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European Journal of Heart Failure 2005 7(4):532-536; doi:10.1016/j.ejheart.2004.07.006
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© 2005 European Society of Cardiology

Plasma NT-proBNP is a potential marker of disease severity and correlates with symptoms in patients with chronic rheumatic valve disease

Vedat Davutoglua,*, Ahmet Celikb, Mehmet Aksoya, Yusuf Sezena, Serdar Soydinca and Nurullah Gunayc

a Department of Cardiology, School of Medicine, Sahinbey Medical Center, Gaziantep University Guneykent mah. Besyuzevler sitesi 7.Blok. Daire: 10, TR-27310-Sahinbey/Gaziantep, Turkey
b Department of Clinical Biochemistry, School of Medicine, Sahinbey Medical Center Gaziantep University, Gaziantep, TR-27310, Turkey
c Department of Emergency Medicine, School of Medicine, Sahinbey Medical Center Gaziantep University, Gaziantep, TR-27310, Turkey

* Corresponding author. Tel.: +90 342 3606060x7507; Fax: +90 342 3603928. E-mail address: davutoglu{at}gantep.edu.tr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: A noninvasive marker of disease severity and presence of symptoms is required in patients with chronic rheumatic valve disease (RVD).

Aims: We sought to test the utility of measuring of N-terminal pro-B type natriuretic peptide (NT-proBNP) in chronic phase RVD. We also evaluated whether echocardiographic measures are interrelated with NT-proBNP levels.

Methods: The study comprised 92 patients with RVD (mean age of 40–14 years) and 50 age/gender-matched control subjects. Functional status was assessed. Detailed echocardiographic examination was performed and mitral valve score was estimated. Venous blood samples were taken for measuring the level of NT-proBNP.

Results: The plasma levels of NT-proBNP rose with increasing severity of mitral valve stenosis (p<0.001), increasing severity of mitral valve score (p<0.001), increasing severity of clinical symptom (p<0.001), increasing severity of mitral regurgitation (p<0.013), presence of mitral valve calcification (p<0.001), presence of tricuspid valve stenosis (p<0.001), increasing severity of tricuspid regurgitation (p<0.011), presence of aortic stenosis (p=0.043), decreasing left ventricular ejection fraction (p<0.001), presence of left atrial thrombus (p=0.0019), and with increasing left atrium dimensions (p=0.002).

Conclusion: NT-proBNP levels in patients with chronic RVD are a potential marker of disease severity and correlates with symptoms.

Key Words: Rheumatic valve disease • NT-proBNP • Mitral valve score • Echocardiography • Functional status

Received April 25, 2004; Revised June 12, 2004; Accepted July 12, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic rheumatic valve disease (RVD) is increasing in incidence and prevalence in developing countries, where rheumatic fever remains a major unresolved health problem [1]. The onset of symptoms is a critical point in the natural history of RVD and is also the most important indication for valve replacement. In the present study, we evaluated N-terminal pro-B type natriuretic peptide (NT-proBNP) levels in patients with chronic RVD as a potential marker of disease severity and the presence of symptoms.

