Probability of diagnosing long QT syndrome in children and adolescents according to the criteria of the HRS/EHRA/APHRS expert consensus statement

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1 European Heart Journal (2016) 37, doi: /eurheartj/ehw072 CLINICAL RESEARCH Arrhythmia/electrophysiology Probability of diagnosing long QT syndrome in children and adolescents according to the criteria of the HRS/EHRA/APHRS expert consensus statement Masao Yoshinaga 1 *, Yu Kucho 1, Makoto Nishibatake 2, Hiromitsu Ogata 3, and Yuichi Nomura 4 1 Department of Pediatrics, National Hospital Organization Kagoshima Medical Center, Shiroyama-cho 8-1, Kagoshima , Japan; 2 Department of Pediatrics, Kagoshima Seikyo Hospital, Kagoshima, Japan; 3 Centers for Public Health Informatics, National Institute of Public Health, Wako, Japan; and 4 Department of Pediatrics, Kagoshima City Hospital, Kagoshima, Japan Received 21 July 2015; revised 15 January 2016; accepted 1 February 2016 See page 2498 for the editorial comment on this article (doi: /eurheartj/ehw104) Aims The present study aimed to determine the probability of diagnosing long QT syndrome (LQTS) in children and adolescents based on the HRS/EHRA/APHRS criteria for LQTS. We used data of a school-based electrocardiographic screening programme in Japan.... Methods The total numbers of subjects who participated in the screening programme between 2008 and 2013 in Kagoshima, and results Japan, were first- and seventh-grade students, aged 6 and 12 years, respectively. The screening process consisted of three steps of examination: the first screening, and the second and third examinations. Among the total subjects, first graders (99.8% of the total) and seventh graders (99.5% of the total) participated in the first screening. After the first, second, and third screening or examinations, the programme determined 10 first and 32 seventh graders as having a high probability of LQTS according to the HRS/EHRA/APHRS criteria for LQTS. The probability of diagnosing LQTS by the screening programme was 1:3298 (0.30/1000) and 1:1080 (0.93/1000) in first and seventh graders, respectively. During the study periods, three subjects of 7th graders were already diagnosed as having LQTS at the first grade. Therefore, the overall probability of diagnosing LQTS was 1:3298 (95% confidence interval, 1:2036 to 1:8673) and 1:988 (95% confidence interval, 1:742 to 1:1477) in first and seventh graders, respectively.... Conclusion This study shows important data on the probability of diagnosing LQTS as 1:3300 in subjects aged 6 years and 1:1000 in those aged 12 years based on the HRS/EHRA/APHRS criteria Keywords Electrocardiogram QT interval Screening Prevalence Introduction Congenital long QT syndrome (LQTS) is a genetic disorder that is characterized by delayed repolarization and a long QT interval on 12-lead electrocardiograms (ECGs). The hallmark of LQTS is syncope or sudden death due to torsade de pointes. 1 3 Sixteen genes related to LQTS have been identified. 3 Since the first description of four cases with deafness and a long QT interval in 1957, 4 huge progress has been achieved in understanding the pathogenesis, diagnosis, and treatment of LQTS. 2,3 The prevalence of LQTS is 1:2000 apparently healthy live births. 5 A nationwide, school-based ECG screening programme for heart diseases in first, seventh, and 10th graders in Japan started in 1994; participation is mandatory. This programme has revealed children and adolescents with prolonged QT intervals. 6 The probability of diagnosing LQTS by this programme is estimated at 1:1200 in the seventh grade. 