Publications by authors named "Stephan Rosenkranz"

188 Publications

Fragile 3D Order in V_{1-x}Mo_{x}O_{2}.

Phys Rev Lett 2021 Sep;127(12):125501

Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama 35487, USA.

The metal-to-insulator transition in rutile VO_{2} has proven uniquely difficult to characterize because of the complex interplay between electron correlations and atomic structure. Here, we report the discovery of the sudden collapse of three-dimensional order in the low-temperature phase of V_{1-x}Mo_{x}O_{2} at x=0.17 and the emergence of a novel frustrated two-dimensional order at x=0.19, with only a slight change in electronic properties. Single crystal diffuse x-ray scattering reveals that this transition from the 3D M1 phase to a 2D variant of the M2 phase results in long-range structural correlations along symmetry-equivalent (11L) planes of the tetragonal rutile structure, yet extremely short-range correlations transverse to these planes. These findings suggest that this two dimensionality results from a novel form of geometric frustration that is essentially structural in origin.
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http://dx.doi.org/10.1103/PhysRevLett.127.125501DOI Listing
September 2021

Disrupted PI3K subunit p110α signaling protects against pulmonary hypertension and reverses established disease in rodents.

J Clin Invest 2021 Oct;131(19)

Department of Cardiology, Heart Center at the University of Cologne, Cologne, Germany.

Enhanced signaling via RTKs in pulmonary hypertension (PH) impedes current treatment options because it perpetuates proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Here, we demonstrated hyperphosphorylation of multiple RTKs in diseased human vessels and increased activation of their common downstream effector phosphatidylinositol 3'-kinase (PI3K), which thus emerged as an attractive therapeutic target. Systematic characterization of class IA catalytic PI3K isoforms identified p110α as the key regulator of pathogenic signaling pathways and PASMC responses (proliferation, migration, survival) downstream of multiple RTKs. Smooth muscle cell-specific genetic ablation or pharmacological inhibition of p110α prevented onset and progression of pulmonary hypertension (PH) as well as right heart hypertrophy in vivo and even reversed established vascular remodeling and PH in various animal models. These effects were attributable to both inhibition of vascular proliferation and induction of apoptosis. Since this pathway is abundantly activated in human disease, p110α represents a central target in PH.
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http://dx.doi.org/10.1172/JCI136939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483754PMC
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

Ferric carboxymaltose in patients with pulmonary arterial hypertension and iron deficiency: a long-term study.

J Cachexia Sarcopenia Muscle 2021 Sep 9. Epub 2021 Sep 9.

Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Cologne, Germany.

Background: Pulmonary arterial hypertension (PAH) is a progressive disease with limited survival. Iron deficiency (ID) correlates with disease severity and mortality. While oral iron supplementation was shown to be insufficient in such patients, the potential impact of parenteral iron on clinical measures warrants further investigation.

Methods: We retrospectively analysed the long-term effects of intravenous ferric carboxymaltose (FCM) on iron status and clinical measures in patients with PAH and ID [ferritin < 100 μg/L or ferritin 100-300 μg/L and transferrin saturation (TSAT) < 20%] who were on stable targeted PAH therapy, compared with matched controls without ID. Patients with ID received a single infusion of FCM (500 to 1000 mg). Clinical measures monitored included exercise capacity, World Health Organization (WHO) functional class, ESC/ERS risk status, and hospitalizations. The observation period was up to 18 months.

Results: One hundred and seventeen patients (mean age 60.9 ± 16.1 years; 64.1% females) with confirmed PAH and on stable targeted therapy for ≥3 months were included (58 with and 59 patients without ID who did not receive FCM). In patients with ID, iron supplementation with FCM resulted in an immediate and sustained improvement of iron status for up to 18 months (serum iron, ferritin, TSAT, all P < 0.01). Fourteen patients in the FCM group received a second FCM infusion after 9.6 ± 4.8 months due to recurrent ID. At 6 and 18 months after FCM infusion, 6 min walk distance improved from 377.5 ± 15.9 at baseline to 412.5 ± 15.1 and 400.8 ± 14.5 m, respectively (both P < 0.05). WHO functional class (P < 0.05) and ESC/ERS risk status also improved, and there was a reduction of hospitalizations for worsening PAH in the 12 months post vs. prior to iron repletion (P = 0.029). No significant changes were observed in the control group. FCM was well tolerated in all patients, with no severe adverse events.

