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(Chest. 2001;120:1562-1569.)
© 2001 American College of Chest Physicians

Big Endothelin-1 and Endothelin-1 Plasma Levels Are Correlated With the Severity of Primary Pulmonary Hypertension*

Christoph Rubens, MD; Ralf Ewert, MD; Michael Halank, MD; Roland Wensel, MD; Hans-Dieter Orzechowski, MD; Heinz-Peter Schultheiss, MD and Gert Hoeffken, MD

* From the Department of Cardiology and Pulmonology (Drs. Rubens and Schultheiss) and Institute of Clinical Pharmacology and Toxicology (Dr. Orzechowski), Benjamin Franklin Hospital, Free University of Berlin, Berlin; German Heart Institute Berlin (Drs. Ewert and Wensel) and Department of Internal Medicine I and Pulmonology (Drs. Halank and Hoeffken), Carl Gustav Carus Hospital, University of Dresden, Dresden, Germany.

Correspondence to: Christoph Rubens, MD, Department of Cardiology and Pulmonology, Benjamin Franklin Hospital, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany; e-mail: ChristophRubens{at}aol.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Primary pulmonary hypertension (PPH) is a rare disease of unknown etiology that is characterized by a poor prognosis. This study was undertaken to investigate possible correlations between endothelin (ET)-1 and big ET-1 plasma levels and the severity of PPH.

Patients: Sixteen consecutive patients with PPH were included.

Interventions: Hemodynamics of patients with PPH were measured by right-heart catheterization, and a 6-min walk test was performed.

Measurements: Plasma levels of the biologically active peptide ET-1 and its precursor big ET-1 were determined in blood samples from the pulmonary artery, peripheral artery, and peripheral vein by radioimmunoassay.

Results: A strong correlation was shown between pulmonary vascular resistance, mean pulmonary artery pressure, cardiac output, cardiac index, 6-min walk data, and elevated plasma levels of big ET-1 as well as mature ET-1 plasma levels at all sites of blood sampling (p < 0.01 and p < 0.05, respectively).

Conclusions: Levels of circulating ET-1 might become a prognostic marker for patients with PPH and serve as a tool for the selection of patients who may benefit from treatment with ET-receptor antagonists.

Key Words: endothelin • hemodynamics • primary pulmonary hypertension


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Primary pulmonary hypertension (PPH) is a disease of unknown etiology characterized by a progressive elevation of pulmonary artery pressure (PAP) that leads to right ventricular failure and death. The mean age at diagnosis is 36 years, the incidence is one to two cases per million people, and the prognosis of the untreated disease is poor with a mean life expectancy of 2.5 years. Although treatment with calcium-channel blockers, prostacyclin derivatives and anticoagulants, or by lung transplantation has increased the mean survival time to 5 years, there is still a need for more effective therapy.1

Pathologic findings in PPH, presumably associated with vasoconstriction and increased vascular resistance, include smooth-muscle cell hypertrophy, intimal hyperplasia, matrix deposition, and in situ thrombosis. These changes in function and morphology in the pulmonary circulation point to an underlying endothelial dysfunction that leads to a decreasing release of vasodilators and antiproliferative agents (prostacyclin, nitric oxide) and an increase in the production of vasoconstrictors and proliferative factors (thromboxane, endothelin [ET]-1).1 2 In this context, the peptide ET-1 is thought to have a significant impact because of its strong vasoactive properties and its effects on cell proliferation and collagen synthesis.3 4 5 6 7

ET-1 is the most potent member of the ET family, which consists of the isopeptides ET-1, ET-2, and ET-3. The primary translation product of the ET-1 gene, prepro-ET-1 (212 amino acids), is cleaved by an intracellular endopeptidase releasing big ET-1 (38 amino acids). The biologically inactive big ET-1 is secreted primarily by endothelial cells and undergoes further processing by ET-converting enzymes (ECEs). ECEs cleave the C-terminal fragment to form the 21-amino-acid peptide ET-1. Two subtypes of ET receptors, the ET-A and ET-B receptors, mediate the known biological actions of ET-1, in particular vasoconstriction and cell proliferation.8 In rat models with monocrotaline-induced or hypoxia-induced pulmonary hypertension (PH), ET-A-receptor antagonists reduced PH and right-heart hypertrophy significantly.9 10

The elevation of mature ET-1 plasma levels in patients with PPH as well as in patients with secondary pulmonary hypertension (SPH), due to pulmonary diseases of known causes or heart diseases, was shown by Stewart et al.11 Whereas a strong correlation between PAP and ET-1 plasma levels was observed in patients with SPH,12 13 Nootens et al14 found correlations between ET-1 plasma levels and right atrial pressure (RAP) as well as pulmonary artery oxygen saturation (SpaO2) in patients with PPH. Giaid et al15 showed increased ET-1 expression in lung vascular endothelial cells in patients with PPH and SPH, which indicated an association between tissue ET-1 expression and circulating ET-1.

