-
Philosophical Transactions of the Royal... Jun 2023Influx of sodium ions through voltage-gated sodium channels in cardiomyocytes is essential for proper electrical conduction within the heart. Both acquired conditions... (Review)
Review
Influx of sodium ions through voltage-gated sodium channels in cardiomyocytes is essential for proper electrical conduction within the heart. Both acquired conditions associated with sodium channel dysfunction (myocardial ischaemia, heart failure) as well as inherited disorders secondary to mutations in the gene encoding for the cardiac sodium channel Nav1.5 are associated with life-threatening arrhythmias. Research in the last decade has uncovered the complex nature of Nav1.5 distribution, function, in particular within distinct subcellular subdomains of cardiomyocytes. Nav1.5-based channels furthermore display previously unrecognized non-electrogenic actions and may impact on cardiac structural integrity, leading to cardiomyopathy. Moreover, and Nav1.5 are expressed in cell types other than cardiomyocytes as well as various extracardiac tissues, where their functional role in, e.g. epilepsy, gastrointestinal motility, cancer and the innate immune response is increasingly investigated and recognized. This review provides an overview of these novel insights and how they deepen our mechanistic knowledge on channelopathies and Nav1.5 (dys)function. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Humans; Channelopathies; Arrhythmias, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Mutation; Cardiomyopathies; Epilepsy
PubMed: 37122208
DOI: 10.1098/rstb.2022.0164 -
Cell Stem Cell Apr 2023Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory...
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory ventricular arrhythmias, termed engraftment arrhythmias (EAs), hampers clinical applications. We hypothesized that EA results from pacemaker-like activity of hPSC-CMs associated with their developmental immaturity. We characterized ion channel expression patterns during maturation of transplanted hPSC-CMs and used pharmacology and genome editing to identify those responsible for automaticity in vitro. Multiple engineered cell lines were then transplanted in vivo into uninjured porcine hearts. Abolishing depolarization-associated genes HCN4, CACNA1H, and SLC8A1, along with overexpressing hyperpolarization-associated KCNJ2, creates hPSC-CMs that lack automaticity but contract when externally stimulated. When transplanted in vivo, these cells engrafted and coupled electromechanically with host cardiomyocytes without causing sustained EAs. This study supports the hypothesis that the immature electrophysiological prolife of hPSC-CMs mechanistically underlies EA. Thus, targeting automaticity should improve the safety profile of hPSC-CMs for cardiac remuscularization.
Topics: Humans; Animals; Swine; Myocytes, Cardiac; Gene Editing; Cell Line; Arrhythmias, Cardiac; Cell- and Tissue-Based Therapy; Cell Differentiation
PubMed: 37028405
DOI: 10.1016/j.stem.2023.03.010 -
Circulation. Genomic and Precision... Aug 2020Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular... (Review)
Review
Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.
Topics: American Heart Association; Arrhythmias, Cardiac; Cardiomyopathies; Cardiovascular Diseases; Genetic Testing; Humans; Hyperlipoproteinemia Type II; Risk Factors; United States; Vascular Diseases
PubMed: 32698598
DOI: 10.1161/HCG.0000000000000067 -
JACC. Clinical Electrophysiology May 2023A new guideline for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death has been published by the European Society of... (Review)
Review
A new guideline for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death has been published by the European Society of Cardiology (ESC). Beside the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline and the 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society (CCS/CHRS) position statement, this guideline provides evidence-based recommendations for clinical practice. As these recommendations are periodically updated integrating the latest scientific evidence, there are similarities in many aspects. Nevertheless, notable differences in the recommendations can be found resulting from different scopes and publication years, differences in data selection, interpretation, and weighing, and regional factors such as differing drug availability. The aim of this paper is to compare specific recommendations to identify differences while acknowledging the commonalities and to provide an overview of the status of current recommendations with a special emphasis on gaps in evidence and future directions of research. Overall, the recent ESC guideline places a greater emphasis on the value of cardiac magnetic resonance, genetic testing in cardiomyopathies and arrhythmia syndromes, and the use of risk calculators for risk stratification. Further significant differences can be found regarding diagnostic criteria for genetic arrhythmia syndromes, the management of hemodynamically well-tolerated ventricular tachycardia, and primary preventive implantable cardioverter-defibrillator therapy.
Topics: United States; Humans; Syndrome; Canada; Arrhythmias, Cardiac; Cardiology; Heart
PubMed: 37225314
DOI: 10.1016/j.jacep.2022.12.008 -
Heart Rhythm Jul 2022
Topics: Arrhythmias, Cardiac; Electrocardiography; Humans
PubMed: 35777885
DOI: 10.1016/j.hrthm.2021.09.012 -
Cardiovascular Research Jul 2020Inherited arrhythmias are disorders caused by one or more genetic mutations that increase the risk of arrhythmia, which result in life-long risk of sudden death. These... (Review)
Review
Inherited arrhythmias are disorders caused by one or more genetic mutations that increase the risk of arrhythmia, which result in life-long risk of sudden death. These mutations either primarily perturb electrophysiological homeostasis (e.g. long QT syndrome and catecholaminergic polymorphic ventricular tachycardia), cause structural disease that is closely associated with severe arrhythmias (e.g. hypertrophic cardiomyopathy), or cause a high propensity for arrhythmia in combination with altered myocardial structure and function (e.g. arrhythmogenic cardiomyopathy). Currently available therapies offer incomplete protection from arrhythmia and fail to alter disease progression. Recent studies suggest that gene therapies may provide potent, molecularly targeted options for at least a subset of inherited arrhythmias. Here, we provide an overview of gene therapy strategies, and review recent studies on gene therapies for catecholaminergic polymorphic ventricular tachycardia and hypertrophic cardiomyopathy caused by MYBPC3 mutations.
Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cardiomyopathy, Hypertrophic; Carrier Proteins; Genetic Predisposition to Disease; Genetic Therapy; Heart Rate; Humans; Mutation; Phenotype; Tachycardia, Ventricular; Treatment Outcome
PubMed: 32321160
DOI: 10.1093/cvr/cvaa107 -
Europace : European Pacing,... Apr 2023There is an increasing proportion of the general population surviving to old age with significant chronic disease, multi-morbidity, and disability. The prevalence of...
EHRA expert consensus document on the management of arrhythmias in frailty syndrome, endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA).
There is an increasing proportion of the general population surviving to old age with significant chronic disease, multi-morbidity, and disability. The prevalence of pre-frail state and frailty syndrome increases exponentially with advancing age and is associated with greater morbidity, disability, hospitalization, institutionalization, mortality, and health care resource use. Frailty represents a global problem, making early identification, evaluation, and treatment to prevent the cascade of events leading from functional decline to disability and death, one of the challenges of geriatric and general medicine. Cardiac arrhythmias are common in advancing age, chronic illness, and frailty and include a broad spectrum of rhythm and conduction abnormalities. However, no systematic studies or recommendations on the management of arrhythmias are available specifically for the elderly and frail population, and the uptake of many effective antiarrhythmic therapies in these patients remains the slowest. This European Heart Rhythm Association (EHRA) consensus document focuses on the biology of frailty, common comorbidities, and methods of assessing frailty, in respect to a specific issue of arrhythmias and conduction disease, provide evidence base advice on the management of arrhythmias in patients with frailty syndrome, and identifies knowledge gaps and directions for future research.
Topics: Humans; Aged; Frailty; Frail Elderly; Consensus; Latin America; Arrhythmias, Cardiac; Cardiac Conduction System Disease
PubMed: 37061780
DOI: 10.1093/europace/euac123 -
Cells May 2023This article reviews progress in the field of cardiac genome editing, in particular, its potential utility in treating cardiac arrhythmias. First, we discuss genome... (Review)
Review
This article reviews progress in the field of cardiac genome editing, in particular, its potential utility in treating cardiac arrhythmias. First, we discuss genome editing methods by which DNA can be disrupted, inserted, deleted, or corrected in cardiomyocytes. Second, we provide an overview of in vivo genome editing in preclinical models of heritable and acquired arrhythmias. Third, we discuss recent advancements in cardiac gene transfer, including delivery methods, gene expression optimization, and potential adverse effects associated with therapeutic somatic genome editing. While genome editing for cardiac arrhythmias is still in its infancy, this approach holds great promise, especially for inherited arrhythmia syndromes with a defined genetic defect.
Topics: Humans; Gene Editing; Tachycardia, Ventricular; Arrhythmias, Cardiac; Myocytes, Cardiac
PubMed: 37408197
DOI: 10.3390/cells12101363 -
Trends in Cardiovascular Medicine Aug 2022Among the inherited ion channelopathies associated with potentially life-threatening ventricular arrhythmia syndromes in nominally structurally normal hearts are the J... (Review)
Review
Among the inherited ion channelopathies associated with potentially life-threatening ventricular arrhythmia syndromes in nominally structurally normal hearts are the J wave syndromes, which include the Brugada (BrS) and early repolarization (ERS) syndromes. These ion channelopathies are responsible for sudden cardiac death (SCD), most often in young adults in the third and fourth decade of life. Our principal goal in this review is to briefly outline the clinical characteristics, as well as the molecular, ionic, cellular, and genetic mechanisms underlying these primary electrical diseases that have challenged the cardiology community over the past two decades. In addition, we discuss our recently developed whole-heart experimental model of BrS, providing compelling evidence in support of the repolarization hypothesis for the BrS phenotype as well as novel findings demonstrating that voltage-gated sodium and transient outward current channels can modulate each other's function via trafficking and gating mechanisms with implications for improved understanding of the genetics of both cardiac and neuronal syndromes.
Topics: Arrhythmias, Cardiac; Brugada Syndrome; Channelopathies; Death, Sudden, Cardiac; Electrocardiography; Humans
PubMed: 34256120
DOI: 10.1016/j.tcm.2021.07.001 -
Praxis Jun 2023Electrical Accidents When persons seek medical help after an electrical injury, physicians have to inquire on the type (AC/DC) and strength of current (>1000V is...
Electrical Accidents When persons seek medical help after an electrical injury, physicians have to inquire on the type (AC/DC) and strength of current (>1000V is considered "high voltage") as well as the exact circumstances (loss of consciousness, falls) of the accident. In the advent of high-voltage accidents, loss of consciousness, arrhythmias, abnormal ECG or elevated troponin levels, in-hospital rhythm monitoring is warranted. In all other cases, the type of extra cardiac injury primarily directs the management. Superficial skin marks may disguise more extensive thermal injuries of inner organs.
Topics: Humans; Electric Injuries; Accidents; Arrhythmias, Cardiac; Troponin; Unconsciousness
PubMed: 37282521
DOI: 10.1024/1661-8157/a004046