Evaluation of QT Interval in β Thalassemia Major Patients in Comparison with Control Group.

BACKGROUND: Cardiac complications are the primary cause of death in patients with b thalassemia major. QTc interval is an indicator of variability of ventricular repolarization and is supposed to be prominent in high risk patients. The aim of this investigation was to evaluate the relationship between QTc interval in β thalassemia major in comparison with the control group. PATIENTS AND METHODS: Sixty β thalassemia major and intermadia patients were enrolled in this analytical cross-sectional study. Thalassemia major and intermadia patients with no clinical symptoms of cardiac disease underwent echocardiographic and stress tests. QTc interval, blood pressure, heart rate, and average serum ferritin levels were measured. Statistical analysis was performed using version 15 SPSS.
RESULTS: Although there was no clinical or echocardiographic sign of cardiac disease and QTc intervals measured before the test were not significantly different between patients and control group (421.7 ± 29.6 vs. 412.4 ± 28.2, P = 0.06), we found that, during stress test, QTc intervals (452.7 ± 30.8 vs. 410.2 ± 26.2, P < 0.001) and heart rate (105 ± 15.1 vs. 89.7 ± 12.3, P < 0.001) were notably greater in β thalassemia major patients compared to the control group, respectively.
CONCLUSION: We found augmented QTc intervals in this group of thalassemia major patients who have neither clinical nor electrocardiographic and gross echocardiographic signs of cardiac disease. QTc interval can be helpful in the cardiac assessment of thalassemia major patients.

INTRODUCTION

Thalassemia major is a congenital defect of globulin chain synthesis, ineffective erythropoiesis and intense anemia.[1] The chronic anemia leads to growth retardation, bone marrow expansion, extramedullary hematopoiesis, splenomegaly, greater intestinal iron absorption, hypercoagulability and higher propensity to infection.[23] Although iron chelator therapy has resulted in incredible progress in the treatment of β thalassemia major, cardiac complications such as heart failure and arrhythmias, caused by the so-called iron-induced cardiomyopathy, may be the primary feature of death in patients with thalassaemia major.[4] The QT interval reveals the duration between the beginning of ventricular depolarization and the end of ventricular repolarization. Prolongation of the QT interval may be correlated with arrhythmogenesis in amount of cardiac disorders.[5] Some reports demonstrated higher dispersal of the QTc interval in a population of young and asymptomatic patients with thalassemia major than in healthy control subjects.[6] Since cardiac function remains normal until late in the field of iron cardiomyopathy, other tools are essential to predict and prevent iron cardiomyopathy. Although liver iron level has been used as a substitute for cardiac iron for many years, the relation between cardiac iron and liver iron is quite complicated.[7]

In this study, we sought to evaluate QT distribution and the relation between QT dispersion and body iron overload among patients with β-thalassemia major.

PATIENTS AND METHODS

Patients

In this cross-sectional study, 60 patients with thalassemia major and thalassemia intermedia, who had been diagnosed since childhood, were enrolled. All these patients had received transfusions frequently and had referred to Firouzgar center for cardiologic follow-up every 6-12 months. Participants were older than 15 years and had no previously evident cardiac disorder. Control group was assigned simply and non-randomly from medical students that were 19-28 years old and did not have any past medical history. Demographic/clinical data and informed written consent were obtained from all of the patients. Ferritin plasma level of patients was also obtained from outpatient clinics. This study was conducted with the approval of our Institution Review Board (IRB).

Echocardiography was performed for all of the patients. In the next step, patients with unremarkable echocardiography underwent Bruce exercise tolerance- test. Bruce method consists of four stages with increasing velocity and in every stage, QT intervals are measured and recorded in electrocardiography papers during the test. In addition, blood pressure and heart rate are measured and recorded during every stage of the test.

Statistical analysis

All data were presented as the mean ± SD. Statistical analyses were performed by SPSS statistical software (version 16.0 for Windows; SPSS Inc, Chicago, IL, U.S.A). Chi-square and independent sample T- tests were used to compare qualitative and quantitative variables respectively. P values less than 0.05 were considered statistically significant and 95% confidence intervals were reported.

RESULTS

Sixty β thalassemia major and/or intermadia patients (40 thalassemia major and 20 intermadia) including 32 males and 28 females and 62 healthy controls (30 males and 32 females) were enrolled in this cross-sectional study. The demographic and hemodynamic characteristics of patients are presented in [Table 1]. There were no significant differences in age and gender between groups. Mean age of b thalassemia and control groups were 25.4 ± 5.9 (ranged 15 to 41) and 25.7 ± 3.1 years old (ranged 20 to 35), respectively. The serum ferritin mean ± SD level was 2396 ± 2058 g/L.

