Publications by authors named "Henning Gall"

111 Publications

Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2.

Commun Biol 2021 08 24;4(1):1002. Epub 2021 Aug 24.

Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Member of the German Center for Lung Research (DZL), Justus-Liebig-University Giessen, Giessen, Germany.

Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH.
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http://dx.doi.org/10.1038/s42003-021-02531-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385080PMC
August 2021

Generation of pulmonary arterial hypertension patient-specific induced pluripotent stem cell lines from three unrelated patients with a heterozygous missense mutation in exon 12, a heterozygous in-frame deletion in exon 3 and a missense mutation in exon 11 of the BMPR2 gene.

Stem Cell Res 2021 Aug 5;55:102488. Epub 2021 Aug 5.

Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany; REBIRTH - Research Centre for Translational and Regenerative Medicine, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Centre for Lung Research (DZL), Germany. Electronic address:

Loss-of-function mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene are common in heritable or idiopathic pulmonary arterial hypertension (PAH), and can result in functional impairment of both endothelial and vascular smooth muscle cells. Here, we report 3 PAH patient-specific induced pluripotent stem cells (iPSC) lines from 3 unrelated patients harbouring different mutations in the BMPR2 gene: a heterozygous missense mutation in exon 12, a heterozygous frame shift deletion in exon 3, and a heterozygous missense mutation in exon 11. These cell lines will serve as a valuable resource to model PAH in vitro.
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http://dx.doi.org/10.1016/j.scr.2021.102488DOI Listing
August 2021

Exercise Hemodynamic Profiling Is Associated With Outcome in Patients Undergoing Percutaneous Mitral Valve Repair.

Circ Cardiovasc Interv 2021 Sep 11;14(9):e010453. Epub 2021 Aug 11.

Department of Cardiology (A.J.R., S.D.K., E.W., U.F.-R., V.M., C.W.H., C.L., C.W.), Kerckhoff-Klinik, Bad Nauheim, Germany.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.010453DOI Listing
September 2021

Osteopontin and galectin-3 as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension.

Biomark Med 2021 Aug 22;15(12):1021-1034. Epub 2021 Jul 22.

Department of Cardiology & Angiology, University of Giessen, Giessen, 35392, Germany.

This study assessed the utility of osteopontin (OPN) and galectin-3 (Gal-3) as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension (PH). We examined plasma levels of OPN and Gal-3 in patients with PH (n = 62), dilated cardiomyopathy (n = 34), left ventricular hypertrophy (LVH; n = 47), and controls without right ventricle (RV) or LV abnormalities (n = 38). OPN and Gal-3 levels were higher in PH, dilated cardiomyopathy and LVH than in the controls. OPN concentrations in PH patients with maladaptive RV were significantly higher than in those with adaptive RV. Gal-3 did not differentiate between adaptive and maladaptive RV remodeling in PH. OPN and Gal-3 levels did not correlate with parameters of LV remodeling. OPN is a potential biomarker of RV maladaptation.
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http://dx.doi.org/10.2217/bmm-2021-0009DOI Listing
August 2021

Impact of SARS-CoV-2-Pandemic on Mental Disorders and Quality of Life in Patients With Pulmonary Arterial Hypertension.

Front Psychiatry 2021 24;12:668647. Epub 2021 Jun 24.

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.

Covid-19 pandemic may affect mental health and quality of life (QoL) in patients with pulmonary arterial hypertension (PAH). We assessed changes in anxiety and depression, quality of life (QoL) and self-described impact of Covid-19 in patients with PAH during the Covid-19 pandemic. This study included 152 patients with PAH from two German referral centers. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS-A and HADS-D) at two different timepoints before and during the Covid-19 pandemic with a median of 232 days between baseline and follow-up. QoL was assessed using EQ-5D and emPHasis-10. Perceived impact of Covid-19 and related regulations and measures were assessed using a set of specific questions and statements. More than two thirds of patients had an unsuspicious HADS-A and HADS-D. Median scores did not differ from baseline for both HADS-A and HADS-D ( = 0.202; = 0.621). Overall, no significant changes in HADS-A or HADS-D categories from baseline to follow up were observed ( = 0.07; = 0.13). QoL did not change between baseline and follow-up. The Covid-19 pandemic had little impact on access to medical care and established PAH therapy. Patients were in agreement with governmental measures and regulations and felt sufficiently safe. First waves of Covid-19 pandemic had little impact on anxiety, depression and QoL in patient with PAH. Established PAH therapy and access to medical care were not affected. Further studies on the impact of prolonged duration of the ongoing Covid-19 pandemic are needed.
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http://dx.doi.org/10.3389/fpsyt.2021.668647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263927PMC
June 2021

Prevalence of Mental Disorders and Impact on Quality of Life in Patients With Pulmonary Arterial Hypertension.

