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European Journal of Heart Failure 2007 9(5):537-541; doi:10.1016/j.ejheart.2006.12.004
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© 2006 European Society of Cardiology

Plasma B-type natriuretic peptide concentration in β-thalassaemia patients

Athanasios Aessoposa, Dimitrios Farmakisa,*, Aikaterini Polonifia, Maria Tsironia, Christina Fragodimitrib, Antonia Hatziliamib, Markisia Karagiorgab and Evanthia Diamanti-Kandarakisa

a Cardiac Outpatient Clinic for Hemoglobinopathies, First Department of Internal Medicine, University of Athens Medical School, Laiko General Hospital Greece
b Thalassemia Unit, Aghia Sophia Children's Hospital Athens, Greece

* Corresponding author. 182 Kallergi St, Piraeus 18544, Greece. Tel./fax: +30 210 461 9778. E-mail address: dimitrios_farmakis{at}yahoo.com


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: Plasma B-type natriuretic peptide (BNP) concentration has significant diagnostic accuracy and prognostic value in various forms of heart disease. Whether BNP is also useful in the evaluation and management of thalassaemia heart disease remains to be determined.

Methods and results: Eighty three thalassaemia major patients; 8 with acutely decompensated heart failure (New York Heart Association [NYHA] class III or IV, group A), 25 with NYHA class II symptoms and impaired systolic left ventricular function (ejection fraction<55% or fractional shortening<30%, group B) and 50 with normal systolic function (group C), as well as 50 healthy controls, were studied. Assessment included history, physical examination, Doppler echocardiography and plasma BNP determination. Mean BNP levels were 431±219 pg/mL (range, 283–890 pg/mL) in group A, 158±31 pg/mL in group B, 176±54 pg/mL in group C and 43±24 pg/mL in controls. BNP levels were significantly higher in group A (p<0.001), but did not differ between groups B and C. Moreover, BNP was not correlated with left ventricular end-diastolic diameter, left ventricular mass, right ventricular diameter index, Doppler diastolic indexes (except in group C), the mean 2-year serum ferritin concentration or the peak serum ferritin concentration in any of the three patient groups.

Conclusion: A potential deficiency of BNP-related neurohormonal mechanisms may impair its clinical usefulness in thalassaemia major.

Key Words: Thalassaemia • Natriuretic peptides • BNP • Heart failure

Received May 25, 2006; Revised September 9, 2006; Accepted December 4, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Cardiac complications in thalassaemia major (TM) represent a leading cause of mortality and are mainly characterized by left ventricular (LV) dysfunction, caused by iron overload, which leads progressively to heart failure and finally death [1,2].

Natriuretic peptide hormones have emerged as important candidates for development of diagnostic tools and therapeutic agents in cardiovascular disease [3]. B-type natriuretic peptide (BNP) is a 32-amino-acid polypeptide released primarily by the ventricular myocardium in response to myocyte stretch [3,4]. BNP levels are elevated in patients with regional or global impairment of LV systolic or diastolic function followed by increased LV wall stretch. BNP levels correlate with both the severity of symptoms and the prognosis of the disease [5,6].

Given the particular pathophysiology of thalassaemia heart disease, in which iron-induced myocardial injury plays a key role, the response of natriuretic peptides may not be the same as that observed in other conditions. The aim of this study was therefore, to assess whether BNP is also useful in the evaluation and management of thalassaemia heart disease.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Study population
The study population was recruited from the Cardiac Outpatient Clinic for Hemoglobinopathies at Laiko General Hospital, Athens, Greece. The initial inclusion criteria included a diagnosis of thalassaemia major and a normal renal function. Three patient groups were studied. Group A consisted of 8 consecutive patients admitted to our Department with acutely decompensated chronic heart failure and New York Heart Association (NYHA) functional class III or IV symptoms. Group B consisted of 25 consecutive patients with NYHA class II symptoms and systolic LV dysfunction. Group C consisted of 50 patients in NYHA class I with normal systolic LV function, matched for age with the patients in group B. Systolic LV dysfunction was defined as an echocardiographically-determined ejection fraction <55% or a fractional shortening <30%, as previously described [2]. Fifty healthy individuals, matched for age and sex, who were non-smokers, with no evidence of anaemia, hepatic, respiratory or cardiovascular disease, served as controls.

