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Table of Contents   
ORIGINAL ARTICLE  
Year : 2019  |  Volume : 12  |  Issue : 1  |  Page : 32-37
N-terminal-pro-b-type natriuretic peptide levels and cardiac hemosiderosis in adolescent β-thalassemia major patients


Department of Child Health, Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Click here for correspondence address and email

Date of Web Publication14-Jan-2019
 

   Abstract 


Background: Iron-induced cardiomyopathy remains the leading cause of mortality in patients with β-thalassemia major. Iron overload cardiomyopathy, which may be reversible through iron chelation, is characterized by early diastolic dysfunction. Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a sensitive biomarker of diastolic dysfunction.
Aim: The aim of the study is to evaluate the diagnostic value of NT-proBNP as a surrogate marker of iron overload examined with magnetic resonance imaging T2-star (MRI T2*).
Methods: Sixty-eight β-thalassemia major patients (10–18 years) with no signs of heart failure underwent NT-proBNP measurement before routine transfusion. All participants prospectively underwent cardiac MRI T2* examination within 3 months (median 19 days). Patients were divided as cardiac hemosiderosis (cardiac MRI T2* <20 ms) and nonhemosiderosis (cardiac MRI T2* >20 ms).
Results: Of 68 patients, the male-to-female ratio was 1:1.1 and the median age was 14.1 years (range: 10–17.8 years). NT-proBNP levels were not different between hemosiderosis and nonhemosiderosis patients (P = 0.233). Further receiver operating characteristic analysis resulted in no significant correlation of NT-proBNP and MRI T2* (area under the curve 0.393, P = 0.233).
Conclusion: Measurement of NT-proBNP levels cannot be used for early detection of cardiac iron overload in adolescent with β-thalassemia major.

Keywords: Adolescent, amino-terminal pro-brain natriuretic peptide, magnetic resonance imaging T2-star, β-thalassemia major

How to cite this article:
Kautsar A, Advani N, Andriastuti M. N-terminal-pro-b-type natriuretic peptide levels and cardiac hemosiderosis in adolescent β-thalassemia major patients. Ann Pediatr Card 2019;12:32-7

How to cite this URL:
Kautsar A, Advani N, Andriastuti M. N-terminal-pro-b-type natriuretic peptide levels and cardiac hemosiderosis in adolescent β-thalassemia major patients. Ann Pediatr Card [serial online] 2019 [cited 2019 Jul 19];12:32-7. Available from: http://www.annalspc.com/text.asp?2019/12/1/32/250151





   Introduction Top


Thalassemia is the most common single-gene disorder in the world with 4.5% population of the world having carrier gene and 300.000–500.000 homozygotes born each year.[1] Chronic hemolysis in β-thalassemia major necessitates regular blood transfusion to maintain adequate tissue oxygenation and leads to increase the risk of iron overload.[2] Lifelong regular transfusion in combination with increase intestinal iron absorption will cause hemochromatosis in various organs.[2],[3] Hemochromatosis alone or in combination with immunogenetic factors is the leading mechanism of heart failure development in β-thalassemia.[4],[5],[6] Although recent advances in iron-chelating agents, iron-related cardiomyopathy remains the leading cause of mortality and morbidity in thalassemia major patients, and once heart failure occurs, the prognosis is poor.[7],[8],[9] Therefore, accurate measurement of cardiac iron is important clinically as detecting early cardiac dysfunction, and adequate chelating agent will reverse the disease process.[10],[11],[12]

Iron overload cardiomyopathy is characterized by early diastolic dysfunction which precedes systolic dysfunction.[13] Serum ferritin level is widely used in the evaluation of thalassemia patient's iron state yet it is not a reliable indicator of cardiac iron.[14] Cardiac magnetic resonance imaging T2-star (MRI T2*) is an easy and highly reproducible measurement technique which correlates better with cardiac iron concentration.[15],[16] However, it is relatively expensive and it is not widely available in developing countries. Doppler echocardiography and tissue Doppler imaging can detect early cardiac dysfunction, but their clinical use is limited due to high operator dependence and poor correlation with cardiac iron.[17]

