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European Journal of Heart Failure 2001 3(4):457-461; doi:10.1016/S1388-9842(01)00168-4
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© 2001 European Society of Cardiology

Tezosentan (an intravenous endothelin receptor A/B antagonist) reduces peripheral resistance and increases cardiac power therefore preventing a steep decrease in blood pressure in patients with congestive heart failure

Gad Cottera,*, Wolfgang Kiowskib, Edo Kaluskia, Isaac Kobrinc, Olga Milovanova, Alon Marmord, Jamal Jafarie, Leonardo Reisine, Ricardo Krakovera, Zvi Vereda and Avi Caspif

a The Cardiology Institute, Assaf-Harofeh Medical Center 70300 Zerifin, Israel
b The Division of Cardiology, University Hospital Zurich, Switzerland
c Actelion Ltd Allschwil, Switzerland
d Rebecca Sieff Government Hospital Safed, Israel
e Ashkelon Hospital Ashkelon, Israel
f Kaplan Hospital Kaplan, Israel

* Corresponding author. Tel.: +972-8-977-9778; fax: +972-8-977-9779.


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objective: This study investigated the effect of tezosentan (an intravenous endothelin-1 receptor antagonist) on vascular resistance and cardiac function and determined the dose response in patients with stable congestive heart failure (CHF) due to left ventricular systolic dysfunction.

Methods: In a double-blind fashion, tezosentan or placebo were administered in ascending doses (5, 20, 50, 100 mg h–1) to 38 CHF (NYHA class III) patients with ejection fraction ≤35%, cardiac index ≤2.7 l min–1 m–2 and pulmonary capillary wedge pressure ≥ 15 mmHg. Systemic vascular resistance index (SVRi) was estimated as mean arterial blood pressure [(MAP-right atrial pressure)÷cardiac index (CI)]. Cardiac function was assessed as cardiac power index (Cpi), calculated as pressure x flow (MAP x CI), where MAP represents pressure and CI represents cardiovascular flow.

Results and discussion: Compared to the placebo, tezosentan induced a dose-dependent decrease in SVRi (–32%), an increase in Cpi (+20%) and a small decrease in MAP (–9%). By contrast, patients treated with nitrate vasodilators or nesiritide (a natriuretic peptide) showed a decrease in SVRi not accompanied by a significant increase in Cpi leading to a steep decrease in MAP.

Conclusions: The use of Cpi in the assessment of the hemodynamic effects of tezosentan, provides a useful alternative characterization of the complex influences of vasodilators on cardiac function in patients with CHF.

Key Words: Tezosentan • Blood pressure • Congestive heart failure

Received December 15, 2000; Revised March 19, 2001; Accepted May 10, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Accurately assessing cardiac function in severe heart failure is important in determining the efficacy of treatment, as well as in the design of clinical trials. Cardiac index (CI) is a classic hemodynamic parameter used to objectively measure the response to therapy in patients with congestive heart failure. However, CI correlates poorly with exercise capacity [1,2] and prognosis [3] in individual patients with heart failure. Cardiac power, an expression of the rate at which the left ventricle does work, is based on instantaneous changes in intracavitary pressure and systolic flow, has been proposed as a means of providing a valid measure of contractile capacity in the setting of congestive heart failure (CHF) [4]. We developed a simplified version of cardiac power, cardiac power index (Cpi), calculated by multiplying mean arterial pressure (MAP) by CI.

We hypothesize that, like any closed circuit composed of a power generator and a conduction system, the best way to characterize the performance of the cardiovascular system is to measure the power generated by the engine (Cpi) and the resistance to flow (SVRi). The pressure in the circuit (MAP) and the flow within it (CI) are only products of the former two variables. Therefore, Cpi and SVRi were used in the present study as the primary variables for the analysis of drug effect. Tezosentan is the first endothelin antagonist designed for the treatment of acute heart failure. This compound is a dual endothelin-1 receptor antagonist with a rapid onset of action and a half-life of 10 min, making it suitable for acute treatment of heart failure.

The aim of this investigation was to compare the effect on cardiac function of tezosentan as assessed by CI and cardiac power (Cpi) and determine the dose response relation of tezosentan in patients with stable congestive heart failure (CHF) due to left ventricular systolic dysfunction.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Design and procedures
A total of 38 patients were recruited from heart failure clinics in Israel and Switzerland and were evaluated during elective right-heart catheterization performed for diagnostic reasons. The clinical diagnosis of ischemic vs. dilated cardiomyopathy was based on clinical and angiographic criteria; i.e. history of prior myocardial infarction or significant coronary artery disease on coronary catheterization. The study protocol was approved by the ethical review boards of the centers involved.

2.1.1. Inclusion criteria
CHF (NYHA class III) with left ventricular ejection fraction ≤35%, cardiac index ≤2.7 l min–1 m–2 and capillary wedge pressure ≥15 mmHg. Hemodynamic measurements were performed at least 1 h after right-heart catheterization and insertion of Swan–Ganz catheter.

