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Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases.To examine the interaction of ET-1 pathway polymorphisms and treatment responses of patients with PAH treated with ET receptor antagonists (ERAs).A total of 1,198 patients with PAH were prospectively enrolled from 45 U.S. and Canadian pulmonary hypertension centers or retrospectively from global sites participating in the STRIDE (Sitaxsentan To Relieve Impaired Exercise) trials. Comprehensive objective measures including a 6-minute-walk test, Borg dyspnea score, functional class, and laboratory studies were completed at baseline, before the initiation of ERAs, and repeated serially. Single-nucleotide polymorphisms from ET-1 pathway candidate genes were selected from a completed genome-wide association study performed on the study cohort.Patient efficacy outcomes were analyzed for a relationship between ET-1 pathway polymorphisms and clinical efficacy using predefined, composite positive and negative outcome measures in 715 European descent samples. A single-nucleotide polymorphism (rs11157866) in the G-protein alpha and gamma subunits gene was significantly associated, accounting for multiple testing, with a combined improvement in functional class and 6-minute-walk distance at 12 and 18 months and marginally significant at 24 months.ET-1 pathway associated polymorphisms may influence the clinical efficacy of ERA therapy for PAH. Further prospective studies are needed.

SUBMITTER: Benza RL

PROVIDER: S-EPMC4731699 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

Benza Raymond L RL Gomberg-Maitland Mardi M Demarco Teresa T Frost Adaani E AE Torbicki Adam A Langleben David D Pulido Tomas T Correa-Jaque Priscilla P Passineau Michael J MJ Wiener Howard W HW Tamari Mayumi M Hirota Tomomitsu T Kubo Michiaki M Tiwari Hemant K HK

American journal of respiratory and critical care medicine 20151201 11

<h4>Rationale</h4>Pulmonary arterial hypertension (PAH) is a progressive fatal disease. Variable response and tolerability to PAH therapeutics suggests that genetic differences may influence outcomes. The endothelin pathway is central to pulmonary vascular function, and several polymorphisms and/or mutations in the genes coding for endothelin (ET)-1 and its receptors correlate with the clinical manifestations of other diseases.<h4>Objectives</h4>To examine the interaction of ET-1 pathway polymor ...[more]

PMID: 26252367

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Project description:BackgroundPulmonary arterial hypertension is a devastating disease, which leads to right heart failure and premature death. Recent evidence suggests that endothelin receptor antagonists may be promising drugs in the treatment of pulmonary arterial hypertension.ObjectivesTo evaluate the efficacy of endothelin receptor antagonists in pulmonary arterial hypertension.Search methodsWe searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE, and the reference section of retrieved articles. Searches are current as of January 2012.Selection criteriaWe included randomised trials (RCTs) and quasi-randomised trials involving patients with pulmonary arterial hypertension.Data collection and analysisFive review authors independently selected studies, assessed study quality and extracted data.Main resultsWe included 12 randomised controlled trials involving 1471 patients. All the trials were of relatively short duration (12 weeks to six months). After treatment, patients treated with endothelin receptor antagonists could walk on average 33.71 metres (95% confidence interval (CI) 24.90 to 42.52 metres) further than those treated with placebo in a six-minute walk test. Endothelin receptor antagonists improved more patients' World Health Organization/New York Heart Association (WHO/NYHA) functional class status than placebo (odds ratio (OR) 1.60; 95% CI 1.20 to 2.14), and reduced the odds of functional class deterioration compared with placebo (OR 0.26; 95% CI 0.16 to 0.42). There was a reduction in mortality that did not reach statistical significance on endothelin receptor antagonists (OR 0.57; 95% CI 0.26 to 1.24), and limited data suggest that endothelin receptor antagonists improve the Borg dyspnoea score and cardiopulmonary haemodynamics in symptomatic patients. Hepatic toxicity was not common, and endothelin receptor antagonists were well tolerated in this population. However, several cases of irreversible liver failure caused by sitaxsentan have been reported that led to license holder for sitaxsentan to withdraw the product from all markets worldwide.Authors' conclusionsEndothelin receptor antagonists can increase exercise capacity, improve WHO/NYHA functional class, prevent WHO/NYHA functional class deterioration, reduce dyspnoea and improve cardiopulmonary haemodynamic variables in patients with pulmonary arterial hypertension with WHO/NYHA functional class II and III. However, there was only a trend towards endothelin receptor antagonists reducing mortality in patients with pulmonary arterial hypertension. Efficacy data are strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in patients treated with endothelin receptor antagonists.

