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(Circulation. 1998;98:2262-2268.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Short-Term Oral Endothelin-Receptor Antagonist Therapy in Conventionally Treated Patients With Symptomatic Severe Chronic Heart Failure
From the Divisions of Cardiology, Departments of Medicine, University Hospital Zürich (G.S., W.K., X.Y., Y.K.), Triemli Hospital Zürich (P.H., S.C, O.B.), and University Hospital Basel (W.S., P.R.), Switzerland.
Correspondence to Prof W. Kiowski, MD, Division of Cardiology, Department of Medicine, University Hospital, CH-8091 Zürich, Switzerland. E-mail karkiw{at}usz.unizh.ch
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Abstract |
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Background—The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown.
Methods and Results—Thirty-six men (mean age±SD, 55±8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4±4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17.4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (-24.2% [-28.1% to -20.3%]) and pulmonary (-19.9% [-28.4% to -11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15.2% [10.8% to 19.6%]) and systemic (-9.3% [-12.3% to -6.4%]) and pulmonary (-9.7% [-16.3% to -3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged.
Conclusions—Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.
Key Words: heart failure • endothelin • hemodynamics • hormones
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There is both indirect and direct evidence that the vasoconstrictor peptide endothelin-1 (ET-1)1 participates in the regulation of vascular tone in patients with chronic heart failure. Thus, plasma levels of ET-1 are elevated, particularly in patients with severe heart failure,2 and intravenous infusion of an endothelin-receptor antagonist decreased both systemic and pulmonary vascular resistance acutely in such patients.3 Furthermore, plasma levels of its precursor big ET-1 are a strong and independent predictor of death in heart failure patients,4 and plasma ET-1 is also related to exercise capacity.5 Thus, therapeutic administration of an endothelin-receptor antagonist theoretically might improve the hemodynamic status of patients with heart failure and alleviate their symptoms. Indeed, venous, arterial, and pulmonary arterial vasodilation and an increase in stroke volume without sympathetic reflex activation were observed immediately after intravenous administration of the endothelin-receptor antagonist bosentan,3 which blocks both type A (ETA) and type B (ETB) receptors.6 However, these effects were seen after ACE inhibitors were discontinued, and no data exist in human heart failure with respect to more prolonged therapy. Because any new heart failure therapy is likely to be used in addition to ACE inhibition and animal experiments demonstrated additive hemodynamic effects of combined endothelin-receptor antagonist and ACE inhibitor therapy,7 we investigated hemodynamic and clinical effects of additional oral bosentan in patients who remained symptomatic despite conventional heart failure therapy, including ACE inhibitors.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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All patients gave written informed consent to this prospective, double-blind, randomized, placebo-controlled clinical study, which was conducted in parallel at 3 centers in Switzerland and approved by the respective ethical committees.
Patients
Thirty-six patients (all male; age, 55.2±8.1 years; range, 34
to 68 years) with clinically stable chronic (>3 months) congestive
heart failure and dyspnea in NYHA class III were studied.
Inclusion criteria were a left ventricular ejection
fraction of <30%, a pulmonary capillary wedge pressure of
15 mm Hg, and/or a resting cardiac index of 
2.5 L ·
min-1 · m-2. All
patients were on stable doses of ACE inhibitors,
diuretics, and digoxin except 1 patient with no digoxia. Oral
anticoagulants (n=30) and antiarrhythmics (n=10, amiodarone)
were continued, but long-acting nitrates and ß-blockers were
discontinued 2 and 5 days, respectively, before the baseline
hemodynamic study to reduce variability due to
differing background medication.
Hemodynamic Measurements
Hemodynamic measurements were obtained for 24
hours, with the patient supine, by standard
techniques3 with a Swan-Ganz thermodilution
catheter and by cannulation of the radial artery. Cardiac output was
determined in duplicate by the thermodilution technique. Systemic and
pulmonary vascular resistances were calculated according to
standard formulas. Heart rate was derived from the continuously
monitored ECG.
Hormone Measurements
Blood for determination of plasma levels of ET-1,
norepinephrine, renin activity, and angiotensin
II (Ang II) was withdrawn from the pulmonary artery, separated,
and stored at -70°C until assay.
