1. Background
β-Thalassemia major (TM) is a severe inherited hemoglobin disorder characterized by absent or markedly reduced β-globin chain synthesis, leading to profound anemia from early childhood and lifelong dependence on regular blood transfusions (1). Although advances in transfusion protocols and iron-chelation therapy have markedly improved survival, TM remains associated with substantial morbidity and premature mortality, largely due to cardiovascular complications (2). The disease is particularly prevalent in the Middle East, South Asia, and the Mediterranean region, where its burden is greatest among children and adolescents, underscoring the need for early cardiovascular surveillance (1).
As survival has improved, cardiac complications have emerged as the leading cause of death in patients with TM (2). Chronic transfusions and increased intestinal iron absorption result in progressive myocardial iron overload, causing oxidative injury, electrical conduction abnormalities, and impaired cardiac function (2, 3). Notably, electrical disturbances often develop before structural or functional abnormalities become apparent on echocardiography, making the electrocardiogram (ECG) an inexpensive and widely accessible tool for early cardiac assessment (4). Previous pediatric studies have reported prolonged QT interval, corrected QT (QTc), QT dispersion (QTd), and PR interval in patients with TM, particularly in those with a greater iron burden (3, 5). These abnormalities reflect impaired ventricular repolarization and are associated with an increased risk of ventricular arrhythmias and sudden cardiac death (4).
Despite these findings, most studies have evaluated only conventional ECG parameters, with limited assessment of ventricular repolarization heterogeneity (6). More recently, the T-peak to T-end (Tpe) interval and its derived indices, including Tpe/QT and Tpe/QTc, have been recognized as sensitive markers of transmural dispersion of ventricular repolarization and electrical instability (7). Although these indices have demonstrated prognostic value in several cardiovascular disorders, evidence regarding their role in pediatric TM remains limited (7, 8). Emerging data suggest that Tpe-derived parameters may detect subtle electrophysiological abnormalities before conventional QT measurements become abnormal (8).
Another limitation of the current literature is the limited use of age- and sex-matched healthy control groups, making it difficult to distinguish disease-related ECG abnormalities from normal developmental changes (9). Moreover, ECG characteristics in children are influenced by age, sex, body mass index (BMI), height, blood pressure, and autonomic maturation (10).
However, BMI may not accurately reflect body composition. A recent cross-sectional study comparing BMI with bioelectrical impedance analysis (BIA) demonstrated that BMI frequently misclassified body composition, highlighting its limitations as a surrogate measure of adiposity and body composition (11). These factors may exert greater effects in TM because of chronic anemia, growth retardation, delayed puberty, and altered cardiovascular physiology (12). Nevertheless, demographic influences have rarely been investigated as independent determinants of ECG abnormalities in pediatric TM, and sex-specific differences remain poorly understood (9, 11, 13).
2. Objectives
This study aimed to comprehensively compare conventional and advanced ECG parameters between children and adolescents with β-thalassemia major and healthy controls and to evaluate the influence of demographic factors on ECG characteristics within the TM group. By incorporating both traditional and novel repolarization indices, including Tpe-derived markers, this study sought to improve understanding of early electrical remodeling in pediatric TM and to provide evidence to support more effective ECG-based risk stratification and cardiac surveillance (2, 7, 10).
3. Methods
3.1. Study Design and Setting
This observational case-control study was conducted at the Pediatric Cardiology and Thalassemia outpatient clinics of Ali Asghar Hospital, affiliated with Zahedan University of Medical Sciences, Zahedan, Iran, between January 2024 and December 2025. The objective was to compare the ECG characteristics of children and adolescents with β-thalassemia major (TM) with those of healthy controls.
Patients with a confirmed diagnosis of TM based on clinical and hematological criteria were consecutively enrolled during routine outpatient follow-up visits. Eligible participants were 10 - 20 years of age, had received regular blood transfusion therapy for at least 1 year, and were able to undergo a standard 12-lead ECG examination.
The control group comprised age- and sex-matched healthy individuals recruited from pediatric outpatient clinics during the same period. Controls had no history of hematologic or cardiovascular disease or other chronic systemic disease. Exclusion criteria for both groups included congenital or structural heart disease, clinically significant arrhythmias requiring treatment, acute infection at the time of assessment, electrolyte disturbances, and the use of medications known to affect cardiac conduction or ventricular repolarization.