Diastolic dysfunction in β-thalassemia major patients is mainly caused by cardiac iron overload.[13] Brain natriuretic peptide (BNP) and amino-terminal pro-BNP (NT-proBNP) are released after increased cardiac stress and volume overload.[18] The increase of NT-proBNP is detected early in the course of the disease and seems to be a reliable indicator for the early detection of cardiac hemosiderosis in adult β-thalassemia patients.[19],[20],[21] However, the clinical use of this assay in children, particularly in adolescents, is limited.

The aim of this study was to explore the possible use of serum NT-proBNP levels in adolescents with β-thalassemia major to detect cardiac hemosiderosis as assessed by MRI T2*.


   Methods Top


Study population

Sixty-eight adolescent patients from Cipto Mangunkusumo Hospital and Tangerang District hospital, aged 10–18 years (36 males and 32 females) with β-thalassemia major, were enrolled in this study during June to November 2017. Inclusion criteria were asymptomatic β-thalassemia major patients with pretransfusion hemoglobin level above 7 g/dL. Patients with clinical sign and symptoms of heart failure and impaired renal and liver function were excluded from the study. All patients were receiving regular blood transfusion every 2–3 weeks and chelation therapy, which had been started before the age of 5 years. At the time of sample collection, 42 patients were receiving deferiprone (DFP) chelation therapy, 10 deferasirox (DFX), 6 combination therapy of DFP and DFX, 9 combination therapy of DFP and deferoxamine (DFO), and 1 combination therapy of DFO and DFX. The local ethics committee approved the study protocol, and written informed consent was obtained from all patients and parents.

Amino-terminal pro-brain natriuretic peptide measurements

All blood samples for NT-proBNP measurement were collected just before their scheduled packed red blood cells transfusion along with routine blood examination and serum ferritin. Samples were collected in tube and were centrifuged at 3000 rpm for 10 min within 2 h. Sera were extracted and stored in −80°C until the analysis day. NT-proBNP was measured by electrochemiluminescence assay technique using the Roche e411 cobas immunoassay analyzer (Roche Diagnostics).

Ferritin measurement

Ferritin levels were determined by electrochemiluminescence technique using the Roche e411 cobas immunoassay analyzer (Roche Diagnostics). The mean serum ferritin value was derived from the mean obtained at 3-month interval over the previous year.

Cardiac iron concentration

T2* MRI was performed at the Department of Radiology, Cipto Mangunkusumo Hospital, using 1.5 Tesla MRI scanner (Siemens Avanto Germany). Myocardial T2* was analyzed using dedicated software (Thalassemia-Tools; Cardiovascular Imaging Solutions, London, United Kingdom) with regions of interest in ventricular septum. Each image was acquired during 11–13 s breath-hold, using a gradient echo sequence. The repetition time was 200 ms, the flip angle used was 20°, echo times was 1.3–23 ms, the base resolution matrix was 128 pixels, the field of view was 39.7 cm and 19.7 cm, and the sampling bandwidth was 125 kHz. Results of cardiac T2* were categorized as severe (T2* <10 ms), mild to moderate (10 ms < T2*<20 ms), and acceptable (T2* >20 ms). The imaging procedure was performed within 3 months after laboratory examination. Clinical chemists and radiologists were blinded to any information regarding patient's medical records.

Statistical analyses

Values are expressed as mean ± standard deviation as indicated. All tests were carried out using SPSS Version 23 software (IBM Corp., NY, USA). The calculation was performed using Pearson's and Spearman's correlation coefficient, independent t-test, Mann–Whitney test, and receiver operating characteristic curve analysis. Statistical significance was set at P < 0.005.