In many patients, the development of symptoms is clear, but in others, symptoms are difficult to assess because of inactivity. In some patients, it may also be unclear whether symptoms are related to RVD. A noninvasive marker of early cardiac decompensation would therefore be helpful in monitoring disease progression in patients with RVD. The most commonly applied investigation to confirm the diagnosis of RVD is echocardiography [2], which offers structural and functional information about the heart. Recent ACC/AHA guidelines for the management of heart failure have emphasized the need for earlier identification and therapy for patients at high-risk of developing heart failure or asymptomatic left ventricular systolic dysfunction as well as those with symptomatic heart failure [3]. The American College of Cardiology and American Heart Association recommend surgery for severe rheumatic valve disease (regurgitation or stenosis) if symptoms occur or if there is evidence of asymptomatic LV dysfunction [2]. However, difficulties in detecting early LV dysfunction, accurately assessing the severity of valve involvement, or recognizing early cardiac symptoms can make it difficult to determine the optimal timing of mitral valve surgery [4]. Measurement of brain natriuretic peptide (BNP) has become a potent diagnostic aid for identifying patients with systolic or diastolic dysfunction and in some valvular heart disease [5,6]. Many publications describe BNP as an excellent marker of LV function and a simple and effective tool to detect heart failure or LV dysfunction. Recently, NT-proBNP was introduced, as a more discerning marker for the detection and evaluation of heart failure than BNP [7]. Because of its longer half-life, a higher sensitivity to detect early stage of LV dysfunction has been proposed for NT-proBNP [7]. To our knowledge, there is currently no information available concerning the use of single or serial measurements of plasma NT-proBNP in therapeutic decision making in patients with chronic RVD. In the context of echocardiographic measures, establishing functional class, which is best determined with plasma BNP, is the most important parameter for modulating therapy in patients with RVD. We therefore sought to test the utility of measuring of NT-proBNP in chronic phase RVD. We also evaluated whether echocardiographic measures are interrelated with NT-proBNP.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Patients with RVD referred to a single cardiac center for echocardiography between June 2003 and November 2003, who met the entry criteria for the study, were invited to participate. Ninety-two patients with RVD on the screening echocardiogram were enrolled in the study. Fifty normal subjects without echocardiographic signs of rheumatic valve were used as controls. Patients with any of the following were excluded: a history of MI, previous cardiac surgery, blood pressure >140/90 mm Hg, abnormal plasma creatinine level, the presence of moderate or severe respiratory disease, malignant or hematologic disease, and the presence of local or systemic infection. The study was approved by the Local Research Ethics Committee, and all subjects gave written informed consent before enrollment.

2.2. Clinical assessment
The presence or absence of symptoms was assessed by two independent cardiologists blinded to the patients' serum NT-proBNP and echocardiographic results. We categorised each patient according to New York Heart Association (NYHA) functional class.

2.3. Echocardiographic data
Complete transthoracic echocardiographic (TTE) studies were performed in all subjects, using a commercially available system (Acuson 128 XP/10C USA). All patients underwent comprehensive examination including M-mode, 2D, and Doppler echocardiography. Analysis was performed off-line by a single experienced echocardiographer (V.D. performs TTE, in approximately 2500–2750 subjects in a year) blinded to the patients' symptom status, previous echocardiographic results and serum NT-proBNP. The LA diameter was estimated from parasternal long axis. The LV end-systolic and end-diastolic volumes and EF were measured from the apical four-chamber view using the modified Simpson's single plane method [8]. Severity of MR was assessed from the regurgitant fraction [9] and vena contracta width [10]. In the setting of equivocal findings between these two methods, the MR score is calculated from visual assessment of LA size, MR jet penetration, mitral continuous-wave Doppler characteristics, pulmonary venous flow pattern, tricuspid regurgitation velocity, and proximal isovelocity surface area radius. If three or more MR score parameters were present, we classified the MR as severe. Mitral valve area was measured by planimetry or pressure half times methods. Aortic valve regurgitation was assessed from the ratio of aortic regurgitant width to left ventricle outflow tract width. Valve regurgitation, including mitral, aortic and tricuspid valves, were graded as 1 (mild), 2 (moderate), 3 (severe). Tricuspid mean gradient >4 mm Hg was accepted as severe tricuspid stenosis. Trans-aortic valve maximum gradient >50 mm Hg was accepted as hemodynamically significant aortic valve stenosis. Rheumatic mitral valve severity was scored as either 1 (mild) or 2 (moderate to severe) for the following parameters: fusion of the commissures, thickening and calcification of the valve leaflets, fusion and shortening of the chordae tendineae, leaflet motion, and subvalvular involvement. Valve severity was reflected as sum of these scores. If none of these parameters was present, the valve morphology was accepted as normal valve. Visible and measurable calcification (minimum diameter=0.5 cm) was accepted as valve calcification. Unmeasurable fine increased echogenity was not accepted as valve calcification.

