Evaluation of QT Dispersion in b Thalassaemia Major Patients

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1 American Journal of Hematology 81: (2006) Evaluation of QT Dispersion in b Thalassaemia Major Patients Zulal Ulger, 1 * Yesim Aydinok, 2 Erturk Levent, 1 Dolunay Gurses, 1 and A. Ruhi Ozyurek 1 1 Department of Pediatric Cardiology, Ege University, Izmir, Turkey 2 Department of Pediatric Hematology, Ege University, Izmir, Turkey Cardiac complications are considered to be the primary cause of death in patients with b thalassaemia major. QT dispersion is a marker variability of ventricular repolarization and is elevated in various high risk groups of patients. This study was carried out in patients with b thalassaemia major to evaluate QT dispersion and to investigate the relationship between QT dispersion and body iron load. Sixty-two b thalassaemia major patients were enrolled into the study. The average serum ferritin levels and liver iron concentration was assessed. For each patient, QT QTc intervals and QT QTc dispersions were calculated and V1S and V5R were measured. All the subjects underwent two-dimensional M mode echocardiogram and Doppler study. LVMI was found higher in thalassaemia major patients compared to control group. b thalassaemia major patients showed significantly higher mean QT, QTc, QTd, and QTcd values compared to the control group. The mean V5R and V1S amplitudes were also higher in b thalassaemia major patients. There was a positive correlation between LVMI and QTc, QTd and QTcd. However, there was no significant correlation between QT dispersion and serum ferritin and liver iron concentration. Prospective longitudinal studies are needed to assess the prognostic significance of these findings. Am. J. Hematol. 81: , VC 2006 Wiley-Liss, Inc. Key words: b thalassaemia major; QT dispersion; left ventricular mass index; liver iron concentration; ferritin INTRODUCTION Cardiac complications such as heart failure and arrhythmias, caused by the so called \iron induced" cardiomyopathy, are considered to be the primary cause of death in patients with b thalassaemia major [1]. QT dispersion (Maximum Minimum QT interval on a standard 12-lead electrocardiogram (ECG)) is a marker variability of ventricular repolarization and is elevated in various high risk groups such as diabetic patients, patients with cardiac failure, and with essential hypertension [2 4]. The present study was carried out in a population of patients with b thalassaemia major, who were under regular follow up by the same center, in order to evaluate QT dispersion in thalassaemia patients and to investigate the relationship between QT dispersion and body iron load. MATERIALS AND METHODS Patients Sixty-two b thalassaemia major patients followed by the Pediatric Hematology Department of Ege Univer- VC 2006 Wiley-Liss, Inc. sity Hospital were enrolled into the study. All patients were requiring regular blood transfusions at 2 4 weekly intervals to maintain hemoglobin levels over 9 g/dl. The patients were receiving iron chelation therapy either as standard desferrioxamine (DFO) mg/kg sc 5 days a week or as deferiprone (DFP), which was given at a daily dose of 75 mg/kg either as a single agent or in combination with DFO (40 50 mg/kg twice weekly). Assessment of Body Iron Burden The average serum ferritin levels of all measurements at 3 monthly intervals over the last 12 months *Correspondence to: Dr. Zulal Ulger, Department of Pediatric Cardiology, Ege University Hospital, 35100, Bornova-Izmir, Turkey. drzulger@hotmail.com Received for publication 18 December 2005; Accepted 25 April 2006 Published online 21 August 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: /ajh.20679

