Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies.
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ABSTRACT:
SUBMITTER: Magi S
PROVIDER: S-EPMC5556354 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Sudden cardiac death (SCD), a sudden pulseless condition due to cardiac arrhythmia, remains a major public health problem despite recent progress in the treatment and prevention of overall coronary heart disease. In this review, we examine the evidence for genetic susceptibility to SCD in order to provide biological insight into the pathogenesis of this devastating disease and to explore the potential for genetics to impact clinical management of SCD risk. Both candidate gene approaches and unbiased genome-wide scans have identified novel biological pathways contributing to SCD risk. Although risk stratification in the general population remains an elusive goal, several studies point to the potential utility of these common genetic variants in high-risk individuals. Finally, we highlight novel methodological approaches to deciphering the molecular mechanisms involved in arrhythmogenesis. Although further epidemiological and clinical applications research is needed, it is increasingly clear that genetic approaches are yielding important insights into SCD that may impact the public health burden imposed by SCD and its associated outcomes.
| S-EPMC3501725 | biostudies-literature
Project description:Purpose of reviewTo survey recent developments in the field of genetics encompassing discovery of new candidate genes, new diagnostic strategies, and new therapies for sudden cardiac death (SCD) syndromes.Recent findingsIn addition to new mutations in known SCD genes, several novel genes not previously implicated in SCD causation have been found, particularly in long QT syndrome (e.g., KCNJ5, AKAP9, SNTA1), idiopathic ventricular fibrillation (e.g., DPP6, KCNJ8), dilated cardiomyopathy (e.g., NEBL), and hypertrophic cardiomyopathy (HCM; e.g., NEXN). Genetic SCD animal models have provided novel insights into the cellular mechanism and pathogenesis of nearly all the major SCD syndromes, which has led to several new drug therapies for patients with genetic arrhythmia syndromes (e.g., flecainide in catecholaminergic polymorphic ventricular tachycardia). Furthermore, genetic contributions to acquired heart diseases are increasingly being recognized. For example, a 21q21 locus is strongly associated with ventricular fibrillation after myocardial infarction. Near this locus is CXADR, a gene encoding a viral receptor implicated in myocarditis and dilated cardiomyopathy. Finally, common variants in cardiac ion channels and proteins likely contribute to common cardiac phenotypes.SummaryMajor strides have been made in uncovering new genes, mechanisms, and syndromes that have significantly advanced the diagnosis and treatment of genetic SCD disorders.
| S-EPMC3145336 | biostudies-literature
Project description: Not available
| S-EPMC3399522 | biostudies-literature
Project description:Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ?11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.
| S-EPMC6988156 | biostudies-literature
Project description:Background Educating cardiologists and health care professionals about cardiovascular genetics and genetic testing is essential to improving diagnosis and management of patients with inherited cardiomyopathies and arrhythmias and those at higher risk for sudden cardiac death. The aim of this study was to understand cardiology and electrophysiology practitioners' current practices, confidence, and knowledge surrounding genetic testing in cardiology and desired topics for an educational program. Methods and Results A one-time survey was administered through purposive email solicitation to 131 cardiology practitioners in the United States. Of these, 107 self-identified as nongenetic practitioners. Over three quarters of nongenetic practitioners reported that they refer patients to genetic providers to discuss cardiovascular genetic tests (n=82; 76.6%). More than half of nongenetic practitioners reported that they were not confident about the types of cardiovascular genetic testing available (n=60; 56%) and/or in ordering appropriate cardiovascular genetic tests (n=66; 62%). In addition, 45% (n=22) of nongenetic practitioners did not feel confident making cardiology treatment recommendations based on genetic test results. Among all providers, the most desired topics for an educational program were risk assessment (94%) and management of inherited cardiac conditions based on guidelines (91%). Conclusions This study emphasizes the importance of access to genetics services in the cardiology field and the need for addressing the identified deficit in confidence and knowledge about cardiogenetics and genetic testing among nongenetic providers. Additional research is needed, including more practitioners from underserved areas.
