European Journal of Cardiovascular Medicine

Thalassemia is characterized by decreased synthesis of one of the two globin chains ( and β globin) and depending on globin chain synthesis that is defective and decreased  and β thalassemia results.¹ Thalassemia major is fatal unless adequate transfusions are started early, in conjunction with intensive chelation therapy.² Estimated prevalence of pathological haemoglobinopathies in India is 1.2/1,000 live births, and approximately 32,400 babies born yearly with a serious hemoglobin disorder.¹

Two major therapeutic options for thalassemia major patients are either a bone marrow transplantation or repeated blood transfusions with chelation therapy. However, frequent blood transfusions cause progressive iron overload in heart leading to cardiac dysfunction, cardiomyopathy and heart failure if not chelated.³ Moreover, Thalassemia is secondary iron overload state due to increased absorption of iron from gut.⁴ Iron toxicity is attributed to the presence of non-transferrin bound iron (NTBI).^5,6 Iron catalyzes the production of free oxygen radicals, by the Haber Weiss and Fenton reactions.⁹

Heart disease has been the predominant cause of death in β-thalassemia major in various cohort studies.⁷ Iron overload cardiomyopathy can only be reversed if intensive chelation is initiated in early periods.^8,9

Several approaches have been used to determine total body iron load, and cardiac iron status including the indirect iron assessment such as serum ferritin, echocardiograph, electrocardiogram (ECG), superconducting quantum interference device biomagnetometry (SQUID) and T2* MRI as well as the direct but invasive assessment such as myocardial biopsy and liver biopsy. However, invasive methods have their limitations in clinical practice.¹⁰

Currently, cardiac MRI (CMR) has been known as a non- invasive technique of choice for monitoring iron overload in the heart.^5,11 But there are some disadvantages of cardiac MRI like cots, time consuming, and unavailable in most of the medical centres. Various ECHO parameters are used to evaluate cardiac function like ejection fraction(EF) and fractional shortening(FS) used for systolic function and peak early diastolic inflow velocity (E), peak late diastolic flow velocity (A), the ratio of E and A (E/A), deceleration time (DT) of early filling velocity¹² and myocardial performance parameter of Tei index or myocardial performance index(MPI) which is a parameter of both systolic and diastolic function.¹³ Left ventricular systolic function remains normal until late in these patients while diastolic indices may be more sensitive to early detection of myocardial iron overload.¹⁴

The present study was designed to find a possible correlation between serum level of ferritin, cardiac function and cardiac iron overload in patients with β–thalassemia.

A descriptive observational study was conducted on patients enrolled at the Thalassemia unit of a tertiary care hospital in India. The study included 50 patients with multi-transfused β-thalassemia major.

The following cases were included in the study:

Patients aged ≥ 3 years to ≤18 years who were diagnosed with β-thalassemia and had received ≥ 10 blood transfusions.

Patients with congenital or acquired heart disease, such as rheumatic heart disease and Kawasaki disease, primary hemochromatosis, patients with non-β-thalassemia transfusion-dependent anemia, history of exposure to cancer chemotherapy, seriously ill patients, or those who had received less than 10 blood transfusions.

After obtaining ethical committee clearance, informed parental consent was obtained from all cases. A detailed medical history and examination were conducted, including information regarding chelation therapy. All investigations were performed pre-transfusion, including hemoglobin, serum ferritin, and echocardiogram in all patients. T2* MRI was performed whenever possible with the consent of the guardians and financial counseling.

T2* MRI: A 1.5 tesla Philips inginia MRI was used to perform T2* cardiac and liver MRI of the patients. T2* was calculated based on the decay curve in milliseconds (ms). Interpretation of heart and liver T2* values is as follows:

Cardiac MRI interpretation¹⁵

Data Analysis: - All data were analyzed statistically. Continuous variables were analyzed using an unpaired t-test and Pearson correlation coefficient, while nominal/categorical variables were analyzed using a chi-square test or Fisher’s exact test. Statistical calculations were performed using MedCalc 12.2.1.0 software.