3.2. Inclusion and Exclusion Criteria
Children and adolescents aged 10 - 20 years with confirmed β-thalassemia major based on clinical findings, hematological parameters, and previous diagnostic evaluation were eligible for inclusion. Patients were required to have received regular blood transfusion therapy for at least 1 year and to be able to undergo standard 12-lead ECG recording.
Healthy age- and sex-matched controls were recruited from pediatric outpatient clinics during the same study period. Controls had no history of hematological disorders, cardiovascular disease, chronic systemic illness, or medication use affecting cardiac conduction.
Participants in both groups were excluded if they had congenital or acquired structural heart disease, documented arrhythmias, electrolyte abnormalities, acute infection at the time of ECG recording, use of QT-prolonging or cardiac conduction-affecting medications, inadequate ECG quality, or incomplete clinical data.
3.3. Sample Size Determination
Because this was an observational case-control study conducted at a tertiary referral center, all eligible children and adolescents with β-thalassemia major who met the inclusion criteria and were available during the study period were consecutively enrolled. Therefore, no formal a priori sample size calculation was performed. The final sample consisted of 45 patients with β-thalassemia major and 45 age- and sex-matched healthy controls. This sample size was considered appropriate for an exploratory comparison of electrocardiographic parameters between the 2 groups.
3.4. Data Collection
3.4.1. Anthropometric Assessment
Anthropometric measurements, including height, weight, and body mass index (BMI), were recorded for all participants using standardized procedures. BMI was calculated as weight (kg) divided by height squared (m2). Based on BMI values, participants were categorized into 2 groups: underweight, defined as BMI < 18.5 kg/m2, and normal weight, defined as BMI 18.5 - 24.9 kg/m2.
3.4.2. Electrocardiographic and Echocardiographic Measurements
Echocardiographic measurements were obtained using standard transthoracic echocardiography performed by an experienced pediatric cardiologist in accordance with pediatric echocardiographic guidelines. Aortic diameter in diastole (AOD) and aortic diameter in systole (AOS) were measured from parasternal long-axis views. A standard 12-lead ECG was recorded for all participants in the supine position using a calibrated digital ECG device (25 mm/s paper speed and 10 mm/mV amplitude). ECG recordings were independently evaluated by 2 blinded observers. All measurements were performed manually using the ECG system's electronic calipers, and the mean value of 3 consecutive cardiac cycles was used for each parameter to reduce measurement variability. The QT interval was measured from the beginning of the QRS complex to the end of the T wave, defined as the point at which the terminal portion of the T wave returned to the isoelectric baseline. The corrected QT interval (QTc) was calculated using Bazett's formula: QTc = QT/√RR. QT dispersion (QTd) was calculated as the difference between the maximum and minimum QT intervals among the available 12 ECG leads. Corrected QT dispersion (QTcd) was calculated as QTcd = QTd/√RR. The T-peak to T-end interval (Tpe) was measured from the peak of the T wave to the end of the T wave and was assessed primarily in the precordial leads in which the T wave had the best amplitude and morphology. The Tpe/QT and Tpe/QTc ratios were calculated as indices of ventricular repolarization heterogeneity. T-wave abnormalities were assessed according to standard ECG interpretation criteria, including changes in T-wave morphology, inversion, flattening, or nonspecific repolarization abnormalities in the precordial leads.
3.5. Statistical Analysis
Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation or median (interquartile range), according to the data distribution assessed using the Shapiro-Wilk test. Comparisons between groups were performed using the independent-samples t-test for normally distributed variables and the Mann-Whitney U test for non-normally distributed variables. Categorical variables were compared using the chi-square test or Fisher exact test, as appropriate. A 2-sided P value < 0.05 was considered statistically significant.
3.6. Ethical Considerations
The study was approved by the Ethics Committee of Zahedan University of Medical Sciences (IR.ZAUMS.REC.1403.225). Written informed consent was obtained from parents or legal guardians, with assent obtained from participants when appropriate.
4. Results
A total of 90 participants were enrolled, including 45 children and adolescents with β-thalassemia major (TM) and 45 healthy controls. The TM group was significantly younger than the control group (P < 0.001), whereas the sex distribution was comparable between groups (P = 0.399). Most demographic, hemodynamic, and electrocardiographic variables were non-normally distributed, whereas aortic diameter in diastole (AOD) and aortic diameter in systole (AOS) were normally distributed.
