An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

The mental health of adolescents and pre-adolescents living with inherited arrhythmia syndromes: a systematic review of the literature.

Potentially fatal arrhythmias add to the mental health challenges of adolescence. This systematic review sought to summarise current knowledge regarding the mental health of adolescents and pre-adolescents diagnosed with inherited arrhythmia syndromes. Searches combining psychological problems with inherited cardiac arrhythmia diagnoses identified 16 studies with paediatric (<18 years) inherited arrhythmia patients. All studies were cross-sectional; 8/16 required an implantable cardioverter defibrillator. Methods were quantitative (n=11), qualitative (n=4), or mixed (n=1), with 14-100% of participants having an inherited arrhythmia syndrome. Mean/median age in 13/16 studies was 12-16 years. Patients and parents reported lower quality of life, particularly in relation to physical function, social relationships, restriction of peer activities, bodily pain, and mental and emotional health. Self-perceptions and behaviour were similar to healthy populations. Rates of anxiety and depression (15-33% of these patients) were not increased in these studies where patients were assessed 2+ years after diagnosis. Higher mental health risk occurred among patients who have a diagnosed sibling, those with cardiomyopathy, and those who report decreased quality of life. Mental health research among youth with inherited arrhythmias is extremely limited and of low quality. Data, primarily from patients 2-4 years after diagnosis or treatment with an implantable cardioverter defibrillator, indicate that quality of life may be decreased and 15-33% experience mental health issues. Future research is required to examine the mental health and quality of life of paediatric patients with inherited arrhythmia syndromes, whether or not they have an implantable cardioverter defibrillator, from time of diagnosis.

A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.

BACKGROUND: Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported mutations within a voltage sensor S4 transmembrane segment and few that are homozygous. Here we report analysis of a novel lidocaine-sensitive recessive mutation, p.R1309H, in the NaV1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome. METHODS AND RESULTS: We expressed the wild type or mutant NaV1.5 heterologously for analysis with the patch-clamp and voltage clamp fluorometry (VCF) techniques. p.R1309H depolarized the voltage-dependence of activation, hyperpolarized the voltage-dependence of inactivation, and slowed recovery from inactivation, thereby reducing the channel availability at physiologic membrane potentials. Additionally, p.R1309H increased the "late" Na(+) current. The location of the mutation in DIIIS4 prompted testing for a gating pore current. We observed an inward current at hyperpolarizing voltages that likely exacerbates the loss-of-function defects at resting membrane potentials. Lidocaine reduced the gating pore current. CONCLUSIONS: The p.R1309H homozygous NaV1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism.

Vital signs after cardiac arrest following withdrawal of life-sustaining therapy: a multicenter prospective observational study.

OBJECTIVE: Controversies regarding the process and timing of the determination of death for controlled organ donation after circulatory death persist. This study assessed the feasibility of conducting a prospective, observational study of continuous monitoring of vital signs for 30 minutes after the clinical determination of death in five Canadian ICUs. Waveform data were analyzed. DESIGN: Prospective observational cohort study. SETTING: One pediatric and four adult Canadian ICUs. PATIENTS: One month of age or older, admitted to the ICU, and for whom a consensual decision to withdraw life-sustaining therapies had been made, with an anticipation of imminent death. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Invasive arterial blood pressure, electrocardiogram, and oxygen saturation plethysmography activity were recorded and reviewed for 30 minutes after declaration of death. Feasibility was assessed (recruitment, consent rate, protocol compliance, and staff satisfaction). Of 188 subjects screened over 16 months, 41 subjects were enrolled (87% consent rate). Data collection was complete for 30 subjects (73% protocol compliance). In four subjects, arterial blood pressure resumed following cessation of activity. The longest period of cessation of arterial blood pressure before resumption was 89 seconds. The duration of resumed activity ranged from 1 to 172 seconds. No cases of sustained resumption of arterial blood pressure activity were recorded, and no instances of clinical autoresuscitation were reported. In nearly all patients (27 of 30), electrocardiogram activity continued after the disappearance of arterial blood pressure. CONCLUSIONS: This is the first observational study to prospectively collect waveform data for 30 minutes after the declaration of death. A future larger study may support initial data suggesting that circulatory function does not resume after more than 89 seconds of absence. Furthermore, persistence of cardiac electrical activity with the documented absence of circulation may not be relevant to declaration of death.

