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J Am Coll Cardiol, 2000; 35:1745-1752
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDIES

Acute hemodynamic and neurohumoral effects of selective ETA receptor blockade in patients with congestive heart failure

Lukas E. Spieker, MDa, Veselin Mitrovic, MD*, Georg Noll, MD, FESCa, Richard Pacher, MD{dagger}, Matthias R. Schulze, MD{ddagger}, J.örg Muntwyler, MD, MPHa, Christoph Schalcher, MDa, Wolfgang Kiowski, MD, FACC, FESCa, Thomas F. Lüscher, MD, FACC, FRCP, FESCa on behalf of the ET 003 Investigators

a Division of Cardiology, University Hospital, Zürich, Switzerland
* Kerckhoff Clinic, Bad Nauheim, Germany
{dagger} Allgemeines Krankenhaus, Wien, Austria
{ddagger} Herz-und Kreislaufzentrum, Cardiology, Dresden, Germany

Manuscript received September 13, 1999; revised manuscript received December 30, 1999, accepted February 21, 2000.

Reprint requests and correspondence: Dr. Thomas F. Lüscher, Cardiology, University Hospital, CH-8091, Zürich, Switzerland
cardiotfl{at}compuserve.com


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

To investigate the hemodynamic effects of the selective endothelin (ET)A receptor antagonist LU135252 in patients with congestive heart failure (CHF).

BACKGROUND

Nonselective ETA/B receptor antagonists improve hemodynamics in patients with CHF. Since ETB receptors mediate the release of nitric oxide and the clearance of ET-1, selective ETA antagonists are of special interest.

METHODS

The hemodynamic effects of a single oral dose of the selective ETA receptor antagonist LU135252 (1, 10, 30, 100 or 300 mg) were investigated in a multicenter study involving 95 patients with CHF (New York Heart Association II–III) with an ejection fraction ≤35%.

RESULTS

Baseline ET-1 positively correlated with pulmonary vascular resistance, pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (MPAP, r = 0.37–0.50, p < 0.0004) but were inversely related to cardiac index (CI; r = –0.36, p = 0.0004). LU135252 dose dependently increased CI and decreased mean arterial pressure and systemic vascular resistance (p < 0.03–0.0002), while heart rate remained constant or decreased slightly. Pulmonary capillary wedge pressure, MPAP, pulmonary vascular resistance and right atrial pressure also decreased significantly (p < 0.035–< 0.0001). Two hours after LU135252, plasma ET-1 did not significantly increase after 1 mg but did so by 23% (p = 0.003), 29% (p = 0.0018), 56% (p < 0.0001) and 101% (p < 0.0001) after 10, 30, 100 and 300 mg, respectively, while plasma catecholamines remained constant.

CONCLUSIONS

In patients with CHF, a single oral dose of the selective ETA receptor antagonist LU135252 improves hemodynamics in a dose-dependent manner without activation of other neurohumoral systems and is well tolerated over a wide dose range.

Abbreviations and Acronyms
  CHF = congestive heart failure
  CI = cardiac index
  ET = endothelin
  MPAP = mean pulmonary artery pressure
  NO = nitric oxide
  PCWP = pulmonary capillary wedge pressure

The vascular endothelium produces and releases endothelin (ET)-1, nitric oxide (NO) and prostacyclin and, thereby, plays a fundamental role in the regulation of vascular tone and structure (1–3). EndothelinA and ETB receptors mediate the vasoconstrictor effects of ET-1 in smooth muscle cells (4–6). Endothelin-1 also induces proliferation of vascular smooth muscle cells and myocardial hypertrophy (7–9). In contrast, endothelial ETB receptors cause vasodilation via release of NO and prostacyclin, which also exert antithrombotic and antiproliferative effects in vascular smooth muscle cells (10–12). Further, ETB receptors in the pulmonary circulation are important for the clearance of ET-1 (13–16).

Increased peripheral resistance is a key feature of congestive heart failure (CHF). Apart from activation of neurohormonal systems—such as the sympathetic nervous system (13) and the renin angiotensin system (14)—there is evidence that increased ET-1 production contributes to vasoconstriction as well. Indeed, plasma levels of ET-1 are elevated, and plasma levels of the precursor of ET-1, big ET-1, are strong, independent predictors of death in patients with heart failure (15–17). In experimental heart failure of the rat, ETA receptor blockade improves survival (18). In patients with CHF, nonselective ETA/B blockade improves pulmonary and systemic hemodynamics (19,20).

