Development of autonomic heart rate modulations during childhood and adolescence.

Autonomic control of heart rate is well known in adult subjects, but limited data are available on the development of the heart rate control during childhood and adolescence. Continuous 12-lead electrocardiograms were recorded in 1045 healthy children and adolescents (550 females) aged 4 to 19 years during postural manoeuvres involving repeated 10-min supine, unsupported sitting, and unsupported standing positions. In each position, heart rate was measured, and heart rate variability indices were evaluated (SDNN, RMSSD, and high (HF) and low (LF) frequency components were obtained). Quasi-normalized HF frequency components were defined as qnHF = HF/(HF + LF). These measurements were, among others, related to age using linear regressions. In supine position, heart rate decreases per year of age were significant in both sexes but lower in females than in males. In standing position, these decreases per year of age were substantially lowered. RMSSD and qnHF indices were independent of age in supine position but significantly decreased with age in sitting and standing positions. Correspondingly, LF/HF proportions showed steep increases with age in sitting and standing positions but not in the supine position. The study suggests that baseline supine parasympathetic influence shows little developmental changes during childhood and adolescence but that in young children, sympathetic branch is less responsive to vagal influence. While vagal influences modulate cardiac periods in young and older children equally, they are less able to suppress the sympathetic influence in younger children.

Speed of heart rate changes during postural provocations in children and adolescents.

Heart rate is under constant autonomic influence but the development of the influence in children is not fully understood. Continuous electrocardiograms were obtained in 1045 healthy school-age children (550 females) during postural provocations with body position changes between supine, sitting, standing, supine, standing, sitting and supine (in this order), 10 min in each position with position changes within 20 s. Heart rate was measured in each position and speed of heart rate changes between positions were assessed by regressions of rates versus timing of individual cardiac cycles. Supine heart rate was gradually decreasing with age: 82.32 ± 9.92, 74.33 ± 9.79, 67.43 ± 9.45 beats per minute (bpm) in tertile age groups < 11, 11-15, > 15 years, respectively (p < 0.0001), with no significant sex difference. Averaged speed of heart rate changes differed little between sexes and age groups but was significantly faster during rate deceleration than acceleration (e.g., supine ↔ standing: 2.99 ± 1.02 vs. 2.57 ± 0.68 bpm/s, p < 0.0001). The study suggests that in children, vagal heart rate control does not noticeably change between ages of approximately 6-19 years. The gradual resting heart rate decrease during childhood and adolescence is likely caused by lowering of cardiac sympathetic influence from sympathetic overdrive in small children to adult-like sympatho-vagal balance in older adolescents.

Intra-Individual Relationship between Heart Rate Variability and the Underlying Heart Rate in Children and Adolescents.

Background/Objective: The relationship between heart rate and heart rate variability (HRV) indices has been repeatedly studied in adults but limited data are available on the relationship in paediatric populations. Methods: Continuous 12-lead electrocardiograms were recorded in 1016 healthy children and adolescents (534 females) aged 4 to 19 years during postural manoeuvres with rapid changes between 10-min positions of supine → sitting → standing → supine → standing → sitting → supine. In each position, the averaged RR interval was measured together with four HRV indices, namely the SDNN, RMSSD, quasi-normalised high-frequency components (qnHF), and the proportions of low- and high-frequency components (LF/HF). In each subject, the slope of the linear regression between the repeated HRV measurements and the corresponding RR interval averages was calculated. Results: The intra-subject regression slopes, including their confidence intervals, were related to the age and sex of the subjects. The SDNN/RR, RMSSD/RR, and qnHF/RR slopes were significantly steeper (p < 0.001) and the (LF/HF)/RR slopes were significantly shallower (p < 0.001) in younger children compared to older children and adolescents. Conclusions: The study suggests that sympathetic and vagal influences on heart rate are present in both younger and older children. With advancing age, the sympatho-vagal balance gradually develops and allows the vagal control to suppress the sympathetic drive towards higher heart rates seen in younger age children.

QRS complex and T wave planarity for the efficacy prediction of automatic implantable defibrillators.

