carotid artery intima-media thickness as a predictor of

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EL-MINIA MED. BULL. VOL. 21, NO. 2, JUNE, 2010
Ismail & El-Sherif
CAROTID ARTERY INTIMA-MEDIA THICKNESS AS A PREDICTOR OF
ATHEROSCLEROSIS IN CHILDREN WITH BETA THALASSEMIA MAJOR
By
Ahlam M. Ismail, MD*, Ashraf M. El-Sherif, MD**
Departments of *Pediatrics, South Valley University
and **Diagnostic Radiology, El-Minia University Egypt
ABSTRACT:
Background: Beta-thalassaemias are characterized by anomalies in the synthesis of
the beta chains of hemoglobin. Individuals with beta-thalassemia major (BTM)
usually present within the first two years of life with severe anemia, requiring regular
red blood cell transfusions. Patients with this disease are at increased risk of early
vascular alteration and atherosclerosis. High resolution ultrasound is a reliable, non
invasive method for detecting early structural and functional atherosclerotic changes
in the arterial wall.
Objective: To measure the carotid artery intima-media thickness (cIMT) in children
with BTM in order to evaluate its relationship to features of iron overload and its use
as a predictor of atherosclerosis in these children.
Patients and Methods: Thirty children with (BTM) and 15 healthy normal controls of
matched age and sex were included. Complete blood count, serum iron, ferritin, lipid
profile and hemoglobin electrophoresis were performed as well as Doppler
ultrasonography to measure the (cIMT) in both patients and controls.
Results: Carotid IMT of thalassemic patients was significantly increased compared to
normal controls with a mean ± SD of (0.46±0.008) and (0.35±0.03 mm) respectively
(p<0.037). There was significant difference of cITM in relation to age and serum
levels of iron, ferritin and total cholesterol but there was no significant difference of
cITM in relation to sex, weight, height, hemoglobin level, and hematocrit percent.
Carotid IMT was significantly different in BTM children in relation to duration of
illness, size of spleen and liver and serum levels of iron and Ferritin. Carotid IMT was
also significantly different in BTM children in relation to frequency of blood
transfusion, use of iron chelating agents, splenectomy and skeletal changes.
Conclusion: Carotid IMT is significantly increased in patients with beta-thalassaemia
major and shows a strong relationship with features of iron overload. We recommend
the routine use of cITM in these patients to predict early atherosclerotic changes as
well as in the follow-up to prevent progression of atherosclerosis. Reducing
hyperlipidemia and body iron load in the thalassemic patients by dietary restriction or
pharmacological therapy and good compliance of iron chelating agents is also
recommended.
KEY WORDS:
Beta
Carotid artery intima
Atherosclerosis
Thalassaemia major (BTM)
Media thickness (cIMT)
thalassaemia is characterized by
anomalies in the synthesis of the beta
chains of hemoglobin resulting in
variable phenotypes ranging from
INTRODUCTION:
Beta-thalassaemia is a group of
hereditary blood disorders first
described by Cooley and Lee1. Beta-
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EL-MINIA MED. BULL. VOL. 21, NO. 2, JUNE, 2010
severe anemia to clinically asymptomatic individuals. Three main forms
have been described; thalassaemia
major, thalassaemia intermedia and
thalassaemia minor2.
Ismail & El-Sherif
the pediatrics department in Qena
University hospital as well as 15
healthy normal children of matched
age and sex included as controls, in the
period from July 2009 to May 2010.
The study was approved by the local
research ethics committee of the
hospital and written informed consent
was obtained from the parents of all
children to share in the study. Children
in the control group were subjected to
through clinical examination and
laboratory investigations including
complete blood count, serum iron,
ferritin, and lipid profile and
hemoglobin electrophoresis to exclude
the presence of b-thalassaemia trait.
They all had normal blood counts and
hemoglobin electrophoresis results.
Measurements of the carotid IMT was
performed to both controls and patients
with thalassaemia.
