DISCUSSION
There are many complications related to the disease in children with
BTM. Cardiac complications are the most important of these complications
that increase mortality and morbidity.17 Studies have
suggested that the most common cardiac complications are heart failure
and arrhythmias.18 It has been proven in many studies
that endothelial dysfunction plays an important role in the pathogenesis
of cardiovascular diseases.19-20 In this study, we
aimed to investigate the effects of ADMA and endocan, which are
responsible for endothelial dysfunction in many non-hematological
cardiac diseases, on cardiovascular function in children with
transfusion-dependent BTM.
ADMA is a modified amino acid found in blood and shows its effect by
blocking the synthesis of NO. In the control of vascular tone, NO plays
a crucial role. As a result, it makes a significant contribution to
atherosclerosis.21 In this study we conducted 39
pediatric patients diagnosed with BTM and gender/age similar 39 healthy
children, and we observed that there was significant difference between
serum ADMA levels (p<0.001). There are some studies similar to
our results showing elevations in plasma ADMA levels in BTM patients. In
the study performed by Gürsel et al. with 31 children diagnosed with BTM
and 36 healthy controls, by comparing serum soluble vascular cell
adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1
(sICAM-1), P-selectin, and Pentraxin-3 levels, a significant
relationship was found between ADMA levels and endothelial
dysfunction.5 In another study conducted with 36 BTM
patients and healthy controls in which echocardiographic features were
compared, it was found that ADMA levels were statistically significantly
higher in the patient group. This result may be interpreted as the
increase in serum ADMA levels in BTM patients is an indicator of
endothelial dysfunction. The hemolytic rate was found to have a positive
correlation with serum ADMA levels.22 This result,
which contradicts with the literature, may be due to the fact that the
average age of our patient group is lower than the studies mentioned
above (82,2±59,1 mo. vs 12 and 11.25 yrs) and that hemolytic disease has
not yet caused significant endothelial dysfunction. However, in our
study, it was observed that there was no correlation between ADMA and
parameters related to disease characteristics in the BTM group (Table
2).
The basic diagnostic parameters of BTM (low levels of Hb, Htc, MCV, RBC,
reticulosit, iron and elevated serum ferritin) were found to be
significantly different in the patient group as expected. In addition,
it was noticed that the ESR (p<0,001) and proBNP (p=0,013)
values were statistically significantly higher in the BTM group (Table
2). Although the proBNP and ESR values were significantly higher in the
patient group with BTM, it was observed that they did not show a
significant correlation with ADMA. In the BTM patient group, cardiac EF
was found to be significantly higher than the control group (Table 4).
Cardiac dysfunction due to iron load is an expected complication, and
many reports have been published showing that cardiac EF is low in BTM
patients.23,24
Endocan is a soluble proteoglycan released by vascular endothelial
cells, which has been linked to the growth of vascular
tissue.14 Endothelial inflammation is crucial in
cardiovascular disease physiopathology25. The
relationship of endocan with endothelial function and inflammation has
been well defined in previous studies on many diseases suc as cancers,
systemic inflammatory diseases and cardiovascular
diseases.26 Since it is an indicator of vascular
endothelial dysfunction, its role in cardiovascular diseases has
attracted the attention of many authors and has been proven by many
studies on the subject.15,27,28 However, the
aforementioned studies were carried out on adults and the levels in BTM
patients, which are well known to disrupt the endothelial integrity of
the endocan, and its relationship with the cardiovascular system have
not been discussed before. It is well known that iron overload causes
toxicity in many organs, including the cardiovascular system, in
b-thalassemic patients. Cardiac mortality and morbidity remain high in
this population, despite the fact that iron chelation therapy has
enhanced prognosis. Endothelial cell activation is well documented, and
vascular complications are more common in BTM.29 In
our study, serum endocan levels in patients with BTM were not found to
be statistical difference (337,5±344,0 pg/mL vs 218,14±171,1 pg/mL)
(p=0,057) (Table 2). To the best of our knowledge, there are no similar
studies in the literature comparing serum endocan levels of healthy
children with beta-thalassemia major patients. It has been shown that
the release of endocan from the endothelium is minimal under
physiological conditions and increase in conditions that lead to
activation such as endothelial disorders.30 In
addition, when endocan and echocardiographic parameters were compared,
no statistically significant relationship was found between them (Table
5). The low average age of the BTM patient group may have contributed to
this result.
When the relationship between ADMA and endocan levels and 16 BTM
patients who had cardiac T2* MR was evaluated, it was observed that
there was no correlation (r=0.157, p= 0.560 and r=-0.133 ve p=0.625
respectively) To our knowledge, there is no study comparing serum
ADMA/endocan levels with cardiac T2 * MR in literature. Both the low
number of BTM patients with cardiac T2 * MRI and the wide distribution
of measurements may have an effect on this result.31The relationship between ADMA and Endocan with echocardiography
parameters was evaluated. However, a significant correlation that would
affect cardiac functions could not be established except tricuspid a.
Interestingly, in the study conducted by Mohamed et al with 30 BTM and
healthy children, tricuspid regurgitant jet velocity was investigated
and it was revealed that high ADMA levels in BTM patients could be
associated with pulmonary hypertension.22 In our study
there was no significant increase in pulmonary artery pressure in BTM
patients.
Soluble vascular cell adhesion molecule (sVCAM-1) and soluble
intercellular adhesion molecule (sICAM-1) are among the most studied
agents in endothelial dysfunction indicator studies in BTM patients.
Serum levels of plasma sVCAM-1 and sICAM-1 molecules have been shown to
increase in inflammation and endothelial
dysfunction.29 However, in a thesis study evaluating
endothelial and cardiac functions using endothelial activation
indicators in BTM patients, it was shown that sVCAM-1, sICAM-1,
neopterin, and Endothelin-1 did not differ in patients with and without
cardiac hypertrophy.32
The strength of our study is that it is the first study in which endocan
was studied in patients with BTM and its relationship with cardiac
functions was investigated. The weakness of the study is that our study
was conducted with a relatively small number of patients and the
inclusion of patients with a low mean age, who were still partially
affected by BTM.
In conclusion, ADMA and endocan are new inflammatory markers found in
systemic inflammatory and cardiovascular diseases that could be used to
predict endothelial damage. Although serum levels of ADMA were found to
be significantly higher in BTM patients, serum endocan and ADMA levels
were not associated with cardiovascular functions. However, for a more
meaningful result, it is necessary to study with more patients with a
higher average age.