Conclusions: In addition to targeted therapy, correction of ID by parenteral iron supplementation with FCM appears feasible and safe, has sustained effects on iron status, and may improve the clinical status and hospitalization rates in patients with PAH. Larger controlled studies are required to confirm this finding.
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http://dx.doi.org/10.1002/jcsm.12764DOI Listing
September 2021

Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial.

Lancet Respir Med 2021 Aug 20. Epub 2021 Aug 20.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH.

Methods: We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18-75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02234141.

Findings: Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm. Change in pulmonary vascular resistance was 6·0 dyn·s/cm (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm (n=35; p=0·21 vs placebo) for 2 mg selonsertib, -28·0 (30·2) dyn·s/cm (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and -21·0 (37·9) dyn·s/cm (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo.

Interpretation: Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1-p38 pathway in PAH is warranted.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2213-2600(21)00032-1DOI Listing
August 2021

A two-dimensional type I superionic conductor.

Nat Mater 2021 Jul 22. Epub 2021 Jul 22.

Materials Science Division, Argonne National Laboratory, Lemont, IL, USA.

Superionic conductors possess liquid-like ionic diffusivity in the solid state, finding wide applicability from electrolytes in energy storage to materials for thermoelectric energy conversion. Type I superionic conductors (for example, AgI, AgSe and so on) are defined by a first-order transition to the superionic state and have so far been found exclusively in three-dimensional crystal structures. Here, we reveal a two-dimensional type I superionic conductor, α-KAgSe, by scattering techniques and complementary simulations. Quasi-elastic neutron scattering and ab initio molecular dynamics simulations confirm that the superionic Ag ions are confined to subnanometre sheets, with the simulated local structure validated by experimental X-ray powder pair-distribution-function analysis. Finally, we demonstrate that the phase transition temperature can be controlled by chemical substitution of the alkali metal ions that compose the immobile charge-balancing layers. Our work thus extends the known classes of superionic conductors and will facilitate the design of new materials with tailored ionic conductivities and phase transitions.
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http://dx.doi.org/10.1038/s41563-021-01053-9DOI Listing
July 2021

Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study.

Lancet Reg Health Eur 2021 Jul 18;6:100122. Epub 2021 May 18.

Department I of Internal Medicine, Medical Faculty and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany.

Background: While the leading symptoms during coronavirus disease 2019 (COVID-19) are acute and the majority of patients fully recover, a significant fraction of patients now increasingly experience long-term health consequences. However, most data available focus on health-related events after severe infection and hospitalisation. We present a longitudinal, prospective analysis of health consequences in patients who initially presented with no or minor symptoms of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. Hence, we focus on mild COVID-19 in non-hospitalised patients.

Methods: 958 Patients with confirmed SARS-CoV-2 infection were observed from April 6th to December 2nd 2020 for long-term symptoms and SARS-CoV-2 antibodies. We identified anosmia, ageusia, fatigue or shortness of breath as most common, persisting symptoms at month 4 and 7 and summarised presence of such long-term health consequences as post-COVID syndrome (PCS). Predictors of long-term symptoms were assessed using an uni- and multivariable logistic regression model.

Findings: We observed 442 and 353 patients over four and seven months after symptom onset, respectively. Four months post SARS-CoV-2 infection, 8•6% (38/442) of patients presented with shortness of breath, 12•4% (55/442) with anosmia, 11•1% (49/442) with ageusia and 9•7% (43/442) with fatigue. At least one of these characteristic symptoms was present in 27•8% (123/442) and 34•8% (123/353) at month 4 and 7 post-infection, respectively. A lower baseline level of SARS-CoV-2 IgG, anosmia and diarrhoea during acute COVID-19 were associated with higher risk to develop long-term symptoms.

Interpretation: The on-going presence of either shortness of breath, anosmia, ageusia or fatigue as long-lasting symptoms even in non-hospitalised patients was observed at four and seven months post-infection and summarised as post-COVID syndrome (PCS). The continued assessment of patients with PCS will become a major task to define and mitigate the socioeconomic and medical long-term effects of COVID-19.

