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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 44  |  Issue : 1  |  Page : 34-39

Brain natriuretic peptide as a sensitive biomarker for early detection of cardiac affection in adult Egyptian patients with β-thalassemia


Department of Clinical Hematology and Bone Marrow Transplantation, Ain Shams University, Cairo, Egypt

Date of Submission01-Oct-2018
Date of Acceptance28-Oct-2018
Date of Web Publication27-Sep-2019

Correspondence Address:
Haydi S. Mohamed
Lecturer of Clinical, Hematology and Bone marrow transplantation, Department of Clinical Hematology and Bone Marrow Transplantation, Ain Shams University, Cairo, 11281
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejh.ejh_38_18

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  Abstract 


Background Cardiac affection by iron overload is the leading cause of mortality and morbidity in patients with β-thalassemia owing to frequent blood transfusion, increased iron absorption, and hemolysis. N-terminal pro-B-type natriuretic peptide is a tool for early detection of cardiac hemosiderosis, as echo findings occur later.
Methods We measured N-terminal pro-B-type natriuretic peptide in 45 β-thalassemia transfusion-dependent patients aged from 16 to 45 years and 30 controls of matched age and sex from Clinical Hematology Department, Ain Shams University hospital, which was correlated with both echo findings and serum ferritin level. Patients with congenital, ischemic heart disease and decompensated heart failure were excluded
Results Brain natriuretic peptides (BNP) levels were higher in patients with β-thalassemia than the control group, with statistical significance. BNP levels were higher in patients with β-thalassemia major than in those with β-thalassemia minor. BNP level was higher in patients who received more frequent blood transfusion. When we correlated BNP level with the echo findings, statistically significant difference was found in patients with high right ventricular systolic pressure (RVSP) ˃ 35 mmHg but not with diastolic dysfunction; also a positive correlation was found between BNP level and ferritin but not the ejection fraction.
Conclusion BNP levels were higher in patients with beta-thalassemia compared to control group and was correlated with the frequency of blood transfusion. BNP levels were correlated with increased RVSP ˃ 35 mmHg but not with early diastolic dysfunction, also BNP levels were correlated with ferritin level but not the ejection fraction.

Keywords: brain natriuretic peptide, cardiac, iron overload, thalassemia


How to cite this article:
El Zimaity MT, Abdelbary HM, Mohamed HS. Brain natriuretic peptide as a sensitive biomarker for early detection of cardiac affection in adult Egyptian patients with β-thalassemia. Egypt J Haematol 2019;44:34-9

How to cite this URL:
El Zimaity MT, Abdelbary HM, Mohamed HS. Brain natriuretic peptide as a sensitive biomarker for early detection of cardiac affection in adult Egyptian patients with β-thalassemia. Egypt J Haematol [serial online] 2019 [cited 2019 Oct 23];44:34-9. Available from: http://www.ehj.eg.net/text.asp?2019/44/1/34/268004




  Introduction Top


Thalassemia is an autosomal recessive hemoglobinopathy characterized by chronic hemolytic anemia that needs regular blood transfusion and iron chelation, which considerably improves the patients’ survival. However, because of iron overload, which adversely affects the heart functions and liver and other organs, cardiac complications are still the primary leading cause of death in β-thalassemia for young adults [1].

Cardiac iron overload is the main cause of death in 50% of transfusion-dependent patients with thalassemia. Heart failure onset remains poorly predictable, because echocardiography remains normal until heart failure clinically manifests. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful tool for early detection of cardiac hemosiderosis. It is released from cardiomyocyte in response to stretching and is correlated with volume overload. It has been established to increase with left ventricular (LV) dysfunction and has a physiological role, including modulation of cardiac muscle, the sympathoinhibitory roles, and natriuresis through modulation of the renin-angiotensin system.

In the early cardiac involvement, the level of NT-proBNP increases before an increase in diastolic pressure, and there is a strong correlation between plasma levels of NT-proBNP and iron overload. A significant relationship between NT-proBNP and some diastolic dysfunctions has been observed. Increasing levels of NT-proBNP in patients with thalassemia with LV diastolic dysfunction is a good biomarker for early diagnosis of LV dysfunction [2].

