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(Chest. 2007;131:101-108.)
© 2007 American College of Chest Physicians

Endothelin-1/Endothelin-3 Ratio*

A Potential Prognostic Factor of Pulmonary Arterial Hypertension

David Montani, MD; Rogerio Souza, PhD; Christoph Binkert, MS; Walter Fischli, PhD; Gerald Simonneau, PhD; Martine Clozel, PhD and Marc Humbert, PhD

* From the Centre des Maladies Vasculaires Pulmonaires (Drs. Montani, Souza, Humbert, and Simonneau), UPRES EA2705, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine-Béclère, Université Paris-Sud, Assistance Publique-Hôpitaux de Paris, Clamart, France; and Actelion Pharmaceuticals Ltd (Drs. Fischli and Clozel, and Mr. Binkert), Allschwil, Switzerland.

Correspondence to: Marc Humbert, PhD, Centre des Maladies Vasculaires Pulmonaires, UPRES EA 2705, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud. 157 rue de la Porte de Trivaux, 92140 Clamart, France; e-mail: marc.humbert{at}abc.aphp.fr

Abstract

Background: Pulmonary arterial hypertension (PAH) is a rare condition characterized by elevated pulmonary artery pressure leading to right-heart failure and death. Endothelin (ET)-1 has been shown to play a significant pathogenic role in PAH. ET-3 has not yet been investigated in PAH.

Methods: ET-1 and ET-3 plasma concentrations were measured in 33 PAH patients prior to any specific PAH therapy and in 9 control subjects. In PAH patients, hemodynamic parameters measured by right-heart catheterization, 6-min walk distance (6MWD), New York Heart Association (NYHA) functional class, and time until lung transplantation or death were recorded.

Results: In patients with PAH, levels of ET-1 were increased while those of ET-3 were decreased, as compared to control subjects (p < 0.005 for both comparisons). ET-1/ET-3 ratio varied little in control subjects, while it increased threefold in PAH patients (p < 0.0001). ET-1 correlated positively with right atrial pressure (RAP), indexed total pulmonary resistance, and negatively with cardiac index and venous saturation of oxygen (SvO2). ET-3 correlated positively with 6MWD. ET-1/ET-3 ratio correlated positively with RAP, negatively with SvO2 and 6MWD, and was also associated with NYHA functional class. ET-1/ET-3 ratio was associated with prognosis in this sample of PAH patients treated with specific therapies.

Conclusions: PAH is characterized by elevated ET-1 and ET-1/ET-3 ratio and decreased ET-3 plasma concentrations. All of them correlate with hemodynamic and clinical markers of disease severity. ET-1/ET-3 ratio might be a novel prognostic factor in PAH. These preliminary data should be validated in a large prospective multicenter cohort of PAH patients.

Key Words: endothelin • endothelin-1 • endothelin-3 • prognostic factor • pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare and severe condition characterized by obstruction of small pulmonary arteries leading to right-heart failure and death.1 In the last decade, the understanding of pathophysiology of PAH has allowed improvement in care of the disease through the development of specific therapies.2 Endothelial dysfunction is a mainstream feature of PAH and results in a decrease of vasodilatator and antiproliferative factors (prostacyclin, nitric oxide) and in an increase in vasoconstrictor and proliferative factors (endothelin [ET]-1).3

ET belongs to a family of 21 amino-acid peptides with three identified subtypes (ET-1, ET-2, and ET-3). They are synthesized from large preproendothelins precursors, cleaved, and then processed into active 21 amino-acid peptides. ET-1 is mainly produced by endothelial cells, with the pulmonary circulation as the most important site of production and clearance.456 ET-2 is not produced by endothelial cells and has no or only a minor role in lungs.4 ET-3 is produced by different cell types including endothelial cells in multiple organs,4 and its role in the lungs is unknown.

