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BACKGROUND: Inherited heart disease has a high prevalence and mortality rate, but its pathogenesis has not yet been clarified. Although relevant animal models have been established to provide a foundation for the pathogenesis research of inherited heart disease, the value of these research results has been significantly reduced due to differences among species. Therefore, a new model is needed to explore its occurrence and development. OBJECTIVE: To review the current role of induced pluripotent stem cells in disease modeling and potential application prospects in various inherited heart diseases. METHODS: The first author searched the relevant articles published nearly 13 years in PubMed from January to March 2023. The search terms were “induced pluripotent stem cell, inherited heart disease, congenital heart disease”. Finally, 76 articles were included for analysis. RESULTS AND CONCLUSION: Since 2007, when induced pluripotent stem cells were induced from human somatic cells, many studies have been reported on disease-specific induced pluripotent stem cells. Due to the ability of disease-specific induced pluripotent stem cells to reproduce disease phenotypes, they are expected to become a new research tool for in vitro disease modeling, used to analyze pathogenesis and develop auxiliary drugs. In the research of cardiovascular genetic diseases, cardiomyocytes derived from patient-specific induced pluripotent stem cells contain gene mutations that are involved in cardiac dysplasia. Therefore, it can be used as a new tool to study the potential mechanisms of inherited heart disease. Up to now, induced pluripotent stem cells-derived cardiomyocytes have been widely used to study the molecular mechanisms of various genetic heart diseases, such as cardiac electrophysiological diseases, cardiomyopathy, and some syndromic inherited heart diseases. [ABSTRACT FROM AUTHOR]

Mutations in ubiquitously expressed presenilin genes (PSENs) lead to early-onset familial Alzheimer's disease (FAD), but patients carrying the mutation also suffer from heart diseases. To elucidate the cardiac myocyte specific effects of PSEN ΔE9, we studied cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) from patients carrying AD-causing PSEN1 exon 9 deletion (PSEN1 ΔE9). When compared with their isogenic controls, PSEN1 ΔE9 cardiomyocytes showed increased sarcoplasmic reticulum (SR) Ca2+ leak that was resistant to blockage of ryanodine receptors (RyRs) by tetracaine or inositol-3-reseceptors (IP 3 Rs) by 2-ABP. The SR Ca2+ leak did not affect electrophysiological properties of the hiPSC-CMs, but according to experiments and in silico simulations the leak induces a diastolic buildup of [Ca2+] near the perinuclear SR and reduces the releasable Ca2+ during systole. This demonstrates that PSEN1 ΔE9 induced SR Ca2+ leak has specific effects in iPSC-CMs, reflecting their unique structural and calcium signaling features. The results shed light on the physiological and pathological mechanisms of PSEN1 in cardiac myocytes and explain the intricacies of comorbidity associated with AD-causing mutations in PSEN1. [Display omitted] • PSEN1 ΔE9 mutation causes sarcoplasmic reticulum Ca2+ leak in hiPSC-cardiomyocytes. • Increased Ca2+-leak causes a diastolic buildup of [Ca2+] near the perinuclear SR. • SR Ca2+-leak reduces the releasable Ca2+ during systole. • The leak does not affect electrical properties of the hiPSC-cardiomyocytes. • In silico simulations reveal complex autoregulation of SR Ca2+ loading in iPSC-CMs. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) is an important public health problem worldwide, accounting for an estimated 6–20% of total mortality. A significant proportion of SCD is caused by inherited heart disease, especially among the young. An autopsy is crucial to establish a diagnosis of inherited heart disease, allowing for subsequent identification of family members who require cardiac evaluation. Autopsy of cases of unexplained sudden death in the young is recommended by both the European Society of Cardiology and the American Heart Association. Overall autopsy rates, however, have been declining in many countries across the globe, and there is a lack of skilled trained pathologists able to carry out full autopsies. Recent studies show that not all cases of sudden death in the young are autopsied, likely due to financial, administrative, and organizational limitations as well as awareness among police, legal authorities, and physicians. Consequently, diagnoses of inherited heart disease are likely missed, along with the opportunity for treatment and prevention among surviving relatives. This article reviews the evidence for the role of autopsy in sudden death, how the cardiologist should interpret the autopsy-record, and how this can be integrated and implemented in clinical practice. Finally, we identify areas for future research along with potential for healthcare reform aimed at increasing autopsy awareness and ultimately reducing mortality from SCD. [ABSTRACT FROM AUTHOR]