Funding: COVIM:"NaFoUniMedCovid19"(FKZ: 01KX2021).
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http://dx.doi.org/10.1016/j.lanepe.2021.100122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129613PMC
July 2021

PH CARE COVID survey: an international patient survey on the care for pulmonary hypertension patients during the early phase of the COVID-19 pandemic.

Orphanet J Rare Dis 2021 05 1;16(1):196. Epub 2021 May 1.

Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.

Background: During the COVID-19 pandemic, most of the health care systems suspended their non-urgent activities. This included the cancellation of consultations for patients with rare diseases, such as severe pulmonary hypertension (PH), resulting in potential medication shortage and loss of follow-up. Thus, the aim of the study was to evaluate PH patient health status evolution, access to health care and mental health experience during the early phase of the pandemic.

Methods: We conducted an online patient survey, available in 16 languages, between 22/05/2020 and 28/06/2020. The survey included questions corresponding to demographic, COVID-19 and PH related information.

Results: 1073 patients (or relatives, 27%) from 52 countries all over the world participated in the survey. Seventy-seven percent (77%) of responders reported a diagnosis of pulmonary arterial hypertension and 15% of chronic thromboembolic PH. The COVID-19 related events were few: only 1% of all responders reported a diagnosis of COVID-19. However, 8% of patients reported health deterioration possibly related to PH, and 4% hospitalization for PH. Besides, 11% of the patients reported difficulties to access their PH expert centre, and 3% interruption of treatment due to shortage of medication. Anxiety or depression was reported by 67% of the participants.

Conclusion: Although COVID-19 incidence in PH patients was low, PH related problems occurred frequently as the pandemic progressed, including difficulties to have access to specialized care. The importance of primary health care was emphasized. Further studies are needed to evaluate the long-term consequences of COVID-related PH care disruption.
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http://dx.doi.org/10.1186/s13023-021-01752-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087873PMC
May 2021

Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.

Lancet Respir Med 2021 06 24;9(6):573-584. Epub 2021 Mar 24.

Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and Inserm U999, Le Kremlin-Bicêtre, France.

Background: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality.

Methods: Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850.

Findings: Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period.

Interpretation: Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality.

Funding: Bayer AG, Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S2213-2600(20)30532-4DOI Listing
June 2021

Pulmonary Hypertension in Patients With COPD: Results From the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA).

Chest 2021 Aug 11;160(2):678-689. Epub 2021 Feb 11.

German Center of Lung Research (DZL), Germany; Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University, Hospital, Heidelberg, Germany.

Background: Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition.

Research Question: Which factors determine the outcome of PH in COPD?

Study Design And Methods: We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH).

Results: The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes.

Interpretation: Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further.

Trial Registry: ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.02.012DOI Listing
August 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

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry.

Respir Med 2021 03 12;178:106220. Epub 2020 Nov 12.

Bayer AG, Global Development, Global Medical Affairs, Berlin, Germany.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.

Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms.

Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]).

Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.
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http://dx.doi.org/10.1016/j.rmed.2020.106220DOI Listing
March 2021

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry.

Respir Med 2020 Dec 3;177:106241. Epub 2020 Dec 3.

Bayer AG, Global Development, Global Medical Affairs, Berlin, Germany.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.

Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms.

Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years.

Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.
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http://dx.doi.org/10.1016/j.rmed.2020.106241DOI Listing
December 2020

CsV_{3}Sb_{5}: A Z_{2} Topological Kagome Metal with a Superconducting Ground State.

Phys Rev Lett 2020 Dec;125(24):247002

Materials Department and California Nanosystems Institute, University of California Santa Barbara, Santa Barbara, California 93106, USA.