Individuals
with
betathalassaemia major (BTM) usually
present within the first two years of
life with severe anemia, requiring
regular red blood cell (RBC)
transfusions3. Patients with BTM may
present with clinical complications in
several organ systems, which results
from the oxidative stress induced by
iron overload4. With the increased life
span of BTM patients, coronary artery
disease may emerge as one of the
important cardiovascular complications5. Patients maintained on a regular
transfusion regimen progressively
develop clinical manifestations of iron
overload with heart dysfunction in
about 33% of them6, 7.
All patients were subjected to the
following work-up assessment:
I. Thorough history taking including the duration of the disease, the
frequency of blood transfusion, the
intake of iron chelating agents
including its types and frequency and
history
of
any
cardiovascular
symptoms suggesting the presence of
heart failure or any atherosclerotic
changes.
II. Clinical examination to determine the presence of any abdominal
organomegally, skeletal changes, or
signs of cardiomegally or heart failure.
III. Laboratory & radiological
investigations to confirm the diagnosis
and severity of the disease and iron
overload status including complete
blood count and reticulocytic count,
hemoglobin electrophoresis, serum
levels of ferritin and iron and iron
binding capacity. Abdominal ultrasound was performed with special
emphasis of the liver and spleen.
Studies have suggested a link
between iron load and risk of
atherosclerosis. Endothelial dysfunction, which is an important precursor
of atherosclerosis, was found in BTM
patients due to peroxidative tissue
injury because of continuous blood
transfusions8.
High resolution ultrasound is a
reliable, non invasive method for
detecting
early
structural
and
functional atherosclerotic changes in
the arterial wall9. Increased carotid
artery intima media thickness (cIMT)
is a structural marker for early
atherosclerosis and it correlates with
the vascular risk factors and to the
severity and extent of coronary artery
disease10, 11.
PATIENTS AND METHODS:
Thirty children with Beta
thalassemia major were selected from
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EL-MINIA MED. BULL. VOL. 21, NO. 2, JUNE, 2010
Carotid duplex study:
All patients and controls were
subjected to B-mode and color-coded
duplex
sonography
of
their
extracranial carotid and vertebral
arteries. All studies were performed
using a LOGIC P6 ultrasound system
(GE medical systems, Milwaukee, WI)
with a 12.0-MHz linear array
transducer. All ultrasound examinations were performed by a single
experienced vascular radiologist who
was unaware of the clinical and
laboratory details of the examined
children. The examined patient was
laid supine with his neck exposed,
extended and the head is slightly
rotated away from the examiner so as
to make the vessel more perpendicular
to the transducer. The examiner sat at
the head of the table with the machine
on his left side. Examination started by
locating the common carotid artery
(CCA) in the lower neck in the
transverse plane. The CCA is followed
proximally until the transducer is
blocked by the clavicle and caudal
angulations is tried to evaluate the
common carotid origin if possible. The
sternocleidomastoid
muscle
and
jugular vein are used as an acoustic
window. The jugular vein is easily
identified as it collapses by minimal
probe pressure and engorges by
suspension of respiration. The CCA is
followed upwards till it widens to form
the carotid bulb, then it bifurcates into
internal and external branches. The
transducer is then rotated 90 degrees to
be parallel to the CCA to have
longitudinal scanning of the CCA, the
bifurcation, the internal carotid artery
(ICA) and external carotid artery
(ECA). The ICA was then followed
distally as far as possible and
optimally until it is lost behind the
mandible. We tried to demonstrate the
bulb, ICA, ECA in one view; however,
it was difficult in many patients.
Differentiation of both internal and
Ismail & El-Sherif
external carotids was then done. The
internal CA is larger, with no neck
branches, usually more posterior and
has an ampullary region of mild
dilatation at its origin. The vessels
were evaluated meticulously for the
presence of subintimal lucency, and
atherosclerotic plaques that bulge into
the lumen, followed by measuring the
intimal plus medial thickness (IMT).
