New potential diagnostic biomarkers for pulmonary hypertension

Tiede, Svenja Lena; Gall, Henning; Dörr, Oliver; Troidl, Christian; Liebetrau, Christoph; Voss, Sandra; Voswinckel, Robert; Schermuly, Ralph Theo; Seeger, Werner; Grimminger, Friedrich; Zeiher, Andreas M.; Dimmeler, Stefanie; Möllmann, Helge; Hamm, Christian W.; Ghofrani, Hossein Ardeschir; Nef, Holger

doi:10.1183/13993003.00187-2015

Cited by 33 publications

(26 citation statements)

References 37 publications

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“…Analysis of NT-proBNP is available in several laboratories, and the normal upper limit is 300 ng/l at our laboratory. While patients with PH can have normal values of BNPs ( 10 ), other studies are in agreement with our finding that a value in the lower spectrum of normal can be useful to discriminate pulmonary from cardiac causes of dyspnoea. In one study, levels of 93 ng/l and 144 ng/l for men and women referred with dyspnoea, respectively, had a sensitivity of 90% for detecting cardiac abnormalities ( 11 ).…”

Section: Discussionsupporting

confidence: 91%

“…BNPs are secreted in response to cardiac strain ( 9 ), and since pathological changes in the pulmonary arteries occur prior to cardiac affection in PH, pulmonary derived biomarkers would be optimal to detect early PH. However, although such biomarkers are hoped to emerge and promising results have recently been obtained with VEGF-family members ( 10 ), they are not yet established in clinical use.…”

Section: Discussionmentioning

confidence: 99%

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NT-proBNP <95 ng/l can exclude pulmonary hypertension on echocardiography at diagnostic workup in patients with interstitial lung disease

Andersen

Mellemkjær

Hilberg

et al. 2016

European Clinical Respiratory Journal

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BackgroundPulmonary hypertension (PH) is a serious complication to interstitial lung disease (ILD) and has a poor prognosis. PH is often diagnosed by screening with echocardiography followed by right heart catheterisation. A previous study has shown that a value of NT-pro-brain natriuretic peptide (NT-proBNP) <95 ng/l could be used to rule out PH in patients with ILD.AimTo evaluate this rule-out test for PH in a new cohort of incident patients with ILD.MethodsAn established database with data from 148 consecutive patients referred from January 2012 to October 2014 was used to identify patients and obtain data from echocardiography, NT-proBNP, diagnosis and lung function. Signs of PH on echocardiography were defined as a tricuspid pressure gradient (TR) ≥40 mmHg, decreased right ventricular systolic function or dilatation. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of NT-proBNP >95 ng/l for signs of PH on echocardiography were calculated. The study was approved by the Danish Health Authority.ResultsIn 118 patients, data from both echocardiography and measurements of NT-proBNP were available. Eleven of these were screened positive for PH on echocardiography. Sensitivity, specificity, NPV and PPV of NT-proBNP <95 ng/l for PH were 100, 44, 16 and 100%, respectively. Furthermore, no patients with left heart failure as the cause of dyspnoea were missed using this cut-off value.ConclusionNT-proBNP <95 ng/l precludes a positive echocardiographic screen for PH in ILD patients at referral for diagnostic workup.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

NT-proBNP <95 ng/l can exclude pulmonary hypertension on echocardiography at diagnostic workup in patients with interstitial lung disease

Andersen

Mellemkjær

Hilberg

et al. 2016

European Clinical Respiratory Journal

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“…8 VEGFR3, which shares structural similarity to VEGFR2, preferentially binds to other members of VEGF ligands (VEGF-C and VEGF-D) and promotes angiogenesis as well as lymphangiogenesis. 9–11 In the context of PAH, components of VEGF signaling have been implicated as potential biomarkers in human disease, 12 and in experimental models, a VEGFR2 antagonist (SU-5416) in conjunction with chronic hypoxia is used routinely to induce pulmonary hypertension (PH) in rodents. 13 While VEGR3 is known to be highly expressed in the lungs (www.gtexportal.org/home/gene/FLT4), 14, 15 its specific role in the pulmonary arterial bed has not been fully defined.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension

et al. 2017

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Background Bone Morphogenetic Protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP type 2 receptors (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. Methods We utilized a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between VEGFR3 and BMPR2. Additional in vitro studies were performed using human endothelial cells, including primary endothelial cells from subjects with PAH. Results Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells (ECs) with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension (PH). Consistent with this data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells (PAECs) from human PAH subjects, and reconstitution of VEGFR3 expression in PAH PAECs restored BMP signaling responses.

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“…Thus, while Ang-1 may be locally upregulated in the lung tissue of patients with PH [20, 21], high levels of Ang-2 may be released under pathological conditions such as PH, and the release of Ang-2 can be promoted by factors that also induce Ang-2 expression, such as hypoxia or increased vascular endothelial growth factor levels. We acknowledge that in animal models or in vitro studies certain pathophysiological features of PH can be attributed to locally produced Ang-1; however, as PH progresses in adult patients, other angiopoietins and growth factors [48] might take center stage and be released into the circulation.…”

Section: Discussionmentioning

confidence: 99%

Circulating Angiopoietin-1 Is Not a Biomarker of Disease Severity or Prognosis in Pulmonary Hypertension

Richter¹,

Tiede²,

Sommer³

et al. 2016

PLoS ONE

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BackgroundCirculating angiopoietin-1 (Ang-1) has been linked to pulmonary hypertension (PH) in experimental studies. However, the clinical relevance of Ang-1 as a biomarker in PH remains unknown. We aimed to investigate the prognostic and clinical significance of Ang-1 in PH using data from the prospectively recruiting Giessen PH Registry.MethodsPatients with suspected PH (without previous specific pulmonary arterial hypertension [PAH] therapy) who underwent initial right heart catheterization (RHC) in our national referral center between July 2003 and May 2012 and who agreed to optional biomarker analysis were included if they were diagnosed with idiopathic PAH, connective tissue disease-associated PAH (CTD-PAH), PH due to left heart disease (PH-LHD), or chronic thromboembolic PH (CTEPH), or if PH was excluded by RHC (non-PH controls). The association of Ang-1 levels with disease severity (6-minute walk distance and pulmonary hemodynamics) was assessed using linear regression, and the impact of Ang-1 levels on transplant-free survival (primary endpoint) and clinical worsening was assessed using Kaplan—Meier curves, receiver operating characteristic (ROC) analyses, and Cox regression.Results151 patients (39, 39, 32, and 41 with idiopathic PAH, CTD-PAH, PH-LHD, and CTEPH, respectively) and 41 non-PH controls were included. Ang-1 levels showed no significant difference between groups (p = 0.8), and no significant associations with disease severity in PH subgroups (p ≥ 0.07). In Kaplan—Meier analyses, Ang-1 levels (stratified by quartile) had no significant impact on transplant-free survival (p ≥ 0.27) or clinical worsening (p ≥ 0.51) in PH subgroups. Regression models found no significant association between Ang-1 levels and outcomes (p ≥ 0.31). ROC analyses found no significant cut-off that would maximize sensitivity and specificity.ConclusionsDespite a strong pathophysiological association in experimental studies, this first comprehensive analysis of Ang-1 in PH subgroups suggests that Ang-1 is not a predictive and clinically relevant biomarker in PH.

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New potential diagnostic biomarkers for pulmonary hypertension

Cited by 33 publications

References 37 publications

NT-proBNP <95 ng/l can exclude pulmonary hypertension on echocardiography at diagnostic workup in patients with interstitial lung disease

NT-proBNP <95 ng/l can exclude pulmonary hypertension on echocardiography at diagnostic workup in patients with interstitial lung disease

Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension

Circulating Angiopoietin-1 Is Not a Biomarker of Disease Severity or Prognosis in Pulmonary Hypertension

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