All patients were on regular blood transfusions and were receiving iron chelation with deferoxamine, administered via a subcutaneous pump at a dose of 40-50 mg/kg/day over 8-12 h, 5-7 days a week during the 2-year period preceding the study.

Baseline assessment included history, physical examination, complete Doppler echocardiography and blood sampling, all performed during a single visit. With the exception of the patients in group A, who were studied on the day of admission, all visits were scheduled in the mid-interval between two planned transfusions. All group B patients were on cardiovascular medication which was withheld for 7 days prior to the visit. Group C patients were not on cardiovascular medication. The study was approved by the local ethics committee and all subjects gave informed consent.

2.2. BNP measurement
Whole blood samples were collected by venipuncture into EDTA tubes. All samples were kept at room temperature and analyzed within 1 h of the draw time, using the Triage BNP assay (Biosite, San Diego, California, U.S.A.).

2.3. Echocardiography
Complete M-mode, two-dimensional and Doppler (pulsed-wave, continuous-wave and colour) echocardiography was performed at rest, using an Aloca ProSound SSD 5500 ultrasound system (Aloca Co, Tokyo, Japan). All echo-Doppler studies were carried out by the same observer (AA). Chamber dimensions were measured according to the recommendations of the American Society of Echocardiography (ASE) [7]. Left ventricular mass was calculated using the ASE-cube formula as corrected by Devereux et al. [8]. Left ventricular end-systolic wall stress was calculated according to the literature [9]. LV volumes were estimated by the method of discs, following the ASE recommendations and using apical two- and four-chamber views [10]. Cardiac dimensions, LV mass and LV volumes were indexed to body surface area to correct for potential differences in body constitution. Left ventricular diastolic function was assessed by the pulsed-Doppler recording of mitral inflow and the pattern of LV filling was evaluated according to the literature [11].

2.4. Statistical analysis
Statistical analysis was performed using the SPSS 10.0 statistical software package (SPSS Inc., Chicago, Illinois). Continuous variables are expressed as mean±1 standard deviation. One-way analysis of variance (ANOVA) was used to compare continuous variables among the study groups, followed by Bonferroni post-hoc analysis for the multiple comparisons between groups. Bivariate correlation was performed to investigate for potential relationships between variables. A p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
Patients' demographic and haematological data are reviewed in Table 1. Mean haemoglobin levels in the 2-year period preceding the study were significantly lower in group A versus group C, but did not differ between groups B and C. Mean 2-year serum ferritin concentration and peak serum ferritin concentration were both significantly higher in group A.


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  		Table 1 Demographic and haematological data in the three thalassaemia patient groups

 
Echocardiographic and Doppler parameters in patients and controls are shown in Table 2. In comparison with controls, thalassaemia patients had significantly larger cardiac diameters and LV volumes, lower LV shortening and ejection fractions (with the exception of group C patients) and increased E and E/A LV diastolic filling indexes. All patients in group A, 17 of 25 in group B (68%) and 20 of 50 patients in group C (42%) had a restrictive LV filling pattern. In a comparison of the three patient groups, group A patients had significantly higher LV diameters, volumes and mass and significantly lower LV shortening and ejection fractions, compared to patients in groups B and C. Similar differences were encountered between groups B and C. Diastolic E/A index was significantly higher in groups A and B compared to group C.