2 902 Ulger et al. were obtained, and liver iron concentration (LIC) was assessed in biopsies using conventional atomic absorption. The patients who have serum ferritin levels over 2,500 mg/l and LIC higher than 15 mg/g dw were considered in increased risk for cardiac complications and early cardiac death. Cardiovascular Evaluation Patients who have a history of myopericarditis, anti-arrhythmic, or cardiovascular medications and use of complete or incomplete bundle branch block on superficial ECG were excluded from the study. The cardiac evaluation was standardized to blood transfusion interval and was performed at a median of 5 days (ranged 1 8) following transfusions. Body weight and height of each patient were measured and body mass index was calculated accordingly. The patients were rested for at least 15 min before blood pressure (BP) measurements and cardiovascular assessments, including electrocardiography and echocardiography. BP was measured twice from the right arm using sphingomanometer with appropriate cuff and the average of two readings was recorded. Standard 12-lead ECGs were recorded at a paper speed of 25 mm/s. Heart rate was calculated from the average RR interval of the tracings. QT intervals were measured manually in blinded fashion from the onset of QRS complex to the end of the T wave on the isoelectric line by the same physician. When U wave was present, the end of the QT interval was considered to be the nadir between the T and U waves. For each lead, three consecutive QT intervals were measured and averaged. QT dispersion (QTd) was defined as the difference between the longest and shortest QT intervals in one ECG record. QT intervals were corrected by heart rate according to Bazett s formula (QTc ¼ QTHRR) [5] and the QTc dispersion was calculated. As an indicator of left ventricular forces, S wave in V1 and R wave in V5 were measured. All the subjects underwent two dimensional M mode echocardiogram and Doppler study using a Vivid 7 system with a 3 MHz transducer (GE Vinmed, Ultrasound AS, Horten, Norway). All the subjects were at rest and lying in the left decubitus position during the examination. Measurements of Left ventricular end diastolic diameter (LVEDD), interventricular septum thickness (IVSTd) and the left ventricular posterior wall thickness at the end of diastole (LVPWTd), the shortening fraction (FS) and the ejection fraction (EF) were obtained from M- mode echocardiographic tracings with 2D imaging. Measurements were determined with standard techniques in accordance with the recommendations of the American Society Echocardiography [6]. Left ventricular mass (LVM) and left ventricular mass index (LVMI) were calculated with standard formulas [7,8]: LVM ¼ (0.8 (1.04 ((LVEDD + IVSTd + LVPWTd) 3 (LVEDD) 3 )) and LVMI ¼ LVM divided by height to the 2.7 power. Pulsed-wave Doppler examination was performed to obtain the following indexes of LV diastolic function: peak mitral inflow velocities at early (E) and late (A) diastole, E/A ratio, early deceleration time, isovolumic relaxation time (IVRT). Average values of these indexes obtained from 5 consecutive cardiac cycles were used for analysis. The control group consisted of 52 (27 males and 25 females) healthy subjects matched for age, gender and body mass index (BMI). They were not suffered from any cardiovascular or hematological disorder, not taking any cardio-active drugs and had normal electrocardiographic and echocardiographic examination. Informed consent was obtained from the study and control groups. Statistical Analysis Statistical analyses were performed by Systat statistical software (version 10.0 for Windows; SPSS Inc, Chicago, IL, U.S.A.). Student T, Chi-square, Pearson s correlation, and linear regression tests were used for data analyses. Statistical significance was taken at P < All data were presented as the mean ± SD. RESULTS The study group consisted of 62 b thalassaemia major patients (32 males and 30 females) aged between (16.4 ± 4.8) years. Fifty two healthy subjects (27 males and 25 females) aged between 10 and 24 (16.2 ± 3.6) years were considered as control group. BMI values in the study and control groups were found 19.5 ± 3.1 and 19.8 ± 2.7 kg/m 2 respectively. The mean pretransfusional hemoglobin levels of the b thalassaemia major patients (9.64 ± 0.64 g/dl) were significantly lower compared to the control group (12.75 ± 1.08 g/dl) (P ¼ 0.000). The serum ferritin and LIC ranged between ( ± ) g/l and mg/g dw (20.83 ± 12.95), respectively, indicating that compliance to chelation therapy was not uniform within the study group. Serum ferritin and LIC levels were found above the threshold for the risk of cardiac disease in 34 and 56% of the patients respectively. At the time of study, hemodynamic parameters of the patients were normal and none of the patients displayed clinical signs of cardiovascular disease. All patients were in sinus rhythm. Also, they did not show any electrocardiographic evidence of cardiac fail-