Front Psychiatry 2021 31;12:667602. Epub 2021 May 31.

Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.

Mental health may affect the quality of life (QoL) in patients with pulmonary arterial hypertension (PAH). However, mental disorders have not been systematically assessed in these patients. We examined the prevalence of mental disorders using structured interviews and determined their impact on QoL in patients with PAH. This study included 217 patients with PAH from two German referral centers. Psychiatric disorders were assessed using the structured clinical interview for DSM-V. QoL was assessed using the WHO Quality of Life questionnaire (short form). The diagnostic value of the Hospital Anxiety and Depression Scale was evaluated by receiver operating characteristic curve analysis. More than one third of the patients had psychological disorders with current or past adjustment disorder (38.2%), current major depressive disorder (23.0%), and panic disorder (15.2%) being the most prevalent mental illnesses. About half of the patients with a history of adjustment disorder developed at least one other mental illness. The presence of mental disorders had a profound impact on QoL. The Hospital Anxiety and Depression Scale ruled out panic disorder and depression disorder with negative predictive values of almost 90%. Mental disorders, in particular adjustment disorder, major depression, and panic disorder, are common in patients with PAH and contribute to impaired QoL in these patients. The Hospital Anxiety and Depression Scale may be used as a screening tool for the most common mental health disorders. Future studies need to address interventional strategies targeting mental disorders in patients with PAH.
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http://dx.doi.org/10.3389/fpsyt.2021.667602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200462PMC
May 2021

Exercise hemodynamics in heart failure patients with preserved and mid-range ejection fraction: key role of the right heart.

Clin Res Cardiol 2021 Jun 10. Epub 2021 Jun 10.

Department of Cardiology, Kerckhoff-Klinik GmbH, Benekestr 2-8, 61231, Bad Nauheim, Germany.

Objective: We sought to explore whether classification of patients with heart failure and mid-range (HFmrEF) or preserved ejection fraction (HFpEF) according to their left ventricular ejection fraction (LVEF) identifies differences in their exercise hemodynamic profile, and whether classification according to an index of right ventricular (RV) function improves differentiation.

Background: Patients with HFmrEF and HFpEF have hemodynamic compromise on exertion. The classification according to LVEF implies a key role of the left ventricle. However, RV involvement in exercise limitation is increasingly recognized. The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/PASP) ratio is an index of RV and pulmonary vascular function. Whether exercise hemodynamics differ more between HFmrEF and HFpEF than between TAPSE/PASP tertiles is unknown.

Methods: We analyzed 166 patients with HFpEF (LVEF ≥ 50%) or HFmrEF (LVEF 40-49%) who underwent basic diagnostics (laboratory testing, echocardiography at rest, and cardiopulmonary exercise testing [CPET]) and exercise with right heart catheterization. Hemodynamics were compared according to echocardiographic left ventricular or RV function.

Results: Exercise hemodynamics (e.g. pulmonary arterial wedge pressure/cardiac output [CO] slope, CO increase during exercise, and maximum total pulmonary resistance) showed no difference between HFpEF and HFmrEF, but significantly differed across TAPSE/PASP tertiles and were associated with CPET results. N-terminal pro-brain natriuretic peptide concentration also differed significantly across TAPSE/PASP tertiles but not between HFpEF and HFmrEF.

Conclusion: In patients with HFpEF or HFmrEF, TAPSE/PASP emerged as a more appropriate stratification parameter than LVEF to predict clinically relevant impairment of exercise hemodynamics. Stratification of exercise hemodynamics in patients with HFpEF or HFmrEF according to LVEF or TAPSE/PASP, showing significant distinctions only with the RV-based strategy. All data are shown as median [upper limit of interquartile range] and were calculated using the independent-samples Mann-Whitney U test or Kruskal-Wallis test. PVR pulmonary vascular resistance; max maximum level during exercise.
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http://dx.doi.org/10.1007/s00392-021-01884-1DOI Listing
June 2021

Validity of echocardiographic tricuspid regurgitation gradient to screen for new definition of pulmonary hypertension.

