HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Chen, M.-C. Articles by Hung, W. C. Search for Related Content PubMed PubMed Citation Articles by Chen, M.-C. Articles by Hung, W. C.

Increased Circulating Endothelin-1 in Rheumatic Mitral Stenosis^*

Irrelevance to Left Atrial and Pulmonary Artery Pressures

^* From the Division of Cardiology (Drs. M-C Chen, Wu, Yip, C-J Chen, Yu, and Hung), Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung; and Department of Biological Sciences (Dr. Chang), National Sun Yat-Sen University, Kaohsiung, Taiwan, Republic of China.

Correspondence to: Mien-Cheng Chen, MD, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123, Ta Pei Rd, Niao Sung Hsiang, Kaohsiung Hsien 83301, Taiwan, Republic of China; e-mail: chenmien{at}ms76.hinet.net

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: Increased plasma endothelin (ET)-1 concentrations have been observed in patients with rheumatic mitral stenosis (MS). However, the mechanisms of increased circulating ET-1 in patients with MS remain unclear.

Methods: We measured plasma concentrations of ET-1 in blood samples from the femoral vein and artery, and right and left atria obtained from 20 patients with moderate-to-severe rheumatic MS before and after percutaneous transluminal mitral valvuloplasty (PTMV) [group 1; 16 patients in chronic atrial fibrillation and 4 patients in sinus rhythm]. In addition, we measured plasma concentrations of ET-1 in the peripheral venous blood samples obtained from 22 control patients (including 14 healthy volunteers in sinus rhythm [group 2] and 8 patients in chronic lone atrial fibrillation [group 3]). Plasma ET-1 concentrations were measured by solid-phase, sandwich enzyme-linked immunosorbent assay.

Results: The peripheral venous plasma concentrations of ET-1 were significantly higher in group 1 patients (2.46 ± 0.90 pg/mL) than in group 2 and group 3 patients (0.74 ± 0.42 pg/mL and 0.99 ± 0.41 pg/mL, respectively [mean ± SD]; p < 0.0001). However, there was no significant difference in the peripheral venous concentrations of ET-1 between group 2 and group 3 patients. In group 1 patients, the plasma ET-1 concentration in the femoral vein (2.46 ± 0.90 pg/mL) was significantly higher than that in the right atrium (2.02 ± 0.69 pg/mL), left atrium (2.11 ± 0.99 pg/mL), and femoral artery (2.05 ± 0.75 pg/mL) [p = 0.0001]. The plasma ET-1 concentration in the femoral vein was not correlated with the mean left atrial pressure (r = 0.05; p = 0.838) and mean pulmonary artery pressure (r = 0.07; p = 0.757). The plasma ET-1 concentration in the left atrium was also not correlated with the mean left atrial pressure (r = 0.11; p = 0.656), mean pulmonary artery pressure (r = 0.06; p = 0.788), or mitral valve area (r = 0.02; p = 0.936). Although the area of mitral valve increased significantly (1.06 ± 0.17 cm² vs 1.48 ± 0.32 cm²; p < 0.0001), and the mean left atrial pressure (23.0 ± 5.1 mm Hg vs 17.6 ± 5.9 mm Hg; p < 0.0001) and mean pulmonary arterial pressure (31.0 ± 7.9 mm Hg vs 25.5 ± 7.0 mm Hg; p < 0.001) fell significantly and immediately after PTMV, there were no significant changes in the plasma ET-1 concentrations in the femoral vein, right atrium, left atrium, and femoral artery immediately after PTMV.

Conclusion: Increased production of ET-1 in the pulmonary circulation in response to increased pulmonary artery pressure was not the mechanism of increased circulating ET-1 concentration in patients with MS. We proposed that one of the mechanisms of increased ET-1 concentration in the femoral vein was increased peripheral ET-1 release due to increased systemic venous pressure and mechanical damage of the endothelium.

