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 clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry.

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

Palpitations, Dizziness, and Syncope in Teenage Girls: Practical Approach of a Pediatric Cardiologist.

Palpitations, dizziness, and syncope are common in seemingly healthy teenage girls. Unfortunately, these symptoms can raise significant concerns in the patient and family, present diagnostic challenges to health care providers, and result in unhelpful and expensive testing and unnecessary restrictions on the patient. The possibility of serious underlying pathology may prompt referral to pediatric subspecialists including cardiology. This article presents some relevant background principles and practical guidelines from the perspective of a pediatric cardiologist. Elements of initial personal and family medical history and physical examination often distinguish benign conditions from more nefarious ones, or direct limited additional testing that ultimately confirms the presence or absence of heart disease. In addition, whether these symptoms are due to a condition that is serious or benign, every patient can benefit from an intervention, sometimes simple education and reassurance, behavioral or dietary modifications, medications, invasive procedures, or referral to other health care providers. [Pediatr Ann. 2022;51(11):e440-e447.].

Medical Management of Infants With Supraventricular Tachycardia: Results From a Registry and Review of the Literature.

Background: Several medication choices are available for acute and prophylactic treatment of refractory supraventricular tachycardia (SVT) in infants. There are almost no controlled trials, and medication choices are not necessarily evidence based. Our objective was to report the effectiveness of management strategies for infant SVT. Methods: A registry of infants admitted to hospital with re-entrant SVT and no haemodynamically significant heart disease were prospectively followed at 11 international tertiary care centres. In addition, a systematic review of studies on infant re-entrant SVT in MEDLINE and EMBASE was conducted. Data on demographics, symptoms, acute and maintenance treatments, and outcomes were collected. Results: A total of 2534 infants were included: n = 108 from the registry (median age, 9 days [0-324 days], 70.8% male) and n = 2426 from the literature review (median age, 14 days; 62.3% male). Propranolol was the most prevalent acute (61.4%) and maintenance treatment (53.8%) in the Registry, whereas digoxin was used sparingly (4.0% and 3.8%, respectively). Propranolol and digoxin were used frequently in the literature acutely (31% and 33.2%) and for maintenance (17.8% and 10.1%) (P < 0.001). No differences in acute or prophylactic effectiveness between medications were observed. Recurrence was higher in the Registry (25.0%) vs literature (13.4%) (P < 0.001), and 22 (0.9%) deaths were reported in the literature vs none in the Registry. Conclusion: This was the largest cohort of infants with SVT analysed to date. Digoxin monotherapy use was rare amongst contemporary paediatric cardiologists. There was limited evidence to support one medication over another. Overall, recurrence and mortality rates on antiarrhythmic treatment were low.

Contexte: De nombreux choix de médicaments existent pour le traitement aigu et prophylactique de la tachycardie supraventriculaire (TSV) réfractaire chez les nourrissons. Or, il n'y a presque pas d'essais contrôlés à ce sujet, et les choix de médicaments ne sont pas nécessairement fondés sur des données probantes. Notre objectif était de faire état de l'efficacité des stratégies de prise en charge de la TSV chez les nourrissons. Méthodologie: Un registre des nourrissons admis à l'hôpital pour une TSV par réentrée, sans cardiopathie d'importance hémodynamique, a été tenu de façon prospective dans 11 centres de soins tertiaires à l'échelle mondiale. De plus, une revue systématique des études sur la TSV par réentrée chez le nourrisson a été effectuée dans MEDLINE et EMBASE. Des données sur les caractéristiques démographiques, les symptômes, les traitements aigus et d'entretien, et les résultats ont été recueillis. Résultats: Un total de 2 534 nourrissons ont été inclus : n = 108 du registre (âge médian de 9 jours [0-324 jours], 70,8 % de sexe masculin) et n = 2 426 de la revue de la littérature (âge médian de 14 jours; 62,3 % de sexe masculin). Le propranolol était le traitement de soins aigus (61,4 %) et d'entretien (53,8 %) le plus fréquent dans le registre, alors que la digoxine a été utilisée occasionnellement (respectivement dans 4,0 % et 3,8 % des cas). Dans la littérature, le propranolol et la digoxine étaient fréquemment utilisés en soins aigus (31 % et 33,2 %) et en traitement d'entretien (17,8 % et 10,1 %) (p < 0,001). Aucune différence n'a été observée entre les médicaments au chapitre de l'efficacité du traitement de soins aigus ou du traitement prophylactique. Le taux de récurrence était plus élevé dans le registre (25,0 %) que dans la littérature (13,4 %) (p < 0,001), et 22 (0,9 %) décès ont été signalés dans la littérature, mais aucun dans le registre. Conclusion: Il s'agit de la plus grande cohorte de nourrissons atteints de TSV analysée à ce jour. De nos jours, les cardiologues pédiatriques prescrivent rarement la digoxine en monothérapie. Peu de données probantes favorisent l'utilisation d'un médicament par rapport à l'autre. Dans l'ensemble, les taux de récurrence et de mortalité sous traitement antiarythmique étaient faibles.

Outcomes of Pediatric Patients With Defibrillators Following Initial Presentation With Sudden Cardiac Arrest.

BACKGROUND: Implantable cardioverter defibrillators (ICD) are recommended for secondary prevention after sudden cardiac arrest (SCA). The outcomes of pediatric patients receiving an ICD after SCA remain unclear. The objective of this study is to evaluate outcomes, future risk for appropriate shocks, and identify characteristics associated with appropriate ICD therapy during follow-up. METHODS: Multicenter retrospective analysis of patients (age ≤21 years) without prior cardiac disease who received an ICD following SCA. Patient/device characteristics, cardiac function, and underlying diagnoses were collected, along with SCA event characteristics. Patient outcomes including complications and device therapies were analyzed. RESULTS: In total, 106 patients were included, median age 14.7 years. Twenty (19%) received appropriate shocks and 16 (15%) received inappropriate shocks (median follow-up 3 years). First-degree relative with SCA was associated with appropriate shocks (P<0.05). In total, 40% patients were considered idiopathic. Channelopathy was the most frequent late diagnosis not made at time of presentation. Neither underlying diagnosis nor idiopathic status was associated with increased incidence of appropriate shock. Monomorphic ventricular tachycardia (hazard ratio, 4.6 [1.2-17.3]) and family history of sudden death (hazard ratio, 6.5 [1.4-29.8]) were associated with freedom from appropriate shock in a multivariable model (area under the receiver operating characteristic curve, 0.8). Time from diagnoses to evaluation demonstrated a nonlinear association with freedom from appropriate shock (P=0.015). In patients >2 years from implantation, younger age (P=0.02) and positive exercise test (P=0.04) were associated with appropriate shock. CONCLUSIONS: The risk of future device therapy is high in pediatric patients receiving an ICD after SCA, irrelevant of underlying disease. Lack of a definitive diagnosis after SCA was not associated with lower risk of subsequent events and does not obviate the need for secondary prophylaxis.

Management and outcomes of atrial fibrillation in 241 healthy children and young adults: Revisiting "lone" atrial fibrillation-A multi-institutional PACES collaborative study.

BACKGROUND: Atrial fibrillation (AF) in healthy children and young adults is rare. Risk of recurrence and treatment efficacy are not well defined. OBJECTIVE: The purpose of this study was to assess recurrence patterns and treatment efficacy in AF. METHODS: A retrospective multicenter cohort study including 13 congenital heart centers was facilitated by the Pediatric & Congenital Electrophysiology Society (PACES). Patients ≤21 years of age with documented AF from January 2004 to December 2018 were included. Demographics, family and clinical history, medications, electrophysiological study parameters, and outcomes related to the treatment of AF were recorded and analyzed. Patients with contributory diseases were excluded. RESULTS: In 241 subjects (83% male; mean age at onset 16 years), AF recurred in 94 patients (39%) during 2.1 ± 2.6 years of follow-up. In multivariable analysis, predictors of AF recurrence were family history in a first-degree relative <50 years of age (odds ratio [OR] 1.9; P = .047) and longer PR interval in sinus rhythm (OR 1.1 per 10 ms; P = .037). AF recurrence was similar whether patients began no treatment (39/125 [31%]), began daily antiarrhythmic therapy (24/63 [38%]), or had an ablation at any time (14/53 [26%]; P = .39). Ablating non-AF substrate with supraventricular tachycardia improved freedom from AF recurrence (P = .013). CONCLUSION: Recurrence of AF in the pediatric population is common, and the incidence of recurrence was not impacted by "no treatment," "medication only," or "ablation" treatment strategy. Ablation of pathways and other reentrant targets was the only intervention that decreased AF recurrence in children and young adults.

Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community.

Importance: The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death. Objective: To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families. Design, Setting, and Participants: Two large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019. Main Outcomes and Measures: The identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families. Results: A homozygous duplication, involving approximately 26 000 base pairs of intergenic sequence, RYR2's 5'UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests. Conclusions and Relevance: In this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning.

A Cautionary Tale on Atrial Capture Management, Biventricular Pacing, and Recurrent Asystole.

Capture management algorithms in current cardiac implantable electronic devices (CIEDs) can enhance device performance and battery longevity. Although generally safe, these algorithms have on rare occasions been implicated in the onset of significant complications, especially in pacemaker-dependent patients. CIEDs implanted in patients with postoperative congenital heart disease (CHD) often require epicardial pacing leads rather than transvenous leads; unfortunately, epicardial leads can experience higher rates of malfunction. We herein report on a young adult with a status of postoperative CHD and complete atrioventricular block following implantation of a epicardial dual-chamber cardiac resynchronization therapy pacemaker (CRT-P; Consulta®; Medtronic, Minneapolis, MN, USA) who developed frequent periods of asystole after malfunction of one of the ventricular leads. The underlying cause of asystole was found to be due to the atrial capture management (ACM) algorithm of the CRT-P device, temporarily converting biventricular to right ventricular-only pacing as part of the algorithm. This case highlights implications of the ACM algorithm in devices with a similar platform for pacemaker-dependent patients.

Ascites secondary to indolent pacemaker infection in a Fontan patient.

This report describes what we believe is the 1st reported case of indolent pacemaker infection's causing abdominal ascites in a patient who has undergone a Fontan operation. Abdominal ascites in a Fontan patient is commonly due to protein-losing enteropathy, systemic venous thrombosis, myocardial dysfunction, chylous ascites, liver cirrhosis, or pancreatitis. Our patient, who had a functional single ventricle, presented with ascites 3 years after undergoing the Fontan operation and pacemaker implantation. After extensive testing and evaluation, we attributed the ascites to indolent infection of the abdominal pacemaker.

Current approaches to catheter ablation for childhood tachycardia.

Many different types of tachycardia are seen throughout childhood, and the optimal management approach depends on the type of tachycardia and the impact and prognosis for each child. For many of these patients, the healthcare provider and family are faced with choosing between chronic medication to suppress tachycardia and catheter ablation to eliminate tachycardia. Widespread experience and significant technological advances over the last 2 decades have improved outcomes and reduced complications of ablation therapy in patients of all ages. At this time, catheter ablation is feasible, safe, and effective for most types of childhood tachycardia, and can be considered electively in children 6 years of age or older. Ablation can also be performed cautiously in infants and small children with difficult and medically refractory arrhythmias. Special modifications in equipment and techniques are required for ablation in the youngest patients and those with structural heart disease.

Transcatheter ablation of supraventricular tachycardia and closure of a large secundum ASD in a Jehovah's Witness.

This report describes successful radiofrequency ablation of typical atrioventricular (AV) node reentrant tachycardiafollowed by transcatheter closure of a large secundum atrial septal defect in a patient of the Jehovah's Witness faith. Both procedures were performed successfully during the same catheterization, without complication or need for blood transfusion.

Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is an uncommon, potentially lethal, ion channelopathy. Standard therapies have high failure rates and little is known about treatment in children. Newer options such as flecainide and left cardiac sympathetic denervation are not well validated. We sought to define treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia. METHODS AND RESULTS: This is a Pediatric and Congenital Electrophysiology Society multicenter, retrospective cohort study of catecholaminergic polymorphic ventricular tachycardia patients diagnosed before 19 years of age. The cohort included 226 patients, including 170 probands and 56 relatives. Symptomatic presentation was reported in 176 (78%). Symptom onset occurred at 10.8 (interquartile range, 6.8-13.2) years with a delay to diagnosis of 0.5 (0-2.6) years. Syncope (P<0.001), cardiac arrest (P<0.001), and treatment failure (P=0.008) occurred more often in probands. ß-Blockers were prescribed in 205 of 211 patients (97%) on medication, and 25% experienced at least 1 treatment failure event. Implantable cardioverter defibrillators were placed in 121 (54%) and was associated with electrical storm in 22 (18%). Flecainide was used in 24% and left cardiac sympathetic denervation in 8%. Six deaths (3%) occurred during a cumulative follow-up of 788 patient-years. CONCLUSIONS: This study demonstrates a malignant phenotype and lengthy delay to diagnosis in catecholaminergic polymorphic ventricular tachycardia. Probands were typically severely affected. ß-Blockers were almost universally initiated; however, treatment failure, noncompliance and subtherapeutic dosing were often reported. Implantable cardioverter defibrillators were common despite numerous device-related complications. Treatment failure was rare in the quarter of patients on flecainide. Left cardiac sympathetic denervation was not uncommon although the indication was variable.

The favorable impact of arrhythmia surgery on total cavopulmonary artery Fontan conversion.

Patients who have undergone atriopulmonary Fontan procedures are at risk for significant atrial arrhythmias and obstructive connections, which have been related to intra-atrial suture lines, atrial enlargement, and somatic growth. Twenty patients (mean age, 17.3 +/- 6.8 years) had conversion to total cavopulmonary artery connection 8.9 +/- 2.1 years after the previous Fontan procedure (for atrial arrhythmias in 19 patients and for obstructive lesions in one). Arrhythmia ablative surgery evolved over the study period from "arrhythmia circuit cryoablation" (cryoablation lesions completing lines of block) to the more standard approaches of modified right-sided Maze and Maze-Cox III procedures. Preoperative functional New York Heart Association class was IV in nine patients, III in nine, and II in two. All patients survived. Two patients had prolonged chest drainage (there was pericardial effusion in one). The average length of hospital stay was 11.3 +/- 5.4 days; chest tubes were removed on day 8.5 +/- 5.4. There were no long-term deaths (mean follow-up period, 20.3 +/- 14.9 months; range, 2 months to 4 years). Late postoperative arrhythmias occurred in two patients who are receiving long-term antiarrhythmic medications. All patients have improved to New York Heart Association class I or II. Total cavopulmonary artery Fontan conversion in association with modified right-sided Maze or Maze-Cox III procedures and pacemaker placement can be accomplished with low morbidity and mortality, and results in functional class improvement and control of life-threatening arrhythmias. Copyright 1999 by W.B. Saunders Company

Bidirectional Glenn with existing transvenous cardioverter-defibrillator leads.

The population of patients with adult congenital heart disease is increasing. A significant number of these patients already have or will require placement of either a transvenous pacemaker or implantable cardioverter defibrillator. In addition to this, some with right ventricular dysfunction might benefit from volume unloading of the right ventricle by the construction of a superior cavopulmonary anastomosis. The usual technique for the bidirectional Glenn anastomosis precludes the presence of upper extremity transvenous hardware. We present a modified technique for the superior cavopulmonary anastomosis when pacing or cardioverter defibrillator leads are present.

Location of accessory connection in infants presenting with supraventricular tachycardia in utero: clinical correlations.

The most common mechanism of fetal tachycardia is orthodromic reciprocating tachycardia utilizing an accessory atrioventricular connection, however, data regarding accessory connection location in patients with fetal tachycardia is limited. To investigate the location of accessory connections in fetal tachycardia, postnatal transesophageal electrophysiology studies were performed at one institution over a 10-year period in 24 infants with documented fetal tachycardia. The 18 infants with inducible orthodromic reciprocating tachycardia were grouped according to accessory connection location, and groups were compared regarding prenatal presentation and clinical course. Left-sided connections were found in 13 (72%) patients, while accessory connection location could not be determined in the remaining 5 (28%) patients. The presence of a left-sided accessory connection was associated with sustained tachycardia, depressed ventricular function, and the need for antiarrhythmic therapy in utero. No other difference in clinical or electrophysiologic data was found between groups. Our findings indicate that a high proportion of patients with fetal tachycardia have left-sided accessory connections, and a left-sided connection may adversely affect fetal hemodynamics and cardiac output.