2.4. Biochemistry
Venous blood samples were taken with the patient resting quietly while semi-recumbent, usual medications were maintained. The blood samples were taken into chilled ethylenediaminetetraacetic acid vacutainers, placed immediately on ice, and centrifuged within 20 min at +4 °C. The plasma was stored at –80 °C before being assayed for NT-proBNP using established radioimmunoassays. Serum NT-proBNP was measured by a double antibody sandwich technique using ElectroChemiLuminescence as signal (Elecsys NT-proBNP, Roche Diagnostics), the intra-assay coefficient of variation was <6% on both normal and elevated levels. Normal reference values are dependent on age and sex, with mean values varying from 3.5 pmol/l in men under 50 years of age to 8.4 pmol/l in women between 50 and 65 years of age (data from manufacturer).

2.5. Statistical analysis
Data were analysed using Statistical Package for Social Sciences (SPSS) 10.0 version. Distribution of the NT-proBNP levels was positively skewed, but was normal after natural logarithmic transformation and all analyses used log-transformed means unless otherwise specified. Numerical values are reported as mean±S.D. or as a proportion of the sample size. For the bivariable analysis, when the variables were parametric, the difference of averages test (Student's t-test) was used; in the case of variables with more than two categories, the one-way ANOVA test was carried out. In the case of nonparametric variables, the Mann–Whitney U-test was used, depending on whether two or more variables were being compared. The correlation between two variables was studied with the Pearson or Spearman test, depending on whether the variables had a normal (parametrical) distribution or not. In all analyses, p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics
Of the 92 patients with rheumatic valve disease, 27 (29.3%) were male and 65 (70.7%) were female; they had a mean age of 40±14 years (range, 15 to 75 years). There were 50 normal control subjects, of whom 11 were male and 39 were female (mean age, 36±10 years; range, 16–62 years). There were no significant differences between groups in respect of age and gender (p=0.071, p=0.3, respectively). The clinical characteristics and echocardiographic measurements of patients with RVD are presented in Table 1.


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  		Table 1 Clinical and echocardiographic characteristics of the rheumatic heart disease group

 
3.2. Correlation between NT-proBNP levels and echocardiographic measures
The plasma levels of NT-proBNP rose with increasing severity of mitral valve stenosis (p<0.001), increasing severity of mitral valve score (p<0.001), increasing severity of clinical symptom (p<0.001) (Fig. 1), increasing severity of MR (p<0.013) (Fig. 2), presence of mitral valve calcification (p<0.001), presence of tricuspid valve stenosis (p<0.001), increasing severity of tricuspid regurgitation (p<0.011), presence of aortic stenosis (p=0.043), decreasing left ventricular ejection fraction (p<0.001), presence of left atrial thrombus (p=0.0019), and with increasing left atrium dimensions (p=0.002). No statistically significant correlation was found between NT-proBNP and severity of aortic regurgitation (p=0.699), left ventricular systolic diameter (p=0.056), and left ventricular diastolic diameter (p=0.329; Tables 2 and 3).


Figure 1
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  		Fig. 1 Diagram showing correlation between NYHA classes and plasma level of NT-proBNP.

 


Figure 2
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  		Fig. 2 Diagram showing correlation between mitral regurgitation (MR) severity and plasma level of NT-proBNP.

 


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  		Table 3 Correlation between NT-proBNP levels and echocardiographic measures in RVD group

 


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  		Table 2 Relation between NT-proBNP level and echocardiographic measures

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The role of NT-proBNP and its relation with severity of rheumatic valve involvement is not yet established. Moreover, association between NT-proBNP and echocardiographic measures is not documented. In this study, we investigated mainly the impact of circulating NT-proBNP on RVD and its severity. The most significant findings from this study are that circulating NT-proBNP levels are associated significantly with the mitral valve score. A positive correlation between circulating NT-proBNP and severity of functional class was also observed. The high level of circulating NT-proBNP might be attributed to severe RVD and functional class.

In this study, the NT-proBNP level increased with increasing MR, severe mitral stenosis, increasing mitral valve score, decreasing left ventricular ejection fraction, increasing left atrial dimension, increasing severity of tricuspid regurgitation, presence of tricuspid valve stenosis, and presence of mitral valve calcification.

