Publications by authors named "Mareike Lankeit"

100 Publications

[Pulmonary Embolism].

Pneumologie 2021 Oct 18;75(10):800-818. Epub 2021 Oct 18.

Pulmonary embolism (PE) is a life-threatening disease and the third most frequent cardiovascular cause of death after stroke and myocardial infarction. The annual incidence is increasing (in Germany from 85 cases per 100000 population in the year 2005 to 109 cases per 100000 population in the year 2015). The individual risk for PE-related complications and death increases with the number of comorbidities and severity of right ventricular dysfunction. Using clinical, laboratory and imaging parameters, patients with PE can be stratified to four risk classes (high, intermediate-high, intermediate-low and low risk). This risk stratification has concrete therapeutic consequences ranging from out-of-hospital treatment of low-risk patients to reperfusion treatment of (intermediate)-high-risk patients. For haemodynamically unstable patients, treatment decision should preferably be made in interdisciplinary "Pulmonary Embolism Response Teams" (PERT). Due to their comparable efficacy and preferable safety profile compared to vitamin-K antagonists (VKAs), non-vitamin K-dependent oral anticoagulants (NOACs) are increasingly considered the treatment of choice for initial and prolonged anticoagulation of patients with pulmonary embolism. Use of low molecular weight heparins (LMWHs) is recommended for PE patients with cancer; however, recent studies indicate that treatment with factor Xa-inhibitors may be effective and safe (in patients without gastrointestinal cancer). Only prolonged anticoagulation (in reduced dosage) will ensure reduction of VTE recurrence and should thus be considered for all patients with unprovoked events.
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http://dx.doi.org/10.1055/a-1029-9937DOI Listing
October 2021

Reduced-dose intravenous thrombolysis for acute intermediate high-risk pulmonary embolism: Rationale and design of the PEITHO-3 trial.

Thromb Haemost 2021 Sep 24. Epub 2021 Sep 24.

Hopital Europeen Georges Pompidou, Paris, France.

Intermediate high-risk pulmonary embolism (PE) is characterised by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent haemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of haemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International Trial (PEITHO)-3 study (EudraCT 2018-000816-96) is a randomised, placebo-controlled, double-blind, multicentre, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate high-risk PE will also fulfil at least one clinical criterion of severity: systolic blood pressure ≤ 110 mmHg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, haemodynamic decompensation or PE recurrence within 30 days of randomisation. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, haemodynamic decompensation, or stroke within 30 days; dyspnoea, functional limitation or RV dysfunction at 6 months and 2 years; and utilisation of healthcare resources within 30 days and 2 years. The study is planned to enrol 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.
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http://dx.doi.org/10.1055/a-1653-4699DOI Listing
September 2021

Impact of Systemic Atherosclerosis on Clinical Characteristics and Short-term Outcomes in Patients with Deep Venous Thrombosis or Thrombophlebitis.

Am J Med Sci 2021 Sep 19. Epub 2021 Sep 19.

Department of Cardiology, Cardiology I, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany.

Background: Venous thromboembolism (VTE) and atherosclerosis are accompanied by substantial cardiovascular mortality; links between both disease entities were reported. We aimed to investigate the impact of systemic atherosclerosis on adverse outcomes in patients with deep venous thrombosis or thrombophlebitis (DVT) and to identify differences in DVT patients with and without systemic atherosclerosis.

Methods: The German nationwide inpatient sample was used for this analysis. Patients admitted for DVT were included in this study and stratified by systemic atherosclerosis (composite of coronary artery disease, myocardial infarction, ischemic stroke, and/or atherosclerotic arterial diseases). We compared DVT patients with (DVT+Athero) and without (DVT-Athero) systemic atherosclerosis and analysed the impact of systemic atherosclerosis on adverse outcomes.

Results: Overall, 489,679 patients with DVT (55.7% females) were included in this analysis. Among these, 53,309 (10.9%) were coded with concomitant systemic atherosclerosis with age-dependent incline. Concomitant PE (4.1% vs.3.8%, P=0.001) was more frequently in DVT-Athero and risk for PE in DVT patients was independently associated with absence of systemic atherosclerosis (OR 0.87 [95%CI 0.83-0.91], P<0.001). In-hospital mortality (3.4% vs.1.4%, P<0.001) and adverse in-hospital events (2.2% vs.0.8%,P<0.001) were more prevalent in DVT+Athero compared to DVT-Athero; both, in-hospital mortality (OR 1.52 [95%CI 1.41-1.63], P<0.001) and adverse in-hospital events (OR 1.49 [95%CI 1.40-1.58], P<0.001) were affected independently of sex, age and comorbidities by systemic atherosclerosis.

Conclusions: Systemic atherosclerosis in DVT patients was accompanied by poorer outcomes. Systemic atherosclerosis was associated with higher bleeding rate and with isolated DVT (without concomitant PE).
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http://dx.doi.org/10.1016/j.amjms.2021.09.002DOI Listing
September 2021

Temporal trends and predictors of inhospital death in patients hospitalised for heart failure in Germany.

Eur J Prev Cardiol 2021 Aug;28(9):990-997

Department of Cardiology, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Germany.

Aims: We investigated trends in incidence, case fatality rate, patient characteristics and adverse inhospital events of patients hospitalised for heart failure in Germany.

Methods And Results: The German nationwide inpatient sample (2005-2016) was used for this analysis. Patients hospitalised due to heart failure were selected for analysis. Temporal trends in the incidence of hospitalisations, case fatality rate and treatments were analysed and predictors of inhospital death were identified. The analysis comprised a total number of 4,539,140 hospitalisations (52.0% women, 81.0% aged ≥70 years) due to heart failure. Although hospitalisations increased from 381 (2005) to 539 per 100,000 population (2016) (β estimate 0.06, 95% confidence interval (CI) 0.06 to 0.07, P < 0.001) in parallel with median age and prevalence of comorbidities, the inhospital case fatality rate decreased from 11.1% to 8.1% (β estimate -0.36, 95% CI -0.37 to -0.35, P < 0.001) and the rate of major adverse cardiovascular and cerebrovascular events (β estimate -0.24, 95% CI -0.25 to -0.23, P < 0.001) decreased from 12.7% to 10.3%. Age 70 years and older (odds ratio (OR) 2.60, 95% CI 2.57 to 2.63, P < 0.001) and cancer (OR 1.93, 95% CI 1.91 to 1.96, P < 0.001) were independent predictors of inhospital death.

Conclusion: Hospitalisations for heart failure increased in Germany from 2005 to 2016, whereas the major adverse cardiovascular and cerebrovascular event rate and inhospital case fatality rate decreased during this period despite higher patient age and increasing prevalence of comorbidities.
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http://dx.doi.org/10.1177/2047487320936020DOI Listing
August 2021

Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial.

Lancet Haematol 2021 Sep 4;8(9):e627-e636. Epub 2021 Aug 4.

Internal and Subintensive Medicine Department, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.

