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European Journal of Heart Failure 2005 7(4):475-478; doi:10.1016/S1388-9842(03)00106-5
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© 2005 European Society of Cardiology

Urotensin II in patients with chronic heart failure{star}

Stefan Krüger, Jürgen Graf, Dagmar Kunz, Tina Stickel, Marc W. Merx, Peter Hanrath and Uwe Janssens*

Medical Clinic I and the Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, University of Technology Aachen, Germany

* Corresponding author. Present address: Medizinische Klinik I, Universitätsklinikum, Rheinisch Westfälische Technische Hochschule, Pauwelsstraße 30, Aachen 52057, Germany. Tel.: +49-241-8089831; Fax: +49-241-8082414. E-mail address: ujanssens{at}ukaachen.de


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Human Urotensin II (hU-II) is the most potent vasoconstrictor known to date. HU-II receptors are predominant in the human heart and arterial vessels, suggesting hU-II to be of importance as a cardiovascular mediator.

Methods: We studied 32 consecutive patients (60±12 years) with chronic heart failure (CHF) and 10 control subjects (54±12 years, n.s.) with cardiopulmonary exercise testing. Blood samples for the measurement of plasma hU-II and big-endothelin-1 (big-ET1) were obtained at rest and at peak exercise.

Results: Peak VO2 was significantly higher in controls than in CHF patients (19.8±3.8 vs. 14.7±3.6 ml min–1 kg–1, P<0.001). Big-ET1 levels were increased in CHF compared to controls at rest (2.8±1.8 vs. 1.7±0.1 fmol/ml, P<0.01) and at peak exercise (2.7±1.7 vs. 1.6±0.2 fmol/ml, P<0.005). HU-II concentrations were comparable in patients with CHF and controls at rest (2990±1104 vs. 3290±508 pg/ml, n.s.) and peak exercise (3063±1185 vs. 3213±1188 pg/ml, n.s.). Resting hU-II levels demonstrated no correlation with peak VO2 in controls or CHF patients.

Conclusions: The measurement of circulating plasma levels of hU-II does not seem to be very helpful in studying the effects of hU-II in human cardiovascular regulation. A local paracrine or autocrine mediator effect of hU-II in CHF is possible.

Key Words: Urotensin II • Chronic heart failure • Endothelin-exercise

Received September 16, 2002; Revised January 15, 2003; Accepted June 16, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Human urotensin II is the most potent mammalian arterial vasoconstrictor identified so far, based on responses in the rat proximal aorta, but it has also vasodilating properties [1]. The response to hU-II varies substantially between species and different types of vessels [2,3]. HU-II receptors are predominant in the human heart and arterial vessels, suggesting a function as cardiovascular mediator [4]. The vasoconstrictor effects of hU-II are mediated by binding to specific high affinity GPR14 receptors [5]. Some authors demonstrate that hU-II produces potent vasoconstriction in humans in vivo [6]. This contrasts with the finding of other studies, that human hU-II demonstrated no significant vasoconstrictor action in either human arteries or veins of small or medium caliber in vitro [7] or in vivo [8].

The aim of this study was to measure hU-II plasma concentrations in patients with and without chronic heart failure (CHF) at rest and exercise, to examine its correlation with exercise capacity and to compare it with big endothelin-1 (big-ET1), the precursor of the potent vasoconstrictor endothelin-1, which is elevated in CHF [9].


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
The study population consisted of 32 consecutive patients with stable CHF and 10 controls without CHF. The study was approved by the local ethics committee, and all patients gave informed written consent. All CHF patients were in a clinically stable condition for at least 6 weeks and showed no signs of acute cardiac decompensation. All CHF patients were on optimized medical CHF therapy including stable doses of ACE inhibitors (91%), diuretics (91%), digoxin (78%) and/or β-blockers (84%), which had been unchanged for at least 6 weeks. CHF was confirmed by left ventricular dysfunction (LVEF<35%) and impairment of exercise capacity (maximal oxygen uptake<25 ml min–1 kg–1). All patients had exertional dyspnea, fatigue or both and were classified as NYHA class II to III. The etiology of heart failure was determined by cardiac catheterization in all patients. LVEF was evaluated with biplane transthoracic echocardiography. None of the controls had left ventricular dysfunction or significant coronary artery disease or signs of myocardial ischemia on stress testing. CHF was caused by idiopathic dilated cardiomyopathy in 19 patients and by coronary artery disease in 13 patients. As shown in Table 1, age, sex, height, body weight and renal function were not significantly different between patients with CHF and controls. All patients performed a standard symptom-limited incremental bicycle exercise test with computerized respiratory gas exchange analysis (Jäger Oxycon Alpha, Würzburg, Germany). Patients are controlled with renal failure (defined as a creatinine value>1.5 mg/dl) were excluded from the study.


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  		Table 1 Patient characteristics

 
2.2. Laboratory investigations
Blood was sampled from a short polyethylene cannula placed in an antecubital vein after 10 min of supine rest prior to exercise and at peak exercise. Test tubes were placed on ice and centrifuged immediately. Plasma samples were stored at –70 °C until analysis. Serum levels of hU-II were measured in a novel sensitive enzyme immunoassay (Immundiagnostik, Bensheim, Germany) according to the instructions of the manufacturer. The assay is based on affinity purified rabbit antibodies raised against synthetic cyclic hU-II peptide. The lower detection limit was 3 pg/ml and the mean recovery was 94%. Interassay variation was lower than 15%. Crossreactivity with human ANP, BNP and somatostatin was <0.01%. Big-ET1 was measured by use of an established commercial ELISA kit (Immundiagnostik, Bensheim, Germany).