Recently discovered alongside its sister compounds KV_{3}Sb_{5} and RbV_{3}Sb_{5}, CsV_{3}Sb_{5} crystallizes with an ideal kagome network of vanadium and antimonene layers separated by alkali metal ions. This work presents the electronic properties of CsV_{3}Sb_{5}, demonstrating bulk superconductivity in single crystals with a T_{c}=2.5  K. The normal state electronic structure is studied via angle-resolved photoemission spectroscopy and density-functional theory, which categorize CsV_{3}Sb_{5} as a Z_{2} topological metal. Multiple protected Dirac crossings are predicted in close proximity to the Fermi level (E_{F}), and signatures of normal state correlation effects are also suggested by a high-temperature charge density wavelike instability. The implications for the formation of unconventional superconductivity in this material are discussed.
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http://dx.doi.org/10.1103/PhysRevLett.125.247002DOI Listing
December 2020

Assessment of the REPLACE study composite endpoint in riociguat-treated patients in the PATENT study.

Pulm Circ 2020 Oct-Dec;10(4):2045894020973124. Epub 2020 Dec 9.

Department of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.

The goal of treatment in patients with pulmonary arterial hypertension is to achieve a low risk status, indicating a favorable long-term outcome. The REPLACE study investigated the efficacy of switching to riociguat in patients with pulmonary arterial hypertension and an insufficient response to phosphodiesterase-5 inhibitors. In this post hoc analysis, we applied the REPLACE composite endpoint of clinical improvement to the placebo-controlled PATENT-1 study of riociguat in pulmonary arterial hypertension and its long-term extension, PATENT-2. Clinical improvement was defined as ≥2 of the following in patients who completed the study without clinical worsening: ≥10% or ≥30 m improvement in 6-minute walking distance; World Health Organization functional class I or II; ≥30% decrease in -terminal prohormone of brain natriuretic peptide. At PATENT-1 Week 12, patients treated with riociguat were more likely to achieve the composite endpoint vs. placebo ( < 0.0001), with similar results in pretreated ( = 0.0189) and treatment-naïve ( < 0.0001) patients. Achievement of the composite endpoint at Week 12 was associated with a 45% reduction in relative risk of death and a 19% reduction in relative risk of clinical worsening in PATENT-2. Overall, these data suggest that use of the REPLACE composite endpoint in patients with pulmonary arterial hypertension is a valid assessment of response to treatment.
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http://dx.doi.org/10.1177/2045894020973124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734510PMC
December 2020

Riociguat: Clinical research and evolving role in therapy.

Br J Clin Pharmacol 2021 07 30;87(7):2645-2662. Epub 2020 Dec 30.

Universite Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension.
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http://dx.doi.org/10.1111/bcp.14676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359233PMC
July 2021

Right ventricular dysfunction and long-term risk of death.

Cardiovasc Diagn Ther 2020 Oct;10(5):1646-1658

Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Sudden cardiac death (SCD), or sudden loss of life-sustaining systemic and cerebral perfusion, is most often due to left ventricular (LV) dysfunction secondary to ischemic or structural cardiac disease or channelopathies. Degeneration of sinus rhythm into ventricular tachycardia and ultimately ventricular fibrillation is the final common pathway for most heart failure patients. Right ventricular (RV) dysfunction is recognized as an independent contributor to worsening heart failure. There is emerging evidence that RV dysfunction may also be an independent predictor of SCD. This review examines the role of RV dysfunction on modifying long term risk of SCD, and explores possible mechanisms that may underlie SCD. The RV has unique anatomy and physiology compared to the LV. Subsequently, we begin with a review of cardiac embryology, focusing on the chambers, valves, coronary arteries, and cardiac conduction system to understand the origins of RV dysfunction. Static and dynamic physiology of the RV is contrasted with that of the LV. Particular emphasis is placed on ventriculo-arterial coupling, mechanical cardiac constraint, and ventricular interdependence. The epidemiology of SCD is briefly reviewed to highlight how causes of SCD are age-specific. In turn, the age-specific causes of RV dysfunction are presented, including those which predominate in childhood and adolescence [arrhythmogenic RV dysplasia (ARVD) and hypertrophic cardiomyopathy (HCM)] and older adulthood (cardiac ischemia, chronic congestive heart failure and post-capillary pulmonary hypertension, and pulmonary hypertension). There is a clear need for additional studies on the independent contribution of RV dysfunction to overall functional capacity, SCD-associated mortality, and non-SCD-associated mortality. Discovery would be aided by the development of prospective cohorts with excellent RV phenotyping, coupled with deeper biologic measurements linking mechanisms to clinically relevant outcomes.
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http://dx.doi.org/10.21037/cdt-20-450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666957PMC
October 2020

The six-transmembrane protein Stamp2 ameliorates pulmonary vascular remodeling and pulmonary hypertension in mice.

