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European Journal of Heart Failure 2003 5(6):775-782; doi:10.1016/S1388-9842(03)00154-5
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© 2003 European Society of Cardiology

Identification of previously undiagnosed left ventricular systolic dysfunction: community screening using natriuretic peptides and electrocardiography

Leong L. Nga,*, Ian Lokea, Joan E. Daviesa, Kamlesh Khuntib, Margaret Stoneb, Keith R. Abramsc, Derek T. Chind and Iain B. Squirea

a Department of Medicine and Therapeutics, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK
b Department of General Practice Leicester LE2 7LX, UK
c Department of Epidemiology, University of Leicester Leicester LE2 7LX, UK
d Department of Cardiology, Glenfield Hospital Leicester LE2 7LX, UK

* Corresponding author. Tel.: +44-0116-252-3132; fax: +44-0116-252-3108 E-mail address: lln1{at}le.ac.uk


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims: We examined strategies to improve the positive predictive value of natriuretic peptides in screening for undiagnosed left ventricular systolic dysfunction (LVSD) in the community. Methods and results: The value of B-type(BNP), N-terminal proB-type (N-BNP) and N-terminal proAtrial(N-ANP) natriuretic peptides was prospectively assessed in 1360 subjects (45–80 years) together with echocardiography and electrocardiography. Seventeen individuals had definite and 13 had borderline, LVSD. Receiver-operating-characteristic (ROC) curve analysis showed the superiority of BNP (ROC areas 0.942 for definite LVSD, P<0.03; 0.934 for borderline LVSD, P<0.003) compared to N-BNP or N-ANP. Peptide levels, major ECG abnormality and ischaemic heart disease (IHD) history were independent predictors of LVSD. Logistic regression modelling incorporating these factors improved ROC areas for all natriuretic peptides. The specificity of all natriuretic peptides is enhanced by consideration of these factors. Conclusions: In population screening for definite LVSD, consideration of plasma natriuretic peptide levels together with the presence of major ECG abnormalities and IHD history reduces by a factor of six (in comparison to consideration of plasma natriuretic peptide levels in isolation) the number of subjects requiring echocardiography to detect one case of LVSD (for BNP, 44 falling to seven). Similar improvements were evident for N-ANP and N-BNP. Inclusion of major ECG abnormalities and IHD history improves the performance of any natriuretic peptide used in screening programmes for ruling in undiagnosed LVSD.

Key Words: Heart failure • Natriuretic peptide • Electrocardiogram

Received April 28, 2003; Revised May 21, 2003; Accepted July 31, 2003


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Chronic heart failure (CHF) is an increasingly important health care issue in societies with increasingly elderly populations [1]. Heart failure hospitalisation rates have increased markedly over the last 20 years [2,3] and while the prevalence of the condition is already 1–2%, this is projected to rise in the next 20 years [4]. CHF is associated with poor prognosis and quality of life [5] and direct costs account for approximately 1–2% of health care expenditure [6]. CHF is most often the result of left ventricular systolic dysfunction (LVSD), which is asymptomatic in approximately 50% of prevalent cases. United Kingdom screening studies have indicated prevalence rates of definite LVSD of 1.8–2.9% [7,8].

The poor prognosis and increasing prevalence of heart failure have led to proposals to adopt screening strategies [9]. As the electrocardiogram (ECG) is normal in significant numbers of patients with LVSD [10,11], the ECG may not be an effective screening tool. Echocardiography is currently the criterion standard for diagnosing LVSD. However, access to echocardiography for many primary care physicians is frequently inadequate. Echocardiography is also subject to operator performance and interpretation and, in terms of population screening, relatively expensive.

Plasma levels of atrial natriuretic peptide (ANP, secreted mainly by the cardiac atria) and of B-type natriuretic peptide (BNP, secreted mainly by the ventricles) are elevated in symptomatic and asymptomatic LVSD [12–14]. ANP and BNP is each cleaved from the respective prohormone, producing biologically inactive peptides, N-terminal proANP (NTproANP or N-ANP) and N-terminal proBNP (NTproBNP or N-BNP), respectively. These N-terminal prohormones are present in plasma at higher concentrations than ANP or BNP. In view of its ventricular origin, BNP may be a better marker of LVSD than ANP.