3 QT Dispersion in b Thalassaemia Major Patients 903 TABLE I. Clinical Characteristics and Echocardiographic Findings of b Thalassaemia Major Patients and Control Group TABLE II. The Electrocardiographic Findings of the Study and Control Groups b Thalassaemia major (n ¼ 62) Control group (n ¼ 52) P b Thalassaemia major (n ¼ 62) Control group (n ¼ 52) P Sex (M/F) 32/30 27/25 >0.05 Mean ages (years) ± ± 3.6 >0.05 BMI (kg/m 2 ) ± ± 2.7 >0.05 Heart rate (bpm) ± ± >0.05 Systolic BP (mmhg) ± ± 10.3 >0.05 Diastolic BP (mmhg) 66.6 ± ± 9.3 >0.05 LVEDD (cm) 4.31 ± ± 0.37 >0.05 IVSTd (cm) 0.74 ± ± 0.08 >0.05 LVPWTd (cm) 0.74 ± ± 0.09 >0.05 EF (%) ± ± 6.39 >0.05 FS (%) ± ± 6.10 >0.05 LVM (g) ± ± >0.05 LVMI (g/m 2.7 ) ± ± * Mitral E (cm/sn) ± ± 11.8 >0.05 Mitral A (cm/sn) ± ± >0.05 Mitral E/A ratio 2.0 ± ± 0.42 >0.05 E deceleration (ms) 128 ± ± 0.32 >0.05 IVRT (ms) 68 ± 8 71 ± 9 >0.05 QT (ms) ± ± * QTc (ms) ± ± * QT dispersion (ms) ± ± * QTc dispersion (ms) ± ± * V5R (mm) ± ± * V1S (mm) 9.60 ± ± * *, statistically significant. *, statistically significant. ure or arrhythmia, and standard echocardiographic evaluations were found normal. In the study group, the mean LVEDD, EF, and FS were 4.31 ± 0.57 mm, (76.9 ± 7.6)%, and (39.4 ± 6.8)%, respectively. There was no statistically significant difference between the study and control groups in gender, mean ages, BMI, heart rate, systolic, and diastolic blood pressure (P > 0.05). However, LVMI was found higher in thalassaemia major patients compared to control group (33.83 ± 8.93 versus ± 8.47 g/m 2.7 ) (P ¼ 0.006) (Table I). There was no statistically significant difference between the study and control groups in the measurements of peak mitral inflow velocities at early (E) and late (A) diastole, E/A ratio, early deceleration time, and isovolumic relaxation time (IVRT) (Table I). In b thalassaemia major patients, the mean values of QT ( ± versus ± ms) and corrected QT interval ( ± versus ± ms), measuring the duration of ventricular depolarization and repolarization, were higher compared to values in the control group. As the markers of variability of ventricular repolarization, QTd and QTcd were measured and b thalassaemia major patients showed significantly higher mean QTd (69.35 ± versus ± 9.25 ms) and QTcd values (88.22 ± versus ± ms) compared to the control group. The mean V5R (19.66 ± 6.72 versus ± 4.52 mm) and V1S (9.60 ± 3.45 versus 7.78 ± 2.00 mm) amplitudes, indicating left ventricular forces, were also higher in b thalassaemia major patients compared to the control group (Table II). Fig. 1. The correlation between QTc and LVMI (r = 0.24, P = 0.015). The clinical characteristics, echocardiographic, and electrocardiographic findings were not differed significantly between the patients with serum ferritin >2,500 mg/l and LIC >15 mg/g dw compared to the patients having serum ferritin and LIC below these limits. There was a positive correlation between LVMI and QTc (r ¼ 0.24, P ¼ 0.015), QTd (r ¼ 0.215, P ¼ 0.03), and QTcd (r ¼ 0.27, P ¼ 0.006) (Figs. 1 and 2). There was also statistically significant correlation between LVMI and V5R (r ¼ 0.26, P ¼ 0.007), V1S (r ¼ 0.23, P ¼ 0.019) (Figs. 3 and 4). However, there was no significant correlation between QT dispersion and serum ferritin and LIC (P > 0.05). DISCUSSION Cardiac complications are reported to cause 71% of deaths in patients with thalassaemia major [9]. Therefore the heart is the target lethal organ in tha-

4 904 Ulger et al. Fig. 2. The correlation between QTcd and LVMI (r = 0.27, P = 0.006). Fig. 4. The correlation between V1S and LVMI (r =0.23, P =0.019). Fig. 3. The correlation between V5R and LVMI (r = 0.26, P = 0.007). lassaemia. Cardiac disease in thalassaemia major is mainly attributed to iron overload gained by transfusions. The greater the body iron burden, the greater the risk of cardiac disease. One study in thalassaemia major patients found that those with at least two-thirds of serial serum ferritin estimations less than 2,500 mg/l had significantly less cardiac disease than those with higher levels [10]. Brittenham et al. [11] studied 59 thalassaemia