Purpose of Review: Pathogenic DNA variants underlie many cardiovascular disease phenotypes. The most well-recognized of these include familial dyslipidemias, cardiomyopathies, arrhythmias, and aortopathies. The clinical presentations of monogenic forms of cardiovascular disease are often indistinguishable from those with complex genetic and non-genetic etiologies, making genetic testing an essential aid to precision diagnosis. Recent Findings: Precision diagnosis enables efficient management, appropriate use of emerging targeted therapies, and follow-up of at-risk family members. Genetic testing for these conditions is widely available but under-utilized. Summary: In this review, we summarize the potential benefits of genetic testing, highlighting the specific cardiovascular disease phenotypes in which genetic testing should be considered, and how clinicians can integrate guideline-directed genetic testing into their practice. [ABSTRACT FROM AUTHOR]

Genetic testing has increasingly been shown to provide critical information regarding the treatment and management of patients with hereditary cardiomyopathies and arrhythmias and is available for a wide variety of conditions. It can provide information regarding arrhythmia risk, lifestyle recommendations, such as exercise avoidance, pharmaceutical therapies, and prognosis. Beyond the proband, genetic testing can be a valuable tool for cascade screening in the family. Genetic testing should be accompanied with genetic counseling, as genetic tests should be accompanied by expert interpretation, support in cascade family evaluation, and psychosocial considerations. Overall, it should be routinely implemented in arrhythmia and cardiomyopathy clinics. [ABSTRACT FROM AUTHOR]

Genetic testing for hypertrophic cardiomyopathy (HCM) is considered a key aspect of management. Communication of genetic test results to the proband and their family members, can be a barrier to effective uptake. We hypothesized that a communication aid would facilitate effective communication, and sought to evaluate knowledge and communication of HCM risk to at‐risk relatives. This was a prospective randomized controlled trial. Consecutive HCM patients attending a specialized clinic, who agreed to participate, were randomized to the intervention or current clinical practice. The intervention consisted of a genetic counselor‐led appointment, separate to their clinical cardiology review, and guided by a communication booklet which could be written in and taken home. Current clinical practice was defined as the return of the genetic result by a genetic counselor and cardiologist, often as part of a clinical cardiology review. The primary outcome was the ability and confidence of the individual to communicate genetic results to at‐risk relatives. The a priori outcome of improved communication among HCM families did not show statistically significant differences between the control and intervention group, though the majority of probands in the intervention group achieved fair communication (n = 13/22) and had higher genetic knowledge scores than those in the control group (7 ± 3 versus 6 ± 3). A total of 29% of at‐risk relatives were not informed of a genetic result in their family. Communication among HCM families remains challenging, with nearly a third of at‐risk relatives not informed of a genetic result. We show a significant gap in the current approach to supporting family communication about genetics. Australian New Zealand Clinical Trials Registry: ACTRN12617000706370. [ABSTRACT FROM AUTHOR]

