Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 27  |  Issue : 2  |  Page : 497-502

Plasma urotensin II as a marker for severity of rheumatic mitral regurgitation


1 Department of Biochemistry, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
2 Department of Cardiology, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
3 Department of Cardiology, Nasser Institute Hospital, Egypt

Date of Submission20-Jul-2013
Date of Acceptance19-Jan-2014
Date of Web Publication26-Sep-2014

Correspondence Address:
Ibrahim Elmadbouh
MD, PhD, Biochemistry Department, Faculty of Medicine, Menoufiya University, Yassin Abdel-Ghaffar St, Shebin El-Kom, Menoufiya
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.141736

Rights and Permissions
  Abstract 

Objectives
The aim of the present study was to measure plasma urotensin II concentrations in patients with rheumatic mitral regurgitation, and to examine its correlation with severity of valve impairment, function [New York Heart Association (NYHA)] class, and pulmonary artery pressure (PAP).
Background
Urotensin II is mainly regarded as a cardiovascular autacoid/hormone; it is associated with different cardiovascular diseases. It might have a pathophysiological role in heart valve disease.
Patients and methods
A total of 35 patients with moderate-to-severe rheumatic mitral valve regurgitation and 20 healthy controls were selected after performing the echocardiography. Plasma urotensin II level was measured for all participants.
Results
Urotensin II level was highly significant in patients with mitral valve regurgitation (1.83 ± 0.92 ng/ml) versus the controls (0.48 ± 0.13 ng/ml, P < 0.001). In addition, there was a significant positive correlation between urotensin II level and left ventricular end-diastolic diameter (LVEDD) (r = 0.318, P = 0.03) and PAP (r = 0.706, P < 0.001), but there was no significant correlation between urotensin II level and left ventricular end-systolic diameter (r = 0.271, P = 0.115). Linear regression analysis of LVEDD (r2 linear = 0.101, P < 0.05) and PAP (r2 linear = 0.498, P < 0.001), two among the multiple echocardiographic parameters that predict elevated urotensin II level, was carried out.
Conclusion
Urotensin II was found to be elevated in patients with rheumatic mitral regurgitation, and positively correlated with increased LVEDD and PAP. Elevation of LVEDD and PAP was found to have a strong prediction for the elevated level of urotensin II. Therefore, urotensin II level may be used as a diagnostic and prognostic marker for severity in patients with rheumatic mitral valvular diseases.

Keywords: Cardiovascular autacoid/hormone, mitral regurgitation, urotensin II


How to cite this article:
Elmadbouh I, Soliman MA, Elhameed AF, Kamal AM. Plasma urotensin II as a marker for severity of rheumatic mitral regurgitation. Menoufia Med J 2014;27:497-502

How to cite this URL:
Elmadbouh I, Soliman MA, Elhameed AF, Kamal AM. Plasma urotensin II as a marker for severity of rheumatic mitral regurgitation. Menoufia Med J [serial online] 2014 [cited 2020 Feb 17];27:497-502. Available from: http://www.mmj.eg.net/text.asp?2014/27/2/497/141736


  Introduction Top


Human urotensin II is an 11 amino-acid cyclic peptide and is expressed in most tissue organs of the body, including the heart and blood vessels, suggesting that urotensin II has a role in cardiovascular diseases [1]. Human urotensin II is the most potent vasoconstrictor, and more potent than endothelin-1, and acts through a G-protein-coupled receptor [1],[2]. Urotensin II and urotensin II receptors are upregulated in a number of cardiovascular disease states, implicating the urotensin II system in the pathogenesis and progression of cardiovascular diseases [3].

Urotensin II has pleiotropic effects within the cardiovascular system, with evidence for modulation of cardiac contractility, vascular tone, cell proliferation, and cell growth. Recent studies have suggested that urotensin II may have a protective effect on the cardiovascular system, whereas others implicate urotensin II as a harmful mediator [4]. Evidence suggests that the condition of the vascular endothelium is a key determinant in how the cardiovascular system responds to urotensin II [1],[4].

In the developing countries of the world, rheumatic fever and rheumatic valve disease (RVD) remain among the significant medical and public health problems [5],[6],[7].