Few large studies have investigated in a prospective fashion the utility of the natriuretic peptides in population screening for undiagnosed LVSD. Elevated plasma BNP was a powerful predictor of the presence of LVSD in a retrospective analysis of the Glasgow MONICA study population [12]. A similar finding for N-BNP was reported from a subpopulation of the ECHOES study [13]. Neither study excluded patients with a prior diagnosis of LVSD or heart failure.

In all screening studies to date the positive predictive value of the natriuretic peptides for the diagnosis of LVSD has been poor. To date no study has assessed the utility of the natriuretic peptides in conjunction with potential cofactors, in particular the ECG, to maximise specificity and hence permitting the ‘ruling in’ of undiagnosed LVSD. We report the results of the Screening for Heart Failure using Echocardiography, ECGs and Natriuretic peptides (SCREEN) study.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Recruitment
Randomly selected men (45–80 years) and women (55–80 years) from 21 general practices (stratified by list size and deprivation scores) in the Leicestershire Health Authority area (population approx. 1 million) were invited for screening. We excluded individuals with a prior confirmed diagnosis of LVSD or heart failure and those for whom screening was considered inappropriate, for example housebound or terminally ill patients. Practice records yielded past medical history [ischaemic heart disease (IHD, including myocardial infarction and angina), hypertension, diabetes, smoking status] and prescribed medication.

2.2. Patient screening
Patients attended the Leicester Royal Infirmary for echocardiography, resting ECG, assessment of ponderal index and blood sampling. Transthoracic echocardiography was performed by one operator (IL) in all patients using a Sonos 5500 instrument (Philips Medical Systems). Measurements of chamber dimensions, peak early transmitral flow velocity (E), atrial flow velocity (A), E/A ratio and deceleration time of the mitral E wave were obtained from the digitised images. Left ventricular function was independently quantified by three investigators (IL, JED, DTC) using two techniques. A 16-segment wall motion index (LVWMI) based on the American Society of Echocardiography model [15] was derived by scoring each LV segment (1=normal, 2=hypokinesis, 3=akinesis and 4=dyskinesis), and dividing the total by the number of segments scored. Left ventricular ejection fraction (LVEF) was calculated using the biplane Method of Discs formula [15]. Recent published work on heart failure in the community reported strong relationships between LVWMI and LVEF as defined above [16]. Therefore, we also assessed the relationship between LVWMI and LVEF in our population.

Each 12-lead ECG was coded independently (IBS, LLN) using the Minnesota criteria [17]. ECGs were analysed for the presence of major (pathological Q wave, left bundle branch block, left ventricular hypertrophy, atrial flutter/fibrillation) and minor abnormalities (left axis deviation, right bundle branch block, poor R-wave progression, atrial hypertrophy, non-specific ST segment change, sinus bradycardia or tachycardia).

2.3. Laboratory methods
Twenty millilitres of venous blood was drawn into pre-chilled Na-EDTA tubes containing aprotinin and plasma stored at –70 °C until assay. Competitive immunoluminometric assays for BNP and N-ANP were based on commercially available antibodies from Peninsular Laboratories Inc. (Belmont, CA) and Phoenix Pharmaceuticals Inc. (Belmont, CA), respectively, following extraction on C18 columns. Biotinylated tracer peptides were purified on reverse-phase C18 HPLC. Streptavidin labelled with methyl-acridinium ester was used to detect bound biotinylated tracer [18]. Unextracted plasma was assayed for N-BNP using a non-competitive immunoluminometric assay as described [19]. The lower limit of detection of N-ANP, BNP and N-BNP was 3.4 fmol/ml, 2.0 fmol/ml and 5.7 fmol/ml, respectively. There was no cross reactivity between assays.