Background: Current guidelines recommend a risk-adjusted treatment strategy for the management of acute pulmonary embolism. This is a particular patient category for whom optimal treatment (anticoagulant treatment, reperfusion strategies, and duration of hospitalisation) is currently unknown. We investigated whether treatment of acute intermediate-risk pulmonary embolism with parenteral anticoagulation for a short period of 72 h, followed by a switch to a direct oral anticoagulant (dabigatran), is effective and safe.

Methods: We did a multinational, multicentre, single-arm, phase 4 trial at 42 hospitals in Austria, Belgium, France, Germany, Italy, Netherlands, Romania, Slovenia, and Spain. Adult patients (aged ≥18 years) with symptomatic intermediate-risk pulmonary embolism, with or without deep-vein thrombosis, were enrolled. Patients received parenteral low-molecular-weight or unfractionated heparin for 72 h after diagnosis of pulmonary embolism before switching to oral dabigatran 150 mg twice per day following a standard clinical assessment. The primary outcome was recurrent symptomatic venous thromboembolism or pulmonary embolism-related death within 6 months. The primary and safety outcomes were assessed in the intention-to-treat population. The study was terminated early, as advised by the data safety and monitoring board, following sample size adaptation after the predefined interim analysis on Dec 18, 2018. This trial is registered with the EU Clinical Trials Register (EudraCT 2015-001830-12) and ClinicalTrials.gov (NCT02596555).

Findings: Between Jan 1, 2016, and July 31, 2019, 1418 patients with pulmonary embolism were screened, of whom 402 were enrolled and were included in the intention-to-treat analysis (median age was 69·5 years [IQR 60·0-78·0); 192 [48%] were women and 210 [52%] were men). Median follow-up was 217 days (IQR 210-224) and 370 (92%) patients adhered to the protocol. The primary outcome occurred in seven (2% [upper bound of right-sided 95% CI 3]; p<0·0001 for rejecting the null hypothesis) patients, with all events occurring in those with intermediate-high-risk pulmonary embolism (seven [3%; upper bound of right-sided 95% CI 5] of 283). At 6 months, 11 (3% [95% CI 1-5]) of 402 patients had at least one major bleeding event and 16 (4% [2-6]) had at least one clinically relevant non-major bleeding event; the only fatal haemorrhage occurred in one (<1%) patient before the switch to dabigatran.

Interpretation: A strategy of early switch from heparin to dabigatran following standard clinical assessment was effective and safe in patients with intermediate-risk pulmonary embolism. Our results can help to refine guideline recommendations for the initial treatment of acute intermediate-risk pulmonary embolism, optimising the use of resources and avoiding extended hospitalisation.

Funding: German Federal Ministry of Education and Research, University Medical Center Mainz, and Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S2352-3026(21)00203-9DOI Listing
September 2021

Outcome of patients with different clinical presentations of high-risk pulmonary embolism.

Eur Heart J Acute Cardiovasc Care 2021 Oct;10(7):787-796

German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Germany.

Aims: The 2019 European Society of Cardiology (ESC) guidelines provide a revised definition of high-risk pulmonary embolism (PE) encompassing three clinical presentations: Cardiac arrest, obstructive shock, and persistent hypotension. This study investigated the prognostic implications of this new definition.

Methods And Results: Data from 784 consecutive PE patients prospectively enrolled in a single-centre registry were analysed. Study outcomes include an in-hospital adverse outcome (PE-related death or cardiopulmonary resuscitation) and in-hospital all-cause mortality. Overall, 86 patients (11.0%) presented with high-risk PE and more often had an adverse outcome (43.0%) compared to intermediate-high-risk patients (6.1%; P < 0.001). Patients with cardiac arrest had the highest rate of an in-hospital adverse outcome (78.4%) and mortality (59.5%; both P < 0.001 compared to intermediate-high-risk patients). Obstructive shock and persistent hypotension had similar rates of adverse outcomes (15.8% and 18.2%, respectively; P = 0.46), but the only obstructive shock was associated with an increased all-cause mortality risk. Use of an optimised venous lactate cut-off value (3.8 mmol/L) to diagnose obstructive shock allowed differentiation of adverse outcome risk between patients with shock (21.4%) and persistent hypotension (9.5%), resulting in a net reclassification improvement (0.24 ± 0.08; P = 0.002).

Conclusion: The revised ESC 2019 guidelines definition of high-risk PE stratifies subgroups at different risk of in-hospital adverse outcomes and all-cause mortality. Risk prediction can be improved by using an optimised venous lactate cut-off value to diagnose obstructive shock, which might help to better assess the risk-to-benefit ratio of systemic thrombolysis in different subgroups of high-risk patients.
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http://dx.doi.org/10.1093/ehjacc/zuab038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483764PMC
October 2021

Prognostic value of right atrial dilation in patients with pulmonary embolism.

ERJ Open Res 2021 Apr 24;7(2). Epub 2021 May 24.

Dept of Internal Medicine and Cardiology, Charité - University Medicine Berlin, Berlin, Germany.

Aims: Right atrial (RA) dilation and stretch provide prognostic information in patients with cardiovascular diseases. We investigated the prevalence, confounding factors and prognostic relevance of RA dilation in patients with pulmonary embolism (PE).

Methods: Overall, 609 PE patients were consecutively included in a prospective single-centre registry between September 2008 and August 2017. Volumetric measurements of heart chambers were performed on routine non-electrocardiographic-gated computed tomography and plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) measured on admission. An in-hospital adverse outcome was defined as PE-related death, cardiopulmonary resuscitation, mechanical ventilation or catecholamine administration.

Results: Patients with an adverse outcome (11.2%) had larger RA volumes (median 120 (interquartile range 84-152) 102 (78-134) mL; p=0.013), RA/left atrial (LA) volume ratios (1.7 (1.2-2.4) 1.3 (1.1-1.7); p<0.001) and MR-proANP levels (282 (157-481) 129 (64-238) pmol·L; p<0.001) compared to patients with a favourable outcome. Overall, 499 patients (81.9%) had a RA/LA volume ratio ≥1.0 and a calculated cut-off value of 1.8 (area under the curve 0.64, 95% CI 0.56-0.71) predicted an adverse outcome, both in unselected (OR 3.1, 95% CI 1.9-5.2) and normotensive patients (OR 2.7, 95% CI 1.3-5.6). MR-proANP ≥120 pmol·L was identified as an independent predictor of an adverse outcome, both in unselected (OR 4.6, 95% CI 2.3-9.3) and normotensive patients (OR 5.1, 95% CI 1.5-17.6).

Conclusions: RA dilation is a frequent finding in patients with PE. However, the prognostic performance of RA dilation appears inferior compared to established risk stratification markers. MR-proANP predicted an in-hospital adverse outcome, both in unselected and normotensive PE patients, integrating different prognostic relevant information from comorbidities.
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http://dx.doi.org/10.1183/23120541.00414-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141828PMC
April 2021

Time trends of pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

Pulm Circ 2021 Apr-Jun;11(2):20458940211008069. Epub 2021 Apr 28.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.

