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European Journal of Heart Failure 2001 3(3):307-313; doi:10.1016/S1388-9842(01)00124-6
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© 2001 European Society of Cardiology

Relations between medical history, clinical findings and plasma N-terminal proatrial natriuretic peptide in patients in primary health care

Jørgen A. Smitha,*, Dag Bruusgaardb, Egil Boddc and Christian Halla

a Institute for Surgical Research University of Oslo Oslo, Norway
b Institute of General Practice and Community Medicine, University of Oslo Oslo, Norway
c Medinnova SF, Norway

* Corresponding author. Research Institute for Internal Medicine, The National Hospital, Oslo 0027, Norway. Tel.: +47-23072786; fax: +47-23073630


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Background: recent studies indicate that measurement of natriuretic peptides may be a valuable tool to improve the quality of the diagnosis of heart failure in general practice.

Aim: the aim of the present study was to examine the relationship between the plasma level of the natriuretic peptide N-terminal proANP and symptoms and signs of heart failure in patients from general practice in the Oslo area.

Methods and Results: we undertook a survey of 499 patients consecutively enrolled from the practice of 27 practitioners. One hundred and twenty-nine patients were classified as having possible or some degree of heart failure. The plasma concentration of N-terminal proANP increased with severity of heart failure as judged from clinical examination. In multivariate analysis age, history of heart disease, plasma creatinine, use of beta-blockers and digitalis, oedemas and atrial fibrillation were the main determinants of plasma N-terminal proANP.

Conclusion: while there was an overall increase in N-terminal proANP values with increasing symptoms and degree of heart failure, no single finding was closely related to N-terminal proANP. Treatment effects and diagnostic errors may both influence the relationship between N-terminal proANP and clinical findings. The current study has demonstrated the feasibility of using N-terminal proANP by general practitioners for the potentially improved diagnosis of heart failure. Further research is required to determine the precise role of this assay in clinical practice.

Key Words: Heart failure • General practice • Natriuretic peptides

Received April 13, 2000; Revised September 20, 2000; Accepted December 28, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
The clinical diagnosis of heart failure is often subject to error. In primary health care 30–70% of such diagnoses may be incorrect [1–3]. The low specificity of clinical symptoms and signs in heart failure, combined with the severe long-term prognosis of this syndrome, underscores the need for objective tools in the diagnostic management of these patients.

The major cause of heart failure is reduced left ventricular function. Ventricular dysfunction is accompanied by increased ventricular as well as atrial wall stretch. This leads to augmented secretion of the cardiac natriuretic peptides atrial natriuretic peptide (ANP 99–126) and brain natriuretic peptide (BNP 77–108) [4,5].

ANP (99–126) is stored in granules in atrial myocytes as a prohormone (proANP [1–126]) [6]. During release from the cell, the prohormone is split into ANP (99–126) and N-terminal proANP (1–98) [7]. Due to its longer half-life in plasma, N-terminal proANP is relatively easy to measure [8,9]. The fact that it is resistant to in vitro degradation, means that it can be sent with ordinary mail systems to a central laboratory for analysis [10].

Elevated plasma concentrations of natriuretic peptides have been reported in patients with congestive heart failure and after myocardial infarction [7,11,12]. The peptide levels are strongly predictive of long-term prognosis [13,14]. Studies from Finland and Great Britain have documented that measurement of natriuretic peptides may be of clinical usefulness in the primary diagnosis of heart failure in the general practice setting, substantially reducing the frequency of false positive diagnoses [2,15].

Measurement of N-terminal proANP has been offered as a regular service to general practitioners in Norway since 1993. As part of an effort aiming to evaluate the utility of these measurements we undertook a survey of patients of general practitioners in the Oslo area. The patients’ medical history, cardiopulmonal symptoms, clinical findings and diagnosis of heart failure as given by the general practitioner were recorded. These variables were then related to the plasma concentration of N-terminal proANP as measured in a blood sample obtained at the same visit.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
The present study comprised 499 individuals of age >65 years who were consecutively included as they visited their physician for any medical reason. Twenty-seven general practitioners located in the Oslo region took part in the study. They filled out a questionnaire about cardiopulmonary symptoms, clinical diagnoses, cardiovascular drug use and findings at clinical examination. In conclusion, an overall clinical evaluation with regard to the presence and degree of heart failure was reported.

The following data were recorded:

  • Previous illnesses: presence of angina pectoris; hypertension; other heart disease; bronchitis; or asthma during the last 12 months.
  • Symptoms: dyspnoea, (a) when walking fast or uphill; (b) when walking on level together with people of the same age; (c) when walking at own speed on level; and (d) during washing or dressing. Orthopnoea during the night, swelled ankles at the end of the day and frequent coughing, expectorate or wheezing in the chest.
  • Clinical signs at examination: dyspnoea, bilateral basal rates or wheezing on lung auscultation, ankle oedema and atrial fibrillation.
  • Overall clinical evaluation: the physician categorised the patients in one of the following groups: (1) No heart failure; (2) light or possible heart failure; (3) heart failure, but compensated and without symptoms; (4) moderate heart failure; and (5) severe heart failure.

