0021-7557/10/86-02/159

Jornal de Pediatria
Copyright © 2010 by Sociedade Brasileira de Pediatria
Original Article

Electrocardiographic markers for the early detection

of cardiac disease in patients with beta-thalassemia major
Kemal Nisli,1 Taner Yavuz,1 Naci Oner,1 Zafer Salcioglu,2 Zeynep Karakas,3
Aygun Dindar,1 Umrah Aydogan,1 Rukiye Eker,1 Turkan Ertugrul1

Abstract

Objective: To comparatively evaluate P-wave dispersion (PWD) in patients with β-thalassemia major (TM) and
healthy control subjects for the early prediction of arrhythmia risk.
Methods: Eighty-one children with β-TM, aged 4-19 years, and 74 healthy children (control group) underwent
routine electrocardiography and transthoracic echocardiography for cardiac evaluation. PWD was calculated as the
difference between the maximum and the minimum P-wave duration.
Results: There was a statistically significant difference between study and control groups in peak early (E) mitral
inflow velocity and E/late (A) velocity ratio. Maximum P-wave duration and PWD were found to be significantly higher
in β-TM patients than in control subjects.
Conclusions: Increased PWD in our β-TM patients might be related to depression of intra-atrial conduction due
to atrial dilatation and increased sympathetic activity. These patients should be closely followed up for risk of life-
threatening arrhythmias.

J Pediatr (Rio J). 2010;86(2):159-162: Thalassemia major, P-wave dispersion, ferritin, cardiac involvement.

Introduction
Cardiac failure and sudden death, the latter probably with a four- to six-fold increase in the risk of developing
due to arrhythmias, remain the major causes of death in atrial fibrillation.5 The present study aimed to comparatively
β-thalassemia major (TM).1 Disease prognosis, however, investigate these electrocardiographic markers in patients
has been modified with regular blood transfusions and iron with β-TM and healthy control subjects for the early prediction
chelation therapy with deferoxamine.2 P-wave dispersion of arrhythmia risk.
(PWD) is a simple electrocardiographic marker that has
been reported to be associated with inhomogeneous and
discontinuous propagation of sinus impulses. It has been Methods
defined as the difference between the maximum and the The study population consisted of two groups: Group I
minimum P-wave duration.3-4 Prolonged P-wave duration – 81 children with β-TM; and group II – 74 healthy children
and increased PWD have been shown to carry an increased (control group) without clinically apparent cardiovascular
risk for atrial fibrillation.4 Cardiomyopathy is associated disease by physical examination, electrocardiography

1. MD, Department of Pediatric Cardiology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
2. MD, Department of Pediatric Hematology, Bakirkoy Education Hospitals, Istanbul, Turkey.
3. MD, Department of Pediatric Hematology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
No conflicts of interest declared concerning the publication of this article.
Suggested citation: Nisli K, Yavuz T, Oner N, Salcioglu Z, Karakas Z, Dindar A, et al. Electrocardiographic markers for the early detection of cardiac disease in
patients with beta-thalassemia major. J Pediatr (Rio J). 2010;86(2):159-162.
Manuscript submitted Nov 26 2009, accepted for publication Dec 28 2009.
doi:10.2223/JPED.1982

159
160 Jornal de Pediatria - Vol. 86, No. 2, 2010 Cardiac involvement in beta-thalassemia major - Nisli K et al.