   Results Top


We studied 68 patients (mean age: 13.9 ± 2.3, 52.9% [n = 36] males, 47.1% [n = 32] females) with transfusion-dependent β-thalassemia major. Patients demographic and baseline characteristics are presented in [Table 1].
Table 1: Baseline characteristics

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Fifty-five (80.8%) of the 68 patients had no evidence of cardiac hemosiderosis, corresponding to T2* >20 ms, whereas 13 (19.1%) patients had cardiac hemosiderosis, corresponding to T2* <20 ms. Of 13 patients with cardiac hemosiderosis, 2 of 13 had severe cardiac hemosiderosis, corresponding to T2*<10 ms. Mean ferritin serum levels were increased in patients with cardiac hemosiderosis (T2* <20 ms) compared to nonsiderosis patients (T2*>20 ms) but were statistically insignificant (P = 0.376) [Table 2]. There were three patients in cardiac hemosiderosis group who had mean ferritin serum <2500 ng/dL.
Table 2: Laboratory examination difference across cardiac iron loading

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There was no difference of NT-proBNP levels between patients with cardiac hemosiderosis and no cardiac hemosiderosis [Table 2]. There were four patients in cardiac hemosiderosis patients whose NT-proBNP levels was higher than the upper limit of normal (160 pg/mL).[22] There was weak yet insignificant correlation between NT-proBNP levels and age (r = 0.07, P = 0.569).

Further ROC analyses resulted in no significant result for NT-proBNP to detect cardiac hemosiderosis (area under the curve [AUC]: 0.39, P = 0.23, confidence interval [CI] 95%: 0.190–0.596) and severe cardiac hemosiderosis (AUC: 0.54, P = 0.85, CI: 95% 0–1) [Figure 1] and [Figure 2].
Figure 1: Receiver operating characteristic curve for predicting cardiac hemosiderosis (T2* <20 ms)

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Figure 2: Receiver operating characteristic curve for predicting severe cardiac hemosiderosis (T2* <10 ms)

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   Discussion Top


This is the first study assessing NT-proBNP levels exclusively in adolescent β-thalassemia patients. The most important finding of the present study is the inability of NT-proBNP to detect cardiac hemosiderosis in adolescent β-thalassemia patients. Furthermore, we demonstrate that NT-proBNP levels do not differ significantly between patients with cardiac hemosiderosis and normal cardiac iron loading.

β-thalassemia major cardiomyopathy is characterized by early diastolic dysfunction which precedes systolic dysfunction.[13],[23] Recent advances in chelation therapy has improved cardiac morbidity so the onset of heart failure occurs at around the third decade.[24] Thalassemia cardiomyopathy is silent in young patients while the early diagnosis is crucial since early intervention could reverse the disease process.[10],[11],[12],[25] Cardiac iron overload mainly occurs at the epicardium, and hence, the conventional endocardial biopsy does not reflect the mean cardiac iron.[16] Measuring cardiac iron loading has become possible using MRI T2* and is well correlated with cardiac iron loading in vivo.[16],[26]

The prevalence of cardiac hemosiderosis in this study (19.1%) was lower than that in other published studies. A study in Hong Kong[27] found 50% abnormal cardiac iron loading while a study in Iran[28] showed a value of 58%. Cardiac iron loading can be detected as early as 6 years of age in a study in China[29] while previous study[30] in our center reported that the youngest abnormal cardiac T2* result was 8 years of age. Although cardiac MRI T2* is the best method to detect cardiac iron overload, there is limited availability in the developing countries. Hence, ferritin serum remains the primary screening tool in our country. In our study, there were three patients with cardiac hemosiderosis who had mean ferritin serum <2500 ng/mL and most patients with high ferritin value did not have cardiac hemosiderosis proven by MRI T2*. Therefore, ferritin levels do not necessarily correlate with cardiac iron overload, and low ferritin value is not free from cardiac complication.[15] The nature of ferritin as an acute-phase reactant and higher prevalence of hepatitis coexistence may limit its use as cardiac marker of hemosiderosis.[31],[32]