Two different G protein-coupled receptors for ETs have been identified, ET receptor A (ETA) and ET receptor B (ETB). ETA has a high affinity for ET-1 and ET-2 and a lower affinity for ET-3, whereas ETB has the same high affinity for the three ETs. In the pulmonary vessels, ETA is expressed on pulmonary smooth-muscle cells, and ETB is expressed on pulmonary endothelial and smooth-muscle cells. Activation of ETA or ETB on pulmonary vascular smooth-muscle cells induce pulmonary vasoconstriction and smooth-muscle cell proliferation.7891011 This is in contrast to the activation of endothelial ETB, which induces the release of vasodilator and antiproliferative agents (nitric oxide and prostacyclin)12 and prevents endothelial cells apoptosis.13

ET-1 is pharmacologically the most potent member of the ET family and induces cell proliferation, fibrosis, and inflammation,4 and is involved in the pathophysiology of PAH.3 ET-3 has been shown to have a vasoconstrictive effect14; however, due to its activation of ETB on endothelial cells, ET-3 may also have some positive effects in PAH. Currently, no data about ET-3 are available in PAH. ET-1 being a ligand of both ETA and ETB receptors, and ET-3 a selective ligand of ETB receptor, we hypothesized that the assessment of the plasma concentrations not only of ET-1 but also of ET-3, and of their ratio, might bring more information than the measurement of ET-1 alone.

Materials and Methods

Subjects
Thirty-three subjects with PAH were included in this study from three different previous studies151617 and were enrolled consecutively during three different time periods between February 1994 and April 1998. Institutional Review Board approval was obtained for these studies, and all patients gave informed consent for these studies and for additional biological studies.151617 PAH was defined by mean pulmonary arterial pressure (mPAP) > 25 mm Hg with normal pulmonary capillary wedge pressure (PCWP) [< 15 mm Hg] on right-heart catheterization. None of the patients had received any specific therapy for PAH prior to the study. Patients were receiving conventional therapy, including oral anticoagulants, diuretics, and long-term oxygen therapy if hypoxemia was present. Nine healthy subjects with no history of cardiac, lung, or vascular disease were also included during the same study period (control group). The characteristics of the control subjects concerning age and gender were not statistically different from PAH patients.

Clinical and Functional Assessment
Routine evaluation at baseline included a medical history, assessment of modified New York Hart Association (NYHA) functional class,18 physical examination, and a nonencouraged 6-min walk distance (6MWD) according to the American Thoracic Society recommendations.19 The distance walked and the lowest oxygen saturation using pulse oximetry (SpO2) during the walk test were recorded.20

Hemodynamic Measurements
A baseline hemodynamic evaluation was performed in all patients according to our previously described protocol.21 Cardiac output was measured by the standard thermodilution technique. Cardiac index (CI) was calculated as cardiac output divided by body surface area (meters squared). The systolic pulmonary arterial pressure, diastolic pulmonary arterial pressure, mPAP, PCWP, right atrial pressure (RAP), and mixed venous oxygen saturation (SvO2) were recorded during right-heart catheterization. Indexed total pulmonary resistance was calculated as (mPAP x 80)/CI.

ET-1 and ET-3 Plasma Concentrations Measurement
In all patients, blood samples were collected at the moment of baseline evaluation. Patients with PAH and control subjects were sampled at the same time, and their samples were stored under the same conditions. ET-1 plasma concentrations were determined using an extraction-free human immunoreactive ET-1 chemiluminescent immunoassay (QuantiGIo QET00; R&D Systems; Minneapolis, MN), which employs the quantitative sandwich enzyme immunoassay technique. The measuring range of the assay is 0.32 to 1,000 pg/mL. The antibodies that were used in the kit cross-react with human ET-1 (100%), human big ET-2 (0.01%), human big ET-1–38 (0.019%), human ET-3 (7.8%), and human ET-2 (27.4%). For ET-1 plasma measurement, SD was 0.06. ET-3 plasma levels were determined with an extraction free human ET-6–3 enzyme-linked immunosorbent assay (JP 17169; IBL Hamburg; Hamburg, Germany). The measuring range of the assay is 0.78 to 100 pg/mL. The antibodies that were used in the kit cross-react with human ET-3 (100%), human ET-2 (19.7%), and human ET-1 (1.9%). For ET-3 plasma measurement, SD was 0.10. ET-1/ET-3 ratio was defined as the ratio of ET-1 plasma concentrations over ET-3 plasma concentrations. All samples were measured in duplicate.