Compared with healthy controls (Table 1), patients with TM had significantly lower body weight and height (both P < 0.001) and lower diastolic blood pressure (P = 0.040). Aortic diameter in diastole was also significantly smaller in the TM group (P < 0.001). Electrocardiographic analysis showed significantly prolonged PR interval (P = 0.014) and P-segment duration (P = 0.022) in patients with TM. Markers of ventricular repolarization were consistently increased, including the QT interval, T-wave duration, T-peak to T-end (Tpe) interval, QT dispersion (QTd), corrected QT interval (QTc), corrected minimum QT (QTminc), corrected QT dispersion (QTcd), Tpe/QT ratio, Tpe/QTc ratio, and Tpe-new (all P < 0.001), indicating greater ventricular repolarization heterogeneity in the TM group.
Table 1.
Comparison of Demographic, Hemodynamic, and Electrocardiographic Parameters Between Thalassemia Patients (TM) and Healthy Controls Using the Mann-Whitney U Test
| Variables and | Mean | SD | Mean Rank | Sum of Ranks | MWU | P-Value |
|---|---|---|---|---|---|---|
| Age Groups | ||||||
| TM | 16.24 | 1.98 | 43.77 | 1969.50 | 934.50 | 0.522 |
| Control | 16.44 | 1.60 | 47.23 | 2125.50 | 934.50 | 0.522 |
| Weight | ||||||
| TM | 37.93 | 10.24 | 28.07 | 1263.00 | 228.00 | < 0.001 |
| Control | 52.16 | 4.71 | 62.93 | 2832.00 | 228.00 | < 0.001 |
| Height | ||||||
| TM | 145.38 | 11.15 | 28.37 | 1276.50 | 241.50 | < 0.001 |
| Control | 160.78 | 4.77 | 62.63 | 2818.50 | 241.50 | < 0.001 |
| Systolic blood pressure | ||||||
| TM | 104.64 | 9.36 | 43.31 | 1949.00 | 914.00 | 0.425 |
| Control | 105.31 | 8.22 | 47.69 | 2146.00 | 914.00 | 0.425 |
| Diastolic Blood Pressure | ||||||
| TM | 65.27 | 8.54 | 39.87 | 1794.00 | 759.00 | 0.040 |
| Control | 69.31 | 6.81 | 51.13 | 2301.00 | 759.00 | 0.040 |
| Aortic diameter in diastole (AOD) | ||||||
| TM | 1.90 | 0.27 | 33.32 | 1499.50 | 464.50 | < 0.001 |
| Control | 2.25 | 0.35 | 57.68 | 2595.50 | 464.50 | < 0.001 |
| Aortic diameter in systole (AOS) | ||||||
| TM | 2.31 | 0.27 | 40.16 | 1807.00 | 772.00 | 0.052 |
| Control | 2.45 | 0.38 | 50.84 | 2288.00 | 772.00 | 0.052 |
| Heart Rate | ||||||
| TM | 90.02 | 13.13 | 47.38 | 2132.00 | 928.00 | 0.495 |
| Control | 88.93 | 16.60 | 43.62 | 1963.00 | 928.00 | 0.495 |
| QT Max | ||||||
| TM | 0.35 | 0.06 | 57.66 | 2594.50 | 465.50 | < 0.001 |
| Control | 0.32 | 0.03 | 33.34 | 1500.50 | 465.50 | < 0.001 |
| QT Min | ||||||
| TM | 0.31 | 0.03 | 49.11 | 2210.00 | 850.00 | 0.177 |
| Control | 0.30 | 0.03 | 41.89 | 1885.00 | 850.00 | 0.177 |
| RR Interval | ||||||
| TM | 0.70 | 0.11 | 44.00 | 1980.00 | 945.00 | 0.584 |
| Control | 0.72 | 0.13 | 47.00 | 2115.00 | 945.00 | 0.584 |
| PR Interval | ||||||