and echocardiography. All participants were selected (36 boys and 38 girls) aged between 4 and 20 (10.9±4.1)
from among subjects attending the hematology service years. Body mass index (BMI) values in the study and control
of two local hospitals. Patients with diabetes mellitus, groups were 17.2±2.4 and 18.8±2.9, respectively. Serum
valvular heart disease, ventricular preexcitation, and ferritin level in β-TM patients ranged from 375 to 4,900
atrioventricular conduction abnormalities were excluded (1,865±876) µg/L, indicating that compliance to chelation
from the study. Cardiac evaluation was performed during therapy was not uniform within this group. At the time of the
the interval between blood transfusions, at a mean of 5 study, all subjects’ hemodynamic parameters were normal,
days (3-7 days) after transfusions. All patients and control and none of them showed clinical signs of cardiovascular
subjects underwent routine transthoracic echocardiographic disease. There were no statistically significant differences
examination (Vivid 3, General Electric, USA), during which between study and control groups regarding sex, mean
M-mode measurements of left ventricular (LV) end-diastolic age, heart rate, and systolic and diastolic blood pressure
and end-systolic diameters and LV ejection fraction (EF) (p > 0.05). However, BMI was lower in β-TM patients than
were made according to the recommendations of the in control subjects (Table 1). Mean LV end-diastolic volume
American Society of Echocardiography.6 To assess overall and EF were, respectively, 43.1±5.2 mm and 64.9±4.1% in
LV diastolic function, typical spectral LV filling curves were the study group, and 42.2±5.8 mm and 65.1±3.9% in the
obtained with conventional pulsed Doppler from a sample control group. There was a statistically significant difference
volume positioned at the tips of the mitral valve leaflets. between study and control groups in the measurements of
Peak mitral inflow velocities in early diastole (E) and after peak E mitral inflow velocity and E/A velocity ratio (Table
atrial contraction (A) were expressed as cm/s. Deceleration 2). Maximum P-wave duration and PWD were found to be
time of peak E filling velocity was measured in milliseconds. significantly higher in β-TM patients than in control subjects.
Overall LV diastolic dysfunction was defined as the presence However, there was no statistically significant difference
of any abnormality of the mitral valve. between study and control groups regarding minimum P-
Twelve-lead electrocardiogram (ECG) was recorded wave duration (Table 3).
for each patient and control subject at a rate of 50 mm/s.
At the time of electrocardiographic recording, all subjects
were in sinus rhythm and none were taking any type of Discussion
antiarrhythmic agent. P-wave duration was measured TM is an inherited hemoglobin disorder resulting in
manually by two of the investigators who were blinded to chronic hemolytic anemia. Heart failure secondary to
the participants’ clinical status. All measurements were myocardial iron overload is the most common cause of
performed using calipers and magnifying lens to improve death in this disease. Iron toxicity in biological systems is
accuracy. The onset of P-wave was defined as the junction believed to be associated with its ability to catalyze the
between the isoelectric line and the beginning of the P-wave generation of free radicals.8 Iron-induced cardiomyopathy
deflection, and the offset of P-wave as the junction between
the end of the P-wave deflection and the isoelectric line.
Maximum and minimum P-wave durations were measured
from the 12-lead surface ECG. Patients with measurable
P-waves in nine or fewer ECG leads were excluded from Table 1 - Characteristics of β-thalassemic patients and healthy
the study. PWD was calculated as the difference between controls
maximum P-wave duration (Pmax) and minimum P-wave
Patients Controls
duration (Pmin) (PWD = Pmax - Pmin).7
Statistical analysis was performed using Mann-Whitney U Age (years) 10.9±4.1 10.9±4.0
test and the chi-square test whenever appropriate. Pearson Sex (M/F, n) 37/44 36/38
correlation test was used to determine the correlation Weight (kg) 31.0±11.6* 41.6±16.2
between electrocardiographic and echocardiographic
Height (cm) 131.9±0.2* 145±0.2
variables. Numerical variables were expressed as
BMI (kg/m2) 17.2±2.4* 18.8±2.9
mean ± standard deviation, and categorical variables were
Systolic blood pressure (mmHg) 108.6±9.5 111.5±8.4
expressed as percentage. P values of < 0.05 were considered
to be statistically significant. Diastolic blood pressure (mmHg) 62.6±8.2 66.1±7.9

Heart rate /minute 87.8±11.6 84.7±15.2

Serum ferritin (µg/dL) 1,865±876 –

Results
BMI = body mass index; F = female; M = male.
The study group was composed of 81 β-TM patients (37 * p < 0.05 vs. healthy controls.
boys and 44 girls) aged between 4 and 19 (10.9±4.1) years, Results expressed as mean ± standard deviation.
Blood samples were drawn in the pretransfusion period, but physical examination
and the control group was composed of 74 healthy subjects was performed in the posttransfusion period.
Cardiac involvement in beta-thalassemia major - Nisli K et al. Jornal de Pediatria - Vol. 86, No. 2, 2010 161