Statistical Analysis
Data are presented as median (interquartile range [IQR]) except if stated otherwise. Comparisons of ET-1 and ET-3 plasma concentrations and ET-1/ET-3 ratio between subjects with PAH and control subjects were assessed by nonparametric Mann-Whitney test. Correlations between ET-1 and ET-3 plasma concentrations and ET-1/ET-3 ratio and hemodynamic parameters and 6MWD were tested using Spearman correlation. Comparison of ET-1/ET-3 ratio according to NYHA functional class was assessed by Kruskal-Wallis test. The Kaplan-Meier method was used to estimate event-free status, considering lung transplantation or death as events. The cut-off date was February 1, 2005. Patients were stratified according to the ET-1/ET-3 ratio, and event-free survival distributions were compared using the log-rank test.

Results

Characteristics of Subjects
Thirty-three patients with PAH were included in this study, 19 of them with idiopathic PAH, 1 with familial PAH, 6 with appetite suppressant-associated PAH, and 7 with PAH associated with other conditions (portopulmonary hypertension, n = 3; HIV infection-associated PAH, n = 1; systemic sclerosis-associated PAH, n = 2; pulmonary venoocclusive disease, n = 1). At the time of blood sampling for ET plasma concentration measurement, none of these patients had been previously treated with specific PAH therapy. Age, gender, hemodynamic parameters, NYHA functional class, and 6MWD of patients with PAH are presented in Table 1 . Patients with PAH included in this study displayed severe disease with poor hemodynamic and clinical parameters. The control group was composed of nine healthy volunteers (four women and five men). After blood samples were obtained, patients with PAH were treated with specific PAH therapy. Twenty-one patients received continuous IV prostacyclin, 2 received the dual ET receptor antagonist bosentan, 1 received combination therapy (prostacyclin and bosentan), 1 received nebulized iloprost, 1 received oral beraprost, and 6 received conventional therapy alone. All patients in class IV received epoprostenol, and patients in class III received prostacyclin, bosentan, or prostacyclin analogues. There was no loss of follow-up until the cut-off date.


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  		Table 1.. Characteristics of Subjects With PAH (n = 33)*

 
ET-1 and ET-3 Plasma Concentrations and ET-1/ET-3 Ratio
ET-1 plasma concentrations were elevated in patients with PAH (median, 2.6 pg/mL; IQR, 2.15 to 4.25 pg/mL) as compared to control subjects (median, 1.8 pg/mL; IQR, 1.05 to 2.02 pg/mL) [p < 0.005; Fig 1 , left, A]. ET-3 plasma concentrations were decreased in patients with PAH (median, 1.9 pg/mL; IQR, 1.47 to 2.62 pg/mL) as compared to control subjects (median, 3.5 pg/mL; IQR, 2.9 to 4.02 pg/mL) [p < 0.001; Fig 1, center, B]. ET-1/ET-3 ratio, which was relatively constant in control subjects (median, 0.49 pg/mL; IQR, 0.46 to 0.61 pg/mL), increased significantly in patients with PAH (median, 1.41 pg/mL; IQR, 0.93 to 2.29 pg/mL) [p < 0.0001; Fig 1, right, C].