Project description:IntroductionInflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ETA) autoantibodies have been implicated in the pathogenesis of PAH, and endothelin receptor antagonists are routinely used treatments for PAH. However, immunological functions of the endothelin B receptor (ETB) remain obscure.MethodsSerum levels of anti-ETB receptor autoantibodies were quantified in healthy donors and SSc patients with or without PAH. Age-dependent effects of overexpression of prepro-endothelin-1 or ETB deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ETB-deficient mice (ETB -/-) were used to prevent congenital Hirschsprung disease. The effects of pulmonary T-helper type 2 (Th2) inflammation on PAH-associated pathologies were analyzed in ETB -/- mice. Pulmonary vascular hemodynamics were investigated in isolated perfused mouse lungs. Hearts were assessed for right ventricular hypertrophy. Pulmonary inflammation and collagen deposition were assessed via lung microscopy and bronchoalveolar lavage fluid analyses.ResultsAnti-ETB autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ETB deficiency led to pulmonary hypertension, pulmonary vascular hyperresponsiveness, and right ventricular hypertrophy with accompanying lymphocytic alveolitis. Marked perivascular lymphocytic infiltrates were exclusively found in ETB -/- mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ETB -/- mice.ConclusionThis study provides evidence for an anti-inflammatory role of ETB. ETB seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ETB autoantibodies may modulate ETB-mediated immune homeostasis.

Project description:Right ventricular function critically affects the prognosis of patients with pulmonary arterial hypertension. We aimed to analyze the prognostic value of right ventricular indices calculated using magnetic resonance imaging and right heart catheterization metrics in pulmonary arterial hypertension. We retrospectively collected data from 57 Japanese patients with pulmonary arterial hypertension and 18 controls and calculated six indices of right ventricular function: two indices of contractility (end-systolic elastance calculated with right ventricular maximum pressure and with magnetic resonance imaging metrics); two indices of right ventricular-pulmonary arterial coupling (end-systolic elastance/arterial elastance calculated with the pressure method (end-systolic elastance/arterial elastance (P)) and with the volume method (end-systolic elastance/arterial elastance (V)); and two indices of right ventricular diastolic function (stiffness (β) and end-diastolic elastance). We compared the indices between controls and patients with pulmonary arterial hypertension and examined their prognostic role. In patients with pulmonary arterial hypertension, end-systolic elastance (right ventricular maximum pressure) was higher (pulmonary arterial hypertension 0.94 (median) vs control 0.42 (mmHg/mL), p < 0.001), end-systolic elastance/arterial elastance (V) was lower (pulmonary arterial hypertension 0.72 vs control 1.69, p < 0.001), and β and end-diastolic elastance were significantly higher than those in the controls. According to the log-rank test, end-systolic elastance/arterial elastance (P) and end-diastolic elastance were significantly associated with the composite event rate. According to the multivariate Cox regression analysis, decreased end-systolic elastance/arterial elastance (P) was associated with a higher composite event rate (hazard ratio 11.510, 95% confidence interval: 1.954-67.808). In conclusion, an increased right ventricular contractility, diastolic dysfunction, and a trend of impaired right ventricular-pulmonary arterial coupling were observed in our pulmonary arterial hypertension cohort. According to the multivariate outcome analysis, a decreased end-systolic elastance/arterial elastance (P), suggestive of impaired right ventricular-pulmonary arterial coupling, best predicted the pulmonary arterial hypertension-related event.

Project description:BackgroundPulmonary arterial hypertension (PAH) is a complex disease characterized by progressive right ventricular (RV) failure leading to significant morbidity and mortality. Investigating metabolic features and pathways associated with RV dilation, mortality, and measures of disease severity can provide insight into molecular mechanisms, identify subphenotypes, and suggest potential therapeutic targets.MethodsWe collected data from a prospective cohort of PAH participants and performed untargeted metabolomic profiling on 1045 metabolites from circulating blood. Analyses were intended to identify metabolomic differences across a range of common metrics in PAH (eg, dilated versus nondilated RV). Partial least squares discriminant analysis was first applied to assess the distinguishability of relevant outcomes. Significantly altered metabolites were then identified using linear regression, and Cox regression models (as appropriate for the specific outcome) with adjustments for age, sex, body mass index, and PAH cause. Models exploring RV maladaptation were further adjusted for pulmonary vascular resistance. Pathway enrichment analysis was performed to identify significantly dysregulated processes.ResultsA total of 117 participants with PAH were included. Partial least squares discriminant analysis showed cluster differentiation between participants with dilated versus nondilated RVs, survivors versus nonsurvivors, and across a range of NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, REVEAL 2.0 composite scores, and 6-minute-walk distances. Polyamine and histidine pathways were associated with differences in RV dilation, mortality, NT-proBNP, REVEAL score, and 6-minute walk distance. Acylcarnitine pathways were associated with NT-proBNP, REVEAL score, and 6-minute walk distance. Sphingomyelin pathways were associated with RV dilation and NT-proBNP after adjustment for pulmonary vascular resistance.ConclusionsDistinct plasma metabolomic profiles are associated with RV dilation, mortality, and measures of disease severity in PAH. Polyamine, histidine, and sphingomyelin metabolic pathways represent promising candidates for identifying patients at high risk for poor outcomes and investigation into their roles as markers or mediators of disease progression and RV adaptation.

Dataset Information

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

Publications

Endothelin-1 Pathway Polymorphisms and Outcomes in Pulmonary Arterial Hypertension.

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