Patients with thalassemia major typically require regular blood transfusions beginning in childhood. Despite iron chelation therapy, heart failure due to post-transfusion iron overload is still the leading cause of death in this disease [1
]. Chelation therapy has been shown to be effective in eliminating cardiac iron and in improving survival. Late in the course of the disease, life-threatening complications such as heart failure and arrhythmias develop. Cardiomyopathy is more common in patients with transfusion-dependent thalassemia (TDT), while pulmonary hypertension is more common in non-transfusion-dependent thalassemia (NTDT), particularly after splenectomy. If intense chelation is undertaken early, dilated cardiomyopathy induced by severe myocardial siderosis may be reversed, but clinical diagnosis is frequently delayed due to the late onset of symptoms. There are few predictors of heart function deterioration. Serum ferritin and hepatic iron accumulation have poor cardiac function correlations, and elevated brain-natriuretic peptide appears only late in the disease’s development [4
]. Once clinically diagnosed heart failure is established, cardiac function can rapidly deteriorate and become fatal. Evaluations of ventricular function, such as changes in ejection fraction over time, have been recommended in the case of thalassemia. However, they identify patients at a late stage. In the absence of myocardial iron loading, impaired cardiac function could be obscured by supranormal left ventricular function in this patient population [6
Attributed to the reason that iron deposits shorten T1, T2, and T2*, direct assessment of myocardial iron-utilizing magnetic resonance relaxation (MR) has recently become essential. Magnetic resonance imaging (MRI) techniques that identify and quantify iron in tissues could assess the amount of hepatic and cardiac iron. In a previous study, T2*sequences were used to identify and reproduce techniques for measuring myocardial iron concentration. If cardiac iron overload is detected, patients at risk of heart failure will be determined before becoming symptomatic [8
Cardiac T2* MRI has recently allowed for more accurate measurement of iron overload in the heart, allowing a better guide for managing iron chelation therapy with single or multiple chelators [8
]. For many years, Thai physicians have been using a standardized and validated analytical method to measure cardiac and hepatic iron overload using a specific T2* MRI sequence [11
]. They implemented a specific T2* MRI sequence to provide a comprehensive measurement of hepatic and myocardial iron overload in a single MRI study. Nevertheless, in thalassemia major patients, the study of extensive cardiac iron status monitoring is still deficient. This study aimed to determine the prevalence of cardiac siderosis among thalassemia major patients in Northeastern Thailand and evaluate the value of using T2* MRI for monitoring cardiac and liver iron overload. Another purpose was to assess the correlation between cardiac T2* MRI and liver iron concentration (LIC), serum ferritin, and left ventricular ejection fraction.
One hundred nineteen patients were included in the study. The baseline patients’ characteristics with normal, marginal, mild to moderate, and severe cardiac siderosis are summarized in Table 1
. There was no significant difference in age, sex, thalassemia type, mean pre-transfusion hemoglobin level, mean baseline ferritin levels, liver iron concentration, and left ventricular ejection fraction among the four groups at baseline.
The prevalence of cardiac siderosis with cardiac T2* MRI ≤ 25 ms was 17.6% (n = 21). Patients with severe cardiac siderosis had a mean cardiac T2* MRI = 8.5 ± 1.5 ms at baseline, which consistently improved over the treatment course of 5 years. At years 3 and 5, significant improvement was noted when cardiac T2* MRI reached a level of 30.3 ± 6.1 ms and 33.9 ± 1.9 ms, respectively (p
< 0.0001) (Table 2
). Those patients who at baseline had a mild to moderate cardiac siderosis with a mean cardiac T2* MRI of 15.8 ± 3.4 ms achieved significant improvement by year 3 when the level reached 34.2 ± 4.6 ms (p
< 0.0001). Patients with baseline marginal cardiac siderosis with mean cardiac T2* MRI of 23.2 ± 1.2 ms achieved significant improvement by year 1 when the level reached 31.8 ± 5.8 ms (p
< 0.0001). Patients with no cardiac siderosis had stable levels of 43.1 ± 7.2 ms at baseline and 43.6 ± 5.6 ms at year 5 (Table 2
). Only one of our patients had a clinical cardiac failure (LVEF of 54% and cardiac T2* MRI of 6.9 ms).
At their baseline MRI, 21 of the 119 patients had a cardiac T2* MRI ≤ of 25 ms. For 16 of these patients, iron chelation therapy was changed: combined therapy was adopted for nine patients (combined regimens of deferiprone and deferoxamine), an increased dosage of the chelating agent used as monotherapy was given to five patients, and the agent used as monotherapy was changed for two patients.