Figure 1
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  		Figure 1.. ET-1 and ET-3 plasma concentrations and ET-1/ET-3 ratio in control subjects and patients with PAH. Left, A: ET-1 plasma concentrations were measured in control subjects (n = 9) and in patients with PAH (n = 26). In patients with PAH, ET-1 plasma concentrations were increased in comparison to control subjects (p < 0.005, Mann-Whitney test). Center, B: ET-3 plasma concentrations were measured in control subjects (n = 9) and in subjects with PAH (n = 26). In patients with PAH, ET-3 plasma concentrations were decreased in comparison to control subjects (p < 0.001, Mann-Whitney test). Right, C: ET-1/ET-3 ratio was defined as the ratio of ET-1 plasma concentrations over ET-3 plasma concentrations. ET-1/ET-3 ratio was calculated in control subjects (n = 9) and in patients with PAH (n = 26). In patients with PAH, ET-1/ET-3 ratio was increased in comparison to control subjects (p < 0.0001, Mann-Whitney test). Each open circle represents measurement in control subjects. Each black circle represents measurement in subjects with idiopathic, familial, or appetite suppressant-associated PAH. Gray shapes represent measurements in PAH associated with other conditions (square for PAH associated with scleroderma, circle for portopulmonary hypertension, triangle for HIV-associated PAH, and diamond for venoocclusive disease).

 
Correlation With Hemodynamic and Clinical Parameters
Considering the whole population of PAH patients (n = 33), ET-1 plasma concentrations positively correlated with RAP (r = 0.46, p = 0.01), lowest SpO2 during 6MWD (r = 0.48, p = 0.02), indexed total pulmonary resistance (r = 0.55, p < 0.05), and negatively correlated with CI (r = – 0.47, p < 0.008) and SvO2 (r = – 0.46, p < 0.05). ET-3 plasma concentrations were positively correlated with 6MWD (r = 0.49, p < 0.01) and negatively with RAP (r = – 0.40, p < 0.05). ET-1/ET-3 ratio was positively correlated with RAP (r = 0.60, p < 0.001) and negatively correlated with SvO2 (r = – 0.52, p < 0.01) and 6MWD (r = – 0.49, p < 0.01) [Fig 2 ]. There was no significant difference for ET-1 between patients stratified for NYHA functional class; however, the levels of ET-3 and ET-1/ET-3 ratio were significantly different. ET-1/ET-3 ratio increased from 0.8 (IQR, 0.73 to 1.28) in patients with NYHA functional class II, to 1.37 (IQR, 0.95 to 2.21) in patients with functional class III, and to 2.39 (IQR, 2 to 2.67) in patients with functional class IV (p < 0.05). In PAH subjects, ET-1 and ET-3 plasma concentrations and ET-1/ET-3 ratio presented no correlation with age nor was there a significant difference according to gender (data not shown).


Figure 2
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  		Figure 2.. Correlation between hemodynamic or clinical parameters and ET-1/ET-3 ratio in subjects with PAH. ET-1/ET-3 ratio positively correlated with RAP (r = 0.60, p < 0.001) [top left] and negatively correlated with SvO2 (r = – 0.52, p < 0.01) [top right] and 6MWD (r = – 0.49, p < 0.01) [bottom]. Black circles represent measurements in subject with idiopathic, familial, or appetite suppressant-associated PAH. Gray shapes represent measurements in PAH associated with other conditions (square for PAH associated with scleroderma, circle for portopulmonary hypertension, triangle for HIV-associated PAH, and diamond for venoocclusive disease).

 
Analysis of Time to Transplantation or Death
Median follow-up was 22.4 months (IQR, 1.4 to 141.1 months). At the end of the follow-up period, 8 of the 33 patients (24.2%) with PAH were still alive without transplant, 9 patients (27.3%) underwent lung transplant, and 16 patients (48.4%) had died.

Neither ET-1 nor ET-3 plasma concentrations were associated with time to lung transplantation or death. No previous data about ET-1/ET-3 exists for the use of a cut-off level for prognosis analysis; thus, considering also our sample size, we decided to stratify our patients according to tertiles of ET-1/ET-3 ratio. Kaplan-Meier curves showed a significant difference among the three ET-1/ET-3 ratio intervals for all patients with PAH (log-rank test, p < 0.001) [Fig 3 ].