OBJECTIVE: To test the hypothesis that in recipients of primary prophylactic implantable cardioverter-defibrillators (ICDs), the non-planarity of ECG vector loops predicts (a) deaths despite ICD protection and (b) appropriate ICD shocks. METHODS: Digital pre-implant ECGs were collected in 1948 ICD recipients: 21.4% females, median age 65 years, 61.5% ischaemic heart disease (IHD). QRS and T wave three-dimensional loops were constructed using singular value decomposition that allowed to measure the vector loop planarity. The non-planarity, that is, the twist of the three-dimensional loops out of a single plane, was related to all-cause mortality (n=294; 15.3% females; 68.7% IHD) and appropriate ICD shocks (n=162; 10.5% females; 87.7% IHD) during 5-year follow-up after device implantation. Using multivariable Cox regression, the predictive power of QRS and T wave non-planarity was compared with that of age, heart rate, left ventricular ejection fraction, QRS duration, spatial QRS-T angle, QTc interval and T-peak to T-end interval. RESULTS: QRS non-planarity was significantly (p<0.001) associated with follow-up deaths despite ICD protection with HR of 1.339 (95% CI 1.165 to 1.540) but was only univariably associated with appropriate ICD shocks. Non-planarity of the T wave loop was the only ECG-derived index significantly (p<0.001) associated with appropriate ICD shocks with multivariable Cox regression HR of 1.364 (1.180 to 1.576) but was not associated with follow-up mortality. CONCLUSIONS: The analysed data suggest that QRS and T wave non-planarity might offer distinction between patients who are at greater risk of death despite ICD protection and those who are likely to use the defibrillator protection.

Intra-subject stability of different expressions of spatial QRS-T angle and their relationship to heart rate.

Three-dimensional angle between the QRS complex and T wave vectors is a known powerful cardiovascular risk predictor. Nevertheless, several physiological properties of the angle are unknown or poorly understood. These include, among others, intra-subject profiles and stability of the angle relationship to heart rate, characteristics of angle/heart-rate hysteresis, and the changes of these characteristics with different modes of QRS-T angle calculation. These characteristics were investigated in long-term 12-lead Holter recordings of 523 healthy volunteers (259 females). Three different algorithmic methods for the angle computation were based on maximal vector magnitude of QRS and T wave loops, areas under the QRS complex and T wave curvatures in orthogonal leads, and weighted integration of all QRS and T wave vectors moving around the respective 3-dimensional loops. These methods were applied to orthogonal leads derived either by a uniform conversion matrix or by singular value decomposition (SVD) of the original 12-lead ECG, giving 6 possible ways of expressing the angle. Heart rate hysteresis was assessed using the exponential decay models. All these methods were used to measure the angle in 659,313 representative waveforms of individual 10-s ECG samples and in 7,350,733 individual beats contained in the same 10-s samples. With all measurement methods, the measured angles fitted second-degree polynomial regressions to the underlying heart rate. Independent of the measurement method, the angles were found significantly narrower in females (p < 0.00001) with the differences to males between 10o and 20o, suggesting that in future risk-assessment studies, different angle dichotomies are needed for both sexes. The integrative method combined with SVD leads showed the highest intra-subject reproducibility (p < 0.00001). No reproducible delay between heart rate changes and QRS-T angle changes was found. This was interpreted as a suggestion that the measurement of QRS-T angle might offer direct assessment of cardiac autonomic responsiveness at the ventricular level.

Short-Term Beat-to-Beat QT Variability Appears Influenced More Strongly by Recording Quality Than by Beat-to-Beat RR Variability.

Increases in beat-to-beat variability of electrocardiographic QT interval duration have repeatedly been associated with increased risk of cardiovascular events and complications. The measurements of QT variability are frequently normalized for the underlying RR interval variability. Such normalization supports the concept of the so-called immediate RR effect which relates each QT interval to the preceding RR interval. The validity of this concept was investigated in the present study together with the analysis of the influence of electrocardiographic morphological stability on QT variability measurements. The analyses involved QT and RR measurements in 6,114,562 individual beats of 642,708 separate 10-s ECG samples recorded in 523 healthy volunteers (259 females). Only beats with high morphology correlation (r > 0.99) with representative waveforms of the 10-s ECG samples were analyzed, assuring that only good quality recordings were included. In addition to these high correlations, SDs of the ECG signal difference between representative waveforms and individual beats expressed morphological instability and ECG noise. In the intra-subject analyses of both individual beats and of 10-s averages, QT interval variability was substantially more strongly related to the ECG noise than to the underlying RR variability. In approximately one-third of the analyzed ECG beats, the prolongation or shortening of the preceding RR interval was followed by the opposite change of the QT interval. In linear regression analyses, underlying RR variability within each 10-s ECG sample explained only 5.7 and 11.1% of QT interval variability in females and males, respectively. On the contrary, the underlying ECG noise contents of the 10-s samples explained 56.5 and 60.1% of the QT interval variability in females and males, respectively. The study concludes that the concept of stable and uniform immediate RR interval effect on the duration of subsequent QT interval duration is highly questionable. Even if only stable beat-to-beat measurements of QT interval are used, the QT interval variability is still substantially influenced by morphological variability and noise pollution of the source ECG recordings. Even when good quality recordings are used, noise contents of the electrocardiograms should be objectively examined in future studies of QT interval variability.