The aim of this study was to evaluate the cardiac iron overload in patients with β-thalassemia using conventional echo and its correlation to serum ferritin and brain natriuretic peptides (BNP) level as a sensitive biomarker for early detection of cardiac affection.


  Materials and methods Top


Study design

The study was a cross-sectional study conducted in the clinical hematology department, Ain Shams University hospital, on 45 patients with β-thalassemia aged from 16 to 45 years and 30 controls of matched age and sex.

Informed consents were obtained from all participants. The study was conducted in accordance with the stipulations of the local ethical and scientific committees of Ain Shams University, and the procedures respected the ethical standards in Helsinki declaration of 1964.

Inclusion criteria

The study included transfusion-dependent patients with thalassemia aged from 16 to 45 years.

Exclusion criteria

Congenital heart disease, ischemic heart disease and any signs of decompensated heart failure were the exclusion criteria.

Methods

All patients were subjected to the following:
  1. Complete history taking including history of blood transfusion, use of chelators and signs, and symptoms of heart failure from all studied group.
  2. Physical examination.


Laboratory investigations

  1. Serum ferritin and brain natriuretic peptide were centrally quantified by enzyme-linked immunosorbent assay technique. Abnormal levels regarding each parameter were investigated.
  2. Echocardiogram.


Blood sampling

Brain natriuretic peptide measurement

A volume of 2 ml of blood sample was collected from the patients before transfusion. It was collected in tubes containing EDTA, which were centrifuged at 3000 rpm for 15 min at 2–8°C within 30 min of collection. They were stored in −80°C till the analysis day. They were measured by an enzyme-linked immunosorbent assay.

After collection of the samples, the reagent and the standard solution were diluted and prepared at room temperature. A volume of 50 μl of the standard was added to the standard test tube and then 40 μl of the sample was added to the sample tube. Thereafter, 10 μl of anti-BNP antibody was added to the sample tube, and then 50 μl of streptavidin HRP was added to both sample and the standard tube. The tube was mixed well, covered in a sealer and incubated for 60 min at 37°C; thereafter, the sealer was removed, and the plate was washed for five times with a wash buffer. After automated washing and aspiration, the tubes were overfilled and blotted on a paper towel. Fifty of substrate solutions were added to each tube, the blue color will be changed into a yellow color, and the optical density was determined by a microplate reader.The manufacturer gave a measuring range of 5–2000 ng/l, and it has a sensitivity of 2.56 ng/l.

Echocardiogram

The heart was visualized from all standard views. It was visualized using standard transthoracic echocardiogram, which involves M-mode, two-dimensional, Doppler flow assessments, and tissue doppler imaging (TDI) measurements.

The cavity dimensions were measured according to the American Society of Echocardiography guidelines. We used the Devereux and Reichek method to measure the LV dimension. We used the biplane area-length formula to measure the atria volume.

Peak early mitral inflow velocity (E) (cm/s), peak late atrial mitral inflow velocity (A) (cm/s), and their ratio, deceleration time (DT) of early diastolic flow (ms), and isovolumic relaxation time (IVRT) (ms) were estimated. Systolic (S′), early diastolic (E′), and late diastolic velocities (A′) were also obtained.

The ratio of early diastolic mitral inflow velocity to early diastolic TDI annular velocity (E/E′) for septal annulus was calculated. Ejection fraction was obtained using modified Simpson’s rule.

Statistical analysis

Statistical presentation and analysis of the present study was conducted using the mean, SD, Student’s t-test, linear correlation coefficient, and analysis of variance tests by SPSS Version 17 (SPSS Inc., Chicago, Illinois, USA).

The confidence interval was set to 95% with a margin of error of 5%, so P values are considered significant if less than 0.05, highly significant if less than 0.001, and nonsignificant if greater than 0.05.


  Results Top


Overall, 75% of the patients were females. Moreover, 71% of the patients were diagnosed as having thalassemia intermediate, whereas 28.8% were diagnosed as having thalassemia major. In addition, 15.56% of the patients had diabetes and 73.33% had cirrhotic liver. Furthermore, 55.56% were HCV positive and 2.22% were HBV positive. Additionally, 35% of patients did not receive any iron chelators, whereas 17.78% received deferoxamine, 20% received deferasirox, and 26% of patients received deferiprone ([Table 1]).
Table 1 Demographic description of population

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A highly statistically significant difference was found in the BNP levels between the patient group and the control group (P<0.001).

