Skip Navigation

European Journal of Heart Failure 2005 7(2):195-198; doi:10.1016/j.ejheart.2004.07.010
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kupari, M.
Right arrow Articles by Lommi, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kupari, M.
Right arrow Articles by Lommi, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2005 European Society of Cardiology

Is the pregnancy hormone relaxin an important player in human heart failure?

Markku Kuparia,*, Tomi S. Mikkolab, Heikki Turtoa and Jyri Lommia

a Division of Cardiology, Department of Medicine, Helsinki University Central Hospital Helsinki, Finland
b Department of Obstetrics and Gynaecology, Helsinki University Central Hospital Helsinki, Finland

* Corresponding author. Tel.: +358 9 47172441; fax: +358 9 47174574. E-mail address: markku.kupari{at}hus.fi


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The pregnancy hormone relaxin has been raised as a new compensatory mediator of cardiac origin in heart failure (HF). We set out to assess the role of relaxin in pressure overload-induced human HF.

Methods: We studied 129 adult patients undergoing cardiac catheterization for isolated aortic valve stenosis (AS). Blood was sampled from the aortic root and, in a subset of 49 patients, from the coronary sinus for the determination of plasma relaxin by enzyme immunoassay. HF was diagnosed when the patient had dyspnea or fatigue on ordinary effort in association with pulmonary wedge pressure >14 mm Hg at catheterization.

Results: Forty-one patients had HF, which was systolic (ejection fraction <50%) in 16 patients and diastolic in 25 patients. The median plasma relaxin was 32 pg/ml (<12–297 pg/ml) in 88 AS patients without HF, 28 pg/ml (<12–825 pg/ml) in the 41 AS patients with HF, and 42 pg/ml (range, <12–100 pg/ml) in 11 control patients free of heart disease (p=0.82). Plasma relaxin did not correlate with any measurement of cardiac structure or function. The concentration gradients of relaxin from the aortic root to the coronary sinus indicated relaxin extraction by the heart in the control patients (median change, –5 pg/ml, p=0.038) vs. relaxin production in patients with systolic HF (median change, +6 pg/ml, p=0.028) (p=0.002 between groups).

Conclusions: Although the heart may release relaxin into the circulation in certain forms of HF, this does not translate into elevated systemic concentrations. Relaxin is not a major player in human HF.

Key Words: Heart failure • Aortic stenosis • Relaxin

Received June 22, 2004; Revised July 10, 2004; Accepted July 21, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Relaxin is an insulin-related polypeptide hormone of human reproduction [1,2]. It stimulates the generation of nitric oxide and cyclic AMP and has a variety of biological activities including vasodilation, induction of collagen breakdown, stimulation of atrial natriuretic peptide secretion, regulation of fluid balance and prevention of platelet aggregation [1,3]. In 2001, Dschietzig et al. [4] reported that plasma relaxin is increased in heart failure (HF) in man and that relaxin mRNA is expressed in myocardium in proportion to the severity of cardiac decompensation. The authors' idea of relaxin as a new compensatory hormone in HF [4] remains unproven, however, since the next controlled study failed to find elevated plasma relaxin in patients with HF [5] and since relaxin also seems to be devoid of prognostic value in these patients [6]. To explore further the issue of relaxin in human HF, we measured plasma relaxin concentrations in a large group of patients having aortic valve stenosis (AS) with or without HF and in control patients free of structural heart disease. As control mediators known to respond in HF, we measured the concentrations of endothelin-1 and N-terminal B-type natriuretic peptide (Nt-BNP) from the same blood samples. We found that relaxin, in striking contrast to both endothelin-1 and Nt-BNP, was not elevated in HF and showed no association with cardiac structure or function in patients with AS.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
We studied 129 patients (64 men) with isolated AS undergoing cardiac catheterization and echocardiography for consideration of valve replacement. Their mean age (±S.D.) was 69±10 years (range, 39–83). The patients constituted a consecutive series except that we excluded individuals with known coronary artery disease, previous cardiac surgery, complicated diabetes and renal failure (serum creatinine >170 µmol/l). As a control group, we studied 11 patients (6 men) undergoing invasive electrophysiological studies. Their mean age was 57±4 years. None had clinical or echocardiographic evidence of structural heart disease and all were in sinus rhythm at the time of our study. None of our female patients was pre-menopausal. The research protocol conformed with the Declaration of Helsinki and was approved by the institutional ethics committee. All participants signed an informed consent document.

