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European Journal of Echocardiography Advance Access originally published online on August 7, 2007
European Journal of Echocardiography 2008 9(3):368-372; doi:10.1016/j.euje.2007.06.003
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Tissue Doppler echocardiography reliably reflects severity of iron overload in pediatric patients with β thalassemia

Suchaya Silvilairat1,*, Rekwan Sittiwangkul1, Yupada Pongprot1, Pimlak Charoenkwan2 and Charlie Phornphutkul1

1 Division of Pediatric Cardiology, Chiang Mai University, Chiang Mai, Thailand
2 Division of Pediatric Hematology, Chiang Mai University, Chiang Mai, Thailand

Received 8 March 2007; accepted after revision 2 June 2007; online publish-ahead-of-print 7 August 2007.

* Corresponding author. Department of Pediatrics, Chiang Mai University, Chiang Mai, 50200, Thailand. Tel: +66 89 761 2855; fax: +66 53 94 6461. E-mail address: ssamana{at}mail.med.cmu.ac.th (S. Silvilairat).


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aims: Tissue Doppler imaging has been recently used to evaluate ventricular function in patients with β thalassemia. In clinical practice, serum ferritin is commonly used to assess the severity of iron overload. The aim of this study was to determine which Doppler findings correlated with serum ferritin.

Methods and results: Thirty-one pediatric patients with transfusion-dependent β thalassemia with normal LVFS were evaluated. Seven patients with serum ferritin <2500 ng/ mL, 13 patients with serum ferritin 2500–5000 ng/mL, and 11 patients with serum ferritin >5000 ng/mL were studied. Diastolic dysfunction was absent in all patients with serum ferritin <2500 ng/mL, and was present in all patients with serum ferritin >5000 ng/mL. Deceleration time (DT) has a significant correlation with serum ferritin (r = –0.59, p < 0.0001). Difference of pulmonary vein atrial reversal flow and mitral valve A wave duration (PVAR – MVA) and early ventricular filling velocity to early diastolic myocardial velocity ratio (E/Em) significantly correlated with serum ferritin (r = 0.49, p = 0.006; r = 0.56, p = 0.001, respectively).

Conclusion: Decreased DT, increased PVAR-MVA duration, and increased E/Em ratio reliably reflected severe iron overload in pediatric patients with β thalassemia. Systolic and diastolic LV function is preserved in patients who have serum ferritin <2500 ng/mL.

Keywords: Tissue Doppler imaging; β Thalassemia; Diastolic dysfunction; Serum ferritin; Iron overload


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
An important complication of β thalassemia is iron deposition in cardiac tissue resulting in degeneration, fibrosis and dysfunction.1 Cardiac disease is the primary cause of death.1–3 Iron-chelation therapy may prevent myocardial dysfunction and early death from cardiac disease.4–10 Despite adequate iron chelation, myocardial function is still worsening due to iron deposition, fibrosis, and chronic anemia. In clinical practice, serum ferritin has been used to assess the effectiveness of treatment. In several studies, diastolic ventricular dysfunction demonstrated in these patients preceded the onset of systolic impairment.11–15 Tissue Doppler echocardiography has been recently used to evaluate early myocardial dysfunction in adult patients with thalassemia.16,17 To our knowledge, no previous studies of tissue Doppler echocardiography have correlated with the degree of iron overload in pediatric patients with β thalassemia. We hypothesized that pulse wave Doppler (PWD) and tissue Doppler imaging (TDI) patterns of diastolic left ventricular (LV) dysfunction would reflect the severity of iron overload. As serum ferritin is commonly used to assess the severity of iron overload, the aim of this study was to determine which Doppler parameters correlated with serum ferritin.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Study patients
We retrospectively reviewed 31 pediatric patients with transfusion-dependent β thalassemia who had serum ferritin and complete echocardiographic evaluations (including TDI) at Chiang Mai University Hospital. Patients with clinical signs of congestive heart failure and left ventricular fractional shortening (LVFS) less than 30% were excluded.

For the purpose of this study, severity of iron overload was defined by serum level of ferritin. Group A patients who had serum ferritin <2500 ng/mL were considered to have mild severity of iron overload. Group B and group C patients had serum ferritin 2500–5000 ng/mL and >5000 ng/mL, respectively. The study protocol was reviewed and approved by the Chiang Mai University Review Board.

Doppler calculations
Doppler echocardiographic examinations were performed using Phillip Sonos 7500. Echocardiographic data were obtained from the echo study closest in time to the serum ferritin measurement. Echocardiographic data included severity of valve dysfunction, LVFS, PWD assessment of mitral valve (MV) and pulmonary venous (PV) flows (ventricular diastolic filling analysis), and TDI. PWD of MV flow were peak early ventricular filling velocity (E), peak atrial contraction velocity (A), A wave duration, and deceleration time (DT). PWD of PV flow were systolic forward flow velocity (PVS), diastolic forward flow velocity (PVD), atrial reversal flow velocity, and atrial reversal flow duration. TDI signal was obtained from an apical four-chamber view at the septal mitral annulus. TDI variables included systolic myocardial velocity (Sm), early diastolic myocardial velocity (Em), late diastolic myocardial velocity (Am), and isovolumic relaxation time (IRT). Doppler characteristics of diastolic LV dysfunction with increased ventricular end-diastolic and left atrial pressure are elevated E/A ratio, decreased DT, PV atrial reversal duration exceeding the A wave duration, decreased Em, and increased E/Em ratio (Figure 1).18–20


Figure 1
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  		Figure 1 Diastolic grading system using PWD of mitral valve and pulmonary vein flow patterns, and TDI. A: atrial contraction velocity; Am: late diastolic myocardial velocity; AR: atrial reversal flow velocity; D: diastolic flow velocity; E: early ventricular filling velocity; Em: early diastolic myocardial velocity; S: systolic flow velocity; Sm: systolic myocardial velocity.

 
Statistical analysis
All statistical calculations were assessed using SPSS Version 11.5, SPSS Inc., Chicago, IL. Comparison between the three groups was performed using t-test, Wilcoxon rank sum, chi-square test, and Fisher's exact test, as appropriate. Linear regression analysis was used to assess the correlation between the Doppler parameters and the serum ferritin.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Thirty-one patients with transfusion-dependent β thalassemia were studied (median age 12 years, range 4–15 years). Fifteen patients (48%) were female. These patients were divided into three groups by the serum level of ferritin (serum ferritin <2500 ng/mL group: 7 patients; serum ferritin 2500–5000 ng/mL group: 13 patients; serum ferritin >5000 ng/mL group: 11 patients). Baseline clinical and hematological characteristics were compared in Table 1. Significantly higher proportion of patients with serum ferritin >5000 ng/mL had undergone splenectomy than both of the other groups. However, age, body surface area, heart rate, blood pressure, hemoglobin, and total transfusion per year were not statistically different between the three groups.


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  		Table 1 Demographic and clinical characteristics of β thalassemia patients according to serum level of ferritin

 
Doppler findings
Observed Doppler values stratified by serum ferritin are summarized in Table 2. Difference of pulmonary vein atrial reversal duration and the mitral valve A wave duration (PVAR–MVA), and early ventricular filling velocity to early diastolic myocardial velocity ratio (E/Em) were increased in the serum ferritin >5000 ng/mL group relative to the other two groups (P = 0.009 and P = 0.008, respectively). DT was decreased in those with serum ferritin >5000 ng/mL relative to both of the other groups (P = 0.001). Diastolic dysfunction was absent in all patients with serum ferritin <2500 ng/mL, and was present in all patients with serum ferritin >5000 ng/mL (Figure 2). Sm in patients with serum ferritin 2500–5000 ng/mL was somewhat lower than that observed in those with serum ferritin <2500 ng/mL (P = 0.03). No other echocardiographic variables including LVFS, E/A, PVS/PVD, Em, and IRT were statistically different between these three groups.


Figure 2
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  		Figure 2 Graphical display comparing the serum ferritin level according to grade of diastolic dysfunction.