Aims: To investigate the role of genetic testing in patients with idiopathic atrioventricular conduction disease requiring pacemaker (PM) implantation before the age of 50 years.Methods and Results: All consecutive PM implantations in Southern Switzerland between 2010 and 2019 were evaluated. Inclusion criteria were: (i) age at the time of PM implantation: < 50 years; (ii) atrioventricular block (AVB) of unknown aetiology. Study population was investigated by ajmaline challenge and echocardiographic assessment over time. Genetic testing was performed using next-generation sequencing panel, containing 174 genes associated to inherited cardiac diseases, and Sanger sequencing confirmation of suspected variants with clinical implication. Of 2510 patients who underwent PM implantation, 15 (0.6%) were young adults (median age: 44 years, male predominance) presenting with advanced AVB of unknown origin. The average incidence of idiopathic AVB computed over the 2010-2019 time window was 0.7 per 100 000 persons per year (95% CI 0.4-1.2). Most of patients (67%) presented with specific genetic findings (pathogenic variant) or variants of uncertain significance (VUS). A pathogenic variant of PKP2 gene was found in one patient (6.7%) with no overt structural cardiac abnormalities. A VUS of TRPM4, MYBPC3, SCN5A, KCNE1, LMNA, GJA5 genes was found in other nine cases (60%). Of these, three unrelated patients (20%) presented the same heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene. Diagnostic re-assessment over time led to a diagnosis of Brugada syndrome and long-QT syndrome in two patients (13%). No cardiac events occurred during a median follow-up of 72 months.Conclusion: Idiopathic AVB in adults younger than 50 years is a very rare condition with an incidence of 0.7 per 100 000 persons/year. Systematic investigations, including genetic testing and ajmaline challenge, can lead to the achievement of a specific diagnosis in up to 20% of patients. Heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene was found in an additional 20% of unrelated patients, suggesting possible association of the variant with the disease. [ABSTRACT FROM AUTHOR]

Knowledge of causes of sudden cardiac death (SCD) according to age is important in clinical decision making and to lower the risk of SCD in family members of the deceased. The purpose of this study was to report overall and sex-stratified causes of SCD according to age in persons aged 1–49 years. The study population consisted of all persons in Denmark aged 1–35 years in 2000–2009 and 36–49 years in 2007–2009, which equals 27.1 million person-years. Danish death certificates, discharge summaries, autopsy reports, and data from nationwide registries were used to identify all SCD cases. The SCD cases were divided into 5-year age groups. In the 10-year study period, there were 14,294 deaths, of which 1362 (10%) were classified as SCD. Potentially inherited cardiac disease accounted for a high proportion (43%–78%) of autopsied SCD in all age groups. A significant proportion (19%–54%) of SCD was caused by sudden arrhythmic death syndrome in all age groups. Autopsy rates in both sudden unexpected death cases and SCD cases declined significantly with increasing age (74% in the youngest age group vs 35% in the oldest). The proportion of SCD cases that were identified with a potentially inherited cardiac disease postmortem was high in all studied age groups, while autopsy rates in sudden and unexpected death cases declined markedly with increasing age. Our findings indicate that diagnoses of inherited heart disease are likely missed in some SCD cases, along with the opportunity for treatment and prevention in surviving relatives. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Implantable cardioverter-defibrillators (ICDs) are an effective treatment in some patients with inherited heart disease, including inherited channelopathies, yet they have also been shown to impact patients’ psychological health. Objective: We sought to improve understanding of the level of anxiety and depression as well as device acceptance among inherited channelopathy patients with an ICD. Methods: Eligible patients seen at Johns Hopkins Hospital were sent a survey, which included the Hospital Anxiety and Depression Scale (HADS), Cardiac Anxiety Questionnaire (CAQ), and the Florida Patient Acceptance Survey (FPAS). Student t tests and χ2 tests were used to identify associations with abnormal anxiety and depression scores. Results: Among eligible patients (n = 65), 32 individuals (49%) completed the survey. The rate of device-related complications was 34%, and 41% of patients experienced 1 or more ICD shocks. Twelve patients (38%) had an abnormal HADS anxiety subscore and 5 patients (16%) had an abnormal HADS depression subscore (score ≥ 8). Secondary-prevention ICDs were associated with an abnormal HADS anxiety subscore (P = .03). Experiencing ICD shock(s), device complications, age, sex, and family history of sudden cardiac death were not statistically associated with anxiety or depression. Overall, respondents demonstrated high device acceptance by FPAS (79.9 ± 2.9, maximum total score 100) and moderately high cardiac-specific anxiety by CAQ total score (1.53 ± 0.12). Conclusion: A high prevalence of generalized anxiety was identified among inherited channelopathy patients with ICDs. High device acceptance and lack of association with ICD shocks or complications indicate that further research is necessary to understand this increased incidence.