Chronic thromboembolic pulmonary hypertension is considered as a rare but severe complication after acute pulmonary embolism and is potentially curable by pulmonary endarterectomy. We aimed to evaluate, over an 11-year period, time trends of in-hospital outcomes of pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension patients and to investigate predictors of the in-hospital course. We analyzed data on the characteristics, comorbidities, treatments, and in-hospital outcomes for all chronic thromboembolic pulmonary hypertension patients treated with pulmonary endarterectomy in the German nationwide inpatient sample between 2006 and 2016. Overall, 1398 inpatients were included. Annual number of pulmonary endarterectomy increased from 67 in 2006 to 194 in 2016 ( < 0.001), in parallel with a significant decrease of in-hospital mortality (10.9% in 2008 to 1.5% in 2016;  < 0.001). Patients' characteristics shifted slightly toward older age and higher prevalence of chronic renal insufficiency and obesity over time, whereas duration of hospital stay decreased over time. Independent predictors of in-hospital mortality were age (OR 1.03 (95%CI: 1.01-1.05);  = 0.001), right heart failure (2.55 (1.37-4.76);  = 0.003), in-hospital complications such as ischemic stroke (6.87 (1.06-44.70);  = 0.044) and bleeding events like hemopneumothorax (24.93 (6.18-100.57);  < 0.001). Annual pulmonary endarterectomy volumes per center below 10 annual procedures were associated with higher rates of adverse in-hospital outcomes. Annual numbers of chronic thromboembolic pulmonary hypertension patients treated with pulmonary endarterectomy increased markedly in Germany between 2006 and 2016, in parallel with a decrease of in-hospital mortality. Our findings suggest that perioperative management of pulmonary endarterectomy, institutional experience, and patient selection is crucial and has improved over time.
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http://dx.doi.org/10.1177/20458940211008069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108078PMC
April 2021

Role of angiopoietin-2 in venous thrombus resolution and chronic thromboembolic disease.

Eur Respir J 2021 May 13. Epub 2021 May 13.

Center for Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany

Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown.ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute PE (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells.Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were also elevated in patients with PE and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and TGF-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels.Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from PE to CTEPH.
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http://dx.doi.org/10.1183/13993003.04196-2020DOI Listing
May 2021

In-hospital outcomes of catheter-directed thrombolysis in patients with pulmonary embolism.

Eur Heart J Acute Cardiovasc Care 2021 May;10(3):258-264

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz (Johannes Gutenberg University Mainz), Langenbeckstrasse 1, 55131 Mainz, Germany.

Aims: Catheter-directed treatment of acute pulmonary embolism (PE) is technically advancing. Recent guidelines acknowledge this treatment option for patients with overt or imminent haemodynamic decompensation, particularly when systemic thrombolysis is contraindicated. We investigated patients with PE who underwent catheter-directed thrombolysis (CDT) in the German nationwide inpatient cohort.

Methods And Results: Data from hospitalizations with PE (International Classification of Disease code I26) between 2005 and 2016 were collected by the Federal Office of Statistics in Germany. Patients with PE who underwent CDT (OPS 8-838.60 or OPS code 8-83b.j) were compared with patients receiving systemic thrombolysis (OPS code 8-020.8), and those without thrombolytic or other reperfusion treatment. The analysis was not prespecified; therefore, our findings can only be considered to be hypothesis generating. We analysed data from 978 094 hospitalized patients with PE. Of these, 41 903 (4.3%) patients received thrombolytic treatment [systemic thrombolysis in 4.2%, CDT in 0.1% (1175 patients)]. Among patients with shock, CDT was associated with lower in-hospital mortality compared to systemic thrombolysis [odds ratios (OR) 0.30 (95% 0.14-0.67); P = 0.003]. Intracranial bleeding occurred in 14 (1.2%) patients who received CDT. Among haemodynamically stable patients with right ventricular dysfunction (intermediate-risk PE), CDT also was associated with a lower risk of in-hospital mortality compared to systemic thrombolysis {OR 0.55 [95% confidence interval (CI) 0.40-0.75]; P < 0.001} or no thrombolytic treatment [0.45 (95% CI 0.33-0.62); P < 0.001].

Conclusion: In the German nationwide inpatient cohort, based on administrative data, CDT was associated with lower in-hospital mortality rates compared to systemic thrombolysis, but the overall rate of intracranial bleeding in patients who received CDT was not negligible. Prospective controlled data are urgently needed to determine the true value of this treatment option in acute PE.
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http://dx.doi.org/10.1093/ehjacc/zuaa026DOI Listing
May 2021

Venous lactate improves the prediction of in-hospital adverse outcomes in normotensive pulmonary embolism.

Eur J Intern Med 2021 04 6;86:25-31. Epub 2021 Feb 6.

German Center for Cardiovascular Research (DZHK), Partner site Berlin, Germany; Clinic of Cardiology and Pneumology, University Medical Center Göttingen, Germany; Department of Internal Medicine and Cardiology, Campus Virchow Klinikum (CVK), Charité - University Medicine Berlin, Germany; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Germany. Electronic address:

Background: Arterial lactate is an established risk marker in patients with pulmonary embolism (PE). However, its clinical applicability is limited by the need of an arterial puncture. In contrast, venous lactate can easily be measured from blood samples obtained via routine peripheral venepuncture.

Methods: We investigated the prognostic value of venous lactate with regard to in-hospital adverse outcomes and mortality in 419 consecutive PE patients enrolled in a single-center registry between 09/2008 and 09/2017.

Results: An optimised venous lactate cut-off value of 3.3 mmol/l predicted both, in-hospital adverse outcome (OR 11.0 [95% CI 4.6-26.3]) and all-cause mortality (OR 3.8 [95%CI 1.3-11.3]). The established cut-off value for arterial lactate (2.0 mmol/l) and the upper limit of normal for venous lactate (2.3 mmol/l) had lower prognostic value for adverse outcomes (OR 3.6 [95% CI 1.5-8.7] and 5.7 [95% CI 2.4-13.6], respectively) and did not predict mortality. If added to the 2019 European Society of Cardiology (ESC) algorithm, venous lactate <2.3 mmol/l was associated with a high negative predictive value (0.99 [95% CI 0.97-1.00]) for adverse outcomes in intermediate-low-risk patients, whereas levels ≥3.3 mmol/l predicted adverse outcomes in the intermediate-high-risk group (OR 5.2 [95% CI 1.8-15.0]).

Conclusion: Venous lactate above the upper limit of normal was associated with increased risk for adverse outcomes and an optimised cut-off value of 3.3 mmol/l predicted adverse outcome and mortality. Adding venous lactate to the 2019 ESC algorithm may improve risk stratification. Importantly, the established cut-off value for arterial lactate has limited specificity in venous samples and should not be used.
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http://dx.doi.org/10.1016/j.ejim.2021.01.021DOI Listing
April 2021

Quality of Life 3 and 12 Months Following Acute Pulmonary Embolism: Analysis From a Prospective Multicenter Cohort Study.