7 The Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asia Pacific Heart Rhythm Society (APHRS) (HRS/EHRA/APHRS) published a Consensus Statement * Corresponding author. Tel: , Fax: , m-yoshi@biscuit.ocn.ne.jp Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Probability of diagnosing long QT syndrome 2491 on the diagnosis and management of patients with inherited primary arrhythmia syndromes in The prevalence of a high probability of LQTS based on this statement is unclear. Therefore, the present study aimed to determine the probability of diagnosing LQTS in children and adolescents based on the HRS/EHRA/APHRS criteria for LQTS using data of the ECG screening programme in Japan. Methods Subjects The total numbers of subjects who had to participate in the schoolbased ECG screening programme during 6 years between 2008 and 2013 in Kagoshima, Japan, were first- and seventh-grade students (Tables 1 and 2). The study was approved by the Ethics Committee of the National Hospital Organization (NHO) Kagoshima Medical Center. Screening process in Kagoshima The screening process of identifying cardiovascular diseases in the school-based screening programme in Kagoshima consisted of three steps of examination: the first screening, and the second and third examinations. In the first screening, students received 12-lead resting ECG recordings at schools at a speed of 25 mm/s. Their parents were asked Table 1 Table 2 Participation of first graders in the screening program in Kagoshima Participation of seventh graders in the screening system in Kagoshima to fill out questionnaires, including written informed consent to participate. Paediatric cardiologists screened subjects who might have cardiovascular diseases using ECGs and questionnaires (content of questionnaire was present in Supplementary material online). All of the subjects, who were thought to need examinations, including a physical examination, chest X-ray, Master two-step test, or echocardiography, were asked to visit Kagoshima City Medical Association Hospital (second examination). In subjects who were screened as having a prolonged QT or borderline QT intervals (i.e. those with shorter QTc values than the criteria, but they were close to the criteria), ECGs at rest and after exercise (Master s two-step test) were obtained at the second screening. When paediatric cardiologists decided that subjects should be further examined, they sent subjects to tertiary centres for cardiovascular diseases. All of the subjects who may have a prolonged QT interval had been introduced to one tertiary centre, the NHO Kagoshima Medical Center, during the study period. Criteria for screening of QT prolongation In the present study, Bazett s formula was used to diagnose LQTS. To screen QT prolongation, an exponential formula (QT/RR 0.31 ) 9 and Fridericia s formula (QT/RR (1/3) ) were also applied from 1993 to 2009 and from 2010 to present, respectively, when subjects showed a high heart rate. Screening criteria by Bazett s formula were 450 and 460 ms 1/2 for males and females, respectively, based on the scoring Total a Participated in the first b Screened c Participated in the second d (99.7%) (100%) (99.9%) (92.6%) (99.8%) (98.3%) (99.7%) (100%) (99.8%) (100%) (99.8%) (100%) Total (99.8%) (98.7%) a Total number of first graders in whom participation in the screening program was mandatory. b Data are shown as the number (percentage) of subjects who participated in the first screening. c Number of subjects who were screened as having some cardiovascular diseases and/or arrhythmias. d Data are shown as the number (percentage) of subjects who participated in the second screening. Total a Participated in the first b Screened c Participated in the second d (99.5%) (98.8%) (99.5%) (97.7%) (99.5%) (99.0%) (99.5%) (93.9%) (99.4%) (95.3%) (99.6%) (100%) Total (99.5%) (97.3%) a Total number of seventh graders in whom participation in the screening program was mandatory. b Data are shown as the number (percentage) of subjects who participated in the first screening. c Number of subjects who were screened as having some cardiovascular diseases and/or arrhythmias. d Data are shown as the number (percentage) of subjects who participated in the second screening.

3 2492 M. Yoshinaga et al. system. 2 Those by the exponential formula were 430, 430, 445, and 450 ms 0.31 for first-grade boys and girls, and seventh-grade boys and girls, respectively. 9 Those by Fridericia s formula were 430, 430, 445, and 445 ms 1/3, respectively. 10 Electrocardiograms with abnormal findings, including prolonged QTc values, were automatically screened by the ECG machines with computerized procedures in Kagoshima. Additionally, all ECGs, including ECGs without abnormal findings by computerized procedures, were manually evaluated by paediatric cardiologists. Measurement and correction of QT intervals QT/RR data used in the manuscript were re-measured by one author (M.Y.) for the present study. QT intervals of three consecutive beats were measured from the onset of the Q wave to the end of the T wave in lead V 5. 1 When the notch was present in more than three leads 11,12 and the notch appeared at the same timing, 12 the T wave was defined as the bifid T wave. QT/RR data for each of the three consecutive beats were corrected by Bazett s and Fridericia s formulas. The mean values for the three consecutive QTcs were used. Final diagnosis of long QT syndrome The final diagnosis of LQTS in the present study was based on the criteria of the HRS/EHRA/APHRS statement. 8 Briefly, LQTS was diagnosed as follows: (i) the presence of an LQTS risk score 3.5 and/or (ii) in the presence of unequivocally pathogenic mutations in LQTS genes, or (iii) in the presence of a QTc 500 ms by Bazett s formula in repeated 12-lead ECG in the absence of a secondary cause of LQTS. Criteria of low heart rate for ages Criteria for the presence or absence of low heart rate (2nd percentile) for ages were needed to calculate the LQTS risk score (points). 2,13 Because criteria for low heart rate for children and adolescents were not present based on the data of a relatively large number of subjects, criteria were created for the present study using the data of the programme in Kagoshima City. Subjects were 9849 first-grade boys, 9518 first-grade girls, seventh-grade boys, and seventh-grade girls who participated in the screening programme between 2006 and 2009 and who did not have any abnormal ECG findings. Criteria for low heart rate (2nd percentile) were 63, 63, 56, and 58 for firstgrade boys and girls, and seventh-grade boys and girls, respectively. Genetic analysis Genetic testing was performed after obtaining written informed consent when the subjects had a past history of LQTS-related symptoms, a family history of LQTS or sudden cardiac death, or they had a high QTc value, usually greater than 500 ms. Genomic DNA was isolated from blood after obtaining written informed consent. Genetic screening for LQT-1 (KCNQ1), -2 (KCNH2), -3 (SCN5A), -5 (KCNE1), -6 (KCNE2), and -7 (KCNJ2) was performed by polymerase chain reaction and direct DNA sequencing. The exons of LQT-8 (CACNA1C) were not analysed because no subjects had abnormal hand/foot findings. The exons of LQT-4 (ANKB), -9 (CAV3), -10 (SCN4B), -1 (AKAP9), -12 (SNTA1), and -13 (KCNJ5) were not analysed because there are no reported cases of these mutations in the Japanese population. The exons of LQT-14 (CALM1) and -15 (CALM2) were not analysed because these mutations were recently identified. Genomic DNA was isolated using a QIAmp DNA Blood Midi Kit (Qiagen, Gaithersburg, MD, USA). Polymerase chain reaction products were purified by AMPure (Beckman Coulter, Brea, CA, USA). After treatment with the BigDye Terminator v1.1 Cycle Sequence Kit (ABI, Warrington, UK) and BigDye X Terminator TM, direct sequencing was performed by the ABI Genetic Analyser (ABI). Statistical analysis Differences in the mean values and prevalence rates were examined using the Mann Whitney U test and Fisher s exact probability test, respectively. Statistical analysis was performed using IBM w SPSS w Statistics Version 21.0 (IBM Japan, Ltd., Tokyo, Japan). A two-tailed probability value of,0.05 was considered statistically significant. Results Participants and screening process The total numbers of the first and seventh graders who had to participate in the screening programme in Kagoshima during the study periods were (Table 1) and subjects (Table 2), respectively. With regard to first graders, (99.8% of the total) subjects participated in the first screening and 389 (1.2% of the participants in the first screening) subjects were screened as having some cardiovascular diseases (Table 1). Of these, 384 (98.7% of screened) subjects participated in the second screening. With regard to seventh graders, (99.5% of the total) subjects participated in the first screening and 586 (2.4% of the participants in the first screening) subjects were screened as having some cardiovascular diseases (Table 2). Of these, 570 (97.3% of screened) subjects participated in the second screening (Figure 1). Among first graders who were screened, 68 (18% of screened subjects) subjects were suspected as having prolonged QT intervals. Of these, 31 subjects were introduced to the NHO Kagoshima Medical Center for further examination (Table 3). Among seventh graders who were screened, 106 (19% of screened subjects) subjects were suspected as having prolonged QT intervals. Of these, 55 subjects were introduced to a tertiary centre for further examination (Table 4). Characteristics of the subjects who attended the second examination with or without further examinations are shown in