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.