Chest 2021 06 3;159(6):2428-2438. Epub 2021 Feb 3.

Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece. Electronic address:

Background: Few data are available on the long-term course and predictors of quality of life (QoL) following acute pulmonary embolism (PE).

Research Question: What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months following an acute PE?

Study Design And Methods: The Follow-up after Acute Pulmonary Embolism (FOCUS) study prospectively followed up consecutive adult patients with objectively diagnosed PE. Patients were considered for study who completed the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire at predefined visits 3 and 12 months following PE. The course of disease-specific QoL as assessed using the PEmb-QoL and the impact of baseline characteristics using multivariable mixed effects linear regression were studied; also assessed was the course of generic QoL as evaluated by using the EuroQoL Group 5-Dimension 5-Level utility index and the EuroQoL Visual Analog Scale.

Results: In 620 patients (44% women; median age, 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease in the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI, -3.2 to -5.5). Female sex, cardiopulmonary disease, and higher BMI were associated with worse QoL at both 3 and 12 months. Over time, the association with BMI became weaker, whereas older age and previous VTE were associated with worsening QoL. Generic QoL also improved: the mean ± SD EuroQoL Group 5-Dimension 5-Level utility index increased from 0.85 ± 0.22 to 0.87 ± 0.20 and the visual analog scale from 72.9 ± 18.8 to 74.4 ± 19.1.

Interpretation: In a large cohort of survivors of acute PE, the change of QoL was quantified between months 3 and 12 following diagnosis, and factors independently associated with lower QoL and slower recovery of QoL were identified. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management.

Clinical Trial Registration: German Clinical Trials Registry (Deutsches Register Klinischer Studien: www.drks.de); No.: DRKS00005939.
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http://dx.doi.org/10.1016/j.chest.2021.01.071DOI Listing
June 2021

High-sensitivity troponin I for risk stratification in normotensive pulmonary embolism.

ERJ Open Res 2020 Oct 21;6(4). Epub 2020 Dec 21.

German Center for Cardiovascular Research (DZHK), partner site Berlin, Germany.

While numerous studies have confirmed the prognostic role of high-sensitivity troponin T (hsTnT) in pulmonary embolism (PE), high-sensitivity troponin I (hsTnI) is inappropriately studied. This study aimed to investigate the prognostic relevance of hsTnI in normotensive PE, establish the optimal cut-off value for risk stratification and to compare the prognostic performances of hsTnI and hsTnT. Based on data from 459 consecutive PE patients enrolled in a single-centre registry, receiver operating characteristic analysis was used to identify an optimal hsTnI cut-off value for prediction of in-hospital adverse outcomes (PE-related death, cardiopulmonary resuscitation or vasopressor treatment) and all-cause mortality. Patients who suffered an in-hospital adverse outcome (4.8%) had higher hsTnI concentrations compared with those with a favourable clinical course (57 (interquartile range (IQR) 22-197) 15 (IQR 10-86) pg·mL, p=0.03). A hsTnI cut-off value of 16 ng·mL provided optimal prognostic performance and predicted in-hospital adverse outcomes (OR 6.5, 95% CI 1.9-22.4) and all-cause mortality (OR 3.7, 95% CI 1.0-13.3). Between female and male patients, no relevant differences in hsTnI concentrations (17 (IQR 10-97) 17 (IQR 10-92) pg·mL, p=0.79) or optimised cut-off values were observed. Risk stratification according to the 2019 European Society of Cardiology algorithm revealed no differences if calculated based on either hsTnI or hsTnT (p=0.68). Our findings confirm the prognostic role of hsTnI in normotensive PE. HsTnI concentrations >16 pg·mL predicted in-hospital adverse outcome and all-cause mortality; sex-specific cut-off values do not seem necessary. Importantly, our results suggest that hsTnI and hsTnT can be used interchangeably for risk stratification.
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http://dx.doi.org/10.1183/23120541.00625-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792860PMC
October 2020

Mid-regional pro-atrial natriuretic peptide and copeptin as indicators of disease severity and therapy response in CTEPH.

ERJ Open Res 2020 Oct 2;6(4). Epub 2020 Nov 2.

Kerckhoff Heart and Thorax Center, Dept of Cardiology, Bad Nauheim, Germany.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) leads to right heart failure. Pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) restore pulmonary haemodynamics and allow cardiac recovery. This study examined the relationship of copeptin and mid-regional pro-atrial natriuretic peptide (MR-proANP) levels to disease severity and therapy response.

Methods: This observational cohort study included 125 patients (55 PEA/70 BPA) who underwent treatment and completed a 6-/12-month follow-up. Biomarkers, measured at baseline, prior to every BPA and at follow-up, were compared to 1) severe disease at baseline (right atrial pressure (RAP) ≥8 mmHg and cardiac index ≤2.4 L·min·m) and 2) optimal therapy response (no persistent pulmonary hypertension combined with a normalised RAP (mean PAP ≤25 mmHg, pulmonary vascular resistance (PVR) ≤3 WU and RAP ≤6 mmHg) or a reduction in mean PAP ≥25%, PVR ≥35% and RAP ≥25%).

Results: Severely diseased patients had higher levels of MR-proANP (320 (246-527) pmol·L 133 (82-215) pmol·L; p=0.001) and copeptin (12.7 (7.3-20.6) pmol·L 6.8 (4.4-12.8) pmol·L; p=0.015) at baseline than the rest of the cohort. At baseline, MR-proANP (area under the curve (AUC) 0.91; cut-off value 227 pmol·L; OR 56, 95% CI 6.9-454.3) and copeptin (AUC 0.70; cut-off value 10.9 pmol·L; OR 1.5, 95% CI 1.2-1.9) identified severely diseased patients. After PEA/BPA, levels of MR-proANP (99 (58-145) pmol·L; p<0.001) and copeptin (6.3 (3.7-12.6) pmol·L; p=0.009) decreased and indicated optimal therapy response (MR-proANP <123 pmol·L (AUC 0.70) and copeptin <10.1 pmol·L (AUC 0.58)).

Conclusion: MR-proANP and copeptin levels are affected in CTEPH and decrease after therapy. MR-proANP identifies a severe disease status and optimal therapy response.
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http://dx.doi.org/10.1183/23120541.00356-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682678PMC
October 2020

Impact of pulmonary embolism on in-hospital mortality of patients with ischemic stroke.

J Neurol Sci 2020 Dec 9;419:117174. Epub 2020 Oct 9.

Department of Cardiology, Cardiology I, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany.

Background: Pulmonary embolism (PE) is a frequent complication in immobile stroke patients and an important cause of death in stroke patients. We aimed to investigate predictors of PE and the impact of PE on survival of ischemic stroke patients.

Methods: Patients were selected by screening the German nationwide inpatient sample (2005-2017) for ischemic stroke (ICD-code I63) and stratified for occurrence of PE (ICD-code I26). Impact of PE on mortality and predictors for PE in ischemic stroke patients were analysed.