Key Words: endothelin-1 • mitral stenosis

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Endothelin (ET)-1 is an endothelium-derived vasoconstrictor peptide with 21-amino acid residues originally isolated from culture media conditioned by porcine aortic endothelial cells.¹ Circulating ET-1 has been shown to be elevated in patients with hypertension, systemic atherosclerosis, and congestive heart failure.^{2 3 4} Circulating ET-1 has also been reported to be elevated in patients with mitral stenosis (MS).^{5 6} The increased regional plasma ET-1 level in the left atrium of patients with MS is attributed to increased production of ET-1 in the pulmonary circulation in response to increased pulmonary artery pressure.⁵ On the contrary, circulating ET concentrations have been demonstrated to increase rapidly after percutaneous transluminal mitral valvuloplasty (PTMV), which significantly reduced left atrial and pulmonary pressures.⁶ Therefore, the mechanisms of increased circulating ET-1 in patients with MS remain unclear. Wagner and associates⁷ demonstrated that in healthy young men, the ET-1 concentration in the peripheral venous plasma is significantly higher than that in the arterial plasma. In addition, the plasma concentration of ET-1 significantly increases after venous stasis. Accordingly, we tested the hypothesis that the elevation of ET-1 concentration in the peripheral venous plasma of patients with MS was irrelevant to the left atrial and pulmonary artery pressures.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study Population
Twenty patients who had symptomatic, moderate-to-severe rheumatic MS (mitral valve area, 1.06 ± 0.17 cm² [mean ± SD]; range, 0.6 to 1.29 cm²) without significant mitral, tricuspid, or aortic regurgitation or left atrial thrombus and had undergone PTMV were studied (group 1). There were 2 men and 18 women (age range, 39 to 72 years; mean age, 55 ± 12 years). Sixteen patients were in chronic atrial fibrillation, and 4 patients were in sinus rhythm. Six patients had a history of cerebral thromboembolism. Ten patients were in New York Heart Association functional class III, and 10 patients were in New York Heart Association functional class II. No patients had a history of malignancy, inflammatory disease, collage vascular disease, renal or liver disease, diabetes mellitus, hypertension, hyperlipidemia, infectious disease, deep venous thrombosis, pulmonary embolism, or recent surgery.

Peripheral venous plasma ET-1 concentrations were also measured in 22 control subjects. The group of control subjects included 14 healthy volunteers in sinus rhythm (group 2) and 8 patients in chronic lone atrial fibrillation without systemic disease or structural heart disease (group 3). In group 3, two patients had a history of systemic arterial thromboembolism. None of the control subjects had a history of active malignancy, inflammatory disease, renal or liver disease, diabetes mellitus, hypertension, hyperlipidemia, deep venous thrombosis, pulmonary embolism, or recent surgery.

Informed consent was obtained from all study subjects. The study protocol was approved by the Institutional Review Committee on Human Research in our institution.

Doppler Echocardiography and Medications
In patients with rheumatic MS, transthoracic echocardiographic examinations were performed on the day of PTMV and before the valvuloplasty procedure and at the 1-week follow-up after PTMV with a 2.5-MHz transducer attached to a commercially available echocardiography Doppler machine (Sonos 5500; Hewlett-Packard; Palo Alto, CA) to assess left atrial dimension and mitral valve area. M-mode measurements were performed according to the recommendation of the American Society of Echocardiography. The mitral valve area was calculated by means of the Doppler pressure half-time method. The severity of mitral, tricuspid, and aortic insufficiency was determined by Doppler color-flow mapping. The absence of left atrial cavity or appendageal thrombus was confirmed by transesophageal echocardiography.

In group 1 patients, warfarin was discontinued for at least 3 days before PTMV. Heparin, 5,000 U, was administered into the left atrium after transseptal puncture in each patient. Diuretics were discontinued on the day of PTMV. Digoxin, beta-blockade, and Ca-blockade were discontinued for at least 5 half-life before study. In group 3 patients, aspirin was discontinued for at least 7 days and warfarin was discontinued for at least 3 days before study. Digoxin and Ca-blockade were discontinued for at least 5 half-life before study.