2.4. Statistical analysis
Statistical analysis was performed using SPSS version 11.0 (SPSS Inc., IL) and Stata (Release 7.0). Natriuretic peptide levels were normalised by log transformation before analysis. Factors and covariates related to LVSD in univariate analysis (P<0.1) were entered in logistic regression analysis to develop prognostic indices for the probability of having LVSD, adjusting where necessary for co-morbidity. The same analysis was performed stepwise (both forward and backward) to assess reliability of the predictors. The resulting prognostic indices were validated using a ‘jack-knifing’ method to correct for development and validation of the models on the same data [20]. The resulting bias-corrected indices were then used to construct receiver-operator-characteristic (ROC) curves. The area under the curves (AUC) and their associated standard errors (S.E.) were estimated using the non-parametric method of Hanley and McNeil [21]. Comparison of AUC of competing ROCs was performed using the method of DeLong et al. [22], which adjusts for the fact that the different AUCs were estimated using the same patients.

The sample size was chosen to enable the probability of disagreement between the methods to be estimated to within 5% using a 99% confidence interval.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
Screening invitations were accepted by 1360 of 2392 patients approached, an overall uptake of 57% (men 56%, women 58%, P=NS). The number of participants with analysable ECG and echo and available blood sample was 1331(Table 1). There was no difference between the general practice mean deprivation scores of those who accepted (+7.14) and those who declined screening (+8.08). Demographic characteristics of the study population are reported in Table 1.


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  		Table 1 Characteristics of study population (n=1331)

 
3.1. Definition of LVSD
LVEF was obtainable in only 1058 (79%) of the subjects whereas LVWMI was computed from 1331 (99.4%) of the population. There was a strong correlation between these parameters (r=0.80, P<0.0005, Fig. 1). Definite LVSD was defined as LVWMI of ≥2 (equivalent to LVEF ≤35% (Fig. 1). Borderline LVSD was defined as LVWMI ≥1.6 and <2 (LVEF 35–45%).


Figure 1
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  		Fig. 1 Relationship between the left ventricular wall motion index score and left ventricular ejection fraction.

 
3.2. Prediction of LVSD
3.2.1. Natriuretic peptides
Seventeen individuals (1.28%) had definite and an additional 13(0.98%) had borderline, LVSD. Plasma concentration of each natriuretic peptide was higher in those with definite LVSD than in those with preserved systolic function: median N-ANP(range) 943(288–3020) fmol/ml vs. 385(5–4115) fmol/ml (P<0.0005); BNP 92.9(19.0–501.2) fmol/ml vs. 17.1 (2.0–275.4) fmol/ml (P<0.0005); N-BNP 301(38–1230) fmol/ml vs. 36(5–1174) fmol/ml, (P<0.0005).

Comparison of the ROC AUCs (Fig. 2, Table 2) showed BNP to be superior to N-ANP(P<0.006) or N-BNP(P<0.03) in the detection of definite LVSD. BNP was also superior to N-ANP(P<0.001) and N-BNP(P<0.003) for detection of the combination of definite and borderline LVSD (Table 2, Fig. 2).


Figure 2
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  		Fig. 2 Receiver operating characteristic curves for BNP, N-BNP and N-ANP levels in the detection of definite LVSD and of definite and borderline LVSD. ROC curves for the prognostic indices derived from each of the logistic models for the three peptides are also shown. LVSD=left ventricular systolic dysfunction.

 


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  		Table 2 Area under the receiver operating characteristic curves (ROC AUCs) for BNP, N-BNP and N-ANP and their respective logistic models for diagnosis of systolic heart failure with specificities and positive predictive values (PPV) for detection of all cases of heart failure (100% sensitivity). Number of subjects that are needed to scan in order to detect a case of heart failure are also reported.