EClinicalMedicine 2021 Apr 5;34:100822. Epub 2021 Apr 5.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Centre (UGMLC, Member of the German Centre for Lung Research (DZL), Klinikstrasse 32, 35392, Germany.

Background: Currently an echocardiographic threshold for the tricuspid regurgitation gradient (TRG) of > 31 mmHg is recommended for screening for pulmonary hypertension (PH). Invasively diagnosed PH was recently redefined as mean pulmonary arterial pressure (mPAP) > 20 mmHg instead of ≥ 25 mmHg. We investigated the ability of TRG to screen for the new PH-definition.

Methods: Retrospective assessment of echocardiography and right heart catheterisation data from 1572 patients entering the Giessen PH-Registry during 2008-2018. Accuracy of different TRG thresholds and other echocardiographic parameters was evaluated using receiver operating characteristic curves.

Findings: 1264 patients fulfilled the new PH-definition. Positive (PPV) and negative predictive values and accuracy of TRG > 46 mmHg were 95%, 39%, and 73%, respectively, for the new PH-definition. Lowering the TRG cut-off to 31 mmHg and below worsened PPV to ≤ 89%. The PPV of TRG for pre-capillary PH (mPAP > 20 mmHg and pulmonary vascular resistance ≥ 3 Wood Units) was ≤ 85%. In patients with TRG ≤ 46 mmHg, tricuspid annular plane systolic excursion/TRG and TRG/right ventricular outflow tract acceleration time were superior to TRG in screening for newly defined pre-capillary PH.

Interpretation: In patients with suspected PH referred to a tertiary care centre, the PPV of TRG to meet the new PH-definition depended strongly on the TRG cut-off used. Our data do not support lowering the TRG cut-off. Combining TRG with other echocardiographic parameters might improve the validity of echocardiographic screening for PH.
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http://dx.doi.org/10.1016/j.eclinm.2021.100822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102717PMC
April 2021

Supplementation with Iron in Pulmonary Arterial Hypertension. Two Randomized Crossover Trials.

Ann Am Thorac Soc 2021 06;18(6):981-988

National Heart and Lung Institute and.

Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. To evaluate the safety and efficacy of parenteral iron replacement in PAH. In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 μg/L or iron <10.3 μmol/L or transferrin saturations <16.4%. Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).
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http://dx.doi.org/10.1513/AnnalsATS.202009-1131OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456720PMC
June 2021

A novel non-invasive and echocardiography-derived method for quantification of right ventricular pressure-volume loops.

Eur Heart J Cardiovasc Imaging 2021 Feb 28. Epub 2021 Feb 28.

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), Klinikstrasse 32, Giessen 35392, Germany.

Aims: We sought to assess the feasibility of constructing right ventricular (RV) pressure-volume (PV) loops solely by echocardiography.

Methods And Results: We performed RV conductance and pressure wire (PW) catheterization with simultaneous echocardiography in 35 patients with pulmonary hypertension. To generate echocardiographic PV loops, a reference RV pressure curve was constructed using pooled PW data from the first 20 patients (initial cohort). Individual pressure curves were then generated by adjusting the reference curve according to RV isovolumic and ejection phase duration and estimated RV systolic pressure. The pressure curves were synchronized with echocardiographic volume curves. We validated the reference curve in the remaining 15 patients (validation cohort). Methods were compared with correlation and Bland-Altman analysis. In the initial cohort, echocardiographic and conductance-derived PV loop parameters were significantly correlated {rho = 0.8053 [end-systolic elastance (Ees)], 0.8261 [Ees/arterial elastance (Ea)], and 0.697 (stroke work); all P < 0.001}, with low bias [-0.016 mmHg/mL (Ees), 0.1225 (Ees/Ea), and -39.0 mmHg mL (stroke work)] and acceptable limits of agreement. Echocardiographic and PW-derived Ees were also tightly correlated, with low bias (-0.009 mmHg/mL) and small limits of agreement. Echocardiographic and conductance-derived Ees, Ees/Ea, and stroke work were also tightly correlated in the validation cohort (rho = 0.9014, 0.9812, and 0.9491, respectively; all P < 0.001), with low bias (0.0173 mmHg/mL, 0.0153, and 255.1 mmHg mL, respectively) and acceptable limits.

