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European Journal of Heart Failure 2007 9(5):531-536; doi:10.1016/j.ejheart.2006.11.004
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© 2006 European Society of Cardiology

NT-proBNP levels and diastolic dysfunction in β-Thalassaemia major patients

Dimitrios Th. Kremastinosa, Dimitrios P. Tsiaprasb,*, Anna G. Kostopouloub, Eftihia S. Hamodrakab, Antigoni S. Chaidarogloub and Evangelia D. Kapsalib

a 2nd University Department of Cardiology, Attikon General Hospital Athens, Greece
b 2nd Department of Cardiology, Onassis Cardiac Surgery Center Athens, Greece

* Corresponding author. Onassis Cardiac Surgery Center, Syngrou 356, 17674 Athens Greece. E-mail address: dtsiapras{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The early diagnosis and treatment of heart failure in β-thalassaemic patients is related to survival. Iron alone or in combination with other factors causes diastolic dysfunction, which usually precedes systolic dysfunction. NT-proBNP is a sensitive biomarker of ventricular dysfunction.

Aim: To evaluate NT-proBNP in non heart failure β-thalassaemic patients.

Methods: Fifty-two β-thalassaemia major patients (mean age: 27.2±12.5 years) with normal LV systolic function, underwent NT-proBNP measurement and a thorough Doppler-echocardiographic and pulsed tissue-Doppler study, 4 days following blood transfusion. Fifty-two age matched healthy controls were also studied.

Results: NT-proBNP and E/E' ratio were increased in thalassaemic patients compared with controls [(469±171 vs 262±51 pmol/l, p<0.001) and (10.8±4.0 vs 6.6±1.1, p<0.001)] and were well correlated (r: 0.54, p<0.01). Although NT-proBNP levels were increased in patients with higher E/E' ratios (E/E' <8: 354±119, 8–15: 516±177, >15: 565±114 pmol/l, ANOVA p: 0.002) this increase only became statistically significant in the 3rd decade of life, while E/E' ratio increased in the 4th decade.

Conclusion: NT-proBNP increases in β-thalassaemia major patients and is related to age and LV diastolic dysfunction. NT-proBNP appears to be an early biomarker of LV diastolic dysfunction, compared with the conventional Echo-Doppler indexes.

Key Words: NT-proBNP • β-thalassaemia major • Diastolic dysfunction

Received April 17, 2006; Revised September 22, 2006; Accepted November 27, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Historically β-thalassaemia only occurred in countries bordering the Mediterranean Sea, extending in a line to countries in the Far East. However, it has now become a universal health problem since thousands of people have emigrated from these countries to the EU and USA. Despite progress in chelation therapy, heart failure is still the main cause of death in patients with β-thalassaemia major [1,2]. Haemochromatosis [2] alone or in combination with immunogenetic factors [3-5] is the main pathogenetic mechanism of heart failure development, usually expressed as either left ventricular (LV) systolic or diastolic dysfunction. Diastolic dysfunction usually precedes systolic dysfunction, and is mainly attributed to myocardial iron deposition [6]. Amino-terminal pro-brain natriuretic peptide (NT-proBNP) seems to be a reliable index for detecting isolated diastolic dysfunction [7], levels of NT-proBNP increase as diastolic pressure in the left or right ventricle rises and the patients’ functional status worsens [8]. In this study we investigated NT-proBNP levels in β thalassaemia patients with preserved left ventricular systolic function.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patient population
We enrolled 60 patients (aged from 5 to 46 years, mean 27±12) with homozygous β-thalassaemia major, consecutively referred to our Outpatient Thalassemia Clinic for routine cardiac follow-up. Inclusion criteria were the lack of symptoms or signs of heart failure and preserved left ventricular systolic function (ejection fraction, by echocardiography, higher than 50%). Patients with (more than mild) valvular disease, signs or symptoms of coronary artery disease, rhythm disturbances, pericardial disease, acute systemic or chronic pulmonary disease and impaired thyroid, renal or liver function were excluded. In all patients, transfusion therapy had been started before the age of 5 years and iron chelation therapy with deferoxamine had been started before the age of 10. Fifteen patients had been receiving deferiprone for chelation therapy for the last 1-2 years. None of the patients had received any cardiological medical treatment. The mean serum ferritin value was derived from the mean of 30 values obtained at 2-month intervals over the previous 5 years.

All patients underwent a thorough clinical, electrocardiographic and echocardiographic examination on the fourth day following blood transfusion, and blood samples were collected for NT-proBNP levels measurements on the same day. The protocol was approved by the hospital institutional review board and written informed consent was obtained from all patients.