Short QT syndrome (SQTS) is a genetic disease characterized by constantly short QT intervals and high risks of sudden death. SQTS6 is one of the identified SQTS genotype variants associated with the CACNA2D1 S755T mutation. However, the pathogenesis of SQTS induced arrhythmias remains unclear. To identify the underlying mechanisms of SQTS6 induced arrhythmias, a multi-scale human ventricle model comprising cell to organ levels was built. Cellular data was fitted at the cell level to reproduce the electrophysiological alterations reported in experiments. The influences were further explored at tissue and organ levels using idealized strand or tissue sheet models, and realistic ventricular slice and three-dimensional organ models. Simulation results suggested that, at the cellular level, the action potential duration (APD) and the effective refractory period (ERP) of myocytes were significantly abbreviated in the mutation condition. The unevenly changed APD and ERP led to transmural heterogeneity remodeling, and resulted in decreased temporal vulnerability. In addition, the S755T mutation shortened the critical length for initiating reentrant spiral waves, which enhanced the spatial vulnerability and provided substrates for reentry arrhythmias. Regarding the sustainability of arrhythmias, the evoked spiral waves or scroll waves persisted in the mutation condition but did not persist in the wild-type condition. The present study clearly suggested that the CACNA1DC S755T mutation can facilitate the initiation and maintenance of ventricular arrhythmias, and therefore contributes to higher risks of ventricular arrhythmias in SQTS6 patients.

With the emerging and mutation of various pathogenic genes,the prevalence of corresponding genetic diseases also increases year by year. The penetrance of potentially pathogenic mutation is often atypical or the mutation manifests itself only in one’s later years,which tends to complicate and delay the diagnosis of genetic heart diseases. With the development and application of new technologies such as machine learning,artificial intelligence（ AI） has become a powerful tool in many fields including personalized medicine,medical imaging,and disease diagnosis. By using AI,we can specifically analyze and summarize the characteristic manifestations of ECG in patients with genetic arrhythmias,contributing to the early diagnosis of related diseases. This paper reviews the latest research progress of AI-enabled ECG utilized in the diagnosis of inherited arrhythmias,mainly including congenital long QT syndrome,Brugada syndrome,and catecholaminergic polymorphic ventricular tachycardia. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) is an important public health problem worldwide, accounting for an estimated 6-20% of total mortality. A significant proportion of SCD is caused by inherited heart disease, especially among the young. An autopsy is crucial to establish a diagnosis of inherited heart disease, allowing for subsequent identification of family members who require cardiac evaluation. Autopsy of cases of unexplained sudden death in the young is recommended by both the European Society of Cardiology and the American Heart Association. Overall autopsy rates, however, have been declining in many countries across the globe, and there is a lack of skilled trained pathologists able to carry out full autopsies. Recent studies show that not all cases of sudden death in the young are autopsied, likely due to financial, administrative, and organizational limitations as well as awareness among police, legal authorities, and physicians. Consequently, diagnoses of inherited heart disease are likely missed, along with the opportunity for treatment and prevention among surviving relatives. This article reviews the evidence for the role of autopsy in sudden death, how the cardiologist should interpret the autopsy-record, and how this can be integrated and implemented in clinical practice. Finally, we identify areas for future research along with potential for healthcare reform aimed at increasing autopsy awareness and ultimately reducing mortality from SCD., Competing Interests: Conflict of interest: I have read the journal’s policy and the authors of this manuscript have the following competing interests. Co-author C.M.A.: Investigator Initiated Grant Support from NHLBI, St. Jude Medical, Roche Diagnostics, and Abbott to Study Biologic Markers of SCD; Advisory Board Member for Element Science, Inc, Medtronic, Illumina Inc, and consultant, Novartis. The remaining authors have declared that no competing interests exist., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined disease associated with a significant risk of ventricular arrhythmias and sudden cardiac death (SCD). Implantable cardioverter-defibrillators (ICDs) are the only effective preventive measure. Over the past 30 years, much effort has been invested in determining predictors of adverse arrhythmic events in these patients. Areas covered: This review summarizes available evidence on risk stratification for ARVC, with an emphasis on recent research findings. While efforts are ongoing to define risk predictors, several recent publications have synthetized and built on this knowledge base. A recently published meta-analysis has clarified the strongest predictors of ventricular arrhythmias in ARVC, which vary depending on the population included. Three management guidelines/expert consensus documents have integrated the previously described risk predictors into proposed ICD recommendations. Furthermore, a risk prediction model has allowed the integration of multiple risk factors to provide individualized risk prediction and to inform shared-decision making regarding ICD implantation. Expert opinion: Over the past few years, knowledge of risk prediction in ARVC has been consolidated and refined. Further improvements may be made by the considering additional predictors such as exercise and by targeting more specific surrogate outcomes for SCD. [ABSTRACT FROM AUTHOR]