The present study was conducted on 50 patients enrolled at Thalassemia unit. The following observations were made (Table 1):

Table 1: Baseline characteristics, echocardiography and MRI findings in study subjects

The mean age ± SD of patients in this study was 11.34± 4.94 years. Out of 50 thalassemia patients, 30 were male and 20 were female. Ferritin value of >2500 ng/ml was observed in 7 patients while value <2500 was seen in 43 patients. Most of patients had ferritin value between 1000 to 1999 (44%).

For various echocardiography parameters, the mean ± SD for ejection fraction, fractional shortening and TAPSE values were found to be 37.54±6.46%, 66.70±7.3% and 24.60±3.38 mm respectively. The mean ± SD value for myocardial performance index (MPI) by tissue Doppler imaging (TDI) was found to be 0.60±0.16. The mean value ± SD for diastolic echocardiographic parameters like deceleration time (DT), E/A ratio, E’, E/E’, TR velocity and LA volume index were found to be 134.34±28.89 ms, 1.49±0.34, 20.15±6.90m/sec,5.33±2.39, 2.32±0.43m/s and 23.32±5.46ml/m² respectively.

T2* MRI was done in14 out of total 50 patients enrolled in our study. Among these 14 patients, 2 patients had abnormal T2* value of heart showing some iron overload in heart.

Out of 50 patients, systolic dysfunction was not present in any of the patients in our study. Out of 50 patients, diastolic dysfunction was present in 2(4%) patients whereas another 2(4%) patients had indeterminate diastolic function and rest 46(92%) patients had normal diastolic function. In ferritin group ≤ 2500 ng/ml, 1 patient (2.33%) had diastolic dysfunction while 1 patient (2.33%) had indeterminate diastolic function. Similarly, in patients with ferritin >2500 ng/ml, 1 patient (14.29%) had diastolic dysfunction while 1 patient (14.29%) had indeterminate diastolic function. Using Chi-square test, this difference between two groups was not statistically significant (p = 0.096).

T2* MRI was done in14 out of total 50 patients enrolled in our study. Among these 14 patients, 2 patients had abnormal T2* value of heart showing some iron overload in heart. The difference in both the groups was found to be statistically non-significant using Chi-square test. (P value=0.129) (Table 2).

Table 2: Patient distribution according to cardiac dysfunction and T2^* MRI findings in relation to ferritin level

Table 3: Correlation between serum ferritin & Echo parameters and T2^* MRI

One of the aims of the study was to find any correlation between serum ferritin and echocardiographic parameters. There was no significant correlation between FS(r=0.141, p value=0.330), E/A ratio(r=0.109, p value=0.453), E’(r=0.057, p value=0.695) and E/E’(r=0.022, p value=0.881) and serum ferritin in our study.

There was negative correlation between EF(r= -0.144, p value=0.319), TAPSE(r= -0.098, p value=0.497) and DT(r=-0.183, p value=0.203) with serum ferritin but it was statistically not significant. Also there was no significant correlation between MPI by TDI (r=0.040, p value=0.7823) with serum ferritin levels (Table 3).

In this study, there was no significant correlation between serum ferritin and T2* MRI values in heart (r=0.351,p value=0.219). Also there was negative correlation between serum ferritin and T2* MRI (Table 3).

Thalassemia is one of the most common hemoglobinopathies in the world.1 These patients require regular blood transfusions and iron chelation therapy because of severe haemolytic anaemia and ineffective erythropoiesis. Ultimately, complications occur due to iron overload leading to cardiac dysfunction. Several approaches have been used to determine total body iron load and cardiac iron status. Recently the focus has shifted to use of echocardiography and T2* MRI for early identification of cardiac dysfunction before over failure sets in because iron overload cardiomyopathy is irreversible.12

The present study was conducted to assess cardiovascular status of multi transfused β thalassemia patients and to assess correlation between serum ferritin, cardiac iron load and cardiac dysfunction. A total for 50 β thalassemia patients between ages 3 to 18 years were taken for the study

with mean age of 11.34±4.94 years. Out of 50 patients, 60% were males and 40% were females. Similar study was done by Siddammanahalli et al16 where 34 β thalassemia patients between age group of 3 to 17 years were enrolled with mean age of 9.21±3.9 years.