Results: Overall, 2,914,546 patients were hospitalized due to ischemic stroke (50.5% females; 69.3% aged ≥70 years) in Germany 2005-2017. Among these, 0.4% had PE and 7.2% died during hospitalization. In-hospital mortality rate of ischemic stroke patients with PE was substantially higher compared to those patients without PE (28.4% vs. 7.1%, P < 0.001). PE was strongly associated with in-hospital death (OR 5.786, 95%CI 5.515-6.070, P < 0.001). Important predictors of PE were cancer (OR 3.165, 95%CI 2.969-3.374, P < 0.001), coagulation abnormalities (OR 2.672, 95CI 2.481-2.878, P < 0.001), heart failure (OR 1.553, 95%CI 1.472-1.639, P < 0.001) and obesity (OR 1.559, 95%CI 1.453-1.672, P < 0.001). Systemic thrombolysis was not beneficial regarding survival in unselected ischemic stroke patients. In contrast, systemic thrombolysis was beneficial in ischemic stroke patients without PE, who had to undergo cardio-pulmonary resuscitation (OR 0.866, 95%CI 0.782-0.960, P = 0.006).

Conclusions: Patients with ischemic stroke revealed still a high in-hospital mortality of 7.2% in Germany. While only a minority of 0.4% of the ischemic stroke patients suffered from occurrence of PE, PE was accompanied by a substantial increase regarding in-hospital mortality. Systemic thrombolysis was beneficial regarding short-term survival in ischemic stroke patients without PE, who had to undergo cardio-pulmonary resuscitation.
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http://dx.doi.org/10.1016/j.jns.2020.117174DOI Listing
December 2020

Exercise right heart catheterization before and after balloon pulmonary angioplasty in inoperable patients with chronic thromboembolic pulmonary hypertension.

Pulm Circ 2020 Jul-Sep;10(3):2045894020917884. Epub 2020 Aug 18.

Kerckhoff Clinic, Department of Cardiology, Bad Nauheim, Germany.

Background: *These authors contributed equally as last authors.Balloon pulmonary angioplasty is an evolving, interventional treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension at rest as well as exercise capacity is considered to be relevant outcome parameters. The aim of the present study was to determine whether measurement of pulmonary hemodynamics during exercise before and six months after balloon pulmonary angioplasty have an added value.

Methods: From March 2014 to July 2018, 172 consecutive patients underwent balloon pulmonary angioplasty. Of these, 64 consecutive patients with inoperable CTEPH underwent a comprehensive diagnostic workup that included right heart catheterization at rest and during exercise before balloon pulmonary angioplasty treatments and six months after the last intervention.

Results: Improvements in pulmonary hemodynamics at rest and during exercise, in quality of life, and in exercise capacity were observed six months after balloon pulmonary angioplasty: WHO functional class improved in 78% of patients. The mean pulmonary arterial pressure (mPAP) at rest was reduced from 41 ± 9 to 31 ± 9 mmHg (p < 0.0001). The mPAP/cardiac output slope decreased after balloon pulmonary angioplasty (11.2 ± 25.6 WU to 7.7 ± 4.1 WU; p < 0.0001), and correlated with N-terminal fragment of pro-brain natriuretic peptide (p = 0.035) and 6-minute walking distance (p = 0.01).

Conclusions: Exercise right heart catheterization provides valuable information on the changes of pulmonary hemodynamics after balloon pulmonary angioplasty in inoperable CTEPH patients that are not obtainable by measuring resting hemodynamics.
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http://dx.doi.org/10.1177/2045894020917884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436823PMC
August 2020

Survival and quality of life after early discharge in low-risk pulmonary embolism.

Eur Respir J 2021 02 4;57(2). Epub 2021 Feb 4.

Emergency Dept, Clinico San Carlos Hospital, IdISSC, Madrid, Spain.

Introduction: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes.

Methods: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism.

Results: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001).

Conclusions: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.
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http://dx.doi.org/10.1183/13993003.02368-2020DOI Listing
February 2021

Definition of tachycardia for risk stratification of pulmonary embolism.

Eur J Intern Med 2020 12 23;82:76-82. Epub 2020 Aug 23.

Center for Thrombosis and Hemostasis (CTH), University Medical Centre of the Johannes Gutenberg University Mainz, Germany; Clinic of Cardiology and Pneumology, University Medical Centre Göttingen, Germany; Department of Internal Medicine and Cardiology, Campus Virchow Klinikum (CVK), Charité - University Medicine Berlin, Germany. Electronic address:

Background: Tachycardia is a reliable predictor of adverse outcomes in normotensive patients with acute pulmonary embolism (PE). However, different prognostic relevant heart rate thresholds have been proposed. The aim of the study was to investigate the prognostic performance of different thresholds used for defining tachycardia in normotensive PE patients.

Methods: We performed a post-hoc analysis of normotensive patients with confirmed PE consecutively included in a single-centre and a multi-centre registry. An adverse outcome was defined as PE-related death, need for mechanical ventilation, cardiopulmonary resuscitation or administration of catecholamines.

Results: Of 1567 patients (median age: 72 [IQR, 59-79] years; females: 46.1%) included in the analysis, 78 patients (5.0%) had an in-hospital adverse outcome. The rate of an adverse outcome was higher in patients with a heart rate ≥100 bpm (7.6%) and ≥110 bpm (8.3%) compared to patients with a heart rate <100 bpm (3.0%). A heart rate ≥100 bpm and ≥110 bpm was associated with a 2.7 (95% CI 1.7-4.3) and 2.4-fold (95% CI 1.5-3.7) increased risk for an adverse outcome, respectively. Receiver operating characteristics analysis revealed a similar area under the curve with regard to an adverse outcome for all scores and algorithm (ESC 2019 algorithm, modified FAST and Bova score) if calculated with a heart rate threshold of ≥100 bpm or of ≥110 bpm.

Conclusions: Defining tachycardia by a heart rate ≥100 bpm is sufficient for risk stratification of normotensive patients with acute PE. The use of different heart rate thresholds for calculation of scores and algorithm does not appear necessary.
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http://dx.doi.org/10.1016/j.ejim.2020.08.009DOI Listing
December 2020

[Antithrombotic Treatment of Pulmonary Embolism].

Dtsch Med Wochenschr 2020 07 15;145(14):970-977. Epub 2020 Jul 15.