| TM | 125.78 | 16.85 | 50.50 | 2272.50 | 787.50 | 0.014 |
| Control | 117.78 | 8.76 | 40.50 | 1822.50 | 787.50 | 0.014 |
| P Duration | ||||||
| TM | 78.22 | 6.84 | 47.53 | 2139.00 | 921.00 | 0.267 |
| Control | 76.22 | 7.77 | 43.47 | 1956.00 | 921.00 | 0.267 |
| P Segment | ||||||
| TM | 47.56 | 14.79 | 49.71 | 2237.00 | 823.00 | 0.022 |
| Control | 41.56 | 5.20 | 41.29 | 1858.00 | 823.00 | 0.022 |
| T Duration | ||||||
| TM | 139.33 | 18.76 | 55.61 | 2502.50 | 557.50 | < 0.001 |
| Control | 126.00 | 10.95 | 35.39 | 1592.50 | 557.50 | < 0.001 |
| Tpe | ||||||
| TM | 77.89 | 12.36 | 60.92 | 2741.50 | 318.50 | < 0.001 |
| Control | 64.00 | 5.70 | 30.08 | 1353.50 | 318.50 | < 0.001 |
| QTd | ||||||
| TM | 0.04 | 0.05 | 63.61 | 2862.50 | 197.50 | < 0.001 |
| Control | 0.02 | 0.02 | 27.39 | 1232.50 | 197.50 | < 0.001 |
| QTc Max | ||||||
| TM | 0.42 | 0.07 | 61.41 | 2763.50 | 296.50 | < 0.001 |
| Control | 0.38 | 0.03 | 29.59 | 1331.50 | 296.50 | < 0.001 |
| QTc Min | ||||||
| TM | 0.37 | 0.03 | 51.76 | 2329.00 | 731.00 | 0.023 |
| Control | 0.36 | 0.02 | 39.24 | 1766.00 | 731.00 | 0.023 |
| QTcd | ||||||
| TM | 0.05 | 0.07 | 64.56 | 2905.00 | 155.00 | < 0.001 |
| Control | 0.02 | 0.02 | 26.44 | 1190.00 | 155.00 | < 0.001 |
| Tpe / QT | ||||||
| TM | 0.26 | 0.30 | 52.90 | 2380.50 | 679.50 | 0.007 |
| Control | 0.20 | 0.02 | 38.10 | 1714.50 | 679.50 | 0.007 |
| Tpe / QTc | ||||||
| TM | 0.22 | 0.26 | 52.18 | 2348.00 | 712.00 | 0.015 |
| Control | 0.17 | 0.02 | 38.82 | 1747.00 | 712.00 | 0.015 |
Within the TM cohort (Table 2), underweight patients had significantly lower systolic blood pressure (P < 0.001), smaller aortic diameter in diastole (P = 0.014) and aortic diameter in systole (P = 0.009), and a lower Tpe/QT ratio (P = 0.021) than those with normal BMI.
Table 2.
Comparison of Hemodynamic and Electrocardiographic Parameters Between Underweight (N = 25) and Normal-Weight (N = 20) Children with Thalassemia
| Variables and BMI Grouping | Mean | SD | Mean Rank | Sum of Ranks | Test Value | P-Value |
|---|---|---|---|---|---|---|
| Systolic blood pressure | ||||||
| Underweight | 100.28 | 6.83 | 17.28 | 432.00 | 107.00 | < 0.001 |
| Normal | 110.10 | 9.36 | 30.15 | 603.00 | 107.00 | < 0.001 |
| Diastolic Blood Pressure | ||||||
| Underweight | 63.24 | 6.88 | 19.90 | 497.50 | 172.50 | 0.074 |
| Normal | 67.80 | 9.84 | 26.88 | 537.50 | 172.50 | 0.074 |
| Aortic diameter in diastole (AOD) | ||||||
| Underweight | 1.82 | 0.26 | - | - | -2.57 | 0.014 |
| Normal | 2.01 | 0.23 | - | - | -2.57 | 0.014 |
| Aortic diameter in systole (AOS) | ||||||
| Underweight | 2.22 | 0.27 | - | - | -2.74 | 0.009 |
| Normal | 2.42 | 0.23 | - | - | -2.74 | 0.009 |
| Heart Rate | ||||||
