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European Heart Journal Advance Access originally published online on September 4, 2006
European Heart Journal 2006 27(19):2353-2361; doi:10.1093/eurheartj/ehl233
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The diagnostic utility of N-terminal pro-B-type natriuretic peptide for the detection of major structural heart disease in patients with atrial fibrillation

Rhidian J. Shelton*, Andrew L. Clark, Kevin Goode, Alan S. Rigby and John G.F. Cleland

Department of Cardiology, Castle Hill Hospital, Cottingham, Kingston-upon-Hull HU16 5JQ, UK

Received 7 February 2006; revised 11 July 2006; accepted 17 August 2006; online publish-ahead-of-print 4 September 2006.

* Corresponding author. Tel: +44 1482 624073; fax: +44 7902 840055. E-mail address: rhidianshelton{at}btopenworld.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 Acknowledgement
 References
 
Aims To assess the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the diagnosis of major structural heart disease (MSHD) in patients with atrial fibrillation (AF) compared with those with sinus rhythm (SR) using receiver operator characteristic (ROC) analysis. NT-proBNP is elevated in MSHD and heart failure (HF). AF, a common finding in HF and MSHD, is also associated with raised plasma NT-proBNP. As a result, the utility of NT-proBNP for predicting MSHD may be reduced.

Methods and results One thousand four hundred and seventy-six patients underwent assessment at a single centre, performed without the knowledge of NT-proBNP levels. MSHD included left ventricular (LV) systolic and diastolic dysfunctions, left-sided valvular disease, right heart disease (including pulmonary hypertension) and severe LV hypertrophy. One hundred and fifty-five patients were excluded due to renal impairment, atrial flutter, or a pacemaker. Seven hundred and ninety-three patients were diagnosed with MSHD. Median NT-proBNP concentrations for patients with MSHD were 960 (IQR 359–2625) pg/mL and 2491 (1443–4368) pg/mL for SR (n=591) and AF (n=202), respectively (P<0.001). Patients without MSHD had NT-proBNP levels of 179 (90–401) pg/mL and 1000 (659–1760) pg/mL for SR (n=454) and AF (n=74), respectively (P<0.001). The area under the ROC curve for NT-proBNP to detect MSHD was 0.79 for SR (95% CI 0.77–0.82) and 0.78 for AF (95% CI 0.72–0.84). NT-proBNP cut-off levels necessary to achieve a 1 in 100 false negative rate were 27.5 (7.5–30.5) pg/ml and 524 (253–662) pg/ml for SR and AF, respectively.

Conclusion NT-proBNP performs as well in patients with SR as in those with AF. However, significantly higher cut-off levels are required for patients with AF to achieve similar levels of diagnostic specificity.

Key Words: Atrial fibrillation • Heart failure • Natriuretic peptides


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Limitations
 Conclusions
 Acknowledgement
 References
 
Major structural heart disease (MSHD) and atrial fibrillation (AF) commonly co-exist and both may contribute to the development of heart failure (HF). Up to 50% of patients with HF over 65 years of age have AF and up to 50% of patients with AF have HF.1,2

Normal plasma concentrations of natriuretic peptides are widely regarded as a useful method for excluding MSHD in patients with suspected HF, with significant prognostic importance. The European Society of Cardiology (ESC) propose selecting patients with suspected HF for further investigation on the basis of having elevated plasma natriuretic peptides.3 However, natriuretic peptides are elevated in several cardiac disorders [including left ventricular systolic dysfunction (LVSD), right ventricular dysfunction,4 valvular disease,5,6 and diastolic dysfunction7] and are subject to many confounding factors (including age, gender,8 renal function,9 and body mass10), which may impact upon its clinical application.

More recently, natriuretic peptides have been found to be elevated in patients with AF even in the absence of HF,11,12 and fall on restoration of sinus rhythm (SR).13–15 As a result, it is unclear whether natriuretic peptides retain their diagnostic utility for HF in the presence of AF; optimal diagnostic cut-off levels are almost certainly different. As AF is common in patients with HF, this is of major concern. Many studies assessing the diagnostic utility of natriuretic peptides have focused narrowly on LVSD but many other forms of MSHD may lead to HF. Among patients with HF, a lower proportion of those in AF will have LVSD and a higher proportion other forms of MSHD, compared with those in SR.16,17 As such, a narrow focus assessing the value of natriuretic peptides for the detection of LVSD only is likely to diminish their significance. It may be clinically more valuable to detect all types of MSHD in this setting.