2.1. Measurement of plasma creatinine and N-terminal proANP
After clinical examination a blood sample was collected and placed in an EDTA containing vacutainer for analysis of plasma creatinine and N-terminal proANP. After separation of plasma, the samples were frozen at –20°C until they were analysed in the laboratory of the Institute for Surgical Research (N-terminal proANP) and Department of Clinical Chemistry (creatinine) at the National Hospital, University of Oslo. The analysis of N-terminal proANP was performed by measuring immunoreactive irANP(1–98) by radioimmunoassay according to Sundsfjord [9]. The laboratory uses the following age-adjusted upper reference limits: 60–70 years, <1200 pmol/l; 70–79 years, <1500 pmol/l; and above 80 years, <2000 pmol/l.

2.2. Statistics
Results were reported as median with 95% confidence interval. Grouped data were compared with the Wilcoxon two-sample test. Correlation between continuous variables was expressed by the Pearson correlation coefficient. Level of significance was set to P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
Three hundred and fifty-six women and 143 men between 65 and 90 years (median, 74 years) were studied. The obtained values for the N-terminal proANP plasma concentration showed a skewed distribution with a median value of 950 (728–903) (range, 289–5535) pmol/l (Fig. 1). The median creatinine value was 86 (82–88) (range, 51–302) mmol/l (N=484).


Figure 1
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  		Fig. 1 Distribution of N-terminal proANP values sub-grouped according to overall clinical classification.

 
We found no significant relation between N-terminal proANP levels and the patients’ sex, weight or height. There was, as illustrated in Fig. 2, a positive correlation between N-terminal proANP and age (r=0.35, P=0.0001) as well as plasma creatinine (r=0.27, P=0.0001).


Figure 2
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  		Fig. 2 Median N-terminal proANP according to age quartile and sub-divided within quartile according to median plasma creatinine. Left panel: no heart failure; right panel: any degree of heart failure on clinical classification.

 
The frequencies of cardiovascular drug use was as follows: diuretics, 20% (loop diuretics 11%, thiazides 9%); nitrates, 14.4%; digitalis, 10.6%; calcium antagonists, 10%; beta-blockers, 9%; anticoagulant agents, 8.8%; ACE-inhibitors, 6%; alpha-blockers, 1.4%; and anti-arrhythmic agents, 1%.

3.1. Relations between N-terminal proANP and clinical parameters
Table 1 lists the frequency of patients with a positive finding of various clinical parameters and the median N-terminal proANP in these patient sub-groups. Patients with a history of angina pectoris or other heart diseases had significantly higher N-terminal proANP levels than those without these ailments. This was not the case for patients with hypertension, asthmatic or bronchitic disorders. With regard to clinical symptoms and signs, patients with dyspnoea on climbing or walking with people of the same age, leg oedema (reported from patient or doctor), rales on lung auscultation and atrial fibrillation all had significantly higher levels of N-terminal proANP than those without these findings.


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  		Table 1 N-terminal proANP and medical history, symptoms, signs, treatment and clinical evaluation

 
In the overall clinical classification (N=497), no patient was classified as having severe heart failure. Patients with possible or mild, compensated or moderate heart failure all had significantly higher median N-terminal proANP values than the remaining patients (Table 1 and Fig. 3). The 368 patients evaluated as not having heart failure had an N-terminal proANP of 751 (702–816) pmol/l as compared to 1026 (850–1257) pmol/l in the 129 patients having any degree of heart failure (P=0.0001). Table 2 shows the relation between overall clinical classification status and frequency of N-terminal proANP above the upper reference limits. Nineteen percent of patients with clinical heart failure had elevated N-terminal proANP values, while this was the case in 6% of those without heart failure.


Figure 3
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  		Fig. 3 Median with 95% confidence interval of N-terminal proANP grouped according to overall clinical heart failure diagnosis. White bar and {square} indicate median with confidence interval of all patients. *: P<0.05 vs. no heart failure.

 


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  		Table 2 Normal or elevated N-terminal proANP in relation to clinical heart failure diagnosis

 
In a multiple stepwise forward regression analysis in which demographic and clinical data were entered into the model (excluding the overall clinical classification), the following variables were independently predictive of N-terminal proANP plasma level: age; history of heart disease; plasma creatinine; use of beta-blocker; use of digitalis; oedema in history; oedema on examination; and atrial fibrillation (r2=0.33).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
In the presently studied population, we found a frequency of heart failure of 26.5%. This is surprisingly high compared to other studies, which report a prevalence between 8 and 16% for subjects aged over 75 years [16]. It is likely that, although doctors were asked to include patients consecutively, they were biased to enter subjects with cardiovascular disease into the study. Furthermore, the relatively high frequency of heart failure may be explained by the fact that we included patients with possible or suspected heart failure in the calculation. This is further supported by the finding of a relatively low use of ACE inhibitors (6.6%) in our population.