2.2. Non-invasive and invasive cardiac studies
Echocardiographic studies were done with an Acuson Sequoia scanner. The details of our methods to assess the stenotic aortic valve and the structure and function of the left ventricle have been reported earlier [7,8]. Left ventricular (LV) mass index (mass/body area) was calculated using an anatomically validated formula [9]. Ejection fraction was determined from the apical 4-chamber view using Simpson's formula.

Right and left heart catheterizations were made via the femoral route. The studies included pressure measurements using fluid-filled catheters, determination of cardiac output by the Fick method and calculation of the aortic valve area by the Gorlin formula. If the aortic valve could not be crossed for a pullback pressure recording (n=13/129), echocardiographic valve area and pressure gradient were substituted for the invasive data. Coronary angiographies were made using selective techniques and analyzed visually. Luminal narrowings exceeding 50% of the reference diameter were considered angiographically significant.

2.3. Diagnosis of HF
HF was diagnosed when the patient had ≥NYHA 2 dyspnea or fatigue on effort associated with pulmonary wedge pressure >14 mm Hg. HF was classified diastolic when LV ejection fraction was ≥50% and systolic with ejection fraction <50%.

2.4. Blood sampling and laboratory analyses
Blood was sampled for biochemical measurements from the aortic root and the coronary sinus at the start of the invasive studies. The samples were taken into prechilled EDTA tubes containing aprotinin, put on ice and centrifuged within 30 min. Plasma was stored at –80 °C until analyses. Coronary sinus was accessible for blood sampling in all control patients and in 48 patients with AS. Relaxin was determined using a commercially available kit (Immundiagnostik, Bensheim, Germany) [4]. The analysis had a detection limit of 12 pg/ml, and the intra-assay coefficient of variation was 8.8%. Of all relaxin measurements, 10% were below the detection limit. In statistical analyses, these measurements were given an arbitrary value of 6 pg/ml (half the detection limit). Endothelin-1 was measured as detailed earlier [10]; the intra-assay coefficient of variation was 5.7%. Nt-BNP was determined with a commercially available enzyme immunoassay (Biomedica, Vienna, Austria); the intra-assay coefficient of variation was 8.5%.

2.5. Statistical analysis
Kruskal–Wallis test was used for comparisons of skewed data (relaxin, Nt-BNP, endothelin-1) across two or more groups. For normally distributed data, the group comparisons were made with ANOVA. The Wilcoxon signed-rank test was used for intragroup comparisons of aortic and coronary sinus relaxin concentrations. Associations of plasma relaxin with the clinical characteristics and with the cardiac measurements were studied using the Kruskal–Wallis test and Spearman's rank correlation coefficients. The analyses were repeated on log transformed relaxin concentrations using ANOVA and Pearson's correlation coefficients. The group data are summarized as median and range for asymmetrically distributed measurements and as mean±S.E.M. for normally distributed data. p-values <0.05 were considered statistically significant. All analyses were made using commercially available statistical software (SYSTAT Version 9.1, Systat).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Plasma relaxin, endothelin-1 and Nt-BNP in patients with and without HF
Of the 129 AS patients, 41 had HF. Table 1 compares patients with and without HF for clinical characteristics and cardiac measurements. Table 2 shows the concentrations of plasma relaxin, endothelin-1 and Nt-BNP in the control group and in the AS groups with and without HF. Endothelin-1 and Nt-BNP were both elevated in patients with HF. Relaxin, by contrast, was not elevated and it was also independent of the type of HF in that its median was 40 pg/ml (range, <12–825 pg/ml) in patients with diastolic HF (n=25) and 18 pg/ml (range, <12–131 pg/ml) in patients with systolic HF (n=16) (p=0.082). Relaxin showed no statistically significant associations with age or sex or medication or with the NYHA class, aortic valve area, LV mass, ejection fraction, pulmonary wedge pressure, plasma endothelin-1 or plasma Nt-BNP. No associations of relaxin with HF or with the cardiac measurements were found either in sex-specific analyses.