These observations suggest that natriuretic peptide levels provide an additional method for assessing the severity and symptoms of mitral valve disease independent from the status of EF. The N-terminal fragment of BNP does not have specific clearance receptors and, therefore, has a longer half-life and a higher plasma concentration than BNP [7]. Previous studies suggest that BNP is primarily synthesized by ventricular myocytes and reflects changes in ventricular function. In the current study, natriuretic peptide secretion in patients with mitral regurgitation and/or mitral stenosis appeared to be related to increases in LA rather than LV wall stress. In this study, the most interesting and obvious conclusion is that the anatomical or functional stretching of the left atrium must have an important role in the augmented secretion of BNP. A possible explanation is that atrial myocytes synthesize BNP in response to the chronic increase in LA pressure. This hypothesis is supported by the demonstration of synthesis of BNP by atrial cardiomyocytes and co-storage of ANP and BNP in atrial granules [11]. NT-proBNP increases in response to enhanced LA pressure or stretching due to hemodynamically important mitral stenosis. Severe MR also augments secretion of NT-proBNP, possibly due to volume overload in LA. Left atrial distention and enhanced pressure secondary to severe mitral stenosis may lead to augmented release of BNP from storage in atrial granule, due to atrial mechanical dysfunction before development of obvious anatomical changes in LA in the presence of normal LV function. In hemodynamically important MR, the possible role of atrial anatomical changes (atrial dilatation, diminishing atrial contractility or ejection fraction due to chronic volume overload) may be important in the augmented release of BNP stored in the atrium, before reduction in LV ejection fraction. However, in our view, chronic mitral stenosis and chronic MR eventually impair both mechanical and functional atrial function during the progressive phase of disease, thus they lead to augmented secretion of NT-proBNP. Results of this study suggest that natriuretic peptide testing may add to the information obtained by echocardiography in the assessment of mitral valve disease in clinical practice. When echocardiographic assessment is technically difficult, low NT-proBNP levels would suggest that mitral valve score is not severe. Measurement of natriuretic peptides may also be useful when it is not clear whether symptoms of dyspnea or fatigue are due to cardiac disease [12].

In our study population, there was a high incidence of tricuspid stenosis. We encounter many cases of complicated mitral stenosis with tricuspid stenosis in routine practice in our region. In developing countries of the world, rheumatic fever and complicated rheumatic heart disease remain significant medical and public health problems.

Prospective follow-up studies are needed to determine whether natriuretic peptides can provide a simple low-cost method for monitoring asymptomatic patients and whether repeated measurements are useful for deciding on timing of surgery.

4.1. Study limitations
We were surprised by the absence of correlation between NT-proBNP and aortic regurgitation. However, in the presented study, the percentage of patients with severe aortic regurgitation was smaller than the percentage of patients with mild (28%) and moderate (38%) aortic regurgitation. This unexpected result may be due to the relatively small proportion of patients with severe aortic regurgitation (14%). Also, we did not find a correlation between left ventricle diameter (systole or diastole) and NT-proBNP. However, we found a strong negative correlation between left ventricle ejection fraction and NT-proBNP. This result implies that in routine practice we should consider left ventricle ejection fraction rather than isolated left ventricle diameters for monitoring patient status. In normal subjects, natriuretic peptides increased with age, were higher in women than in men, and were inversely related to body surface area, as observed in other studies [13]. Further studies are needed to determine how the impact of age, gender, and body surface area on natriuretic peptide levels influences the interpretation of plasma levels. Exercise testing has been proposed as a method of identifying patients with severe RVD. However, exercise testing needs to be performed with close monitoring and is contraindicated in symptomatic patients; thus, it was not undertaken in this study. Further studies comparing the clinical value of exercise testing and natriuretic peptide levels in apparently asymptomatic patients with RVD are needed.

4.2. Conclusions
NT-proBNP levels in patients with chronic RVD is a potential marker of disease severity and correlates with symptoms.


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

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