The aim of this study was to evaluate the correlation of big ET-1 and ET-1 plasma levels with the severity of PPH. The severity of PPH was determined by hemodynamic data and clinical parameters (6-min walk test and New York Heart Association [NYHA] class). Separate analysis of plasma levels of the precursor big ET-1 and mature ET-1 was performed, because big ET-1 is thought to be a more reliable indicator for the activation of the ET-1 system due to a longer plasma half-life and much less tissue extraction.16


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Sixteen patients with PPH were consecutively enrolled in this study. Mean PAP (PAPmean) was > 25 mm Hg at rest or > 30 mm Hg during exercise. SPH was excluded according to the diagnostic criteria used by the National Institutes of Health.17 Further exclusion criteria were myocardial infarction 6 months prior to inclusion, renal failure with a creatinine level > 200 µmol/L, abnormal liver function, acute inflammation, and neoplasia. All patients gave informed consent. The study protocol was approved by the local ethics committee. The investigation conformed to the principles outlined in the Declaration of Helsinki.

Hemodynamics
Hemodynamic parameters were measured during acute vasodilator testing performed routinely to predict the long-term response to oral vasodilator therapy or during follow-up evaluations with patients receiving oral vasodilators and prostacyclin derivatives by aerosolization or IV administration. For right-heart catheterization, we used a Swan-Ganz catheter (Baxter Swan-Ganz 8 French CCO/VIP; Baxter; Irvine, CA). Catheterization via jugular, subclavian, antecubital, and femoral veins revealed systolic PAP (PAPsyst), diastolic PAP (PAPdiast), PAPmean, cardiac output (CO), cardiac index (CI), pulmonary capillary wedge pressure (PCWP), right arterial pressure (RAP), and pulmonary vascular resistance (PVR). Radial artery catheterization revealed heart rate (HR), systolic artery pressure, diastolic artery pressure, mean systemic artery pressure (SAPmean), and systemic vascular resistance (SVR). Pressures were monitored on a multichannel recorder (Hewlett Packard; Böblingen, Germany). CO was determined by the Fick method. Values for vascular resistance were calculated as follows:

PVR = 80(PAPmean - PCWP)/CO and

SVR = 80(SAPmean - RAP)/CO defined in dyne · s · cm - 5

All measurements were performed at room air and at rest > 30 min after the placement of the catheters.

6-min Walk Test
Nine patients performed the 6-min walk test according to standard protocol.

Measurement of big ET-1 and Mature ET-1
Blood samples from the peripheral artery and vein and from the pulmonary artery were drawn into precooled tubes that contained potassium ethylenediamine-tetra-acetic acid and immediately centrifuged at 4°C. Plasma samples were kept frozen at - 70°C.

Plasma big ET-1 and mature ET-1 levels were determined by extraction-based competitive radioimmunoassays (Biomedica; Vienna, Austria). Peptides were extracted from plasma using Sep-Pack C18 cartridges (Waters Corporation; Milford, MA) and eluted using methanol/water solutions according to the recommendations of the manufacturer. The eluted fraction was vacuum concentrated (Univapo 150 H; Uniequip; Martinsried, Germany) at room temperature and reconstituted in assay buffer immediately before the radioimmunoassay. A 24-h incubation period at 2°C to 8°C with the primary antibody (rabbit anti-big ET-1 antibody and rabbit anti-ET-1/2 antibody, respectively) was followed by the addition of tracer (125I-big ET-1 and 125I-ET-1, respectively) and a second incubation period (24 h for big ET-1 and 6 h for ET-1/2). Separation of the bound from the unbound ligands was achieved by a precipitating reagent that consisted of the secondary antibody and polyethylene glycol. All determinations were done in duplicate. Reactivity of the primary anti-big ET-1 antibody was 100% with big ET-1 and 82% with the C-terminal fragment of big ET-1. Cross reactivity with mature ET peptides was < 1%. Intra-assay variation of the big ET-1 radioimmunoassay was 4.9%. Reactivity of the primary anti–ET-1/2 antibody was 100% with ET-1, 142% with ET-2, 98% with ET-3, < 1% with big ET-1 (1–38), and < 1% with big ET-1 (22–38). Intra-assay variation of the ET-1/2 radioimmunoassay was 13.3%.