Abstract Background Our knowledge of hypertrophic cardiomyopathy (HCM) mainly originates from quarternary centres. The objective is to assess the current management of HCM patients in a large multicentre French register according to the level of expertise. Methods and results A total of 1431 HCM patients were recruited across 26 (11 expert and 15 non-expert) centres in REMY, a prospective hospital-based register of adult HCM patients. A sarcomeric origin was suspected in 1284 (89.7%) patients [261 (20.3%) with a reported gene mutation, 242 (18.8%) genotype-negative], while 107 (7.5%) had a diagnosis of non-sarcomeric HCM. Patients managed in non-expert centres were older (P < 0.01) and presented more often with NYHA III/IV class dyspnoea (P < 0.01), congestive heart failure (P < 0.01), low LEVF (P < 0.01), less often with a syncope history (P < 0.01) and lower LV obstruction (P < 0.01) than patients in expert centres. Genotype positive sarcomeric aetiologies were less frequent in non-expert centres (P < 0.01). The use of diagnostic and prognostic tests as cardiac MRI (P < 0.001), genetic (P < 0.001) and alpha-galactosidase A enzyme level testing (P < 0.001), Holter ECG (P < 0.001), and exercise test (P < 0.001), was lower in non-expert centres. Septal ablation procedures using alcohol (P < 0.001) or myectomy (P < 0.001) were more frequent in expert centres. Conclusion In real life practice, only a minority of HCM patients are identified as sarcomere positive as per genetic testing. The management of HCM patients varies according to the centre's level of expertise, with less access to diagnostic and prognostic tests in non-expert centres. Non-sarcomeric HCM may therefore be overlooked despite specific treatment in some aetiologies. [ABSTRACT FROM AUTHOR]

In the past few years, the use of specific cell types derived from induced pluripotent stem cells (iPSCs) has developed into a powerful approach to investigate the cellular pathophysiology of numerous diseases. Despite advances in therapy, heart disease continues to be one of the leading causes of death in the developed world. A major difficulty in unravelling the underlying cellular processes of heart disease is the extremely limited availability of viable human cardiac cells reflecting the pathological phenotype of the disease at various stages. Thus, the development of methods for directed differentiation of iPSCs to cardiomyocytes (iPSC-CMs) has provided an intriguing option for the generation of patient-specific cardiac cells. In this review, a comprehensive overview of the currently published iPSC-CM models for hereditary heart disease is compiled and analysed. Besides the major findings of individual studies, detailed methodological information on iPSC generation, iPSC-CM differentiation, characterization, and maturation is included. Both, current advances in the field and challenges yet to overcome emphasize the potential of using patient-derived cell models to mimic genetic cardiac diseases. [ABSTRACT FROM AUTHOR]

