Adolescence and Cardiac Channelopathies: Predicting Engagement in High-Risk Behavior

The purpose of the current study was to explore the type and frequency of engagement in low to high-risk behaviors in adolescents with cardiac channelopathies. Additionally, predictive factors of engagement in developmentally typical behaviors were explored. Individuals ages 13-22 (female = 84.6%; average age = 19.53) with cardiac channelopathies (n = 10) and without any chronic health conditions (n = 4) completed a series of questionnaires examining self-reported quality of life, illness perceptions, problem solving, and risk-taking behaviors. Findings demonstrated that adolescents with cardiac conditions believe that their conditions are controllable, and they experience a moderate amount of medically-related symptoms. Adolescents with and without cardiac channelopathies self-reported similar levels of quality of life. Adolescents with cardiac channelopathies had significantly better overall social problem solving skills than the control condition; in addition, they had better problem identification, solution evaluation, and reorganization skills than participants without cardiac channelopathies. Whether certain factors are predictive of engagement in risk-taking behaviors was unable to be examined, due to small sample size. There were no differences in risk-taking behaviors between participants with and those without cardiac channelopathies. However, participants with cardiac channelopathies self-reported engagement in behaviors that can impact their health. Future studies should continue to examine risk-taking within this medical population and identify variables that are predictive of risk-taking

Sudden Cardiac Death: Epidemiology, Pathogenesis and Management

Sudden cardiac death (SCD) is an unexpected sudden death due to a heart condition, that occurs within one hour of symptoms onset. SCD is a leading cause of death in western countries, and is responsible for the majority of deaths from cardiovascular disease. Moreover, SCD accounts for mortality in approximately half of all coronary heart disease patients. Nevertheless, the recent advancements made in screening, prevention, treatment, and management of the underlying causes has decreased this number. In this article, we sought to review established and new modes of screening patients at risk for SCD, treatment and prevention of SCD, and the role of new technologies in the field. Further, we delineate the current epidemiologic trends and pathogenesis. In particular, we describe the advancement in molecular autopsy and genetic testing, the role of target temperature management, extracorporeal membrane oxygenation (ECMO), cardiopulmonary resuscitation (CPR), and transvenous and subcutaneous implantable cardioverter devices (ICDs)

The role of genetic testing in unexplained sudden death.

Most sudden deaths are because of a cardiac etiology and are termed sudden cardiac death (SCD). In younger individuals coronary artery disease is less prevalent and cardiac genetic disorders are more common. If sudden death is unexplained despite an appropriate autopsy and toxicologic assessment the term sudden arrhythmic death syndrome (SADS) may be used. This is an umbrella term and common underlying etiologies are primary arrhythmia syndromes with a familial basis such as Brugada syndrome, long QT syndrome, and subtle forms of cardiomyopathy. The first clinical presentation of these conditions is often SCD, which makes identification, screening, and risk stratification crucial to avert further deaths. This review will focus on genetic testing in the context of family screening. It will address the role of the "molecular autopsy" alongside current postmortem practices in the evaluation of SADS deaths. We describe the current data underlying genetic testing in these conditions, explore the potential for next-generation sequencing, and discuss the inherent diagnostic problems in determination of pathogenicity

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40-50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype-phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype-phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families

Ethnic and racial differences in Asian populations with ion channelopathies associated with sudden cardiac death

Cardiovascular diseases are associated with several morbidities and are the most common cause of worldwide disease-related fatalities. Studies show that treatment and outcome-related differences for cardiovascular diseases disproportionately affect minorities in the United States. The emergence of ethnic and racial differences in sudden cardiac death (SCD) and related ion channelopathies complicates cardiovascular disease prevention, diagnosis, management, prognosis, and treatment objectives for patients and physicians alike. This review compiles and synthesizes current research in cardiac ion channelopathies and genetic disorders in Asian populations, an underrepresented population in cardiovascular literature. We first present a brief introduction to SCD, noting relevant observations and statistics from around the world, including Asian populations. We then examined existing differences between Asian and White populations in research, treatment, and outcomes related to cardiac ion channelopathies and SCD, showing progression in thought and research over time for each ion channelopathy. The review also identifies research that explored phenotypic abnormalities, device usage, and risk of death in Asian patients. We touch upon the unique genetic risk factors in Asian populations that lead to cardiac ion channelopathies and SCD while comparing them to White and Western populations, particularly in the United States, where Asians comprise approximately 7% of the total population. We also propose potential solutions such as improving early genetic screening, addressing barriers affecting access to medical care and device utilization, physician training, and patient education on risks