Table 5. Subjects who had further examinations showed significantly longer QTc values and LQTS risk scores than those without further examinations both at the first screening and second examination in both the first and seventh graders (Table 5, Figure 2). QTc values at the first screening were longer than those at the second examination in all of the groups (with and without further examinations in the first and seventh graders) (Figure 2). The distribution of the risk scores of subjects who were introduced to the tertiary centre for first and seventh graders is shown in Supplementary material online, respectively. Among subjects with a high probability of LQTS, five seventh graders had a past history of syncope; one exercise-related syncope and four at rest or sleeping. After diagnosis, one seventh grader had syncope during sleeping (Table 6). Probability of diagnosing long QT syndrome based on the criteria of the HRS/EHRA/APHRS statement Ten subjects who were first graders and 32 subjects who were seventh graders were diagnosed based on the criteria of the HRS/EHRA/APHRS statement (Table 6). QTc values and risk scores were not different between the first and seventh graders. All of the subjects were diagnosed as having LQTS because they had risk scores of 3.5 points, except for one subject. A 13-year-old girl showed a QTc value by Bazett s formula of and her resting

4 Probability of diagnosing long QT syndrome 2493 Figure 1 The flow of patients and the time point of the different screenings. Table 3 Prevalence of long QT syndrome in the first graders Participated a Screened b Further Ex c High probability d Prevalence : : : : : :2826 Total :3298 a Number of subjects who participated in the first screening. bnumber of subjects who were suspected as having prolonged QT intervals at the first screening. c Subjects who were recommended to have a further examination at the second screening. All of the subjects who were recommended to have a further examination visited one tertiary centre. d Number of subjects with a high probability of LQTS. heart rate was 42 beats per minute. Because her heart rate was low, genetic testing was performed after obtaining an informed consent. The genetic testing revealed an SCN5A mutation (5963T.G, L1988R). Finally, the prevalence of probability of diagnosing LQTS by the programme was 1:3298 and 1:1080 in first and seventh graders, respectively.

5 2494 M. Yoshinaga et al. Table 4 Prevalence of long QT syndrome in seventh graders Participated a Screened b Further Ex c High probability d Prevalence : : : : : :1912 Total :1080 a Number of subjects who participated in the first screening. b Number of subjects who were suspected as having prolonged QT intervals at the first screening. c Subjects who were recommended to have a further examination at the second screening. All of the subjects who were recommended to have a further examination visited one tertiary centre. d Number of subjects with a high probability of LQTS. Table 5 First graders Seventh graders Without further With further P-value Without further With further P-value examination examination Ex examination Ex examination Number of subjects 34 a b During the study periods, three subjects of 7th graders were already diagnosed as having a high probability of LQTS at the first grade in the present study, indicating that the overall probability of diagnosing LQTS in the seventh graders was 1:988. The prevalence of LQTS in the seventh grade was significantly higher than that in the first grade (P ¼ 0.001). Genetic testing Characteristics of subjects who visited the second screening with or without further examination First screening QTc (Bazett) , , QTc (Fridericia) , , Second screening At rest QTc (Bazett) , , After exercise QTc (Bazett) , , LQTS risk score Mean , , Range The data are expressed as the mean + standard deviation. a Among 68 subjects who were screened at the first screening in Table 3, three subjects were excluded in this table; one subject had complete atrioventricular block, one had received surgical treatment for Coarctation of the aorta & ventricular septal defect, and one had been treated for acute lymphocytic leukaemia. b Among 55 subjects who were further examined in Table 4, three subjects were excluded in this table; one subject had atrial septal defect, one was suspected to have catecholaminergic polymorphic ventricular tachycardia, and one had short QT interval, but not long QT interval. Genetic testing was performed in seven of 10 first graders and 24 of 42 seventh graders with a moderate or high probability of LQTS (Table 7). The yield of genetic testing was 70% (7/10) in first graders and 42% (10/24) in seventh graders. Of 42 subjects with a high probability of LQTS, a 12-year-old male had a digenic mutation of SCN5A and KCNE1. Including these mutations, genetic testing revealed six KCNQ1, five KCNH2, four SCN5A, and one KCNE1 mutation. Discussion The present study showed the probability of diagnosing LQTS was 1:3298 (0.30/1000) in first graders and 1:1080 (0.93/1000) in seventh graders in the general paediatric population using a schoolbased ECG screening programme based on the HRS/EHRA/APHRS criteria. During the study periods, three subjects of 7th graders were already diagnosed as having a high probability of LQTS at the first grade in the present study, indicating that the overall probability of diagnosing LQTS in the seventh graders was 1:988.