The present article addresses clinical challenges associated with the choice of the anticoagulant agent, the definition of the duration of anticoagulant treatment and the assessment of the risk-to-benefit ratio of prolonged anticoagulation for patients with pulmonary embolism (PE).Anticoagulation is performed with unfractionated heparin (UFH) in hemodynamically unstable patients and with low molecular weight heparins (LWMH) or fondaparinux in normotensive patients. In patients with high or intermediate clinical probability of pulmonary embolism, anticoagulation should be initiated without delay while awaiting the results of diagnostic tests. LMWH and fondaparinux are preferred over UFH in the initial anticoagulation of PE since they are associated with a lower risk of bleeding.All patients with PE require therapeutic anticoagulation for at least three months. The current 2019 guidelines of the European Society of Cardiology (ESC) recommend that all eligible patients should be treated with a non-vitamin K antagonist oral anticoagulant (NOAC) in preference to a vitamin K antagonist (VKA). In patients with active cancer, Apixaban, Edoxaban and Rivaroxaban are effective alternatives to treatment with LMWH.The decision on the duration of anticoagulation should consider both, the individual risk of PE recurrence and the individual risk of bleeding. The risk for recurrent PE after discontinuation of treatment is related to the features of the index PE event. While patients with a strong transient risk factor have a low risk of recurrence and anticoagulation can be discontinued after three months, patients with strong persistent risk factor (such as active cancer) have a high risk of recurrence and thus should receive anticoagulant treatment of indefinite duration. Given the favourable safety profile of NOACs (especially if a reduced dosage of Apixaban or Rivaroxaban is initiated after at least six months of therapeutic anticoagulation), extended oral anticoagulation of indefinite duration should be considered for all patients with intermediate risk of recurrence.
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http://dx.doi.org/10.1055/a-0955-3379DOI Listing
July 2020

Sex-specific and age-related seasonal variations regarding incidence and in-hospital mortality of pulmonary embolism in Germany.

ERJ Open Res 2020 Apr 22;6(2). Epub 2020 Jun 22.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany.

Background: Studies have reported seasonal variations regarding the incidence and the short-term mortality of pulmonary embolism (PE). The aim of this study was to identify sex-specific and age-related differences in seasonal patterns regarding hospitalisations and mortality of PE patients.

Methods: We analysed the impact of seasons on incidence and in-hospital mortality of male and female hospitalised PE patients in Germany (2005-2015) based on the German nationwide inpatient sample.

Results: The German nationwide inpatient sample comprised 885 806 hospitalisations due to PE (2005-2015). Seasonal variations of both incidence (p=0.021) and in-hospital mortality (p<0.001) were of significant magnitude. Quarterly annual incidence (25.5 23.7 of 100 000 citizens per year, p=0.021) and in-hospital mortality (17.0% 16.7%, p=0.008) were higher in winter than in summer. Risk of in-hospital mortality in winter was slightly higher (OR 1.03 (95% CI 1.01-1.06), p=0.015) compared to summer, independently of sex, age and comorbidities. Additionally, we observed sex-specific differences during seasons: the highest number of hospitalisations of PE patients of both sexes was during winter, whereas the nadir of male patients was in spring and that of female patients was in summer. Both sexes showed a maximum of in-hospital mortality in spring. Seasonal variation regarding incidence and mortality was pronounced in older patients.

Conclusion: Incidence and the in-hospital mortality of PE patients showed a significant seasonal variation with sex-specific differences. Although it has to be hypothesised that the seasonal variation of PE is multifactorially dependent, variation in each season was not explained by seasonal differences regarding age, sex and the prevalence of important comorbidities.
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http://dx.doi.org/10.1183/23120541.00181-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306502PMC
April 2020

Temporal trends and predictors of inhospital death in patients hospitalised for heart failure in Germany.

Eur J Prev Cardiol 2020 Jun 30:2047487320936020. Epub 2020 Jun 30.

Department of Cardiology, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Germany.

Aims: We investigated trends in incidence, case fatality rate, patient characteristics and adverse inhospital events of patients hospitalised for heart failure in Germany.

Methods And Results: The German nationwide inpatient sample (2005-2016) was used for this analysis. Patients hospitalised due to heart failure were selected for analysis. Temporal trends in the incidence of hospitalisations, case fatality rate and treatments were analysed and predictors of inhospital death were identified. The analysis comprised a total number of 4,539,140 hospitalisations (52.0% women, 81.0% aged ≥70 years) due to heart failure. Although hospitalisations increased from 381 (2005) to 539 per 100,000 population (2016) (β estimate 0.06, 95% confidence interval (CI) 0.06 to 0.07,  < 0.001) in parallel with median age and prevalence of comorbidities, the inhospital case fatality rate decreased from 11.1% to 8.1% (β estimate -0.36, 95% CI -0.37 to -0.35,  < 0.001) and the rate of major adverse cardiovascular and cerebrovascular events (β estimate -0.24, 95% CI -0.25 to -0.23,  < 0.001) decreased from 12.7% to 10.3%. Age 70 years and older (odds ratio (OR) 2.60, 95% CI 2.57 to 2.63,  < 0.001) and cancer (OR 1.93, 95% CI 1.91 to 1.96,  < 0.001) were independent predictors of inhospital death.

Conclusion: Hospitalisations for heart failure increased in Germany from 2005 to 2016, whereas the major adverse cardiovascular and cerebrovascular event rate and inhospital case fatality rate decreased during this period despite higher patient age and increasing prevalence of comorbidities.
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http://dx.doi.org/10.1177/2047487320936020DOI Listing
June 2020

Defining right ventricular dysfunction by echocardiography in normotensive patients with pulmonary embolism.

Pol Arch Intern Med 2020 09 24;130(9):741-747. Epub 2020 Jun 24.

Center for Thrombosis and Hemostasis and Center for Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Clinic of Cardiology and Pneumology, University Medical Center Goettingen, Goettingen, Germany; Department of Internal Medicine and Cardiology, Campus Virchow Klinikum, Charité – University Medicine, Berlin, Germany

Introduction: Although the prognostic value of various echocardiographic parameters of right ventricular dysfunction (RVD) was reported in normotensive patients with acute pulmonary embolism (PE), there is no generally accepted definition of RVD.

Objectives: The aim of the study was to compare echocardiographic parameters for the prediction of an adverse 30‑day outcome and create an optimal definition of RVD.                                     Patients and methods: Echocardiographic parameters including the right ventricular to left ventricular diameter ratio (RV to LV ratio) and tricuspid annular plane systolic excursion (TAPSE) to predict PE‑related mortality, hemodynamic collapse, or rescue thrombolysis within the first 30 days were directly compared in 490 normotensive patients with PE.

Results: An adverse outcome (AO) was present in 31 patients (6.3%); 8 of them (1.6%) died due to PE. Systolic blood pressure, RV to LV ratio, and TAPSE were independent predictors of AO. The receiver operator characteristic yielded an area under the curve of 0.737 (0.654-0.819; P <0.001) for the RV to LV ratio and 0.75 (0.672-0.828; P <0.001) for TAPSE with regard to an AO. The hazard ratio for AO was 2.5 for the RV to LV ratio of more than 1 (95% CI, 1.2-5.7; P <0.03) and 3.8 for TAPSE of less than 16 mm (95% CI, 1.74-8.11; P = 0.001). A combined RVD criterion (TAPSE <16 mm and RV to LV ratio >1) was present in 60 patients (12%), and showed a positive predictive value of 23.3% with a high negative predictive value of 95.6% regarding an AO (HR, 6.5; 95% CI, 3.2-13.3; P <0.001).