QRS micro-fragmentation as a mortality predictor.

AIMS: Fragmented QRS complex with visible notching on standard 12-lead electrocardiogram (ECG) is understood to represent depolarization abnormalities and to signify risk of cardiac events. Depolarization abnormalities with similar prognostic implications likely exist beyond visual recognition but no technology is presently suitable for quantification of such invisible ECG abnormalities. We present such a technology. METHODS AND RESULTS: A signal processing method projects all ECG leads of the QRS complex into optimized three perpendicular dimensions, reconstructs the ECG back from this three-dimensional projection, and quantifies the difference (QRS 'micro'-fragmentation, QRS-µf) between the original and reconstructed signals. QRS 'micro'-fragmentation was assessed in three different populations: cardiac patients with automatic implantable cardioverter-defibrillators, cardiac patients with severe abnormalities, and general public. The predictive value of QRS-µf for mortality was investigated both univariably and in multivariable comparisons with other risk factors including visible QRS 'macro'-fragmentation, QRS-Mf. The analysis was made in a total of 7779 subjects of whom 504 have not survived the first 5 years of follow-up. In all three populations, QRS-µf was strongly predictive of survival (P < 0.001 univariably, and P < 0.001 to P = 0.024 in multivariable regression analyses). A similar strong association with outcome was found when dichotomizing QRS-µf prospectively at 3.5%. When QRS-µf was used in multivariable analyses, QRS-Mf and QRS duration lost their predictive value. CONCLUSION: In three populations with different clinical characteristics, QRS-µf was a powerful mortality risk factor independent of several previously established risk indices. Electrophysiologic abnormalities that contribute to increased QRS-µf values are likely responsible for the predictive power of visible QRS-Mf.

Influence of heart rate correction formulas on QTc interval stability.

Monitoring of QTc interval is mandated in different clinical conditions. Nevertheless, intra-subject variability of QTc intervals reduces the clinical utility of QTc monitoring strategies. Since this variability is partly related to QT heart rate correction, 10 different heart rate corrections (Bazett, Fridericia, Dmitrienko, Framingham, Schlamowitz, Hodges, Ashman, Rautaharju, Sarma, and Rabkin) were applied to 452,440 ECG measurements made in 539 healthy volunteers (259 females, mean age 33.3 ± 8.4 years). For each correction formula, the short term (5-min time-points) and long-term (day-time hours) variability of rate corrected QT values (QTc) was investigated together with the comparisons of the QTc values with individually corrected QTcI values obtained by subject-specific modelling of the QT/RR relationship and hysteresis. The results showed that (a) both in terms of short-term and long-term QTc variability, Bazett correction led to QTc values that were more variable than the results of other corrections (p < 0.00001 for all), (b) the QTc variability by Fridericia and Framingham corrections were not systematically different from each other but were lower than the results of other corrections (p-value between 0.033 and < 0.00001), and (c) on average, Bazett QTc values departed from QTcI intervals more than the QTc values of other corrections. The study concludes that (a) previous suggestions that Bazett correction should no longer be used in clinical practice are fully justified, (b) replacing Bazett correction with Fridericia and/or Framingham corrections would improve clinical QTc monitoring, (c) heart rate stability is needed for valid QTc assessment, and (d) development of further QTc corrections for day-to-day use is not warranted.

Spatial distribution of physiologic 12-lead QRS complex.

