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Here we preregister the analysis plan for confirmatory analyses with the final BT sample.

ZusammenfassungKongenitale Pulmonalarterienstenosen sind eine seltene Ursache der pulmonalen Hypertonie (PH). Die Erkrankung wird in ihrer Häufigkeit vermutlich unterschätzt, und sie sollte in der Abklärung einer PH bedacht werden.Die Vorstellung einer 43-jährigen Patientin erfolgte zur Therapieoptimierung und Evaluation einer möglichen Lungentransplantation mit der Arbeitsdiagnose kongenitale Pulmonalarterienstenosen.Die Patientin beklagte eine seit der frühen Kindheit bestehende Belastungsdyspnoe aktuell entsprechend WHO-FC-Klasse II–III.Die Krankengeschichte zeigte die Erstdiagnose einer primären pulmonalarteriellen Hypertonie (IPAH) vor 17 Jahren. Es erfolgte eine PH-spezifische Medikation in wechselnden Kombinationen. Im Rahmen eines Zentrumswechsels erfolgte eine Reevaluation, und bei Nachweis eines typischen Mismatch mit normaler Ventilation, jedoch keilförmig gestörter Perfusion in der Lungenszintigrafie wurde eine chronisch thromboembolische pulmonale Hypertonie (CTEPH) vermutet. Die Pulmonalis-Angiografie zeigte ausschließlich subsegmental gelegene Stenosierungen sowie Gefäßabbrüche mit korrespondierenden Minderperfusionen, passend zu einer CTEPH. Im Rahmen der ersten Intervention erfolgte aufgrund der ungewöhnlichen Morphologie der pulmonalarteriellen Läsionen eine Erweiterung der Diagnostik mittels optischer Kohärenztomografie (OCT). Bei der Patientin fand sich kein endoluminales Material, jedoch eine kräftige Gefäßwand. Damit wurde die Diagnose einer pumonalen Hypertonie bei kongenitalen Pulmonalarterienstenosen mit In-situ-Thrombosierung gestellt.

BackgroundDefective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown.MethodsANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells.ResultsCirculating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-β1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels.ConclusionOur findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH.

Introduction Copeptin is the C-terminal fragment of the precursor protein of vasopressin. In acute pulmonary embolism, copeptin has been suggested to be a strong predictor of outcome and to provide additional predictive value to the established cardiac biomarkers high-sensitivity cardiac troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP). Chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in about 5% of patients who survive acute pulmonary embolism. Individualized risk stratification remains a challenge in the work-up of CTEPH patients. Purpose The current study investigated whether copeptin has the potential to aid the stratification of patients who have experienced pulmonary embolism and CTEPH patients. We examined the baseline (BL) levels and dynamics of copeptin during therapy in CTEPH patients who underwent balloon pulmonary angioplasty (BPA) or pulmonary endarterectomy (PEA). Moreover, the study compared copeptin levels between patients with or without therapy response. Methods The study included a total of 125 CTEPH patients scheduled for treatment. A total of 78 underwent staged BPA and 64 underwent PEA. In accordance with recent studies from our group, therapy success was defined as a decrease in meanPAP ≥25% and PVR ≥35% or a normalization below the thresholds defining pulmonary hypertension. Blood samples were collected at BL, prior to each BPA session in the BPA cohort, and at follow-up (FU) 6 months after BPA or 12 months after PEA. Copeptin was measured in thawed serum aliquots by an immunochemical method. Results The 78 patients in the BPA cohort underwent a mean of 6 BPA procedures each; there were a total of 413 interventions. The hemodynamic clinical and functional status the CTEPH patients improved after BPA and PEA therapy: meanPAP (BL: 43±9 mmHg vs. FU: 27±9 mmHg; p The median serum levels of copeptin [BL 7.7 (4.6–14.2) pmol/L vs. FU 6.3 (3.9–12.5); p=0.009] and NT-proBNP [BL: 811 (157–1857) ng/L vs. FU: 142 (72–335) ng/L p Conclusions Copeptin levels are elevated in CTEPH patients compared with normal values in the literature. Although copeptin is known to provide additional value in the context of risk stratification in acute pulmonary embolism, it failed to provide additional diagnostic benefit in CTEPH in the current study. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): SFB 1213 area CP01