Conclusions: Defining RVD on echocardiography by the RV to LV ratio of more than 1 combined with TAPSE of less than 16 mm identified patients with an increased risk of 30‑day PE‑related mortality, hemodynamic collapse, or rescue thrombolysis, while patients without this sign had a very good 30‑day prognosis.
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http://dx.doi.org/10.20452/pamw.15459DOI Listing
September 2020

Fatality rates and use of systemic thrombolysis in pregnant women with pulmonary embolism.

ESC Heart Fail 2020 10 21;7(5):2365-2372. Epub 2020 Jun 21.

Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Langenbeckstrasse 1, Mainz, 55131, Germany.

Aims: Data on the early course and use of systemic thrombolysis in pregnant women with pulmonary embolism associated or not with haemodynamic failure are scarce. We investigated these aspects using the information from the German Nationwide Inpatient Registry (years 2005-2016).

Methods And Results: In Germany, all diagnoses referring to hospitalized patients are coded according to the International Classification of Diseases and Related Health Problems, 10th Revision with German Modification. We analysed data of pregnant women aged 18-50 years for whom the following diagnoses were recorded during hospitalization: (i) pulmonary embolism (I26) during pregnancy or peripartum (O09) or (ii) obstetric thromboembolism (O88.2). Haemodynamic failure at any time during the in-hospital stay was defined as need for cardiopulmonary resuscitation (OPS code 8-77) or the presence of shock (International Classification of Diseases and Related Health Problems, 10th Revision with German Modification code R57). The primary study outcome was in-hospital death. A total of 8 271 327 births were registered in Germany from 2005 to 2016. During this 12 year time period, there were 1846 hospitalizations for pregnancy-associated pulmonary embolism in patients aged 18-50, corresponding to 2.2 [95% confidence interval (CI): 2.1-2.3] cases every 10 000 births and 0.2% of all hospitalizations for pulmonary embolism in Germany. The median age was 31 years, and the median length of hospitalization was 8 days. A total of 63 deaths were reported, corresponding to an overall in-hospital fatality rate of 3.4% (95% CI: 2.7-4.4) and a pulmonary embolism-related mortality rate of 0.8 (95% CI: 0.6-1.0) per 100 000 (live) births per year. Pulmonary embolism-related deaths in hospitalized pregnant women represented 14% of all maternal deaths recorded in Germany between 2005 and 2016. A total of 135 (7.3%) women had haemodynamic failure, of whom 51 (37.8%) received systemic thrombolysis and 50 (37.0%) died.

Conclusions: Pulmonary embolism-related fatality remains substantial in pregnant women with pulmonary embolism and represents a frequent cause of maternal mortality. The use of systemic thrombolysis was reported in one third of pregnant women with pulmonary embolism and haemodynamic failure. Better preventive and management strategies should be urgently implemented in this vulnerable patient group.
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http://dx.doi.org/10.1002/ehf2.12775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524052PMC
October 2020

Impact of obesity on adverse in-hospital outcomes in patients undergoing percutaneous mitral valve edge-to-edge repair using MitraClip® procedure - Results from the German nationwide inpatient sample.

Nutr Metab Cardiovasc Dis 2020 07 18;30(8):1365-1374. Epub 2020 Apr 18.

Heart Center Mainz, Center of Cardiology, Cardiology I, University Medical Center Mainz (Johannes Gutenberg-University Mainz), Mainz, Germany.

Background And Aim: The number of percutaneous edge-to-edge mitral regurgitation (MR) valve repairs with MitraClip® implantations increased exponentially in recent years. Studies have suggested an obesity survival paradox in patients with cardiovascular diseases. We investigated the influence of obesity on adverse in-hospital outcomes in patients with MitraClip® implantation.

Methods And Results: We analyzed data on characteristics of patients and in-hospital outcomes for all percutaneous mitral valve repairs using the edge-to-edge MitraClip®-technique in Germany 2011-2015 stratified for obesity vs. normal-weight/over-weight. The nationwide inpatient sample comprised 13,563 inpatients undergoing MitraClip® implantations. Among them, 1017 (7.5%) patients were coded with obesity. Obese patients were younger (75 vs.77 years,P < 0.001), more often female (45.4% vs.39.5%,P < 0.001), had more often heart failure (87.1% vs.79.2%,P < 0.001) and renal insufficiency (67.0% vs.56.4%,P < 0.001). Obese and non-obese patients were comparable regarding major adverse cardiac and cerebrovascular events (MACCE) and in-hospital death. The combined endpoint of cardio-pulmonary resuscitation (CPR), mechanical ventilation and death was more often reached in non-obese than in obese patients with a trend towards significance (20.6%vs.18.2%,P = 0.066). Obesity was an independent predictor of reduced events regarding the combined endpoint of CPR, mechanical ventilation and death (OR 0.75, 95%CI 0.64-0.89,P < 0.001), but not for reduced in-hospital mortality (P = 0.355) or reduced MACCE rate (P = 0.108). Obesity class III was associated with an elevated risk for pulmonary embolism (OR 5.66, 95%CI 1.35-23.77,P = 0.018).

Conclusions: We observed an obesity paradox regarding the combined endpoint of CPR, mechanical ventilation and in-hospital death in patients undergoing MitraClip® implantation, but our results failed to confirm an impact of obesity on in-hospital survival or MACCE.
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http://dx.doi.org/10.1016/j.numecd.2020.04.009DOI Listing
July 2020

[Update diagnosis and therapeutic management of pulmonary embolism].

Dtsch Med Wochenschr 2020 06 3;145(11):710-715. Epub 2020 Jun 3.

Medizinische Klinik mit Schwerpunkt Kardiologie, Campus Virchow-Klinikum (CVK), Charité-Universitätsmedizin Berlin.

Pulmonary embolism (PE) is a life-threatening disease and the third most frequent cardiovascular cause of death after stroke and myocardial infarction. The annual incidence is increasing. The recently published 2019 guidelines of the European Society of Cardiology integrate numerous new study findings and provide updated diagnostic and therapeutic algorithms. A standardized diagnostic approach based on clinical probability, D-dimer levels, compression sonography of the leg veins and (if necessary) CTPA should also be applied in pregnant patients with suspected PE. Assessment of right ventricular function on imaging should be part of risk stratification in every patient; the RV/LV diameter ratio can be assessed on CTPA performed for diagnosis of PE. Low risk patients are eligible for home treatment if no other reasons for hospitalization are present. Treatment decision for hemodynamically unstable patients should be made by interdisciplinary Pulmonary Embolism Response Teams. NOACs are recommended as the therapy of choice for anticoagulation of patients with PE. The duration of anticoagulation should be at least 3 months and prolonged anticoagulation should be considered for all patients without a strong triggering reversible risk factor.
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http://dx.doi.org/10.1055/a-0984-7323DOI Listing
June 2020

Validation of a fast prognostic score for risk stratification of normotensive patients with acute pulmonary embolism.

