Patients with type 1 diabetes mellitus (T1DM) may present a number of complications, many of which appear as early as in childhood. Among them, cardiac arrhythmias may occur and even be life-threatening. In 1991, Tattersall and Gill were the first to report a number of unexplained deaths without any obvious cause in the autopsy, referring to them with the term “dead in bed syndrome” (1). Sudden death syndrome is attributed to cardiac causes that may lead to sudden loss of consciousness and occur unexpectedly in persons with a stable state of health at least 1 day before (2). It is considered to be caused by sudden onset of ventricular tachyarrhythmias and has been associated with QT prolongation (3); acute hypoglycemia on a background of cardiac autonomic neuropathy or possible genetic influences have also been implicated (4).
QT interval represents the time from beginning of ventricular depolarization to completion of repolarization. Because QT typically increases with slow heart rates and decreases with rapid rates, the heart rate corrected QT interval (QTc) has been proposed as a more appropriate measure of QT (5). According to the literature, QTc prolongation has been suggested as an independent marker of increased mortality in patients with T1DM (6–9) as well as a marker for the early recognition of abnormalities of the autonomic nervous system, especially cardiac autonomic neuropathy, in patients with diabetes (10, 11). On the contrary, it is known that manifestations of abnormal autonomic function, which constitute a severe complication of T1DM, can be identified rather early, even during adolescence (12–16). Besides, QTc prolongation and cardiac autonomic neuropathy in general have been associated with increased likelihood of ventricular arrhythmias, Torsades de pointes syndrome, or sudden death, at least in adult patients with T1DM, whereas, in T1DM children, this correlation has not yet been established (5, 17).
To sum up, measuring QTc is a simple procedure and might be helpful in detecting patients that need a thorough cardiological investigation and possibly therapeutical intervention. However, to date, scarce data are available concerning QT abnormalities in children with T1DM. There is only one previous study in the literature, screening children with T1DM children for the prevalence of QT abnormalities in comparison with their nondiabetic peers (18). Yet, there have been published reports that examined in this age group the association of QT with hypoglycemia during exercise (19) or at night during 24-h continuous blood glucose monitoring (20, 21), diabetic ketoacidosis (22, 23), genetic factors (14), autonomic neuropathy (12–16), and subclinical cardiac dysfunction (24, 25). Nevertheless, the latter studies do not reflect the true prevalence of QT interval prolongation in this age group of T1DM patients. Thus, the aim of the present study was to test the hypothesis that QT/QTc abnormalities are present in children and adolescents with T1DM more frequently than in healthy controls, to evaluate how often they are detected, and to investigate if they are associated with any other parameters of diabetes.
Materials and methods
After reviewing medical records of 85 patients with T1DM, who attended the outpatient clinic of the 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, 62 of them were selected if they fulfilled the following inclusion criteria: Caucasian ancestry, age below 17 years, diabetes duration above 1 year, and average glycated hemoglobin (HbA1c) level below 10.5%. All patients were treated with a basal-bolus insulin regimen with more than two subcutaneous injections daily. Sixty-two age- and gender-matched healthy children and adolescents without diabetes were also voluntarily included in the study to serve as controls. Exclusion criteria for both patients and controls were the detection of depolarization abnormalities on the electrocardiogram or the presence of an acute or chronic condition such as infection, ketoacidosis, retinopathy, persistent microalbuminuria, neuropathy, hypertension, electrolyte disturbances, a personal history of cardiorespiratory disease, thyroidopathy, malignancy, uremia, or a family history of sudden death or long QT syndrome in first-degree relatives. If they had previously received medication that could cause QT prolongation or used substances that could affect cardiac function, at least 1 week before recruitment, they were excluded as well. Manifestation of hypoglycemia during the last 24 h before inclusion was also considered as exclusion criterion.
The Scientific Ethics Committee of the Faculty of Medicine, Aristotle University of Thessaloniki, approved the protocol of the study and informed written consent was obtained from parents/guardians of all participants.