Considerable numbers of young adults are in need of valve surgery. The primary consideration in the management of adults with valvular heart disease is the status of the symptom, emphasizing the importance of the clinical history. Besides assessment of valve anatomy, careful monitoring of the symptoms because of chronic RVD is important during follow-up [6].

Furthermore, echocardiographic screening of asymptomatic patients who have severe RVD remains the best tool for risk stratification and surgical indication. Attentive echocardiographic evaluation for objective signs of severity and complications of valve disease is recommended for patients with doubtful symptoms [7],[8].

Recently, the chronic phase of RVD is associated with ongoing plasma inflammatory mediators (e.g. atrial and brain natriuretic peptides), which correlate strongly with the severity of valve involvement, valve scarring, subsequent valve calcification, and decreasing New York Heart Association (NYHA) class [8].

Many studies have been conducted on the cardiovascular relation of urotensin II and documented elevated plasma urotensin II level in congestive heart failure [9],[10],[11], coronary artery disease [2,3], and hypertension [1].

However, the role of plasma urotensin II level in patients with the RVD was not yet clear [12]. The present study was conducted to measure plasma urotensin II concentrations in patients with rheumatic mitral regurgitation, and to examine its correlation with the severity of valve impairment, function (NYHA) class, and pulmonary artery pressure (PAP).


  Patients and methods Top


This study was conducted to detect plasma urotensin II in patients with rheumatic mitral regurgitation at the Cardiology Department of Menoufiya University Hospital and Nasser Institute Hospital, Cairo, Egypt, from March 2011 to February 2012.

Inclusion criteria

A total of 35 patients with isolated rheumatic mitral valve regurgitation, and another 20 healthy controls after performing echocardiography, were included in this study.

Exclusion criteria

The exclusion criteria included any concomitant valve lesion (e.g. aortic valve disease), more than mild mitral stenosis, ischemic heart disease, severe systolic heart failure, and any other congenital heart disease.

Written informed consent was obtained from all patients included in this study and they were subjected to the following: full history taking, complete general and local examination of the heart, chest, and abdomen, and ECG. In addition, blood samples were evaluated for plasma urotensin II concentration.

Echocardiographic study

Full M-mode, two-dimensional, and Doppler echocardiographic study was conducted on all patients included in the study, using GE vivid III echocardiography machine. Four-chamber, five-chamber, and two-chamber apical views were obtained. Parasternal long-axis and short-axis views were also obtained.

Plasma urotensin II measurement

Human plasma urotensin II was measured by an enzyme-linked immunoassay method. A specific and sensitive enzyme-linked immunoassay kit was used for this assay (Phoenix Pharmaceutical Inc., California, USA). The intra-assay and interassay coefficients of variations were less than 15% and less than 5%, respectively. The minimum detectable concentration was 0.06 ng/ml. There was no cross-reactivity with endothelin-1, angiotensin II, PAMP-20, I-ANP-28, bradykinin, and neurotensin, but there was less than 15.7% cross-reactivity with urotensin II-related peptides.

Blood samples were collected into Lavender vacutainer tubes, which contained EDTA and aprotinin (0.6 IU/ml of blood). Then, plasma was stored at -70°C until the day of the assay (not exceeding 20 days). Plasma extraction and assay of urotensin II was performed according to the manufacturer's instructions. The standard peptide was solved in the assay buffer that contained NaH 2 PO 4 , Na 2 HPO 4 , NaCl, EDTA, BSA, and sodium azide [10]. A standard curve was obtained from the known concentrations of standard peptide on the log scale (x-axis), and its corresponding optical density reading (carried out at 450 nm) on the linear scale (y-axis). There was negligible difference with regard to optical properties at the actual wavelength between the medium for standards and the plasma extract. The concentration of urotensin II in a sample was determined by locating its optical density on the y-axis, and then drawing a horizontal line to intersect with the standard curve. From this point, a vertical line was drawn to intersect the x-axis, and the urotensin II concentration of the sample was calculated. If necessary, samples were diluted before the assay, and then the measured concentration was multiplied by their respective dilution factors.