Pacemaker therapy of postoperative arrhythmias after pediatric cardiac surgery.

OBJECTIVE: To summarize the practical operation of temporary pacemakers in common use pertinent to the intensivist caring for the postcardiac patient. Pacemaker therapy is commonly required in the postoperative period after congenital cardiac surgery. DATA SYNTHESIS: Monitoring the hemodynamic status and availability of equipment for resuscitation is always important in any patient requiring a temporary pacemaker. Two important scenarios to consider in the pediatric intensive care unit are: 1) the patient in whom pacing has been initiated to optimize cardiac function; and 2) the patient without demonstrable spontaneous electrical activity or with extreme bradycardia. A number of different models of temporary pacemaker are available. Management of the child requiring cardiac pacing requires an understanding of the indications for pacing, a thorough knowledge of the available pacemaker, and an ability to troubleshoot problems. CONCLUSIONS: As the most common arrhythmias post congenital cardiac surgery involve either rate or conduction abnormalities, temporary pacemaker systems are a common form of electrical therapy in the postoperative period.

The measurement of the QT and QTc on the neonatal and infant electrocardiogram: a comprehensive reliability assessment.

BACKGROUND: An electrocardiogram has been proposed to screen for prolonged QT interval that may predispose infants to sudden death in the first year of life. Understanding the reliability of QT interval measurement will inform the design of a screening program. METHODS: Three pediatric cardiologists measured the QT/RR intervals on 60 infant electrocardiograms (median age 46 days), from leads II, V5 and V6 on three separate occasions, 7 days apart, according to a standard protocol. The QTc was corrected by Bazett's (QTcB), Fridericia's (QT(CFrid)), and Hodges' (QTcH) formulae. Intraobserver and interobserver reliability were assessed by intraclass correlation coefficients (ICC), limits of agreement and repeatability coefficients for single, average of two and average of three measures. Agreement for QTc prolongation (> 440 msec) was assessed by kappa coefficients. RESULTS: QT interval intraobserver ICC was 0.86 and repeatability coefficient was 25.9 msec; interobserver ICC increased from 0.88 for single observations to 0.94 for the average of 3 measurements and repeatability coefficients decreased from 22.5 to 16.7 msec. For QTcB, intraobserver ICC was 0.67, and repeatability was 39.6 msec. Best interobserver reliability for QTcB was for the average of three measurements (ICC 0.83, reproducibility coefficient 25.8 msec), with further improvement for QTcH (ICC 0.92, reproducibility coefficient 16.69 msec). Maximum interobserver kappa for prolonged QTc was 0.77. Misclassification around specific cut points occurs because of the repeatability coefficients. CONCLUSIONS: Uncorrected QT measures are more reliable than QTcB and QT(CFrid). An average of three independent measures provides the most reliable QT and QTc measurements, with QTcH better than QTcB.

Stress reactivity in healthy child offspring of parents with anxiety disorders.

Several studies suggest that anxiety disorders (AD) involve dysregulation of the autonomic nervous system (ANS) and hypothalamic-pituitary (HPA) axis. However, it is unknown if alterations in these biological systems are premorbid markers of AD risk or a state-dependent feature of anxiety. This study examined ANS and HPA-axis response to a laboratory stressor in healthy child offspring of parents with (n = 55) and without (n = 98) a history of AD. High frequency heart rate variability (HF-HRV) was assessed during sitting and standing baseline conditions and during a speech task where participants remained standing. Salivary cortisol was measured at baseline and at 15, 30, 45 and 60 min post-speech. Subjective anxiety was assessed with a visual analogue scale. Children of parents with AD displayed reduced HRV and a blunted cortisol response to the speech task compared to children of non-anxious parents. No risk group effect was found for anxiety ratings. These preliminary data suggest that healthy children of anxious parents exhibit altered stress reactivity to an acute laboratory stressor. Further research is needed to confirm findings and identify mechanisms that may account for altered self-regulation processes to a stressor in children at familial risk for AD.

A review of five cardiology journals found that observer variability of measured variables was infrequently reported.