6 Probability of diagnosing long QT syndrome 2495 Figure 2 QTc values at the first screening and second examination in subjects with and without further examination after the second examination in the first and seventh graders. Subjects who had further examinations showed significantly longer QTc values than those without further examinations both at the first screening and second examination in both the first and seventh graders. QTc values at the first screening were longer than those at the second examination in all of the groups (with and without further examinations in the first and seventh graders). Table 6 Characteristics of subjects with a high probability of long QT syndrome who were diagnosed by the programme First Seventh P-values graders graders... N Age 7.0 (0.8) 12.7 (0.4) Sex 5/5 17/ QTc (by Bazett s formula) 477 (17) 478 (17) 0.61 Risk score (points) 4.9 (0.9) 4.5 (0.8) 0.28 Family history of LQTS Family history of sudden death Past history of syncope Syncope after diagnosis Follow-up periods (years) 3.4 (2.4) 2.8 (1.5) 0.84 The prevalence of LQTS is generally 1: ,8 This prevalence was based on a large study conducted in Italy. 5 This previous study showed that 17 infants among a cohort of neonates were affected by LQTS, and that the prevalence of LQTS was 1:2534 in Caucasian infants. Of the 17 infants, 16 were diagnosed with LQTS because of the presence of QT prolongation and diseasecausing mutations, and one was diagnosed because the father of the infant with a QTc of 482 ms also had an extremely prolonged QTc (581 ms). The authors hypothesized that the prevalence of LQTS is close to 1:2000, considering the presence of some infants without genetic analysis in the study. 5 Another study that was conducted in Japan showed that 4 of month-old infants (1:1071) had prolonged QT intervals from follow-up ECGs, and that two infants (1:2143) required medication because of progressive prolongation of QT intervals. 14 A previous study based on the school-based ECG screening programme estimated that the probability of diagnosing prolonged QT intervals was 1:1164 (4/4655) in the seventh grade. 7 However, these estimates were based on different criteria for LQTS. Societies of HRS/EHRA/APHRS published a Consensus Statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes in 2013, including those of LQTS. 8 However, there are no data on the prevalence of a high probability of LQTS based on the HRS/EHRA/APHRS criteria. The present study showed the difference in probability of diagnosing LQTS among graders. The prevalence of a high probability of LQTS in seventh graders by the programme in the present study (1:1080) was similar to that in a previous study (1:1164). 7 This finding suggests that the probability of diagnosing LQTS in the seventh grade, (i.e. 12-year-old children) is 1:1000 to 1:1200. The probability of diagnosing LQTS in the first grade was determined in the present study. The reason why the probability of diagnosing LQTS in first graders in the present study was lower than that in previous studies in infants is unclear. The cumulative probability of aborted cardiac arrest or cardiac death is extremely low between 1 and 10 years old when no cardiac event is present in first year. The cumulative prevalence of a high probability of LQTS-related symptoms increases after 1 year to young adulthood. 15 QTc values increase by age during school-aged children and adolescents. 7,10 In one cohort study, the prevalence of a high probability of LQTS was 0 (0/4655) at the first grade and 1/1164 (4/4655) at the seventh grade, 7 indicating that it increases from the first to the seventh grades. A longer QTc value was shown as one of the greatest risk factors. 15 These data suggest that the probability of diagnosing LQTS based on ECG findings is low during elementary school years. Interestingly, QTc values at the first screening were longer than those at the second examination in all of the groups with or without further examinations (Table 5, Figure 2). A difference between the first screening and second ECG examination was the circumstances of the ECG recording. ECGs at the first screening were recorded at schools and those at the second examination were recorded at hospitals. Whether the difference in the situation of recording affected the QT intervals is unclear. There are limitations to the present study. The main limitation is that genetic testing was not performed for all subjects who were introduced to the NHO Kagoshima Medical Center. If genetic testing had been adopted in all subjects, the prevalence of LQTS would have been higher than that in the present study, even in first graders, as previously shown. 