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  		Table 2 Echocardiographic-Doppler data in the three thalassaemia patient groups and the controls

 
Mean BNP levels were 431±219 pg/mL (range, 283-890 pg/mL) in group A, 158±31 pg/mL (range, 111-222 pg/mL) in group B, 176±54 pg/mL (range, 58-289 pg/mL) in group C and 43±24 pg/mL in controls (normal values are reported to be <100 pg/mL). Group A patients had significantly higher BNP levels than all other groups (p<0.001). Similarly, controls had significantly lower BNP levels with respect to all three thalassaemia patient groups (p<0.001). However, mean BNP did not differ significantly between groups B and C. Furthermore, BNP was correlated with E and E/A diastolic indexes in group C patients (r=0.579 and 0.486, respectively, both p<0.01), while no such correlation was found in groups A and B. Finally, LV ejection fraction, LV end-diastolic diameter and volume, LV mass, LV end-systolic wall stress, right ventricular diameter, mean 2-year serum ferritin concentration or the peak serum ferritin concentration were not correlated with BNP levels in any of the three patient groups.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
BNP, along with the rest of natriuretic peptides, is believed to play a fundamental role, in compensation of heart failure, participating in cardiovascular remodelling and volume homeostasis [12]. BNP has a number of beneficial systemic effects, including increase in urinary volume and sodium output, peripheral vasodilation, central and peripheral sympathetic nervous system inhibition, renin-angiotensin-aldosterone axis inhibition, myocardial lusitropic action and possibly anti-proliferative and anti-apoptotic effects in cardiac and vascular tissues [3]. Recent studies have stressed the diagnostic value of BNP in establishing or ruling out the diagnosis of heart failure in patients presenting with dyspnoea, as well as its prognostic significance in predicting morbidity and mortality both in patients with heart disease and in the general population [12-14].

Three previous reports of atrial natriuretic peptide (ANP) levels in thalassaemia major patients have also shown that in asymptomatic patients with normal systolic LV function, natriuretic peptide levels are elevated compared to normal subjects [15-17]. Furthermore, two of these studies of ANP in β-thalassaemia, plus a recent one on BNP and the present study also agree that natriuretic peptide levels correlate closely with the presence of diastolic LV dysfunction [16-18]. This finding suggests that BNP may be an early marker of cardiac impairment in thalassaemia major cases with normal systolic LV function. In the third of the previously reported studies on ANP in thalassaemia major patients with normal LV function, although basal ANP levels were elevated, no additional increase in ANP was observed after volume overload following transfusion, in contrast to normal subjects who were transfused with a similar amount of blood [15]. The absence of the expected ANP response to volume overload made the authors question the usefulness of ANP measurement for the evaluation of thalassaemia major patients.

Accordingly, in the present study, thalassaemia major with clinical symptoms of heart failure, impaired systolic LV function, cardiac remodelling and often diastolic LV dysfunction did not show the expected increase in BNP levels. As a matter of fact, patients with impaired LV contractility (group B), whose shortening fraction ranged between 22% and 25%, despite having been off cardiovascular medication for a week and with NYHA class II symptoms, had similar BNP levels to the asymptomatic patients with normal LV contractility (group C). Moreover, although patients admitted for severe heart failure with NYHA class III or IV symptoms (group A) had higher BNP concentrations than patients with systolic LV dysfunction and NYHA II symptoms (group B), the values never reached those generally encountered in decompensated heart failure of other causes. The mean BNP level in group A was 431 pg/mL, which is lower than the 600 pg/mL threshold used in clinical practice for the definite diagnosis of dyspnoea of cardiac origin and much less than the values observed in patients with similarly severe heart failure. In fact, only one of the eight patients in group A had a BNP level higher than 600 pg/mL. Moreover, factors that may affect BNP response such as LV end-diastolic diameter, LV mass, LV end-systolic wall stress and right ventricular diameter did not show any correlation with BNP levels. Similarly, mean 2-year serum ferritin concentration and peak serum ferritin concentration were not correlated with BNP. On the other hand, although BNP was correlated with diastolic LV function indices in patients with preserved LV function, in those with impaired systolic LV function, the coexistence of diastolic dysfunction did not seem to affect BNP measurements.