OBJECTIVE: To investigate the reporting of the analysis of interobserver and intra-observer variability within clinical research studies from five high-impact cardiology journals published in 2005. STUDY DESIGN AND SETTING: A cross-sectional study using a combined electronic and manual search identified 180 of 511 eligible articles that reported the assessment of observer variability. Sixty of these were randomly selected for detailed review. RESULTS: The proportion of the 60 studies reporting interobserver variability, intra-observer variability, or both were 27%, 17%, and 53%, respectively. The reported methodological design of interobserver and intra-observer analyses included a specific protocol in 42% and 33%, identified observers as independent in 31% and 17%, as blinded in 50% and 31%, and identified a prior statistical plan in only 33% and 36%, respectively. Pearson correlation was the most reported measure for continuous variables, and the methods of Bland and Altman were reported in 15% of interobserver and 14% of intra-observer studies, respectively. For categorical variables, a kappa statistic was reported in 82% and 80%, respectively. CONCLUSION: Reliability assessment is hampered by unclear and incomplete reporting of interobserver and intra-observer analysis. For continuous variables, inappropriate methods were most frequently reported as being done.

Discrepant DNA analysis in three patients with inherited arrhythmia: molecular genetic test results deserve a second glance.

Molecular results provide a basis for diagnosis, risk assessment, medical management and genetic counseling. Unlike other areas of laboratory medicine, molecular genetic tests are rarely repeated. We describe three patients with suspected inherited arrhythmia in whom genetic testing was arranged via clinical and/or research laboratories. In all three instances, initial test results appeared falsely negative, with no deleterious mutations detected by various methodologies in selected long-QT or catecholaminergic polymorphic ventricular tachycardia-related genes. Discordant results emerged upon repeat analysis in separate laboratories. The cases highlight the importance of clinical judgment and assessment of genetic test results and methodology, in addition to the role of re-testing in molecular genetic medicine, particularly in the case of uninformative negative results.

Molecular autopsy in the sudden cardiac death of a young woman: a first Canadian report.

Standard autopsy of young victims with sudden cardiac death commonly does not identify a specific pathological diagnosis. In such cases, sudden cardiac death may be secondary to a genetic condition predisposing the patient to ventricular arrhythmias. Failure to identify a genetic etiology for an unexpected sudden death may leave surviving family members at risk for a similar tragedy. The case of a 21-year-old woman who died suddenly while at rest is presented. Molecular genetic analysis of tissue retrieved from the regional coroner's office identified a novel missense mutation in the KCNH2 gene, a gene known to cause the long QT syndrome.

Evaluation of computerized interpretation of the pediatric electrocardiogram.

The purpose of this research was to determine the frequency and factors affecting disagreement between pediatric cardiologist (MD1 or MD2) and the computer-assisted interpretation (CAI) of pediatric electrocardiograms from patients with heart disease (HD, n = 586) or normal heart (n = 561). Significant disagreement was found in HD (146/586, 25%) compared with normal heart (64/561, 11%) (P < .001). The CAI overinterpreted prolonged QT, sinus rhythm with ectopy, and right ventricular hypertrophy; CAI underinterpreted sinus rhythm, sinus arrhythmia, and right bundle branch block (P < .05). Increased disagreement was independently associated with HD (odds ration [OR], 2.2), younger patient age at the time of the electrocardiogram, if the computer interpretation had more than 3 separate diagnostic statements (OR, 3.2) and if the overreading cardiologist was MD1 (OR, 2.9). Although CAI is helpful, pediatric cardiologists were more likely to disagree with the computer in rhythm diagnosis, recognition of bundle branch block, hypertrophy, and QT interval analysis.

Sudden cardiac death in children and adolescents between 1 and 19 years of age.