Valvuloplasty Procedure
PTMV was performed by the transseptal approach with the use of an Inoue balloon catheter. Details of the procedure have been described previously.⁸ In brief, an Inoue balloon catheter (Toray Medical Corporation; Tokyo, Japan) was inserted into the left ventricle via transseptal approach. The distal half of the balloon was inflated in this position, and the balloon was pulled back to the mitral valve orifice. The balloon was then fully inflated and pulled back to the left atrium before being deflated. When additional balloon dilatation was required, the same procedure was repeated.

Hemodynamic Measurements
In group 1 patients, mean pressure in the right atrium, pulmonary artery, left atrium, ascending aorta, and femoral artery were obtained before and after valvuloplasty. Cardiac output was determined by the thermodilution method. The following variables were determined: total pulmonary resistance and pulmonary vascular resistance. In group 2 and group 3 patients, arterial BP of the right arm was measured by sphygmomanometry at the time of blood collection, with the patients in the supine position, and mean arterial BP was calculated as one third of the pulse pressure plus the diastolic BP.

Blood Sample Collection and Measurement of Plasma ET-1 Concentrations
Blood samples were obtained in the fasting, nonsedative state at 9 to 10 AM in the control and study groups to exclude the possible influence of circadian variations.⁹ In group 1 patients, blood was obtained from the femoral vein and artery through introducer sheaths immediately after puncture with the patients in the supine position for at least 20 min. Right atrial blood was obtained through balloon catheter, and left atrial blood was obtained immediately after transseptal puncture before heparin administration. Another set of blood samples from the femoral vein, femoral artery, and right and left atria were obtained 10 min after optimal PTMV. Five mL of blood was drawn into an evacuated tube containing K₃ ethylenediamine tetra-acetic acid (Vacutainer; Becton Dickinson; Franklin Lakes, NJ). At the 1-week and 4-week follow-ups after PTMV, 5 mL of peripheral venous blood was obtained under minimal tourniquet pressure from the antecubital vein using a sterile 22-gauge needle syringe in a single attempt, with the patients in the supine position for at least 20 min. In group 2 and group 3 subjects, blood was obtained under minimal tourniquet pressure from the antecubital vein using a sterile 22-gauge needle syringe in a single attempt, with the study subjects in the supine position for at least 20 min, and 5 mL of blood was drawn into a Vacutainer containing K₃ ethylenediamine tetra-acetic acid. Blood samples with gross hemolysis were discarded. Mixtures of blood and K₃ ethylenediamine tetra-acetic acid were immediately centrifuged at 3,000 revolutions per minute for 10 min (model 5400; Kubota Corporation; Tokyo, Japan). The plasma was immediately separated and frozen at - 80°C until the assay. Blood samples were also withdrawal for whole blood counts, and biochemical and electrolyte measurements by standard laboratory methods.

The ET-1 concentration of human plasma samples was quantified with the use of a commercially available, solid-phase, sandwich enzyme-linked immunosorbent assay kit (R&D Systems; Minneapolis, MN) after extraction. The samples were processed according to the instructions of the manufacturer. Because the solid-phase, sandwich enzyme-linked immunosorbent assay consists of two antibodies, they have higher specificity than conventional radioimmunoassays.¹⁰ Before assay, 500 µL plasma samples were thoroughly mixed with 750 µL of extraction solvent (acetone:1 N HCL:water [40:1:5]) and centrifuged at 14,000 revolutions per minutes for 20 min in a refrigerated centrifuge at 4°C. The supernatant was decanted and dried down under reduced pressure in a centrifugal evaporator (Speed Vac SC110, Refrigerated Vapor Trap RVT100, Valupump VLP120; Savant Instruments; Holbrook, NY). The pellet was reconstituted in 0.25 mL sample diluent and vortexed for 30 s. The samples, which included standards in buffer and reconstituted extracts of the quality control and test samples and an enzyme (horseradish peroxidase)-labeled second antibody, were sequentially added to a 96-well microplate precoated with an anti–ET-1 antibody. After 1 h of incubation at room temperature and removal of unbound materials, the amount of enzyme-conjugated tracer bound to the wells was detected through reaction with a substrate specific for the enzyme. The reaction product was measured by using a microplate reader (MRX; Dynex Technologies; Chantilly, VA) and reading the absorbance at 450 nm with a correction wavelength of 630 nm. The assay was sensitive to detect < 1.0 pg/mL of ET-1. The cross-reactivity of ET-2, ET-3, and big ET in this assay were 45%, 14%, and < 1%, respectively, according to the manufacturer of the assay kits. A standard curve was determined with the use of the mean absorbance values of the included ET-1 standards, and the ET-1 concentrations in all unknown plasma samples were then calculated with linear regression. All standards and samples were tested in duplicate. The mean intra-assay coefficient of variance was 6.2% in our laboratory.