All patients were receiving either angiotensin converting enzyme inhibitors (ACEi) or angiotensin(AT) II antagonists and diuretics.

2.1.2. Exclusion criteria
Significant hypotension or hypertension, myocardial infarction within 4 weeks, hemodynamically relevant arrhythmias, valvular heart disease or myocardititis, significant lung, hepatic or autoimmune disease, creatinine >200 µmol l–1 or cerebrovascular event within 12 months.

2.2. Study protocol
Patients were randomized in a double-blind fashion to receive ascending doses of intravenous tezosentan (5, 20, 50 and 100 mg over 1 h each) or placebo. Cardiac output was measured by thermodilution and MAP was determined by a centrally located arterial line. Cardiac performance was assessed using Cpi calculated as MAPxCI. Systemic vascular resistance index (SVRi) was calculated as (MAP-right atrial pressure)÷CI. Pulmonary vascular resistance was calculated as [(mean pulmonary pressure–capillary wedge pressure)]÷cardiac output.

2.3. Statistical analysis
Analysis was performed on the intent-to-treat population. Continuous variables were analyzed using the students t-test. Also, 95% confidence intervals were computed. Categorical variables were analyzed using the {chi}2-test. P-values ≤0.05 were considered significant. Demographic and baseline data were analyzed descriptively.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Thirty-eight patients were recruited to this study. The full details of the study results will be published elsewhere [5]. Baseline parameters and background medications are summarized in Table 1. At the end of the 4-h treatment period (i.e. 100-mg h–1 dose), tezosentan induced a dose-dependent increase in Cpi compared to placebo, 22 vs. 4%, P≤0.01, respectively (Table 2). The corresponding values for CI were 34 and 7%, P≤0.01. The MAP decreased by 9% and 3% (P=0.54) in the tezosentan- and placebo-treated patients, respectively. The increase in Cpi and the decrease in SVRi were parallel and dose-dependent, reaching a maximum at a tezosentan infusion of 50 mg h–1 (Fig. 1).


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  		Table 1 Demographics and baseline characteristics

 


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  		Table 2 Changes in hemodynamic variables after 4 h of tezosentan infusion (100 mg h–1 dose)

 


Figure 1
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  		Fig. 1 Changes (mean±S.D.) in Cpi (diamond) and SVRi (square) with ascending doses of tezosentan. Cpi, cardiac power index; SVRi, systemic vascular resistance index.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
By incorporating both pressure and flow variables, Cpi provides an assessment of cardiac performance that may better reflect the complicated influences of vasodilator therapy. Cardiac index is actually a measure of cardiovascular flow and is therefore determined by the interaction of cardiac contractility (Cpi) and the resistance to flow (SVRi). Hence it is not a primary measure of cardiac function but rather the result of the above-mentioned interaction.

Most patients with heart failure also have coronary atherosclerotic disease with coronary resistance arteries maximally dilated distal to the obstruction. As a result, coronary blood flow in the region distal to the obstruction is not autoregulated and is highly dependent on systemic blood pressure. When vasodilators induce marked reduction in MAP, coronary flow distal to the occlusion may decrease, thereby aggravating rather than improving cardiac status [6,7]. This phenomenon is thought to be the main mechanism responsible for the U-shaped relationship of nitrate vasodilator treatment with response. Therefore, these agents have a small therapeutic ratio requiring very close blood pressure monitoring during high-dose administration [8].

The value of determining Cpi is illustrated by calculating it from data reported by Leier et al. [9] comparing it to the CI reported by these investigators. They described the effect of increasing doses and maintenance intravenous administration of isosorbide dinitrate (ISDN), nitroglycerin (NTG), and nitroprusside (NTP) in patients with stable NYHA class III or IV chronic CHF. SVR was markedly decreased by these drugs, while Cpi did not increase (Fig. 2) leading to a steep decrease in MAP. In contrast, in the present study, tezosentan induced a modest decrease in MAP, accompanied by a significant increase in Cpi (Fig. 2). This finding is of importance since a decrease in SVR without a parallel decrease in MAP may reduce the incidence of hypotension, leading to an improved therapeutic ratio for tezosentan relative to nitrate vasodilators in the treatment of acute decompensated CHF.


Figure 2
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  		Fig. 2 Parallel comparison of percent change from baseline (BL) for tezosentan (TEZ), LU135252 (LU), sitaxentan (SIT), isosorbide dinitrate (ISDN), nitroglycerin (NTG), and nitroprusside (NTP) and nesiritide in cardiac power index (Cpi, solid bar), cardiac index (CI, open bar), and mean arterial pressure (MAP, hatched bar).

 
Colucci et al. [10] recently reported results (Fig. 2) showing that nesiritide in patients with CHF had an effect on hemodynamic variables similar to that of nitrate vasodilators (i.e. increasing CI and decreasing SVR with a small effect on Cpi, hence reducing MAP significantly). Indeed, in their study, hypotension occurred in 41% of patients with high-dose nesiritide and 23% of patients on the low-dose, compared to 11% of patients treated with conventional therapy. The hypotension observed in some nesiritide-treated patients may have precipitated several episodes of renal failure. These findings emphasize the U-shaped response curve of vasodilators that decrease SVR without improving Cpi in the treatment of heart failure.