Conclusion: The novel echocardiographic method is an acceptable alternative to invasively measured PV loops to assess contractility, RV-arterial coupling, and RV myocardial work. Further validation is warranted.
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http://dx.doi.org/10.1093/ehjci/jeab038DOI Listing
February 2021

Right ventricular pressure-volume loop shape and systolic pressure change in pulmonary hypertension.

Am J Physiol Lung Cell Mol Physiol 2021 05 3;320(5):L715-L725. Epub 2021 Mar 3.

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

Right ventricular (RV) function determines outcome in pulmonary arterial hypertension (PAH). RV pressure-volume loops, the gold standard for measuring RV function, are difficult to analyze. Our aim was to investigate whether simple assessments of RV pressure-volume loop morphology and RV systolic pressure differential reflect PAH severity and RV function. We analyzed multibeat RV pressure-volume loops (obtained by conductance catheterization with preload reduction) in 77 patients with PAH and 15 patients without pulmonary hypertension in two centers. Patients were categorized according to their pressure-volume loop shape (triangular, quadratic, trapezoid, or notched). RV systolic pressure differential was defined as end-systolic minus beginning-systolic pressure (ESP - BSP), augmentation index as ESP - BSP/pulse pressure, pulmonary arterial capacitance (PAC) as stroke volume/pulse pressure, and RV-arterial coupling as end-systolic/arterial elastance (Ees/Ea). Trapezoid and notched pressure-volume loops were associated with the highest afterload (Ea), augmentation index, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, stroke work, B-type natriuretic peptide, and the lowest Ees/Ea and PAC. Multivariate linear regression identified Ea, PVR, and stroke work as the main determinants of ESP - BSP. ESP - BSP also significantly correlated with multibeat Ees/Ea (Spearman's ρ: -0.518, < 0.001). A separate retrospective analysis of 113 patients with PAH showed that ESP - BSP obtained by routine right heart catheterization significantly correlated with a noninvasive surrogate of RV-arterial coupling (tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio; ρ: -0.376, < 0.001). In conclusion, pressure-volume loop shape and RV systolic pressure differential predominately depend on afterload and PAH severity and reflect RV-arterial coupling in PAH.
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http://dx.doi.org/10.1152/ajplung.00583.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174826PMC
May 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

Temporarily switching from oral to intravenous selexipag in patients with pulmonary arterial hypertension: safety, tolerability, and pharmacokinetic results from an open-label, phase III study.

Respir Res 2021 Feb 3;22(1):34. Epub 2021 Feb 3.

Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.

Background: The oral IP receptor agonist selexipag is approved for the long-term treatment of pulmonary arterial hypertension (PAH). Treatment interruptions should be avoided due to the progressive nature of the disease. An intravenous (IV) formulation of selexipag was developed to provide a treatment option for short-term interruptions to oral selexipag. In this prospective, multicenter, open-label study, the safety, tolerability, and pharmacokinetics of temporarily switching between oral and IV selexipag were investigated (NCT03187678, ClinicalTrials.gov).

Methods: PAH patients receiving stable oral selexipag doses were enrolled. Following three consecutive IV selexipag infusions patients resumed oral selexipag. Corresponding IV and oral doses were selected to achieve comparable exposure to the active metabolite of selexipag. Safety outcomes were monitored throughout, and pharmacokinetic samples were obtained after oral and IV administration.

Results: All 20 patients completed the study. Fifteen patients had adverse events (AEs), most were mild, and none resulted in discontinuation. Headache was the most common AE throughout the study (four patients). Three serious AEs occurred in two patients with underlying comorbidities when oral dosing had resumed. There were no changes in WHO functional class for any patient and no clinically symptomatic changes in blood pressure were observed. Comparable exposure to the active metabolite of selexipag was demonstrated following corresponding oral and IV selexipag doses.

Conclusions: Temporarily switching between corresponding doses of oral and IV selexipag was well-tolerated with no unexpected safety findings and comparable exposure to the active metabolite. Treatment with IV selexipag is a feasible option to bridge temporary oral selexipag treatment interruptions.
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http://dx.doi.org/10.1186/s12931-020-01594-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856757PMC
February 2021

Reply to "Risk stratification in PH associated with interstitial lung disease: The Holy Grail?"