 


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  		Table 2 Comparison of the PWD and tissue Doppler data in serum ferritin groups

 
Relationship of pulse wave Doppler and tissue Doppler data to serum ferritin
The serum ferritin was skewed toward more severe iron overloading (median = 3820 ng/mL, range 673–9140 ng/mL), since the majority received iron chelation at the older age. Results of the relationship between the Doppler data and serum ferritin are graphically displayed in Figure 3. The DT was most closely correlated to the serum ferritin (r = –0.59, P < 0.0001). Difference of PVAR – MVA duration and an E/Em ratio significantly correlated with serum ferritin (r = 0.49 and r = 0.56, respectively).


Figure 3
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  		Figure 3 Linear regression analysis comparing the PWD and tissue Doppler data, in serum ferritin. DT: deceleration time; E/Em: early ventricular filling velocity to early diastolic myocardial velocity ratio; PVAR – MVA: difference of pulmonary vein atrial reversal duration and mitral valve A wave duration.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our findings support the hypothesis that PWD and TDI patterns of diastolic LV dysfunction reflect the severity of iron overload. Diastolic LV dysfunction was absent in all patients with serum ferritin <2500 ng/mL and was present in all patients with serum ferritin >5000 ng/mL. Difference of PVAR – MVA duration and E/Em were significantly increased in the serum ferritin >5000 ng/mL group relative to both of the other groups. DT was significantly decreased in patients with serum ferritin >5000 ng/mL. These Doppler parameters significantly correlated to the serum ferritin. In fact, decreased DT, pulmonary vein atrial reversal duration exceeding the A wave duration, and increased E/Em ratio are characteristics of diastolic LV dysfunction with increased ventricular end-diastolic pressure and increased left atrial pressure.

Olivieri et al. reported that the cardiovascular prognosis in patients with homozygous β thalassemia was excellent if serum ferritin was below 2500 ng/mL.21 Bosi et al. demonstrated that patients with serum ferritin >2500 ng/mL had the lowest LVEF.22 As per the results, the serum level of ferritin below 2500 ng/mL has been considered the safe level. Our study confirms this assumption, demonstrating that diastolic LV dysfunction was absent in all patients with serum ferritin <2500 ng/mL who have normal LVFS. The previous studies showed that predictors of cardiac mortality were LV restrictive filling pattern and decreased LVEF.23–25 Therefore, serum ferritin should be maintained below 2500 ng/mL in patients with transfusion-dependent β thalassemia by adequate chelation therapy.

Complete Doppler assessment of diastolic LV function in pediatric patients should be interpreted by both MV flow signal and PV flow pattern.26 The grading system provides a semi-quantitative approach to classify the severity of diastolic ventricular performance.27 TDI has been the additional modality for assessment of diastolic ventricular function.19,28,29 Ommen et al. revealed the combined variable of E/Em provided the better estimate of LV filling pressure than other methods.30 In the present study, PWD of MV and PV flow patterns including TDI were evaluated for grading the diastolic ventricular function. The grade of diastolic function was correlated to the serum level of ferritin. Also, Doppler parameters of diastolic dysfunction including decreased DT, increased PVAR – MVA duration, and increased E/Em ratio were significantly correlated to serum ferritin.

In our study, diastolic ventricular dysfunction was demonstrated in patients with the normal LVFS. Sm in patients with serum ferritin 2500–5000 ng/mL was somewhat lower than those with serum ferritin <2500 ng/mL (p = 0.03). In fact, Sm in serum ferritin 2500–5000 ng/mL group was below the normal range value of healthy children.31 Therefore, TDI may be the early detection of systolic ventricular dysfunction.

There are some limitations in our study due to its retrospective nature. Since some patients who did not have tissue Doppler examination were excluded, there might be a selective bias. However, this is a preliminary study of tissue Doppler echocardiography correlated with the degree of iron overload in pediatric patients with β thalassemia. Long-term prospective study of the echocardiographic assessment for systolic and diastolic ventricular function in larger numbers of pediatric patients with β thalassemia including younger age is warranted.

Conclusion
Decreased DT, increased PVAR – MVA duration, and increased E/Em ratio reliably reflected severe iron overload. Systolic and diastolic LV function is preserved in patients who have serum ferritin <2500 ng/mL. TDI should be a routine part of the echocardiographic assessment in pediatric patients with β thalassemia.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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