Accordingly, we investigated the diagnostic utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with persistent AF by assessing its sensitivity, specificity, and predictive value for the presence of MSHD in patients with suspected HF, with and without AF.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Limitations
 Conclusions
 Acknowledgement
 References
 
Study population
The study was reviewed and approved by the Hull and East Yorkshire Ethics Committee. Consecutive patients referred to a community HF clinic (but otherwise unselected) for assessment were identified over 18 months. Patients were referred by their General Practitioner or hospital physician as having suspected HF based upon appropriate symptoms (predominantly dyspnoea) and/or signs. The overwhelming majority of patients were assessed as outpatients (85.8%). 154 patients with renal impairment (serum creatinine >180 µmol/L; n=103), a cardiac pacemaker (n=51), or atrial flutter (n=16) were excluded from analysis, as these factors are also known to increase plasma concentrations of natriuretic peptides.18,19

A standard medical history, including current therapy was taken and physical examination performed on all patients, including a 6 min walk test. Cardiac rhythm was assessed in all patients using standard 12-lead electrocardiography. All available previous ECG tracings were reviewed for evidence of prior rhythm disturbance. Persistent AF was defined in accordance with joint ESC, American Heart Association (AHA), and American College of Cardiology (ACC) guidelines20 as the continued presence of AF for at least 7 days, prior to assessment (retrospective data obtained from medical records). The persistent nature of AF was further clarified during 4-monthly patient follow-up (i.e. all patients remained in AF throughout the follow-up period).

All elements of patient assessment including symptoms, physical examination, electrocardiography, venesection, and echocardiography were performed on the same day.

Echocardiography
Echocardiography was performed in all patients without the knowledge of NT-proBNP levels. M-mode, 2D images, and colour flow Doppler recordings were obtained using a ‘Vivd’ Five (GE Healthcare, UK) system operating at 3.4 MHz. Measurements were taken in accordance with American Echocardiography Society/European Association of Echocardiography guidelines.21,22

Echocardiography was carried out by one of three trained operators. LV systolic function was assessed by attempted measurement of ejection fraction (EF) using Simpson's biplane method in all subjects (possible in 65% of subjects), and in all subjects by estimation on a scale of normal–mild–mild-to-moderate–moderate–moderate-to-severe–severe impairment. LV function was assessed by a second operator blind to the assessment of the first; where there was disagreement on the severity of LV dysfunction, the echocardiogram was reviewed jointly with the third operator and a consensus reached.

MSHD classification
MSHD consisted of the following cardiac disorders: LVSD, LV diastolic dysfunction (LVDD), right heart disease (RHD), severe LV hypertrophy (LVH), and left-sided valvular disease. Diagnostic criteria for each subgroup were as follows.

  1. LVSD: an LVEF <40% or a qualitative assessment of LV systolic impairment of greater than mild severity and/or marked LV dilatation (>4.1 cm/m2) unless secondary to severe valve regurgitation.
  2. LVDD: the presence of both left atrial dilation (>2.5 cm/m2)23 and LVH (both interventricular septal thickness and posterior wall thickness >11 mm) plus abnormal mitral valve inflow based on the European Study Group on diastolic heart failure criteria24 and/or abnormal mitral annular velocity using tissue Doppler analysis, where possible.25
  3. RHD: right ventricular dilation of at least moderate severity (equal to or greater than LV area), moderate or severe tricuspid regurgitation assessed using colour flow, continuous, and pulsed-wave Doppler imaging and right atrial size,26 or pulmonary hypertension (pulmonary artery systolic pressure >50 mmHg).
  4. Severe LVH: defined as both interventricular septal thickness and posterior wall thickness >13 mm or a diagnosis of hypertrophic obstructive cardiomyopathy according to AHA/ACC criteria.27
  5. Left-sided valvular disease: at least moderate valvular regurgitation or stenosis based on the American Society of Echocardiography classification28–30 or a prosthetic heart valve. Moderate aortic and mitral stenosis were further defined as (a) a peak aortic ejection velocity >3 m/s (or >2.5 m/s in the presence of LVSD) and (b) mitral valve area <1.5 cm2.