Tukey test showed a statistically significant difference in BNP level between thalassemia major group and intermediate groups when compared with each other (P<0.01) and when compared with the control group (P<0.001) ([Table 2]).
Table 2 Brain natriuretic peptide level in patients versus the control group

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The mean BNP level was higher in patients who received more frequent blood transfusion, with a highly statistically significant difference (P<0.001) ([Table 3]).
Table 3 The correlation between the frequency of transfusion and the brain natriuretic peptide level

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Moreover, 60% of the patients had normal echo, 17% had diastolic dysfunction (grade 1–2), whereas 22% had elevated right ventricular systolic pressure (RVSP) greater than 35 mmHg ([Table 4]).
Table 4 Echo findings in the study population

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A significant statistical correlation was found between the echo findings and BNP level (P=0.004). The BNP levels were higher in the patients with high RVSP greater than 35 mmHg, with a highly statistically significant difference by using Tukey test ([Table 5]).
Table 5 The correlation between the echo findings and brain natriuretic peptide level

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A positive correlation was found between BNP level and ferritin but not the ejection fraction ([Figure 1]).
Figure 1 Correlation between the brain natriuretic peptides and ferritin and ejection fraction.

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  Discussion Top


Cardiac affection by iron overload is the leading cause of mortality and morbidity in patients with thalassemia. Mortality owing to a cardiac cause accounts for 50% of cases, which is considered the dominant cause of death. The natural history of the cardiac affection is usually silent in untreated patient, but by time it becomes progressive till cardiac failure occurs.

In a study done by Kremastinos [3] the 5-year survival for patients presenting with heart failure (ages 24±5 years) was only 48%.

The main causes of cardiomyopathy in patients with thalassemia are increasing intestinal absorption of iron, hemolysis, and lifelong blood transfusions. When intracellular iron increases, it is metabolized, releasing reactive oxidative species, which damage the cell membrane, and interfere with the respiratory chain in the mitochondria. It could also lead to cardiac fibrosis as well [4].

NT-proBNP is more stable and has a longer half-life of ∼2 h compared with brain natriuretic peptide. Increasing levels of NT-proBNP in patients with thalassemia with LV diastolic dysfunction are a good biomarker for early diagnosis of LV dysfunction. In the early phases of the cardiac involvement, the level of NT-proBNP increases before an increase in diastolic pressure, and there is a strong relationship between plasma levels of NT-proBNP and iron overload [5].

There is a controversy among different studies regarding the relationship between iron overload and BNP level.

In our study, BNP level was higher in the patient group when compared with the control group (P<0.001) and it was also elevated in patients with thalassemia major more than thalassemia intermediate (P=0.01).

Our study has also shown a positive correlation between BNP levels and frequency of transfusion, as patients with frequent blood transfusion twice per month had higher BNP level (P<0.001).

In our study, we conducted echo for the thalassemia population. We evaluated them for systolic impairment, diastolic dysfunction, and elevated RVSP. Overall, 60% of the study population had normal echo, 17% had diastolic dysfunction (grade 1–2), and 22% had elevated RVSP greater than 35 mmHg; then, we correlated the BNP level with these echo findings. The results of our study have shown statistically significant correlation between the BNP level and the right ventricular pressure greater than 35 mmHg (P=0.004). This came in agreement with the study done by Adrish et al. [6] who conducted a retrospective study on 1670 patients, and approximately 167 met the criteria. About 77% of the male and 55% of the female patients showed apositive relation between BNP level and the RVSP (P<0.0001) [6].

Allanore et al. [7] also correlated the BNP level with echo findings in 40 patients with scleroderma. They showed a moderate correlation between the BNP and the elevated RVSP (P=0.006), which matched with our study results.

The pathogenesis of pulmonary hypertension in thalassemia are distinct and overlapping, which are mainly owing to chronic hemolysis associated with decrease in nitric oxide level, resulting in platelet activation and adhesion and increase of vasoactive peptide endothelin-1, and also iron overload, owing to repeated blood transfusion, leading to endomyocardial fibrosis, culminating in heart failure. Hypercoagulability leads to microvascular and macrovascular thrombosis, and splenectomy increases platelet activation, all these factors contribute to the development of pulmonary hypertension [1].