Basic Res Cardiol 2020 11 13;115(6):68. Epub 2020 Nov 13.

Cologne Cardiovascular Research Center (CCRC), and Center for Molecular Medicine Cologne (CMMC), Klinik III Für Innere Medizin, Herzzentrum Der Universität Zu Köln, Kerpener Str. 62, 50937, Köln, Germany.

Six-transmembrane protein of prostate (Stamp2) protects from diabetes and atherosclerosis in mice via anti-inflammatory mechanisms. As chronic inflammation is a hallmark of pulmonary arterial hypertension (PAH), we investigated the role of Stamp2. Stamp2 expression was substantially reduced in the lung of humans with idiopathic PAH, as well as in experimental PAH. In Stamp2-deficient mice, hypoxia modestly aggravated pulmonary vascular remodeling and right ventricular pressure compared to WT. As endothelial cell (EC) and pulmonary arterial smooth muscle cell (PASMC) phenotypes drive remodeling in PAH, we explored the role of Stamp2. Knock-down of Stamp2 in human EC neither affected apoptosis, viability, nor release of IL-6. Moreover, Stamp2 deficiency in primary PASMC did not alter mitogenic or migratory properties. As Stamp2 deficiency augmented expression of inflammatory cytokines and numbers of CD68-positive cells in the lung, actions of Stamp2 in macrophages may drive vascular remodeling. Thus, PASMC responses were assessed following treatment with conditioned media of primary Stamp2 or WT macrophages. Stamp2 supernatants induced PASMC proliferation and migration stronger compared to WT. A cytokine array revealed CXCL12, MCP-1 and IL-6 as most relevant candidates. Experiments with neutralizing antibodies confirmed the role of these cytokines in driving Stamp2's responses. In conclusion, Stamp2 deficiency aggravates pulmonary vascular remodeling via cross-talk between macrophages and PASMC. Despite a substantial pro-inflammatory response, the hemodynamic effect of Stamp2 deficiency is modest suggesting that additional mechanisms apart from inflammation are necessary to induce severe PAH.
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http://dx.doi.org/10.1007/s00395-020-00826-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666299PMC
November 2020

Real-Life Multimarker Monitoring in Patients with Heart Failure: Continuous Remote Monitoring of Mobility and Patient-Reported Outcomes as Digital End Points in Future Heart-Failure Trials.

Digit Biomark 2020 May-Aug;4(2):45-59. Epub 2020 Jun 30.

Bayer AG, Experimental Medicine Cardiovascular/Hematology, Wuppertal, Germany.

Aims: Heart failure (HF) affects approximately 26 million people worldwide. With an aging global population, innovative approaches to HF evaluation and management are needed to cope with the worsening HF epidemic. The aim of the Real-Life Multimarker Monitoring in Patients with Heart Failure (REALIsM-HF) study (NCT03507439) is to evaluate a composite instrument comprising remote, real-time, activity-monitoring devices combined with daily electronic patient-reported outcome (ePRO) items in patients who have been hospitalized for HF and are undergoing standard HF assessment (e.g., 6-min walking distance [6MWD], blood biomarkers, Kansas City Cardiomyopathy Questionnaire [KCCQ], and echocardiography).

Methods: REALIsM-HF is an ongoing, 12-week, observational study enrolling 80-100 patients aged ≥45 years with HF with preserved ejection fraction (HFpEF; EF ≥45%) or reduced EF (HFrEF; EF ≤35%). Statistical analyses will include examining the association between data from wearables (the AVIVO mobile patient management patch or VitalPatch biosensor, and the DynaPort MoveMonitor), daily ePROs, and conventional HF metrics (e.g., serum/plasma biomarkers, 6MWD, KCCQ, and echocardiographic parameters). The feasibility of and patient compliance with at-home devices will be documented, and the data captured for the purpose of establishing reference values in patients with HFpEF or HFrEF will be summarized.