The results of the present investigation are consistent with the findings of two recent studies assessing the hemodynamic effects of two other endothelin receptor antagonists, LU135252 [11] and sitaxentan [12] in patients with chronic compensated CHF. In these studies, increased Cpi (+15% and +20%, respectively) and decreased SVR (–26% and –11%, respectively) with only small changes in MAP (–7% and +3%, respectively) were observed. In the study of sitaxentan, the lack of decrease in MAP was even interpreted as an indication that sitaxentan does not produce peripheral vasodilatation.

The mechanisms by which the acute administration of endothelin antagonists are able to improve cardiac contractility while inducing a decrease in left ventricular filling (wedge) pressure are not understood. Firstly, it seems that it occurs both with the non-selective ET A/B antagonist (tezosentan) and the selective ET A antagonists (LU135252 and sitaxentan). For all these endothelin antagonists the effect on SVRi decrease, Cpi increase and MAP change was roughly the same. Secondly, the potential benefit of endothelin receptor antagonism in heart failure may be related to its effect on the contractile state of the heart. While ET-1 exerts positive inotropic effects in normal myocardium [13], there is experimental and clinical evidence to suggest that in failing myocardium, ET-1 exerts negative inotropic effects [14,15]. Accordingly, antagonizing these deleterious actions of excessive ET-1 in patients with heart failure may help restore contractile properties in the failing myocardium


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Cardiac power index is an alternative method of evaluating cardiac function and may represent a potential advance over a purely flow-derived parameter like CI. By accounting for decreases in systemic blood pressure, Cpi may more accurately reflect the complex influences of vasodilators on cardiac function in heart failure. Using Cpi in the assessment of the treatment effect of tezosentan in CHF patients, distinguishes the drug from the presently used nitrate vasodilators, by its ability to significantly decrease SVR and increase Cpi, in the absence of a steep decline in MAP commonly observed when administering nitrate vasodilators.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Benge W, Litchfield R, Marcus M. Exercise capacity in patients with severe left ventricular dysfunction. Circulation (1980) 61:955–959.[Abstract/Free Full Text]
  2. Franciosa J, Park M, Levine T. Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol (1981) 47:33–39.[CrossRef][Web of Science][Medline]
  3. Lipkin D, Canepa-Anson R, Stephens M, et al. Factors determining symptoms in heart failure: comparison of fast and slow exercise tests. Br Heart J (1986) 55:439–445.[Abstract/Free Full Text]
  4. Tan L.B. Clinical and research implications of new concepts in the assessment of cardiac pumping performance in heart failure. Cardiovasc Res (1987) 21:615–622.[Abstract/Free Full Text]
  5. Schalcher C, Cotter G, Reisin L et al. The dual endothelin–receptor antagonist tezosentan acutely improves hemodynamic parameters in patients with advanced heart failure. Am Heart J 2001:Submitted.
  6. Bussmann W, Schofer H, Kurita A, et al. Nitroglycerin in acute myocardial infarction. X. Effect of small and large doses of nitroglycerin on sigma ST segment deviation — experimental and clinical results. Clin Cardiol (1979) 2:106–112.[Medline]
  7. Jugdutt B, Warnica J. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location. Circulation (1988) 78:906–919.[Abstract/Free Full Text]
  8. Cotter G, Faibel H, Barash P, et al. High-dose nitrates in the immediate management of unstable angina: optimal dosage, route of administration, and therapeutic goals. Am J Emerg Med (1998) 16:19–24.
  9. Leier C.V, Bambach D, Thompson M.J, et al. Central and regional hemodynamic effects of intravenous isosorbide dinitrate, nitroglycerin and nitroprusside in patients with congestive heart failure. Am J Cardiol (1981) 48:1115–1123.[CrossRef][Web of Science][Medline]
  10. Colucci W, Elkayam U, Horton P.H, et al. Intravenous nesiritide, a natriuretic peptide in the treatment of decompensated congestive heart failure. New Engl J Med (2000) 243:246–253.
  11. Spieker L, Mitrovic V, Noll G, et al. Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure. ET 003 Investigators. J Am Coll Cardiol (2000) 35:1745–1752.[Abstract/Free Full Text]
  12. Givertz M, Colucci W, LeJemtel T, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation (2000) 101:2922–2927.[Abstract/Free Full Text]
  13. Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol (1999) 61:391–415.[CrossRef][Web of Science][Medline]
  14. Onishi K, Ohno M, Little W, et al. Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure. J Pharmacol Exp Ther (1999) 288:1214–1222.[Abstract/Free Full Text]
  15. MacCarthy P, Grocott-Mason R, Prendergast B, et al. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ET(A) receptor antagonist. Circulation (2000) 101:142–147.[Abstract/Free Full Text]

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