Background: Physical activity is associated with improved quality of life. Patients with an implantable cardioverter defibrillator (ICD) face unique clinical and psychological challenges. Factors such as fear of ICD shock may negatively impact on physical activity, while a sense of protection gained from the ICD may instil confidence to be active. Aim: We aimed to examine the impact of an ICD on physical activity levels and factors associated with amount of activity. Methods: Two cross-sectional studies were conducted. Accelerometer data (seven-day) was collected in March–November 2015 for 63 consecutively recruited hypertrophic cardiomyopathy patients, with or without an ICD, aged ⩾18 years. A survey study was conducted in July–August 2016 of 155 individuals aged ⩾18 years with an inherited heart disease and an ICD in situ. Results: Based on the International Physical Activity Questionnaire, mean leisure time physical activity was 239 ± 300 min/week with 51% meeting physical activity guidelines. Accelerometry showed that mean moderate–vigorous physical activity was the same for patients with and without an ICD (254 ± 139 min/week versus 300 ± 150 min/week, p=0.23). Nearly half of survey participants (n=73) said their device made them more confident to exercise. Being anxious about ICD shocks was the only factor associated with not meeting physical activity guidelines. Conclusions: Patients with inherited heart disease adjust differently to their ICD device, and for many it has no impact on physical activity. Discussion regarding the appropriate level of physical activity and potential barriers will ensure best possible outcomes in this unique patient group. [ABSTRACT FROM AUTHOR]

The sudden death is defined as the unexpected death that occurs within an hour of the onset of symptoms. This type of death has a high social, media and economic impact. The first cause is of cardiac origin, and within this, the ischemic heart disease is the most frequent, but family heart diseases (channelopathies and cardiomyopathies) are more important in children and young people, where they represent the first cause of sudden cardiac death. These family heart diseases have a clear genetic substrate that justifies the indication of an adequate study of the relatives of the deceased. According to the data of the Spanish population of the 2013 census (46.7 million inhabitants) in the Valencian Community, which represents 10% of this population, it is estimated that there are 20.000 people with some potentially lethal heart disease. Given the importance and the social impact of sudden death of cardiac origin, and since the medical-legal autopsy has limitations to diagnose the underlying disease in these types of deaths, the most opportune strategy is the multidisciplinary approach, which is why in 2008, the Family Sudden Death and Family Heart Diseases Unit was created in this region. [ABSTRACT FROM AUTHOR]

Purpose of Review: Genetic testing has become an important element in the care of patients with inherited cardiac conditions (ICCs). The purpose of this review is to provide clinicians with insights into the utility of genetic testing as well as challenges associated with interpreting results. Recent Findings: Genetic testing may be indicated for individuals who are affected with or who have family histories of various ICCs. Various testing options are available and determining the most appropriate test for any given clinical scenario is key when interpreting results. Newly published guidelines as well as various publicly accessible tools are available to clinicians to help with interpretation of genetic findings; however the subjectivity with respect to variant classification can make accurate assessment challenging. Summary: Genetic information can provide highly useful and relevant information for patients, their family members, and their healthcare providers. Given the potential ramifications of variant misclassification, expertise in both clinical phenotyping and molecular genetics is imperative in order to provide accurate diagnosis, management recommendations, and family risk assessment for this patient population. [ABSTRACT FROM AUTHOR]