major patients who were more than 7 years old. All patients who died had LIC more than 15 mg/g dw, and this level has been subsequently regarded as an index of high risk of death from cardiac disease. Recently, the value of serum ferritin and liver iron has been questioned by the accurate indirect measure of cardiac iron using the MRI T2* technique, which has provided a new insight to cardiac risk. A T2* value less than 20 ms has been found to correlate with the presence of cardiac dysfunction, detected by echocardiography, Holter monitoring, or the need for cardiac therapy [12]. The studies indicated that myocardial T2* is very poorly correlated with the measurements of ferritin and liver iron. In that case, direct measures of myocardial iron using myocardial T2* are giving new insights to the management of chelation therapy in the patients with iron overload. Once heart failure develops, the outlook is usually poor. The cardiomyopathy may be reversible if iron chelating treatment is intensified in time, but the early diagnosis of iron-induced cardiomyopathy with established clinical techniques such as echocardiography and stress radionuclide angiography has had limited success [13]. In particular, overt 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 relentless. The QT interval is a measure of the duration of ventricular depolarization and repolarization [14]. In the patients with Long QT syndrome and healthy

5 QT Dispersion in b Thalassaemia Major Patients 905 population, prolonged QT interval predicts ventricular arrhythmias and sudden death [15,16]. QT dispersion on a standard 12-lead ECG is a marker of variability of ventricular repolarization. It has been hypothesized that increased QTc dispersion reflects increased spatial differences in myocardial recovery time [17]. QTc dispersion is elevated in various high risk groups such as diabetic patients, patients with cardiac failure, and in patients with cardiac failure or hypertension [2 4]. QT dispersion predicts sudden cardiac death following myocardial infarction and in patients with cardiac failure or hypertension [18,19]. QTc dispersion in b thalassaemia major patients have not been studied previously. In this study, we detected that although there was no any clinical or echocardiographic signs of cardiac disease, QTc interval and QTc dispersion were greater in b thalassaemia major patients compared to the control group. LVMI was higher in the thalassaemia major patients compared to the control group and there was a positive correlation between LVMI and QTc dispersion. On the surface ECG, an increasing of QT dispersion was considered as an independent risk factor for increased risk of sudden death and ventricular arrhythmias in patients with pathologic left ventricular hypertrophy caused by hypertension [4,19] and, hypertrophy cardiomyopathy [20]. In a similar way, increased QTc dispersion may also be an indicator of higher risk for arrhythmia and sudden death in thalassaemia major patients. In vitro and in vivo studies have shown that a myocardial iron might change electrical conduction of the cardiomyocytes and lead to sudden death in the patients with iron overload [21,22]. The mechanism of arrhythmia induced by iron accumulation might be due to the loss of functional Na + channels and enhance Na channel inactivation, resulting in a reduced overshoot of cardiac action potential. In the heart, iron deposition is heterogeneous, with the greatest amount of iron in the left side of the ventricular septum and free wall, especially in the epicardium, followed by that in the right ventricle and less in the atria. This characteristic pattern of chronic iron deposition within the heart might contribute to the arrhythmogenecity of iron accumulation [23,24]. In this study, we did not find any correlation between QT dispersion and liver iron concentrations or serum ferritin level levels of the patients. It would be suggested that liver iron and serum ferritin may not exactly reflect cardiac iron deposition. Indeed, Wood et al. [25] showed lack of correlation between liver iron and cardiac iron deposition in a large cohort. In thalassemia patients, QT dispersion may be caused by myocardial iron deposition or another factor, for instance left ventricular