Table 1

Demographic and hemodynamic characteristics of β thalassaemia major/intermedia patients and control group

Additionally, there were no significant differences in serum creatinine and hemoglobin level between both groups.

Electrocardiographic (EKG) and standard echocardiographic findings were normal and all patients were in sinus rhythm. Also, they did not show any electrocardiographic evidence of cardiac failure or arrhythmia. The systolic and diastolic blood pressure values were remarkably lower in β thalassemia group (P = 0.001), while the heart rate was higher in β thalassemia compared with control group (105.1 ± 15.1 vs. 89.7 ± 12.3, P = 0.001). As shown in [Table 2], measurement of corrected QT (QTc) interval values before and during exercise test revealed that resting QTc interval was slightly longer in β thalassemia group compared with the control with no statistical significance (422.3 ± 30.2 vs. 413.6 ± 23.1, P = 0.08). But QTc interval during exercise became prolonged in β thalassemia patients that were considerably higher compared with control group [Table 2].

Table 2

The electrocardiographic findings of the study and control groups

We compared effect of serum ferritin levels >1000 g/L and <1000 g/L on QTc interval among β thalassemia patients in which the results showed no significant difference between groups (P > 0.05).

DISCUSSION

Despite remarkable iron chelator therapy in the treatment of β thalassemia major, cardiomyopathy and heart failure are the major causes of death in patients with β thalassemia major.[1-3] In accordance with other studies, we showed that QTc interval values augmented during exercise test in the young and clinically asymptomatic patients with β thalassemia suggesting early abnormal myocardial repolarization.[89] Several studies report that these QT indices are helpful for recognizing changes in cardiac repolarization as structural and ultra structural injury, especially in patients inclined to sudden cardiac death.[10]

Similar to our findings, Ulger et al. detected that although there were no clinical or echocardiographic signs of cardiac disease, QTc intervals were superior in β thalassemia major patients compared to the control group.[11] In our study, the resting QTc interval was slightly higher in β thalassemia patients compared with the healthy controls with no statistical difference.

In b thalassemia patients of our study, systolic and diastolic blood pressures were significantly lower than control group; however, heart rate was more among b thalassemia patients. This could be explained by the fact that thalassemia major is a chronic high-output state, and therefore, maintaining a normal mean systemic blood pressure requires reduced vascular resistance.[12]

Previous studies have reported that serum ferritin level less than 2500 ng/dL is associated with better cardiovascular prognosis. Moreover, serum ferritin less than 1000 ng/dL is associated with normal left ventricular ejection fraction (LVEF). Here in, the mean serum ferittin in β thalassemia major and intermedia patients was 2806 and 2004, respectively.[13] Thirty percent patients had serum ferritin upper than 2500 ng/dl, which indicates that compliance to chelation therapy was not uniform within the study group. This may also explain the absence of heart failure and significant valve diseases in the current study population.

The QT interval is a measure of identifying ventricular depolarization and repolarization. The prolongation of QT interval predicts increased risk of life threatening ventricular arrhythmias and sudden death.[14] Ulger and colleagues revealed that left ventricular myocardial infarction e(LVMI) was higher in thalassaemia major patients compared to the control group and there was a positive association between LVMI and QTc dispersion.[11] In this study, we detected that although there was no clinical or echocardiographic signs of cardiac disease, QTc interval and QTc dispersion were higher in β thalassaemia major patients compared to the control group.

Once heart failure develops, the outlook is usually poor in thalassemia patients. The cardiomyopathy may be reversible if iron chelating treatment is strengthened in time, but the early diagnosis of iron-induced cardiomyopathy with established clinical techniques such as echocardiography and stress radionuclide angiography has had imperfect success.[15] In particular, explicit dysfunction on echocardiography presents late stage in the disease process and the progression from mildly abnormal echocardiographic parameters to fulminant cardiac failure is often rapid and insistent.[16]

CONCLUSION

QTc dispersion can be used in the cardiac assessment of thalassemia major patients. It has high reproducibility as a non-massive tool. Prospective studies are considered necessary to elucidate the relationship between the prolongation of QTc dispersion and consequent cardiac events in thalassemia patients.