A possible explanation of the observed discrepancy between plasma BNP levels and LV function in β-thalassaemia patients could be the presence of iron overload, which is considered to be the primary cause of cardiac and other complications in regularly transfused cases. Iron, and primarily its unbound fraction, is believed to exert its action mainly by inducing free radical production, hence causing oxidative damage to cell membranes and other cellular structures. Iron-induced heart disease is the main cause of mortality in thalassaemia patients; however, the endocrine system is also particularly vulnerable to iron overload. As a matter of fact, endocrine dysfunction represents the most frequently encountered complication in thalassaemia patients, leading to a wide spectrum of endocrine abnormalities, including gonadal insufficiency, hypothyroidism, diabetes mellitus, hypoparathyroidism and growth hormone deficiency [1]. In this context, since the heart has been known to be an endocrine organ since the 1950s [3], cardiac iron overload may potentially affect myocardial endocrine function. Thus, multiple points in the BNP pathway may be disturbed, leading to an inadequate BNP response.

The observed elevation of basal BNP levels in asymptomatic thalassaemia patients with normal LV function may be related to the high output state resulting from chronic anaemia in combination with the frequent occurrence of diastolic LV dysfunction and the fact that iron-induced deterioration of BNP production may not yet be severe in these patients. In contrast, symptomatic patients with clearly impaired systolic LV function probably have a more profound impairment of BNP production. Indeed, recent studies to assess myocardial iron load by magnetic resonance imaging have shown that thalassaemia major patients with impaired systolic LV function also have severe cardiac iron overload [19].

On the other hand, according to MRI studies, thalassaemia major patients with normal systolic function have a variety of different degrees of myocardial iron load. In other words, patients with significant myocardial iron overload may have impaired BNP production before obvious systolic LV function develops. Furthermore, a wide variety of factors affect the degree of iron burden and hence the resulting iron-induced complication, including BNP deterioration, in different thalassaemia populations. These factors include the intensity of prior therapy, patients' compliance with the proposed regimens, the variable efficacy of iron chelators as well as the genetic heterogeneity of the disease. Thus, thalassaemia patients in different study populations may have a different degree of BNP response to LV wall stretch.

The results of the present study are in line with those recently published by Tanner et al. [20] which showed that BNP was weakly related to myocardial iron load, as assessed by cardiovascular magnetic resonance T2* imaging, and was abnormal only in a small number of patients with impaired LV function. Similarly to thalassaemia, in diabetes mellitus, which is also associated with a particular form of cardiomyopathy, it has also been shown that BNP levels cannot be used for the detection of mild LV diastolic dysfunction in asymptomatic patients [21].

Both in the present and in previous studies, we used a cut-off value for LV ejection fraction of 55%, which is higher than the widely applied 50% [2]. It has been previously shown that thalassaemia is characterized by a high output state, as a result of the chronic tissue hypoxia resulting from chronic anaemia, and therefore a LV ejection fraction around 50% may mask an impaired LV function status [2,22,23].

The present study, with the limitation of the relatively small number of patients with severely impaired cardiac function, suggests a defective BNP response in thalassaemia major patients. The impaired responsiveness of BNP implies in turn the loss of a complex compensatory mechanism, a fact that may potentially play a role in the pathogenesis of thalassaemia heart disease. On the other hand, iron overload, which seems to be responsible for the deterioration of both LV function and BNP production, may not allow a clear prediction of cardiac condition by BNP measurement, especially in the presence of systolic LV dysfunction. Based on the results of the present study, BNP may not be an appropriate tool to discriminate between patients with and without LV dysfunction. Given the particularities associated with thalassaemia heart disease, further investigation in this field is warranted to clarify the diagnostic validity of natriuretic peptides in this population and at the same time to add to our understanding of the pathogenetic pathways underlying this complex condition.


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

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This Article
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