ET-1 plasma concentrations were determined as previously described3 8 with polyclonal rabbit antiserum RAS 6901 (anti-ET-1). Cross-reactivity of antiserum with the precursor big ET-1, ET-1, and ET-3 is <10%. The range for ET-1 in normal subjects with this assay was 2.0 to 4.6 ng/L (mean, 3.3±0.66 ng/L).
Plasma norepinephrine was measured by high-performance liquid chromatography9 (normal range, 0.66 to 3.85 nmol/L; mean, 1.86±0.88 nmol/L).
Plasma renin activity (PRA) was measured by radioimmunoassay (normal range, 8.8 to 36 mL U/L) and plasma Ang II concentrations with a radioimmunoassay after solid-phase extraction with SepPak C1810 (normal range, 3.8 to 30 ng/L; mean, 12.1±5.7 ng/L).
Laboratory Analysis and Safety Data
Urinalysis, red and white blood cell counts, and multipanel
blood chemistry were performed at screening and on days 1, 7, 14, and
21.
Study Protocol
After screening, patients were admitted to the hospital on the
morning of day 1 in the fasting state without their regular morning
doses of medications. After placement of catheters and blood sampling,
hemodynamic measurements were repeated until variation
of cardiac output was <10%, and the last value was taken as baseline.
Next, bosentan 1000 mg or matching placebo (2:1 randomization) was
given orally, together with a standard hospital breakfast and each
patient's morning dose of diuretics and digoxin. The ACE
inhibitor was administered 3 hours later because of safety
concerns regarding hypotension during coadministration of 2
vasodilators. However, this allowed an assessment of bosentan effects
at the time of peak plasma levels (V. Charlon, PhD, written
communication, May 1998) against the background of chronic but
without interference from acute ACE inhibition.
Hemodynamics were measured repeatedly (at 1, 2, 3, 4,
6, 8, 12, 16, and 24 hours). Twelve hours after the first dose, the
second dose of study medication was administered together with a meal,
and standard evening medication and the ACE inhibitor 4
hours later. After the last measurements, catheters were removed. Vital
signs were reassessed immediately before and 3 hours after the third
dose of study medication, which was now given
simultaneously with all other medications, including the
ACE inhibitor during breakfast. Patients were then
discharged and instructed to take the study medication twice daily
together with food in addition to their standard medication. After 1
week, NYHA class, clinical status, and vital signs were assessed. After
2 weeks, patients were readmitted to the hospital, and all procedures
were repeated in an identical way. Patients were then discharged
without study medication and followed up clinically for at least 1
additional month by ambulatory visit or telephone interview.
Statistical Analysis
All patients were included in the safety analysis.
However, for hemodynamic evaluation, only paired data
from days 1 and 14 were analyzed.
All calculations were performed with the StatView 4.5 (Abacus Inc) statistical program. Results are expressed as mean±SD. ANOVA was used to examine differences between the study groups at baseline. Because hemodynamics were assessed repeatedly, ANOVA for repeated measurements was performed for all changes from baseline over the 12-hour dosing interval to test for overall drug effects. In addition, an unpaired t test was used to calculate differences and 95% CIs between placebo- and bosentan-treated patients based on all changes for the first 3 hours (ie, without interference from acute ACE inhibition) and for the entire dosing interval of 12 hours (ie, including the effects of ACE inhibition from 3 to 12 hours). The trough effect was calculated as change from baseline obtained predrug in the morning of day 14. Hormone measurements were compared with their baseline values by paired t test and differences between groups by unpaired t test.
A value of P<0.05 (2-tailed) was considered to indicate a significant difference.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Baseline patient characteristics are shown in Tables 1 through 3
.
Placebo- and bosentan-treated patients were comparable in most regards,
but patients assigned to bosentan had a somewhat higher ejection
fraction, stroke volume index, and systolic blood pressure and
significantly lower heart rate, suggesting somewhat greater
hemodynamic impairment in the placebo group. Baseline
plasma ET-1 levels were positively correlated with pulmonary
capillary wedge (r=0.44, P<0.05), right atrial
(r=0.54, P<0.01), and pulmonary artery
mean (r=0.46, P<0.05) pressures and
pulmonary vascular resistance (r=0.48,
P<0.05) and negatively with stroke volume index
(r=-0.51, P<0.05).
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Safety and Clinical Outcome
One patient developed supine systolic blood pressure
<90 mm Hg on the first day of bosentan treatment. Therapy was
discontinued after 2 days because of persisting symptomatic
hypotension. Two additional patients complained of dizziness;
hypotension was noted on the second day of therapy, but symptoms
subsided, and they continued bosentan therapy. Furthermore, 3 patients
reported dizziness without detectable hypotension, and 2 of the 6
patients with dizziness reported mild headaches. Weight did not differ
from baseline after 2 weeks (79.8±10.4 versus 79.4±9.6 kg in
bosentan-treated and 79.2±11.1 versus 79.6±10.8 kg in placebo-treated
patients). There were no specific changes of laboratory values. In
particular, serum creatinine (93±25 versus 94±32
µmol/L) and liver function tests (ALAT, ASAT, 
-GT) remained
unchanged during 2 weeks of bosentan and 1 week later. Two
bosentan-treated patients declined to undergo repeat
hemodynamic evaluation. In bosentan-treated patients,
dyspnea improved by 1 NYHA class in 9, was unchanged in 11, and
worsened in 4; in the placebo group, 1 patient improved, 8 were
unchanged, and 3 became worse (P=0.18).
Hemodynamic Effects
Hemodynamic measurements at baseline and 3
hours after administration of standard medication and study drug in the
morning (ie, before intake of ACE inhibitor) are shown in
Table 3
. Although placebo did not change hemodynamics,
bosentan significantly decreased arterial,
pulmonary artery, and right atrial pressures and increased
cardiac index within the first 3 hours on day 1 compared with placebo.
Accordingly, both calculated systemic and pulmonary vascular
resistances were significantly reduced. Heart rate did not change;
thus, the increase in cardiac index was due to a significant increase
in stroke volume index. As shown in Figures 1 and 2,
these differences persisted after 3 hours when ACE
inhibitors were added. Figure 3 summarizes the differences between
placebo- and bosentan-treated patients with respect to all measurements
obtained over a period of 12 hours after study drug intake on both
study days. As shown, the effect of bosentan persisted to a similar
extent after 2 weeks with respect to arterial,
pulmonary artery, and cardiac filling pressures, whereas
cardiac (15.2% [10.8% to 19.6%]) and stroke volume (15.6% [8.8%
to 20.1%]) indexes had increased further compared with bosentan
effect on day 1 (both P<0.01); likewise, systemic (-9.3%
[-12.3% to -6.4%]) and pulmonary (-9.7% [-16.3% to
-3.1%]) vascular resistances had decreased further (both
P<0.01) without change of heart rate.
|
) or bosentan 1000 mg () over
the first 12 hours. Data represent absolute changes (
) from
baseline (ie, before drug intake). Diuretics, digoxin,
bosentan, or placebo was given together with breakfast at 0 hours and
ACE inhibitor at 3 hours (arrow). RAP indicates right
atrial pressure; PCWP, pulmonary capillary wedge
pressure; MPAP, mean pulmonary artery pressure; MAP, mean
arterial pressure; CI, cardiac index; SVI, stroke volume
index; SVR, systemic vascular resistance; and PVR, pulmonary
vascular resistance. *P<0.05, **P<0.01,
repeated-measures ANOVA.
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).
Abbreviations as in Figure 1
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) and on
day 14 (
). Data are expressed as percent changes from baseline (day
1 before drug intake); lines indicate 95% CIs of difference from
placebo. BP indicates blood pressure; PAP, pulmonary artery
pressure; other abbreviations as in Figure 1
At trough (before drug intake in the morning of day 14; Table 3 and
Figure 2), bosentan-treated patients had lower arterial
pressure, higher cardiac and stroke volume indexes, and reduced
systemic and pulmonary vascular resistances. Pulmonary
arterial and left and right heart filling pressures were
not significantly different from baseline.
Neurohormonal Effects
Baseline neurohormones were not different in the two groups (Table 4). After the morning dose of
diuretic, digoxin, and study drug, plasma ET-1 increased by
134±70% after 3 hours in the bosentan-treated group
(P<0.01) and was unchanged with placebo. PRA and Ang II
levels increased similarly in the two groups, and plasma
norepinephrine remained unchanged.
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Compared with day 1, plasma ET-1 was elevated in bosentan-treated patients on the morning of day 14 before drug intake and unchanged in the placebo group. Plasma ET-1 increased 3 hours after bosentan, but the rise was less than that on day 1 (134±70% versus 37±38%, P<0.05). Neither baseline plasma ET-1 levels nor its changes during therapy predicted the clinical or hemodynamic response to bosentan.
Before drug intake, PRA and Ang II levels were similar on days 1 and 14, and the increases after diuretic administration were unchanged in the placebo group. In contrast, increases in PRA (175±226% versus 58±94%, P<0.05) and plasma Ang II (201±236% versus 89±116%, P<0.05) were attenuated in the bosentan group on day 14 compared with day 1. Norepinephrine remained unchanged during the study in both groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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These data show that short-term oral endothelin-receptor blockade with bosentan resulted in improved hemodynamics without neurohormonal stimulation in patients who were symptomatic despite triple-drug heart failure therapy, including an ACE inhibitor. These data confirm that endogenously released ET-1 is important for the regulation of elevated vascular tone in these patients3 11 and suggest that its antagonism may be useful as adjunct therapy.
As expected, the combination of 2 vasodilators resulted in symptomatic hypotension in 3 patients and withdrawal from the study in 1. However, the fixed-dose drug regimen probably contributed to this problem. Moreover, the optimal dose of bosentan is not known, but in a small, open-label trial using a dose of 500 mg BID,12 we observed hemodynamic changes from day 1 to day 14 of a magnitude similar to those in this trial. This indicates that lower dosages of bosentan than the one used in this study also elicit hemodynamic effects.
Bosentan caused venous, pulmonary artery, and arterial vasodilation when acting alone, eg, in the first 3 hours after study drug administration, and when combined with ACE inhibitors for the remainder of the dosing interval. These changes were seen on top of effective long-term ACE inhibition, as hemodynamically reflected in almost normal baseline values of systemic vascular resistance. This hemodynamic constellation probably also explains why the absolute magnitude of the hemodynamic effects was not larger. In addition, pulmonary vascular resistance, which was elevated despite chronic ACE inhibition, was markedly reduced by bosentan. Elevated cardiac filling pressures and pulmonary hypertension are independent risk factors for survival in severe heart failure, and reversal of pulmonary hypertension by drug therapy improved prognosis in cardiac transplant candidates,13 rendering the present findings potentially important.
The effects seen after the first dose were not only maintained during prolonged therapy but were even more marked with regard to systemic and pulmonary artery vasodilation and increases in cardiac index after 2 weeks. The mechanism behind this finding is not clear. Possibly, reversing the long-term cardiovascular trophic effects of ET-1 is of greater importance than vasodilation due to endothelin-receptor blockade per se. This view would be compatible with animal experiments showing that endothelin-receptor antagonism improved survival in rats with heart failure after myocardial infarction,14 15 ie, the model that predicted the clinical effectiveness of ACE inhibitors in humans.16 Whether 2 weeks of therapy would be enough for such an effect is unknown.
Interestingly, the dilatory effect did not result in reflex tachycardia, a finding similar to that obtained after acute administration of bosentan in heart failure patients.3 The mechanism(s) behind this observation are not clear, but reduced baroreceptor sensitivity in heart failure patients17 probably contributes to this effect. Arterial pressure and systemic and pulmonary vascular resistance were still decreased 12 hours after the last dose of bosentan, whereas cardiac filling pressures, which reflect venous tone in the absence of weight and volume changes, were unchanged. Different binding characteristics of bosentan to venous and arterial endothelin receptors might be a possible explanation. Indeed, ETB-mediated vasoconstriction might predominate on the venous side.18 Because bosentan, a mixed ETA- and ETB-receptor antagonist,6 is somewhat more potent at the ETA receptor, this pharmacological property might explain the longer-lasting effect of bosentan on the arterial side.
Bosentan did not affect basal PRA or Ang II and catecholamine levels, indicating that basal activity of these systems is not influenced by endogenously released ET-1.19 After 2 weeks, however, bosentan attenuated the increases of PRA and Ang II levels after diuretic intake. We have no ready explanation for this effect, but interactions of reduced renal perfusion and natriuresis could render the system partially ET-1 dependent after stimulation with a diuretic.
Plasma ET-1 more than doubled within 3 hours after the first dose of bosentan. This might be explained by dissociation or prevention of binding of ET-1 from its receptors, in particular from the ETB receptor, which is believed to act as a clearance receptor.20 However, ET-1 levels increased 2- to 3-fold after specific ETA-receptor blockade in rabbits, which brings into question the clearance function of the ETB receptor.21 Plasma ET-1 was still significantly increased 12 hours after bosentan, which might indicate residual receptor occupancy at the end of the dosing interval. The response of plasma ET-1 after the morning dose of bosentan was attenuated on day 14, although hemodynamic effects were more pronounced compared with day 1. One might speculate that the hemodynamic improvement brought about by bosentan might have resulted in a relative decrease in ET-1 levels, as seen in heart failure patients treated with a ß-blocker.22
As in previous studies,3 23 baseline plasma ET-1 levels were significantly correlated with several indexes of hemodynamic impairment. However, neither baseline ET-1 levels nor increases seen after bosentan correlated with the hemodynamic effects of endothelin-receptor blockade. A closer relationship might exist between the response to endothelin-receptor blockade and tissue levels of this paracrine/autocrine system.
Bosentan is a mixed ETA/ETB-receptor antagonist.6 Stimulation of endothelial ETB receptors leads to vasodilation.24 Accordingly, attenuation of endothelin-mediated vasodilator effects by bosentan cannot be excluded. Comparative studies will be necessary to show whether selective ETA-receptor blockade alone has even greater hemodynamic effects.
Limitations
Placebo- and bosentan-treated patients were not ideally matched
with regard to baseline hemodynamics and concomitant
medication. Although inclusion of a placebo group and standardization
of food intake served as a control for the stability of the population
and for non–drug-related interventions (eg, food intake) throughout
the 24-hour monitoring period, one obviously must be careful not to
extend our findings to a population that might be sicker than the group
that received bosentan in this trial. Also, nonstandardized use of ACE
inhibitors might have influenced our results. However, the
majority of patients in both groups received enalapril twice daily, and
more patients in the bosentan group received short-acting captopril.
Thus, it is unlikely that nonstandardized use of ACE
inhibitors significantly influenced the
hemodynamic measurements obtained during the first 3
hours in the morning.
We did not objectively quantify the degree of functional impairment of patients. Therefore, the severity of functional impairment might have been overestimated in some patients. This might be of importance because the target population for future administration of endothelin antagonists will be primarily NYHA class III to IV patients.
Pretreatment with long-acting nitrates and ß-blockers was stopped before the trial. Potentially, patients maximally prevasodilated with long-acting nitrates and ACE inhibitors could have an attenuated response to bosentan. Also, endogenous nitric oxide inhibits ET-1 synthesis.25 Conceivably, exogenous nitric oxide donors may have similar effects. However, there was no difference in the hemodynamic response to bosentan in patients previously treated with nitrates.
Finally, we did not see any untoward effects other than hypotension in this trial using a fixed and, presumably, high dose of bosentan.12 However, reversible increases of serum ALAT and ASAT were found after 4 weeks of treatment with bosentan in some hypertensive patients.26 It is possible that the 2-week treatment period was too short to see such effects in our patients. It is obvious that the proper dose and the safety of bosentan will have to be established in long-term trials.
Conclusions
ET-1 plays an important role in the regulation of vascular tone in
patients with severe heart failure. Counteracting vascular ET-1 effects
by short-term administration of an orally active, mixed
ETA/ETB-receptor
antagonist improved hemodynamics in
patients who were symptomatic with standard triple-drug
therapy. These effects were observed without neurohormonal activation
or volume retention. Further investigations are warranted to study the
safety of long-term endothelin-receptor antagonist therapy
and its effects on symptoms, morbidity, and mortality in such
patients.
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Acknowledgments |
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This study was supported by an educational grant from F. Hoffmann-LaRoche, Ltd, Basel, Switzerland, and from the Swiss National Science Foundation (grant 32-43612.95).
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Footnotes |
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Guest Editor for this article was Wilson S. Colucci, MD, Boston Medical Center, Boston, Mass.
Received June 8, 1998; revision received July 14, 1998; accepted July 21, 1998.
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  V. V. McLaughlin, S. L. Archer, D. B. Badesch, R. J. Barst, H. W. Farber, J. R. Lindner, M. A. Mathier, M. D. McGoon, M. H. Park, R. S. Rosenson, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association Developed in Collaboration With the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1573 - 1619. [Full Text] [PDF]
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 Writing Committee Members, V. V. McLaughlin, S. L. Archer, D. B. Badesch, R. J. Barst, H. W. Farber, J. R. Lindner, M. A. Mathier, M. D. McGoon, M. H. Park, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in Collaboration With the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association Circulation, April 28, 2009; 119(16): 2250 - 2294. [Full Text] [PDF]
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 S. Phuphanich, K. A. Carson, S. A. Grossman, G. Lesser, J. Olson, T. Mikkelsen, S. Desideri, J. D. Fisher, and for the New Approaches to Brain Tumor Therapy (NAB Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma Neuro-oncol, August 1, 2008; 10(4): 617 - 623. [Abstract] [Full Text] [PDF]
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N. F. Kelland and D. J. Webb Clinical Trials of Endothelin Antagonists in Heart Failure: A Question of Dose? Experimental Biology and Medicine, June 1, 2006; 231(6): 696 - 699. [Abstract] [Full Text] [PDF]
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J. Goddard, C. Eckhart, N. R. Johnston, A. D. Cumming, A. J. Rankin, and D. J. Webb Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor-Mediated and Nitric Oxide-Dependent Mechanism J. Am. Soc. Nephrol., October 1, 2004; 15(10): 2601 - 2610. [Abstract] [Full Text] [PDF]
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M. A. Konstam and D. DeNofrio Endothelin Expression and the Progression of Heart Failure: Exemplifying the Vagaries of Therapeutic Development Circulation, January 20, 2004; 109(2): 143 - 145. [Full Text] [PDF]
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J. A. Schirger, H. H. Chen, M. Jougasaki, O. Lisy, G. Boerrigter, A. Cataliotti, and J. C. Burnett Jr Endothelin A Receptor Antagonism in Experimental Congestive Heart Failure Results in Augmentation of the Renin-Angiotensin System and Sustained Sodium Retention Circulation, January 20, 2004; 109(2): 249 - 254. [Abstract] [Full Text] [PDF]
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S C Apostolopoulou, S Rammos, Z S Kyriakides, D J Webb, N R Johnston, D V Cokkinos, and D T. Kremastinos Acute endothelin A receptor antagonism improves pulmonary and systemic haemodynamics in patients with pulmonary arterial hypertension that is primary or autoimmune and related to congenital heart disease Heart, October 1, 2003; 89(10): 1221 - 1226. [Abstract] [Full Text] [PDF]