 
3.2.2. Regression analysis
Potential factors or covariates included in logistic regression analysis for univariate determinants of definite and/or borderline LVSD were plasma natriuretic peptide, age, gender, plasma creatinine, major ECG abnormality, minor ECG abnormality, body mass index and past history of IHD, diabetes or hypertension. Neither a history of hypertension nor diabetes predicted LVSD. Factors significant on univariate analysis (plasma peptide level, gender, major ECG abnormality, IHD history, plasma creatinine) were entered into multivariate logistic regression analysis. Independent predictive factors for definite LVSD for all peptides were peptide level, presence of major ECG abnormalities and IHD history (Table 3). The same factors and gender, were predictors of definite and borderline LVSD.


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  		Table 3 Multivariate analysis for determinants of definite or definite and borderline systolic heart failure, using BNP, N-BNP and N-ANP

 
Fig. 2 shows the ROC curves for diagnosis of definite and definite and borderline, LVSD derived from the logistic models of peptide levels, presence of major ECG abnormalities and IHD history. It is clear that the specificities of all models (at 100% sensitivity) were markedly improved compared to that of each peptide level alone (Fig. 2, Table 2). ROC AUCs were also greatly improved.

The ECG alone was neither sensitive nor specific for the identification of definite and/or borderline LVSD. Of the 17 individuals with definite LVSD, the ECG was normal in 2 (12%). Thus, the ECG alone could not attain 100% sensitivity for detection of LVSD. The finding of one or more minor ECG abnormalities had a specificity of 60.7% and PPV of 3.1% for detecting definite LVSD.

Table 2 also illustrates the number of individuals requiring echocardiography to detect one case (definite and definite and borderline, LVSD). If relying on echocardiography alone to detect one case of definite or definite and borderline LVSD in our population, we need to scan 78.3 and 44.4 subjects, respectively. These numbers are reduced by between 27 and 44% for detection of definite LVSD using any of the peptides. The use of logistic functions including peptide levels, presence of major ECG abnormalities and IHD history (and gender for borderline LVSD), led to uniform reduction in the number needing echocardiography to detect one case of LVSD. Although the performance of all peptide tests was improved, BNP retained its superiority in detection of definite (P<0.04) and definite and borderline, LVSD (P<0.001).


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
This is the first prospective study to compare the utility of various natriuretic peptides in combination with the ECG for the identification of previously undiagnosed LVSD. For the identification of LVSD, BNP is superior to N-BNP or ANP. Moreover, the positive predictive value of any of the natriuretic peptides is enhanced markedly by consideration of easily identifiable ECG abnormalities.

To date few studies have assessed the utility of natriuretic peptides in the diagnosis of LVSD in unselected populations [12,13,23–25]. Three studies assessed the value of BNP [23,24] or N-BNP alone [13] and two compared the relative utility of BNP and N-ANP, concluding that BNP was superior [12,25]. While studies (including the present one) uniformly agree that ‘normal’ natriuretic peptide levels effectively rules out LVSD, the positive predictive value of natriuretic peptides used alone has been weak. No previous study examined strategies to maximise the specificity and positive predictive value of the peptides at 100% sensitivity, in order to minimise the number of subjects requiring echocardiography to ‘rule-in’ cases.

The current study demonstrates clearly the superiority of BNP over N-ANP and N-BNP in the diagnosis of LVSD. This has implications in the debate over which natriuretic peptide to use, as both BNP and N-BNP are commercially available as diagnostic tests. While the positive predictive value of BNP alone was very low at 2.2%, we specifically excluded patients with a prior diagnosis of LVSD, as any screening programme is unlikely to target such individuals. Thus, our approach is likely to reflect the true predictive value of natriuretic peptides in such programmes. The positive predictive value of a screening test increases with the prevalence of the condition. The prevalence of definite LVSD in the current population was 1.28%, approximately half that in studies which did not exclude patients with a prior diagnosis of LVSD [12,13].