hypertrophy. In this study, there was a significant correlation between LVMI and QT dispersion. Cardiac iron deposition was not evaluated with cardiac MRI in this study. So, either patients with or without cardiac iron deposition can have different serum ferritin and LIC, and without cardiac MRI, it is not possible to report accurately which patients in the present study have increased QT dispersion due to cardiac iron deposition or due to cardiac hypertrophy. As a conclusion, increased QTc intervals and QTcd dispersion have been found in this group of thalassemia major patients who have neither clinical nor electrocardiographic and gross echocardiographic signs of cardiac disease. Because of its high reproducibility as a noninvasive method, QTc dispersion can be used in the cardiac care of thalassemia major patients. Prospective studies are needed to clarify the relationship between the prolongation of QTc dispersion and subsequent cardiac events in thalassemia patients. REFERENCES 1. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004;89: Wei K, Dorian P, Newman D, Langer A. Association between QT dispersion and autonomic dysfunction in patients with diabetes mellitus. J Am Coll Cardiol 1995;26: Barr CS, Naas A, Freeman M, Lang CC, Struthers AD. QT dispersion and sudden unexpected death in chronic heart failure. Lancet 1994;343: Mayet J, Shahi M, McGrath K, et al. Left ventricular hypertrophy and QT dispersion in hypertension. Hypertension 1996;28: Bazett HC. An analysis of the time relations of electrocardiograms. Heart 1920;7: Sahn DJ, DeMaria A, Kisslo J, Weyman A. The committee on M mode standardization of the American Society of Echocardiography. Results of a survey of echocardiographic measurements. Circulation 1978;58: Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Anatomic validation of the method. Circulation 1977;55: De Simone G, Daniels SR, Devereux RB, et al. Left ventricular mass and body size in normotensive children and adults: Assessment of allometric relations and the impact of overweight. J Am Coll Cardiol 1992;20: Zurlo MG, De Stefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassemia major. Lancet 1989;2: Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous b-thalassemia. N Engl J Med 1994;331: Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331: Cohen AR, Galanello R, Pennell DJ, Cunningham MJ, Vichinsky E. Thalassemia. Hematology (Am Soc Hematol Educ Program) 2004; Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001;22:

6 906 Ulger et al. 14. Malik M, Batchvarov V. QT dispersion. In: Camm AJ, Armonk KY, editors. Clinical Approaches to Tachyarrhythmias, Vol 12. New York: Futura; pp Kautzner J, Malik M. QT interval dispersion and it s clinical utility. Pacing Clin Electrophysiol 1997;20: Schouten EG, Dekker JM, Meppelink P, Kok FJ, Vandenbroucke JP, Pool J. QT interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation 1991;84: Day CP, McComb JM, Campbell RW. QT dispersion: An indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990;63: Mirvis DM. Spatial variation of QT intervals in normal persons and patients with acute myocardial infarction. J Am CollCardiol 1985;5: Balanescu S, Galinier M, Fourcade J, et al. Correlation between QT interval dispersion and ventricular arrhythmia in hypertension. Arch Mal Coeur Vaiss 1996;89: Sakata K, Shimizu M, Yamaguchi M, et al. QT dispersion and left ventricular morphology in patients with hypertrophic cardiomyopathy. Heart 2003;89: Kuryshev YA, Brittenham GM, Fujioka H, et al. Decreased sodium and increased transient outward potassium currents in iron-loaded cardiac myocytes. Implications for the arrhythmogenesis of human siderotic heart disease. Circulation 1999;100: Schwartz KA, Li Z, Schwartz DE, Cooper TG, Braselton WE. Earliest cardiac toxicity induced by iron overload selectively inhibits electrical conduction. J Appl Physiol 2002;93: Buja LM, Roberts WC. Iron in the heart. Etiology and clinical significance. Am J Med 1971;51: Fitchett DH, Coltart DJ, Littler WA, et al. Cardiac involvement in secondary haemochromatosis: A catheter biopsy study and analysis of myocardium. Cardiovasc Res 1980;14: Wood JC, Tyszka JM, Carson S, Nelson MD, Coates TD. Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease. Blood 2004;103: