Relationship between sodium channel function and clinical phenotype in SCN5A variants associated with Brugada syndrome.

The identification of a pathogenic SCN5A variant confers an increased risk of conduction defects and ventricular arrhythmias (VA) in Brugada syndrome (BrS). However, specific aspects of sodium channel function that influence clinical phenotype have not been defined. A systematic literature search identified SCN5A variants associated with BrS. Sodium current (INa ) functional parameters (peak current, decay, steady-state activation and inactivation, and recovery from inactivation) and clinical features (conduction abnormalities [CA], spontaneous VA or family history of sudden cardiac death [SCD], and spontaneous BrS electrocardiogram [ECG]) were extracted. A total of 561 SCN5A variants associated with BrS were identified, for which data on channel function and clinical phenotype were available in 142. In the primary analysis, no relationship was found between any aspect of channel function and CA, VA/SCD, or spontaneous BrS ECG pattern. Sensitivity analyses including only variants graded pathogenic or likely pathogenic suggested that reduction in peak current and positive shift in steady-state activation were weakly associated with CA and VA/SCD, although sensitivity and specificity remained low. The relationship between in vitro assessment of channel function and BrS clinical phenotype is weak. The assessment of channel function does not enhance risk stratification. Caution is needed when extrapolating functional testing to the likelihood of variant pathogenicity.

Systematic re-evaluation of SCN5A variants associated with Brugada syndrome.

BACKGROUND: A large number of SCN5A variants have been reported to underlie Brugada syndrome (BrS). However, the evidence supporting individual variants is highly heterogeneous. OBJECTIVE: We systematically re-evaluated all SCN5A variants reported in BrS using the 2015 American college of medical genetics and genomics and the association for molecular pathology (ACMG-AMP) guidelines. METHODS: A PubMed/Embase search was performed to identify all reported SCN5A variants in BrS. Standardized bioinformatic re-analysis (SIFT, PolyPhen, Mutation Taster, Mutation assessor, FATHMM, GERP, PhyloP, and SiPhy) and re-evaluation of frequency in the gnomAD database were performed. Fourteen ACMG-AMP rules were deemed applicable for SCN5A variant analysis. RESULTS: Four hundred and eighty unique SCN5A variants were identified, the majority of which 425 (88%) were coding variants. One hundred and fifty-six of 425 (37%) variants were classified as pathogenic/likely pathogenic. Two hundred and fifty-eight (60%) were classified as variants of uncertain significance, while a further 11 (3%) were classified as benign/likely benign. When considering the subset of variants that were considered "null" variants separately, 95% fulfilled criteria for pathogenicity/likely pathogenicity. In contrast, only 17% of missense variants fulfilled criteria for pathogenicity/likely pathogenicity. Importantly, however, only 25% of missense variants had available functional data, which was a major score driver for pathogenic classification. CONCLUSION: Based on contemporary ACMG-AMP guidelines, only a minority of SCN5A variants implicated in BrS fulfill the criteria for pathogenicity or likely pathogenicity.

Risk Stratification for Sudden Cardiac Death in Repaired Tetralogy of Fallot.

There has been significant progress in the prevention of sudden cardiac death in repaired tetralogy of Fallot. Contemporary cohorts report greater survival attributable to improved surgical techniques, heart failure management, and proactive strategies for risk stratification and management of ventricular arrhythmias including defibrillator implantation and ablation technology. Over the last 25 years, our understanding of predictive risk factors has also improved from invasive and more limited measures to individualized risk prediction scores based on extensive demographic, imaging, electrophysiological, and functional data. Although each of these contemporary scoring systems improves prediction, there are important differences between the study cohorts, included risk factors, and imaging modalities that can significantly affect interpretation and implementation for the individual patient. In addition, accurate phenotyping of disease complexity and anatomic repair substantially modulates this risk and the mechanism of sudden death. Routine implementation of risk stratification within repaired tetralogy of Fallot management is important and directly informs primary prevention defibrillator implantation as well as consideration for proactive invasive strategies including ventricular tachycardia ablation and pulmonary valve replacement. Assessment and risk stratification by a multidisciplinary team of experts in adult congenital heart disease are crucial and critical. Although we have increased understanding, reconciliation of these complex factors for the individual patient remains challenging and often requires careful consideration and discussion with multidisciplinary teams, patients, and their families.