If the patients are divided into two groups based on serum ferritin levels (Group 1 with serum ferritin ≤ 2500ng/ml and group 2 with serum ferritin > 2500ng/ml) as was done in study by Syed et al17 and Eghbali et al18, both the groups were comparable to each other with no significant difference in age and sex distribution.

The mean value of parameters for systolic function like Fractional shortening, Ejection fraction (EF) and TAPSE were found to be 37.54±6.46%, 66.70±7.3% and 24.60±3.38 mm respectively. The mean value ± SD for diastolic echocardiographic parameters like deceleration time (DT), E/A ratio, E’,E/E’, TR velocity and LA volume index were found to be 134.34±28.89 ms, 1.49±0.34, 20.15±6.90m/sec,5.33±2.39, 2.32±0.43m/s and 23.32±5.46ml/m2 respectively.

Similar results were found in study by Eghbali et al18 where mean EF was found to be 60±7%. In a study by Barbero et al19, similar results were seen. The mean values of TAPSE, DT, E/A ratio and E/E’ were found to be 24.1±3.5mm, 182±35ms, 1.48±0.46 and 4.8±1.35 respectively.

All the patients in this study had normal EF, FS and TAPSE. No systolic dysfunction was not present in any of patients in this study. Whereas diastolic parameters like DT, E/A ratio, E’,E/E’ ratio, TR velocity and LA volume index were abnormal in 14(28%), 4(8%), 1(2%), 3(6%), 7(14%) and 3(6%) patients respectively. Diastolic dysfunction was present in 4%( n=2) of the patients and another 4%( n=2) had indeterminate diastolic function who need to be followed up and may land in diastolic failure in future. This shows that diastolic dysfunction precedes systolic dysfunction in thalassemia patients. These findings are consistent with study done by Hyder et al20 where isolated diastolic dysfunction was present in 30%(n=15) patients and systolic dysfunction was present in only 4%(n=2) patients.

In regard to correlation between serum ferritin and echocardiographic parameters. there was no significant correlation between FS(r=0.141, p value=0.330), E/A ratio(r=0.109, p value=0.453), E’(r=0.057, p value=0.695) and E/E’(r=0.022, p value=0.881) and serum ferritin was found.

There was insignificant negative correlation between EF(r= -0.144, p value=0.319), TAPSE(r= -0.098, p value=0.497) and DT(r=-0.183, p value=0.203) with serum ferritin. Similar results were found in studies by Nesheli et al21 and Sayed et al17 where they found no significant correlation between serum ferritin and echocardiographic parameters.

Out of 50 thalassemia patients in our study, T2* MRI was done in 14 patients. The mean T2* value for heart in our study were found to be 27.79±9.98ms. Out of these 14 patients, 12(85.71%) patients had normal T2* heart values indicating no siderosis in heart, 1(7.14%) patient had mild siderosis and 1(7.14%) had moderate siderosis and none of the patient showed severe iron overload in heart. Similar results were found in study by Merchant et al22 where mean T2* value for heart was found to be 23.45±13.4ms and 50% patients had no cardiac siderosis, 33.3% had mild to moderate cardiac siderosis and 16.7% had severe cardiac sisderosis. In the present study no significant correlation was found between T2* heart values and serum ferritin levels(r= 0.351, p value=0.219). This is similar to results found in study by Merchant et al22 and Sarvestani et al23 where they found no correlation in serum ferritin levels of patients with or without cardiac siderosis. This shows that serum ferritin cannot be used as a marker to predict iron overload in heart.

We conclude from the present study that a significant percentage of thalassemia patients have cardiac dysfunction. Diastolic dysfunction precedes systolic dysfunction in thalassemia patients. Serum ferritin does not correlate with cardiac iron overload as well as with cardiac dysfunction and should not be used to determine cardiac siderosis and this point should be considered while treating these patients. MPI by tissue doppler can be used to assess cardiac dysfunction in asymptomatic β thalassemia patients even when traditional echocardiographic parameters are normal.

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