2.3. Statistics
Statistical analysis was performed by paired Student's t test and {chi}2 statistic. Correlations were performed using Pearson's correlation. P value<0.05 was considered statistically significant.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Left ventricular ejection fraction and peak VO2 were significantly lower in CHF patients. HU-II plasma concentrations (Fig. 1a) at rest were comparable in patients with CHF (2990±1104 pg/ml, range 1730–7010 pg/ml) and in controls (3290±508 pg/ml, range 2710–3750 pg/ml, n.s.). Also, there was no significant difference in hU-II between male and female patients with or without CHF and no correlation between age and hU-II in both groups. HU-II plasma levels at peak exercise did not increase significantly (Fig. 2) and did not differ between patients with CHF and controls (3063±1185 vs. 3213±1188 pg/ml, n.s.). HU-II plasma concentrations at peak exercise showed only weak correlation with peak VO2 in CHF patients (r=0.25, P<0.01; Fig. 3). In addition, resting hU-II levels demonstrated no correlation with peak VO2 in controls or CHF patients. Big-ET1 levels (Fig. 1b) were increased in CHF patients compared to controls at rest (2.8±1.8 vs. 1.7±0.1 fmol/ml, P<0.01) and after exercise (2.7±1.7 vs. 1.6±0.2 fmol/ml, P<0.005). In CHF peak VO2 correlated with big-ET1 levels at rest (r=–0.55, P<0.01) and peak exercise (r=–0.56, P<0.01).


Figure 1
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  		Fig. 1 Plasma concentrations of human urotensin II (a) and big endothelin (b) at rest and at peak exercise. Values are mean±S.D.

 


Figure 2
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  		Fig. 2 Plasma concentrations of human urotensin II at rest and at peak exercise in CHF patients (a) and controls (b).

 


Figure 3
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  		Fig. 3 Scatter plot of human urotensin II concentrations at peak exercise vs. peak oxygen uptake (peak VO2) in CHF patients.

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
To the best of our knowledge, this is the first report on in vivo studies of hU-II plasma concentrations in CHF at exercise. HU-II plasma levels allowed no discrimination between patients with and without CHF. Physical exercise with its hemodynamic changes did not lead to significant changes in circulating hU-II either in CHF patients or in controls. In contrast, big-ET1, an established precursor of the vasoconstrictor endothelin-1, demonstrated significant elevation in CHF patients compared to controls at rest as well as after exercise. Totsune et al. [10] found, raised hU-II levels in chronic renal failure patients. They speculated that hU-II might act as an important circulating vasoactive hormone in cardiovascular regulation. With respect to our findings this hypothesis is questionable. Therefore, as hU-II has no direct vasodilating or vasoconstricting effect in intact human arteries and veins of small or medium caliber [7,8]. An alternative explanation might be the marked species difference in the effect of hU-II. However, a lack of difference in plasma concentrations of hU-II between CHF and healthy controls does not rule out a role of hU-II in cardiovascular regulation. If involved in cardiovascular homeostasis, hU-II is likely to be produced and to act locally, not only in the blood vessels but also in the myocardium. This is supported by a recent study reporting a strong expression of hU-II in cardiomyocytes, and to a lesser extent in vascular smooth muscle cells of patients with end stage CHF [4]. In addition, there was significantly less myocardial hU-II expression in patients with early stage CHF and to know about the myocardial expression in healthy controls. Furthermore, a significant up-regulation of hU-II receptors was found in the myocardium of patients with end-stage CHF in this study [4].

The circulating levels of hU-II measured in our study were low, compared to previous studies [10]. This suggests that hU-II acts as a locally released mediator rather than a circulating hormone. Most locally released mediators such as endothelin-1 are released in the direction of the smooth muscle, where the peptide binds to the vascular smooth muscle receptors with little peptide escaping into the circulation [11–13]. Therefore, it can be difficult to detect changes in plasma as a result of disease processes. Ideally, measurements should be made in target tissues, but this is not applicable in a routine clinical setting. As a result of these problems, strategies have evolved to measure plasma levels of big-ET1 as a precursor of the mature peptide to identify increased synthesis associated with the disease such as CHF.

One potential limitation of our study is the measurement of hU-II, a mature peptide on the one side, and big-ET1, the precursor of endothelin-1 on the other side. We measured big-ET1 instead of endothelin-1, because, it is reported that elevation of ‘immunoreactive ET-1’ in severe heart failure consists mainly of the prohormone big-ET1 [13]. The study by Cowburn [14] confirmed big ET as the major contributor of ‘immunoreactive ET’. It was only in the sicker patients with LVD and elevated mean pulmonary artery pressure >30 mm Hg, that ET-1 was elevated, whereas big ET was more sensitive and also significantly different between controls and the CHF patients, who were less sick. It is possible that in our study, ET-1 levels might have been no greater than in controls. But for this reason, we have chosen the more sensitive and specific big ET and not ET-1 in our study. Unfortunately, a test to measure the precursor of hU-II was not available to us. The determination of hU-II is a new method. Therefore, one has to be careful in interpreting the results of different studies, since discrepancies between different studies could be the result of different methods and tests used. This could explain the results of Richards et al. [15], who used a new radioimmunoassay for the measurement of plasma urotensin II in patients with heart failure and controls. With this test, they found higher plasma urotensin II levels in patients with heart failure than in controls, which is contrary to our results.

In conclusion, the measurement of circulating plasma levels of hU-II does not seem to be of great relevance in studying the effects of hU-II in the human cardiovascular regulation. A local paracrine or autocrine mediator effect of hU-II in CHF is possible. The cardiovascular role of hU-II in humans deserves further study, preferably by using a specific antagonist of hU-II.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
{star} No author has a fiscal interest, consulting or lecture arrangement, or has received research support from a company dealing in products used in the study. Back


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

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