Statistical Analysis
Continuous variables were described as mean ± SD. Categorical variables were compared using the Fisher exact test (two tailed). The difference in plasma ET-1 concentrations in peripheral venous blood between patients who were in sinus rhythm and those with atrial fibrillation was compared using Student t test (two tailed). Continuous variables within the same group were compared using paired t test. The plasma ET-1 concentrations in the peripheral venous blood obtained before PTMV, and at the 1-week and 4-week follow-ups after PTMV were compared using the repeated-measures analysis of variance (ANOVA). A Dunnett test was used for post hoc comparisons. Continuous variables among the three groups were compared using the one-way ANOVA. The Tukey procedure was used for post hoc comparisons. Multiple stepwise logistic regression analysis was used to determine independent variables between groups 1 and group 3 patients. The correlation between plasma ET-1 concentrations and age, hemodynamic, or echocardiographic variables was performed with a Pearson correlation. Statistical analysis was performed with statistical software (SAS for Windows, Version 8.02; SAS Institute; Cary, NC). A probability value < 0.05 was considered statistically significant.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Comparison of Baseline Characteristics and Peripheral Venous Plasma ET-1 Concentrations Among the Three Groups
The baseline characteristics for each group are summarized in Table 1 . There was no significant difference among the three groups in terms of use of beta-blockade, Ca-blockade, amiodarone, propafenone, aspirin, blood cell counts, and biochemistry data. The duration of atrial fibrillation of group 1 patients did not differ from that of group 3 patients (p = not significant). Group 3 patients were significantly older than group 2 subjects, and the use of warfarin in group 1 and group 3 patients was significantly more frequent than that of group 2 patients. There were fewer male patients in group 1 than in groups 2 and 3. The mean arterial pressure of group 1 patients was significantly higher than that of group 2 or group 3 patients (p < 0.006); however, the pressure difference between group 1 patients and group 2 or group 3 patients was within normal limits, as the femoral arterial pressure is normally higher than right brachial arterial pressure. The peripheral venous plasma ET-1 level of group 1 patients was significantly higher than that of group 2 or group 3 patients (p < 0.0001) [Table 1 ]. The peripheral venous plasma ET-1 level of group 2 subjects did not differ from that of group 3 patients. By multiple stepwise logistic regression analysis, only peripheral venous plasma ET-1 level was significantly higher in group 1 patients than in group 3 patients (p < 0.006).

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Correlation between age and the peripheral venous plasma ET-1 concentrations in healthy volunteers.