Statistical analysis

Data of all patients were collected and fed to the computer and analyzed using statistical package SPSS for PC version 16.5. Descriptive statistics were calculated using mean and SD for continuous variables and percentage for categorical variables. Nonpaired Student's t-test was conducted to find out the presence of significant difference between groups in continuous variables. c2 -Test was conducted to find out the presence of significant difference between groups in categorical variables [11]. Pearson correlation coefficient was carried out to find out the presence of significant correlation between urotensin II and the different parameters. P-value less than 0.5 was considered significant with a confidence interval of 95%.


  Results Top


This study was conducted on 35 patients with rheumatic mitral regurgitation and another 20 age-matched and sex-matched healthy controls.

[Table 1] shows that the mean age of the studied patients was 42 ± 4.2 years; there were 15 male (42.8%) and 20 female (57.2%) patients. Of the 35 patients, 20 (57.1%) had atrial fibrillation, and no one was in NYHA class I or IV, but 18 patients (51.4%) had NYHA class II, and 17 patients (48.6%) had NYHA class III.
Table 1: General and demographic characteristics of all participants

Click here to view


In the healthy control group, their mean age was 42.4 ± 3.3 years; there were nine male (45%) and 11 female (55%) patients. All patients of this group were in sinus rhythm and they were apparently healthy individuals.

There was no significant difference between the two groups regarding their mean age or their sex distribution (P > 0.05).

The PAP, left atrial dimension, left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) were significantly higher among the patient group than that of the healthy controls (P < 0.001). Ejection fraction was significantly lower among the patient group than that of the healthy controls (P < 0.001) [Table 2].
Table 2: Echocardiographic study of all participants

Click here to view


The mean urotensin II level among the studied patients was 1.83 ± 0.92 ng/ml, and it was 0.48 ± 0.13 ng/ml for the controls. The difference between the two groups was highly significant (P < 0.001) [Table 3].
Table 3: Urotensin II level among the studied patients and controls

Click here to view


There was a significant positive correlation between urotensin II level and LVEDD (r = 0.318, P = 0.03). However, there was no significant correlation with LVESD (r = 0.271, P = 0.115). There was no significant correlation between urotensin level and the clinical or other echocardiographic parameters [Table 4].
Table 4: Pearson correlation between urotensin II level and the different studied parameters among patients with mitral regurgitation

Click here to view


Our results showed that the linear regression analysis of PAP (r2 linear = 0.498, P < 0.001) [Figure 1]a and LVEDD (r2 linear = 0.101, P < 0.05) [Figure 1]b, two among the multiple echocardiographic factors that predict elevated urotensin II level, was carried out.
Figure 1:

Click here to view



  Discussion Top


Human urotensin II has several cardiovascular actions, including potent vasoactive, and cardiac inotropic and hypertropic properties [13].

Altered plasma concentrations of urotensin II in diseases, such as heart failure, essential hypertension, renal disease, diabetes, and liver cirrhosis [14], have raised the notion that urotensin II may be a useful biomarker in detecting disease onset or progression [15].

This study was conducted on 35 patients with rheumatic mitral regurgitation, and another 20 age-matched and sex-matched healthy controls.

Results of the current study showed that the mean age of the studied patients was 42 ± 4.2 years; there were 15 male (42.8%) and 20 female (57.2%) patients. Of the patients, 20 (57.1%) had atrial fibrillation, and no one was in NYHA class I or IV; however, 18 patients (51.4%) had NYHA class II and 17 patients (48.6%) had NYHA class III.

In the healthy control group, their mean age was 42.4 ± 3.3 years, they were nine male (45%) and 11 female (55%). All patients of this group were in sinus rhythm and they did not complain of any degree of dyspnea. There was no significant difference between the two groups regarding their mean age or their sex distribution (P > 0.05).

Results of the current study showed that the PAP, left atrial dimension, LVEDD, and LVESD were significantly higher among the patient group than that of the healthy controls (P < 0.001). Ejection fraction was significantly lower among the patient group than that of the healthy controls (P < 0.001).

Our results showed that the mean urotensin II level among the studied patients was 1.83 ± 0.92 ng/ml, and it was 0.48 ± 0.13 ng/ml for the controls. The difference between the two groups was highly significant (P < 0.001).

Our results are in agreement with the study by Ozer et al. [12] who studied 71 patients with RVD (mean age 40 ± 12 years, 17 female patients) and 25 normal individuals (mean age 40 ± 7 years, eight female patients). They assessed their NYHA functional class, RVD severity and PAP, and measured plasma urotensin II levels. They found that urotensin II level was significantly higher in patients with rheumatic heart disease.