The normal physiologic range of QRS complex duration spans between 80 and 125 ms with known differences between females and males which cannot be explained by the anatomical variations of heart sizes. To investigate the reasons for the sex differences as well as for the wide range of normal values, a technology is proposed based on the singular value decomposition and on the separation of different orthogonal components of the QRS complex. This allows classification of the proportions of different components representing the 3-dimensional representation of the electrocardiographic signal as well as classification of components that go beyond the 3-dimensional representation and that correspond to the degree of intricate convolutions of the depolarisation sequence. The technology was applied to 382,019 individual 10-s ECG samples recorded in 639 healthy subjects (311 females and 328 males) aged 33.8 ± 9.4 years. The analyses showed that QRS duration was mainly influenced by the proportions of the first two orthogonal components of the QRS complex. The first component demonstrated statistically significantly larger proportion of the total QRS power (expressed by the absolute area of the complex in all independent ECG leads) in females than in males (64.2 ± 11.6% vs 59.7 ± 11.9%, p < 0.00001-measured at resting heart rate of 60 beats per minute) while the second component demonstrated larger proportion of the QRS power in males compared to females (33.1 ± 11.9% vs 29.6 ± 11.4%, p < 0.001). The analysis also showed that the components attributable to localised depolarisation sequence abnormalities were significantly larger in males compared to females (2.85 ± 1.08% vs 2.42 ± 0.87%, p < 0.00001). In addition to the demonstration of the technology, the study concludes that the detailed convolution of the depolarisation waveform is individual, and that smoother and less intricate depolarisation propagation is the mechanism likely responsible for shorter QRS duration in females.

Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under ß-adrenergic stimulation.

The variant c.926C > T (p.T309I) in KCNQ1 gene was identified in 10 putatively unrelated Czech families with long QT syndrome (LQTS). Mutation carriers (24 heterozygous individuals) were more symptomatic compared to their non-affected relatives (17 individuals). The carriers showed a mild LQTS phenotype including a longer QTc interval at rest (466 ± 24 ms vs. 418 ± 20 ms) and after exercise (508 ± 32 ms vs. 417 ± 24 ms), 4 syncopes and 2 aborted cardiac arrests. The same haplotype associated with the c.926C > T variant was identified in all probands. Using the whole cell patch clamp technique and confocal microscopy, a complete loss of channel function was revealed in the homozygous setting, caused by an impaired channel trafficking. Dominant negativity with preserved reactivity to ß-adrenergic stimulation was apparent in the heterozygous setting. In simulations on a human ventricular cell model, the dysfunction resulted in delayed afterdepolarizations (DADs) and premature action potentials under ß-adrenergic stimulation that could be prevented by a slight inhibition of calcium current. We conclude that the KCNQ1 variant c.926C > T is the first identified LQTS-related founder mutation in Central Europe. The dominant negative channel dysfunction may lead to DADs under ß-adrenergic stimulation. Inhibition of calcium current could be possible therapeutic strategy in LQTS1 patients refractory to ß-blocker therapy.

Sex and Rate Change Differences in QT/RR Hysteresis in Healthy Subjects.

While it is now well-understood that the extent of QT interval changes due to underlying heart rate differences (i.e., the QT/RR adaptation) needs to be distinguished from the speed with which the QT interval reacts to heart rate changes (i.e., the so-called QT/RR hysteresis), gaps still exist in the physiologic understanding of QT/RR hysteresis processes. This study was designed to address the questions of whether the speed of QT adaptation to heart rate changes is driven by time or by number of cardiac cycles; whether QT interval adaptation speed is the same when heart rate accelerates and decelerates; and whether the characteristics of QT/RR hysteresis are related to age and sex. The study evaluated 897,570 measurements of QT intervals together with their 5-min histories of preceding RR intervals, all recorded in 751 healthy volunteers (336 females) aged 34.3 ± 9.5 years. Three different QT/RR adaptation models were combined with exponential decay models that distinguished time-based and interval-based QT/RR hysteresis. In each subject and for each modelling combination, a best-fit combination of modelling parameters was obtained by seeking minimal regression residuals. The results showed that the response of QT/RR hysteresis appears to be driven by absolute time rather than by the number of cardiac cycles. The speed of QT/RR hysteresis was found decreasing with increasing age whilst the duration of individually rate corrected QTc interval was found increasing with increasing age. Contrary to the longer QTc intervals, QT/RR hysteresis speed was faster in females. QT/RR hysteresis differences between heart rate acceleration and deceleration were not found to be physiologically systematic (i.e., they differed among different healthy subjects), but on average, QT/RR hysteresis speed was found slower after heart rate acceleration than after rate deceleration.