BACKGROUND: Understanding pediatric sudden cardiac death (SCD) may inform age-specific prevention strategies. OBJECTIVE: To characterize potential underlying causes of SCD in children and adolescents METHODS: We performed a retrospective population-based study in Ontario, Canada, of all SCD cases in a 5-year period (2005-2009) involving persons aged 1-19 years identified from the comprehensive database of the Office of the Chief Coroner. Of 1204 coroner's cases, 351 potential SCD cases were reviewed. RESULTS: Of 116 cases of adjudicated SCD, there was no identifiable cause of death in 60 (52%). The majority were males (66%), and median age was 12.7 years. The incidence of SCD was greatest between 1 and 2 years (3.14 per 100,000 person-years), decreased, and then increased to 1.01 per 100,000 person-years (15-19 years). Autopsy findings were normal in 29 of 35 (83%) of children younger than 5 years and were more likely to be abnormal in those 10 years and older (odds ratio 9.0; 95% confidence interval 3.3-24.9). In 9%, the pathology findings may be of uncertain significance. Most events occurred in the home (68%). Activity level at the time of the event was associated with both age group (χ(2) = 34.9; P < .001) and autopsy findings (χ(2) = 28.9; P < .001). Events during moderate or vigorous activity were more common in those older than 10 years 16 of 66 (24%), and the majority had abnormal autopsy findings 13 of 18 (72%). DISCUSSION: Death in the very young is often caused by presumed primary arrhythmia syndromes, and death during exertion is typically seen in those with structural heart disease. CONCLUSION: These differences should inform age-specific diagnostic and prevention strategies.

Procainamide infusion in the evaluation of unexplained cardiac arrest: from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER).

BACKGROUND: Provocative testing with sodium channel blockers is advocated for the evaluation of unexplained cardiac arrest (UCA) with the primary purpose of unmasking the typical ECG features of Brugada syndrome. The Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) systematically assesses subjects with UCA or a family history of sudden death (FHSD). OBJECTIVE: The purpose of this study was to determine the clinical yield of procainamide infusion in a national registry of subjects with either UCA or a FHSD. METHODS: Subjects with either UCA or a FHSD without evidence of a Brugada pattern at baseline underwent procainamide testing (15 mg/kg to a maximum of 1 g at 50 mg/min). A test was considered positive for Brugada pattern if there was an increase in ST elevation >1 mm or if there was >1 mm of new ST elevation in leads V1 and/or V2. Genetic testing was performed on the basis of phenotype detection. RESULTS: Procainamide testing was performed in 174 subjects (age 46.8 ± 15.4 years, 47% female). Testing provoked a Brugada pattern in 12 subjects (6.9%), 5 of whom had no ST abnormalities at baseline. No subjects with a negative procainamide challenge were subsequently diagnosed with Brugada syndrome. Genetic testing was conducted in 10 of the 12 subjects with a provoked Brugada pattern and was positive for a mutation in the SCN5A gene in 1. CONCLUSION: Irrespective of the baseline ECG, procainamide testing provoked a Brugada pattern in a significant proportion of subjects with UCA or a FHSD, thereby facilitating a diagnosis of Brugada syndrome, and is recommended in the workup of UCA.

Activity intensity during free-living activities in children and adolescents with inherited arrhythmia syndromes: assessment by combined accelerometer and heart rate monitor.

BACKGROUND: International guidelines recommend restriction of activities for many children and adolescents with inherited arrhythmia syndromes to moderate activity (<7 metabolic equivalents [METs]). We hypothesized that moderate levels of intensity would be exceeded during free-living daily activity in these individuals when assessed objectively by combined heart rate and accelerometry monitor (Actiheart). METHODS AND RESULTS: Participants wore the Actiheart for ≤7 days on 2 occasions after a maximal exercise test that was used to calibrate the monitor individually against intensity levels. Of 16 participants, 13 (81%) had long QT syndrome, 9 (56%) were female, and median age was 12 years. Monitors were worn for a median (range) of 13 (6-14) days, and a mean (SD) of 11.3 (1.7) hours per day. Vigorous (7 MET) and very vigorous (10 MET) thresholds were exceeded by 15 and 13 participants, respectively. The median (interquartile range), individual, total weekly time spent >7 MET threshold was 113 (65-330) minutes, whereas such time spent >10 MET threshold was 53 (9-115) minutes. Total time>7 MET threshold was 2.3% of monitor wear time. There were no differences in time above threshold between male and female participants (P=0.357) or among those with different levels of activity restriction (P=0.769). CONCLUSIONS: Current recommended activity guidelines are frequently exceeded during routine free-living activities in young participants with inherited arrhythmia syndromes. Whether this indicates increased risk for these individuals or excessively restrictive guidelines remains to be determined.

Lone atrial fibrillation in the pediatric population.