Where appropriate, measurements were indexed to body surface area, calculated using the Haycock formula.31

Patients could belong to any combination of diagnostic groups with the exception of LVDD. LVSD was considered the dominant cause of HF whenever it was observed, followed in hierarchical fashion, by left sided valvular disease and then RHD. LVDD was not diagnosed when important LVSD, RHD or valve disease was present. By definition patients could have both LVDD and LVH, in which case LVH (in the absence of LA dilatation) was considered the subordinate diagnosis.

Measurement of NT-proBNP levels
Blood samples were collected by venepuncture into 6 ml ETDA tubes. Samples were centrifuged at 4°C; plasma was then removed and frozen at –80°C prior to analysis. Samples were analysed using the Roche NT-proBNP electrochemiluminescent assay and testing performed on an Elecsys 1010 analyzer (Roche diagnostics, Mannheim, Germany). Assay precision, analytical sensitivity, interferences, and stability have all been previously described.32 Haemoglobin, C-reactive protein, and serum creatinine were measured from the same blood sample.

Statistical analysis
Variable distribution was tested using one-sample Kolmogorov–Smirnov test. For normally distributed variables, data are presented as mean±standard deviation; for skewed distributions, data are presented as median (IQR) and compared using the Mann–Whitney U test. Comparisons of NT-proBNP values among diagnostic groups were made using t-tests for independent samples and analysis of variance. Normality was examined by plotting histograms of residuals. Log-transformed values for NT-proBNP were used in these analyses to reduce the effects of skewness within the distribution. To evaluate the value of NT-proBNP, we compared the sensitivity, specificity, and accuracy at various cut-off levels for AF and SR. The diagnostic utility of NT-proBNP for predicting MSHD was compared using receiver operating characteristic (ROC) curves (adjusted for age and sex). Results are expressed in terms of area under the curve (AUC) and 95% CI for this area. Bootstrapping was used to establish 95% CIs (using 1000 resamples) for the diagnostic NT-proBNP thresholds and sensitivity/specificity.33 Multivariable regression analysis was used to identify predictors of elevated NT-proBNP levels in patients with and without MSHD. Variables included in the model were selected on the basis of biological plausibility as evidenced in previous publications. Analysis was performed using SPSS (Chicago, IL, USA) for Windows, version 12.0.1 statistical software.

One of the statistical issues to address is the problem of multiple testing in multivariable linear regression, when many variables are present and the possible inflation of Type I error. There is no consensus among statisticians on what procedure to adopt to allow for multiple comparisons.34 Hence, we have followed the recommendation of Perneger and not adjusted for this.35


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Limitations
 Conclusions
 Acknowledgement
 References
 
One thousand four hundred and seventy-six patients were enrolled over 18 months, usually (85.8%) as outpatients. One hundred and fifty-five patients were excluded from analysis as described previously. Two hundred and seventy-six patients (20.9%) had persistent AF and 82 of the 1045 patients in SR had previous documented episodes of paroxysmal AF. Patients with paroxysmal AF were included in the SR group as they were in SR at the time of analysis. Clinical characteristics are shown in Table 1.


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  		Table 1 Clinical characteristics

 
Major structural heart disease
Seven hundred and ninety-three (60%) patients were found to have MSHD, 536 of whom had LVSD, 44 LVDD, 120 RHD, and 220 had significant left-sided valvular disease (Figure 1). NT-proBNP was significantly higher in patients with MSHD compared with those without (P<0.001). Table 2 presents information on median NT-proBNP (IQR) values for the various subgroups of MSHD. Median NT-proBNP values were highest in patients with RHD when associated with any other MSHD subgroup [3478 (1375–6495) pg/mL], although this may reflect the high prevalence of AF within this group (51%).


Figure 2331
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  		Figure 1 Overview of NT-proBNP values (median and inter-quartile ranges) in various patient groups, stratified according to echocardiographic classification and cardiac rhythm. (Asterisk) Exclusion criteria include any of (i) permanent pacemaker, (ii) creatinine >180 µmol/L, or (iii) atrial flutter.

 

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  		Table 2 Plasma NT-proBNP (median and inter-quartile range) concentrations in MSHD and its various subgroups

 
Atrial fibrillation
The prevalence of AF was 23.4% in the MSHD group (50.8% in RHD, 34.1% in valvular disease, and 19.4% in LVSD) compared with 15.1% in those without MSHD (P<0.001). About 68.2% of patients with AF had MSHD (most commonly LVSD), compared with 56.6% of those with SR. Patients with AF were older, more likely to have cerebrovascular disease, peripheral oedema, a higher serum creatinine, resting heart rate, larger left atrium, and shorter 6 min walk distance than those in SR (Table 2).