Patients with thalassemia usually present with early diastolic dysfunction that is attributed to the thin wall of the right ventricle, so they are easily affected by the toxicity of cardiac iron deposition. We had studied the level of BNP with diastolic dysfunction, which was elevated, but it had no statistically significant difference. This result is consistent with the study done by Alizadeh et al. [8] who recruited 50 patients with thalassemia in a cross-sectional study, where the BNP level was correlated with the diastolic dysfunction. The diastolic dysfunction was assessed using ratio between velocities of the mitral inflow E wave to E′ mitral annular velocity ratio (E/E′). Accordingly, they were divided into three groups: group 1 with no diastolic dysfunction (E/E′<8), group 2 with suspected diastolic dysfunction (E/E′=8–15), and group 3 with documented diastolic dysfunction (E/E′>15). There was no statistical significance between the BNP level in all groups. There is also no statistical significance between BNP level and serum ferritin and type of iron chelators used [8].

Kremastinos et al. [9] had recruited 70 patients with thalassemia and divided them into three group based on their diastolic dysfunction: group A patients without diastolic dysfunction (E/E′ ratio <8), group B patients with suspected diastolic dysfunction (E/E′ ratio 8–15), and group C patients with documented diastolic dysfunction (E/E′ ratio >15). The BNP level was increased in patients with documented LV dysfunction, and it had predictive value for latent diastolic dysfunction. Their results were contrary to our study, which could be attributed to the small population size, as we had only 8 patients with diastolic dysfunction of 45 patients with thalassemia.

Our results were also consistent with Delaporta et al. [10] They have studied the relation between the BNP levels and the cardiac iron load based on the results of cardiac MRI in 187 patients with thalassemia. The BNP levels were elevated in patients with thalassemia in comparison with the control (P=0.001). The BNP levels were increased in the severe cardiac hemosiderosis relative to the patients without cardiac hemosiderosis [10].

Similarly, Mehrzad et al. [2] have studied the BNP level in 50 patients with thalassemia and correlated it with cardiac hemosiderosis. They divide the patients with thalassemia into three groups based on their cardiac iron load: group A T2*>20 ms, group B patients with mild to moderate cardiac iron overload (10 ms<T2*<20 ms), and group C, patients with severe cardiac iron overload (T2*<10 ms). BNP level was higher in group C but not statistically significant. These contradicting results could be attributed to the small population size [2].

Regular blood transfusion in thalassemia and iron chelation improve the patients’ survival. However a consequence of blood transfusion is iron overload, which adversely affect the heart, liver, and other organs.

Liver cirrhosis is a common complication in thalassemia. It usually occurs owing to numerous factors, such as hemosiderosis and transfusion-related infections. Patients with cirrhotic are complicated with portal hypertension. It usually occurs owing to increased portal vein resistance and increased blood flow owing to splenic arteries vasodilation. Portal hypertension would cause hypovolemia, arterial hypotension leading to hyperdynamic circulation with renal hypo perfusion, and subsequently salt and water retention. These will aggravate the systolic and diastolic dysfunction, thus affecting the BNP level [11].

We correlated the BNP level among our patients with cirrhosis. The BNP level was higher in the patients with cirrhosis without statistical significance. These results are contradicted by Radvan et al. [12] who had studied the prognostic value of the BNP level in cirrhotic non-cardiac patients especially those who are presented with severe fluid retention and ascites. There was a significant statistical correlation between the BNP level and severity of liver disease among the patients with cirrhosis. The lack of statistical significance is most likely because our patients had no signs of decompensation or fluid retention [12].

We evaluated the BNP level also among the diabetic patients in our studied population. It was elevated among them, but it was not statistically significant. Few studies have been conducted to evaluate the relation between diabetes and the BNP level. The results found by Dal et al. [13] are consistent with our study. They studied the effect of better glycemic control with the BNP level in a prospective study done on 79 diabetic patients. A significant decrease in the BNP level occurred in patients with improved glycemic control, and it was statistically correlated with the glycated hemoglobin (Ha1C) [13].Iron overload increases oxidative stress and endothelial dysfunction, which occur early in life. It causes both left and right cardiac dysfunction through secondary hemochromatosis. Serum ferritin is an intracellular protein, where it stores iron in the tissue. It is secreted in small amount in the plasma, which correlates with tissues stores. When iron increases in the body exceeding the protein binding capacity, it deposits in the tissue [14].