| Underweight | 91.56 | 12.89 | 24.60 | 615.00 | 210.00 | 0.360 |
| Normal | 88.10 | 13.51 | 21.00 | 420.00 | 210.00 | 0.360 |
| QT Max | ||||||
| Underweight | 0.35 | 0.04 | 21.62 | 540.50 | 215.50 | 0.420 |
| Normal | 0.35 | 0.08 | 24.73 | 494.50 | 215.50 | 0.420 |
| QT Min | ||||||
| Underweight | 0.31 | 0.03 | 20.82 | 520.50 | 195.50 | 0.190 |
| Normal | 0.32 | 0.03 | 25.73 | 514.50 | 195.50 | 0.190 |
| RR Interval | ||||||
| Underweight | 0.69 | 0.11 | 21.34 | 533.50 | 208.50 | 0.341 |
| Normal | 0.72 | 0.12 | 25.08 | 501.50 | 208.50 | 0.341 |
| PR Interval | ||||||
| Underweight | 126.40 | 18.90 | 22.92 | 573.00 | 248.00 | 0.953 |
| Normal | 125.00 | 14.33 | 23.10 | 462.00 | 248.00 | 0.953 |
| P Duration | ||||||
| Underweight | 78.40 | 8.00 | 23.52 | 588.00 | 237.00 | 0.638 |
| Normal | 78.00 | 5.23 | 22.35 | 447.00 | 237.00 | 0.638 |
| P Segment | ||||||
| Underweight | 48.00 | 16.33 | 22.68 | 567.00 | 242.00 | 0.814 |
| Normal | 47.00 | 13.02 | 23.40 | 468.00 | 242.00 | 0.814 |
| T Duration | ||||||
| Underweight | 142.40 | 20.06 | 25.02 | 625.50 | 199.50 | 0.225 |
| Normal | 135.50 | 16.69 | 20.48 | 409.50 | 199.50 | 0.225 |
| Tpe | ||||||
| Underweight | 81.00 | 12.75 | 25.64 | 641.00 | 184.00 | 0.092 |
| Normal | 74.00 | 10.95 | 19.70 | 394.00 | 184.00 | 0.092 |
| QTd | ||||||
| Underweight | 0.05 | 0.03 | 23.96 | 599.00 | 226.00 | 0.545 |
| Normal | 0.03 | 0.08 | 21.80 | 436.00 | 226.00 | 0.545 |
| QTc Max | ||||||
| Underweight | 0.43 | 0.04 | 22.42 | 560.50 | 235.50 | 0.740 |
| Normal | 0.42 | 0.09 | 23.73 | 474.50 | 235.50 | 0.740 |
| QTc Min | ||||||
| Underweight | 0.37 | 0.03 | 21.86 | 546.50 | 221.50 | 0.514 |
| Normal | 0.38 | 0.02 | 24.43 | 488.50 | 221.50 | 0.514 |
| QTcd | ||||||
| Underweight | 0.06 | 0.03 | 24.46 | 611.50 | 213.50 | 0.404 |
| Normal | 0.04 | 0.09 | 21.18 | 423.50 | 213.50 | 0.404 |
| Tpe / QT | ||||||
| Underweight | 0.23 | 0.03 | 27.04 | 676.00 | 149.00 | 0.021 |
| Normal | 0.30 | 0.45 | 17.95 | 359.00 | 149.00 | 0.021 |
| Tpe / QTc | ||||||
| Underweight | 0.19 | 0.03 | 26.00 | 650.00 | 175.00 | 0.087 |
| Normal | 0.25 | 0.38 | 19.25 | 385.00 | 175.00 | 0.087 |
Sex-based comparisons (Table 3) indicated that female patients had significantly higher diastolic blood pressure than male patients (P = 0.038), whereas no other ECG parameters differed significantly between sexes.
Table 3.
Comparison of Hemodynamic and Electrocardiographic Parameters by Sex in Children with Thalassemia (Girls, N = 25; Boys, N = 20)
| Variables and Gender | Mean | SD | Mean Rank | Sum of Ranks | MWU Test | P-Value |
|---|---|---|---|---|---|---|
| Systolic blood pressure | ||||||
| Girls | 104.80 | 8.73 | 23.28 | 582.00 | 243.00 | 0.872 |