The plasma ET-1 concentration in the femoral vein (2.46 ± 0.90 pg/mL) was significantly higher than that in the right atrium (2.02 ± 0.69 pg/mL), left atrium (2.11 ± 0.99 pg/mL), and femoral artery (2.05 ± 0.75 pg/mL) [p = 0.0001; Fig 2 ]. There were no significant changes in the plasma ET-1 concentration in the femoral vein, right atrium, left atrium, and femoral artery immediately after PTMV (Table 2 ). However, plasma ET-1 concentration in the peripheral venous blood obtained before PTMV fell significantly at the 1-week and 4-week follow-ups after PTMV (before, 2.46 ± 0.90 pg/mL; 1 week after, 1.59 ± 0.70 pg/mL; 4 weeks after, 1.72 ± 1.26 pg/mL; p < 0.0001). The plasma ET-1 concentration in the peripheral venous blood obtained at the 1-week follow-up did not differ from that obtained at the 4-week follow-up after PTMV. The prevalvuloplasty plasma ET-1 concentration in the femoral vein was weakly correlated with the mean prevalvuloplasty right atrial pressure (r = 0.42; p = 0.065), although the difference did not reach statistical significance. The plasma ET-1 concentration in the femoral vein was not correlated with the mean left atrial pressure (r = 0.05; p = 0.838), mean pulmonary artery pressure (r = 0.07; p = 0.757), total pulmonary resistance (r = 0.24; p = 0.332), and pulmonary vascular resistance (r = 0.21; p = 0.399). The plasma ET-1 concentration in the left atrium was also not correlated with the mean left atrial pressure (r = 0.11; p = 0.656), mean pulmonary artery pressure (r = 0.06; p = 0.788), mitral valve area (r = 0.02; p = 0.936), total pulmonary resistance (r = 0.15; p = 0.542), and pulmonary vascular resistance (r = 0.06; p = 0.816).

View larger version (10K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Plasma ET-1 concentrations were determined by solid-phase, sandwich enzyme-linked immunosorbent assay in the blood obtained from the femoral vein (FV), femoral artery (FA), left atrium (LA), and right atrium (RA) of patients with rheumatic MS. The plasma ET-1 concentration in the femoral vein was significantly higher than that in the right atrium, left atrium, or femoral artery (*p = 0.0001).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

Elevated Plasma ET-1 Concentration in Patients With Rheumatic MS
Yamamoto and associates⁵ demonstrated that in 10 patients with MS, ET-1 levels were significantly higher in the left atrial blood samples than in the right atrial blood samples, which were not significantly different from those in peripheral venous blood samples obtained from normal subjects. In addition, the increased plasma ET-1 level in the left atrium was correlated with mean pulmonary artery pressure and 1/mitral valve area and was attributed to increased production of ET-1 in the pulmonary circulation in response to increased pulmonary artery pressure. However, Kinoshita and associates⁶ demonstrated that there were no significant differences in the concentrations of plasma ET in the femoral vein, pulmonary artery, left atrium, and ascending aorta in patients with MS. In addition, the plasma ET concentration in the femoral vein was slightly but significantly higher than that in the antecubital vein of healthy volunteers, and there was a positive correlation between the mean left atrial pressure and the femoral venous plasma ET concentration in the MS patients before PTMV. Interestingly, in their study, the femoral venous plasma ET concentrations paradoxically increased after PTMV, which significantly reduced left atrial and pulmonary artery pressures. In the present study, we found that in patients with MS, the plasma ET-1 concentration in the femoral vein was significantly higher than that in the right atrium, left atrium, and femoral artery. We also found that the plasma ET-1 concentrations in the femoral vein and left atrium before PTMV were not correlated with the mean left atrial pressure and mean pulmonary artery pressure. Moreover, although the mean left atrial and pulmonary arterial pressures fell significantly and immediately after PTMV, there were no significant changes in the plasma ET-1 concentrations in the femoral vein, right atrium, left atrium, and femoral artery immediately after PTMV. Therefore, our results did not support that increased production of ET-1 in the pulmonary circulation in response to increased pulmonary artery pressure was the mechanism of increased circulating ET-1 concentration in patients with rheumatic MS.

