Hypertrophic cardiomyopathy (HCM) was traditionally described as an autosomal dominant Mendelian disease but is now increasingly recognized as having a complex genetic aetiology. Although eight core ...genes encoding sarcomeric proteins account for >90% of the pathogenic variants in patients with HCM, variants in several additional genes (ACTN2, ALPK3, CSRP3, FHOD3, FLNC, JPH2, KLHL24, PLN and TRIM63), encoding non-sarcomeric proteins with diverse functions, have been shown to be disease-causing in a small number of patients. Genome-wide association studies (GWAS) have identified numerous loci in cardiomyopathy case-control studies and biobank investigations of left ventricular functional traits. Genes associated with Mendelian cardiomyopathy are enriched in the putative causal gene lists at these loci. Intriguingly, many loci are associated with both HCM and dilated cardiomyopathy but with opposite directions of effect on left ventricular traits, highlighting a genetic basis underlying the contrasting pathophysiological effects observed in each condition. This overlap extends to rare Mendelian variants with distinct variant classes in several genes associated with HCM and dilated cardiomyopathy. In this Review, we appraise the complex contribution of the non-sarcomeric, HCM-associated genes to cardiomyopathies across a range of variant classes (from common non-coding variants of individually low effect size to complete gene knockouts), which provides insights into the genetic basis of cardiomyopathies, causal genes at GWAS loci and the application of clinical genetic testing.
When genetic burden reaches threshold Walsh, Roddy; Tadros, Rafik; Bezzina, Connie R
European heart journal,
10/2020, Letnik:
41, Številka:
39
Journal Article
Recenzirano
Odprti dostop
Abstract
Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary ...causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.
The atrioventricular (AV) node generates half of the AV delay needed for blood pumping and filters atrial impulses that could otherwise induce life‐threatening ventricular arrhythmias. It is also a ...pacemaker and a key target in the treatment of cardiac arrhythmias. The special roles of the AV node primarily arise from its slow conduction, long refractory period, and cellular automaticity. However, efforts to establish the dynamics of these properties and their interaction led to many controversies. In fact, the AV node's behavior is so complex that it seems to escape broadly applicable rules. This review summarizes progresses made in resolving these issues and in integrating the multiple roles of the AV node within a common functional model. Presented evidence shows that the rate‐dependent conduction and refractory properties of the AV node can be reliably characterized and reconciled from nodal responses to S1S2S3 protocols. It also supports the concept that dual pathways constitute a feature of the normal AV node and account for its overall conduction and refractory properties. In this model, the posterior extension and compact node provide the core of the slow and fast pathway, respectively. The transitional tissues and lower nodal bundle provide a common proximal and distal pathway, respectively. These pathways would also support bidirectional conduction. The dual pathway involvement can also be extended to widely variable AV nodal responses, such as Wenckebach cycles, hysteresis, and ventricular response to atrial fibrillation. In brief, the intricate AV nodal behavior may obey a limited set of accessible and definable rules.
Abstract Sex differences in cardiac electrophysiological properties and arrhythmias are evident in epidemiologic and investigative studies as well as in daily patient care. At the supraventricular ...level, women are at increased risk of sick sinus syndrome and atrioventricular (AV) node re-entrant tachycardia, whereas men manifest more AV block and accessory pathway–mediated arrhythmias. At the ventricular level, women are generally at higher risk of long QT–associated arrhythmias, whereas men are more likely to present with early repolarization, idiopathic ventricular fibrillation, and Brugada syndromes. Great advances have been made in unraveling the fundamental mechanisms underlying sex differences in ventricular arrhythmias, particularly those associated with abnormal repolarization. Conversely, the basis for male-predominant arrhythmia risk in structural heart disease and differences in supraventricular arrhythmia susceptibility are poorly understood. Beyond biological differences, arrhythmia occurrence and patient care decisions are also influenced by gender-related factors. This article reviews the current knowledge regarding the nature and underlying mechanisms of sex differences in basic cardiac electrophysiology and clinical arrhythmias.
The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts ...to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval QTc), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.
La pandémie de COVID-19 a donné lieu à des initiatives visant à accélérer l’étude et l’utilisation de médicaments susceptibles d’améliorer le pronostic des patients, mais dont l’innocuité et l’efficacité n’ont pas encore été établies. Les auteurs tentent de formuler des lignes directrices raisonnables quant à l’emploi d’agents antimicrobiens, notamment la chloroquine, l’hydroxychloroquine, l’azithromycine et l’association lopinavir-ritonavir, dont les bienfaits demeurent incertains, mais qui sont susceptibles d’accroître le risque d’allongement de l’intervalle QT et de proarythmie ventriculaire. Durant la pandémie, les efforts visant à limiter la propagation de la maladie et à atténuer au minimum les tensions exercées sur les ressources en soins de santé commandent une restriction des interventions médicales et des tests non nécessaires. Pour que le risque de proarythmie médicamenteuse demeure au plus bas, nous recommandons les mesures suivantes : 1) arrêter l’administration de médicaments non nécessaires aussi susceptibles d’allonger l’intervalle QT; 2) déterminer qui sont les patients ambulatoires présentant un risque faible et n’ayant pas besoin de subir d’autres tests (absence d’antécédents d’allongement de l’intervalle QT ou de syncope inexpliquée, d’antécédents familiaux de mort cardiaque subite prématurée ou de traitement médicamenteux susceptible d’allonger l’intervalle QT, et/ou intervalle QT corrigé QTc normal connu); et 3) réaliser des examens initiaux chez les patients hospitalisés ou chez ceux qui sont exposés à un risque plus élevé. Si les examens électrocardiographiques initiaux révèlent un allongement modéré de l’intervalle QTc, un traitement pourrait être administré sous réserve de l’optimisation de la médication et de l’administration d’électrolytes. Si l’allongement de l’intervalle QTc est marqué, il faut éviter d’administrer des médicaments susceptibles d’allonger davantage cet intervalle, ou encore consulter un spécialiste pour pouvoir traiter le patient en prenant les précautions qui s’imposent. Ces recommandations sont formulées à l’heure où il n’existe encore aucun traitement efficace connu contre la COVID-19; il faudra les revoir lorsque d’autres données relatives à l’efficacité et à l’innocuité des agents en cause seront disponibles.