Objective To observe the gene mutation types in a Chinese Han hypertrophic cardiomyopathy ( HCM) family and to explore its effect on clinical phenotype. Methods We selected 1 Chinese Han HCM family，including 13 family members，among whom 5 were diagnosed as HCM. New generation of high-throughput sequencing technology ( NGS) was used to sequence the 44 genes of the target genomes associated with human cardiomyopathy of the proband. The results indicated that the proband carried p-myosin heavy chain ( MYH7 ) gene Arg663His in exon 18 and troponin I ( TNNI3 ) gene c.470C > T in exon 7. The mutations of the two genes in other members of the family were detected by the dideoxy chain-termination method，and the clinical manifestations of HCM patients with MYH7 and TNNI3 gene mutations were analyzed. Results The proband and his sister carried MYH7 gene exon 18 Arg663His mutation and TNNI3 gene exon 7 c. 470C > T mutation，and the age of onset was respectively 2 and 1 years old. The ECG showed abnormal Q wave，ST-T changes，and left ventricular high voltage. Echocardiography showed left atrium enlargement，the thickest part of interventricular septum was 25 and 23 mm，SAM was positive，and the left ventricular outflow pressure were 80 and 6 8 mmHg，respectively. The probands mother，uncle and grandfather carried Arg663His mutation in MYH7 gene exon 18，and the age of onset was 21，19，and 30 years old，respectively. The ECG showed ST-T changes and left ventricular high voltage. Echocardiography showed that the thickest part of interventricular septum were 16，18，and 18 mm，respectively，SAM were negative，and no left ventricular outflow tract obstruction. The proband's cousin only carried Arg663His mutation in MYH7 gene exon 18. There were no obvious clinical symptoms， and no abnormalities in ECG and echocardiogram. Conclusions The TNNI3 gene in the HCM family underwent de novo mutation，and the MYH7 gene mutation was inheri ted. The patients with double mutations of MYH7 and TNNI3 gene presented a younger onset age, severe clinical phenotype and poor prognosis. [ABSTRACT FROM AUTHOR]

Inherited heart disease causing electric instability in the heart has been suggested to be a risk factor for sudden unexpected death in epilepsy (SUDEP). The purpose of this study was to reveal the correlation between epilepsy-related sudden unexpected death (SUD) and inherited heart disease. Twelve epilepsy-related SUD cases (seven males and five females, aged 11-78 years) were examined. Nine cases fulfilled the criteria of SUDEP, and three cases died by drowning. In addition to examining three major epilepsy-related genes, we used next-generation sequencing (NGS) to examine 73 inherited heart disease-related genes. We detected both known pathogenic variants and rare variants with minor allele frequencies of <0.5%. The pathogenicity of these variants was evaluated and graded by eight in silico predictive algorithms. Six known and six potential rare variants were detected. Among these, three known variants of LDB3, DSC2 and KCNE1 and three potential rare variants of MYH6, DSP and DSG2 were predicted by in silico analysis as possibly highly pathogenic in three of the nine SUDEP cases. Two of three cases with desmosome-related variants showed mild but possible significant right ventricular dysplasia-like pathology. A case with LDB3 and MYH6 variants showed hypertrabeculation of the left ventricle and severe fibrosis of the cardiac conduction system. In the three drowning death cases, one case with mild prolonged QT interval had two variants in ANK2. This study shows that inherited heart disease may be a significant risk factor for SUD in some epilepsy cases, even if pathological findings of the heart had not progressed to an advanced stage of the disease. A combination of detailed pathological examination of the heart and gene analysis using NGS may be useful for evaluating arrhythmogenic potential of epilepsy-related SUD. [ABSTRACT FROM AUTHOR]

Identification of the first echocardiographic manifestations of hypertrophic cardiomyopathy may be important for clinical management and our understanding of the pathogenesis. We studied the development of pre-diagnostic echocardiographic changes in young relatives to HCM patients during long-term years follow-up. HCM-relatives not fulfilling the diagnostic criteria for HCM and age of <18 years were included in this study. We performed echocardiographic evaluations at inclusion and after 12 ± 1 years follow-up. Based on family screening of 11 sarcomere genes, CRYAB, α-GAL, and titin, we evaluated: (1) non-carriers (known family mutation ruled out-controls), (2) carriers (phenotype negative gene mutation carriers) and (3) phenotype negative relatives with unknown genetic status (relatives from families without identified mutations). At inclusion (age 11 ± 5 years), there were no differences in echocardiographic chamber dimensions, systolic or diastolic function between the three groups. During follow-up (age 23 ± 5 years), carriers (n = 8) developed lower left ventricular end-diastolic dimension (LVEDd) compared to non-carriers (n = 23) (41 ± 4 vs. 46 ± 4 mm; p = 0.04) and a higher ratio of early left ventricular filling velocity and early diastolic velocity of lateral mitral annulus (E/e' 6 ± 1 vs. 5 ± 1; p = 0.003). No significant differences in LVEDd or E/e' were found between relatives with unknown genetic status (n = 24) and non-carriers though Z-scores for these parameters were >2 in a subset of relatives with unknown genetic status. Children carrying pathogenic sarcomere gene mutations develop reduced LVEDd and increased E/e' as first pre-diagnostic echocardiographic manifestations during follow-up into adulthood. [ABSTRACT FROM AUTHOR]