The present study showed that there was a significant positive correlation between urotensin II level and PAP (r = 0.706, P < 0.001); there was also a significant positive correlation with LVEDD (r = 0.318, P = 0.03). There was no significant correlation between urotensin level and the other clinical or echocardiographic parameters. In addition, linear regression analysis of PAP (r2 linear = 0.498, P < 0.001) and LVEDD (r2 linear = 0.101, P < 0.05), two among the multiple echocardiographic factors that predict elevated urotensin II level, was carried out.

These results are in agreement with the study by Ozer et al. [12] who found that urotensin II was significantly correlated with mitral regurgitation (r = 0.226, P = 0.02), PAP (r = 0.320, P = 0.01), and NYHA class (r = 0.213, P = 0.03). There was a positive correlation between urotensin II levels and severity of mitral regurgitation (r = 0.248, P = 0.01). In the linear regression analysis, only PAP was predictive of urotensin II (b = 0.3, P = 0.02). They concluded that plasma urotensin II is elevated in chronic RVD, associated with severe mitral and tricuspid valve regurgitation. Furthermore, urotensin II level is correlated with NYHA functional class, and the increase in PAP is predictive of plasma urotensin II.

The LVEDD was found to be a predictive of urotensin II level in this study and these results are not in agreement with the results of the study by Ozer et al. [12]; moreover, this difference may be owing to the fact that our patients had a more dilated left ventricular dimensions and more impaired left ventricular systolic function.

Our results also agreed with the study by Douglas et al. [16], who studied the expression of myocardial urotensin II in patients with heart failure. They found a strong expression of urotensin II in the cardiomyocytes and, to a lesser extent, in the vascular smooth muscle cells of patients with CHF. They also found that the myocardial expression of urotensin II correlated significantly with LVEDD (P = 0.0092) and inversely with ejection fraction (P = 0.0002). They suggested a possible role of urotensin II in the cardiac dysfunction and remodeling characteristic of CHF.

Quaile et al. [17] also found that urotensin II is an endogenous peptide upregulated in failing hearts. To date, insights into the myocardial actions of urotensin II have been obscured by its potent vasoconstrictor effects and interspecies differences in physiological responses to urotensin II. They examined the direct effects of exogenous urotensin II on in-vitro contractility in nonfailing and failing human myocardial trabeculae. They found that urotensin II modulates contractility independent of vasoconstriction with opposite effects in failing and nonfailing hearts. Positive inotropic responses to urotensin II alone suggests that increased endogenous urotensin II constrains contractility in the failing hearts through an autocrine and/or paracrine mechanism. These findings support a potential therapeutic role for urotensin II in heart failure.

Our results showed that pulmonary hypertension was a strong predictor of urotensin II level and this could be explained by that urotensin II was quickly revealed to be a very potent vasoconstrictor. The action of urotensin II was found to be independent of endothelial cells and to work through the mobilization of intracellular calcium as well as through the stimulation of extracellular calcium influx [18].

As mentioned above, the actions of urotensin II in the pulmonary circulation are quite variable {19}. These variations at different levels of the pulmonary circulation make it difficult to understand the role of urotensin II in pulmonary hypertension.

Limitations and recommendations of the study

The present study indicates that urotensin II level may have a diagnostic and prognostic role in the pathophysiology of rheumatic heart disease and myocardial damage associated with valvular affection. This study consisted of relatively small number of patients. Therefore, it is recommended to have further studies with larger groups of patients to assess the relation between urotensin II and severity of all valvular lesions. It would be attractive to demonstrate the relationship between urotensin II and plasma N-terminal brain natriuretic peptide in the same sample.


  Conclusion Top


Urotensin II was found to be elevated in patients with rheumatic mitral regurgitation, positively correlated with increased in LVEDD and pulmonary hypertension. The elevation of LVEDD and pulmonary hypertension was found to have a strong prediction for the elevated level of urotensin II.