Although there are good reasons to develop ET receptor antagonists for the treatment of CHF, it remains controversial whether nonselective ETA/B receptor antagonists or selective ETA receptor antagonists should be used. Since ETB receptors stimulate the release of NO, which is impaired in heart failure (21), and are also involved in the pulmonary clearance of ET-1 (22–25), selective ETA receptor antagonists are of particular interest. We investigated the hemodynamic and neurohumoral effects of a single oral dose of LU135252, a selective ETA endothelin receptor antagonist, in patients with CHF.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   A total of 100 patients with CHF with an ejection fraction ≤35% as assessed by echocardiography or isotope ventriculography of any underlying cause (except primary organic valvular heart disease) participated in a prospective multicenter trial (for centers see Acknowledgments). Each patient gave written, informed consent, and this study was approved by the local ethical committees of each of the participating centers.

Inclusion and exclusion criteria.   The following baseline criteria had to be met for inclusion: pulmonary capillary wedge pressure (PCWP) ≥14 mm Hg or cardiac index (CI) ≤2.8 l/min/m2. Exclusion criteria were acutely decompensated heart failure (New York Heart Association IV), sustained or symptomatic systemic hypotension (systolic blood pressure ≤90 mm Hg), acute myocardial infarction within three months before study enrollment, unstable angina pectoris, primary valvular heart disease, continued pacemaker rhythm, stroke within six months before study enrollment, introduction of beta-adrenergic blocking agent therapy within three months before study enrollment, pregnancy or lactation, liver disease, renal failure (creatinine >220 µmol/l) and exposure to any investigational drug during the last month before study entry.

Experimental protocol.   Patients continued their usual medications except on the investigational day. All drugs with impact on hemodynamic parameters were discontinued the morning of the study. Different open-label dosage levels (1, 10, 30, 100 and 300 mg) were studied in different patient groups.

After recording stable hemodynamic baseline values for 30 min, LU135252 was administered orally with 200 ml water. Arterial blood pressure and hemodynamic variables were measured at 30, 60, 90, 120, 180 and 240 min after oral administration of the drug. Blood samples were drawn from the atrial part of the Swan-Ganz catheter or a peripheral vein shortly before the hemodynamic measurements. Electrocardiographic monitoring was performed throughout the entire investigational period. Four hours after administration of LU135252, the Swan-Ganz catheter was withdrawn. For safety reasons, the patients spent the following night in the hospital.

Hemodynamic measurements.   Cardiac output (average of at least two measurements) was determined by thermodilution with a Swan-Ganz catheter inserted through a sheath introducer system in a jugular or cubital vein and propagated to the pulmonary artery. Right atrial pressure, systemic and pulmonary artery pressure and PCWP were measured. Cardiac index and systemic and pulmonary vascular resistance were calculated using standard formula. Heart rate was obtained from electrocardiogram monitoring.

Determination of plasma levels.   Blood samples were drawn at baseline and 30, 60, 90, 120, 180 and 240 min after administration of LU135252. Plasma, obtained by centrifugation, was stored at –70°C until analysis. Plasma levels of ET-1 and catecholamines were assayed 15 min before and 120 and 240 min after administration of the study drug using methodology described previously (26–28). Plasma norepinephrine in healthy subjects averaged 208 ± 75 pg/ml with the assay used. The concentration of ET-1 in plasma from healthy control subjects with this assay was 2.8 ± 0.5 pg/ml (27).

Statistical analysis.   Means and proportion of baseline characteristics were calculated overall and by treatment assignment. The average mean change of the hemodynamic variables at 120, 180 and 240 min according to treatment assignment was estimated with repeated-measurement analysis of covariance, adjusting for the respective baseline values and assuming compound symmetry among the three time categories (SAS PROC MIXED). For all hemodynamic parameters, time and time*dose interaction was not significant. For the estimated changes of the five treatment doses, statistical significance was assumed at a Bonferroni-adjusted p value of <0.05/5 = 0.01. To test the dose-response effect, dose was entered as an ordinal variable into the model, and significance was defined as an alpha level of <0.05.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Patients’ characteristics and medication.   Five of the 100 patients entering the study were excluded because they did not fulfill the hemodynamic inclusion criteria or because they met one or more exclusion criteria. Baseline demographic and hemodynamic characteristics of the 95 study patients are shown in Table 1. The concomitant cardiovascular medication of the study patients is listed in Table 2.