Demographic data, anthropometric measurements, and laboratory examinations
All measurements took place in a quiet, warm, adequately illuminated room at 8:00 am. Demographic data and history were recorded and participants underwent a routine physical examination, including determination of pubertal stage. Weight (Scale SECA 711, Hamburg, Germany) and height (Harpenden stadiometer, Veeder-Root, Elizabethtown, NC, USA) were also measured, and body mass index (BMI) was calculated as weight (kg)/height2 (m). Blood pressure was measured in the sitting position, with a conventional sphygmomanometer on the right arm, three times with a 5-min interval and the average of the last two measurements was used in the statistical analyses. After a 10-min rest, a 12-lead electrocardiogram with a rhythm strip was recorded (Nihon Kohden, Cardiofax ECG machine). According to the recommendations of the American Heart Association (26), the lead II was used for the measurements and the mean of three consecutive beats was calculated, because a single cardiac cycle is considered insufficient to represent a person’s long-term QTc interval length. The QT interval was defined as the time period between the onset of the QRS complex and the end of the down-slope of the T wave. The end of the T wave was defined using the extrapolation of its down-slope to the baseline (27). To avoid systematic bias, all recordings were taken at a paper speed of 25 mm/s with an amplitude of 10 mm/mV, and QT calculations were performed by the same observer. In addition, QTc interval, which is a standardized measure of the QT and describes the QT interval of the same person at a heart rate of 60 beats/min, was calculated by applying the most widely used Bazett’s formula (QTc=QT/RR1/2) (26). The previous of the QT R-R length was used for the correction in three consecutive beats. Glycemic control was estimated for each patient through averaging the values of HbA1c, which had been measured with a DCA 2000 analyzer (Bayer Corp., Elkhart, IN), during the past 12 months.
Groups and definition of cutoff points
For interpretation of QTc interval, we used previously published data; based on them, a QTc≥440 ms was considered abnormally prolonged, whereas a QTc<440 ms were considered normal (6, 28).
Statistical analysis was performed with the use of SPSS software version 19.0. Data are presented as frequencies and percentages for categorical variables and as mean±SD for all continuous variables, unless otherwise stated. All continuous variables were tested for normal distribution by Kolmogorov-Smirnov test or Shapiro-Wilk test, as appropriate. Differences in continuous variables between groups were tested with an unpaired t test or its nonparametric Mann-Whitney U test. Categorical variables were compared using the χ2-test. In the T1DM group, correlations between QT/QTc length and disease parameters were calculated with Pearson or Spearman correlation coefficients, as appropriate. Standard multiple linear regression models were also performed to adjust for contribution of independent variables to the variance of the dependent variable (QT/QTc). All tests were two-sided and the level for statistical significance was set at p<0.05.
Sample size calculation
The sample size was determined using a formula for dichotomous variables, rates, or proportions (29), after taking into consideration a previous report that described a difference of 20% in the proportion of those who present prolonged QT/QTc interval between type 1 diabetic patients and healthy controls (18). Roughly, it was calculated that a sample size of at least 53 participants in each study group would provide a 80% statistical power to detect a 20% between group difference in the proportion of those who present prolonged QT/QTc interval (for a two-sided test and α=0.05). Therefore, the sample size of 62 patients in each group of the present study satisfied this criterion; thus, the present study can be considered sufficiently powered.
Baseline data of the study participants are shown in Table 1. In each subgroup, 33 males and 29 females were finally included. Their age ranged between 2.5 and 17 years and mean age was 10.5 years. Mean duration of diabetes in T1DM patients was 4.4 years.
|T1DM patients (n=62)||Controls (n=62)||p-Value|
|SBP, mm Hg||108.8±14.0||105.4±13.1||0.318|
|DBP, mm Hg||61.4±7.1||63.6±8.9||0.420|
|Age at onset, years||6.1±3.6||–||–|
|DIU per kg, U||0.94±0.19||–||–|
Analyses between groups in the whole sample
As shown in Table 1, QTc and QT were longer in the patients’ group compared with controls (p=0.003 and p<0.001, respectively). When data were compared after adjustment for gender, BMI, and pubertal stage, significant differences between patients and controls disappeared (QT: 352.4±8.7 vs. 353.7±11.3 ms; p=0.500 and QTc: 411.6±8.1 vs. 410.0±8.8 ms; p=0.297, respectively).
Analyses between groups separately for males and females
When comparisons were made separately for males and females, QT remained significantly longer in both T1DM males and females compared with their healthy controls (males: 367.5±27.9 vs. 346.6±26.3 ms; p=0.002 and females: 354.4±29.2 vs. 342.0±29.9 ms; p=0.03, respectively); on the contrary, QTc remained significantly longer only in T1DM females (males: 406.94±23.55 vs. 401.4±27.3 ms; p=0.381 and females: 429.3±23.4 vs. 407.2±18.4 ms; p<0.001, respectively).