View this table:
[in this window]
[in a new window]

  		Table 1 Characteristics of patients with aortic valve stenosis with and without heart failure

 


View this table:
[in this window]
[in a new window]

  		Table 2 Plasma relaxin, endothelin-1 and Nt-BNP concentrations in patients with aortic stenosis and in the control group

 
Fig. 1 shows the concentration gradients of relaxin from the aorta to the coronary sinus in the control group and in patients with AS grouped by the presence and type of HF. A statistically significant difference was found across the four groups (p=0.015). Of note, the heart extracted relaxin in the control patients (median change, –5 pg/ml; range from –26 to +7 pg/ml, p=0.038) but released it into the circulation in patients with systolic HF (median gradient, +6 pg/ml; range from 0 to +71 pg/ml, p=0.028).


Figure 1
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Transcardiac plasma relaxin gradients in the control patients free of structural heart disease (n=11) and in patients with aortic valve stenosis (AS) free of heart failure (HF–, n=33), with diastolic heart failure (DHF, n=8) and with systolic heart failure (SHF, n=7). The p-values are from Kruskal–Wallis nonparametric analysis of variance.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We studied plasma relaxin concentrations in consecutive patients with severe isolated AS. We found no association of relaxin with either the presence of heart disease in general or with the presence, type or severity of HF in particular. Although there were some differences in the transcardiac relaxin gradients, these did not translate into different systemic concentrations.

Dschietzig et al. [4] were the first to study the role of relaxin in human HF. They reported that plasma relaxin concentrations were 4- to 6-fold in moderate HF, and 12- to 16-fold in severe HF, compared with concentrations in patients free of heart disease. Plasma relaxin was related not only to the clinical severity of HF but also to LV filling pressure and cardiac index. Furthermore, relaxin mRNA was expressed in human myocardium, and severely failing hearts released relaxin into the coronary venous circulation [4].

Our failure to find an association of plasma relaxin with HF is in striking contrast with the data cited above [4]. The disagreement defies an easy explanation. It may be of importance that all patients with HF in the German study suffered from systolic LV dysfunction due to ischemic or dilated cardiomyopathy, while our patients predominantly had diastolic HF due to LV pressure overload. Further, one half of patients in the former study were in NYHA class 4 needing intensive care [4] while the majority of our patients had stable HF of moderate severity. Yet, our patients had HF severe enough to result in elevations in circulating endothelin-1 and Nt-BNP [11,12]. Differences in the studied cohorts do not therefore fully settle the discrepancy, the more so as Dschietzig et al. found that relaxin was abnormally high even in moderate HF. Importantly, relaxin concentrations in patients without heart disease were actually more discriminatory between the results of these two studies than plasma relaxin in patients with HF. In the German study [4], the mean plasma relaxin in patients without structural heart disease was as low as ~2 pg/ml compared with the median of 42 pg/ml in our work. Comparable other data on plasma relaxin in people free of HF [5,13] are in strong support of our results.

Our data on the transcardiac relaxin gradients (Fig. 1) suggest that the heart extracts relaxin in the absence of structural heart disease while releasing it into the circulation in systolic HF. These findings agree with the observation by Fisher et al. [13] in patients free of HF and with the data of Dschietzig et al. [4] in patients with severe HF. Whether the heart extracts or releases relaxin may not depend only on the rate of relaxin synthesis but also on other factors like the density and affinity of relaxin receptors in the myocardium [14]. Why the release of relaxin from the heart did not elevate systemic concentrations in systolic HF is difficult to explain. Theoretically, it could be due to enhanced relaxin clearance, but a more plausible explanation is that among the sources of relaxin the heart in reality serves but a marginal role.

We conclude that plasma relaxin concentrations are not elevated in HF caused by LV pressure overload in man. There may be some true release of relaxin from the heart in certain forms of HF, but this does not translate into elevated concentrations in the systemic circulation. Relaxin is not a generally important player in human HF.


   Acknowledgements
 
We thank Drs. Markku Mäkijärvi and Hannu Parikka for help in the study of the control patients, Liisa Blubaum for skilful clinical assistance and Tomi Silvennoinen for help in the laboratory analyses. This work was supported by grants from (1) Sigrid Juselius Foundation, Helsinki, Finland; (2) Research Foundation of Helsinki University Central Hospital, Helsinki, Finland; and (3) Finnish Foundation for Cardiovascular Research, Helsinki, Finland.