Table 2 - Echocardiographic findings in β-thalassemic patients associated with manifest heart failure.12 Tissue Doppler
and healthy controls
imaging (TDI) analysis disclosed, in these patients, an early
Patients Controls myocardial dysfunction likely to be related specifically to this
initial iron overload, as suggested by the correlation with
LV end-diastolic volume 43.15±5.21 42.19±5.8 cardiac T2* values.13 In our study we could not evaluate

LVEF 64.93±4.14 65.14±3.96

patients by cardiac MRI or TDI, which becomes the main
limitation of this study.
E 99.78±12.86* 87.35±11.9
A 55.42±9.14 52.45±10.98 Restrictive LV filling is known to be associated with iron-
E/A ratio 1.83±0.31* 1.71±0.31 induced cardiomyopathy. Thus, the prognostic significance
of diastolic echocardiographic findings has been questioned
A = peak mitral inflow velocity after atrial contraction; E = peak mitral inflow velocity even in TM.14 The E/A ratio, however, which is one of the
in early diastole; LV = left ventricle; LVEF = left ventricular ejection fraction.
* p < 0.05 vs. healthy controls. most widely used criteria for restrictive LV filling, was
Results expressed as mean ± standard deviation. significantly increased in TM both in fit patients and in
In ß-thalassemic patients, echocardiography was performed in the posttransfusion
period. those with evident heart disease, probably representing the
effect of iron overload.15 In our study, the main difference
of β-TM patients vs. controls was restrictive diastolic filling
Table 3 - Electrocardiographic findings in β-thalassemic patients pattern, even when they were asymptomatic and had
and healthy controls normal LV function.

Patients Controls Cardiac complications of TM were first described prior

to the introduction of chelation therapy. Atrial arrhythmias
Pmax 102.99±4.64 92.85±4.97* were observed in half of the patients, and repetitive
Pmin 67.4±3.06 65.32±7.76 ventricular tachycardia was present in a minority.16 However,
PWD 35.07±4.80 26.85±4.55* the value of monitoring cardiac function to the long-term
management of TM remains unclear, which is partly because
Pmax = maximum P-wave duration; Pmin = minimum P-wave duration;
the prognostic significance of diastolic abnormalities,
PWD = P-wave dispersion.
* p < 0.05 vs. healthy controls. which appear early in the disease process, is unknown.14
Results expressed as mean ± standard deviation.
Additionally, once congestive heart failure was present,
systolic abnormalities were evident by echocardiography.
These observations have led some investigators to question
is a restrictive cardiomyopathy that manifests as systolic the value of noninvasive monitoring of cardiac function in
or diastolic dysfunction and/or ventricular arrhythmias the management of thalassemia.17
secondary to increased iron deposition in the myocardium. Depression of intra-atrial conduction causes a
Chelation therapy with deferoxamine has been associated lengthening of P-wave.18 In addition, it is now well accepted
with a marked decrease in morbidity and mortality in that a new and simple electrocardiographic marker, PWD,
patients with TM.9 Recent studies have suggested that also represents inhomogeneous and discontinuous atrial
deferiprone provides greater cardiac protection against conduction and has predictive value especially for paroxysmal
iron-induced heart disease than deferoxamine.10 In our atrial fibrillation.19-21 In healthy children, P-wave duration
study, all patients underwent standard deferoxamine has been reported to range from 50 to 100 ms.22 PWD has
therapy (40-50 mg/kg, subcutaneously, 5 days/week). been studied in some other cardiac conditions such as atrial
Currently, there is a need for a reliable test for the enlargement, obesity, hypertension, atrial septal defect,
presymptomatic identification of cardiomyopathy, since pulmonary stenosis, and dilated cardiomyopathy.23-24 Tükek
conventional assessment of ventricular function by et al.25 reported that increased sympathetic activity leads
echocardiography and nuclear techniques has not proven to a significant elevation in PWD. Therefore, the increased
adequate.11 Cardiac MRI measurement with T2* shows a PWD observed in our patients might be partly related to
weak relationship with cardiac function until a critical level an elevation in sympathetic activity, which might, in turn,
is reached, followed by rapid deterioration, which explains increase the risk of arrhythmias.
why identification of abnormal systolic function is a late
sign of iron toxicity. Iron clears more slowly from the heart
than the liver, thus contributing to the high mortality rates
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