Figure 3
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  		Figure 3.. Event-free survival analysis according to ET-1/ET-3 ratio in all patients with PAH (n = 33). Time until death or transplantation was assessed by Kaplan-Meier analysis. Tertiles were defined as high ET-1/ET-3 ratio (> 2, n = 11), median ET-1/ET-3 ratio (> 1 and ≤ 2, n = 11), and low ET-1/ET-3 ratio (≤ 1, n = 11) [p < 0.001 by log-rank test]. Cum = cumulative.

 
Discussion

In this study, we have demonstrated that PAH is characterized by an imbalance of ET plasma concentrations, with an increase of ET-1 and a decrease of ET-3 plasma concentrations in comparison with control subjects. We have demonstrated that ET-1/ET-3 ratio was well correlated with many clinical and hemodynamic prognostic factors in PAH and that the presence of an increased ET-1/ET-3 ratio was associated with worse prognosis in this sample of PAH patients.

As previously described, we have found that ET-1 plasma concentrations were elevated in PAH and correlated with markers of severity of the disease. Rubens et al22 showed that ET-1 and big-ET-1 plasma concentrations correlated with hemodynamic parameters and 6MWD. These authors22 have suggested that circulating ET-1 might be a good prognostic marker for evolution of PAH. However, in this study, 8 of the 16 patients with PAH were already receiving prostacyclin analogues at the time of ET-1 or big ET-1 measurement.22 We analyzed correlations with markers of disease severity in a sample of patients prior to initiation of specific PAH therapies. We showed that ET-1 was increased in every one of the different subgroups of PAH, suggesting that ET-1 is a hallmark of PAH. However, although we have found correlations with hemodynamic parameters in these patients, ET-1 plasma concentrations were not related with prognosis in our study.

For the first time, we have shown that ET-3 plasma concentrations decreased in PAH and correlated with clinical parameters of severity of PAH (low 6MWD, NYHA functional class). Only few studies focused on ET-3 in PAH. Chang et al23 studied the evolution of ET-1 and ET-3 plasma concentrations in 22 subjects with pulmonary hypertension associated with valvular heart disease. After surgery and decrease of pulmonary arterial pressure, a significant decrease of ET-1 plasma concentrations was observed with a nonsignificant increase of ET-3.23 In our present study, although ET-3 plasma concentrations correlated with major prognostic factors of the disease (6MWD and NYHA functional class), ET-3 were not related with time to transplantation or death. The mechanism of the decrease in ET-3 was not studied in the present work, and it remains to be seen whether this decrease is independent of the increase in ET-1 or secondary to the increase in ET-1 plasma concentrations, and whether it due to a decrease in release, an increase in binding onto ETB, or both.

We hypothesize that ET-3 might counterbalance ET-1 effects through its activation of endothelial ETB. The respective role of ETA or ETB is relatively well established in normal situation, but there is still a doubt about the action of ETB in PAH. Namiki et al24 showed that both ET-1 and ET-3 could induce vasodilatation in precontracted pulmonary arteries, only when the endothelium was intact. Activation of endothelial ETB induces the release of vasodilator and antiproliferative agents (nitric oxide and prostacyclin)12 and prevents endothelial cells apoptosis.13 In animals models, Crawley et al25 showed that ET-3 had vasodilator effects on isolated pulmonary arteries, which could be blocked by nitric oxide synthesis inhibitor. These authors25 have also shown that ET-3 was able to completely reverse hypoxic vasoconstriction, probably by activation of ETB since ET-3 is considered as the physiologic ligand of this site.26 Endothelial ETB is also responsible for the clearance of circulating plasma ET-1.2728 However, most of these experiments were performed using injection of exogenous ET-3, which may not reflect the role of endogenous ET-3, and it still not sure whether endogenous ET-3 is also a ligand for smooth-muscle cell ETB that is upregulated in pulmonary hypertension.29 Nevertheless, we can speculate that an ET-3 decrease could lead to a reduction in nitric oxide and prostacyclin release and might promote vasoconstriction and smooth-muscle cell proliferation in pulmonary arteries from PAH patients.