| Boys | 104.45 | 10.32 | 22.65 | 453.00 | 243.00 | 0.872 |
| Diastolic Blood Pressure | ||||||
| Girls | 67.20 | 7.08 | 26.60 | 665.00 | 160.00 | 0.038 |
| Boys | 62.85 | 9.72 | 18.50 | 370.00 | 160.00 | 0.038 |
| Aortic diameter in diastole (AOD) | ||||||
| Girls | 1.91 | 0.25 | - | - | 0.31 | 0.759 |
| Boys | 1.89 | 0.30 | - | - | 0.31 | 0.759 |
| Aortic diameter in systole (AOS) | ||||||
| Girls | 2.32 | 0.24 | - | - | 0.46 | 0.651 |
| Boys | 2.29 | 0.31 | - | - | 0.46 | 0.651 |
| Heart Rate | ||||||
| Girls | 92.28 | 12.44 | 25.78 | 644.50 | 180.50 | 0.112 |
| Boys | 87.20 | 13.74 | 19.53 | 390.50 | 180.50 | 0.112 |
| QT Max | ||||||
| Girls | 0.35 | 0.07 | 21.40 | 535.00 | 210.00 | 0.350 |
| Boys | 0.36 | 0.04 | 25.00 | 500.00 | 210.00 | 0.350 |
| QT Min | ||||||
| Girls | 0.31 | 0.03 | 22.08 | 552.00 | 227.00 | 0.580 |
| Boys | 0.31 | 0.03 | 24.15 | 483.00 | 227.00 | 0.580 |
| RR Interval | ||||||
| Girls | 0.69 | 0.11 | 20.72 | 518.00 | 193.00 | 0.191 |
| Boys | 0.72 | 0.11 | 25.85 | 517.00 | 193.00 | 0.191 |
| PR Interval | ||||||
| Girls | 123.20 | 13.76 | 21.76 | 544.00 | 219.00 | 0.362 |
| Boys | 129.00 | 19.97 | 24.55 | 491.00 | 219.00 | 0.362 |
| P Duration | ||||||
| Girls | 77.60 | 5.97 | 22.06 | 551.50 | 226.50 | 0.394 |
| Boys | 79.00 | 7.88 | 24.18 | 483.50 | 226.50 | 0.394 |
| P Segment | ||||||
| Girls | 45.60 | 11.93 | 22.12 | 553.00 | 228.00 | 0.518 |
| Boys | 50.00 | 17.77 | 24.10 | 482.00 | 228.00 | 0.518 |
| T Duration | ||||||
| Girls | 140.40 | 20.51 | 23.42 | 585.50 | 239.50 | 0.801 |
| Boys | 138.00 | 16.73 | 22.48 | 449.50 | 239.50 | 0.801 |
| Tpe | ||||||
| Girls | 79.20 | 14.41 | 24.08 | 602.00 | 223.00 | 0.490 |
| Boys | 76.25 | 9.30 | 21.65 | 433.00 | 223.00 | 0.490 |
| QTd | ||||||
| Girls | 0.03 | 0.07 | 21.34 | 533.50 | 208.50 | 0.295 |
| Boys | 0.05 | 0.03 | 25.08 | 501.50 | 208.50 | 0.295 |
| QTc Max | ||||||
| Girls | 0.42 | 0.08 | 23.84 | 596.00 | 229.00 | 0.631 |
| Boys | 0.43 | 0.05 | 21.95 | 439.00 | 229.00 | 0.631 |
| QTc Min | ||||||
| Girls | 0.38 | 0.03 | 24.14 | 603.50 | 221.50 | 0.514 |
| Boys | 0.37 | 0.03 | 21.58 | 431.50 | 221.50 | 0.514 |
| QTcd | ||||||
| Girls | 0.04 | 0.08 | 22.18 | 554.50 | 229.50 | 0.639 |
| Boys | 0.06 | 0.04 | 24.03 | 480.50 | 229.50 | 0.639 |
| Tpe / QT | ||||||
| Girls | 0.30 | 0.40 | 25.00 | 625.00 | 200.00 | 0.251 |
| Boys | 0.21 | 0.03 | 20.50 | 410.00 | 200.00 | 0.251 |
| Tpe / QTc | ||||||
| Girls | 0.25 | 0.34 | 23.30 | 582.50 | 242.5 | 0.864 |
| Boys | 0.18 | 0.03 | 22.63 | 452.50 | 242.5 | 0.864 |
Age-stratified analysis (Table 4) showed that younger patients had significantly lower systolic blood pressure (P = 0.040) and smaller aortic diameter in systole (P = 0.031) than older patients.
Table 4.