Conclusions: The REALIsM-HF study is to evaluate the longitudinal daily activity profiles of patients with HF and correlate these with changes in serum/plasma biomarker profiles, symptoms, quality of life, and cardiac function and morphology to inform the use of wearable activity monitors for developing novel therapies and managing patients.
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http://dx.doi.org/10.1159/000507696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548956PMC
June 2020

Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry.

J Heart Lung Transplant 2020 12 30;39(12):1435-1444. Epub 2020 Sep 30.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany.

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward's minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival.
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http://dx.doi.org/10.1016/j.healun.2020.09.011DOI Listing
December 2020

Pulmonary hypertension associated with left-sided heart failure.

Curr Opin Cardiol 2020 11;35(6):610-619

Clinic III for Internal Medicine, Heart Center at the University of Cologne.

Purpose Of Review: Pulmonary hypertension is a common phenomenon in heart failure patients that is highly relevant for morbidity and outcome. Although postcapillary in nature, the pathophysiology of pulmonary hypertension in patients with heart failure with reduced or preserved ejection fraction is complex, and decisions about management strategies remain challenging.

Recent Findings: Recently, the hemodynamic definitions and subclassification of postcapillary pulmonary hypertension have been revisited. The distinction between isolated postcapillary pulmonary hypertension (IpcPH) and combined post and precapillary pulmonary hypertension (CpcPH) and their definition are essential. Novel data on the prognostic impact of hemodynamic variables and right ventricular function highlight the importance of cardiopulmonary interaction in patients with left-sided heart failure (LHF). Furthermore, the impact of management strategies including medical therapy, remote hemodynamic monitoring, and interventional approaches on hemodynamics and outcome has recently been investigated. Here, we critically review recent developments and future considerations in this field, and highlight distinct treatment strategies targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function.

Summary: Detailed hemodynamic characterization and proper phenotyping are essential for prognostication and the management of patients with pulmonary hypertension associated with LHF, both in clinical practice and when addressing research questions.
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http://dx.doi.org/10.1097/HCO.0000000000000791DOI Listing
November 2020

Impact of SARS-CoV-2 pandemic on pulmonary hypertension out-patient clinics in Germany: a multi-centre study.

Pulm Circ 2020 Jul-Sep;10(3):2045894020941682. Epub 2020 Jul 23.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.

Pulmonary hypertension is frequently underdiagnosed, and referral is delayed with subsequent impact on outcomes. During the SARS-CoV-2 pandemic, restrictions on daily life and changes in hospitals' daily routine care were introduced in Germany. This multi-centre study provides evidence for a negative influence of these restrictions on patient care in pulmonary hypertension expert referral centres.
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http://dx.doi.org/10.1177/2045894020941682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378724PMC
July 2020

Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies).

Pulm Circ 2020 Jul-Sep;10(3):2045894020942121. Epub 2020 Jul 16.

Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and Institut National de la Santé et de la Recherche Médicale Unité 999, Le Kremlin-Bicêtre, France.

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg-maximum ( = 131 pretreated patients) and placebo ( = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: -8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.
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http://dx.doi.org/10.1177/2045894020942121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366414PMC
July 2020

Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF).

Eur J Heart Fail 2020 10 9;22(10):1891-1901. Epub 2020 Aug 9.

Internal Medicine III Cardiology, Angiology, Intensive Care, Saarland University Medical Centre, Homburg, Germany.

Aims: Heart failure (HF) leads to repeat hospitalisations and reduces the duration and quality of life. Pulmonary artery pressure (PAP)-guided HF management using the CardioMEMS™ HF system was shown to be safe and reduce HF hospitalisation (HFH) rates in New York Heart Association (NYHA) class III patients. However, these findings have not been replicated in health systems outside the United States. Therefore, the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) evaluated the safety, feasibility, and performance of this device in Germany, The Netherlands, and Ireland.