2.2. Control subjects
Fifty-two healthy, age matched volunteers (range 5-46, mean 27.2±12.5 years) with no clinical, electrocardiographic or echocardiographic evidence of cardiovascular disease were randomly selected to serve as control subjects.

2.3. Echocardiographic study
Echocardiograms were performed using the commercially available Vivid 7 (GE Vingmed, Horten, Norway) echocardiographic system. The study was carried out with the subject in the left decubitus position, using multifrequency 2.5-5 MHz phased array transducers. The heart was scanned from all standard views and 2 cardiac cycle loops from each view were digitally stored on optical disks. M-Mode, 2D and Doppler examination methodology has been previously described [6]. Measurements of cavity dimensions were carried out according to ASE guidelines [9]. Volumes were calculated using the biplane Simpson's rule.

In order to record the mitral inflow pattern, the sample volume was placed at the tips of the mitral leaflets with the aid of colour Doppler. For Tissue Doppler Velocity recordings, the sample volume was placed at the basal interventricular septum (at the mitral annulus), as this has been shown to have better correlation with LV diastolic pressure [10]. Care was taken for the ultrasound beam to be parallel to the interventricular septum. Tissue velocities were recorded at a speed of 100 mm/sec using optimal filters and scale.

2.4. NT-proBNP measurements
In the β-thalassaemia patients, blood samples for the measurement of NT-proBNP were drawn on the 4th day following transfusion. Blood samples for patients and controls were collected following 30 min rest in the supine position, 5 cc samples were collected in BD Vacutainer SST gel clotter tubes. All samples were centrifuged at 3000 c/min for 10 min at 4 °C within 30 min of collection. Plasma was extracted and stored in –80 °C until analysis. All samples were assayed in duplicate. NT-proBNP measurements were performed with a competitive enzyme immunoassay kit from Biomedica (Wien, Austria). This assay uses a polyclonal NT-proBNP (8-29) antibody directed at the NT-proBNP molecule. Intra-assay and inter-assay variability was 4-6.5% and 3.8-4.4%, respectively.

2.5. Intra-and Inter-Observer variability
Intra-observer variability in assessment of Doppler and tissue Doppler measurements was determined by measuring 10 cardiac cycles in 10 mitral flow and mitral annular velocity tracings on two separate occasions. The determination of inter-observer variability was based on analysis of the same sets of cardiac cycles by an independent observer. Linear regression analysis was used for both parameters.

2.6. Statistical analysis
All tests were carried out using the commercially available Statistica 6.0 software package. Data are presented as mean±1 SD, while a chi-square test for goodness of fit was performed to test if the distribution of observations was normal (Gaussian). If parameters were not normally distributed, statistical testing was performed following logarithmic transformation. Statistically significant differences between 2 groups of continuous variables were determined by using the unpaired student's t-test and the non-parametric Mann-Whitney U, as appropriate. One-way Analysis of Variance (ANOVA) was used to assess the differences between three or more consecutive groups; post hoc adjustments for multiple comparisons were assessed with Bonferroni’s method. Correlation of NT-proBNP values and quantitative parameters was estimated using Spearman rank correlation test and linear regression analysis. A value of p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Of the 60 patients enrolled, three were excluded due to chronic hepatitis, two due to hypothyroidism and three due to paroxysmal supraventricular arrhythmia. Therefore, 52 patients (mean age 27.2±12.5 years, 32 male) were included in the study.

3.1. Clinical findings
Patients and controls were well matched for age; however, body surface area was lower in the patient group. At the time of examination, there was no significant difference in heart rate between the groups, but systolic and diastolic blood pressures were lower in patients than controls (Table 1).


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  		Table 1 Clinical, haematological and biochemical characteristics of β-thalassaemia major patients and healthy controls

 
3.2. Haematological and biochemical profile
Haemoglobin levels, which ranged from 10.8 to 12.9 g/dL (mean 11.8±0.4 g/dL), were significantly lower in the patient than in the control group (Table 1), and patients' mean serum ferritin was 1888±855 ng/mL. NT-proBNP levels were significantly higher in the patients than in the controls (469±171 vs 262±51 pmol/l, p<0.001).

3.3. Echocardiographic-Doppler Findings
Left ventricular, left atrial and right ventricular echocardiographic study findings are summarized in Table 2. Left ventricular dimensions and volumes were slightly increased in the thalassaemic patients compared to the controls, but there was no difference in fractional shortening or ejection fraction. Maximal left atrial and right ventricular diameters were also increased in the patient group.