J Heart Lung Transplant 2021 04 12;40(4):317. Epub 2021 Jan 12.

Department of Internal Medicine, University Hospital Giessen, German Center of Lung Research (DZL), Giessen, Germany; Department of Medicine, University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.healun.2021.01.003DOI Listing
April 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

Physical Activity and Mental Health of Patients with Pulmonary Hypertension during the COVID-19 Pandemic.

J Clin Med 2020 Dec 12;9(12). Epub 2020 Dec 12.

Department of Exercise Physiology and Sports Therapy, Institute of Sports Science, Justus Liebig University Giessen, 35394 Giessen, Germany.

The aim of the study was to analyze the effect of personal restrictions on physical activity, mental health, stress experience, resilience, and sleep quality in patients with pulmonary hypertension (PH) during the "lockdown" period of the COVID-19 pandemic. In total, 112 PH patients and 52 age-matched healthy control subjects completed a questionnaire on the topics of physical activity, mental health, resilience, and sleep quality. PH patients had significantly lower physical activity, mental health, and sleep quality compared to age-matched healthy controls. Physical activity positively correlated with mental health and sleep quality in the PH group. Mental wellbeing and life satisfaction could be predicted by total physical activity, sleep, stress level, and resilience. PH patients appeared as an especially vulnerable group, demanding interventions to promote an active lifestyle and protect mental health in these patients. This could be helpful in counseling on how to carry out physical activity while maintaining infection control.
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http://dx.doi.org/10.3390/jcm9124023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763755PMC
December 2020

Bayesian Inference Associates Rare Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.

Circ Genom Precis Med 2020 Dec 15. Epub 2020 Dec 15.

Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay & AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire & INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.

- Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor () gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in . Four additional PAH cases with rare likely loss-of-function variants in were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. - The Bayesian inference approach allowed us to independently validate , which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
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http://dx.doi.org/10.1161/CIRCGEN.120.003155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892262PMC
December 2020

Congestive nephropathy: a neglected entity? Proposal for diagnostic criteria and future perspectives.

ESC Heart Fail 2021 02 30;8(1):183-203. Epub 2020 Nov 30.

Department of Internal Medicine II, Division of Nephrology, University Hospital Giessen and Marburg, Klinikstrasse 33, 35392, Giessen, Germany.

Venous congestion has emerged as an important cause of renal dysfunction in patients with cardiorenal syndrome. However, only limited progress has been made in differentiating this haemodynamic phenotype of renal dysfunction, because of a significant overlap with pre-existing renal impairment due to long-term hypertension, diabetes, and renovascular disease. We propose congestive nephropathy (CN) as this neglected clinical entity. CN is a potentially reversible subtype of renal dysfunction associated with declining renal venous outflow and progressively increasing renal interstitial pressure. Venous congestion may lead to a vicious cycle of hormonal activation, increased intra-abdominal pressure, excessive renal tubular sodium reabsorption, and volume overload, leading to further right ventricular (RV) stress. Ultimately, renal replacement therapy may be required to relieve diuretic-resistant congestion. Effective decongestion could preserve or improve renal function. Congestive acute kidney injury may not be associated with cellular damage, and complete renal function restoration may be a confirmatory diagnostic criterion. In contrast, a persistently low renal perfusion pressure might induce renal dysfunction and histopathological lesions with time. Thus, urinary markers may differ. CN is mostly seen in biventricular heart failure but may also occur secondary to pulmonary arterial hypertension and elevated intra-abdominal pressure. An increase in central venous pressure to >6 mmHg is associated with a steep decrease in glomerular filtration rate. However, the central venous pressure range that can provide an optimal balance of RV and renal function remains to be determined. We propose criteria to identify cardiorenal syndrome subgroups likely to benefit from decongestive or pulmonary hypertension-specific therapies and suggest areas for future research.
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http://dx.doi.org/10.1002/ehf2.13118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835563PMC
February 2021

CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension.

Eur Respir J 2021 04 1;57(4). Epub 2021 Apr 1.

University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany.