| S-EPMC9075463 | biostudies-literature
Project description:Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention.
| S-EPMC4465108 | biostudies-literature
Project description:The prevention of sudden cardiac death (SCD) in cardiomyopathies (CM) remains a challenge. The current guidelines still favor the implantation of devices for the primary prevention of SCD only in patients with severely reduced left ventricular ejection fraction (LVEF) and heart failure (HF) symptoms. The implantation of an implantable cardioverter-defibrillator (ICD) is a protective barrier against arrhythmic events in CMs, but the benefit does not outweigh the cost in low risk patients. The identification of high risk patients is the key to an individualized prevention strategy. Cardiac magnetic resonance (CMR) provides reliable and reproducible information about biventricular function and tissue characterization. Furthermore, late gadolinium enhancement (LGE) quantification and pattern of distribution, as well as abnormal T1 mapping and extracellular volume (ECV), representing indices of diffuse fibrosis, can enhance our ability to detect high risk patients. CMR can also complement electro-anatomical mapping (EAM), a technique already applied in the risk evaluation and in the ventricular arrhythmias ablation therapy of CM patients, providing a more accurate assessment of fibrosis and arrhythmic corridors. As a result, CMR provides a new insight into the pathological substrate of CM. CMR may help identify high risk CM patients and, combined with EAM, can provide an integrated evaluation of scar and arrhythmic corridors in the ablative therapy of ventricular arrhythmias.
| S-EPMC7460122 | biostudies-literature
Project description:Arrhythmic sudden cardiac death (SCD) may be caused by ventricular tachycardia/fibrillation or pulseless electric activity/asystole. Effective risk stratification to identify patients at risk of arrhythmic SCD is essential for targeting our healthcare and research resources to tackle this important public health issue. Although our understanding of SCD because of pulseless electric activity/asystole is growing, the overwhelming majority of research in risk stratification has focused on SCD-ventricular tachycardia/ventricular fibrillation. This review focuses on existing and novel risk stratification tools for SCD-ventricular tachycardia/ventricular fibrillation. For patients with left ventricular dysfunction or myocardial infarction, advances in imaging, measures of cardiac autonomic function, and measures of repolarization have shown considerable promise in refining risk. Yet the majority of SCD-ventricular tachycardia/ventricular fibrillation occurs in patients without known cardiac disease. Biomarkers and novel imaging techniques may provide further risk stratification in the general population beyond traditional risk stratification for coronary artery disease alone. Despite these advances, significant challenges in risk stratification remain that must be overcome before a meaningful impact on SCD can be realized.
| S-EPMC4466101 | biostudies-literature
Project description:Although the occurrence of sudden cardiac death (SCD) in a young person is a rare event, it is traumatic and often widely publicized. In recent years, SCD in this population has been increasingly seen as a public health and safety issue. This review presents current knowledge relevant to the epidemiology of SCD and to strategies for prevention, resuscitation, and identification of those at greatest risk. Areas of active research and controversy include the development of best practices in screening, risk stratification approaches and postmortem evaluation, and identification of modifiable barriers to providing better outcomes after resuscitation of young SCD patients. Institution of a national registry of SCD in the young will provide data that will help to answer these questions.
| S-EPMC5033115 | biostudies-literature
Project description:The prevention and treatment of sudden cardiac death (SCD) remains a significant public health challenge. For patients with a history of sudden death attributable to ventricular arrhythmia, implantable cardioverter-defibrillator (ICD) therapy is a mainstay of treatment, although these patients remain at high risk for recurrent ventricular arrhythmia and defibrillator therapies. In this review, we summarize landmark clinical trials evaluating the efficacy of ICD therapy in secondary prevention patients, review clinical outcomes including mode of death in survivors of SCD, and highlight the role for systematic diagnostic evaluation. We additionally discuss the invasive electrophysiological management of these patients, including ICD selection and programming as well as the role and timing of antiarrhythmic drug therapy and catheter ablation. Finally, we frame future challenges and needs to advance the care for secondary prevention patients.
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