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  		Table 1 Main Demographic and Hemodynamic Data of the Study Patients (n = 95)

 

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  		Table 2 Concomitant Cardiovascular Drugs of the Study Patients

 
Plasma endothelin and hemodynamics at baseline.   Baseline hemodynamics at baseline according to treatment group are shown in Table 3. Baseline ET-1 averaged 2.7 ± 0.1 pg/ml (range 1.3–7.9 pg/ml). Baseline ET-1 plasma levels positively correlated with pulmonary vascular resistance (r = 0.50, p < 0.0001), PCWP (r = 0.37, p = 0.004), mean pulmonary artery pressure (MPAP) (r = 0.46, p < 0.0001), systemic vascular resistance (r = 0.21, p = 0.051) and right atrial pressure (r = 0.22, p = 0.03; Fig. 1). In contrast, (Fig. 2) ET-1 levels were inversely related to CI (r = –0.36, p = 0.0004). Baseline ET-1 levels were not correlated with heart rate nor with systemic mean arterial pressure. The correlation between hemodynamic parameters was not altered by exclusion of the single patient with a very high ET plasma level and remained highly significant (correlation between ET-1 plasma levels and MPAP, r = 0.42, p < 0.0001; PCWP, r = 0.34, p = 0.001; CI, r = 0.34, p = 0.001).


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  		Table 3 Baseline Hemodynamic Parameters According to Treatment Group

 


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  		Figure 1 Correlations between baseline endothelin (ET)-1 plasma levels and hemodynamic parameters in patients with chronic heart failure (n = 91). Mean pulmonary artery (MPAP, mm Hg; top) and pulmonary capillary wedge pressure (PCWP, mm Hg; middle) correlated positively with ET-1 plasma levels, while cardiac index (ml·min–1·m–2; bottom) was inversely associated with ET-1 levels.

 


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  		Figure 2 Changes of cardiac index and systemic vascular resistance 4 h after administration of different dosages of LU135252, a selective ETA receptor antagonist. *p < 0.05; **p ≤ 0.0002.

 
Hemodynamic effects.   Arterial circulation
The hemodynamic changes after administration of LU135252 are shown in Table 4. LU135252 led to a dose-dependent increase in CI. The average mean increases in CI after 1, 10, 30, 100 or 300 mg of LU135252, respectively, were +8%, +11% (both NS), +13% (p < 0.01), +19% (p < 0.01) and 22% (p < 0.01). Mean arterial pressure decreased by 5%, 5%, 3%, 5% and 10% (p < 0.01 for all dosages). Accordingly, systemic vascular resistance decreased dose dependently by 11% to 27% (p < 0.01 for all dosages except 1 mg). Importantly, heart rate remained stable. After 24 h, LU135252 still reduced arterial blood pressure by –5% (p = 0.06), –6% (p = 0.016), 0.1% (NS), –15% (p = 0.008) and –10% (p = 0.0016). The lack of a strict dose dependency of the blood pressure lowering effect is explained by accidental, nonsignificant differences in the baseline blood pressure between the dosage groups (Table 3).


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  		Table 4 Mean Hemodynamic Baseline Values and Absolute Changes According to Treatment

 
Pulmonary circulation
The changes in pulmonary hemodynamics after administration of LU135252 are shown in Table 4. Right atrial pressure was reduced by 12% to 19% (p < 0.01 for 30 and 100 mg). Mean pulmonary artery pressure decreased by 10% to 20% (p < 0.01 for all dosages except 1 mg). Pulmonary capillary wedge pressure was reduced by 15% to 25% (p < 0.01). Pulmonary vascular resistance dose dependently decreased by 6% to 26% (p < 0.01 for 100 and 300 mg).

Endothelin plasma levels after ETA blockade.   Two hours after LU135252, plasma ET-1 dose dependently increased by 6% after administration of 1 mg of the ETA antagonist (p = 0.47), by 23% after 10 mg (p = 0.003), by 29% after 30 mg (p = 0.002), by 56% after 100 mg (p < 0.0001) and by 101% after 300 mg (p < 0.0001), respectively (Fig. 3).



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  		Figure 3 Changes of endothelin-1 plasma levels after administration of various dosages of the selective ETA receptor antagonist LU135252. There was a dose-dependent increase in plasma ET-1 levels. *p < 0.003 vs. baseline.

 
Plasma catecholamines.   Baseline plasma norepinephrine levels averaged 531 ± 78 ng/ml and baseline epinephrine levels 56 ± 6 ng/ml.

Baseline norepinephrine plasma levels positively correlated with pulmonary vascular resistance (r = 0.49, p < 0.0001), with systemic vascular resistance (r = 0.31, p = 0.01), with mean arterial blood pressure (r = 0.29, p = 0.016), with MPAP (r = 0.47, p < 0.0001), with PCWP (r = 0.32, p = 0.009) and with right atrial pressure (r = 0.38, p = 0.0016) but not with CI (r = –0.21, p = 0.09) nor heart rate (r = 0.18, p = 0.15). Norepinephrine plasma levels were positively correlated with ET-1 plasma levels (r = 0.57, p = 0.004).

Epinephrine plasma levels only correlated with PCWP (r = 0.41, p = 0.0006) and with MPAP (r = 0.34, p = 0.005) but not with the other hemodynamic parameters. Also, there was no significant correlation between epinephrine and ET-1 plasma levels. Epinephrine, however, correlated with norepinephrine levels (r = 0.62, p = 0.023).

Plasma catecholamines remained stable or decreased slightly after administration of LU135252.

Plasma levels of LU135252.   Plasma levels of the selective ETA receptor antagonist LU135252 increased dose dependently after single oral administration of various dosages. Peak plasma levels occurred between 120 and 180 min after administration (at 180 min: 31 ± 4 ng/ml after 1 mg, 430 ± 40 after 10 mg, 1,006 ± 103 ng/ml after 30 mg, 4,092 ± 560 ng/ml after 100 mg and 14,266 ± 1,221 ng/ml after 300 mg; ptrend < 0.0001) and remained elevated over 24 h (ptrend < 0.0001).

Safety.   Fourteen adverse events were recorded in the patients receiving LU135252 (Table 5): one patient developed hypotension after 30 mg of LU135252 and one patient developed markedly elevated pulmonary artery pressure (71/38 mm Hg, mean 51 mm Hg) pulmonary edema (after 10 mg). Four cases (5.3%) of mild to moderate headache occurred. In two patients bilirubin levels increased (four-fold and two-fold) without increases in liver transaminases and alkaline phosphatase. One case of ventricular tachycardia was classified as unlikely to be related to the study medication. One patient had a decrease in platelet count (from 371'000 to 128'000 ml–1) 15 min before administration of the study drug, which spontaneously normalized 4 h later (to 255'000 ml–1). The same patient experienced a headache and a decrease in activated partial prothrombin time 240 min after the study drug, which also normalized spontaneously. One case of neck pain, one case of high glucose and one case of preexisting anemia were classified as unrelated. All patients recovered without sequelae.


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  		Table 5 Adverse Events

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study demonstrates that a single oral dose of the selective ETA receptor antagonist LU135252 has marked beneficial hemodynamic effects in patients with chronic heart failure. Cardiac index increased, while systemic vascular resistance decreased in a dose-dependent manner, as did pulmonary vascular resistance. Importantly, these favorable effects occurred in the absence of neurohormonal stimulation or increases of heart rate. The improvement in hemodynamics was comparable with that observed with nonselective ETA/B receptor antagonists but was accompanied by a smaller increase in ET-1 plasma levels (23,24). The results substantiate the concept that ET-1 importantly contributes to increased peripheral resistance and to the decrease in cardiac output in chronic heart failure.

Hemodynamic effects of selective ETA antagonism in heart failure.   Increased peripheral resistance is a key feature of CHF that further impairs cardiac performance. Vasoconstriction is a consequence of the activation of several neurohormonal systems, e.g., the sympathetic nervous system (13,29) and the renin angiotensin system (18). In line with this concept, ET-1 plasma levels are elevated in heart failure patients and correlate with hemodynamic severity (15,17,19,30,31). Also, in this large population of patients with CHF, we found a close positive relation of ET-1 plasma levels with systemic and pulmonary pressures and resistances and an inverse relation to cardiac output. In this study, LU135252 led to venous, pulmonary and arterial vasodilation and caused a pronounced increase in cardiac output. There were no signs of an activation of the sympathetic nervous system after administration of LU135252. Indeed, both plasma catecholamine levels and heart rate remained stable in spite of the marked hemodynamic effects. The hemodynamic effects of LU135252 as well as the presence of the compound in plasma lasted for approximately 24 h. The dose dependency of the effects of LU135252 on CI and pulmonary vascular resistance was quite obvious; higher dosages were hemodynamically clearly more effective than the lower dosages. In contrast to hypertension, dose selection is difficult in CHF as there is no documented surrogate end point for morbidity and mortality. Although the hemodynamic effects of LU135252 may be favorable, not all drugs with such effects improved prognosis in CHF (e.g., milrinone, flosequinan) (32–34). The fact that ET correlates with prognosis (15–17), however, strongly suggests that blockade of the system may be clinically important for morbidity and mortality.

Endothelin plasma levels in heart failure.   Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death (16,35). Thus, ET antagonists are of great clinical interest as mortality remains high in patients with CHF in spite of currently available drugs. Endothelin-1 exerts its vasoconstrictive effects through activation of ETA and ETB receptors on vascular smooth muscle cells. The ETA receptor also mediates proliferation of vascular smooth muscle cells (9). In contrast, ETB receptors on endothelial cells mediate the release of vasodilating and antiproliferative NO and prostaglandins (10–12) and are involved in the clearance of ET-1 (22–25). Indeed, selective ETB antagonism exerts unfavorable hemodynamic effects (36,37). Therefore, there is particular interest in selective ETA receptor antagonists as therapeutic agents in chronic heart failure. As in previous studies with other ET-1 receptor antagonists, ET-1 plasma levels increased significantly after administration of the selective ETA receptor antagonist LU135252, presumably due to displacement of ET-1 from its receptors. However, changes in plasma ET-1 were clearly smaller than those observed after administration of bosentan, a nonselective ETA/B receptor antagonist although the selective ETA receptor antagonist LU135252 was at least as hemodynamically potent as the combined ETA/B receptor antagonist, both on the arterial and venous side of the circulation (4,19,20,38,39). Thus, the present findings suggest that selective ETA blockade, which does not interfere with ETB receptors, does not impair clearance of ET-1 from the human circulation (22–25). This can have clinical relevance as elevated ET-1 plasma levels in chronic heart failure are, in part, due to down-regulation of lung ETB receptors with subsequent reduced clearance of ET-1 (40,41). Further, the risk of adverse events after drug withdrawal (e.g., rebound vasoconstriction) seems to be much lower.

Safety and tolerability.   The ETA receptor antagonist LU135252 was generally well tolerated. In this study, there was one episode of pulmonary edema in a patient with markedly elevated pulmonary artery pressure and one episode of hypotension. In a previous study on the hemodynamic effects of another selective ETA receptor antagonist, BQ-123, an episode of syncope and bradycardia was described, which also occurred in a patient with markedly elevated pulmonary artery pressure (42). Special care may, therefore, be required when starting endothelin antagonists in patients with severe chronic heart failure, as is the case with angiotensin-converting enzyme inhibitors or beta-blockers (43).

Study limitations.   This study has several limitations. First, since only short-term hemodynamic and neurohormonal effects were studied, valid conclusions concerning long-term safety and efficacy cannot be drawn yet. Second, for safety reasons, all drugs with impact on hemodynamics were halted before administration of the study drug. Therefore, interactions with other drugs may be more important in daily practice than under the conditions of this study. Third, the study was not placebo-controlled but, rather, compared a wide range of dosages of an active drug (i.e., LU135252). However, in previous studies, placebo did not exert any hemodynamic effects in patients with heart failure under the experimental conditions utilized in these patients (19,20). Also, the striking dose-dependency of the effects of LU135252 on CI and pulmonary vascular resistance strongly argues for a very specific mode of action. To address these limitations, further studies are, therefore, under way.

Summary and conclusions.   In summary, this study for the first time shows in a large patient population that the selective ETA receptor antagonist LU135252 improves hemodynamics in patients with chronic heart failure. Administration of LU135252 was not accompanied by neurohormonal stimulation and caused smaller increases in ET-1 plasma levels than the previously reported nonselective ETA/B receptor antagonists. The results suggest that ETA receptors are of primary importance for the hemodynamic abnormalities in CHF and support the concept that ETB receptors play an important role in clearance of ET-1 from the human circulation.


   Acknowledgments
 
The authors would like to acknowledge the participating centers: Allgemeines Krankenhaus, Vienna, Austria (R. Pacher); Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark (C. Torp-Pedersen); Kerckhoff-Klinik GmbH, Bad Nauheim, Germany (V. Mitrovic); Herz-und Kreislaufzentrum-Abteilung Kardiologie, Dresden, Germany (M. R. Schulze); Institute of Cardiology, Silesian Med. Academy, Katowice, Poland (M. Tendera); Instytut Kardiologii CMUJ, Krakow, Poland (A. Dziatkowiak); Clinic of Cardiology, Clinical Hospital, Lodz, Poland (M. J. Kosmider); Klinika Kardiologii, Szczecin, Poland (Z. Kornacewicz-Jach); Clinic of Cardiology, Warsaw, Poland (W. Ruzyllo); Clinic of Cardiology, Silesian Medical Academy, Zabrze, Poland (L. Polonski); Cardiology, University Hospital, Zurich, Switzerland (T. F. Lüscher). The authors thank Sidney Shaw (Berne, Switzerland) for determination of ET-1 plasma levels. The study was organized, in part, by InterCorNet (Clinical Research Center, Zurich, Switzerland).


   Footnotes
 
This study was supported by Knoll Pharmaceuticals, Ludwigshafen, Germany.


   References
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 Methods
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 Discussion
 References
 

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