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T. F. Luscher, F. Enseleit, R. Pacher, V. Mitrovic, M. R. Schulze, R. Willenbrock, R. Dietz, V. Rousson, D. Hurlimann, S. Philipp, et al. Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ETA) Receptor Blockade in Chronic Heart Failure: The Heart Failure ETA Receptor Blockade Trial (HEAT) Circulation, November 19, 2002; 106(21): 2666 - 2672. [Abstract] [Full Text] [PDF]
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J J V McMurray Heart failure in 10 years time: focus on pharmacological treatment Heart, October 1, 2002; 88(90002): ii40 - 46. [Full Text] [PDF]
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M. Clozel, C. Qiu, C.-S. Qiu, P. Hess, and J.-P. Clozel Short-term endothelin receptor blockade with tezosentan has both immediate and long-term beneficial effects in rats with myocardial infarction J. Am. Coll. Cardiol., January 2, 2002; 39(1): 142 - 147. [Abstract] [Full Text] [PDF]
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S.-M. Herrmann, K. Schmidt-Petersen, J. Pfeifer, A. Perrot, N. Bit-Avragim, C. Eichhorn, R. Dietz, R. Kreutz, M. Paul, and K.J. Osterziel A polymorphism in the endothelin-A receptor gene predicts survival in patients with idiopathic dilated cardiomyopathy Eur. Heart J., October 2, 2001; 22(20): 1948 - 1953. [Abstract] [PDF]
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P.J. Cowburn and J.G.F. Cleland Endothelin antagonists for chronic heart failure: do they have a role? Eur. Heart J., October 1, 2001; 22(19): 1772 - 1784. [PDF]
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G. Torre-Amione, J.-B. Durand, S. Nagueh, M. T. Vooletich, I. Kobrin, and C. Pratt A Pilot Safety Trial of Prolonged (48 h) Infusion of the Dual Endothelin-Receptor Antagonist Tezosentan in Patients With Advanced Heart Failure Chest, August 1, 2001; 120(2): 460 - 466. [Abstract] [Full Text] [PDF]
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S. McElvy, S. G. Greenberg, J. L. Mershon, D. S. Yang, C. Magill, and K. E. Clark Mechanism of uterine vascular refractoriness to endothelin-1 in pregnant sheep Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H804 - H812. [Abstract] [Full Text] [PDF]
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J. P. Loennechen, A. Stoylen, V. Beisvag, U. Wisloff, and O. Ellingsen Regional expression of endothelin-1, ANP, IGF-1, and LV wall stress in the infarcted rat heart Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2902 - H2910. [Abstract] [Full Text] [PDF]
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J. B. Park and E. L. Schiffrin ETA Receptor Antagonist Prevents Blood Pressure Elevation and Vascular Remodeling in Aldosterone-Infused Rats Hypertension, June 1, 2001; 37(6): 1444 - 1449. [Abstract] [Full Text] [PDF]
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Y. Kakinuma, T. Miyauchi, K. Yuki, N. Murakoshi, K. Goto, and I. Yamaguchi Novel Molecular Mechanism of Increased Myocardial Endothelin-1 Expression in the Failing Heart Involving the Transcriptional Factor Hypoxia-Inducible Factor-1{{alpha}} Induced for Impaired Myocardial Energy Metabolism Circulation, May 15, 2001; 103(19): 2387 - 2394. [Abstract] [Full Text] [PDF]
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L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1493 - 1505. [Abstract] [Full Text] [PDF]
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 D. D. Ivy, I. F. McMurtry, M. Yanagisawa, C. E. Gariepy, T. D. Le Cras, S. A. Gebb, K. G. Morris, R. C. Wiseman, and S. H. Abman Endothelin B receptor deficiency potentiates ET-1 and hypoxic pulmonary vasoconstriction Am J Physiol Lung Cell Mol Physiol, May 1, 2001; 280(5): L1040 - L1048. [Abstract] [Full Text] [PDF]
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G. Torre-Amione, J. B. Young, J.-B. Durand, B. Bozkurt, D. L. Mann, I. Kobrin, and C. M. Pratt Hemodynamic Effects of Tezosentan, an Intravenous Dual Endothelin Receptor Antagonist, in Patients With Class III to IV Congestive Heart Failure Circulation, February 20, 2001; 103(7): 973 - 980. [Abstract] [Full Text] [PDF]