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001) and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in receiver operating characteristic analysis (area under the curve (AUC) 0.79). There was no significant difference between the AUCs of CILP1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) (AUC 0.82). High CILP1 (cut-off value for maladaptive RV of ≥4373 pg·mL) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (p<0.001) and higher NT-proBNP levels (p<0.001).CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.
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http://dx.doi.org/10.1183/13993003.01192-2019DOI Listing
April 2021

Advanced risk stratification of intermediate risk group in pulmonary arterial hypertension.

Pulm Circ 2020 Oct-Dec;10(4):2045894020961739. Epub 2020 Oct 7.

Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.

In 301 treatment-naïve patients with pulmonary arterial hypertension stratified by the European Society of Cardiology/European Respiratory Society risk score, further stratification of intermediate-risk patients based on six-minute walk distance and the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio identified a subset with mortality rates comparable to low-risk patients.
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http://dx.doi.org/10.1177/2045894020961739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545769PMC
October 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

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

Risk assessment in severe pulmonary hypertension due to interstitial lung disease.

J Heart Lung Transplant 2020 10 25;39(10):1118-1125. Epub 2020 Jun 25.

Department of Internal Medicine, Justus-Liebig University Giessen, Giessen, Germany. Electronic address:

Background: The updated hemodynamic definition of pulmonary hypertension (PH) due to interstitial lung disease (ILD) differentiates severe and non-severe phenotypes, but no further risk stratification strategy has been established or validated for severe PH due to ILD. We aimed to assess the prognostic value of a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH risk stratification scheme in severe PH due to ILD.

Methods: We retrospectively analyzed 185 patients with severe PH (mean pulmonary artery pressure of ≥35 mm Hg or ≥25 mm Hg with cardiac index <2.0 liter/min/m) due to ILD who were enrolled in the Giessen PH Registry after being referred for invasive diagnostic work-up of suspected PH during 1995‒2018. A truncated ESC/ERS risk stratification scheme (based on 8 parameters from the full scheme) was applied. Kaplan-Meier and univariate Cox regression analyses were used to evaluate transplant-free survival and hazard ratios, respectively.

Results: During follow-up (median [interquartile range]: 19 [7-40] months), 146 events occurred. Using baseline data for risk stratification, 5-year transplant-free survival of low-, intermediate-, and high-risk groups was 43%, 15%, and 4%, respectively (log-rank p = 0.010; hazard ratio of high- vs low-risk group: 3.116 [95% CI: 1.428-6.800]). Using follow-up data (at 11 [6.0-32.5] months) for risk stratification, 5-year survival of low-, intermediate-, and high-risk groups was 22%, 3%, and 0%, respectively (log-rank p = 0.005).

Conclusions: The truncated ESC/ERS scheme was clinically useful and demonstrated prognostic relevance in severe PH due to ILD.
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http://dx.doi.org/10.1016/j.healun.2020.06.014DOI Listing
October 2020

Data Integration into OMOP CDM for Heterogeneous Clinical Data Collections via HL7 FHIR Bundles and XSLT.

Stud Health Technol Inform 2020 Jun;270:138-142

UGMLC, German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.

Data integration is an important task in medical informatics and highly impacts the gain out of existing health information data. These tasks are using implemented as extract transform and load processes. By introducing HL7 FHIR as an intermediate format, our aim was to integrate heterogeneous data from a German pulmonary hypertension registry into an OMOP Common Data Model. First, domain knowledge experts defined a common parameter set, which was subsequently mapped to standardized terminologies like LOINC or SNOMED-CT. Data was extracted as HL7 FHIR Bundle to be transformed to OMOP CDM by using XSLT. We successfully transformed the majority of data elements to the OMOP CDM in a feasible time.
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http://dx.doi.org/10.3233/SHTI200138DOI Listing
June 2020

Right ventricular dyssynchrony: from load-independent right ventricular function to wall stress in severe pulmonary arterial hypertension.

Pulm Circ 2020 Apr-Jun;10(2):2045894020925759. Epub 2020 May 18.

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.

Right ventricular (RV) dyssynchrony has been related to outcome in pulmonary arterial hypertension. Prospectively, we performed echocardiography with measurement of right ventricular dyssynchrony and pressure-volume loop catheterization in 27 pulmonary arterial hypertension patients. Afterload and diastolic function emerged as determinates of wall stress, which results in dyssynchrony.
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http://dx.doi.org/10.1177/2045894020925759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235672PMC
May 2020

A comprehensive echocardiographic method for risk stratification in pulmonary arterial hypertension.

Eur Respir J 2020 09 24;56(3). Epub 2020 Sep 24.

University Hospital Giessen und Marburg GmbH, Pulmonary Hypertension Division, Medical Clinic II, Giessen, Germany.

Question Addressed: Echocardiography is not currently considered as providing sufficient prognostic information to serve as an integral part of treatment goals in pulmonary arterial hypertension (PAH). We tested the hypothesis that incorporation of multiple parameters reflecting right heart function would improve the prognostic value of this imaging modality.

Methods And Main Results: We pooled individual patient data from a total of 517 patients (mean age 52±15 years, 64.8% females) included in seven observational studies conducted at five European and United States academic centres. Patients were subdivided into three groups representing progressive degrees of right ventricular dysfunction based on a combination of echocardiographic measurements, as follows. Group 1 (low risk): normal tricuspid annular plane systolic excursion (TAPSE) and nonsignificant tricuspid regurgitation (TR) (n=129); group 2 (intermediate risk): normal TAPSE and significant TR or impaired TAPSE and nondilated inferior vena cava (IVC) (n=256); group 3 (high risk): impaired TAPSE and dilated IVC (n=132). The 5-year cumulative survival rate was 82% in group 1, 63% in group 2 and 43% in group 3. Low-risk patients had better survival rates than intermediate-risk patients (log-rank Chi-squared 12.25; p<0.001) and intermediate-risk patients had better survival rates than high-risk patients (log-rank Chi-squared 26.25; p<0.001). Inclusion of other parameters such as right atrial area and pericardial effusion did not provide added prognostic value.

Answer To The Question: The proposed echocardiographic approach integrating the evaluation of TAPSE, TR grade and IVC is effective in stratifying the risk for all-cause mortality in PAH patients, outperforming the prognostic parameters suggested by current guidelines.
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http://dx.doi.org/10.1183/13993003.00513-2020DOI Listing
September 2020

Evaluation of pulmonary hypertension by right heart catheterisation: does timing matter?

Eur Respir J 2020 09 3;56(3). Epub 2020 Sep 3.

Dept 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.

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http://dx.doi.org/10.1183/13993003.01892-2019DOI Listing
September 2020

Comparison of MRI and VQ-SPECT as a Screening Test for Patients With Suspected CTEPH: CHANGE-MRI Study Design and Rationale.

Front Cardiovasc Med 2020 9;7:51. Epub 2020 Apr 9.

Sheffield Pulmonary Vascular Disease Unit, Royal Hallamhire Hospital, Sheffield, United Kingdom.

The diagnostic strategy for chronic thromboembolic pulmonary hypertension (CTEPH) is composed of two components required for a diagnosis of CTEPH: the presence of chronic pulmonary embolism and an elevated pulmonary artery pressure. The current guidelines require that ventilation-perfusion single-photon emission computed tomography (VQ-SPECT) is used for the first step diagnosis of chronic pulmonary embolism. However, VQ-SPECT exposes patients to ionizing radiation in a radiation sensitive population. The prospective, multicenter, comparative phase III diagnostic trial TEP diosis urope - MRI (CHANGE-MRI, ClinicalTrials.gov identifier ) aims to demonstrate whether functional lung MRI can serve as an equal rights alternative to VQ-SPECT in a diagnostic strategy for patients with suspected CTEPH. Positive findings are verified with catheter pulmonary angiography or computed tomography pulmonary angiography (gold standard). For comparing the imaging methods, a co-primary endpoint is used. (i) the proportion of patients with positive MRI in the group of patients who have a positive SPECT and gold standard diagnosis for chronic pulmonary embolism and (ii) the proportion of patients with positive MRI in the group of patients with negative SPECT and gold standard. The CHANGE-MRI trial will also investigate the performance of functional lung MRI without i.v. contrast agent as an index test and identify cardiac, hemodynamic, and pulmonary MRI-derived parameters to estimate pulmonary artery pressures and predict 6-12 month survival. Ultimately, this study will provide the necessary evidence for the discussion about changes in the recommendations on the diagnostic approach to CTEPH.
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http://dx.doi.org/10.3389/fcvm.2020.00051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161347PMC
April 2020
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