Natriuretic peptides are secreted in response to increased cardiac volume and pressure overload. The release results in improved myocardial relaxation in response to myocardial stretch through vasoconstriction as well as sodium and water retention.[33] Previous studies dealing with NT-proBNP in β-thalassemia patients have shown that NT-proBNP is a sensitive biomarker to detect systolic and latent diastolic dysfunction, while NT-proBNP is slightly more sensitive than BNP due to its longer half-life.[19],[20],[30],[34]

A previous study from Tanner et al. observed that BNP was weakly related to myocardial iron and only abnormal in high values of cardiac MRI T2*.[10] Association of natriuretic peptide and cardiac iron was documented for the first time in the study of 187 asymptomatic β-thalassemia major patients by Delaporta et al.[21] They reported that NT-proBNP levels were significantly higher in patients with cardiac hemosiderosis (T2* <20 ms) and the correlation of NT-proBNP and cardiac MRI T2* was only significant in cardiac hemosiderosis patients.[21] Our present study observed that there was no significant difference between NT-proBNP levels and cardiac hemosiderosis, and NT-proBNP levels cannot be used to discriminate cardiac hemosiderosis status. Another study from Mehrzad et al. also found that NT-proBNP levels did not correlate with cardiac hemosiderosis while significant increase was only found in severe cardiac hemosiderosis patients (T2*<10 ms).[35] Most of the reported studies only include adult population as their participants and very few include children and adolescents.[10],[21],[35]

A study from Kremastinos et al.[19] suggested that NT-proBNP levels are related to age and this increase only became significant in the third decade of life. Kremastinos' study included a very wide range of participant's age (5 until 46 years). Another study by Balkan et al.[20] reported that NT-proBNP secretion begins early in the phase of the disease before overt diastolic dysfunction. They also did not find any correlation between the increase of NT-proBNP and diastolic parameter indices mainly due to narrow age range in the third decade of life. The reason for insignificant result in the present study may be due to earlier age's participants when the increase of NT-proBNP levels has not occurred. We presume that the increase of NT-proBNP in thalassemia patient may not be evident in adolescent population due to better chelation strategies.[8],[24],[36] The evidence of diastolic dysfunction as an early sign of cardiomyopathy could not be appreciated since we did not assess diastolic parameters using more sensitive tools such as tissue Doppler imaging.[19],[37] It is important to note also that some variables may affect plasma NT-proBNP levels, including the assay used, age, body mass index (lower levels with higher body mass index), and genetic factors.[38] Another potential bias was the duration of NT-proBNP measurements and imaging evaluation. Sample collection of NT-proBNP could not be drawn at the same time of imaging evaluation (mean duration: 19 days). This reason as well as earlier age of participants may lead to lack of significant discrimination of NT-proBNP and cardiac hemosiderosis.[19],[21]

Therefore, it is still important to perform MRI T2* to detect cardiac iron loading. The sensitivity and specificity of MRI T2* are appreciable and it is the standard of care most thalassemia centres according to thalassemia international federation's guideline.[39] MRI T2* could identify individuals at risk of iron overload cardiomyopathy before it becomes evident.[15],[16] Detection of early cardiac dysfunction is of utmost importance since appropriate chelation therapy could allow complete recovery of heart function.[10],[11],[12],[39]


   Conclusion Top


NT-proBNP levels do not differ between adolescent β-thalassemia patients with cardiac hemosiderosis and no cardiac hemosiderosis. Consequently, this biomarker is unlikely to be valuable as an early detection tool of cardiac hemosiderosis in adolescent β-thalassemia patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ 2008;86:480-7.  Back to cited text no. 1
    
2.
Hershko C. Iron loading and its clinical implications. Am J Hematol 2007;82:1147-8.  Back to cited text no. 2
    
3.
Martin A, Thompson AA. Thalassemias. Pediatr Clin North Am 2013;60:1383-91.  Back to cited text no. 3
    
4.
Kremastinos DT, Tiniakos G, Theodorakis GN, Katritsis DG, Toutouzas PK. Myocarditis in beta-thalassemia major. A cause of heart failure. Circulation 1995;91:66-71.  Back to cited text no. 4
    