Statistical Analysis
All data are presented as mean ± SD. The correlation of big ET-1 and ET-1 plasma levels with hemodynamic and clinical parameters was tested using Spearman’s correlation coefficient revealing p and r values. Statistical significance was accepted at p <= 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Characteristics
Eleven women and 5 men with PPH were consecutively included in the study. They were aged 26 to 67 years (mean age, 43.6 ± 12.7 years). PAPmean was 54 ± 10 mm Hg (range, 39 to 78 mm Hg), PAPsyst was 81 ± 16 mm Hg (range, 58 to 116 mm Hg), and PAPdiast was 38 ± 8 mm Hg (range, 28 to 51 mm Hg). PVR ranged from 524 to 2,598 dyne · s · cm- 5, and the mean was 1,318 ± 689 dyne · s · cm- 5. These and other parameters are given in Table 1 . Three patients underwent lung transplantation, and five patients died within 6 months after inclusion in the study. On recruitment, eight patients were receiving treatment with iloprost by aerosolization (n = 4) or IV administration (n =4).


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  		Table 1.. Patient Characteristics*

 
Correlations of Big ET-1 and Mature ET-1 Plasma Levels With Hemodynamic and Clinical Parameters
Mean big ET-1 plasma levels of PPH patients were 6.3 ± 4.2 fmol/mL in the peripheral artery, 6.2 ± 4.2 fmol/mL in the peripheral vein, and 6.3 ± 4.0 fmol/mL in the pulmonary artery. Mean plasma levels of mature ET-1 in PPH patients were 0.93 ± 0.58 fmol/mL in the peripheral artery, 0.99 ± 0.53 fmol/mL in the peripheral vein, and 0.95 ± 0.52 fmol/mL in the pulmonary artery (Table 2 ). Big ET-1 plasma levels revealed a significant correlation with PVR, PA Pmean, CO, and CI at all sampling sites (Table 3 , Fig 1 ). Circulating mature ET-1 concentrations showed a similar association with PVR, PAPmean, CO, and CI at all sampling sites, with the exception of the lack of a correlation between ET-1 and CI in the venous blood (Table 4 and Fig 2 ). In nine patients who underwent 6-min walk testing, a strong correlation between exercise and big ET-1 and ET-1 plasma levels could be shown (Tables 3 , 4) . Big ET-1 and ET-1 plasma levels were not associated with age, sex, NYHA functional class, HR, systemic artery pressure (SAP), SVR, and RAP (Tables 3 , 4) . Treatment with iloprost (n = 8) revealed nonsignificant lower big ET-1 and ET-1 plasma levels compared with the untreated group (Table 5 ).


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  		Table 2.. Big ET-1 and ET-1 Plasma Levels*

 

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  		Table 3.. Correlations of Big ET-1 Plasma Levels With the Severity of PPH*

 


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  		Figure 1.. Correlation between peripheral venous big ET-1 plasma levels and PVR (top, A), PAPmean (middle, B), and CO (bottom, C). Lines represent linear regression.

 

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  		Table 4.. Correlations of Mature ET-1 Plasma Levels With the Severity of PPH*

 


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  		Figure 2.. Correlation between peripheral venous mature ET-1 plasma levels and PVR (top, A), PAPmean (middle, B), and CO (bottom, C). Lines represent linear regression.

 

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  		Table 5.. Iloprost Treatment and Big ET-1/ET-1 Plasma Levels*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The current study demonstrates a strong correlation between big ET-1 and mature ET-1 plasma levels and the severity of PPH in man. Previous studies11 12 14 18 showed elevated circulating mature ET-1 plasma levels in patients with PPH and SPH. In patients with PPH, Nootens et al14 found a correlation between mature ET-1 and RAP as well as SpaO2. To our knowledge, no previous study has addressed mature ET-1 as well as big ET-1 plasma levels to find the best marker that reflects disease-associated alterations of the ET system most accurately.