Comparison of Hemodynamic and Electrocardiographic Parameters by Age Group in Children with Thalassemia (< 15 Years, N = 19; > 15 Years, N = 26)
| Variables and Age Groups | Mean | SD | Mean Rank | Sum Ranks | MWU Test | P-Value |
|---|---|---|---|---|---|---|
| Systolic Blood Pressure | ||||||
| < 15 | 101.21 | 8.09 | 18.34 | 348.50 | 158.50 | 0.040 |
| > 15 | 107.15 | 9.57 | 26.40 | 686.50 | 158.50 | 0.040 |
| Diastolic Blood Pressure | ||||||
| < 15 | 63.84 | 8.83 | 20.13 | 382.50 | 192.50 | 0.206 |
| > 15 | 66.31 | 8.33 | 25.10 | 652.50 | 192.50 | 0.206 |
| Aortic diameter in diastole (AOD) | ||||||
| < 15 | 1.82 | 0.25 | -1.80 | 0.079 | ||
| > 15 | 1.96 | 0.27 | -1.80 | 0.079 | ||
| Aortic diameter in systole (AOS) | ||||||
| < 15 | 2.21 | 0.26 | -2.23 | 0.031 | ||
| > 15 | 2.38 | 0.26 | -2.23 | 0.031 | ||
| Heart Rate | ||||||
| < 15 | 90.16 | 14.05 | 23.37 | 444.00 | 240.00 | 0.872 |
| > 15 | 89.92 | 12.71 | 22.73 | 591.00 | 240.00 | 0.872 |
| QT Max | ||||||
| < 15 | 0.35 | 0.04 | 20.61 | 391.50 | 201.50 | 0.285 |
| > 15 | 0.36 | 0.08 | 24.75 | 643.50 | 201.50 | 0.285 |
| QT Min | ||||||
| < 15 | 0.31 | 0.03 | 22.21 | 422.00 | 232.00 | 0.716 |
| > 15 | 0.31 | 0.03 | 23.58 | 613.00 | 232.00 | 0.716 |
| RR Interval | ||||||
| < 15 | 0.71 | 0.12 | 23.18 | 440.50 | 243.50 | 0.936 |
| > 15 | 0.70 | 0.11 | 22.87 | 594.50 | 243.50 | 0.936 |
| PR Interval | ||||||
| < 15 | 122.11 | 14.75 | 20.42 | 388.00 | 198.00 | 0.147 |
| > 15 | 128.46 | 18.04 | 24.88 | 647.00 | 198.00 | 0.147 |
| P Duration | ||||||
| < 15 | 77.89 | 9.18 | 22.89 | 435.00 | 245.00 | 0.942 |
| > 15 | 78.46 | 4.64 | 23.08 | 600.00 | 245.00 | 0.942 |
| P Segment | ||||||
| < 15 | 44.21 | 10.71 | 20.55 | 390.50 | 200.50 | 0.169 |
| > 15 | 50.00 | 16.97 | 24.79 | 644.50 | 200.50 | 0.169 |
| T Duration | ||||||
| < 15 | 142.11 | 21.75 | 24.24 | 460.50 | 223.50 | 0.570 |
| > 15 | 137.31 | 16.38 | 22.10 | 574.50 | 223.50 | 0.570 |
| Tpe | ||||||
| < 15 | 80.26 | 15.5 | 23.84 | 453.00 | 231.00 | 0.681 |
| > 15 | 76.15 | 9.41 | 22.38 | 582.00 | 231.00 | 0.681 |
| QTd | ||||||
| < 15 | 0.04 | 0.02 | 20.63 | 392.00 | 202.00 | 0.253 |
| > 15 | 0.04 | 0.07 | 24.73 | 643.00 | 202.00 | 0.253 |
| QTc Max | ||||||
| < 15 | 0.42 | 0.04 | 19.87 | 377.50 | 187.50 | 0.171 |
| > 15 | 0.43 | 0.09 | 25.29 | 657.50 | 187.50 | 0.171 |
| QTc Min | ||||||
| < 15 | 0.37 | 0.03 | 21.34 | 405.50 | 215.50 | 0.468 |
| > 15 | 0.38 | 0.03 | 24.21 | 629.50 | 215.50 | 0.468 |
| QTcd | ||||||
| < 15 | 0.05 | 0.03 | 20.50 | 389.50 | 199.50 | 0.274 |
| > 15 | 0.05 | 0.08 | 24.83 | 645.50 | 199.50 | 0.274 |
| Tpe / QT | ||||||
| < 15 | 0.23 | 0.04 | 26.21 | 498.00 | 186.00 | 0.159 |
| > 15 | 0.28 | 0.4 | 20.65 | 537.00 | 186.00 | 0.159 |
| Tpe / QTc | ||||||
| < 15 | 0.19 | 0.04 | 26.34 | 500.50 | 183.50 | 0.144 |
| > 15 | 0.24 | 0.34 | 20.56 | 534.50 | 183.50 | 0.144 |
5. Discussion
The present study demonstrated significant differences in several structural, hemodynamic, and electrocardiographic parameters between children and adolescents with β-thalassemia major (TM) and healthy controls. Patients with TM showed prolongation of several atrioventricular conduction and ventricular repolarization indices, including the PR interval, QT interval, QTc, QT dispersion (QTd), corrected QT dispersion (QTcd), the T-peak to T-end interval (Tpe), and Tpe-derived ratios. These findings are consistent with previous reports describing altered ventricular repolarization patterns in patients with TM, suggesting increased electrical heterogeneity of the myocardium (6, 8, 14). Similar electrophysiological abnormalities have also been reported by Noori et al. in children with iron deficiency anemia; however, these changes improved following iron therapy, whereas the persistent abnormalities observed in TM likely reflect chronic myocardial iron overload rather than anemia alone (5, 7, 9). However, because the present study was cross-sectional and did not include long-term rhythm follow-up, these ECG abnormalities should be interpreted as markers of altered cardiac electrical characteristics rather than confirmed predictors of ventricular arrhythmia or sudden cardiac death. Several mechanisms may contribute to the observed ECG changes in children with TM. Chronic transfusion therapy, persistent anemia, and the metabolic consequences of β-thalassemia may contribute to myocardial remodeling and disturbances in ventricular repolarization. Iron accumulation has been proposed as an important contributor to cardiac involvement in TM through oxidative stress, cellular injury, and disruption of ion-channel function involved in cardiac conduction and repolarization (15-18).