Heart Rate Influence on the QT Variability Risk Factors.

QT interval variability, mostly expressed by QT variability index (QTVi), has repeatedly been used in risk diagnostics. Physiologic correlates of QT variability expressions have been little researched especially when measured in short 10-second electrocardiograms (ECGs). This study investigated different QT variability indices, including QTVi and the standard deviation of QT interval durations (SDQT) in 657,287 10-second ECGs recorded in 523 healthy subjects (259 females). The indices were related to the underlying heart rate and to the 10-second standard deviation of RR intervals (SDRR). The analyses showed that both QTVi and SDQT (as well as other QT variability indices) were highly statistically significantly (p < 0.00001) influenced by heart rate and that QTVi showed poor intra-subject reproducibility (coefficient of variance approaching 200%). Furthermore, sequential analysis of regression variance showed that SDQT was more strongly related to the underlying heart rate than to SDRR, and that QTVi was influenced by the underlying heart rate and SDRR more strongly than by SDQT (p < 0.00001 for these comparisons of regression dependency). The study concludes that instead of QTVi, simpler expressions of QT interval variability, such as SDQT, appear preferable for future applications especially if multivariable combination with the underlying heart rate is used.

Problems with Bazett QTc correction in paediatric screening of prolonged QTc interval.

BACKGROUND: Bazett formula is frequently used in paediatric screening for the long QT syndrome (LQTS) and proposals exist that using standing rather than supine electrocardiograms (ECG) improves the sensitivity of LQTS diagnosis. Nevertheless, compared to adults, children have higher heart rates (especially during postural provocations) and Bazett correction is also known to lead to artificially prolonged QTc values at increased heart rates. This study assessed the incidence of erroneously increased QTc values in normal children without QT abnormalities. METHODS: Continuous 12-lead ECGs were recorded in 332 healthy children (166 girls) aged 10.7 ± 2.6 years while they performed postural manoeuvring consisting of episodes (in the following order) of supine, sitting, standing, supine, standing, sitting, and supine positions, each lasting 10 min. Detailed analyses of QT/RR profiles confirmed the absence of prolonged individually corrected QTc interval in each child. Heart rate and QT intervals were measured in 10-s ECG segments and in each segment, QTc intervals were obtained using Bazett, Fridericia, and Framingham formulas. In each child, the heart rates and QTc values obtained during supine, sitting and standing positions were averaged. QTc durations by the three formulas were classified to < 440 ms, 440-460 ms, 460-480 ms, and > 480 ms. RESULTS: At supine position, averaged heart rate was 77.5 ± 10.5 beat per minute (bpm) and Bazett, Fridericia and Framingham QTc intervals were 425.3 ± 15.8, 407.8 ± 13.9, and 408.2 ± 13.1 ms, respectively. At sitting and standing, averaged heart rate increased to 90.9 ± 10.1 and 100.9 ± 10.5 bpm, respectively. While Fridericia and Framingham formulas showed only minimal QTc changes, Bazett correction led to QTc increases to 435 ± 15.1 and 444.9 ± 15.9 ms at sitting and standing, respectively. At sitting, Bazett correction identified 51, 4, and 0 children as having the QTc intervals 440-460, 460-480, and > 480 ms, respectively. At sitting, these numbers increased to 118, 11, and 1, while on standing these numbers were 151, 45, and 5, respectively. Irrespective of the postural position, Fridericia and Framingham formulas identified only a small number (< 7) of children with QT interval between 440 and 460 ms and no children with longer QTc. CONCLUSION: During screening for LQTS in children, the use of Bazett formula leads to a high number of false positive cases especially if the heart rates are increased (e.g. by postural manoeuvring). The use of Fridericia formula can be recommended to replace the Bazett correction not only for adult but also for paediatric ECGs.

Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1.

BACKGROUND: Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported. OBJECTIVES: This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1. METHODS: Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis. RESULTS: We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00). CONCLUSIONS: Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.

Heart Rate Dependency and Inter-Lead Variability of the T Peak - T End Intervals.

The electrocardiographic (ECG) assessment of the T peak-T end (Tpe) intervals has been used in many clinical studies, but several related physiological aspects have not been reported. Specifically, the sources of the Tpe differences between different ECG leads have not been systematically researched, the relationship of Tpe duration to underlying heart rate has not been firmly established, and little is known about the mutual correspondence of Tpe intervals measured in different ECG leads. This study evaluated 796,620 10-s 12-lead ECGs obtained from long-term Holters recorded in 639 healthy subjects (311 female) aged 33.8 ± 9.4 years. For each ECG, transformation to orthogonal XYZ lead was used to measure Tpe in the orthogonal vector magnitude (used as a reference for lead-to-lead comparisons) and to construct a three-dimensional T wave loop. The loop roundness was expressed by a ratio between its circumference and length. These ratios were significantly related to the standard deviation of Tpe durations in different ECG leads. At the underlying heart rate of 60 beats per minute, Tpe intervals were shorter in female than in male individuals (82.5 ± 5.6 vs 90.0 ± 6.5 ms, p < 0.0001). When studying linear slopes between Tpe intervals measured in different leads and the underlying heart rate, we found only minimal heart rate dependency, which was not systematic across the ECG leads and/or across the population. For any ECG lead, positive Tpe/RR slope was found in some subjects (e.g., 79 and 25% of subjects for V2 and V4 measurements, respectively) and a negative Tpe/RR slope in other subjects (e.g., 40 and 65% for V6 and V5, respectively). The steepest positive and negative Tpe/RR slopes were found for measurements in lead V2 and V4, respectively. In all leads, the Tpe/RR slope values were close to zero, indicating, on average, Tpe changes well below 2 ms for RR interval changes of 100 ms. On average, longest Tpe intervals were measured in lead V2, the shortest in lead III. The study concludes that the Tpe intervals measured in different leads cannot be combined. Irrespective of the measured ECG lead, the Tpe interval is not systematically heart rate dependent, and no heart rate correction should be used in clinical Tpe investigations.

Individually Rate Corrected QTc Intervals in Children and Adolescents.

Accurate evaluation of the appearance of QTc sex differences during childhood and adolescence is intricate. Inter-subject differences of individual QT/RR patterns make generic heart rate corrections inaccurate because of fast resting heart rates in children. The study investigated 527 healthy children and adolescents aged 4-19 years (268 females, 50.9%). All underwent continuous ECG 12-lead monitoring while performing postural changes during a 70-min investigative protocol to obtain QT interval measurements at different heart rates. On average, more than 1200 ECG measurements (QT interval and its 5-min history of preceding RR intervals) were made in each subject. Curvilinear QT/RR regression involving intra-individual correction for QT/RR hysteresis were calculated in each subject. The projection of the QT/RR regressions to the heart rate of 60 beats per minute defined individually corrected QTc intervals. In males, gradual QTc shortening by about 15 ms appeared during the ages of 13-19 years synchronously with the incidence of secondary sex signs (p = 0.016). On the contrary, whilst gradual QTc prolongation by about 10 ms appeared in females, it occurred only during ages 16-19 years and was not related to the incidence of secondary sex signs (p = 0.18). The study also showed that in children and adolescents, linear QT/RR models fit the intra-subject data significantly more closely than the log-linear models (p < 0.001). The study speculates that hormonal shifts during puberty might be directly responsible for the QTc shortening in males but that QTc prolongation in females is likely more complex since it was noted to follow the appearance of secondary sex signs only after a considerable delay.

Automation bias in medicine: The influence of automated diagnoses on interpreter accuracy and uncertainty when reading electrocardiograms.

INTRODUCTION: Interpretation of the 12­lead Electrocardiogram (ECG) is normally assisted with an automated diagnosis (AD), which can facilitate an 'automation bias' where interpreters can be anchored. In this paper, we studied, 1) the effect of an incorrect AD on interpretation accuracy and interpreter confidence (a proxy for uncertainty), and 2) whether confidence and other interpreter features can predict interpretation accuracy using machine learning. METHODS: This study analysed 9000 ECG interpretations from cardiology and non-cardiology fellows (CFs and non-CFs). One third of the ECGs involved no ADs, one third with ADs (half as incorrect) and one third had multiple ADs. Interpretations were scored and interpreter confidence was recorded for each interpretation and subsequently standardised using sigma scaling. Spearman coefficients were used for correlation analysis and C5.0 decision trees were used for predicting interpretation accuracy using basic interpreter features such as confidence, age, experience and designation. RESULTS: Interpretation accuracies achieved by CFs and non-CFs dropped by 43.20% and 58.95% respectively when an incorrect AD was presented (p < 0.001). Overall correlation between scaled confidence and interpretation accuracy was higher amongst CFs. However, correlation between confidence and interpretation accuracy decreased for both groups when an incorrect AD was presented. We found that an incorrect AD disturbs the reliability of interpreter confidence in predicting accuracy. An incorrect AD has a greater effect on the confidence of non-CFs (although this is not statistically significant it is close to the threshold, p = 0.065). The best C5.0 decision tree achieved an accuracy rate of 64.67% (p < 0.001), however this is only 6.56% greater than the no-information-rate. CONCLUSION: Incorrect ADs reduce the interpreter's diagnostic accuracy indicating an automation bias. Non-CFs tend to agree more with the ADs in comparison to CFs, hence less expert physicians are more effected by automation bias. Incorrect ADs reduce the interpreter's confidence and also reduces the predictive power of confidence for predicting accuracy (even more so for non-CFs). Whilst a statistically significant model was developed, it is difficult to predict interpretation accuracy using machine learning on basic features such as interpreter confidence, age, reader experience and designation.

Hypersensitivity to material and environmental burden as a possible cause of late complications of cardiac implantable electronic devices.

Aims: To evaluate whether patients with late complications of pacemakers or implantable cardioverter-defibrillators have hypersensitivity reactions to some of the materials used in generators or in electrodes, or to environmental metal burden. Methods and results: The cohort consisted of 20 men and 4 women (mean age: 62.3 ± 17.2 years) who had a history of late complications of implanted devices. The control group involved 25 men and 8 women (mean age: 64.6 ± 14.0 years) who had comparable devices, but no history of late complications. Lymphocyte transformation test was used to evaluate hypersensitivity to eight metal pollutants (antimony, manganese, mercury, molybdenum, nickel, platinum, tin, and titanium) selected by results of questionnaires on environmental burden, and by material analysis of generators and electrode surfaces. Exposures to metal pollutants were approximately the same in patients and in controls. Titanium alloy used in generators contained at least 99.32% of titanium and trace levels of other metals; higher levels of tin and platinum were detected in electrode surfaces. Hypersensitivity reactions to mercury and tin were significantly more frequent in patients than in controls (patients and controls: mercury: 68.2 and 31.1%, respectively; P = 0.022; tin: 25.0 and 3.2%, respectively; P = 0.035). In contrast, hypersensitivity to manganese was significantly more frequent in controls than in patients (patients and controls: 13.6 and 50.0%, respectively; P = 0.008). Conclusion: Our findings suggest a possible relation between hypersensitivity to metals used in implantable devices or to environmental metal burden and the occurrence of their late complications.

The role of computerized diagnostic proposals in the interpretation of the 12-lead electrocardiogram by cardiology and non-cardiology fellows.

INTRODUCTION: Most contemporary 12-lead electrocardiogram (ECG) devices offer computerized diagnostic proposals. The reliability of these automated diagnoses is limited. It has been suggested that incorrect computer advice can influence physician decision-making. This study analyzed the role of diagnostic proposals in the decision process by a group of fellows of cardiology and other internal medicine subspecialties. MATERIALS AND METHODS: A set of 100 clinical 12-lead ECG tracings was selected covering both normal cases and common abnormalities. A team of 15 junior Cardiology Fellows and 15 Non-Cardiology Fellows interpreted the ECGs in 3 phases: without any diagnostic proposal, with a single diagnostic proposal (half of them intentionally incorrect), and with four diagnostic proposals (only one of them being correct) for each ECG. Self-rated confidence of each interpretation was collected. RESULTS: Availability of diagnostic proposals significantly increased the diagnostic accuracy (p<0.001). Nevertheless, in case of a single proposal (either correct or incorrect) the increase of accuracy was present in interpretations with correct diagnostic proposals, while the accuracy was substantially reduced with incorrect proposals. Confidence levels poorly correlated with interpretation scores (rho≈2, p<0.001). Logistic regression showed that an interpreter is most likely to be correct when the ECG offers a correct diagnostic proposal (OR=10.87) or multiple proposals (OR=4.43). CONCLUSION: Diagnostic proposals affect the diagnostic accuracy of ECG interpretations. The accuracy is significantly influenced especially when a single diagnostic proposal (either correct or incorrect) is provided. The study suggests that the presentation of multiple computerized diagnoses is likely to improve the diagnostic accuracy of interpreters.