Abstract
Aims
The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous ...reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors.
Methods and results
We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. The diagnosis of SCVF was obtained in 19/24 (79%) individuals by documented ventricular fibrillation during follow-up. Ventricular arrhythmia was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control.
Conclusion
Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes.
Graphical Abstract
Short-coupled ventricular fibrillation (SCVF) is a distinct primary electrical disorder accounting for at least 6.6% of otherwise idiopathic VF. Quinidine is highly effective for SCVF.
Arrhythmia-induced cardiomyopathy (AIC) is characterized by left ventricular systolic dysfunction for which the primary cause is arrhythmia. The hallmark of AIC is its reversibility once the ...arrhythmia is properly controlled. Any tachyarrhythmia can potentially cause AIC (often called “tachycardiomyopathy”), with atrial fibrillation (AF) being by far the most common in clinical practice. The pathophysiological mechanisms underlying AIC need further clarification, but the available evidence, principally from animal models, implicates metabolic dysfunction due to increased oxygen requirements, neurohormonal adaptive mechanisms, and cellular Ca2+ mishandling as important contributors. Tachycardia is a common denominator of most cases of AIC, but other components specific to the patient and the arrhythmia have been implicated. The diagnosis of AIC requires the exclusion of a primary causative role of other conditions such as hypertension, primary cardiomyopathies, and valve disease, which may require specific pharmacological and invasive therapies. Catheter ablation is emerging as a safe and effective alternative to antiarrhythmic medication and has an established role in the management of AIC. Recent studies showing improved cardiac function and mortality rates in patients with heart failure and concomitant AF dramatically illustrate the often-unrecognized scope of AIC and the potential benefits of interventional therapy. Major AF trials do not otherwise focus specifically on AIC, and careful analysis of the literature is necessary to appreciate the clinical characteristics and therapeutic implications. This contemporary review summarizes the current understanding of pathophysiological mechanisms underlying AIC, discusses the clinical implications, and offers a general approach to management, with a particular focus on AF-induced cardiomyopathy.
La cardiomyopathie induite par l’arythmie (CIA) est caractérisée par la dysfonction systolique du ventricule gauche, dont la cause principale est l’arythmie. La caractéristique principale de la CIA est sa réversibilité dès que l’arythmie est bien maîtrisée. Toute tachyarythmie peut potentiellement causer une CIA (souvent appelée « tachycardiomyopathie »), y compris la fibrillation auriculaire (FA), qui est de loin la plus fréquente dans la pratique clinique. Les mécanismes physiopathologiques sous-jacents à la CIA doivent être clarifiés, mais les données probantes existantes, principalement celles des modèles animaux, montrent que la dysfonction métabolique due aux besoins accrus en oxygène, aux mécanismes adaptatifs neurohormonaux et aux anomalies cellulaires Ca2+ y a contribué de manière importante. La tachycardie est le dénominateur commun de la plupart des cas de CIA, mais d’autres éléments propres au patient et l’arythmie ont été mis en cause. Le diagnostic de CIA nécessite l’exclusion d’un rôle causal principal d’autres maladies telles l’hypertension, les cardiomyopathies primaires et les valvulopathies, qui peuvent exiger des traitements pharmacologiques et invasifs particuliers. L’ablation par cathéter s’impose comme une solution sûre et efficace aux antiarythmiques. Son rôle est établi dans la prise en charge de la CIA. De récentes études qui montrent l’amélioration de la fonction cardiaque et la réduction des taux de mortalité chez les patients atteints concomitamment d’insuffisance cardiaque et de FA illustrent de façon frappante l’ampleur souvent méconnue de la CIA et les avantages potentiels des traitements interventionnels. Les principaux essais sur la FA n’ont par ailleurs pas expressément porté sur la CIA; des analyses prudentes de la littérature sont nécessaires pour apprécier les caractéristiques cliniques et les retombées thérapeutiques. La présente revue contemporaine résumera les connaissances actuelles sur les mécanismes physiopathologiques sous-jacents à la CIA, traitera des retombées cliniques et proposera une approche générale de prise en charge, notamment en ce qui concerne la cardiomyopathie induite par la FA.
Abstract
Aims
Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced ...PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG).
Methods and results
In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose–response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P < 0.01 for all). PRSBrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline, and family history of BrS are independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74).
Conclusion
We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.
Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield ...and clinical utility of genetic testing in UCA using whole-exome sequencing (WES).
Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of 'explained' cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest.
Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.
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