Twelve‐lead and signal‐averaged electrocardiographic parameters among beta‐thalassemia major patients

Abstract Background The majority of beta thalassemia major (β‐TM) patients suffer from cardiac disease, while a significant proportion of them die suddenly. Twelve‐lead and signal‐averaged electrocardiography (SAECG) are simple, inexpensive, readily available tools for identifying an unfavorable arrhythmiological substrate by detecting the presence of arrhythmias, conduction abnormalities, and late potentials (LPs) in these patients. Methods A total of 47 β‐TM patients and 30 healthy controls were submitted to 12‐lead and signal‐averaged electrocardiography. Basic electrocardiographic parameters and prevalence of LPs were recorded. Basic echocardiographic parameters were estimated by transthoracic echocardiography. T2* was calculated by cardiac magnetic resonance imaging wherever available. Results β‐TM patients demonstrated a more prolonged PR interval (167.74 msec vs 147.07 msec) (P = .043), a higher prevalence of PR prolongation (21.05% vs 0%) (P = .013), and a higher prevalence of LPs (18/47, 38.3% vs 2/30, 6.7%) (P = .002) compared with controls. The prevalence of atrial fibrillation among b‐TM patients was estimated at 10.64%. Patients had also greater E/e′ ratio (8.35, SD = 2.2 vs 7, SD = 2.07) (P = .012) and LAVI (30.7 mL/m2, SD = 8.76 vs 24.6 mL/m2, SD = 6.57) (P = .002) than controls. Regression analysis showed that QTc and LAVI could correctly predict the presence of LPs in the 80.9% of the patients. Conclusions β‐TM patients have a higher prevalence of a prolonged PR interval, atrial fibrillation, and LPs. Twelve‐lead and SAECG performance was feasible in all subjects and constitutes a readily available tool for assessing myocardial electrophysiological alterations in this patient group.


| INTRODUC TI ON
Thalassemia syndromes are among the most common inherited diseases around the world, 1

particularly in countries around
Mediterranean Sea and Middle East. 2 Beta thalassemia major (β-TM) is the most severe type, rendering β-TM patients transfusion-dependent lifelong. 3 The life expectancy of β-TM patients has increased lately as a consequence of progress in diagnostic and therapeutic protocols, 4 ranging between 36 and 45 years. 5 Transfusion dependency leads to iron accumulation in many organs with deleterious consequences. 6 The heart is, among other organs, affected significantly by excess iron burden. 7 Cardiac disorders were by far the leading cause of death among β-TM patients in the past decades, although iron chelation therapy resulted in significant reduction in cardiac related deaths. 8 Apart from end-stage heart failure, a significant proportion of β-TM patients die suddenly. 5,9 Indeed, according to a recent National Registry in Greece, 10.18% of the β-TM patients suffered sudden cardiac death. 5 Atrial fibrillation prevalence among β-TM patients varies in literature, ranging from 10% to 33.8%. 10 Signal-averaged electrocardiography (SAECG) is an attractive method for the arrhythmiological assessment of β-TM patients, by detecting slow conducting areas in the ventricular myocardium, the so-called late potentials (LPs). Such abnormal signals have been reported among young β-TM patients from Lebanon and Italy, ranging from 3 to 31.5%. [11][12][13] In the same context, previous studies from Greek 14 and Turkish, 15 β-TM patients reported prevalent QRS fragmentation, using 12-lead ECG.
Taking into account recent progress in diagnostic and therapeutic methods resulting in life prolongation, a new study on β-TM patients in Greece seems reasonable and promising. The aim of this study is to reveal and describe any electrocardiographic abnormalities in a cohort of Greek β-TM patients compared with a matched control group, pointing to the presence of an unfavorable arrhythmiological substrate, even at early asymptomatic state.

| ME THODS
In the present cross-sectional study, 47 β-TM patients who were referred to the Cardiology Unit for Hemoglobinopathies of the Cardiology Department at General Hospital of Athens Ippokrateio and a control group of 30 apparently healthy, age and gender matched, individuals were submitted to standard 12-lead ECG and SAECG according to a protocol described by ACC expert consensus document. 16  In case of a prolonged standard QRS duration >120 msec, the modified SAECG criteria were applied. 17 The acceptable noise level was set at <0.5 μV. QT interval was corrected for heart rate by means of the Bazett equation. QTc > 440 msec in men and >460 msec in women were considered prolonged.
A MAC 5000 resting ECG analysis system (GE MARQUETTE, Fairfield, CT, U.S.A.) was used for all cases.  were included in the initial model. Consequently, backward conditional elimination of the variables was used to assess for those with higher significance when predicting the presence or not of LPs. Variables with a P-value higher than .10 were excluded for the model. A P-value of ≤.05 was considered statistically significant. SPSS 23 statistics software (IBM-Armonk) was used for statistical analysis.

| Demographics and comorbidities
Basic demographic characteristics and comorbidities are demonstrated in Table 1. Study patients and controls were age and gender matched, while none of the patients had arterial hypertension.

| SAECG
SAECG parameters of both groups are presented in Table 2

| Echocardiography
Regarding basic echocardiographic parameters (Table 1) Table 3 summarizes the demographic characteristics, comorbidities, electrocardiographic, echocardiographic, and CMR findings among patients according to the presence or absence of LPs. Age did not differ significantly between LPs-positive and LPs-negative patients.

| Characteristics of LP-positive and LPnegative patients
Neither hypothyroidism nor diabetes mellitus was more prevalent among LP-positive patients.
Heart rate, electrical axis, and PR interval did not differ between the subgroups, while QTc duration was more prolonged among LPs-  (Table 4).

| Follow up
During the first year of follow up, one patient developed symptoms.

| D ISCUSS I ON
The main finding in our study is that β-TM patients have a higher prevalence of a prolonged PR interval (17.02%), atrial fibrillation (10.64%), and LPs (38.3%). These findings are in agreement with previous reports. [9][10][11][12][13]18 However, it is the first study that quantifies the prevalence of PR interval prolongation and LPs in a β-TM population of advanced age (mean value 40.91 years) compared with previous studies. [11][12][13] Additionally, our study is unique in terms of combining data from patient comorbidities, electrocardiography, echocardiography, and CMR.
Studies concerning the prevalence of conduction abnormalities among β-TM populations are lacking. Conduction disturbances are thought to occur at a latter stage of iron overload cardiomyopathy. 19 The recent progress in medical treatment of these patients heralds prolongation of life expectancy and consequently higher prevalence of conduction abnormalities than has been previously recognized.

| CON CLUS IONS
The current study attempts to bring electrical conduction abnormalities among β-TM patients to the foreground, an area that has been neglected until now, since the majority of studies focused on systolic or diastolic impairment of the heart function. The demonstration of higher prevalence of PR interval prolongation and LPs among β-TM patients experiencing significant life prolongation nowadays calls for closer patient surveillance and increased physician alertness. It is likely that the timely application of appropriate treatment may have significant impact on survival and quality of life in this unique cardiomyopathy patient population as well.

CO N FLI C T O F I NTE R E S T
Authors declare no conflict of interests for this article.