5.
Kremastinos DT, Flevari P, Spyropoulou M, Vrettou H, Tsiapras D, Stavropoulos-Giokas CG, et al. Association of heart failure in homozygous beta-thalassemia with the major histocompatibility complex. Circulation 1999;100:2074-8.  Back to cited text no. 5
    
6.
Economou-Petersen E, Aessopos A, Kladi A, Flevari P, Karabatsos F, Fragodimitri C, et al. Apolipoprotein E epsilon4 allele as a genetic risk factor for left ventricular failure in homozygous beta-thalassemia. Blood 1998;92:3455-9.  Back to cited text no. 6
    
7.
Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: Data from the UK thalassaemia register. Lancet 2000;355:2051-2.  Back to cited text no. 7
    
8.
Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004;89:1187-93.  Back to cited text no. 8
    
9.
Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077-84.  Back to cited text no. 9
    
10.
Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation 2007;115:1876-84.  Back to cited text no. 10
    
11.
Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas V. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Br J Haematol 2010;148:466-75.  Back to cited text no. 11
    
12.
Porter JB. Optimizing iron chelation strategies in beta-thalassaemia major. Blood Rev 2009;23 Suppl 1:S3-7.  Back to cited text no. 12
    
13.
Kremastinos DT, Tsiapras DP, Tsetsos GA, Rentoukas EI, Vretou HP, Toutouzas PK, et al. Left ventricular diastolic Doppler characteristics in beta-thalassemia major. Circulation 1993;88:1127-35.  Back to cited text no. 13
    
14.
Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001;22:2171-9.  Back to cited text no. 14
    
15.
Kirk P, He T, Anderson LJ, Roughton M, Tanner MA, Lam WW, et al. International reproducibility of single breathhold T2* MR for cardiac and liver iron assessment among five thalassemia centers. J Magn Reson Imaging 2010;32:315-9.  Back to cited text no. 15
    
16.
Carpenter JP, He T, Kirk P, Roughton M, Anderson LJ, de Noronha SV, et al. On T2* magnetic resonance and cardiac iron. Circulation 2011;123:1519-28.  Back to cited text no. 16
    
17.
Leonardi B, Margossian R, Colan SD, Powell AJ. Relationship of magnetic resonance imaging estimation of myocardial iron to left ventricular systolic and diastolic function in thalassemia. JACC Cardiovasc Imaging 2008;1:572-8.  Back to cited text no. 17
    
18.
Weber M, Hamm C. Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine. Heart 2006;92:843-9.  Back to cited text no. 18
    
19.
Kremastinos DT, Tsiapras DP, Kostopoulou AG, Hamodraka ES, Chaidaroglou AS, Kapsali ED, et al. NT-proBNP levels and diastolic dysfunction in beta-thalassaemia major patients. Eur J Heart Fail 2007;9:531-6.  Back to cited text no. 19
    
20.
Balkan C, Tuluce SY, Basol G, Tuluce K, Ay Y, Karapinar DY, et al. Relation between NT-proBNP levels, iron overload, and early stage of myocardial dysfunction in β-thalassemia major patients. Echocardiography 2012;29:318-25.  Back to cited text no. 20
    
21.
Delaporta P, Kattamis A, Apostolakou F, Boiu S, Bartzeliotou A, Tsoukas E, et al. Correlation of NT-proBNP levels and cardiac iron concentration in patients with transfusion-dependent thalassemia major. Blood Cells Mol Dis 2013;50:20-4.  Back to cited text no. 21
    
22.
Nir A, Lindinger A, Rauh M, Bar-Oz B, Laer S, Schwachtgen L, et al. NT-pro-B-type natriuretic peptide in infants and children: Reference values based on combined data from four studies. Pediatr Cardiol 2009;30:3-8.  Back to cited text no. 22
    