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F. Ammarguellat, I. Larouche, and E. L. Schiffrin Myocardial Fibrosis in DOCA-Salt Hypertensive Rats : Effect of Endothelin ETA Receptor Antagonism Circulation, January 16, 2001; 103(2): 319 - 324. [Abstract] [Full Text] [PDF]
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T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]
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Y.-T. Shen, P. S Buie, J. J Lynch, S. M Krause, and X.-L. Ma Chronic therapy with an ETA/B receptor antagonist in conscious dogs during progression of congestive heart failure: Intracellular Ca2+ regulation and nitric oxide mediated coronary relaxation Cardiovasc Res, November 1, 2000; 48(2): 332 - 345. [Abstract] [Full Text] [PDF]
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D. L. Moraes, W. S. Colucci, and M. M. Givertz Secondary Pulmonary Hypertension in Chronic Heart Failure : The Role of the Endothelium in Pathophysiology and Management Circulation, October 3, 2000; 102(14): 1718 - 1723. [Abstract] [Full Text] [PDF]
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R. B. New, A. C. Sampson, M. K. King, J. W. Hendrick, M. J. Clair, J. H. McElmurray III, J. Mandel, R. Mukherjee, Marc de Gasparo, and F. G. Spinale Effects of Combined Angiotensin II and Endothelin Receptor Blockade With Developing Heart Failure : Effects on Left Ventricular Performance Circulation, September 19, 2000; 102(12): 1447 - 1453. [Abstract] [Full Text] [PDF]
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E. Thorin, M. Lucas, P. Cernacek, and J. Dupuis Role of ETA receptors in the regulation of vascular reactivity in rats with congestive heart failure Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H844 - H851. [Abstract] [Full Text] [PDF]
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M. M. Givertz, W. S. Colucci, T. H. LeJemtel, S. S. Gottlieb, J. M. Hare, M. T. Slawsky, C. V. Leier, E. Loh, J. M. Nicklas, and B. E. Lewis Acute Endothelin A Receptor Blockade Causes Selective Pulmonary Vasodilation in Patients With Chronic Heart Failure Circulation, June 27, 2000; 101(25): 2922 - 2927. [Abstract] [Full Text] [PDF]
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L. E. Spieker, V. Mitrovic, G. Noll, R. Pacher, M. R. Schulze, J.o. Muntwyler, C. Schalcher, W. Kiowski, T. F. Luscher, and on behalf of the ET 003 Investigators Acute hemodynamic and neurohumoral effects of selective ETA receptor blockade in patients with congestive heart failure J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1745 - 1752. [Abstract] [Full Text] [PDF]
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J. Bohlender, S. Gerbaulet, J. Kramer, M. Gross, M. Kirchengast, and R. Dietz Synergistic Effects of AT1 and ETA Receptor Blockade in a Transgenic, Angiotensin II-Dependent, Rat Model Hypertension, April 1, 2000; 35(4): 992 - 997. [Abstract] [Full Text] [PDF]
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C. A. Walker, F. A. Crawford Jr, and F. G. Spinale MYOCYTE CONTRACTILE DYSFUNCTION WITH HYPERTROPHY AND FAILURE: RELEVANCE TO CARDIAC SURGERY J. Thorac. Cardiovasc. Surg., February 1, 2000; 119(2): 388 - 400. [Full Text] [PDF]
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T. Mishima, M. Tanimura, G. Suzuki, A. Todor, V. G. Sharov, S. Goldstein, and H. N. Sabbah Effects of long-term therapy with bosentan on the progression of left ventricular dysfunction and remodeling in dogs with heart failure J. Am. Coll. Cardiol., January 1, 2000; 35(1): 222 - 229. [Abstract] [Full Text] [PDF]
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J.-J. Boffa, P.-L. Tharaux, S. Placier, R. Ardaillou, J.-C. Dussaule, and C. Chatziantoniou Angiotensin II Activates Collagen Type I Gene in the Renal Vasculature of Transgenic Mice During Inhibition of Nitric Oxide Synthesis : Evidence for an Endothelin-Mediated Mechanism Circulation, November 2, 1999; 100(18): 1901 - 1908. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin Role of Endothelin-1 in Hypertension Hypertension, October 1, 1999; 34(4): 876 - 881. [Abstract] [Full Text] [PDF]
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