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European Journal of Heart Failure 2005 7(1):87-93; doi:10.1016/j.ejheart.2004.03.009
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© 2004 European Society of Cardiology

Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction

Gedske Daugaardb,*, Ulrik Lassenb, Peter Biec, Erling Bjerregaard Pedersend, Kaare Troels Jensend, Ulrik Abildgaarde, Birger Hessea and Andreas Kjaera

a Department of Clinical Physiology and Nuclear Medicine Rigshospitalet, Denmark
b Department of Oncology 5073, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark
c Department of Physiology, Odense University Denmark
d Department of Medicine, Holsterbro Hospital Denmark
e Department of Cardiology, Gentofte Hospital Denmark

* Corresponding author. Tel.: +45-35454677; fax: +45-35456966. E-mail address: gedske{at}rh.dk


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: The use of anthracyclines in treatment of cancer is limited by cardiotoxicity of these compounds and may lead to heart failure. Therefore monitoring of cardiac function is necessary during therapy.

Aim: We evaluated the value of natriuretic peptides (N-terminal pro-atrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP)) for monitoring and predicting anthracycline induced cardiotoxicity using radionuclide left ventricular ejection fraction (EF) measurements as reference.

Methods and results: A total of 107 consecutive patients receiving anthracycline as part of their chemotherapy for malignant disease were studied. Plasma concentrations of the peptides were measured by radioimmunoassay and EF by radionuclide cardiography. For reduced EF values, i.e. below 0.50 a fairly strong correlation was found between N-ANP or BNP and EF. Of 48 patients with serial EF and peptide measurements, 19% showed a significant EF decrease (>0.10) and ended with a final EF value below 0.50. Baseline EF was no predictor of a change in EF during treatment. Neither baseline levels of N-ANP or BNP nor a change in the same variables during therapy were predictive of a change in EF.

Conclusions: In spite of correlations between peptide concentrations and reduced EF values neither baseline values nor serial measurements can safely substitute EF monitoring in patients undergoing anthracycline therapy.

Key Words: Natriuretic peptides • ANP • BNP • Cardiotoxicity • Heart failure • Anthracyclines

Received April 25, 2002; Revised December 11, 2003; Accepted March 20, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Anthracyclines such as doxorubicin and epirubicin are efficient anti-cancer drugs. However, their use is limited by cardiotoxicity, which eventually may lead to congestive heart failure (CHF). Cardiotoxicity is related to cumulative dose [1], however, the susceptibility to this severe side effect is largely individual and it is therefore of importance to identify patients that are at risk for developing heart failure. Although myocardial biopsies are considered the gold standard, the invasiveness excludes its clinical use. Instead, monitoring of left ventricular ejection fraction (EF) is generally accepted as the gold standard [2]. In adults, serial EF measurements are performed most often by means of radionuclide cardiography (MUGA) due to its high reproducibility. The clinical value of serial EF determinations has been demonstrated in several studies [2–4]. Furthermore, changes in EF as determined by MUGA correlated with signs of cardiotoxicity in myocardial biopsies [5]. It has also been found that development of clinical CHF is preceded by decreases in EF [2–4]. Guidelines have been suggested on the basis of these observations. In brief, it is recommended to measure EF either from before start of treatment or after administration of half the maximal cumulative dose and that EF determinations should be repeated prior to each subsequent dose. A decline in EF of more than 0.10 in absolute values to an EF of less than 0.50 should lead to discontinuation of treatment [3]. Following these guidelines, the risk of developing CHF can be reduced four-fold [3]. Although a routine procedure, serial MUGA determinations of EF may be a strain for the patients and an economical and logistical challenge for the system. Therefore, in recent years the use of biochemical markers instead of imaging methods has been suggested. The role of natriuretic peptides as markers of cardiac function is now well established [6]. Thus atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are closely related to the degree of CHF and to EF [7,8]. BNP is primarily released from the ventricles of the heart and reflects the filling pressure in the left ventricle. ANP is primarily released in response to atrial distension. For practical reasons often the N-terminal part of pro-ANP (N-ANP) is measured instead of the bioactive ANP due to the longer half-life in plasma of N-ANP. So far, only a few studies have measured ANP [9,10], N-ANP [11] and BNP [12] during anthracycline treatment and no clear overall conclusion has emerged yet, whether it is clinically useful or not.

The aim of the present study was therefore to evaluate the value of N-ANP and BNP for monitoring and prediction of anthracycline induced cardiotoxicity in cancer chemotherapy. As reference we used EF determinations by MUGA.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study population
One hundred and seven consecutive patients with disseminated malignant disease were included. All patients were treated with anthracyclines, 62% with epirubicin and 38% with doxorubicin. Thirteen patients in addition received radiotherapy against their left chest wall. Details of the study group and the treatments given are summarized in Table 1. None of the patients had suffered from congestive heart failure before treatment, or had recent (<6 months) myocardial infarction, significant heart valve disease, significant cardiac arrhythmia or overt renal or hepatic failure.