23.
Spirito P, Lupi G, Melevendi C, Vecchio C. Restrictive diastolic abnormalities identified by Doppler echocardiography in patients with thalassemia major. Circulation 1990;82:88-94.  Back to cited text no. 23
    
24.
Kremastinos DT, Farmakis D, Athanasios D, Hahalis G, Hamodraka E. β-thalassemia cardiomyopathy: History, present considerations, future perspectives. Circ Heart Fail 2010;24:113-9.  Back to cited text no. 24
    
25.
Kremastinos DT, Tsetsos GA, Tsiapras DP. Heart failure in beta thalassemia: A 5-year follow-up study. Am J Med 2001;111:349-54.  Back to cited text no. 25
    
26.
Kirk P, Roughton M, Porter JB, Walker JM, Tanner MA, Patel J, et al. Cardiac T2* magnetic resonance for prediction of cardiac complications in thalassemia major. Circulation 2009;120:1961-8.  Back to cited text no. 26
    
27.
Leung AW, Chu WC, Lam WW. Magnetic resonance imaging assessment of cardiac and liver iron load in transfusion dependent patients. Pediatr Blood Cancer 2009;53:1054-9.  Back to cited text no. 27
    
28.
Majd Z, Haghpanah S, Ajami GH. Serum ferritin levels correlation with heart and liver MRI and LIC in patients with transfusion-dependent thalassemia. Iran Red Crescent Med J 2015;17:e24959.  Back to cited text no. 28
    
29.
Yang G, Liu R, Peng P, Long L, Zhang X, Yang W, et al. How early can myocardial iron overload occur in beta thalassemia major? PLoS One 2014;88:e283-5.  Back to cited text no. 29
    
30.
Wahidiyat PA, Liauw F, Sekarsari D, Putriasih SA, Berdoukas V, Pennell DJ. Evaluation of cardiac and hepatic iron overload in thalassemia major patients with T2* magnetic resonance imaging. Hematology 2017;22:501-7.  Back to cited text no. 30
    
31.
Wood JC. Guidelines for quantifying iron overload. Hematology Am Soc Hematol Educ Program 2014;2014:210-5.  Back to cited text no. 31
    
32.
Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an index of iron stores. N Engl J Med 1974;290:1213-6.  Back to cited text no. 32
    
33.
Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357-68.  Back to cited text no. 33
    
34.
Kremastinos DT, Hamodraka E, Parissis J, Tsiapras D, Dima K, Maisel A, et al. Predictive value of B-type natriuretic peptides in detecting latent left ventricular diastolic dysfunction in beta-thalassemia major. Am Heart J 2010;159:68-74.  Back to cited text no. 34
    
35.
Mehrzad V, Khajouei AS, Fahami E. Correlation of N-terminal pro-B-type natriuretic peptide levels and cardiac magnetic resonance imaging T2* in patients with β-thalassaemia major. Blood Transfus 2016;14:516-20.  Back to cited text no. 35
    
36.
Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, et al. Survival and complications in thalassemia. Ann N Y Acad Sci 2005;1054:40-7.  Back to cited text no. 36
    
37.
Silvilairat S, Sittiwangkul R, Pongprot Y, Charoenkwan P, Phornphutkul C. Tissue doppler echocardiography reliably reflects severity of iron overload in pediatric patients with beta thalassemia. Eur J Echocardiogr 2008;9:368-72.  Back to cited text no. 37
    
38.
Raymond I, Groenning BA, Hildebrandt PR. The influence of age, sex and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of the general population. Heart 2003;89:745-51.  Back to cited text no. 38
    
39.
Walker M, Wood J, Taher A. Cardiac complications in thalassaemia major. In: Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V, editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). 3rd ed. Cyprus: TIF Publication; 2014. p. 98-113.  Back to cited text no. 39
    

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Correspondence Address:
Dr. Najib Advani
Department of Child Health, Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/apc.APC_49_18

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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