IMT was measured in 1-cm segment
proximal to the dilation of the carotid
bulb, referred to as CCA, and always
in plaque-free segments. For each
subject, three measurements on both
sides were obtained on the anterior,
lateral, and posterior projection of the
far wall. Values for the different
projections and for right and left
arteries were then averaged. Two enddiastolic frames were selected and
analyzed for mean cIMT, and the
average reading from these two frames
was calculated for both right and left
carotid arteries. The average of the two
sides was considered the patient’s
overall mean CIMT.
Statistical analysis:
The data were statistically
analyzed using Student’s t-test, one
way ANOVA, and chi-square (linear
by linear correlation) tests, as
applicable (with a preset probability of
P<0.05). Experimental results were
presented as arithmetic mean±SD.
Statistical tests were conducted using
the SPSS software package, version 16
(SPSS Inc., Chicago, IL, USA) on a
personal computer.
RESULTS:
The study included 30 children
with B thalassemia major and 20
healthy children with matched age and
sex. The thalassemic children were 19
males (65.5 %) and 11 femaleS (45.5
%). Their ages ranged from 1- 12 years
with mean ± SD of 7.2±3.4 years. The
normal control group included 10
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males (65.5%) and 5 females (48.3%).
Their ages ranged from 1- 12 years
with mean±SD of 6.5±3.5 years. The
disease duration of the patients with
BTM ranged from 0.5 to 11 years with
mean ± SD of 6.3±3.3 years.
Ismail & El-Sherif
Table (1) shows that cIMT in the
thalassaemic patients were significantly increased compared to the
normal controls (Figure 1-3). The
mean ± SD of cIMT was (0.46±0.008
and 0.35±0.03 mm) in BTM patients
and
the
controls
respectively
(p<0.037).
Table (1): Comparative study of cIMT between BTM patients and controls
BTM (n:30)
(mean ± SD)
cIMT (mm) 0.46±0.008
* Significant p value <0.05.
Controls (n:15)
(mean ± SD)
0.35±0.03
Table (2) shows a comparison of
cIMT in BTM patients in relation to
their data. There was significant
difference of cITM in relation to age,
serum iron level, ferritin level and total
cholesterol
level
with
P<0.03,
P<0.002, P<0.001and P< 0.0001
P value
0.037 *
respectively. On the other hand, there
was no significant difference of cITM
in relation to the patient’s sex, weight,
height,
hemoglobin
level,
and
hematocrit percent with P-values of:
P<0.671, P<0.34, P<0.26, P<0.085 and
P< 0.093 respectively.
Table (2): Comparative study of cIMT ^ in patients with BTM in relation to their data
Patient’s data
BTM (N=30)
(mean ± SD)
Age (years)
7.21±3.39
Sex (M/F)
19/11
Weight (kgs)
17.04±4.6
Height (cms)
110±18
Hb.( gm/dl)
9±1.18
Ht (%)
26.5±3.2
Iron (mcg/dl)
350.7±109.3
Ferittin (ng/ml)
408.7±191.4
Total Cholesterol (mg/dl)
245±123.7
* Significant P-value < 0.05.
** Highly significant P-value < 0.005
^
cIMT: Mean ± SD 0.06 ± 0.008
Table (3) shows that cIMT was
significantly different in children with
BTM in relation to features suggestive
of iron overload such as duration of
P value
0.03*
0.671
0.34
0.26
0.085
0.093
0.002**
0.001**
0.0001**
illness, frequency of blood transfusion,
use of iron chelating agents, size of
liver and spleen, splenectomy, skeletal
changes and iron & ferritin levels.