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  		Table 1 Characteristics of the study population

 
A total of 204 simultaneous EF determinations and plasma samples for natriuretic peptide measurements were obtained: 59 patients had one measurement, 22 patients had two, 11 patients had three, eight patients had four, and seven patients had five measurements.

The local scientific ethical committee approved the study, and all participants gave their written informed consent.

2.2. General protocol
Prior to anthracycline administration the patients were clinically examined, including symptoms and signs of heart failure, and classified according to the NYHA classification. EF was measured by means of multiple ECG gated radionuclide cardiography (MUGA). During the MUGA study a blood sample was drawn from an antecubital vein for measurements of N-terminal pro ANP (N-ANP) and brain natriuretic peptide (BNP). Blood samples were drawn while the individual was in a supine position and after 30 min of rest. Samples were stored at –20 °C for a maximum of 6 months. We have previously found that storage of ANP and BNP samples for up to 2 years does not influence the measured values.

Since the aim of the study was to evaluate whether hormone measurements could substitute LVEF by MUGA, pretreatment values were not assessed. Pretreatment values of LVEF and natriuretic peptides are not acquired in the daily routine in patients undergoing treatment with antracyclines unless the patient has an anamnesis with cardiac disease. In most patients the first measurements were therefore obtained when half of the maximal cumulative anthracycline dose was administered.

The study was performed over a fixed period of time (January 1999–April 2000). All patients treated with antracyclines in this period were eligible and were consecutively included into the study irrespective of the cumulative dose of antracycline they had received. Therefore, some patients have one measurement and other have several.

None of the patients had heart problems before treatment.

2.3. Radionuclide cardiography (MUGA)
The study was obtained as a routine MUGA study (24 frames/cycle, 64x64 matrix size, word mode) with a GE Starcam with a small field-of-view (30 cm) in the left anterior oblique position aiming at optimal separation of right and left ventricles, often with a slight caudal tilt, after iv. injection of 700 (600–800) MBq 99mTc-labelled human serum albumin.

EF below 50% was considered abnormal. The confidence interval of a single measurement of LVEF by MUGA is ±0.05 in our laboratory, thus a decrease of ≥0.10 in EF over time was considered significant. For patients with more than 2 measurements the difference between first and last measurement was used as the change for further analysis.

2.4. Peptide assays
Blood samples were collected into chilled tubes containing EDTA and aprotinin. The samples were immediately spun and plasma separated and stored at –20 °C until measurement of N-ANP and BNP.

N-ANP (1-30) was measured in extracts of plasma by a commercially available radioimmunoassay kit (Peninsula RIK9126, lot 961494). Extraction was performed as previously described [13].

BNP was measured by a radioimmunoassay technique [14]. In brief, immunoreactive BNP was extracted by use of Sep-Pak C18 cartridges eluted by 80% ethanol in 4% acetic acid. Radioimmunoassay was performed using a rabbit anti-BNP antibody produced as previously described [14]. There was no cross reactivity with ANP. Intra- and interassay coefficients of variation were 6% and 11%, respectively. The detection limit was 0.5 pmol/l.

2.5. Statistical evaluation
Data are presented as mean±S.E.M. if not stated otherwise. Differences within groups were tested by paired t-test and between groups by unpaired t-test analyses. P<0.05 was considered significant. Correlations between variables were tested by means of linear regression.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Ejection fraction
Out of the 48 patients who had more than one EF and natriuretic peptide determination, three patients (6%) developed clinical congestive heart failure (NYHA II–III). Fifteen of the 48 patients (31%) also experienced a decrease in EF of ≥0.10 (range: 0.10–0.22). Nine (19%) of these patients had a reduced, final EF (<0.50). The course of EF values in these nine patients is shown in Fig. 1.


Figure 1
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  		Fig. 1 Serial measurements of EF by radionuclide cardiography (MUGA), ANP and BNP in 9 patients that had a significant decrease in EF and a final EF less than 0.50.

 
The baseline EF (0.59±0.03) and age (54±4 years) of patients that decreased in EF during treatment was similar to that of patients with stable values (EF: 0.56±0.02, age: 55±2 years).

3.2. N-ANP and BNP
Low EF values were associated with high N-ANP and BNP concentrations, both for all samples (n=208) and for only the first sample of each patient (N=107). However, the relation is not a simple, linear one, nor is it a linear correlation to the logarithmic transformation. The best model seems to be a bi-linear model with a breaking point around EF=0.50, i.e. the lower, normal limit of EF. Using this model we found a highly positive correlation between EF and N-ANP (r=0.78; P<0.001) and BNP (r=0.76; P<0.001) for EF values below 0.50, whereas no significant correlation was found for EF≥0.50 (Fig. 2). Neither the changes in N-ANP and BNP (Fig. 3) nor the baseline levels (Fig. 4) were correlated to the changes in EF.


