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European Journal of Heart Failure 2004 6(6):757-760; doi:10.1016/j.ejheart.2004.04.018
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© 2004 European Society of Cardiology

Plasma brain natriuretic peptide levels in patients with rheumatic heart disease

Zehra Gölbaþya,*, Özgül Uçarb, Ayse Geçer Yükselb, Okan Gülelb, Sinan Aydogdub and Vasfi Ulusoyb

a Department of Cardiology, Ankara Türkiye Yüksek Ihtisas Hospital Attar sok. No: 14/3, GOP, 06700, Ankara, Turkey
b Department of Cardiology, Ankara Numune Education and Research Hospital Ankara, Turkey

* Corresponding author. Tel.: +90-532-632-8480; fax: +90-312-310-3460.. E-mail address: zgolbasi{at}hotmail.com


   Abstract
Top
 Abstract
1. Background
 2. Aims
 3. Methods
 4. Results
 5. Discussion
 References
 
Background: Brain natriuretic peptide (BNP) is a cardiac hormone secreted from the ventricular myocardium as a response to ventricular volume expansion and pressure overload. Rheumatic heart disease (RHD) is still an important cause of heart failure in developing countries.

Aims: To measure BNP levels in patients with RHD and to determine whether BNP concentrations correlate with clinical and echocardiographic findings.

Methods: Eighty-eight patients with rheumatic valve disease and 24 age- and sex-matched healthy subjects were entered in the study. BNP was measured using the Triage B-Type Natriuretic Peptide test (Biosite Diagnostics, San Diego, CA). Transthoracic echocardiography was performed in all patients to assess the severity of the valve disease and for the measurement of pulmonary artery pressure.

Results: The plasma concentrations of BNP were significantly higher in patients with rheumatic heart disease than in control subjects (232±294 vs. 14±12 pg/ml, p<0.0001). The plasma BNP level was significantly higher in NYHA class III+IV than in class II (463±399 vs. 192±243 pg/ml, p<0.0001) and in NYHA class II than in class I (192±243 vs. 112±135 pg/ml, p<0.001). The independent determinants of higher BNP levels were NYHA functional class and systolic pulmonary artery pressure in multivariate analysis.

Conclusion: We found increased plasma BNP levels in patients with rheumatic heart disease compared with healthy subjects.

Key Words: Brain natriuretic peptide • Mitral stenosis • Rheumatic heart disease • Atrial fibrillation

Received June 27, 2003; Revised February 10, 2004; Accepted April 22, 2004


   1. Background
Top
 Abstract
 1. Background
2. Aims
 3. Methods
 4. Results
 5. Discussion
 References
 
Human brain natriuretic peptide (BNP) is thought to be mainly produced from the ventricular myocardium [1,2]. BNP has diuretic, natriuretic, and vasodilator activities [3]. It has been reported that plasma BNP levels are increased in states of left ventricular overload, such as left ventricular failure or left ventricular hypertrophy [4,5]. Rheumatic heart disease (RHD) is still an important cause of heart failure in developing countries. Although there are a few studies of BNP levels in patients with mitral stenosis [6–8], to our knowledge, no previous study has systematically assessed the levels of BNP and the factors stimulating BNP secretion in rheumatic heart disease.


   2. Aims
Top
 Abstract
 1. Background
 2. Aims
3. Methods
 4. Results
 5. Discussion
 References
 
The aims of this study were (1) to measure BNP levels in patients with rheumatic heart disease and (2) to determine whether BNP concentrations correlate with clinical and echocardiographic findings.


   3. Methods
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
4. Results
 5. Discussion
 References
 
The investigation conforms with the principles outlined in the Declaration of Helsinki. The protocol was approved by the local ethics committee, and written informed consent was obtained from each patient before entry into the study.

3.1. Patients
A total of 91 patients with chronic rheumatic heart disease were enrolled; however, three patients had a previous history of myocardial infarction and/or electrocardiographic findings of myocardial infarction and were therefore excluded from the study. Eighty-eight patients (66 women, 22 men; mean age: 43.0±15.0 years, range: 15–80) were assessed. Six (7%) patients had isolated mitral stenosis, 7 (8%) patients had isolated mitral regurgitation, 13 (15%) patients had combined mitral stenosis and mitral regurgitation, and 62 (70%) patients had combined mitral and aortic valve disease. Tricuspid stenosis was detected in one patient and ejection fraction was measured below 45% in two patients, all had combined mitral and aortic valve disease. Atrial fibrillation was detected in 29 (33%) patients. Patients were stratified according to baseline functional class: 27 (31%) patients were NYHA class I, 40 (45%) patients were NYHA class II, 19 (22%) patients were NYHA class III, and 2 (2%) patients were NYHA class IV.