Effect of AF on plasma natriuretic peptide concentrations
NT-proBNP was significantly higher in patients with AF, regardless of structural heart disease (Figure 2). Patients with MSHD had median NT-proBNP concentrations of 969 (IQR 367–2634) pg/mL and 2491 (1443–4368) pg/mL for SR (n=591) and AF (n=202), respectively (P<0.001). In patients without MSHD, NT-proBNP levels were 179 (90–401) pg/mL and 1000 (659–1760) pg/mL for SR (n=454) and AF (n=74), respectively (P<0.001). This difference was maintained if the analysis was confined to patients with LVSD (P<0.001).


Figure 2332
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  		Figure 2 Box plots showing median NT-proBNP levels with respect to MSHD and cardiac rhythm. Boxes show interquartile ranges and bars represent 1.5*(inter-quartile range).

 
There was no significant difference in NT-proBNP concentrations between patients with AF and no MSHD and those with SR and MSHD [1000 (659–1760) vs. 969 (367–2634) pg/mL, respectively (P=0.450)]. Even after adjusting for age, sex, and creatinine, no difference in NT-proBNP levels was seen.

The results of multivariable regression analysis to predict elevated NT-proBNP values in patients with and without MSHD are shown in Table 3. AF was significantly associated with elevated NT-proBNP levels, regardless of whether MSHD was present or not (ß=0.335, P<0.001; ß=0.116, P=0.001 for MSHD absent and present, respectively). However, AF appears to play a greater role in NT-proBNP production in those patients without MSHD.


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  		Table 3 Predictors of NT-proBNP in patients with (in italics) and without MSHD, using multivariable regression analysis

 
There was a small but significant correlation between left atrial size (indexed to body surface area) and NT-proBNP levels [r=0.161, P (one-tailed) <0.001], even after adjusting for MSHD, AF, age, sex, creatinine, and body mass index.

Diagnostic performance of NT-proBNP
The ROC curve (adjusted for age and sex) illustrating the sensitivity and specificity of NT-proBNP for detecting MSHD in patients with SR (n=1045) and AF (n=286) is shown in Figure 3. The area under the ROC curve for NT-proBNP to detect MSHD was 0.79 for those in SR (95% CI 0.77–0.82) and 0.78 for those in AF (95% CI 0.72–0.84).


Figure 2333
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  		Figure 3 ROC curve (adjusted for age and sex) comparing the sensitivity and specificity of NT-proBNP for predicting MSHD in patients with SR and AF. AUC is significant (P<0.001) for both SR and AF. Optimal cut-off values (using Youden's index) are significantly higher for AF.

 
On the basis of current recommended NT-proBNP cut-off values (125 pg/mL for patients aged ≤75 and 450 pg/mL for those aged >75) for patients aged ≤75, NT-proBNP had sensitivity 89%, specificity 43%, accuracy 69%, and negative predictive value of 76% for detecting MSHD in the presence of SR; for patients with AF, sensitivity was 100% and specificity 0%. For patients >75 years, NT-proBNP achieved sensitivity 75%, specificity 68%, accuracy 72%, and negative predictive value of 65% for those with SR, compared with sensitivity 100% and specificity 3% for AF. Almost all patients with AF having NT-proBNP values above current age recommended cut-offs, regardless of cardiac function. The utility for NT-proBNP for diagnosing MSHD in patients with AF at various cut-off levels is shown in Table 4.


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  		Table 4 Utility of NT-proBNP for the detection of MSHD in patients with AF at various cut-off levels (95% CIs)

 
Table 5 shows optimal NT-proBNP cut-off values according to cardiac rhythm and age. Optimal cut-off values were determined using Youden's index.36 Significantly higher values are required for patients with AF (regardless of age) compared with SR [365 (169–791) vs. 1764 (1029–1859) pg/mL, respectively] to achieve similar levels of sensitivity and specificity. NT-proBNP cut-off values were also determined for patients with SR and AF assuming a false negative rate of 1 in 100 (i.e. one patient with MSHD will be missed for every 100 assessed), equivalent to a sensitivity of 99%. Again significantly higher cut-off values [27.5 (7.5–30.5) vs. 524 (253–662) pg/mL for SR and AF, respectively] are required to achieve such a high, but a more clinically relevant sensitivity.