De grands progrès ont été réalisés pour prévenir la mort subite d'origine cardiaque chez les patients ayant une tétralogie de Fallot réparée (TFr). Dans les cohortes contemporaines, l'amélioration du taux de survie peut être attribuée à l'évolution des techniques chirurgicales, à la prise en charge de l'insuffisance cardiaque et à la mise en place de stratégies proactives pour la stratification du risque d'arythmies ventriculaires et pour leur prise en charge, notamment par l'implantation de défibrillateurs et l'ablation. Au cours de 25 dernières années, les moyens utilisés pour caractériser les facteurs de risque à valeur prédictive sont passés de mesures limitées et invasives à l'établissement de scores individualisés basés sur de grands corpus de données démographiques, électrophysiologiques, fonctionnelles et d'autres issues de l'imagerie. Bien que chacun de ces systèmes contemporains d'évaluation du risque permette de raffiner notre capacité prédictive, des différences importantes entre les cohortes à l'étude, les facteurs de risque considérés et les modalités d'imagerie peuvent influencer l'interprétation des scores et les soins prodigués à un patient en particulier. De plus, la description phénotypique exacte de la complexité de la maladie et de la réparation anatomique permet de moduler la stratification du risque de mort subite d'origine cardiaque et son mécanisme possible. Il importe que la stratification du risque fasse partie intégrante de la prise en charge de la TFr puisqu'elle oriente directement le choix de mettre ou non en place un défibrillateur en prévention primaire, et qu'elle fasse partie de l'équation lorsque des stratégies invasives proactives, comme l'ablation de la tachycardie ventriculaire ou le remplacement de la valve pulmonaire, sont envisagées. La mesure et la stratification du risque par une équipe multidisciplinaire d'experts en cardiopathies congénitales sont donc des étapes cruciales. Même si les connaissances se sont affinées au fil du temps, il peut être difficile de faire la synthèse de ces facteurs complexes dans le cas d'un patient en particulier. C'est pourquoi il faut bien souvent se tourner vers l'équipe multidisciplinaire, le patient et ses proches pour évaluer rigoureusement les options.

Optimising Large Animal Models of Sustained Atrial Fibrillation: Relevance of the Critical Mass Hypothesis.

BACKGROUND: Large animal models play an important role in our understanding of the pathophysiology of atrial fibrillation (AF). Our aim was to determine whether prospectively collected baseline variables could predict the development of sustained AF in sheep, thereby reducing the number of animals required in future studies. Our hypothesis was that the relationship between atrial dimensions, refractory periods and conduction velocity (otherwise known as the critical mass hypothesis) could be used for the first time to predict the development of sustained AF. METHODS: Healthy adult Welsh mountain sheep underwent a baseline electrophysiology study followed by implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 50 Hz bursts of 30 s duration over an 8-week period whilst sheep were monitored for AF. RESULTS: Eighteen sheep completed the protocol, of which 28% developed sustained AF. Logistic regression analysis showed only fibrillation number (calculated using the critical mass hypothesis as the left atrial diameter divided by the product of atrial conduction velocity and effective refractory period) was associated with an increased likelihood of developing sustained AF (Ln Odds Ratio 26.1 [95% confidence intervals 0.2-52.0] p = 0.048). A receiver-operator characteristic curve showed this could be used to predict which sheep developed sustained AF (C-statistic 0.82 [95% confidence intervals 0.59-1.04] p = 0.04). CONCLUSION: The critical mass hypothesis can be used to predict sustained AF in a tachypaced ovine model. These findings can be used to optimise the design of future studies involving large animals.

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure.

Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two-AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.