The control group consisted of 24 healthy, age- and gender-matched subjects (17 women, 7 men; mean age 42±13 years).

3.2. Brain natriuretic peptide measurement
Blood samples were collected by venipuncture into tubes containing potassium EDTA. The blood samples were analyzed within half an hour of the draw time. Before analysis, each tube was inverted several times to ensure homogeneity. BNP was measured using the Triage B-Type Natriuretic Peptide test (Biosite Diagnostics). The test is self-processing and produces a result within 15 min. The detection range of the BNP assay is 5–1300 pg/ml. The precision, analytic sensitivity, and stability characteristics of this system have been previously described [9,10].

3.3. Echocardiographic measurement
Echocardiographic examination was performed by experienced sonographers using a GE Vingmed System FiVe ultrasound machine. M-mode, two-dimensional, and Doppler echocardiograms were obtained with the subjects in the left lateral decubitis position. Left ventricular and left atrial dimensions were measured in the parasternal long axis view. M-mode left ventricular diastolic dimension was measured at the onset of QRS complex and from the leading edge of the interventricular septum to the leading edge of the posterior wall according to American Society of Echocardiography recommendations [11]. End-systolic dimension was measured from peak downward motion of the interventricular septum. Left ventricular end-diastolic diameter greater than 56 mm or 31 mm/m2 and end-systolic diameter greater than 40 mm or 21 mm/m2 were defined as dilatation. Left ventricular ejection fraction was obtained by the Teichholz equation. Left ventricular dimensions were measured by two-dimensional echocardiography when M-mode beam was not perpendicular to walls [12]. Interventricular wall thickness was measured from the leading edge of the left septal echo to the trailing edge of the right septal echo and posterior left ventricular wall thickness was measured from the leading edge of the endocardium to the leading edge of the epicardium at the R wave of the electrocardiogram. The right ventricle was defined as dilated if the diastolic diameter, obtained from the parasternal long axis view by M-mode echocardiography, exceeded 20 mm/m2. When M-mode measurements were not available, right ventricular area equal or greater than left ventricular area in apical four chamber view was accepted as right ventricular dilatation. Left atrial diameter was measured by two-dimensional echocardiography from the parasternal long axis view from trailing edge to leading edge, a left atrial diameter greater than 40 mm was accepted as enlargement. Rheumatic valvular disease was diagnosed based on echocardiographic detection of typical B-mode features, such as thickening of valve leaflets and chordal apparatus, restricted leaflet seperation, diastolic doming of the anterior mitral leaflet, commisural fusion or M-mode detection of diminished mitral E–F slope, and upward movement of posterior mitral leaflet in early diastole [13]. Mitral stenosis was quantified by planimetry of two-dimensional images, Doppler measurement of transvalvular gradients, and estimation of valve area by the pressure half-time method [14–16]. Doppler methods including assessment of regurgitant jet characteristics (length, height, area, and width at the vena contracta) were used in the assessment of the severity of valvular regurgitation [17]. Tricuspid stenosis was quantified by Doppler measurement of transvalvular gradients and estimation of valve area by the pressure half-time method [18]. Aortic stenosis was quantified by Doppler measurements of transvalvular gradients and estimation of valve area by the continuity method [19]. The maximal velocity of tricuspid regurgitant jet was assessed by continuous wave Doppler echocardiography from a low parasternal, long-axis view of the right ventricular inflow or apical and subcostal views. The pressure gradient between the right ventricle and right atrium was calculated by applying the Bernoulli equation [20]. An estimate of right atrial pressure by use of phasic respiratory inferior vena caval dimensions was added to the transtricuspid gradient in order to calculate peak pulmonary artery systolic pressure [21]. Pulmonary hypertension was diagnosed if pulmonary artery systolic pressure was over 35 mm Hg. Measurements represent an average of three beats for patients in sinus rhythm and 10 beats for patients in atrial fibrillation.

3.4. Statistics
Data were analysed using SPSS for Windows statistical package and are presented as mean±SD. Differences between mean values were analysed by Student's unpaired t-test. Univariate comparisons between groups were made with nonparametric tests: Kruskal–Wallis tests for multigroup comparisons and Mann–Whitney tests for two-group comparisons. Linear and nonparametric regression was used as appropriate with BNP levels as the dependent variable and age, gender, presence of atrial fibrillation, NYHA class, left ventricular ejection fraction, left and right atrial and right ventricular diameters, and systolic pulmonary artery pressure as independent variables. The chi-square test and Fischer's probability test were used to compare proportions. Differences were considered significant when p<0.05.