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EL-MINIA MED. BULL. VOL. 21, NO. 2, JUNE, 2010
Ismail & El-Sherif
Table (3): Comparative study of cIMT@ and features suggestive of iron overload in
patients with BTM
Duration of illness in years
Blood transfusions
(frequent/not frequent)
Iron chelating agents
(regular/irregular)
Splenomegally
BTM (N=30)
(mean ± SD)
6.3±3.3
0.03*
19/11
(63.33/36.67%)
11/12^
0.002**
7.2±2.2
0.029*
6.3±1.9
0.003**
12/18
(44.4/77.8%)
350.7±109.3
0.04**
Hepatomegally
Splenectomy
Yes/No
Iron (mcg/dl)
P value
Ferittin (ng/ml)
408.7±191.4
Skeletal changes
20/10
Yes/No
(66.67/33.33%)
^ 7 patients were not on iron chelation agents
* Significant P-value < 0.05.
** Highly significant P-value < 0.005
@
cIMT: Mean ± SD 0.06 ± 0.008
300
0.05*
0.002**
0.001**
0.04*
EL-MINIA MED. BULL. VOL. 21, NO. 2, JUNE, 2010
Ismail & El-Sherif
Figure 1: Long-axis view of the normal carotid wall anatomy on ultrasound. The
intima and adventia produces echogenic parallel lines (arrows) with an intervening
echo void representing the media.
Figure 2: Long-axis view and Doppler spectrum of the right CCA showing normal
intima-media thickness of 0.03-cm in a 10-year-old healthy child
Figure 3: Long-axis view and Doppler spectrum of the right CCA showing increased
intima-media thickness of 0.06-cm in an 11-year-old child with thalassaemia
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EL-MINIA MED. BULL. VOL. 21, NO. 2, JUNE, 2010
Ismail & El-Sherif
hematocrit percent. This also comes in
harmony with those of Tantawy et al
2009,14 who concluded that in
thalassaemic patients, cIMT was
positively correlated with age, Hb F,
ferritin and cholesterol levels, and that
atherogenic lipid profiles in young
thalassaemic patients with increased
CIMT highlights their importance as
prognostic factors for vascular risk
stratification.
DISCUSSION:
Beta-thalassaemias are a group
of hereditary blood disorders1. Betathalassemias are characterized by
anomalies in the synthesis of the beta
chains of hemoglobin2. Individuals
with beta-thalassaemia major (BTM)
usually present within the first two
years of life with severe anemia,
requiring regular red blood cell (RBC)
transfusions3. With the increased life
span of BTM patients, coronary artery
disease may emerge as one of the
important cardiovascular complications5. There is multi-factorial
etiology of left ventricular failure in
patients with beta-thalassaemia major.
Thus, apart from myocardial iron
deposition and myocarditis, stiffness of
both carotid and brachial-radial
arteries and arterial dysfunction may
also be contributory12.
Iron overload is usually
associated
with
regular
blood
transfusions which lead to transfusional haemosiderosis in patients with
chronic anaemia as in children with
BTM(15). These changes occur initially
in reticulo-endothelial system and
secondary to all parenchymal organs,
mainly heart, pancreas, pituitary gland,
and gonads, with cytotoxic effects16.
So, accumulation of iron has been
implicated as a risk of cardiovascular
disease, because of the catalytic role of
iron, causing oxidative stresses on the
vessel wall17-19.
Increased carotid artery intimamedia thickness (cIMT) is a structural
marker for early atherosclerosis and it
correlates with the vascular risk factors
and to the severity and extent of
coronary artery disease10,11.
We also found that cIMT was
significantly different in children with
BTM in relation to features suggestive
iron overload as duration of illness,
frequency of blood transfusion, use of
iron chelating agents, size of liver and
spleen, splenectomy, skeletal changes
and iron & ferritin levels. This comes
in harmony with the results of a
previous study that was carried out by
Cheung et al, 2002,20 who found that
iron overloading in patients with betathalassaemia
major
results
in
alterations of arterial structures with
disruption of elastic tissue and
calcification. This finding also comes
in harmony with those of Ramakrishna
et al., 200321 and with many other
epidemiological studies concluding
that iron is an important factor in the
process of atherosclerosis22 and carotid
IMT is considered an early marker of
In our study we found that the
cIMT of thalassaemic patients was
significantly increased compared to
controls with P-value <0.037. This
finding comes in concordance with the
results of Cheung et al., 2006, (13) who
found an increase in the cIMT in
patients with BTM compared to
controls. This also comes in harmony
with Tantawy et al 2009, 14 who found
the same results in their study.