Clin Res Cardiol 2020 Aug 6;109(8):1008-1017. Epub 2020 Feb 6.

Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Background: Recent studies demonstrate an improved prognostic performance of the 2014 European Society of Cardiology (ESC) algorithm for risk stratification of patients with pulmonary embolism (PE) compared to the 2008 ESC algorithm. The modified FAST and Bova scores appear especially helpful to identify PE patients at intermediate-high risk.

Methods: We validated the prognostic performance of the modified FAST score compared to other scores for risk stratification in a post-hoc analysis of 868 normotensive PE patients included in the prospective Italian Pulmonary Embolism Registry. In-hospital adverse outcome was defined as PE-related death, mechanical ventilation, cardiopulmonary resuscitation or administration of catecholamines.

Results: Overall, 27 patients (3.1%) had an adverse outcome and 32 patients (3.7%) died. The rate of an adverse outcome was highest in the intermediate-high risk classes of the 2019 ESC algorithm (7.5%) and the modified FAST score (5.3%) while the Bova score failed to discriminate between intermediate-low and intermediate-high-risk patients. Patients classified as intermediate-high risk by the 2019 ESC algorithm (Odds Ratio [OR], 4.2 [95% CI, 1.9-9.0]) and modified FAST score (OR, 2.8 [1.3-6.2]) had a higher risk of an adverse outcome compared to patients classified by the Bova score (OR, 1.6 [0.7-3.7]). The c-index was higher for the 2019 ESC algorithm and the modified FAST score (AUC, 0.69 [0.58-0.79] and 0.67 [0.59-0.76]) compared to the Bova score (AUC, 0.64 [0.55-0.73]).

Conclusions: The 2019 ESC algorithm provided the best prognostic performance, but also the modified FAST score accurately stratified normotensive PE patients in different risk classes while the Bova score failed to identify patients at highest risk.
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http://dx.doi.org/10.1007/s00392-019-01593-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376081PMC
August 2020

Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation.

Int J Mol Sci 2019 Dec 31;21(1). Epub 2019 Dec 31.

Center for Cardiology, Cardiology I, University Medical Center Mainz, D-55131 Mainz, Germany.

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks ("middle-aged") were compared to tissue or cells from mice aged 16 weeks ("adult"). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.
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http://dx.doi.org/10.3390/ijms21010282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981748PMC
December 2019

Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Nonresolution in Mice Via Endothelin-1: Potential Role for Chronic Thromboembolic Pulmonary Hypertension.

Circ Res 2020 01 21;126(2):162-181. Epub 2019 Nov 21.

From the Center for Cardiology, Cardiology I (M.L.B., C.L., N.S.R., R.G., L.H., T.M., K.S.), University Medical Center Mainz, Germany.

Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by defective thrombus resolution, pulmonary artery obstruction, and vasculopathy. TGFβ (transforming growth factor-β) signaling mutations have been implicated in pulmonary arterial hypertension, whereas the role of TGFβ in the pathophysiology of CTEPH is unknown.

Objective: To determine whether defective TGFβ signaling in endothelial cells contributes to thrombus nonresolution and fibrosis.

Methods And Results: Venous thrombosis was induced by inferior vena cava ligation in mice with genetic deletion of TGFβ1 in platelets (Plt.TGFβ-KO) or TGFβ type II receptors in endothelial cells (End.TGFβRII-KO). Pulmonary endarterectomy specimens from CTEPH patients were analyzed using immunohistochemistry. Primary human and mouse endothelial cells were studied using confocal microscopy, quantitative polymerase chain reaction, and Western blot. Absence of TGFβ1 in platelets did not alter platelet number or function but was associated with faster venous thrombus resolution, whereas endothelial TGFβRII deletion resulted in larger, more fibrotic and higher vascularized venous thrombi. Increased circulating active TGFβ1 levels, endothelial TGFβRI/ALK1 (activin receptor-like kinase), and TGFβRI/ALK5 expression were detected in End.TGFβRII-KO mice, and activated TGFβ signaling was present in vessel-rich areas of CTEPH specimens. CTEPH-endothelial cells and murine endothelial cells lacking TGFβRII simultaneously expressed endothelial and mesenchymal markers and transcription factors regulating endothelial-to-mesenchymal transition, similar to TGFβ1-stimulated endothelial cells. Mechanistically, increased endothelin-1 levels were detected in TGFβRII-KO endothelial cells, murine venous thrombi, or endarterectomy specimens and plasma of CTEPH patients, and endothelin-1 overexpression was prevented by inhibition of ALK5, and to a lesser extent of ALK1. ALK5 inhibition and endothelin receptor antagonization inhibited mesenchymal lineage conversion in TGFβ1-exposed human and murine endothelial cells and improved venous thrombus resolution and pulmonary vaso-occlusions in End.TGFβRII-KO mice.

Conclusions: Endothelial TGFβ1 signaling via type I receptors and endothelin-1 contribute to mesenchymal lineage transition and thrombofibrosis, which were prevented by blocking endothelin receptors. Our findings may have relevant implications for the prevention and management of CTEPH.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101077PMC
January 2020

Risk factors for chronic thromboembolic pulmonary hypertension - Importance of thyroid disease and function.

Thromb Res 2020 01 31;185:20-26. Epub 2019 Oct 31.

Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Department of Internal Medicine and Cardiology, Campus Virchow Klinikum (CVK), Charité - University Medicine Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Germany. Electronic address:

Introduction: Although a number of risk factors for chronic thromboembolic pulmonary hypertension (CTEPH) have been reported, the exact prevalence is controversial and varies between published cohorts. The aim of the present study was to investigate the prevalence of risk factors in operable CTEPH patients with special emphasis on thyroid disease and function.

Material And Methods: Overall, 228 CTEPH patients (47.7% female; median age 63 [IQR 52-72] years) scheduled for pulmonary endarterectomy between 01/2014 and 12/2015 were studied. Prevalence of risk factors was assessed, and patients were classified according to their thyroid function based on laboratory measurements.

Results: As many as 86.0% of patients reported a history of pulmonary embolism (PE; of those, 24.5% were diagnosed with "acute" PE less than six months before the diagnosis of CTEPH), 80.7% of patients had a blood group non-0 and 24.1% of patients had known thyroid disease (of those, 78.2% hypothyroidism). Laboratory measurements revealed thyroid dysfunction in 10.5% of patients (of those, 54.8% had no known thyroid disease). Patients with hypothyroid function had higher WHO functional classes, NT-proBNP levels and a lower cardiac index compared to patients with euthyroid function.

Conclusions: The prevalence of a history of PE and blood group non-0 was higher than previously reported. However, a relevant proportion of patients might have suffered from pre-existing CTEPH rather than acute PE. Thyroid disease and dysfunction were frequent and hypothyroid function associated with more severe disease.
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http://dx.doi.org/10.1016/j.thromres.2019.10.025DOI Listing
January 2020
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