4 Secondarily, about one half of screened subjects at the first screening were not received further examination after the second screening (Tables 3 and 4). The aim of the first screening of this screening system about prolonged QT intervals is to exclude the possibility of false-negative type of missdiagnosis. Table 5 and Figure 2 showed that subjects without further examination after second screening had shorter QTc values and lower LQTS risk scores; however, there may still be patients with

7 2496 M. Yoshinaga et al. Table 7 Yield of genetic testing Scores Subjects a Tested b Identified c Gene Nucleotide change Amino acid change Mutation type (First graders) KCNQ1 1637C.T S546L Missense KCNH2 454 Insertion C P151fs + 179X Flameshift KCNH2 d G745fs + 54X Flameshift/ Deletion +TTT Deletion SCN5A 3578G.A R1193Q Missense KCNH2 d G745fs + 54X Flameshift/ Deletion +TTT Deletion (Seventh graders) KCNQ1 1927G.A G643S Missense KCNQ1 993C.A C331X Nonsense SCN5A & KCNE1 5963T.G L1988R Missense & 253G.A D85N Missense KCNQ1 1552C.T R518X Nonsense KCNQ1 1927G.A G643S Missense KCNH2 1899C.A N633K Missense SCN5A 3578G.A R1193Q Missense KCNQ1 1637C.T S546L Missense KCNH2 2861G.A R954H Missense SCN5A 5963T.G L1988R Missense a Number of subjects who had a risk score (point) of left-sided one. b Number of subjects who had genetic testing. c Number of subjects whose mutation was identified. d These girls were sisters but they visited the centre after screening. LQTS in subjects without further examination, suggesting that the probability of diagnosing LQTS may be higher. Another limitation is that there was a difference in the prevalence of a high probability of LQTS among calendar years (Tables 3 and 4). The reasons for this difference are unknown. All of the QTc values were automatically evaluated by ECG machines and manually evaluated by paediatric cardiologists. The reason for the difference in the prevalence of a high probability of LQTS among calendar years should be further examined. Implications of the present study are that the probability of diagnosing LQTS could be used as reference data in the era of the presence of a screening system for heart diseases. Cost-effective studies are required for an ECG-based screening system for heart diseases. The present study shows one of the most important model input variables, the probability of diagnosing LQTS in children and adolescents, in a cost-effective analysis for the prevention of sudden cardiac death. 16,17 To perform a cost-effective analysis of an ECG screening system, we need to know the probability of diagnosing LQTS in the general population and the cumulative prevalence of symptoms in subjects who are screened for the two major causes of sudden cardiac death in the young: LQTS and hypertrophic cardiomyopathy. Therefore, the cumulative prevalence of symptoms in subjects with LQTS, and the prevalence of hypertrophic cardiomyopathy and cumulative prevalence of symptoms in the subjects with hypertrophic cardiomyopathy who are screened need to be further determined. Conclusions This study shows important data on the probability of diagnosing LQTS as 1:3300 in subjects aged 6 years and 1:1000 in those aged 12 years based on the HRS/EHRA/APHRS criteria. Supplementary material Supplementary material is available at European Heart Journal online. Authors contributions M.Y. and H.O. performed statistical analysis. M.Y. handled funding and supervision. M.Y., Y.K., M.N., and Y.N. acquired the data. M.Y., Y.K., M.N., and Y.N. conceived and designed the research. M.Y. drafted the manuscript. M.Y., Y.K., M.N., and Y.N. made critical revision of the manuscript for key intellectual content. Y.K. performed genetic testing.

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