There were two possible mechanisms that contributed to the increased ET-1 concentration in the femoral vein of patients with MS. First, in healthy volunteers, the venous plasma ET-1 concentration has been demonstrated to be significantly higher than the arterial plasma ET-1 concentration.⁷ In addition, after venous stasis for 10 min, the venous plasma ET-1 concentration significantly increased approximately twofold than the basal venous plasma ET-1 concentration. It is well known that in addition to endothelium, many tissues and organs can produce ET-1.¹¹ The plasma half-life of ET-1 is short, < 10 min. The circulating ET-1 is predominantly eliminated from circulation by the lung and to a lesser extent, by the kidney, heart, and liver.^{11 12 13} Additionally, the reduced ET-1 concentrations in the renal and hepatic veins as a result of extraction by the two organs also contributed to the lower concentration of ET-1 in the right atrium. Therefore, it was reasonable to observe a significantly increased ET-1 level in the femoral vein, compared to that in the left and right atria and femoral artery. We proposed that one of the mechanisms of increased ET-1 level in the femoral vein of patients with MS was increased peripheral ET-1 release due to increased systemic venous pressure and mechanical damage of the endothelium. This hypothesis was further supported by the concomitant observations that there were no significant changes in the femoral venous plasma ET-1 concentration and the mean right atrial pressure immediately after PTMV. In addition, as the area of mitral valve increased significantly after PTMV, the plasma ET-1 concentration in the peripheral venous blood fell significantly at the 1-week and 4-week follow-ups after PTMV, indicating that the elevated ET-1 concentration had a relation to the underlying pathophysiology of MS and there was a delayed response to the successful systemic hemodynamic relief. Second, it has been shown that mitral valve T-cell lines from patients with chronic rheumatic heart disease produce significant amounts of tumor necrosis factor- in response to M5 streptococcal N-terminal peptide,¹⁴ and increased ET-1 messenger RNA expression has been observed after treatment of cultured endothelial cells with tumor necrosis factor-.¹¹ These findings may contribute to the heart lesion progression after recurrence of the streptococcal infection and increased ET-1 levels in patients with rheumatic MS.

Plasma ET-1 Concentration in Lone Atrial Fibrillators
Brundel and associates¹⁵ demonstrated that the increase of pro–ET-1 messenger RNA in atrial tissue of patients with atrial fibrillation is not caused by increased electrical stimulation per se, as its expression was unchanged in patients with atrial fibrillation and without valve disease, and the increase of pro–ET-1 messenger RNA in atrial tissue seems dependent on the underlying valve disease. In our study, we also found that the peripheral venous plasma ET-1 level of lone atrial fibrillators did not differ from that of healthy volunteers.

Correlation Between Age and Peripheral Venous Plasma ET-1 Concentration
Lerman and associates,² using radioimmunoassay kits, demonstrated that there was no correlation between age and venous plasma ET concentration in normal subjects. In our study, we found that there was a significant correlation between age and the peripheral venous plasma ET-1 concentration in healthy volunteers. There were two possible reasons to explain this discrepancy. First, the different observations between our study and a previous study² may be due to different immunoassay techniques with different cross-reactivity with ET-2, ET-3, and big ET. Second, we could not completely exclude the possibility that in our healthy volunteers, there were variable degrees of subclinical atherosclerosis, which has been shown to correlate with circulating ET-1 levels.

There were several limitations in this study. First, the immunoassay kit for ET-1 used in this study had 45% cross-reactivity with ET-2 and 14% with ET-3. Therefore, the ET measured in this study may actually include ET-1 and ET-1–related proteins. Second, we could not exclude factors other than increased systemic venous pressure that regulate ET-1 gene expression and account for the elevated ET-1 concentration in patients with MS. Finally, the plasma ET-1 concentration in femoral vein was weakly correlated with the mean right atrial pressure, although the difference did not reach statistical significance. This could be due to a type-2 error. We believed that the correlation between the femoral venous plasma ET-1 concentration and the mean right atrial pressure should become significant with increasing number of study patients.

In conclusion, in patients with moderate-to-severe MS, the plasma ET-1 concentration in the femoral vein was significantly higher than that in the right atrium, left atrium, and femoral artery. In addition, the plasma ET-1 concentrations in the femoral vein and left atrium were not correlated with the mean left atrial pressure and mean pulmonary artery pressure.

	Footnotes

 
Abbreviations: ANOVA = analysis of variance; ET = endothelin; MS = mitral stenosis; PTMV = percutaneous transluminal mitral valvuloplasty

This study was supported by a grant No. CMRP1139 from Chang Gung Memorial Hospital, Chang Gung University.

Received for publication March 11, 2003. Accepted for publication July 18, 2003.