Our main finding was a clear relationship between median N-terminal proANP and different degrees of heart failure as evaluated by the physician (Fig. 3). The more severe the heart failure, the higher the median N-terminal proANP value. These findings confirm previous studies showing that N-terminal proANP concentration raises with increasing severity of cardiac dysfunction [17]. Not surprisingly, elements of clinical history and subjective symptoms related to ventricular dysfunction such as previous heart disease, dyspnoea and oedema were also significantly related to N-terminal proANP. Interestingly, orthopnea, which is usually considered to be a heart failure symptom, was not accompanied by increased N-terminal proANP values.

In the multivariate analysis both age and plasma creatinine were independently related to N-terminal proANP. The relation to plasma creatinine may be explained by earlier findings indicating that N-terminal proANP is cleared mainly by renal excretion [18]. N-terminal proANP has been found to reach high values in advanced age, even when clinical heart disease is not present [19]. The mechanism behind this relationship is unclear, although deterioration of diastolic cardiac function occurring with increasing age may contribute.

We found an independent relationship between N-terminal proANP and the use of beta blockers and digitalis. Previous data [19,20] indicate that use of beta blockers leads to higher N-terminal proANP values, although the mechanism behind this remains unclear. The independent relationship between the use of digitalis and N-terminal proANP has not previously been reported.

As many as 104 of the 129 patients classified as having possible or some degree of heart failure, had normal N-terminal proANP values. Previous findings indicate that treatment of heart failure may depress elevated natriuretic peptide levels [21–23]. Furthermore, in many cases the diagnosis of heart failure may be erroneous. Earlier studies have shown that 30–70% of the patients referred from primary health care with a suspected diagnosis of heart failure do not appear to have cardiac dysfunction [1,2]. The possibility of an erroneous diagnosis might be further exaggerated in the present study since patients classified as having possible heart failure were included in the heart failure group. It is likely that many ‘heart failure’ patients seen by the general practitioner is treated on the basis of an erroneous diagnosis. In such cases, further investigation might confirm the absence of cardiac abnormalities and a gradual reduction of treatment under careful clinical monitoring might be indicated. Repeated measurement of natriuretic peptides may be a potentially helpful monitoring tool in this situation.

Twenty-two of the 368 patients evaluated as not having heart failure had elevated N-terminal proANP levels. Three of these had atrial fibrillation that is known to increase atrial pressures [24]. An additional 10 patients were taking beta blockers which has been associated with natriuretic peptide increase [20]. Finally, some of these patients may have undiagnosed ventricular dysfunction. According to the results of a study from northern Glasgow, approximately 1.5% of asymptomatic patients in general practice had left ventricular systolic dysfunction [25]. Conceivably, asymptomatic diastolic dysfunction may also increase Nt-terminal proANP levels [26].

Due to the high level of uncertainty in the clinical diagnosis of heart failure, examination with objective diagnostic methods is required [27]. Echocardiography has been identified as a standard tool in this setting. However, echocardiography may not in the foreseeable future be available to all patients with a possible heart failure diagnosis. Measurement of N-terminal proANP or other natriuretic peptides might be an easily accessible and low cost objective tool for the general practitioner aiding in the selection of patients that should be referred to further assessment [2,15,25]. This would be expected not only to reduce the number of unnecessary referrals for echocardiography, but also to reduce the number of false positive diagnoses based on clinical examination alone.

It has recently been suggested that natriuretic peptide testing may be of value in the screening of asymptomatic patients [28]. It is still not known, however, whether asymptomatic patients selected in this way would benefit from heart failure treatment. Some support for this concept may be found in the results of the SOLVD prevention study in which patients with left ventricular systolic dysfunction but no or only light symptoms, benefited from ACE inhibitor treatment [29].

In summary, we have reported the relations between plasma N-terminal proANP and symptoms and signs of heart failure in primary health care. While there was an overall increase in N-terminal proANP values with increasing symptoms and degree of heart failure, no single finding was closely related to N-terminal proANP. We suggest that N-terminal proANP measurement is a simple pathway to supplementary objective information regarding cardiac function. While the present study shows the feasibility of Nt-proANP measurement in general practice, further research is needed to define its precise role in this setting.


   Acknowledgements
 
We would like to thank Tor Haldorsen, Section of Medical Statistics, University of Oslo, for advice on statistical analyses. Ellen Lund Sagen, Ellen Bjerkhaug and Lise Bjørnskau provided excellent technical assistance. The following general practitioners were participating investigators: Rannei Andersen; Lindbjørg Bahgat; Odd Boyesen; Dag Bruusgaard; Rolf Faste Nielsen; Marit Hegde Næss; Elsa M. Hjerkinn; Mette Horgen; Sven Haaverstad; Reidar Johansen; Anne Signe Iren Karlsen; Jon Torgeir Lunde; Anker Nielsen; Lars Nordlie; Petter Norenberg; Øystein Pihlstrøm; Ragnar Rabe; Andreas Rydning; Svein Sandblost; Trond Skjolden; Ingeborg Skulberg; Jørgen Smith; Anna Stavdal; Kirsten Varslot; Svein Wiel; Asbjørn Økland; and Thorbjørn Aanje.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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