In this study, we have observed that ET-1 and ET-3 plasma concentrations were variable; but interestingly, ET-1/ET-3 ratio was relatively constant in control subjects, suggesting that there might be a balance between these two ETs in physiologic situations. Interestingly, the use of ET-1/ET-3 ratio added valuable information in our PAH sample. Neither ET-1 nor ET-3 were associated with time to lung transplantation or death in PAH. By contrast, ET-1/ET-3 ratio was related to time to lung transplantation or death in this population. The absence of previous studies forced us to analyze our sample with the use of percentiles based on the hypothesis that the observed imbalance between ETs could be a prognostic factor of the disease (greater ET-1/ET-3 ratio for more severe patients). Indeed, patients within the higher tertile of ET-1/ET-3 ratio (ratio > 2) had a very poor prognosis, all patients being dead or undergoing transplantation within 60 months. Once our sample size is one of the limitations of our study, the cut-off value of 2 for ET-1/ET-3 ratio, as a determinant of prognosis, is to be confirmed in a larger population study, although our results strongly support this assumption.

Our study has limitations. Firstly, these preliminary data are based on a small patient population and should be validated in a large prospective multicenter cohort of PAH patients. The small sample size may have influenced the lack of correlation of ET-1 and ET-3 separately with prognosis; however, the behavior of ET-1/ET-3 ratio in control subjects reinforces the possible balance that exists in the ET system at normal conditions. Furthermore, our cohort of 33 patients, receiving the best possible care at the given time, monitored during several years, gave us the unique opportunity to evaluate long-term prognosis according to baseline ET-1/ET-3 ratio. A study30 has been launched recently in France in order to prospective collect plasma samples of PAH patients; this multicenter, prospective study will allow the confirmation of cut-off values of ET-1/ET-3 ratio found in our study. Another limitation of our study lies on the fact that we did not address whether PAH-specific therapies modified ET-1/ET-3 ratio and, if so, whether this change could be a predictor of prognosis as previously shown for brain natriuretic peptides.31 Interestingly, a reduction in circulating ET-1 has been demonstrated in PAH patients treated with continuous IV epoprostenol, a therapy significantly improving hemodynamics, exercise tolerance, and survival in PAH patients in NYHA functional class III or IV.21323334 Therefore, future studies should analyze whether PAH therapies alter ET-1/ET-3 ratio and if this ET-1/ET-3 ratio reduction would correlate with better outcome.

In conclusion, in PAH, the imbalance of ETs, defined by elevated ET-1 and decreased ET-3 plasma concentrations, could be one of the pathway of the endothelial dysfunction, related to the initiation and progression of PAH. This imbalance, reflected by the ET-1/ET-3 ratio, correlated with hemodynamic and clinical parameters of PAH severity. Furthermore, in our cohort of patients treated with specific PAH therapies, ET-1/ET-3 ratio appeared to be a potential noninvasive prognostic factor in PAH, and appeared as a better marker of prognosis than ET-1 alone.

Acknowledgements

We thank Virginie Sippel for expert technical performance in the measurement of ET-1 and ET-3; Olivier Sitbon (Service de Pneumologie et Réanimation respiratoire, Hôpital Antoine-Béclère, Clamart, France) for helpful comments during the preparation of this article; and Frederic Perros for technical support.

Footnotes

Abbreviations: CI = cardiac index; ET = endothelin; ETA = endothelin receptor A; ETB = endothelin receptor B; IQR = interquartile range; mPAP = mean pulmonary arterial pressure; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; RAP = right atrial pressure; 6MWD = 6-min walk distance; SpO2 = oxygen saturation using pulse oximetry; SvO2 = mixed venous oxygen saturation

An abstract of this work was presented at the 2005 European Respiratory Society Meeting, Copenhagen, Denmark, September 17–21, 2005.

Support was provided by the European Respiratory Society, Fellowship No. 192.

The authors have no conflicts of interest to disclose.

Received for publication March 16, 2006. Accepted for publication July 31, 2006.

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