Venous endotelin-1 (ET-1) and brain natriuretic peptide (BNP) plasma levels during 6-month bosentan treatment for pulmonary arterial hypertension

Vizza, Carmine Dario; Letizia, Claudio; Petramala, Luigi; Badagliacca, Roberto; Poscia, Roberto; Zepponi, Enrico; Crescenzi, E.J.; Nona, Alfred; Benedetti, Giulia; Ferrante, Fabio; Sciomer, Susanna; Fedele, Francesco

doi:10.1016/j.regpep.2008.08.002

Cited by 18 publications

(15 citation statements)

References 29 publications

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“…Elevated plasma ET-1 levels previously predicted clinical worsening in idiopathic PAH patients on bosentan therapy (22), but it is unknown whether ET-1 levels predict therapeutic response in a broader PAH cohort. Interestingly, plasma levels of ET-1 and BNP have been signi cantly correlated in patients with PAH, generating the hypothesis that increased levels of ET-1 may result from systemic neurohormonal activation (21). ERA therapy is known to acutely increase ET-1 levels in patients with PAH (23), re ecting an incompletely characterized neuro-hormonal or other feedback regulation loop, although the elevations in ET-1 levels may fade with chronic ERA therapy (21).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, plasma levels of ET-1 and BNP have been signi cantly correlated in patients with PAH, generating the hypothesis that increased levels of ET-1 may result from systemic neurohormonal activation (21). ERA therapy is known to acutely increase ET-1 levels in patients with PAH (23), re ecting an incompletely characterized neuro-hormonal or other feedback regulation loop, although the elevations in ET-1 levels may fade with chronic ERA therapy (21). In our cohort, ET-1 levels were lowest in patients with PAH on PDE-5i, and highest in patients on the combination of ERA and PDE-5i therapies.…”

Section: Discussionmentioning

confidence: 99%

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Treatment-related biomarkers in pulmonary hypertension patients on oral therapies

Swaminathan

Zhu

Tapson

et al. 2020

Preprint

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Background: Multiple classes of oral therapy are available for the treatment of pulmonary arterial hypertension (PAH), but there is little to guide clinicians in choosing a specific regimen or therapeutic class. We aimed to investigate whether treatment-relevant blood biomarkers can predict therapy response in prevalent PAH patients.Methods: This prospective cohort study longitudinally assessed biomarkers along the endothelin-1 (ET-1) and nitric oxide (cGMP, ADMA, SDMA, nitrite, and S-nitrosohemoglobin) pathways along with the cGMP/NT-proBNP ratio over 12 months in patients with WHO Group 1 PAH on oral PAH-specific therapies. The relationship between biomarkers and 6MWD at the same and future visits was examined using mixed linear regression models adjusted for age. As cGMP can be elevated when NT-proBNP is elevated, we also tested the relationship between 6MWD and the cGMP/NT-pro BNP ratio. Patients with PAH with concomitant heart or lung disease or chronic thromboembolic pulmonary hypertension (CTEPH) were included in a sensitivity analysis.Results: The study cohort included 58 patients with PAH treated with either an endothelin receptor antagonist (27.6%), phosphodiesterase-5 inhibitor (29.3%) or a combination of the two (43.1%). Among biomarkers along the current therapeutic pathways, ET-1 and the cGMP/NT-proBNP ratio associated with same visit 6MWD (p = 0.02 and p=0.03 respectively), and ET-1 predicted future 6MWD (p=0.02). ET-1 (p=0.01) and cGMP/NT-proBNP ratio (p=0.04) also predicted future 6MWD in the larger cohort (n = 108) of PAH patients with concomitant left heart disease (n = 17), lung disease (n = 20), or CTEPH (n = 13). Finally, in the larger cohort, SDMA associated with 6MWD at the same visit (p = 0.01) in all subgroups and ADMA associated with 6MWD in PAH patients with concomitant lung disease (p=0.03) and PAH patients on ERA therapy (p = 0.01).Conclusions: ET-1, cGMP/NTproBNP ratio, and dimethylarginines ADMA and SDMA are mediators along pathways targeted by oral PAH therapies that associate with or predict 6MWD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Treatment-related biomarkers in pulmonary hypertension patients on oral therapies

