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 Impact of the Auckland Cellulitis Pathway on Length of Hospital Stay, Mortality Readmission Rate, and Antibiotic Stewardship.

BACKGROUND: The Dundee classification of cellulitis severity, previously shown to predict disease outcomes, provides an opportunity to improve the management of patients with cellulitis. METHODS: We developed and implemented a pathway to guide the management of adults with cellulitis based on their Dundee severity class, and measured its effect on patient outcomes. We compared the outcomes in patients admitted to Auckland City Hospital (ACH) between July 2014 and July 2015 (the baseline cohort) with those in patients admitted between June 2017 and June 2018 (the intervention cohort). RESULTS: The median length of stay was shorter in the intervention cohort (0.7 days, interquartile range (IQR) 0.1 to 3.0 days) than in the baseline cohort (1.8 days, IQR 0.1 to 4.4 days; P < .001). The 30-day mortality rate declined from 1.8% (19/1092) in the baseline cohort to 0.7% (10/1362; P = .02) in the intervention cohort. The 30-day cellulitis readmission rate increased from 6% in the baseline cohort to 11% (P < .001) in the intervention cohort. Adherence to the ACH cellulitis antibiotic guideline improved from 38% to 48% (P < .01) and was independently associated with reduced length of stay. CONCLUSIONS: The implementation of the Auckland cellulitis pathway, readily generalizable to other settings, improved the outcomes in patients with cellulitis, and resulted in an annual saving of approximately 1000 bed days.

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.

Atrial Standstill in the Pediatric Population: A Multi-Institution Collaboration.

BACKGROUND: Atrial standstill (AS) is a rare condition characterized by absence of electrical activity within the atria. Studies to date have been limited. OBJECTIVES: The authors sought to describe the clinical characteristics, genetics, and outcomes of patients with AS. METHODS: This was a retrospective multicenter study of patients <18 years at AS diagnosis, defined as absence of atrial activity documented during an electrophysiology study, device placement, or noninvasive rhythm tracings and confirmed by echocardiogram. Patients with acquired disorders were excluded. Clinical details and genetic variants were recorded and analyzed. RESULTS: Twenty patients were diagnosed at a median age of 6.6 years (IQR: 2.9-10.8 years). Arrhythmias included 16 (80%) with atrial/supraventricular arrhythmias and 8 (40%) with ventricular tachycardia, including 4 with cardiac arrests. A type 1 Brugada pattern was documented in 4. Pacemakers were implanted in 18 (90%). Although atrial leads were attempted in 15, only 4 achieved pacing at implantation. During a median follow-up of 6.9 years (IQR: 1.2-13.3 years), 7 (35%) had thromboembolic events. Of these, none had atrial pacing, 6 were not on anticoagulation, and 1 was on aspirin. Genetic testing identified SCN5A variants in 13 patients (65%). Analyses suggest SCN5A loss-of-function may be one mechanism driving AS. Ventricular arrhythmias and cardiac arrest were more commonly seen in patients with biallelic SCN5A variants. CONCLUSIONS: AS may be associated with loss-of-function SCN5A variants. Patients demonstrate atrial and ventricular arrhythmias, and may present challenges during device placement. Patients without the capacity for atrial pacing are at risk for thromboembolic events and warrant anticoagulation.

Complications associated with revision of Sprint Fidelis leads: report from the Canadian Heart Rhythm Society Device Advisory Committee.

BACKGROUND: It has been observed that replacement of an implantable cardioverter-defibrillator generator in response to a device advisory may be associated with a substantial rate of complications, including death. The risk of lead revision in response to a lead advisory has not been determined previously. METHODS AND RESULTS: Twenty-five implantable cardioverter-defibrillator implantation and follow-up centers from the Canadian Heart Rhythm Society Device Advisory Committee were surveyed to assess complication rates as a result of lead revisions due to the Sprint Fidelis advisory issued in October 2007. As of June 1, 2009, there had been 310 lead failures found in 6237 Sprint Fidelis leads in Canada (4.97%) over a follow-up of 40 months. There were 469 leads to be revised, 66% for confirmed fracture. Of the patients who underwent revision, 95% had a new lead inserted, whereas 4% had a pace/sense lead added. The lead was removed in 248 cases (53%), by simple traction in 61% and by laser lead extraction in 33%. Complications were encountered in 14.5% of the lead revisions; 7.25% of these were major, whereas 7.25% were minor. There were 2 deaths (0.43%). The overall risk of complications (19.8%) was greater in those who underwent lead removal at the time of revision than in those whose leads were abandoned (8.6%; P=0.0008). CONCLUSIONS: The overall rate of major complications that arose from lead revision due to the Sprint Fidelis advisory was significant. This must be taken into account when lead revision is planned in those patients who have not yet demonstrated an abnormality in lead performance.

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.

Sudden death in a young man with catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial condition that presents with exercise-induced syncope or sudden death in children or young adults. In most cases the disease is caused by a mutation in the cardiac ryanodine receptor (RyR2) gene. Current evidence suggests that primary therapy for CPVT is beta blockade and implantable cardioverter defibrillator (ICD) placement. There is a recent report of a patient with CPVT who died despite appropriate ICD therapies, and we report a similar case. Our patient died after probably initially receiving inappropriate ICD shocks for atrial fibrillation. We recommend that utmost efforts should be made to prevent shocks including repeated exercise testing to confirm suppression of PVT.

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.

Electrocardiographic differentiation of typical atrioventricular node reentrant tachycardia from atrioventricular reciprocating tachycardia mediated by concealed accessory pathway in children.

The value of the electrocardiogram (ECG) in children with supraventricular tachycardia (SVT) is unclear. The noninvasive differentiation of typical atrioventricular node reentrant tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT) mediated by concealed accessory pathway conduction is clinically important, as it helps in counseling and potentially facilitates ablation procedures. One hundred forty-eight ECGs showing narrow QRS complex SVT were obtained from children before successful radiofrequency catheter ablation. An initial 102 ECGs were analyzed by 3 blinded observers to assess the utility of various electrocardiographic findings. No electrocardiographic criteria were found to discriminate between SVT mechanisms on 1- to 3-channel Holter/event recorder tracings (n = 32); their interpretation mainly (55%) resulted in an incorrect SVT diagnosis. On 12-lead ECGs (n = 70), the 2 arrhythmias were accurately diagnosed in 76% of patients; 5 findings were found to be discriminators of tachycardia mechanism. Predictors of AVRT were visible P waves in 74% of cases (sensitivity 92%; specificity 64%), RP intervals of > or =100 ms in 91% (sensitivity 84%; specificity 91%), and ST-segment depression of > or =2 mm in 73% of cases (sensitivity 52%; specificity 82%). Pseudo r' waves in lead V(1) and pseudo S waves in the inferior leads during tachycardia predicted AVNRT in 100% of cases (sensitivity 55% and 20%, respectively; specificity 100% for both). Based on these results, we developed a new diagnostic 12-lead electrocardiographic algorithm for pseudo r'/S waves, RP duration, and ST-segment depression during tachycardia. Two observers tested the algorithm in 46 (21 AVNRT; 25 AVRT) additional cases; they correctly diagnosed the SVT mechanism in 91% and 87%, respectively. Thus, the stepwise use of diagnostically relevant 12-lead electrocardiographic parameters helps to more accurately differentiate mechanisms of reentrant SVT.