الفهرس 
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Abstract
Thalassemia syndromes are a heterogeneous group of hemoglobin disorders which exhibit decreased or absent production of normal globin chains (Origa, 2017).
Chronic hemolytic anemia results from a defect in hemoglobin synthesis, which leads to the reduced synthesis of β-globin chains. Hemolytic anemia is characterized by its severity, its development during the first year of life and its requirement of life-long transfusion therapy (Kremastinos et al,2010). This hemoglobin disorder leads to β-Thalassemia, one of the most common inherited blood disorders of thalassemia births (Origa, 2017). Two clinical forms of β-thalassemia have been distinguished, depending on clinical severity: thalassemia major and thalassemia intermedia.
β-Thalassemia major is the typical phenotype, arising either from homozygous or compound heterozygous defects (Tanner et al, 2007; Hakeem et al, 2018). Transfusion-dependent Thalassemia patients receive more iron than is normal. This iron accumulation causes damage to various body organs, mainly the heart, which is very sensitive to iron toxicity (Gujja et al ,2010 ), but also the liver and endocrine organs (Carpenter et al,2012).
Heart failure due to myocardial siderosis is a result of the heart tissues’ slow removal of excess iron (Gillin et al,1975; Noetzli et al,2008 ; Aydinok et al,2015 ; Pennell et al,2015).
Therefore, myocardial iron measurement is an important step in determining the risk of cardiac complications (Pennell et al, 2006) and in tailoring the appropriate iron-chelation treatment for transfused thalassemia major patients (Tanner et al,2007; Soltanpour and Davari, 2018).
Cardiac T2* magnetic resonance imaging (MRI), using an intense magnetic field, can successfully assess iron deposition in cardiac muscles. The values derived from ”T2*MRI” are inversely proportional to tissue iron levels. Most recorded cases of heart failure in thalassemia patients to date have occurred in patients with very low T2* values (Pennell et al, 2006; Pepe et al, 2006; Habib et al,2016).
In particular, myocardial T2* values less than 20 milliseconds (ms) indicate cardiac iron overload, while in severe cardiac iron overload, the T2* value is less than 10 ms (Tanner et al,2007).
Amlodipine (AML) is a dihydropyridine calcium channel blocker that competitively inhibits the calcium channel to prevent calcium influx into the cell (Lee et al,2011) Its antioxidant property has been proven in various studies (Rosenkranz et al,2006; Salehi et al,2012).
The present study was designed to demonstrate the efficacy of amlodipine, in addition to chelation therapy, in reducing myocardial iron concentration Also , the study aimed to investigate the correlations between cardiac and hepatic iron concentration, myocardial and hepatic T2* values, along with serum ferritin level and left ventricle ejection fraction.
The study was designed as a single center, prospective randomized, placebo–controlled trial with allocation of a 1:1 ratio. The study was carried out in Beni-Suef University Hospital, Egypt. Thalassemia is prevalent in this city, as it serves neighboring villages where the disease is also common. Ethical committee approval (Ethical committee code: FWA00015574) and written informed consent from parents or caregivers were obtained before the start of the study. The clinical trial registry number is PACTR201902478249291.
Patients eligible for enrollment at baseline were male or female aged between 6 and 20 years old with β-Thalassemia major. Potential participants had been diagnosed with thalassemia major (TM), due to the presence of microcytic hypochromic anemia and hemoglobin electrophoresis. Additionally, patients who had been receiving regular blood transfusions during the past two years, with a serum ferritin (SF) level more than 1000 ng /ml, were also considered. Participants were excluded if they were more than 20 years old, their SF was less than 1000 ng /ml, they experienced heart failure (ejection fraction (EF) less than 30%), they were contraindicated to undergo the MRI scan, or they were expected to change their chelation therapy regimen during the next 6 months.
Patients were invited to participate during a visit to the outpatient hematology clinic at Beni-Seuf University Hospital (BUH). Once they met the inclusion criteria and signed the consent form, blood samples were collected for hematological and chemical analysis, and MRI scans were performed.
After doing the MRI scans and other laboratory tests, patients were allocated into either the iron chelator (Deferasirox) plus amlodipine group (2.5 mg/day for patients weighing less than 30 kg and 5 mg/day for patients weighing more than 30 kg or the iron chelator Deferasirox placebo group (Exjade; 20-40 mg/kg/day) for 6 months (Pennell et al,2011). The clinical pharmacist generated a computer list to randomly allocate the patients to either the drug or placebo group. The study medications were dispensed at each monthly visit and the patients were informed as to the group to which they were assigned.
Statistical analysis
Using G*Power software version 3.1.9.2 (Post hoc detection of power), we conducted a one-sided two sample t-test using the major variables. We calculated a sample size of 20 in each group (Amlodipine and placebo) achieving nearly 100%, depending on effect size, with a significance level (α) of 0.05, normality of data and 2-tailed analysis.
All the data were expressed as mean ±SD, with differences among the groups from baseline to 6 months compared for all continuous parameters. Independent t-tests were performed for the parametric variables and a Mann Whitney test for the non-parametric variables (particularly MIC, serum ferritin, LIC, liver T2*, myocardial T2*). The respective changes in the MIC, LIC and serum ferritin within each group were not normally distributed, so we compared them using the Wilcoxon rank test and paired sample t-test for the normally distributed parameters. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) computer software (version 22), IBM software, USA. Differences were considered statistically significant at p<0.05.
Results
The Baseline Demographic and Clinical characteristics
The baseline demographic characteristics showed no significant differences between the amlodipine and the placebo groups, with the exception of the age at onset, liver T2* and liver iron concentration (LIC), with more iron deposition found in the livers of the placebo group patients. The initial MIC showed no statistically significant differences in the patients allocated to placebo or amlodipine treatment, with a mean ± SD of 0.74 ± 0.11 mg/g vs 0.76 ± 0.11 mg/g, respectively (P=0.87).
Myocardial iron concentration:
The addition of amlodipine to the standard chelator therapy showed a significant reduction in the MIC, from 0.76±0.11 mg/g at baseline to 0.51±0.07 mg/g after 6 months (p< 0.001) figure 2. Also, a significant change in the myocardial T2* was noted after 6 months; the addition of amlodipine increased the myocardial T2* from 40.63±5.45 ms at baseline to 43.25±5.35 ms (p< 0.001).
The MIC significantly increased in patients receiving the placebo after 6 months of the trial, from 0.74±0.11 mg/g to 0.8±0.11 mg/g (p<0.001). Additionally, the myocardial T2* significantly decreased, from 53.23±6.61 ms at baseline to 52.99±6.6 ms after 6 months (p = 0.009) (Figure 3). The differences between the groups were significantly in favor of the amlodipine treatment group.
Serum ferritin
The serum ferritin level did not change significantly in either of the two groups by the end of the study, measuring 1929 ±421.06 ng/ml for the amlodipine group and 2759 ±340.73 ng/ml for the placebo group (p =0.925).
Liver iron concentration:
The absolute changes in LIC were not significant in either the placebo or the amlodipine groups. However, a significant difference was found in the relative liver T2* after 6 months, as the liver T2* decreased in the placebo group from a mean of 20.19 ± 2.21 ms to 20.00 ± 2.23 ms (p = 0.004), while no significant change in the relative LIC was noted after 6 months.
Left ventricular ejection fraction:
The mean ± SD left ventricular ejection fraction remained stable and within the normal range after 6 months of treatment for both groups. The amlodipine group baseline measure was 62.28±0.79 %, while at month 6, it was 62.40±0.76 %, an absolute change of -0.125 ± 0.64 (p=0.398). For the placebo group, the baseline was 63.40±0.55 %, while at month 6, it was 63.10±0.57 %, with an absolute change of 0.3 ± 1.12 (p= 0.249).
Minor changes in chelation therapy were allowed during the study, particularly for patients with severe iron overload or those who experienced side effects from the treatment. This consisted of minor adjustments in the Deferasirox dose. No patients switched to other chelators during the 6 months of the study.
Finally we recommend to add amlodipine to the standard chelation therapy in patients with transfusion dependent thalassemia major. Also, it is very important to detect myocardial iron concentration in thalassemia major patients by using the noninvasive cardiac T2* procedure.