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  		Table 2 Echocardiographic study of β-thalassaemia major patients and healthy controls

 
Mitral inflow and mitral annular tissue velocity Doppler echocardiographic findings are summarized in Table 3. Mitral E wave velocity was increased in the patient group, but there was no difference in A wave. E/A ratio was increased in patients and the E wave deceleration time decreased.


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  		Table 3 Doppler echocardiographic and tissue doppler velocity study of β-thalassaemia major patients and healthy controls

 
The mitral annulus tissue Doppler study showed decreased systolic and diastolic velocity waves in the patient group. Mitral inflow E wave velocity to E' mitral annular velocity ratio (E/E') was higher in the thalassaemic patients compared to the control subjects (p<0.001), (Table 3).

3.4. NT-proBNP and diastolic indexes
NT-proBNP levels did not have any correlation with haemoglobin levels or left ventricular systolic function indexes. They were better correlated (among all echocardiographic parameters) with the ratio of E wave mitral flow/E' wave mitral annular velocity (r: 0.54, p<0.01), (Fig. 1). Multivariate analysis showed that age was an independent factor for NT-proBNP increase. For every year, there was a 7.22 pmol/l increase in NT-proBNP levels (p<10–4, r: 0,529). A correlation was also detected between NT-proBNP levels and mean ferritin levels (r: 0.43, p<0.01).


Figure 01
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  		Fig. 1 Correlation of NT-proBNP levels with the E mitral/E'mitral annular velocity ratio (E/E') in the whole spectrum of patients with preserved left ventricular function.

 
The patient population was divided into 3 groups according to E/E' ratio. Cut off values of 8 and 15 were used, as these have been shown to discriminate patients with low and high left ventricular end diastolic pressure [10]. Seven patients had an E/E' ratio >15 and were considered as patients with diastolic dysfunction and 17 had an E/E' ratio <8 and were considered normal. Twenty-eight patients were in the "grey-intermediate" echo-Doppler zone with an E/E' ratio between 8 and 15. However, NT-proBNP levels showed a statistically significant increase in the groups with a higher E/E' ratio (ANOVA p=0.002) which was detected from the 2nd (intermediate) group (1st vs 2nd p<0.05), (Table 4, Fig. 2).


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  		Table 4 Clinical, haematological and biochemical parameters in β-thalassaemia major patients with increasing values of E mitral/E' mitral annulus velocity ratio (Group 1: E/E' <8, Group 2: E/E':8-15, Group 3: E/E' >15)

 


Figure 02
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  		Fig. 2 NT-proBNP levels in β-thalassaemia major patients with increasing E/E' ratios (Group 1: E/E' <8, Group 2: E/E': 8-15, Group 3: E/E' >15).

 
Haemoglobin levels were similar between these 3 groups, while age and total transfused blood units showed an increase in the groups with a higher E/E' ratio (ANOVA p<0.001 for both). Mean serum ferritin was also increased in the 3rd (E/E' ratio >15) group (ANOVA p=0.025, 1st vs 3rd p<0.05), (Table 4).

In order to further study the effect of aging on NT-proBNP levels and diastolic dysfunction, the patient population was divided into decades. Both NT-proBNP levels and E/E' ratio showed a statistically significant increase throughout patients' life (Table 5). NT-proBNP levels appear to increase earlier, in the 3rd decade of life, being significantly higher than levels in the 1st or 2nd decade (p=0.03). On the other hand, E/E' ratio seems to increase later in life, being significantly higher only in the 4th decade (1st vs 4th p: 0.04).


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  		Table 5 NT-proBNP levels and E mitral/E' mitral annulus velocity ratio (E/E') in different decades of patients' lives

 
Linear regression analysis of echocardiographic and Doppler measurements showed a correlation coefficient of 0.95-0.98 for intra-observer and 0.93-0.96 for inter-observer variability.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This is the first study assessing NT-proBNP levels in β-thalassaemia major. The most important finding of the present study is the increase of NT-proBNP in β-thalassaemia patients compared with normal controls. This is more evident in the 3rd decade of life before the conventional Doppler indexes become apparently abnormal. The latter implies that the increase of NT-proBNP seems to be a prodromal finding of early diastolic dysfunction. In addition, we also found a positive correlation between NT-proBNP, patients’ age and mean serum ferritin while no correlation was observed between NT-proBNP and haemoglobin, indicating that haemoglobin levels do not significantly affect NT-proBNP changes.

