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In this chapter, an overview is provided on idiopathic ventricular fibrillation (IVF) and early repolarization. Idiopathic ventricular fibrillation is a tragic and notoriously difficult disease entity to manage. The IVF patients in whom a cardiac arrest occurs are generally considered healthy and do not show any currently identifiable abnormalities that denote their increased risk for malignant and life-threatening arrhythmias. Importantly, IVF can be inheritable and tear through families. The number of patients who survive their first manifestation of the disease is low, and the recurrence rate of IVF is appreciable. Treatment in patients who survived their event is performed by implantation of a cardioverter defibrillator (ICD) and a decrease of the risk of IVF recurrence may be achieved by prescription of quinidine. During a VF storm, administration of isoproterenol can be essential, and possibly also sedation might be effective. Research into the origin and genetic underpinning of IVF is limited by its malignant character, yet has revealed genetic variants in the DPP6 gene and CALM1 gene that impact on cellular cardiac electrophysiology. In contrast, early repolarization is a description of electrocardiographic variants with elevation, slurring, or notching in the terminal QRS complex or early ST segment. Although considered a benign electrocardiographic characteristic for many decades, in the past decade associations have been made with a propensity to sudden cardiac arrest by VF. Importantly, early repolarization is of very common occurrence in many young and healthy individuals. The description of a rare malignant association has spurred scientific interest in this phenomenon. Fortunately, its benign prognosis is still valid for the vast majority of individuals who display an early repolarization pattern. The challenge for the future will be to delineate benign from malignant variants of early repolarization, the development of aids in risk stratification and a better understanding underlying pathophysiology on cellular and genetic level, to further guide clinicians and patients.

Cardiac arrhythmias are a major cause of death and disability. A large number of experimental cell and animal models have been developed to study arrhythmogenic diseases. These models have provided important insights into the underlying arrhythmia mechanisms and translational options for their therapeutic management. This position paper from the ESC Working Group on Cardiac Cellular Electrophysiology provides an overview of (i) currently available in vitro, ex vivo, and in vivo electrophysiological research methodologies, (ii) the most commonly used experimental (cellular and animal) models for cardiac arrhythmias including relevant species differences, (iii) the use of human cardiac tissue, induced pluripotent stem cell (hiPSC)-derived and in silico models to study cardiac arrhythmias, and (iv) the availability, relevance, limitations, and opportunities of these cellular and animal models to recapitulate specific acquired and inherited arrhythmogenic diseases, including atrial fibrillation, heart failure, cardiomyopathy, myocarditis, sinus node, and conduction disorders and channelopathies. By promoting a better understanding of these models and their limitations, this position paper aims to improve the quality of basic research in cardiac electrophysiology, with the ultimate goal to facilitate the clinical translation and application of basic electrophysiological research findings on arrhythmia mechanisms and therapies.

The aims of this centre-based survey, promoted and disseminated by the European Heart Rhythm Association (EHRA) was to investigate the current practice for the investigation of Sudden Unexplained Death in the Young (SUDY) amongst European countries. An online questionnaire composed of 21 questions was submitted to the EHRA Research Network, European Cardiac Arrhythmia Genetics (ECGen) Focus Group members, and European Reference Network GUARD-Heart healthcare partners. There were 81 respondents from 24 European countries. The majority (78%) worked in a dedicated clinic focusing on families with inherited cardiac conditions and/or SUDY or had easy access to a nearby one. On average, an autopsy was performed in 43% of SUDY cases. Macroscopic examination of the body and all organs were completed in 71% of cases undergoing autopsy, and expert cardiac examination in 32%. Post-mortem genetic testing was requested on average in 37% of Sudden Arrhythmic Death Syndrome (SADS) cases, but not at all by 20% of survey respondents. Psychological support and bereavement counselling for SADS/SUDY families were available for ≤50% of participants. Whilst electrocardiogram (ECG) and echocardiography were largely employed to investigate SADS relatives, there was an inconsistent approach to the use of provocative testing with exercise ECG, sodium channel blocking drugs, and/or epinephrine and genetic testing. The survey highlighted a significant heterogeneity of service provision and variable adherence to current recommendations for the investigation of SUDY, partly attributable to the availability of dedicated units and specialist tests, genetic evaluation, and post-mortem examination.

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.