Analyses between groups with prolonged and normal QTc interval
In the total group, 11.3% (14 of 124) was diagnosed as having a prolonged QTc interval (QTc≥440 ms). Moreover, the overall risk of having abnormally prolonged QTc interval in T1DM patients compared with healthy controls was estimated to be six times higher in the former group than the latter (Table 2). Moreover, male gender was associated with decreased odds for demonstrating a value of QTc above 440 ms [odds ratio (OR), 2.8; 95% confidence interval (CI), 0.173–1.374; p=0.02].
|T1DM patients (n=62)||Controls (n=62)||OR (95% CI)||p-Value|
|Prolonged QTc interval (≥440 ms)||12 (19.4%)||2 (3.2%)||6.000 (1.400–25.706)||<0.001|
Analyses between groups with prolonged QTc interval
The majority of T1DM patients with a prolonged QTc interval (QTc≥440 ms), compared with controls with a prolonged QTc interval as well, were predominantly younger (10.3±0.9 vs. 14.2±1.0 years; p<0.001), females (9 of 12 vs. 0 of 2; p<0.001), and pubertal (12 of 12 vs. 2 of 2; p<0.001). They also demonstrated lower height (143.7±5.3 vs. 165.9±5.9 cm; p<0.001), weight (41.3±4.0 vs. 57.6±4.0 kg; p<0.001), and BMI (19.2±0.5 vs. 20.9±0.4 kg/m2; p<0.001) as well as lower levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP) (107.5±5.5 vs. 117.6±3.4 mm Hg and 63.2±3.1 vs. 68.6±2.6 mm Hg, respectively; both p<0.05).
Correlation analysis between QT/QTc intervals and disease parameters in patients with T1DM
The results of univariate correlation analysis between QT and QTc intervals and disease parameters for T1DM patients are summarized in Table 3. A significant positive association between QT interval and age, weight, height, and age at onset of diabetes was noted, whereas a trend to positive correlation with BMI and pubertal stage was also found. It is noteworthy that the association of age and age at disease onset with QT was eliminated after adjusting for heart rate and only pubertal stage was found to be significantly correlated with QTc.
|Age at onset||0.309||0.015||0.049||0.708|
|DIU per kg||0.066||0.612||0.071||0.583|
In this study, we determined QT/QTc intervals in children and adolescents with T1DM and age- and gender-matched healthy controls. It was found that youngsters with T1DM presented more often QT/QTc prolongation on the electrocardiogram. Furthermore, 19.4% of the diabetic population manifested prolonged QTc interval, a finding that is in accordance with that of Giunti et al. (28) and Suys et al. (18) who reported a prolongation of QTc in 18%–23% of patients with T1DM. Interestingly, the presence of prolonged QTc has also been described in 47%–53% of newly diagnosed children with T1DM and diabetic ketoacidosis (22, 23); nonetheless, these disturbances were attributed to ketosis and remained in only 3%–13% of the patients after ketoacidosis. The present study is novel because it confirmed the high prevalence of QT prolongation in this age group of T1DM patients, in comparison with their healthy peers, as well as the lack of association with disease duration and glycemic status. In addition, it was also shown for the first time that T1DM youths had a sixfold increased risk for developing an abnormally prolonged QTc interval. All these findings confirm that abnormalities of ventricular repolarization may be present in patients with diabetes, even in the younger age groups, thus suggesting an additional aggravating factor that may at least partially contribute to severe ventricular dysrhythmias or even sudden death in T1DM patients.
What is also interesting in our study is that QT interval was positively associated with patients’ age but not diabetes duration or glycemic control. Similar findings have been previously reported in most studies conducted in T1DM youth (18, 20) but not in all; a twin study described that patients with a disease duration above 14 years had longer QTc than did their nondiabetic cotwins, thus associating QTc prolongation with long diabetes duration as well as with genetic factors (14). Inversely, adult T1DM patients have been shown to present a positive association of QTc interval prolongation with age, diabetes duration, and poor metabolic control (28). This discrepancy between studies in adults and children with T1DM could be attributed to the short range of ages and diabetes duration in pediatric studies. Besides, the presence of autonomic dysfunction in childhood diabetes is limited (16). On the contrary, it is also reasonable not to find any overall association of QT with HbA1c, as QT interval prolongation is mainly associated with the blood glucose levels at the time period of ECG recording and not with the overall glycemic control; indeed, QT prolongation during hypoglycemia (19–21) or hyperglycemia and ketosis (22, 23) may occur anytime during the course of the disease and in patients with different degrees of glycemic control but is recovered after the management of ketoacidosis. In our study, male gender was also associated with decreased possibility of demonstrating long QTc, whereas patients with QTc prolongation were all pubertal and predominantly females. In agreement with our findings, a strong association of female gender with longer QT and QTc intervals has been previously reported in studies on patients with T1DM (28), with the exception of that of Murphy et al. (20). Suys et al. also reported that echocardiographic signs of left ventricular dysfunction were more pronounced among female children and adolescents with T1DM (24). Actually, previous studies in normal subjects have reported that QTc interval is longer in females than in males (15), and this is more pronounced after the onset of puberty (30) possibly due to hormonal changes. The acute effects of progesterone, estradiol, and testosterone on cardiac ion channels that are critical for QT intervals were demonstrated in the study by Yang et al. (31); in that study, it was shown that progesterone and testosterone hasten repolarization and reduce QT interval, whereas estrogens increase QT interval by reducing repolarizing current, thus resulting in QT interval fluctuations through the menstrual cycle in females.