Nevertheless, direct assessment of iron burden, including serum ferritin or cardiac MRI T2*, was not available in the present study; therefore, the specific contribution of myocardial iron overload to the observed ECG abnormalities cannot be confirmed. The findings should instead be interpreted as reflecting the complex cardiovascular effects associated with TM.
Previous studies have suggested that advanced repolarization indices, including Tpe, Tpe/QT, and Tpe/QTc, may provide additional information regarding ventricular repolarization heterogeneity beyond conventional QT measurements (14). In the present study, these parameters differed significantly between patients with TM and controls, suggesting that detailed ECG analysis may help identify subtle electrical alterations before clinically apparent cardiac dysfunction develops. However, further prospective studies incorporating cardiac imaging, iron-burden assessment, and long-term follow-up are required to determine the clinical and prognostic significance of these markers.
Nutritional status was also associated with cardiovascular characteristics among patients with TM. Underweight participants had lower systolic blood pressure, smaller aortic diameter in diastole and in systole, and differences in the Tpe/QT ratio compared with participants with normal BMI, whereas most ECG parameters did not differ significantly. These findings suggest that reduced nutritional status in TM may primarily influence cardiovascular growth and hemodynamic parameters rather than causing widespread alterations in cardiac electrical conduction. Previous studies have similarly emphasized the relationship between malnutrition, impaired growth, and cardiovascular changes in pediatric populations (17-19). Therefore, nutritional evaluation should remain an important component of comprehensive care for children with TM.
Age-related analyses showed that older children had higher systolic blood pressure and a larger aortic diameter in systole, findings compatible with normal cardiovascular maturation during childhood and adolescence (20-22). In contrast, most ECG parameters did not show significant age-related differences within the TM group, suggesting that disease-related factors may have a greater influence on electrical characteristics than developmental changes alone. Similarly, sex differences were limited, with only diastolic blood pressure showing a significant difference between male and female participants. Although sex-related variations in cardiac electrophysiology have been described in healthy populations, the effects of chronic anemia, transfusion dependency, and disease-related physiological changes may modify these differences in children with TM (8, 15, 22).
Overall, our findings indicate that children and adolescents with β-thalassemia major exhibit measurable alterations in cardiac electrical parameters compared with healthy controls, including changes in conventional and advanced ventricular repolarization indices. These findings support the potential value of comprehensive ECG evaluation as part of cardiovascular surveillance in pediatric TM. Nevertheless, the clinical implications of these ECG abnormalities, including their ability to predict arrhythmia development or adverse cardiac outcomes, require confirmation through larger longitudinal studies incorporating detailed assessment of iron status, cardiac imaging, and clinical follow-up (14). This study has several limitations. First, the cross-sectional design precludes assessment of temporal relationships and causal associations between β-thalassemia-related factors and ECG abnormalities. Second, the relatively small sample size from a single tertiary referral center may limit statistical power for subgroup analyses and generalizability to other populations. Third, cardiac iron-burden parameters, such as cardiac magnetic resonance imaging (T2*), were not available for all participants. Finally, longitudinal follow-up was not performed; therefore, the predictive value of ECG abnormalities for future arrhythmias or cardiac events could not be assessed.
5.1. Conclusions
Children and adolescents with β-thalassemia major exhibit significant electrocardiographic abnormalities, particularly prolonged ventricular repolarization indices, indicating increased electrical instability compared with healthy controls. Nutritional status influenced cardiovascular structure and hemodynamics, whereas age had a modest effect and sex had minimal impact on cardiovascular parameters. These findings support the use of routine ECG evaluation, including advanced repolarization markers, for early detection and monitoring of cardiac involvement in pediatric patients with β-thalassemia major.