An analysis of the change in T2* values over time showed a significant improvement in cardiac T2* MRI (Table 3
, Figure 1
). A significant reduction in liver iron concentration over time was also demonstrated (Table 3
, Figure 2
Patients were given different iron chelation regimens to optimize chelation effectiveness during this retrospective study. The majority of the patients with cardiac siderosis were on desferrioxamine (DFO) chelation (52.4%), and most of the patients without cardiac siderosis received deferasirox (DFX) iron chelation therapy (50%) (Table 4
). Iron clearance from the heart has been shown to have slow kinetics. To assess the efficacy of cardiac iron chelators, prospective longitudinal studies are required. Patients with cardiac siderosis received a significantly lower volume of red cell transfusion relative to the patients without cardiac siderosis (Table 4
No significant correlation was detected between cardiac T2* MRI and liver iron concentration, serum ferritin, and LVEF (Figure 3
). During one year, three years, and five years’ follow-up periods, cardiac T2* MRI in patients with severe cardiac siderosis had significantly improved from 8.5 ± 1.49 ms at baseline to 17.05 ± 3.43 ms, 30.33 ± 6.1 ms, and 33.9 ± 1.9 ms (p
< 0.0001), respectively. Patients with severe, mild-moderate, marginal, and no cardiac siderosis had mean LIC values (mg/g dw) of 23.9 ± 6.5, 21.6 ± 13.3, 25.3 ± 7.7, and 19.9 ± 5.5 at baseline, respectively, whereas LVEF (%) was 58.3 ± 11.1, 61.9 ± 13.6, 59.5 ± 13.2, and 63.6 ± 14.5, respectively.
In previous studies, myocardial iron deposition was found to be unrelated to serum ferritin, liver iron concentration, and even myocardial biopsy [8
]. However, as seen in recent studies in patients with thalassemia major (TM), cardiac T2* MRI tends to comply with iron measures by myocardial biopsy and post-mortem hearts [16
]. In patients with transfusion-dependent thalassemia, non-invasive serial monitoring of cardiac T2* MRI for cardiac siderosis is now practical. In TM patients, we present the sequence of annual cardiac T2* MRI measurements. Patients were given various iron chelation regimens to improve chelation efficacy during our study. We observed cardiac T2* MRI improvement from the first year in all cardiac siderosis subgroups and normalization at three years in patients with severe cardiac siderosis (Table 2
While sequential heart function quantification recognizes patients at increased risk of cardiac mortality [6
], identifying high-risk patients early, before cardiomyopathy develops, and treating them with appropriate therapy would be preferred [2
]. Cardiac siderosis (T2* of ≤ 25 ms) in this retrospective cohort study was 17.6%. This result was much lower than those previously reported by various studies that reported a prevalence of up to 86% [14
]. The TM major patients in the present study had a 3.4% prevalence of severe cardiac siderosis. Previous studies have reported higher prevalence rates of severe cardiac siderosis [19
]. Heart failure occurs in only one patient with severe cardiac siderosis. No patient died in our five-year retrospective cohort study.
In our study, initial cardiac T2* MRI values below 25 ms resulted in adjusted iron chelation therapy in 16 cases, with cardiac T2* MRI values marginally below 25 ms in five patients. The cardiac MRI results improved as the iron chelation therapy was intensified, and no confirmed cases of heart failure occurred.
In severe cardiac siderosis cases, the impaired ventricular function was reported in up to 62 percent of patients [19
]. According to a previous study, the systolic function has low sensitivity for detecting elevated myocardial iron. The study’s authors found that 18% of their patients had elevated myocardial iron with a normal ejection fraction [20
]. Left ventricular function deteriorates as myocardial T2* decreases and is followed by left ventricular dilation and hypertrophy. Three patients with severe cardiac siderosis in the present study were asymptomatic and had a normal ejection fraction. Clinically significant myocardial complications, such as heart failure and life-threatening ventricular arrhythmias, are more likely to occur in these patients. These complications could be avoided if their chelation regimen was optimized [8
]. The decrease in heart failure rates in our patients with severe cardiac siderosis may be attributed to strict monitoring, aggressive treatment, and chelation optimization.
No correlation was found between cardiac T2* and liver iron concentration in the present study. This has been previously described in various studies, with a significant disassociation between liver and heart iron values [4
]. Since there is no correlation, cardiac T2* MRI cannot be predicted from LIC and vice versa. This was demonstrated using organ-specific iron uptake/release mechanisms. Furthermore, there are variations in iron elimination; for example, chelation therapy will eliminate iron from the liver more rapidly than from the heart, allowing liver iron to normalize while myocardial iron remains elevated [12
During the five-year follow-up period, mean LVEF increased and improved cardiac T2* MRI in our study. Nevertheless, no substantial relationship was found between the percent of improvement in cardiac T2* and the percent shift in LVEF. This could be attributed to the limited sample size and the fact that most participants had normal LVEF.
The present study’s limitation is the small number of severe cardiac siderosis participants and the low incidence of heart failure patients, and there were differences in length of time between MRI scans.