Figure 2
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  		Fig. 2 Scatterplots of N-ANP (upper panel) and BNP (lower panel) in 107 patients. For EF values <0.50 a significant correlation was found with N-ANP (r=–0.78; P<0.001) and for BNP (r=–0.76; P<0.001). For EF≥0.50 no correlation was found (N-ANP: r=–0.15, P>0.05; BNP: r=–0.02, P>0.05).

 


Figure 3
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  		Fig. 3 Scatterplots of change in N-ANP (upper panel) and BNP (lower panel) in relation to change in EF during treatment with anthracyclines in 48 patients with serial determinations. No correlation was found between change in EF and N-ANP (r=–0.02; P>0.05) or in BNP (r=–0.20; P>0.05). LVEF.

 


Figure 4
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  		Fig. 4 Scatterplots of baseline levels of N-ANP (upper panel) and BNP (lower panel) in relation to change in EF during treatment with anthracyclines in 48 patients. No correlation was found between change in EF and N-ANP (r=–0.02; P>0.05) or BNP (r=–0.20; P>0.05).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The aim of the present study was to evaluate whether measurements of natriuretic peptides in a safe way could replace EF determinations as a monitoring tool for anthracycline induced cardiotoxicity. We found strong correlations between baseline EF levels and the natriuretic peptides for patients with reduced EF. This is in accordance with several previous studies in cardiac patients demonstrating that increased plasma concentrations of natriuretic peptides reflect impaired cardiac function [7]. For normal levels of EF no such correlation with natriuretic peptide were found, indicating that the peptide release is not increased without impaired cardiac function.

It is important, however, to emphasize that disagreements between the methods does not necessarily disqualify the use of natriuretic peptides. In one study the prognostic value of natriuretic peptides was actually stronger than EF in patients with CHF [15]. This has not yet been demonstrated in prediction of cardiac failure development, and we did not design the study to evaluate the prognostic values of the different methods, i.e. MUGA determination of EF was used as the reference.

In this study the correlations between N-ANP or BNP and EF were comparable. However, the natriuretic peptides reflect different aspects of cardiac dysfunction. BNP is mainly released from the ventricles in response to increased filling pressure. ANP is released from the atria in response to stretch. It has previously been suggested that changes in diastolic function precede changes in systolic function in response to anthracycline induced cardiotoxicity [16–18]. If this is true, ANP could be a good early marker since impaired diastolic filling would lead to increased stretch and thereby ANP release. That ANP and BNP do not reflect the same aspects of CHF, is supported by an only moderate correlation between the two peptides in our study.

Only 3% of the patients developed clinical CHF. This is in accordance with a previous study using the same criteria for cessation of therapy as we did. They found that 2.9% developed clinical CHF [3]. In a large retrospective study of more than 4000 patients an incidence of clinical CHF of 2.2% was found [1]. However, in our study almost 20% of the patients with serial EF measurements had a significant decrease in EF to a level below the normal limits and anthracycline treatment had to be discontinued. This supports the recommendation of monitoring cardiac function in anthracycline treated patients, since a decision algorithm similar to ours was observed to reduce the number of patients developing overt CHF from 21% to 2.9% [3].

Can we predict which patients will have a decrease in EF values? In a retrospective study it was found that low baseline EF and high age were predictive of developing clinical heart failure [19]. However, we did not find any difference in baseline EF or age between the group with a decrease in EF and those without. Thus, simply measuring baseline EF does not seem useful for predicting which patients are likely to experience clinical cardiotoxicity from anthracycline. Therefore, with a generally accepted, lower normal EF limit of 0.50 natriuretic peptide measurements are not a sufficiently sensitive alternative to serial measurements of EF during anthracycline therapy.

It has previously been suggested that the potential value of N-ANP is in the long-term follow-up, rather than during chemotherapy [11]. In another study, it was found that BNP increased during anthracycline treatment but that the increase was transient and thus not predictive of the clinical course [12] and only individuals in whom BNP remained elevated developed overt CHF, also suggesting a potential role for BNP in long-term follow-up albeit not as a guide for anthracycline interruption [12].

However, instead of baseline values it is possible that serial measurements of the natriuretic peptides could be useful. We therefore compared the change in N-ANP and BNP with that of EF. Unfortunately we did not find any correlation at all. Serial measurements of natriuretic peptides therefore do not seem useful as a substitute for serial EF measurements.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Although we found a strong correlation between N-ANP or BNP and EF neither baseline values nor serial measurements of these peptides seem useful as a substitute for serial EF measurements in patients treated with anthracyclines. Whether the natriuretic peptides posses long-term prognostic information in patients treated with anthracyclines remains to be shown.


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

  1. Von Hoff D.D., Layard M.W., Basa P., Davis H.L. Jr, Von Hoff A.L., Rozencweig M., et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med (1979) 91(5):710–717.[Abstract/Free Full Text]
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  13. Schutten H.J., Johannessen A.C., Torp-Pedersen C., Sander-Jensen K., Bie P., Warberg J. Central venous pressure--a physiological stimulus for secretion of atrial natriuretic peptide in humans? Acta Physiol Scand (1987) 131(2):265–272.[Web of Science][Medline]
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