Swaminathan

Zhu

Tapson

et al. 2020

Preprint

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“…ET-1, a potent vasoconstrictor produced by vascular endothelial and smooth muscle cells, was higher in the non-transfused thalassemia patients and is known to have a role in the development of pulmonary vascular dysfunction and PH [42,43] and found to. Further study of its value in treating and monitoring TRV in thalassemia is needed, in particular since treatment with ET-1 antagonists has shown benefit in patients with PH and an improvement was noted in a reported case of a thalassemia patient with PH[44].…”

Section: Discussionmentioning

confidence: 99%

Elevated tricuspid regurgitant jet velocity in subgroups of thalassemia patients: insight into pathophysiology and the effect of splenectomy

Singer¹,

Kuypers²,

Fineman

et al. 2014

Ann Hematol

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A high tricuspid regurgitant jet velocity (TRV) signifying risk for or established pulmonary hypertension (PH) is a serious complication in thalassemia patients. The underlying pathophysiology in thalassemia sub-groups and potential biomarkers for early detection and monitoring are not well defined, in particular as they relate to spleen removal. To better understand some of these unresolved aspects, we examined 76 thalassemia patients (35 non-transfused), 25 splenectomized non-thalassemia patients and 12 healthy controls. An elevated TRV (>2.5m/sec) was found in 25/76 (33%) of the patients, confined to non-transfused or those with a late start of transfusions, including patients with hemoglobin H-constant spring, a finding not previously described. These non, or late-transfused patients (76% splenectomized) had significantly increased platelet activation (sCD40L), high platelet count, endothelial activation (endothelin-1) and hemolysis (LDH, plasma free-Hb), while hypercoaguable and inflammatory markers were not significantly increased. The same markers were increased in the 7 patients with confirmed PH on cardiac catheterization, suggesting their possible role for screening patients at risk for PH. A combination of hemolysis and absence of spleen is necessary for developing a high TRV, as neither chronic hemolysis in the non-splenectomized thalassemia patients, nor splenectomy without hemolysis, in the non-thalassemia patients, resulted in an increase in TRV.

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“…Previously, BNP serum levels have been shown to correlate with severity of disease and to be independent predictors of survival [ 23 ]. However, only limited and inconclusive data is available concerning the effects of long-term bosentan treatment on BNP serum levels [ 24 ]. Lately, after 16 weeks of bosentan in 12 PAH patients, BNP tended to be lower without reaching statistical significance [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

Droste¹,

Rohde²,

Völkers³

et al. 2009

Respir Res

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BackgroundIn idiopathic pulmonary arterial hypertension (IPAH), peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1), to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist) improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction.MethodsIn 32 IPAH-patients (19 female, WHO functional class II (n = 10), III (n = 22); (data presented as mean ± standard deviation) pulmonary vascular resistance (11 ± 5 Wood units), lung function, 6 minute walk test (6-MWT; 364 ± 363.7 (range 179.0-627.0) m), systolic pulmonary artery pressure, sPAP, 79 ± 19 mmHg), and NT-proBNP serum levels (1427 ± 2162.7 (range 59.3-10342.0) ng/L) were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day).Results and DiscussionAt baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 ± 25 and 45 ± 24% predicted. Total lung capacity was 95.6 ± 12.5% predicted and residual volume was 109 ± 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 ± 19 and 53 ± 69 m, respectively; p < 0.01; whereas sPAP decreased by 7 ± 14 and 10 ± 19 mmHg, respectively; p < 0.05. NT-proBNP serum levels tended to be reduced by 123 ± 327 and by 529 ± 1942 ng/L; p = 0.11). There was no difference in expiratory flows or lung volumes during 3 and 12 months.ConclusionThis study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

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Venous endotelin-1 (ET-1) and brain natriuretic peptide (BNP) plasma levels during 6-month bosentan treatment for pulmonary arterial hypertension

Cited by 18 publications

References 29 publications

Treatment-related biomarkers in pulmonary hypertension patients on oral therapies

Treatment-related biomarkers in pulmonary hypertension patients on oral therapies

Elevated tricuspid regurgitant jet velocity in subgroups of thalassemia patients: insight into pathophysiology and the effect of splenectomy

Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

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