Our most important finding is the significant improvement in the diagnosis of LVSD achieved by considering cofactors concurrently with plasma peptide levels. Logistic regression analysis yielded models containing plasma peptide level, presence of major ECG abnormalities and IHD history (and gender when borderline LVSD was included). It has been suggested that primary care physicians [26] lack the skills to interpret ECGs. However, the predictive value of the ECG appears not to lie in interpreting subtle changes but in detecting easily recognisable, major abnormalities. With the developed models, screening can achieve 100% sensitivity of LVSD detection with specificities greatly improved from those achieved using peptide levels or the ECG alone. However, even after modelling, BNP retained its superiority over alternative natriuretic peptides, detecting all cases of definite LVSD with 92.7% specificity. The implications, in terms of the potential cost of screening programmes, are clear. The developed algorithms do not rely on an arbitrary ‘cut-off’ BNP level and could easily be incorporated into equipment for the measurement of plasma BNP levels. In clinical practice this may allow the identification with greater accuracy of patients likely to have LVSD. Consequently, the number proceeding to echocardiography in order to detect a case is minimised to approximately 6–7 individuals. This would permit its use to rule-in LVSD in the community, complementing its diagnostic utility in the emergency room [14] and its prognostic utility in acute coronary syndromes [27].

The value of the ECG alone in the prediction of LVSD has been unclear to date. The ECG was abnormal in 75% and 38% of participants in the Glasgow [7] and Birmingham [8] studies, respectively. In the current study, the abnormal ECG considered alone lacked sensitivity and specificity for LVSD diagnosis and is, therefore, an inadequate screening tool for LVSD.

A recent report from the Framingham database studied the usefulness of BNP and N-ANP in identifying LVSD in a population very similar to ours [25]. This study, like ours, excluded those with known heart failure and studied the utility of ECG abnormalities added to natriuretic peptide values. The conclusion of this study, that natriuretic peptides are of limited usefulness in screening, is in marked contrast to ours. Differences in echocardiographic and assay techniques may have contributed to disparities between the two studies. While the area under the ROC curve for N-ANP was very similar to ours, that for BNP (0.79 for men, 0.85 for women) was much lower than our observed value of 0.94 for this peptide. The previous investigators excluded 6.3% of their population due to inadequate echocardiograms and used a composite of visually estimated semi-quantitative LVEF or fractional shortening rather than LVWMI to assess LV systolic function. Furthermore, to this, previous studies employing echocardiographically derived LVEF excluded up to a fifth of subjects screened due to inadequate images [8], relying on visually estimated systolic function in the remainder. We used the wall motion index to define LVSD, permitting inclusion of virtually the whole studied population, an approach justified by recent reports of strong relationships between these two measures of LVSD [16] and confirmed by the robust correlation reported in the present study.

4.1. Limitations of study
It is important to reiterate that this study was conducted in a population of individuals from primary care none of whom had an a priori diagnosis of heart failure or LVSD. Importantly, prescribed medication had no influence on the results of our analysis. The validity of our model in other populations remains to be established. In particular, the value and cost-effectiveness of the natriuretic peptides and the ECG in high-risk populations, and in ethnic minorities, should be examined. Our results refer only to the prediction of left ventricular systolic dysfunction. The predictors of parameters of diastolic dysfunction remain unclear.


   5. Conclusions
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In this cohort of over 1300 patients drawn from primary care and without a prior diagnosis of heart failure, BNP was superior to either N-ANP or N-BNP in diagnosing LVSD. Using BNP alone, over 50% of a population would require echocardiography to identify all LVSD cases. The finding of any one of only four major ECG abnormalities (atrial fibrillation, pathological Q-wave, left ventricular hypertrophy, or left bundle branch block) and an ischaemic heart disease history reduces this number by over 85%. Similar improvements are evident with the other natriuretic peptides N-ANP and N-BNP. While we have not performed a cost-effectiveness analysis on this data, the combination of plasma BNP with analysis of the ECG is likely to improve significantly the cost-effectiveness of screening for LVSD in unselected populations.


   Acknowledgements
 
This study was funded by the NHS New and Emerging Applications of Technology program. We thank Ms Sonja Jennings and Ms Paulene Quinn for excellent technical assistance and Ms Charlotte Bates and Ms Marion Campton for assistance with echocardiography.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
{star} Sources of support: National Health Service (NHS) new and emerging applications of technology program.


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

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