BACKGROUND: There are few reports of pediatric studies of atrial fibrillation (AF). We sought to describe the clinical characteristics, management strategies, and recurrence rates and to identify predictors of AF recurrence in a contemporary pediatric population. METHODS: A retrospective review was performed of patients ≤ 18 years with lone AF who were seen at 4 pediatric institutions from 1996-2011. Patients with AF in the setting of thyroid disease, ventricular pre-excitation, coexisting congenital heart disease, or a history of cardiac surgery were excluded. Demographics, clinical presentation, investigations, treatment, and follow-up were analyzed. RESULTS: Forty-two patients were diagnosed with a first episode of lone AF, and 4 of these cases were later classified as persistent AF. Thirty-one (74%) were male patients, median age was 15.3 years, and median (interquartile range [IQR]) duration of AF episode was 12 (IQR, 7-24) hours. AF recurred in 39% (15 of 38) of patients. The Kaplan-Meier median time to estimated recurrence was 19 months. By univariate analysis, initial AF episode duration was associated with a higher risk of recurrence (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1-1.02; P = 0.034). Sex, age, family history, size of the left atrium, and history of cardioversion were not associated with recurrence. Recurrence with another supraventricular tachyarrhythmia (SVT) was observed in 6 of 38 (16%) patients, and 12 patients underwent electrophysiology (EP) study, with 6 patients receiving ablation. CONCLUSIONS: Our reported rate of recurrence of 39% is important when counseling pediatric patients and their parents on the expected course and treatment goals.

Scope and nature of sudden cardiac death before age 40 in Ontario: a report from the cardiac death advisory committee of the office of the chief coroner.

BACKGROUND: Understanding sudden cardiac death in the young may inform prevention strategies. OBJECTIVE: To determine the scope and nature of sudden death in a geographically defined population. METHODS: We performed a retrospective population-based cohort study in Ontario, Canada, of all sudden cardiac death cases involving persons aged 2-40 years identified from the 2008 comprehensive Coroner database. Of 1741 Coroner's cases, 376 were considered potential sudden cardiac death cases and underwent review. RESULTS: There were 174 cases of adjudicated sudden cardiac death from a population of 6,602,680 persons aged 2-40 years. Structural heart disease was present in 126 cases (72%), 78% of which was unrecognized. There was no identifiable cause of death in 48 cases (28%), representing primary arrhythmia syndromes. The majority of decedents were men (76%) over the age of 18 (90%). The overall incidence of sudden cardiac death increased with age from 0.7/100,000 (2-18 years) to 2.4/100,000 (19-29 years) to 5.3/100,000 (30-40 years) person-years. Persons experiencing sudden cardiac death before age 30 were more likely to have a primary arrhythmia syndrome (odds ratio 2.97; P<.001). The majority of events occurred in the home (72%); 33% of the events in children/adolescents and 9% of the events in adults occurred during reported moderate or vigorous exercise (P = .002). There were no pediatric deaths during organized competitive sports. CONCLUSIONS: The incidence of sudden cardiac death increases with age, typically occurring in a man at rest in the home with unrecognized underlying heart disease or a primary arrhythmia syndrome. Prevention strategies should consider targeting identification of unrecognized structural heart disease and primary arrhythmia syndromes.

Charting a course for cardiac electrophysiology training in Canada: the vital role of fellows in advanced cardiovascular care.

Canadian electrophysiology (EP) fellowship programs have evolved in an ad hoc fashion over 30 years. This evolution has occurred in many fields in medicine and is natural when innovators and pioneers attract research fellows who help change the status quo from predominantly research to a predominantly clinical application and focus. Fellows not only push their supervisors and their centres into new areas of inquiry but also function at the most advanced level to encourage and teach junior trainees and to provide examples of excellence to residents, medical students, and other health professionals. Funding for fellows has never been provided in the traditional way through the Ministry of Health or the Ministry of Advanced Education. Each Canadian centre has over the years found novel ways to fund fellowship programs, and many centres have used value-adds from procurement programs. These sources of funding are eroding as provincial government agencies are beginning to assume procurement responsibilities and local flexibility to fund fellowships is lost. In particular, provincial government agencies feel that valuable financial resources should be restricted to Canadian trainees only, despite the international consensus that fellowship is an essential time for advanced trainees to travel abroad to acquire a broad a range of experience, learn new techniques and approaches, make lifelong research connections, and hopefully return home with these skills and expertise. This article summarizes the long history of EP fellowship training in Canada, as well as EP fellowship experiences at home and abroad by Canadian electrophysiologists, in an attempt to contextualize these new realities.