patients on dual antiplatelet therapy with aspirin and prasugrel or ticagrelor (n = 80 each). Cut-off values for high on-treatment residual platelet reactivity (HRPR) in response to adenosine diphosphate (ADP) or arachidonic acid (AA) were defined according to previous studies showing an association of HRPR with the occurrence of adverse ischemic outcomes. ADP- inducible platelet aggregation was 33% and 37% ( = 0.07) by LTA and 19 AU and 20 AU ( = 0.38) by MEA in prasugrel- and ticagrelor-treated patients, respectively. AA- inducible platelet aggregation was 2% and 3% by LTA and 15 AU and 16 AU by MEA, (all ≥ 0.3) in patients on prasugrel and ticagrelor, respectively. By LTA, HRPR ADP and HRPR AA were seen in 5%/5% and in 4%/ 13% of patients receiving prasugrel- and ticagrelor, respectively. By MEA, HRPR ADP and HRPR AA were seen in 3%/ 25% and 0%/24% of prasugrel- and ticagrelor-treated patients, respectively. ADP-inducible platelet reactivity by MEA correlated significantly with LTA ADP in prasugrel-treated patients (r = 0.4, < 0.001), but not in those receiving ticagrelor (r = 0.09, = 0.45). AA-inducible platelet aggregation by LTA and MEA did not correlate in prasugrel- and ticagrelor-treated patients. Sensitivity/specificity of HRPR by MEA to detect HRPR by LTA were 25%/99% for MEA ADP and 100%/79% for MEA AA in prasugrel-treated patients, and 0%/100% for MEA ADP and 70%/83% for MEA AA in ticagrelor-treated patients. In conclusion, on-treatment residual ADP-inducible platelet reactivity by LTA and MEA shows a significant correlation in prasugrel- but not ticagrelor-treated patients. However, in both groups LTA and MEA revealed heterogeneous results regarding the classification of patients as responders or non-responders to P2Y inhibition.
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http://dx.doi.org/10.1177/1074248420968706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010888PMC
May 2021

Interleukin-6 level is a powerful predictor of long-term cardiovascular mortality in patients with acute coronary syndrome.

Vascul Pharmacol 2020 12 7;135:106806. Epub 2020 Oct 7.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria; Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CEPT), Medical University of Warsaw, Warsaw, Poland. Electronic address:

Background: The interleukin-6 (IL-6) pathway has a crucial role in the pathogenesis of atherosclerosis, the main cause of cardiovascular diseases. We aimed to characterize the predictive value of inflammatory biomarkers on long-term cardiovascular mortality in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).

Methods: This prospective observational study included 322 consecutive patients with ACS undergoing PCI. Blood-derived biomarkers IL-6 and high-sensitivity C-reactive protein (hsCRP) were assessed at the time point of ACS. Patients were followed-up for 6 years. Long-term cardiovascular mortality was our primary endpoint. Adjusted Cox-regression analysis was used for prediction of events.

Results: Elevated IL-6 values (≥3.3 pg/mL) emerged as an independent and the most powerful predictor for cardiovascular mortality: the ROC analysis showed that IL-6 was more accurate for cardiovascular mortality prediction as compared to hsCRP (IL-6: AUC = 0.72; 95%CI: 0.62-0.81; p = 0.009 vs hsCRP: AUC = 0.56; 95%CI: 0.41-0.72; p = 0.445). The positive predictive value of IL-6 for mortality was 9%, the negative predictive value 99%, sensitivity 94% and specificity 48%. The primary endpoint of long-term cardiovascular death occurred more frequently in patients with high vs low IL-6 (9.0% vs 0.5%, p = 0.001). The multivariate Cox regression analysis revealed that patients with high IL-6 (≥3.3 pg/mL) values were at 8.6-fold higher hazard to die than those with low IL-6 (<3.3 pg/mL) levels (adj. hazard ratio [HR] = 8.60, 95%CI: 1.07-69.32; p = 0.043).

Conclusion: In the setting of ACS, high IL-6 values are associated with substantial long-term cardiovascular mortality. Further, IL-6 performs as a superior predictor for cardiovascular death as compared to hsCRP.
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http://dx.doi.org/10.1016/j.vph.2020.106806DOI Listing
December 2020

Evolution of outcome and complications in TAVR: a meta-analysis of observational and randomized studies.