4.1. NT-proBNP and BNP
Previous studies dealing with natriuretic peptides in β-thalassaemia, found that atrial natriuretic peptide (ANP) is increased in asymptomatic patients with diastolic dysfunction [11,12].

NT-proBNP and BNP have emerged as sensitive biomarkers for the diagnosis, prognosis and treatment of heart failure [13-15]. Patients with established diastolic dysfunction (E/E'>15) have significantly increased NT-proBNP levels while no correlation seems to exist between NT-proBNP and E' mitral annulus velocity wave [16], which is a relatively load-independent indicator of left ventricular relaxation. The role of BNP in the diagnosis of mild forms of LV diastolic dysfunction is still uncertain [17]. In contrast, NT-proBNP which circulates at higher plasma concentrations and also has a longer half-life in comparison with BNP, seems to be a more accurate biomarker in detecting patients with isolated LV diastolic dysfunction [7].

4.2. E/E' ratio
Transmitral flow velocity in combination to annular flow velocity E/E' has been shown to be the best Doppler echo predictor of diastolic dysfunction, by combining the influence of transmitral pressure and myocardial relaxation [10,18-20]. However, recent studies have shown that Doppler indexes are not useful for the detection of mild diastolic dysfunction [21,22]. Mild diastolic dysfunction is associated with increased filling pressures at exertion only and, therefore, is possibly to be missed by conventional echo Doppler study, which is usually performed at rest.

4.3. Left and right ventricular dysfunction in β-thalassaemia major
Myocardial iron deposition does not affect LV relaxation but directly causes LV myocardial diastolic dysfunction which is expressed as transmitral pseudo-normalized or restrictive blood flow velocity pattern [6]. Iron deposition alone does not necessarily lead to heart failure development without the co-existence of other factors. In 1964, Engle et al observed that patients who died of congestive heart failure had a wide range of iron transfused (3-104 g) and age (6 to 31 years) [1]. Later, it was documented that the pathogenetic mechanisms of heart failure in β-thalassaemia major are poorly understood and multifactorial in aetiology [23]. Apart from the direct toxic effect of iron deposited in the myocardium, the immunogenetic background of the patients plays also an important role [3-5].

In addition, immune mediated myocardial dysfunction acts through immunologic or genetically defined mechanisms in combination with the repetitive antigenic stimulus due to multi-blood transfusions and iron chelation therapy [3,4,24]. Heart failure presents as LV dilatation and systolic dysfunction in the vast majority of patients (82.7%). In the remaining patients, it is expressed as right ventricular dilatation and systolic dysfunction either alone [25] or in combination with LV myocardial restriction and high pulmonary artery pressures [6].

In this respect, iron seems to be the protagonist in heart failure development, causing diastolic dysfunction before the heart failure symptoms become evident [6]. Therefore, early diagnosis of diastolic dysfunction in β-thalassaemic patients is important, as it has been shown that early diagnosed heart failure treated with intensification of iron chelation therapy, higher haemoglobin levels and ACE inhibitors, had a better survival [26] reaching that observed in the non-thalassaemic heart failure population.

4.4. Study limitations
Iron deposition in the myocardium causes mild to moderate fibrosis and disruption of sarcomeres along with iron containing granules between myofibrils. Cardiac Magnetic Resonance can be used to estimate the amount of iron deposition in the myocardium at the time of examination, while mean serum ferritin is highly correlated with the total amount of iron deposited in the organ and tissues, which finally leads to chronic fibrosis of the myocardium [27]. In this study we measured 5-year mean serum ferritin levels in order to better estimate the consequences of chronic iron myocardial deposition.

β-thalassaemia is a multifactorial disease; however, all our patients had normal function of their vital organs and systems. Therefore, NT-proBNP changes reflect left ventricular dysfunction.

4.5. Clinical implications
Traditionally, β-thalassaemia major patients with heart failure died within 1 year of onset of symptoms [1]. By intensification of iron chelation therapy and improving mean haemoglobin levels, 5-year survival has reached 48% [26]. Since NT-proBNP is elevated in patients with LV diastolic dysfunction, a progressive increase in NT-proBNP for individual patients could be used as a starting point for intensification of iron chelation therapy and improvement in haemoglobin levels, before the appearance of heart failure symptoms.

In conclusion, NT-proBNP levels increase before Doppler echocardiographic indexes become apparently abnormal, consequently this biomarker might be used in clinical practice as an early index of LV diastolic dysfunction in β-thalassaemic patients.


   Acknowledgement
 
The authors are indebted to Mr. Pantelis Bagos for his contribution to statistical analysis.


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

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