	References

TOP Abstract Introduction Materials and Methods Results Discussion References

 

1. Yanagisawa, M, Kurihara, H, Kimura, S, et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332,411-415[CrossRef][Medline]
2. Lerman, A, Edwards, BS, Hallett, JW, et al Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991;325,997-1001[Abstract]
3. Wei, CM, Lerman, A, Rodeheffer, RJ, et al Endothelin in human congestive heart failure. Circulation 1994;89,1580-1586[Abstract/Free Full Text]
4. Kiowski, W, Sutsch, G, Hunziker, P, et al Evidence for endothelin-1–mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346,732-736[CrossRef][ISI][Medline]
5. Yamamoto, K, Ikeda, U, Mito, H, et al Endothelin production in pulmonary circulation of patients with mitral stenosis. Circulation 1994;89,2093-2098[Abstract/Free Full Text]
6. Kinoshita, O, Yoshimi, H, Nagata, S, et al Rapid increase in plasma endothelin concentrations during percutaneous balloon dilatation of the mitral valve in patients with mitral stenosis. Br Heart J 1993;69,322-326[Abstract/Free Full Text]
7. Wagner, OF, Nowotny, P, Vierhapper, H, et al Plasma concentrations of endothelin in man: arterio-venous differences and release during venous stasis. Eur J Clin Invest 1990;20,502-505[ISI][Medline]
8. Jui-Sung, Hung Atrial septal puncture technique in percutaneous transluminal mitral commissurotomy: mitral valvuloplasty using the Inoue balloon catheter technique. Cathet Cardiovasc Diagn 1992;26,275-284[ISI][Medline]
9. Lin, JJ, Huang, CX, Fang, CH, et al Circadian variation in ischemic threshold inpatients with stable angina: relation to plasma endothelin-1. Angiology 2002;53,409-413[ISI][Medline]
10. Suzuki, N, Matsumoto, H, Miyauchi, T, et al Sandwich-enzyme immunoassays for endothelin family peptides. J Cardiovasc Pharmacol 1991;17,S420-S422
11. Rubanyi, GM, Polokoff, MA Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 1994;46,325-415[ISI][Medline]
12. Dupuis, J, Cernacek, P, Tardif, JC, et al Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension. Am Heart J 1998;135,614-620[CrossRef][ISI][Medline]
13. Nucci, GD, Thomas, R, D’Orleans-Juste, P, et al Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci U S A 1988;85,9797-9800[Abstract/Free Full Text]
14. Guilherme, L, Cunha-Neto, E, Tanaka, AC, et al Heart-directed autoimmunity: the case of rheumatic fever. J Autoimmun 2001;16,363-367[CrossRef][ISI][Medline]
15. Brundel, BJJM, Van Gelder, IC, Tuinenburg, AE, et al Endothelin system in human persistent and paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2001;12,737-742[CrossRef][ISI][Medline]

This article has been cited by other articles:

				H.-K. Yip, C.-J. Wu, H.-W. Chang, C.-H. Yang, T.-H. Yu, Y.-H. Chen, and C.-L. Hang Prognostic Value of Circulating Levels of Endothelin-1 in Patients After Acute Myocardial Infarction Undergoing Primary Coronary Angioplasty Chest, May 1, 2005; 127(5): 1491 - 1497. [Abstract] [Full Text] [PDF]

				M.-C. Chen, H.-W. Chang, S.-S. Juang, H.-K. Yip, and C.-J. Wu Increased Plasma Levels of Soluble P-Selectin in Rheumatic Mitral Stenosis Chest, July 1, 2004; 126(1): 54 - 58. [Abstract] [Full Text] [PDF]

				D. S. G. Conway, G. Y. H. Lip, M.-C. Chen, T. Hirai, K. Sakurai, and H. Inoue Further Insights Into the Prothrombotic State in Mitral Stenosis and Atrial Flutter Chest, June 1, 2004; 125(6): 2361 - 2363. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Chen, M.-C. Articles by Hung, W. C. Search for Related Content PubMed PubMed Citation Articles by Chen, M.-C. Articles by Hung, W. C.