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  		Table 5 Diagnostic thresholds for NT-proBNP according to age and cardiac rhythm

 
LV systolic dysfunction
LVSD was diagnosed in 40.5% of referred patients with SR and 40.9% of patients with AF. There was no difference in LVEF between AF and SR (31.0±7.8 vs. 29.7±8.2%, P=0.209), respectively. Median NT-proBNP values in patients with LVSD were 1139 (IQR 538–3206) pg/mL and 2890 (1908–4826) pg/mL for SR and AF, respectively (P<0.001).

A stronger correlation was seen between NT-proBNP and LVEF for SR [r=–0.199, P (one-tailed) <0.001] when compared with AF (r=–0.150, P=0.031), while controlling for MSHD, age, sex, creatinine, NYHA class, and body mass index.

The area under the ROC curve (adjusted for age and sex) for NT-proBNP to detect LVSD was 0.79 (95% CI 0.77–0.82) for patients with SR and 0.76 (95% CI 0.71–0.82) for those with AF.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Limitations
 Conclusions
 Acknowledgement
 References
 
These data show that NT-proBNP is elevated in patients with AF regardless of whether they have LVSD or other important structural heart disease. As a tool for predicting MSHD in general, or LVSD in particular, NT-proBNP performs as well in patients in SR as in those with AF. However, significant adjustment of cut-off values is necessary for patients with AF.

Our results support and further enhance the recent subgroup analysis of the ‘Breathing Not Properly’ study, which outlined the effect of AF upon BNP in patients with acute dyspnoea.12 Significant higher levels of BNP were found in dyspnoeic patients with AF but without HF, compared with SR. Interestingly and in contrast to our results, BNP levels were similar in HF patients with AF and SR. We found that the presence of AF resulted in significantly higher NT-proBNP values for MSHD and all of its subgroups including LVSD. One explanation for this relates to the difference in study populations. In the study by Knudsen et al., BNP samples were collected from patients presenting to the emergency department with acute dyspnoea, in contrast to our cohort which predominantly comprised patients with subacute and chronic dyspnoea, evaluated as outpatients. From a pathophysiological viewpoint, patients presenting acutely may have relatively greater ventricular wall stress than those in our study, effectively reducing the atrial component of NT-proBNP/BNP production. The NT-proBNP values seen in our study may be predominantly driven by AF per se. The study by Knudsen et al. also included patients with paroxysmal AF (46% of patients were in SR at the time of BNP sampling) which may have further diluted the impact of AF upon BNP. All patients in our study were in AF at the time of analysis.

The mechanisms by which BNP levels increase in patients with AF are unclear. Ventricular myocardium is widely regarded as the main source of BNP; however, it is entirely feasible that BNP may be secreted from the atria of the patients with HF and/or AF. Patients with persistent AF have increased proBNP messenger ribonucleic acid expression within the atria (right atrial appendage).37 Moreover, selective catheterization of the coronary sinus has suggested that BNP is produced within the atria in AF.38 Similar pathological changes are seen in the atria of patients with AF to those seen in the ventricular myocardium of patients with cardiac failure.39 However, these changes may help explain the elevation of natriuretic peptides in chronic AF, but not in acute AF. BNP is elevated in paroxysms of AF and returns toward normal following restoration of SR,40,41 suggesting that AF per se in addition to any effect of co-morbidity is an important determinant of NT-proBNP. The haemodynamic consequences associated with loss of atrial contraction may contribute to impairment of cardiac function, thus elevating BNP. Furthermore, the irregular ventricular rhythm may result in prolonged filling periods leading to greater ventricular diastolic stress and changes in LV diastolic pressure from beat to beat, again stimulating BNP. Inadequate control of ventricular rate, frequently associated with AF, may also lead to impairment of ventricular function (tachycardia-induced cardiomyopathy) resulting in a further elevation of NT-proBNP.42