Methods And Results: A total of 234 NYHA class III patients (68 ± 11 years, 22% female, ≥1 HFH in the preceding year) from 31 centres were implanted with a CardioMEMS sensor and underwent PAP-guided HF management. One-year rates of freedom from device- or system-related complications and from sensor failure (co-primary outcomes) were 98.3% [95% confidence interval (CI) 95.8-100.0] and 99.6% (95% CI 97.6-100.0), respectively. Survival rate was 86.2%. For the 12 months post- vs. pre-implant, HFHs decreased by 62% (0.60 vs. 1.55 events/patient-year; hazard ratio 0.38, 95% CI 0.31-0.48; P < 0.0001). After 12 months, mean PAP decreased by 5.1 ± 7.4 mmHg, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall/clinical summary scores increased from 47.0 ± 24.0/51.2 ± 24.8 to 60.5 ± 24.3/62.4 ± 24.1 (P < 0.0001), and the 9-item Patient Health Questionnaire sum score improved from 8.7 ± 5.9 to 6.3 ± 5.1 (P < 0.0001).

Conclusion: Haemodynamic-guided HF management proved feasible and safe in the health systems of Germany, The Netherlands, and Ireland. Physician-directed treatment modifications based on remotely obtained PAP values were associated with fewer HFH, sustainable PAP decreases, marked KCCQ improvements, and remission of depressive symptoms.
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http://dx.doi.org/10.1002/ejhf.1943DOI Listing
October 2020

Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research.

Thromb Haemost 2020 Jul 30;120(7):1004-1024. Epub 2020 May 30.

New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, United States.

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.
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http://dx.doi.org/10.1055/s-0040-1713152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516364PMC
July 2020

Identifying potential parameters associated with response to switching from a PDE5i to riociguat in RESPITE.

Int J Cardiol 2020 Oct 24;317:188-192. Epub 2020 May 24.

Clinic for Respiratory Medicine, Hannover Medical School, member of the German Center for Lung Research (DZL), Hannover, Germany.

Background: RESPITE evaluated patients with pulmonary arterial hypertension and an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i) who switched to riociguat. This post hoc analysis assessed response to this switch in parameters associated with clinical improvement.

Methods: RESPITE was a 24-week, uncontrolled pilot study (n = 61). Differences in functional, hemodynamic, and cardiac function parameters, REVEAL risk score (RRS), and biomarkers were compared between responders (free from clinical worsening, World Health Organization functional class I/II, and ≥30 m improvement in 6-min walking distance at Week 24) and non-responders.

Results: Of 51 patients (84%) completing RESPITE, 16 (31%) met the responder endpoint. At baseline, there were significant differences between responders and non-responders in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15), and RRS, whereas there were no differences in hemodynamics or cardiac function. At Week 24, responders had significant improvements in pulmonary arterial compliance, pulmonary vascular resistance, and mean pulmonary arterial pressure, while non-responders showed no significant change. Cardiac efficiency and stroke volume index significantly improved irrespective of responder status.

Conclusions: NT-proBNP, GDF-15, and RRS were identified as potential predictors of response in patients switching from PDE5i to riociguat. Further prospective controlled studies are needed to confirm the association of these parameters with response.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.044DOI Listing
October 2020

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry.

J Clin Med 2020 05 13;9(5). Epub 2020 May 13.

Missionsärztliche Klinik gGmbH, Abteilung für Innere Medizin, 97074 Würzburg, Germany.

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension.

Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data.

Methods And Results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients´ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy ( = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status.

Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.
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http://dx.doi.org/10.3390/jcm9051456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290703PMC
May 2020

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 06 17;75(23):2950-2973. Epub 2020 Apr 17.

Center for Bioethics and Social Science in Medicine, University of Michigan, Ann Arbor, Michigan; Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan.

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.jacc.2020.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164881PMC
June 2020

Flow rate variance of a fully implantable pump for the delivery of intravenous treprostinil in pulmonary arterial hypertension.

Pulm Circ 2020 Jan-Mar;10(1):2045894020910136. Epub 2020 Mar 13.

German Center for Lung Research (DZL), Giessen, Germany.

Implantable infusion pumps might improve the convenience and safety of intravenous treprostinil for pulmonary arterial hypertension. The LENUS Pro® pump (approved in Europe) has a fixed flow rate. Based on 126 pumps and 2853 refills, we retrospectively analyzed the actual flow rate from 09/2010 to 09/2018. A relevant flow rate variance is evident after three years; therefore, flow rate monitoring and dose adjustment are mandatory.
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http://dx.doi.org/10.1177/2045894020910136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074510PMC
March 2020
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