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

  1. Bani D. Relaxin: a pleiotropic hormone. Gen. Pharmacol. (1997) 28:13–22.[Web of Science][Medline]
  2. Bathgate R.A.D., Samuel C.S., Burazin T.C.D., et al. Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene: novel members of the relaxin peptide family. J. Biol. Chem. (2002) 277:1148–1157.[Abstract/Free Full Text]
  3. Fisher C., MacLean M., Morecroft I., et al. Is the pregnancy hormone relaxin also a vasodilator peptide secreted by the heart? Circulation (2002) 106:292–295.[Abstract/Free Full Text]
  4. Dschietzig T., Richter C., Bartsch C., et al. The pregnancy hormone relaxin is a player in human heart failure. FASEB J. (2001) 15:2187–2195.[Abstract/Free Full Text]
  5. Kruger S., Graf J., Merx M.W., et al. Relaxin kinetics during dynamic exercise in patients with chronic heart failure. Eur. J. Intern. Med. (2004) 15:54–56.[CrossRef][Medline]
  6. Fisher C., Berry C., Blue L., Morton J.J., McMurray J. N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Heart (2003) 89:879–881.[Abstract/Free Full Text]
  7. Lindroos M., Kupari M., Heikkila J., Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J. Am. Coll. Cardiol. (1993) 21:1220–1225.[Abstract]
  8. Kupari M., Koskinen P., Virolainen J. Correlates of left ventricular mass in a population sample aged 36 to 37 years. Circulation (1994) 89:1050–1059.
  9. Devereux R.B., Alonso D.R., Lutas E.M., et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am. J. Cardiol. (1986) 57:450–458.[CrossRef][Web of Science][Medline]
  10. Ylikorkala O., Orpana A., Puolakka J., Pyörälä T., Viinikka L. Postmenopausal hormonal replacement decreases plasma levels of endothelin-1. J. Clin. Endocrinol. Metab. (1995) 80:3384–3387.[Abstract]
  11. Wei C.M., Lennan A., Rodeheffer R.J., et al. Endothelin in human congestive heart failure. Circulation (1994) 89:1580–1586.[Abstract/Free Full Text]
  12. Ruskoaho H. Cardiac hormones as diagnostic tools in heart failure. Endocr. Rev. (2003) 24:341–356.[Abstract/Free Full Text]
  13. Fisher C., Al-Benna S., Kirk A., Morton J.J., McMurray J.J.V. Transcardiac and transpulmonary gradients in the putative new cardiovascular hormone relaxin. Heart (2003) 89:789–790.[Free Full Text]
  14. Hsu S.Y., Nakabayashi K., Nishi S., et al. Activation of orphan receptors by the hormone relaxin. Science (2002) 295:671–674.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
E. E. Shaw, P. Wood, J. Kulpa, F. H. Yang, A. J. Summerlee, and W. G. Pyle
Relaxin alters cardiac myofilament function through a PKC-dependent pathway
Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H29 - H36.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
Q. Xu, E. D. Lekgabe, X.-M. Gao, Z. Ming, G. W. Tregear, A. M. Dart, R. A. D. Bathgate, C. S. Samuel, and X.-J. Du
Endogenous Relaxin Does Not Affect Chronic Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis
Endocrinology, February 1, 2008; 149(2): 476 - 482.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
L. De Luca, A. Mebazaa, G. Filippatos, J. T. Parissis, M. Bohm, A. A. Voors, M. Nieminen, F. Zannad, A. Rhodes, A. El-Banayosy, et al.
Overview of emerging pharmacologic agents for acute heart failure syndromes
Eur J Heart Fail, February 1, 2008; 10(2): 201 - 213.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
X.-l. Moore, S.-l. Tan, C.-y. Lo, L. Fang, Y.-D. Su, X.-M. Gao, E. A. Woodcock, R. J. Summers, G. W. Tregear, R. A. D. Bathgate, et al.
Relaxin Antagonizes Hypertrophy and Apoptosis in Neonatal Rat Cardiomyocytes
Endocrinology, April 1, 2007; 148(4): 1582 - 1589.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Kupari, M.
Right arrow Articles by Lommi, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kupari, M.
Right arrow Articles by Lommi, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?