In our study we also found that
in thalassaemic patients, there was
significant difference of cITM in
relation to patient’s age, iron, ferritin
and total cholesterol levels. But there
was no significant difference of cITM
in relation to patient’s sex, weight,
height,
hemoglobin
level,
and
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EL-MINIA MED. BULL. VOL. 21, NO. 2, JUNE, 2010
atherosclerotic process and is currently
used to assess the presence and the
progression of atherosclerosis23, 24.
Ismail & El-Sherif
Syndromes. 4th ed. Oxford: Blackwell
Science; 2001:133-91.
5- Aessopos A, Farmakis D,
Tsironi M, et al. Endothelial function
and arterial stiffness in sicklethalassemia patients. Atherosclerosis.
2007;191(2):427-32.
6 - Borgna-Pignatti C, Cappellini
MD, De Stefano P, Del Vecchio GC,
Forni GL, Gamberini MR, Ghilardi R,
Origa R, Piga A, Romeo MA, Zhao H,
Cnaan A:" Survival and complications
in thalassemia". Ann N Y Acad Sci
2005, 1054:40-47.
7- Borgna-Pignatti C, Rugolotto S,
De Stefano P, Zhao H, Cappellini MD,
Del Vecchio GC, Romeo MA, Forni
GL, Gamberini MR, Ghilardi R, Piga
A, Cnaan A: "Survival
and
complications in patients with
thalassaemia major treated with
transfusion
and
deferoxamine".
Haematologica 2004, 89:1187-1193.
8- Hahalis G, Kremastinos DT,
Terzis G, et al. Global vasomotor
dysfunction and accelerated vascular
aging in b-thalassaemia major. Atherosclerosis. 2008;198(2):448-57.
9- Aggoun Y, Szezepanski I,
Bonnet D. Non invasive assessment of
arterial stiffness and risk of
atherosclerotic events in children.
Pediatr Res. 2005;58(2):173-8.
10- Järvisalo MJ, Raitakari M,
Toikka JO, et al. Endothelial dysfunction and increased arterial intimamedia thickness in children with type-1
diabetes.
Circulation.2004;
109
(14):1750-5.
11- Cheung YF. Arterial Stiffness
in Children and Teenagers: An
Emerging Cardiovascular Risk Factor.
HK J Paediatr, 2005;10:299-306
12- Kremastinos DT, Flevari P,
Spyropoulou M, Vrettou H, Tsiapras
D, Stavropoulos-Giokas CG. Association of heart failure in homozygous
beta-thalassaemia with the major
histocompatibility complex. Circulation 1999; 100:2074-8.
CONCLUSION:
We conclude that patients with
beta-thalassaemia major should be
considered to have an increased risk of
early
vascular
alteration
and
atherosclerosis. Iron overload is
implicated as a risk of cardiovascular
disease, because of its catalytic role
causing oxidative stresses on vessel
wall. Carotid IMT is considered an
early marker of atherosclerotic
process. The clinical importance of our
study is in the prevention of the
progression of atherosclerosis in early
stages by decreasing body iron load in
the thalassaemic patients. It is
important to determine if these patients
are in need of specific treatment for
hyperlipidemia by dietary restriction or
pharmacological therapy. Decrease in
body iron load can be achieved by
good compliance of iron chelating
therapy. We recommend using carotid
artery
intima-media
thickness
measurement as a non-invasive and
early diagnostic method for early
detection of atherosclerosis in patients
with beta thalassaemia major.
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‫الملخص العربى‬
‫قياس سمك جدار الشريان السباتى كمؤشر لتصلب الشرايين لدى األطفال‬
‫المصابين بمرض انيميا البحر المتوسط ( الثالتيميا)‬
‫يتميز مرض انيميا البحر المتوسط (الثالثيميا) بحدوث تشوهات فى سالسل البيتا فى‬
‫الهيموجلوبين‪ .‬وغالبا ما تظهر اعراض المرض فى غضون العامين األولين فى صوره انيميا‬
‫شديده والتى تتطلب عمليات نقل منتظمه للدم‪ .‬ويصبح هؤالء المرضى فى حاله خطر متزايد‬
‫من مضاعفات المرض والتى تشمل حدوث تغيرات فى جداراألوعيه الدمويه تؤدى الى مرض‬
‫تصلب الشرايين‪ .‬وقد وجد انه باستخدام الموجات فوق الصوتيه يمكن تحديد هذه التغييرات التى‬
‫تحدث فى جدران الشرايين مبكرا وبالتالى يمكن الحد من مرض تصلب الشرايين‪.‬‬
‫هدف البحث‪:‬‬
‫قياس سمك الطبقه المبطنه للشريان الثباتى فى األطفال المصابين بمرض انيميا البحر‬
‫المتوسط الثالثيميا وكذلك تقييم عالقته بعالمات زياده الحديد وايجاد ما اذا كان هناك امكانيه‬
‫الستخدام سمك هذه الطبقه المبطنه للشريان السبتى كمؤشر مبكر لتصلب الشرايين فى هؤالء‬
‫األطفال‪.‬‬
‫المرضى وطرق البحث‪:‬‬
‫اشتملت الدراسه على ‪ 30‬طفال مصابين بمرض انيميا البحر المتوسط الثالثيميا و‪15‬‬
‫طفال من االصحاء كمجموعة ضابطة مطابقين لهم فى الجنس والعمر‪ .‬تم اجراء عد كامل للدم‬
‫وتحديد نسبه الحديد والفيريتين فى الدم وكذلك نسبه الدهون الكليه والهيموجلوبين الكهربائى وتم‬
‫عمل دوبلر بالموجات فوق الصوتية للشريان السباتى للمرضى واألطفال االصحاء وتحديد سمك‬
‫الطبقه المبطنه له‪.‬‬
‫نتائج البحث‪:‬‬
‫فى هذه الدراسه وجدنا زياده كبيره فى سمك الطبقه المبطنه للشريان السباتى لالطفال‬
‫المصابين بانيميا البحر المتوسط بالمقارنه باالطفال االصحاء‪.‬كما وجد ان هناك اختالف كبير‬
‫فى سمك الطبقه المبطنه للشريان السباتى فى المرضى بالنسبه للعمر ونسبه الحديد والفيريتين‬
‫فى الدم وكذلك بالنسبه للكوليستيرول الكلى وفتره االصابة بالمرض وحجم الكبد والطحال‪.‬‬
‫ولكننا لم نجد فرق كبير بينه وبين الجنس او الوزن او الطول او مستوى الهيموجلوبين‬
‫والكرياتينين فى الدم‪.‬‬
‫الخالصه‪:‬‬
‫هناك زياده كبيره فى سمك بطانه الشريان السباتى فى األطفال المصابين بمرض انيميا‬
‫البحر المتوسط الثالثيميا بالمقارنه باألطفال األصحاء كما وان هناك عالقه قويه بين عالمات‬
‫زياده الحديد فيهم وبين سمك بطانه الشريان السباتى وبالتالى يمكن استخدامه كمؤشر للتنبؤ‬
‫المبكر بمرض تصلب الشرايين مما يجعلنا نحاول منع حدوثه عن طريق الحد من الدهون فى‬
‫التغذيه واستخدام األدويه لتقليل الدهون وكذلك تقليل الحديد فى دم األطفال المرضى عن طريق‬
‫األستخدام المنظم لألدويه التى تؤدى الى التخلص منه‪.‬‬
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