In our study, we used serum ferritin as a marker of iron overload in thalassemia. There was a significant positive correlation between the ferritin and the BNP level (P=0.048).

Tanner et al. [15] had recruited 167 patients, where they studied the cardiac hemosiderosis and its relation to the echo finding, the BNP level, and serum ferritin. BNP level was weakly correlated with cardiac iron overload, and the serum ferritin was weakly correlated with cardiac iron overload as well, which does not matched with our study results [15].


  Conclusion Top


In our study, we concluded that BNP levels were higher in patients with β-thalassemia compared with the control group. It was correlated with the frequency of transfusion and the RVSP, thus it can be used as an early predictor of cardiac dysfunction.

A future perspective

Further studies should be conducted on a larger scale with a larger population correlating the BNP with cardiac MRI in patients with thalassemia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Dustin RF, Roberto FM. Pulmonary hypertension associated with thalassemia syndromes. Ann N Y Acad Sci 2016; 1368:127–139.  Back to cited text no. 1
    
2.
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 β2-thalassaemia major. Blood Transfus 2016; 14:516–520.  Back to cited text no. 2
    
3.
Kremastinos DT. Heart failure in beta-thalassemia. Congest Heart Fail 2001; 7:312–314.  Back to cited text no. 3
    
4.
Pennell DJ, Porter JB, Cappellini MD, El-Beshlawy A, Chan LL, Aydinok Y et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in beta-thalassemia. Blood 2010; 115:2364–2371.  Back to cited text no. 4
    
5.
Noor M, Alireza T, Maryam NM et al. Diagnostic Value of NT-pro BNP Biomarker and Echocardiography in Cardiac Involvements in Beta-thalassemia Patients. Int J Pediatr 2017; 5:6077–6094.  Back to cited text no. 5
    
6.
Adrish M, Nannaka VB, Cano EJ, Bajantri B, Diaz-Fuentes G et al. Significance of NT-pro-BNP in acute exacerbation of COPD patients without underlying left ventricular dysfunction. Int J Chron Obstruct Pulmon Dis 2017; 13:1183–1189.  Back to cited text no. 6
    
7.
Allanore Y, Borderie D, Meune C et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis Rheum 2003; 48:3503–3508.  Back to cited text no. 7
    
8.
Alizadeh B, Badiee Z, Mahmoudi M et al. Evaluating the correlation between serum NT-proBNP level and diastolic dysfunction severity in beta-thalassemia major patients. J Tehran Heart Cent 2016; 11:68–72.  Back to cited text no. 8
    
9.
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. 9
    
10.
Delaporta P, Kattamis A, Apostolakou F, Boiu S, Bartzeliotou A, Tsouka E, Papassotiriou I et al. Correlation of NT-proBNP levels and cardiac iron concentration in patients with transfusion-dependent thalassemia major. Blood Cells Mol Dis 2013; 50:20–24.  Back to cited text no. 10
    
11.
Kautz L, Jung G, Du X, Gabayan V, Chapman G, Nasoff M et al. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood 2015; 126:2031–2037.  Back to cited text no. 11
    
12.
Radvan M, Svoboda P, Radvanova J, Stumar J, Scheer P. Brain natriuretic peptide in decompensation of liver cirrhosis in non-cardiac patients. Hepatogastroenterology 2009; 56:181–185.  Back to cited text no. 12
    
13.
Dal K, Ata N, Yavuz B, Sen O, Deveci OS, Aksoz Z et al. The relationship between glycemic control and BNP levels in diabetic patients. Cardiol J 2014; 21:252–256.  Back to cited text no. 13
    
14.
Devaki RN, Harisha SA, Shree Harsha V, Vinod Kumar HR, PooJitha K. Serum ferritin levels in patients of beta-thalassaemia major, receiving repeated blood transfusion. Indian J Appl Res 2015; 5:7.  Back to cited text no. 14
    
15.
Tanner MA, Galanello R, Dessi C, Westwood MA, Smith GC, Nair SV et al. Myocardial iron loading in patients with thalassemia major on deferoxamine chelation. J Cardiovasc Magn Reson 2006; 8:543–547.  Back to cited text no. 15
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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