Our results indicated that urotensin II level may have a diagnostic and prognostic role in the pathophysiology of rheumatic heart disease and myocardial damage associated with valvular affection.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.Cheung BM, Leung R, Man YB, Wong LY. Plasma concentration of urotensin II is raised in hypertension. J Hypertens 2004; 22 :1341-1344.  Back to cited text no. 1
    
2. Khan SQ, Bhandari SS, Quinn P, Davies JE, Ng LL. Urotensin II is raised in acute myocardial infarction and low levels predict risk of adverse clinical outcome in humans. Int J Cardiol 2007; 117 :323-328.  Back to cited text no. 2
    
3. Pakala R. Role of urotensin II in atherosclerotic cardiovascular diseases. Cardiovasc Revasc Med 2008; 9 :166-178.  Back to cited text no. 3
    
4. Russell FD. Urotensin II in cardiovascular regulation. Vasc Health Risk Manag 2008; 4 :775-785.  Back to cited text no. 4
    
5. Marcus RH, Sareli P, Pocock WA Barlow JB. The spectrum of severe rheumatic mitral valve disease in a developing country: correlations among clinical presentation, surgical pathologic findings, and hemodynamic sequelae. Ann Intern Med 1994; 120 :177-183.  Back to cited text no. 5
    
6. Rizvi SF, Khan MA, Kundi A, Marsh DR, Samad A, Pahsa O. Status of rheumatic heart disease in rural Pakistan. Heart 2004; 90 :394-399.  Back to cited text no. 6
    
7. Ozer O, Davutoglu V, Sari I, Akkoyun DC, Sucu M. The spectrum of rheumatic heart disease in the Southeastern Anatolia endemic region: results from 1,900 patients. J Heart Valve Dis 2009; 18 :68-72.  Back to cited text no. 7
    
8. Sari I, Davutoglu V. Association of chronic subclinical inflammation with severity and progression of rheumatic valve disease. Int J Cardiol 2008; 124 :263.  Back to cited text no. 8
    
9. Ng LL, Loke I, O′Brien RJ, Squire IB, Davies JE. Plasma urotensin in human systolic heart failure. Circulation 2002; 106 :2877-2880.  Back to cited text no. 9
    
10.Richards AM, Nicholls MG, Lainchbury JG, Fisher S, Yandle TG. Plasma urotensin II in heart failure. Lancet 2002; 360 :545-546.  Back to cited text no. 10
    
11.Krüger S, Graf J, Kunz D, Stickel T, Merx MW, Hanrath P, Janssens U. Urotensin II in patients with chronic heart failure. Eur J Heart Fail 2005; 7 :475-478.  Back to cited text no. 11
    
12.Ozer O, Davutoglu V, Sari I, Akkoyun DC, Sucu M. Plasma urotensin II as a marker for severity of rheumatic valve disease. Tohoku Exp Med 2009; 218 :57-62.  Back to cited text no. 12
    
13.Douglas SA, Dhanak D, Johns DG. From ′gills to pills′: urotensin-II as a regulator of mammalian cardiorenal function. Trends Pharmacol Sci 2004; 25 :76-85.  Back to cited text no. 13
    
14.Carmine Z, Mallamaci F. Urotensin II: a cardiovascular and renal update. Curr Opin Nephrol Hypertens 2008; 17 :199-204.  Back to cited text no. 14
    
15.Jarolim P. Serum biomarkers for heart failure. Cardiovasc Pathol 2006; 15 :144-149.  Back to cited text no. 15
    
16.Quaile MP, Kubo H, Kimbrough CL, Douglas SA, Margulies KB. Direct inotropic effects of exogenous and endogenous urotensin-II: divergent actions in failing and nonfailing human myocardium. Circ Heart Fail 2009; 2 :39-46.  Back to cited text no. 16
    
17.Gardiner SM, March JE, Kemp PA, Davenport AP, Bennett T. Depressor and regionally-selective vasodilator effects of human and rat urotensin II in conscious rats. Br J Pharmacol 2001; 132 :1625-1629.  Back to cited text no. 17
    
18.MacLean M, Alexander D, Stirrat A, et al. Contractile responses to human urotensin-II in rat and human pulmonary arteries: effect of endothelial factors and chronic hypoxia in the rat. Br J Pharmacol 200013:201-204.  Back to cited text no. 18
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Patients and methods
Results
Discussion
Conclusion
Acknowledgements
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed618    
    Printed9    
    Emailed0    
    PDF Downloaded62    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]