Sci Rep 2020 09 23;10(1):15568. Epub 2020 Sep 23.

Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Aim of the present analysis was to collect and pool all available data currently in the literature regarding outcomes and complications of all approved TAVR prosthesis and to assess the transition from first to next generation TAVR devices by directly comparing both in regard of procedure related complications. Transcatheter aortic valve replacement is a well established treatment modality in patients with severe aortic stenosis deemed to be inoperable or at unacceptable risk for open heart surgery. First generation prostheses were associated with a high rate of peri-procedural complications like paravalvular regurgitation, valve malpositioning, vascular complications and conduction disorders. Refinement of the available devices incorporate features to address the limitations of the first-generation devices. A PRISMA checklist-guided systematic review and meta-analysis of prospective observational studies, national and device specific registries or randomized clinical trials was conducted. Studies were identified by searching PUBMED, SCOPUS, Cochrane Central Register of Controlled Trials and LILACs from January 2000 to October 2017. We extracted and pooled data on both mortality and complications from 273 studies for twelve different valves prostheses in a total of 68,193 patients. In second generation prostheses as compared to first generation devices, we observed a significant decrease in mortality (1.47 ± 1.73% vs. 5.41 ± 4.35%; p < 0.001), paravalvular regurgitation (1.75 ± 2.43vs. 12.39 ± 9.38, p < 0.001) and MACE. TAVR with contemporary next generation devices has led to an impressive improvement in TAVR safety driven by refined case selection, improved procedural techniques and increased site experience.
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http://dx.doi.org/10.1038/s41598-020-72453-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511292PMC
September 2020

Nonculprit Lesion Severity and Outcome of Revascularization in Patients With STEMI and Multivessel Coronary Disease.

J Am Coll Cardiol 2020 09;76(11):1277-1286

Population Health Research Institute, Hamilton, Ontario, Canada; McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada. Electronic address: https://twitter.com/PHRIresearch.

Background: In the COMPLETE (Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI) trial, angiography-guided percutaneous coronary intervention (PCI) of nonculprit lesions with the aim of complete revascularization reduced major cardiovascular (CV) events in patients with ST-segment elevation myocardial infarction (MI) and multivessel coronary artery disease.

Objectives: The purpose of this study was to determine the effect of nonculprit-lesion stenosis severity measured by quantitative coronary angiography (QCA) on the benefit of complete revascularization.

Methods: Among 4,041 patients randomized in the COMPLETE trial, nonculprit lesion stenosis severity was measured using QCA in the angiographic core laboratory in 3,851 patients with 5,355 nonculprit lesions. In pre-specified analyses, the treatment effect in patients with QCA stenosis ≥60% versus <60% on the first coprimary outcome of CV death or new MI and the second co-primary outcome of CV death, new MI, or ischemia-driven revascularization was determined.

Results: The first coprimary outcome was reduced with complete revascularization in the 2,479 patients with QCA stenosis ≥60% (2.5%/year vs. 4.2%/year; hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.47 to 0.79), but not in the 1,372 patients with QCA stenosis <60% (3.0%/year vs. 2.9%/year; HR: 1.04; 95% CI: 0.72 to 1.50; interaction p = 0.02). The second coprimary outcome was reduced in patients with QCA stenosis ≥60% (2.9%/year vs. 6.9%/year; HR: 0.43; 95% CI: 0.34 to 0.54) to a greater extent than patients with QCA stenosis <60% (3.3%/year vs. 5.2%/year; HR: 0.65; 95% CI: 0.47 to 0.89; interaction p = 0.04).

Conclusions: Among patients with ST-segment elevation MI and multivessel coronary artery disease, complete revascularization reduced major CV outcomes to a greater extent in patients with stenosis severity of ≥60% compared with <60%, as determined by quantitative coronary angiography.
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http://dx.doi.org/10.1016/j.jacc.2020.07.034DOI Listing
September 2020

Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension.

Basic Res Cardiol 2020 09 3;115(6):58. Epub 2020 Sep 3.

Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Pulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the kinase insert domain protein receptor (kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr) and held them in an environmental chamber with 10% FiO or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3 endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of Kdr. Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.
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http://dx.doi.org/10.1007/s00395-020-0811-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471204PMC
September 2020
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