   4. Results
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
5. Discussion
 References
 
Patient characteristics including severity of valvular disease are shown in Table 1. The plasma concentrations of BNP were significantly higher in patients with rheumatic heart disease than in control subjects (232±294 vs. 14±12 pg/ml, p<0.0001). Compared to patients with only mitral valve lesion, patients with multivalvular disease had significantly higher plasma BNP levels (284±329 vs. 109±140 pg/ml, p<0.001). Patients with pure mitral stenosis had higher BNP concentrations compared with healthy subjects (86±48 vs. 14±12 pg/ml, p<0.001). The plasma BNP concentration of patients with aortic stenosis was also significantly higher than that in the patients without aortic stenosis (390±362 vs. 197±267 pg/ml, p<0.01). There were only two patients who had systolic dysfunction. The mean BNP value of these patients was high (799±192 pg/ml). There was no correlation between BNP concentration and ejection fraction in patients with normal ejection fraction (r=–0.114). The plasma BNP level was significantly higher in NYHA class III+IV than in class II (463±399 vs. 192±243 pg/ml, p<0.0001) and in NYHA class II than in class I (192±243 vs. 112±135 pg/ml, p<0.001). BNP concentration was significantly higher in patients with atrial fibrillation than in patients with sinus rhythm (382±340 vs. 158±239 pg/ml, p<0.0001). There were statistically significant associations between higher levels of BNP and left atrial dilatation (p<0.0001), left ventricular dilatation (p<0.01), right ventricular dilatation (p<0.05), right atrial dilatation (p<0.0001), and pulmonary hypertension (p<0.0001). Positive correlation was observed between severity of systolic pulmonary artery pressure and plasma BNP levels (r=0.465) (Fig. 1). The independent determinants of higher BNP levels were NYHA functional class and systolic pulmonary artery pressure in multivariate analysis. No correlation was found between plasma BNP levels and severity of regurgitant lesion (r=0.233).


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  		Table 1 Patient characteristics (n=88)

 


Figure 1
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  		Fig. 1 Bar graph illustrating correlation between echocardiographic peak pulmonary artery systolic pressure and plasma BNP levels. sPAP=systolic pulmonary artery pressure.

 

   5. Discussion
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Discussion
References
 
In this cross-sectional study of patients with rheumatic heart disease, we found that the plasma concentration of BNP was significantly increased compared with healthy subjects. The independent determinants of higher BNP levels were NYHA functional class and systolic pulmonary artery pressure in multivariate analysis.

The plasma level of BNP is elevated in patients with congestive heart failure and increases in proportion with the degree of left ventricular dysfunction and the severity of symptoms of heart failure [4,22]. In our study, plasma BNP was increased in NYHA class I patients and continued to increase in more advanced stages. However, there was an overlap in BNP levels between the NYHA classification groups. This overlap may be due to subjectivity of the NYHA classification system.

The plasma BNP concentration of patients with aortic stenosis was found to be significantly higher than that of patients without aortic stenosis. The elevated afterload (by increasing left ventricular systolic wall stress) seems to be the principal stimulus for BNP secretion in patients with aortic stenosis.

The plasma levels of BNP in patients with pure mitral stenosis were found to be higher than that of healthy subjects. Although the amount of BNP secreted from the atria is very small compared to that from the ventricles in patients with congestive heart failure, BNP is also secreted from the atria [2,23,24]. In a study of patients with isolated right ventricular overload, it was demonstrated that plasma BNP levels increased in proportion to the extent of right ventricular dysfunction in pulmonary hypertension [25]. BNP might also be released from atrial and right ventricular tissue in our patients with pure mitral stenosis.

The BNP levels of patients with atrial fibrillation were found to be significantly higher than for patients in sinus rhythm. This may be due to left atrial enlargement, hemodynamic impairment, or other hormonal alteration. In our study, patients with atrial fibrillation had greater left atrial diameter and higher NYHA functional class than patients in sinus rhythm.

BNP levels may be used as a complementary tool to the clinical and echocardiographic evaluation of patients with rheumatic heart disease. Further prospective studies are needed to establish the importance of BNP in the follow up and management of patients with rheumatic heart disease.


   References
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Discussion
 References
 

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