2020 APHRS/HRS Expert Consensus Statement on the Investigation of Decedents with Sudden Unexplained Death and Patients with Sudden Cardiac Arrest, and of Their Families.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families

High-risk features and predictors of unexplained syncope in the young SCD-SOS cohort

Introduction: The Sudden Cardiac Death-Screening of Risk FactOrS survey included a 12-lead ECG plus a digital-based questionnaire and aimed to screen for warning signs of diseases that may course with sudden cardiac death in children and young adults. We aimed to estimate the prevalence of unexplained syncope (US) and characterize its high-risk features and predictors in this cohort. // Methods &Results: We determined the most probable etiology of transient loss of consciousness (TLOC) episodes based on clinical criteria. US was an exclusion diagnosis and we analyzed its potential clinical and ECG predictors. Among 11,878 individuals, with a mean age of 21±6 (range 6-40) years-old, the cumulative incidence of TLOC was 26.5%, 76.2% corresponding to females. Reflex syncope was present in 66.4%, orthostatic hypotension in 8.2% and 14.8% of the individuals had US. Unexplained syncope was independently associated with age <18years-old (OR 1.695; 95%CI 1.26-2.29,p=0.001), male gender (OR 1.642; 95%CI 1.22-2.22,p=0.001), participation in competitive sports (OR 1.644;95%CI 1.01-2.66,p=0.043), syncope during exertion and/or palpitations preceding syncope (OR 2.556; 95%CI 1.92-3.40,p<0.001), syncope after exertion (OR 2.662; 95%CI 1.73-4.10,p<0.001), fever context (OR 9.606; 95%CI 4.13-22.34,p<0.001), isolated previous syncopal episode (OR 2.780; 95%CI 0.2.06-3.75,p<0.001) and history of palpitations requiring medical care (OR 1.945; 95%CI 1.14-3.31,p=0.014). We found no ECG predictors of US in this population. // Conclusions: The cumulative incidence of TLOC in children and young adults is high and remains unexplained in an important proportion of individuals. We identified eight clinical characteristics that may be useful for the risk stratification of individuals evaluated in a non-acute setting

Inherited calcium channelopathies in the pathophysiology of arrhythmias.

Regulation of calcium flux in the heart is a key process that affects cardiac excitability and contractility. Degenerative diseases, such as coronary artery disease, have long been recognized to alter the physiology of intracellular calcium regulation, leading to contractile dysfunction or arrhythmias. Since the discovery of the first gene mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2001, a new area of interest in this field has emerged-the genetic abnormalities of key components of the calcium regulatory system. Such anomalies cause a variety of genetic diseases characterized by the development of life-threatening arrhythmias in young individuals. In this Review, we provide an overview of the structural organization and the function of calcium-handling proteins and describe the mechanisms by which mutations determine the clinical phenotype. Firstly, we discuss mutations in the genes encoding the ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2). These proteins are pivotal to the regulation of calcium release from the sarcoplasmic reticulum, and mutations can cause CPVT. Secondly, we review defects in genes encoding proteins that form the voltage-dependent L-type calcium channel, which regulates calcium entry into myocytes. Mutations in these genes cause various phenotypes, including Timothy syndrome, Brugada syndrome, and early repolarization syndrome. The identification of mutations associated with 'calcium-handling diseases' has led to an improved understanding of the role of calcium in cardiac physiology

From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies.

In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1-3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype-phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials