Keywords Beta-thalassemia major - cardiac single-photon-emission computed tomography - myocardial
ischemia - myocardial perfusion imaging
Introduction
Beta-thalassemia, a hereditary blood disorder, is a chronic hemolytic anemia caused
by impaired synthesis of the beta hemoglobin (Hb) chain resulting in an intense decline
in the red blood cell life span leading to variable phenotypes ranging from severely
anemic to clinically asymptomatic individuals.[1 ] There are three types of thalassemia, including thalassemia major (TM), thalassemia
intermedia, and thalassemia minor. TM is usually diagnosed within the first 2 years
of life with severe anemia.[1 ]
After diagnosing TM, regular blood transfusion and chelation treatment are very important
for survival. However, these transfusions lead to siderosis in the myocardium and
cardiac dysfunction would develop depending on the frequency and duration of transfusions.[2 ] The iron deposition in the heart is the main cause of morbidity and mortality in
TM patients.
Studies have found a relationship between the development of cardiovascular complications
and elevated iron levels.[3 ] Iron, which is an important part of several enzymes, becomes very cytotoxic when
excess amounts are deposited in the tissues of TM patients due to repeated blood transfusions.[4 ] Iron-induced cardiac dysfunction manifests as congestive heart failure (CHF), different
arrhythmias, and regional wall motion abnormalities. Moreover, excess iron may accelerate
lipid peroxidation due to pro-oxidant properties causing early atherogenesis.[3 ] Iron-induced CHF is the most prevalent cause of mortality in these patients.
Early diagnosis of beta-thalassemia may lead to fast chelation therapy resulting in
a finer life. Since iron accumulates in the myocardium, biopsy is the most accurate
procedure for beta-thalassemia diagnosis, but since it is an invasive technique, it
is not usually preferred clinically. In these patients, the cardiac function is evaluated
using noninvasive techniques such as magnetic resonance imaging (MRI), computed tomography
(CT) scan, and echocardiography. A recent study investigated various conventional
echocardiography parameters to evaluate cardiac function in patients with asymptomatic
thalassemia.[5 ] Cardiac dysfunction is associated with a poor prognosis because echocardiography
parameters are normal until cardiac dysfunction is clinically manifest.[6 ],[7 ] New echocardiographic techniques such as tissue Doppler imaging (TDI) can be used
to evaluate cardiac function and to monitor and identify subclinical heart failure.[8 ],[9 ] T2* cardiovascular MRI is the best method for screening cardiac iron load. It can
identify cardiac iron overload before cardiac dysfunction occurs; therefore, management
strategies can be implemented instantly. However, this method is expensive and unavailable
in many regions.[10 ]
It has been shown that stress radionuclide ventriculography (RNV) can be used to detect
functional abnormalities in thalassemia patients during exercise before they become
apparent at rest.[11 ] Furthermore, studies have revealed that some cardiac failures in TM patients, such
as regional wall motion abnormalities that frequently occur in the septum as early
damage, can be detected by 99m TC-tetrofosmin myocardial perfusion scintigraphy.[4 ],[12 ] Since heart failure and its extent can be detected with cardiac gated single-photon-emission
CT (SPECT), this study was conducted to evaluate cardiac perfusion and function in
TM patients using 99m TC-MIBI cardiac gated SPECT.
Materials and Methods
Study population
TM patients who had regular blood transfusions and periodic checkups with a negative
history coronary artery disease (CAD) or cardiac symptoms were included in this study.
Inclusion criteria were a definitive diagnosis of TM by Hb electrophoresis and confirmation
of the TM diagnosis by hematological tests available in the patient's medical records.
Exclusion criteria were a history of acute coronary syndrome, myocardial ischemia,
previous myocardial infarction, and cardiomyopathy. Patients with insufficient data
were also excluded from the study.
CAD was evaluated using myocardial perfusion imaging (MPI)–gated SPECT imaging in
the nuclear medicine department of a university affiliated hospital. MPI results were
compared with the obtained paraclinical data.
A questionnaire containing demographic and medical data was provided for all patients
by an expert pediatrician. All of them were on Desferal chelation therapy and none
of the patients had clinical signs of heart failure. The study protocol was explained
to patients and their parents and informed consent was obtained from them. This study
was in accordance with the Declaration of Helsinki and was approved by the Ethics
Committee of Bushehr University of Medical Sciences (registration code: IR.BPUMS.REC.1396.26/date:
June 19, 2017).
Single-photon-emission computed tomography acquisition protocol
On the same day, a stress-rest protocol was used for gated MPI acquisition. Pharmacologic
stress was induced through intravenous injection of 0.56 mg/kg dipyridamole over 4
min. 99m Tc-sestamibi at a dose of about 20 mCi was injected intravenously for each phase and
SPECT was performed after at least 60 min in the supine position with a dual-head
scintillation camera (Vertex-Plus, ADAC Laboratories, Silicon Valley, USA) equipped
with a low-energy high-resolution collimator. Thirty-two projections (20 s/projection)
were obtained using step-and-shoot acquisition method in the 90° setting (from 45°
right anterior oblique to 45° left anterior oblique), and also, gated in the rest
phase was obtained with an R-wave trigger at eight frames per cardiac cycle and stored
in a 64 × 64 matrix. No attenuation correction was used in the processing. Image reconstruction
was done using the filtered back-projection method by Butterworth filters with a cutoff
of 0.45 and order of 9.0. The raw data were reconstructed for all projections by an
experienced technologist in nuclear cardiology. An experienced nuclear medicine specialist
supervised the cardiac SPECT protocol.
All images were interpreted visually by two experienced practitioners who reached
consensus on findings. The nuclear medicine specialists were blind to the data of
the cases.
Echocardiography protocol
A Samsung echocardiography machine with a 3.5 MHz transducer was used for electrocardiography.
The patients were positioned in left lateral decubitus at rest and parasternal long-axis
and short-axis and apical two- and four-chambers views were obtained. The lower limit
of normal left ventricular ejection fraction (LVEF) was considered 50%. Visual scores
were used for regional wall motion of the LV myocardium according to the following
scale: normal = 0; mild hypokinesia = 1; moderate hypokinesia = 2; severe hypokinesia
= 3; and dyskinetic = 4. Moreover, ejection fraction, end-systolic cavity dimensions,
and left ventricular end-diastolic volume were measured. Furthermore, pulmonary arterial
pressure (PAP) was measured in some patients.
Blood measurements
Laboratory data including low-density lipoprotein, high-density lipoprotein, cholesterol,
triglyceride, alanine transaminase (ALT), aspartate aminotransferase (AST), Hb, ferritin,
and the amount of blood transfusion during a year were extracted from patients' medical
records.
Statistical analysis
Quantitative data were presented as the mean ± standard deviation with ranges given
when appropriate. Qualitative data were expressed as percentage. Chi-square was used
to analyze qualitative variables. SPSS Statistics 21 (IBM Corporation, Somers, NY,
USA) was used for the statistical analysis. P < 0.05 was considered significant.
Results
Demographic data
In total, 24 patients including 14 men (58.3%) and 10 women (41.7%) aged 15–36 years
with a mean age of 24.3 ± 6.5 years' old were enrolled. Splenectomy had been performed
in 14 patients (58.3%) and all of them were on Desferal chelation therapy [[Table 1 ]].
Table 1 Statistical description of data
Hematologic data
The mean amount of blood transfusion during a year was 7435.23 ± 3802.75 cc, and mean
Hb level was 8.17 ± 0.57 g/dL (from 7 to 9.1 g/dL), and the mean ferritin level was
2374.75 ± 2033.19 ng/ml (from 300 to 7820 ng/ml). Other laboratory parameters are
presented in [[Table 1 ]].
Echocardiography data
According to the results of echocardiography, the mean LVEF was 54.45% ± 6.18% in
the patients. The mean PAP measured was 29.12 ± 6.24 mmHg in eight patients. Diastolic
dysfunction was observed in all of the patients.
Cardiac gated single-photon-emission computed tomography
Myocardial perfusion scan (MPS) was normal in all patients. The mean LVEF was 58.88%
± 13.45%. Moreover, the mean end-diastolic volume, transient ischemic dilation, and
lung-to-heart uptake ratio was 85.22 ± 44.17 ml, 0.94 ± 0.13, and 0.33 ± 0.09, respectively.
Data analysis
There was no significant association between measured LVEF on scan and echocardiography
(P > 0.05). In terms of hematological results, there was a significant association
between the Hb and ferritin level and the amount of blood transfusion (P = 0.02 and
P = 0.00, respectively). In addition, there was no significant association between
the level of ALT and the amount of blood transfusion (P > 0.05) and between the level
of ferritin (P > 0.05) and the level of AST (P > 0.05).
Discussion
Patients with TM suffer from serious chronic anemia and iron overload due to regular
blood transfusions. Clinical manifestations of iron overload, including hypogonadism
(35%–55%), hypothyroidism (9%–11%), hypoparathyroidism (4%), diabetes (6%–10%), liver
fibrosis, and cardiac dysfunction (33%), develop in TM patients maintained on a regular
transfusion regimen.[1 ] In these patients, cardiac dysfunction is the main clinical problem and a leading
cause of mortality, especially in the second decade.[13 ] Considering that myocardial hemochromatosis may develop without clinical manifestations,[14 ] a noninvasive procedure that can detect cardiac dysfunction in early stages is very
helpful in these patients. Although rest echocardiography can identify functional
and anatomical abnormalities in some patients prior to the onset of clinical manifestations,
the majority of the patients without clinical CHF do not show conclusive echocardiographic
evidence at rest.[15 ] T2*MRI is the best screening modality and can detect cardiac iron overload before
the development of cardiac failure. Nevertheless, this method is expensive and is
not available in many centers.[9 ]
In this study, cardiac gated SPECT was used to evaluate cardiac dysfunction in asymptomatic
patients with TM. None of the patients had signs of cardiac problems. MPS was within
the normal range in all of the patients. Moreover, LVEF obtained from gated SPECT
was in the normal range. Few studies have investigated the value of MPS in cardiac
assessment of patients with TM. Gedik et al.[4 ] found regional cardiac wall motion abnormalities in TM patients. This early injury
is mostly located in the septum and can be identified with MPS. In another study,
Küçük et al.[2 ] evaluated myocardial perfusion using thallium scan and left ventricular function
using rest RNV. The results showed that in TM patients, ischemia and fixed defects
might be observed in stress MPS as a result of heart involvement. However, RNV was
preferred for the early detection of subclinical cardiomyopathy. In another study,
exercise MPS was used to determinate the mechanism of myocardial ischemia in sickle
beta-thalassemia patients. It was found that physical stress might lead to myocardial
ischemia in patients with normal coronary arteries and elicit painful crises.[12 ] All of the patients in the present study had major thalassemia and none of them
had a sickle cell-related allele. Moreover, perfusion defects or ST depression were
not observed on electrocardiogram during the stress phase of the study. Therefore,
the existence of sickle cell-related allele in sickle beta-thalassemia patients is
a predisposing factor for myocardial ischemia and painful crises during physical stress.
According to the results of echocardiography, although LVEF was in the normal range
in all patients, all of them suffered from diastolic dysfunction. In one study, systolic
and diastolic functions of the left ventricle were assessed using TDI and it was found
that diastolic indices of the LV showed higher early diastolic filling of LV and E/A
ratio suggesting a restrictive diastolic pattern and stiff myocardial wall in the
patients.[16 ] Similarly, Yaprak et al.[17 ] found that patients had a significantly higher E-wave and lower A-wave and E/A ratio
velocity indicating a restrictive pattern while no correlation was found with the
Hb level.
This study had some limitations. The most important limitation was its small sample
size, which may necessitate further investigation. Moreover, the association between
possible perfusion abnormalities and cardiac iron overload should be investigated
in future studies using state-of-the-art technologies like positron-emission tomography-MRI.
In addition, for a more accurate assessment of diastolic dysfunction in cardiac gated
SPECT for comparison with echocardiography, it is better to use 16 frames per cardiac
cycle instead of 8 frames per cardiac cycle,[18 ] but it was not done in the present study.
Conclusion
According to the results of MPI, cardiac perfusion and LVEF were within normal limits
in all asymptomatic patients. In the absence of any perfusion abnormality, the use
of MPI in patients with asymptomatic beta-TM is not recommended for diagnosing myocardial
ischemia.