The exact mechanism that leads to QT abnormalities in patients with diabetes is not yet totally understood. Electrophysiological studies revealed decreases in several potassium currents, including transient outward, rapid delayed, or slow delayed rectifier potassium current (32), as well as in L-type calcium currents that may alter evoked and spontaneous calcium release from the sarcoplasmic reticulum in cardiac myocytes (33). Prolongation of QT wave may also be affected by hypoglycemia or hyperglycemia. Prolonged QTc has been previously detected in young T1DM patients during exercise (19) or during spontaneous overnight hypoglycemia (20, 21) and independently associated with the frequency of severe hypoglycemias, even after adjustment for diabetes complications including autonomic neuropathy (34). However, in another study, hypoglycemias did not result in significant changes in the QT interval corrected for heart rate (35). Besides, Robinson et al. also managed to induce experimentally QT prolongation during hypoglycemia and prevent it by blockade (36). It has been previously described that acute hypoglycemia induces abnormalities in the cellular potassium transfer, hypokalemia, transient elevation of adrenaline, prolonged cardiac repolarization, and subsequent prolongation of QTc (37), whereas low renin-angiotensin system activity has been described to be associated with more pronounced QT prolongation during hypoglycemia as well (38). On the contrary, acute hyperglycemia has been found to alter myocardial ventricular repolarization in patients with T1DM and in healthy volunteers (39). It seems that hyperglycemia may lead to electrical instability of the heart due to a rise of the intracellular calcium in the cardiac myocytes, increased sympathetic activity (40), or increased production of reactive oxidant species (41). Besides, in a study of young patients with T1DM, lower plasma concentrations of vitamin C, which is an agent with known antioxidant properties, seemed to be related with higher QTc interval (42). Furthermore, ketosis during diabetic ketoacidosis has been associated with the development of QT interval prolongation. A significant positive correlation was found between QTc values and initial anion gap in patients during diabetic ketoacidosis (22, 23) as well as with hydroxybutyrate measurements and serum bicarbonate concentrations in children treated with ketogenic diet (43), thus suggesting a direct relationship between ketosis and QTc prolongation. According to other studies, fatal arrhythmias may also be associated with the development of cardiac autonomic neuropathy. It has already been described that the prevalence of QT prolongation was significantly higher in patients with T1DM and autonomic neuropathy compared with those without this complication (44–46), in contrast to others that did not associate QT interval prolongation with autonomic neuropathy in T1DM patients (47, 48). Actually, in adults and adolescents with T1DM and impaired indices of autonomic neuropathy (12–16), a relative sympathetic overactivity during night has been observed, in association with impaired circadian variation of blood pressure, QT interval prolongation, and increased left ventricular diameters, leading to diabetic cardiomyopathy (25). These phenomena may be further aggravated during episodes of nocturnal hypoglycemia (36). In addition, it has been proposed a unifying hypothesis that nocturnal hypoglycemia, impaired autonomic function, and increased sympathovagal balance are all associated with QTc prolongation (49). Finally, it has previously assumed that significant cardiac arrhythmias are likely to occur in the presence of an underlying cardiac disease, such as mitral valve prolapse, which has an increased prevalence in autoimmune endocrine diseases, and functionally is often associated with cardiac dysautonomia (50).
Undoubtedly, when interpreting our data, certain issues have to be considered. The electrocardiogram is only an expression of the electrical activity of the heart in a certain moment; therefore, any attempt of generalizing our findings is rather a simplified approach. Although use of the value of 440 ms as cutoff for detecting abnormal QT interval is well accepted and widely used in the literature, conclusions obtained from such analyses should also be carefully interpreted, because normal variation of QT interval has not been established in the pediatric population yet (17).
In conclusion, the present study shows that children and adolescents with T1DM have a greater risk for QT/QTc interval prolongation. These abnormalities seem to be more pronounced among female adolescents and not associated with diabetes duration or glycemic control. As QT interval prolongation has been associated with increased risk of arrhythmias and left ventricular dysfunction, children and adolescents with T1DM should be periodically investigated for electrocardiographic abnormalities. A closer cardiology follow-up and further investigation for detection of impaired indices of autonomic neuropathy is recommended in paediatric population having T1DM.
The study was supported by the Research Committee of the Aristotle University of Thessaloniki (Project: Postgraduate. course “Adolescent medicine,” code project 83023, Principal Investigator: Assistant Professor Assimina Galli-Tsinopoulou). The authors thank all children and adolescents who participated in the study as well as their parents/guardians.
Conflict of interest statement
The authors have no conflicts of interest to disclose.
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