Background Chronic thromboembolic pulmonary hypertension (CTEPH) leads to right heart failure. Pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) restore pulmonary haemodynamics and allow cardiac recovery. This study examined the relationship of copeptin and mid-regional pro-atrial natriuretic peptide (MR-proANP) levels to disease severity and therapy response. Methods This observational cohort study included 125 patients (55 PEA/70 BPA) who underwent treatment and completed a 6-/12-month follow-up. Biomarkers, measured at baseline, prior to every BPA and at follow-up, were compared to 1) severe disease at baseline (right atrial pressure (RAP) ≥8 mmHg and cardiac index ≤2.4 L·min−1·m−2) and 2) optimal therapy response (no persistent pulmonary hypertension combined with a normalised RAP (mean PAP ≤25 mmHg, pulmonary vascular resistance (PVR) ≤3 WU and RAP ≤6 mmHg) or a reduction in mean PAP ≥25%, PVR ≥35% and RAP ≥25%). Results Severely diseased patients had higher levels of MR-proANP (320 (246–527) pmol·L−1 versus 133 (82–215) pmol·L−1; p=0.001) and copeptin (12.7 (7.3–20.6) pmol·L−1 versus 6.8 (4.4–12.8) pmol·L−1; p=0.015) at baseline than the rest of the cohort. At baseline, MR-proANP (area under the curve (AUC) 0.91; cut-off value 227 pmol·L−1; OR 56, 95% CI 6.9–454.3) and copeptin (AUC 0.70; cut-off value 10.9 pmol·L−1; OR 1.5, 95% CI 1.2–1.9) identified severely diseased patients. After PEA/BPA, levels of MR-proANP (99 (58–145) pmol·L−1; p, The assessment of cardiac stress and impact of therapy is crucial in CTEPH. Serum levels of MR-proANP are associated with haemodynamic disease severity and therapy response, and might thus support individualised patient management. https://bit.ly/2QKwb7x

Background * These authors contributed equally as last authors. Balloon pulmonary angioplasty is an evolving, interventional treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension at rest as well as exercise capacity is considered to be relevant outcome parameters. The aim of the present study was to determine whether measurement of pulmonary hemodynamics during exercise before and six months after balloon pulmonary angioplasty have an added value. Methods From March 2014 to July 2018, 172 consecutive patients underwent balloon pulmonary angioplasty. Of these, 64 consecutive patients with inoperable CTEPH underwent a comprehensive diagnostic workup that included right heart catheterization at rest and during exercise before balloon pulmonary angioplasty treatments and six months after the last intervention. Results Improvements in pulmonary hemodynamics at rest and during exercise, in quality of life, and in exercise capacity were observed six months after balloon pulmonary angioplasty: WHO functional class improved in 78% of patients. The mean pulmonary arterial pressure (mPAP) at rest was reduced from 41 ± 9 to 31 ± 9 mmHg (p

The aim of this study was to assess effects of balloon pulmonary angioplasty (BPA) on right ventricular (RV) mechanical dysfunction in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) via MRI.MRI at 1.5 Tesla and right heart catheterization were performed before and 6 months after BPA in 30 CTEPH patients (mean age 63.4 ± 10.6 years; 17 female). Feature-tracking strain analysis, including global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain, was performed and compared with right ventricular function, myocardial remodelling (assessed by native T1 times), and pulmonary haemodynamics (mean pulmonary arterial pressure and pulmonary vascular resistance).RVEF (35.9% to 48.4%) increased and mPAP (42.1 mmHg to 33.1 mmHg) and PVR (551.8 to 377.7 dyn∙s/cmRV mechanical dysfunction, pulmonary haemodynamics, and myocardial remodelling are markedly improved by BPA. Moreover, RV strain values showed good correlations with RV function, pulmonary haemodynamics, and myocardial remodelling. Therefore, strain analysis might provide new insights regarding therapy outcome, monitoring, and prognosis.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often caused by recurrent emboli. These are also frequently found in patients with myeloproliferative diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening was conducted for pathogenic variants using a gene panel based on next generation sequencing. CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients 4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A&gt, T p.Lys691*) in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant, c.1849G&gt, T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected (p &lt, 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought. The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be considered also for CTEPH patients.