In the current investigation, cross-reactivity of the big ET-1 antibody with ET-1 was < 1% and cross-reactivity of the ET-1 antibody with big ET-1 was < 1%. However, in the previous studies11 12 14 mentioned above that detected increased ET-1 plasma levels in patients with PH, cross-reactivities with big ET-1 of the ET-1 antibody applied were 10%, 17%, and 76%, respectively. Studies using ET-1 antibodies that showed significant cross-reactivity with big ET-1 do not sufficiently discriminate circulating mature ET-1 and big ET-1 plasma levels and therefore tend to overestimate mature ET-1 plasma levels. Although plasma levels of both peptides were correlated with the severity of PPH in our study, mature ET-1 plasma levels were very low and tended to be less strongly associated than those of big ET-1 (Tables 3 , 4 and Fig 1 , 2 ). Furthermore, differentiated determination of ET-1 and big ET-1 has significant implications because, in contrast to big ET-1, up to 50% of mature ET-1 in healthy subjects and 40% in patients with PH is cleared during the pulmonary passage via the ET-B receptor,12 19 which contributes to its short half-life and low plasma levels. Measurement of mature ET-1 alone reflects elevated production and reduced pulmonary clearance. The much higher plasma levels of big ET-1 compared with levels of mature ET-1 observed in our study are likely to be caused by the longer plasma half-life of big ET-1, which is not cleared during pulmonary passage and thus more appropriately represents secretion of the peptide.16 In contrast to Stewart et al11 and Dupuis et al,12 who found a tendency of higher ET-1 plasma levels in the arterial blood when compared with those in the venous blood that points to a transpulmonary gradient, the current study shows similar big ET-1 and mature ET-1 plasma levels at all sites of blood sampling. Concerning mature ET-1, this observation may be caused by rapid pulmonary clearance of ET-1. In the case of big ET-1, a part of it released by pulmonary vasculature may be cleaved by ECE-1, as suggested from findings of an increased immunoreactivity of lung ECE-1 in patients with PH,20 which equalizes plasma levels at arterial and venous sampling sites. However, due to similar plasma levels at all sampling sites and the trend of a stronger correlation with hemodynamics of the precursor peptide big ET-1, we conclude that the determination of venous big ET-1 plasma levels is a sufficient approach to find out the relationship of activated ET-1 release to the severity of the disease.

As discussed in earlier investigations,11 15 determination of circulating as well as tissue ET-1 did not clarify the contribution of the ET system to the etiology of PPH. Hypoxia, shear stress, and mediators, such as angiotensin II, transforming growth factor-ß, interleukin-1, thrombin, epinephrine, and endotoxins are known as stimulators of ET-1 release, but to our knowledge, no data exist about these interactions in patients with PH.1 8 In human pulmonary artery endothelial cell cultures, stimulation of the ET-1 promoter by thrombin and the increase of hypoxia-induced transcription of ET-1 by proinflammatory agents such as lipopolysaccaride, interleukin-1, and tumor necrosis factor-{alpha} were shown.21 22 Animal models of PH revealed alterations of growth factor transcripts, which included transforming growth factor-ß, platelet-derived growth factor B, and vascular endothelial cell growth factor, as well as activated ET-1 synthesis.23 However, the relevance of PH animal models for human disease has not been established. In humans, circulating big ET-1 and ET-1 plasma levels in PPH patients in comparison with SPH patients and the investigation of the tissue expression of all components of the ET system (ET-1, ECE-1, ET receptors) may clarify the role of ET in the pathophysiology of the disease.

Summarizing the results of previous studies and our data, the activation of the ET system in patients with PPH is correlated with the severity of the disease, suggesting a role in the progression of the disease. This is supported by a follow-up study24 showing that hemodynamic improvement in PPH by infusion of epoprostenol was associated with a reduction of ET-1 production and/or an increase of pulmonary ET-1 clearance. This finding is in agreement with a trend to decreased ET-1 and big ET-1 levels of iloprost-treated patients in our study (Table 5) . Although treatment with prostacyclin derivatives has become an established therapeutic strategy, antagonism of an activated ET system itself may be an additional or even superior approach. This is supported by animal models, which demonstrated a reduction in PH and right-heart hypertrophy after treatment with ET-A–receptor antagonists,9 10 and by a human study by Kiowski et al,25 which showed a reduction in PH in heart failure patients by treatment with a nonselective ET-A/ET-B–receptor antagonist.

In conclusion, our data demonstrate a significant correlation between ET-1 plasma levels and the severity of PPH. In patients with PPH, big ET-1 plasma levels seem to reflect ET-1 release more accurately and may serve as a marker for disease severity, which can be easily determined from a single venous blood sample. Further studies should address the potential predictive value of big ET-1 plasma levels with regard to prognosis as well as the therapeutic benefit of ET-receptor antagonists.


   Acknowledgements
 
We thank Sabine Knueppel for performing the radioimmunoassay. Ksenia Ivantchikova enrolled the PPH patients in this study. We also thank Tonie Derwent for editorial assistance.


   Footnotes
 
Abbreviations: CI = cardiac index; CO = cardiac output; ECE = endothelin-converting enzyme; ET = endothelin; HR = heart rate; NYHA = New York Heart Association; PAP = pulmonary artery pressure; PAPdiast = diastolic pulmonary artery pressure; PAPsyst = systolic pulmonary artery pressure; PAPmean = mean pulmonary artery pressure; PH = pulmonary hypertension; PPH = primary pulmonary hypertension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; SAP = systemic arterial pressure; SAPmean = mean systemic artery pressure; SpaO2 = pulmonary artery oxygen saturation; SPH = secondary pulmonary hypertension; SVR = systemic vascular resistance

Received for publication May 17, 2000. Accepted for publication May 25, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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