This analysis is based upon an evaluation of a clinical service designed to offer a ‘one-stop’ diagnostic service for patients with HF symptoms or suspected of having major LV dysfunction. Many patients were already receiving diuretics, ACE-inhibitors, and beta-blockers as would be expected in patients with a high prevalence of hypertension and ischaemic heart disease. Loop diuretics are recommended for the treatment of heart or renal failure in the UK and are seldom used for hypertension. The high proportion of patients referred on loop diuretics probably reflects willingness to use these agents based upon a clinical diagnosis alone for the relief of symptoms. This heterogeneity in practice may reduce the diagnostic value of NT-proBNP but reflects the clinical reality in which testing with NT-proBNP has to perform. In the outpatient care setting, both symptomatic and asymptomatic patients with chronic stable systolic HF may present with a wide range of plasma NT-proBNP levels. Previous reports suggest that up to 21% of symptomatic patients have plasma BNP levels that are below what would be considered ‘diagnostic’.43 This may explain why cut-off values (for patients in SR) providing 99% negative predictive values are relatively low at 26(11–27) spg/mL for those ≤75 years and 81 (81–117) pg/mL for those >75 years.

Although we have demonstrated that NT-proBNP may provide an equally sensitive test for MSHD in the presence of AF (if adjusted for), measuring NT-proBNP levels solely for the purpose of diagnosing structural heart disease may be of little clinical value in this setting (its prognostic value is yet to be defined). As our results suggest, a large proportion of patients with AF (and symptoms suggestive of HF) have MSHD (70%), and as such one could argue that all patients with AF should be referred directly for echocardiography rather than using natriuretic peptides to determine the need for further evaluation. However, if BNP is to be considered as a potential screening tool for HF, it may be the initial and sole investigation on which to base the need for further investigation or specialist referral in patients who present to their primary care physician. Despite current ESC/ACC/AHA guidelines20 on the management of AF advising echocardiography as an initial investigation, these guidelines are predominantly aimed at cardiologists and not at primary care physicians, many of who do not have direct access to echocardiography services. Furthermore, the diagnosis of AF may often be missed in primary care.44,45

If NT-proBNP is to be a useful diagnostic test, it has to be robust and applicable to a wide range of unselected patients. Our paper highlights yet another significant confounding factor for primary care physicians to address when interpreting BNP results and stresses the importance of considering whether such a test is appropriate in a given situation.


   Limitations
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
Conclusions
 Acknowledgement
 References
 
Our cohort represents patients referred by their primary care physician with symptoms suggestive of HF. It does not take into account the patients with AF who are not referred (asymptomatic or undetected) or those who are referred elsewhere for other reasons, e.g. palpitations. Although BNP is likely to be elevated in these situations,11 care should be taken generalizing our findings to include all patients with AF.

The diagnosis of diastolic dysfunction using echocardiographic criteria has inherent difficulties, especially in patients with AF. Several methods exist including mitral inflow Doppler analysis, colour flow propagation, and tissue Doppler analysis. However, none are ideal for accurately establishing or quantifying diastolic dysfunction. In order to address these limitations, we sought further evidence to support the finding of diastolic dysfunction in our patients. In addition to abnormal echocardiography indices, the presence of both LVH and LA dilatation was required. As a result, some patients with ‘milder’ forms of diastolic dysfunction may not have been detected. However, our objective was to determine the diagnostic utility of NT-proBNP for ‘MSHD’.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
Acknowledgement
 References
 
We have shown that AF causes an elevation of NT-proBNP in patients without MSHD and across the entire spectrum of MSHD. A great deal of care needs to be taken interpreting NT-proBNP results in light of the individual patient's age, sex, body mass index, cardiac rhythm, renal function, and clinical presentation. If NT-proBNP is to be used as a screening tool in patients with AF, significant adjustments to current proposed cut-off levels are required to maintain its diagnostic utility.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 Acknowledgement
References
 
We are grateful to the following physicians for their assistance with data collection: J. Ghosh, K. Lalakota, P.H. Loh, S.D. Thackray, L. Tin, P. Velavan, J. Windram, N. Nikitin, and K.K. Witte.

Conflict of interest: J.G.F.C. has received grants and speaker's honoraria from Roche Diagnostics related to the clinical use of natriuretic peptides.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Limitations
 Conclusions
 Acknowledgement
 References
 

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  3. Remme W and Swedberg K. (2001) Guidelines for the diagnosis and treatment of chronic heart failure. Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Eur Heart J 22:1527–1560.[Free Full Text]
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  6. Golbasy Z, Ucar O, Yuksel AG, Gulel O, Aydogdu S, Ulusoy V. (2004) Plasma brain natriuretic peptide levels in patients with rheumatic heart disease. Eur J Heart Fail 6:757–760.[CrossRef][Web of Science][Medline]
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