Discriminating between rare benign and pathogenic variation is a key challenge in clinical genetics, particularly as increasing numbers of nonsynonymous single-nucleotide polymorphisms (SNPs) are identified in resequencing studies. Here, we describe an approach for the functional annotation of nonsynonymous variants that identifies functionally important, disease-causing residues across protein families using multiple sequence alignment. We applied the methodology to long QT syndrome (LQT) genes, which cause sudden death, and their paralogues, which largely cause neurological disease. This approach accurately classified known LQT disease-causing variants (positive predictive value = 98.4%) with a better performance than established bioinformatic methods. The analysis also identified 1078 new putative disease loci, which we incorporated along with known variants into a comprehensive and freely accessible long QT resource (), based on newly created Locus Reference Genomic sequences (). We propose that paralogous annotation is widely applicable for Mendelian human disease genes. Hum Mutat 33:1188-1191, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aims To evaluate paediatric relatives of first- and non-first-degree family victims with a history of premature sudden cardiac death (SCD) or aborted cardiac arrest (ACA). Methods and results Thirty-six consecutive referred families after SCD (n = 29) or ACA (n = 7) of a family member were analysed. Referral was either due to an inherited heart disease identified after autopsy, post-event, or family evaluation (n = 20 families) or due to sudden unexplained death (SUD, n = 16 families). In 3 of 16 (19%) SUD families, an inherited heart disease was diagnosed by evaluation of the paediatric relatives. In 5 of 25 (20%) referred paediatric relatives of SUD families, an inherited heart disease was identified, mainly sinus node dysfunction (n = 3). A total of 13 of 33 (39%) referred paediatric relatives of families with known inherited heart disease were affected, mainly with cardiomyopathy (n = 5) and primary electrical disease (n = 7). Prevention of SCD was initiated in 16 of the affected children by implantation of an antibradycardia device (n = 3), an implantable cardioverter defibrillator (ICD, n = 6), and/or antiarrhythmic medication (n = 8). Appropriate and successful ICD discharges occurred in four. Conclusion A stepwise, comprehensive clinical investigation of SCD or ACA families identifies a substantial number of paediatric relatives at risk of SCD. This allows for targeted prevention by effective treatments and evaluation of further relatives. [ABSTRACT FROM PUBLISHER]

Sudden cardiac death (SCD) may be the first and final manifestation of several heart diseases. In the young, SCD is often caused by a hereditary cardiac disease. As the most frequently seen inherited cardiac diseases have an autosomal-dominant pattern of inheritance, half of the first-degree relatives are at risk of having or developing the same disease. Therefore, screening of these high-risk relatives is a rational approach to reduce the incidence of SCD. To offer family screening and counseling, the cause of death should be carefully established. Autopsy is only performed in a limited number of cases. We advocate for systematic autopsies in SCD, because positive findings are crucial for choosing the optimal screening program for the relatives. A negative autopsy makes identification of at-risk population difficult. However, this finding also provides clues to the cardiologist, because a limited number of inherited cardiac diseases associated with SCD are without any structural changes. In other cases, the autopsy may reveal noncardiac causes of death, which is also important for reassuring the relatives. However, in cases with no autopsy or negative findings, thorough clinical examinations and selective genetic screening of relatives may identify a likely diagnosis in more than 50% of affected families. There is a need for consensus regarding routine evaluation of SCD cases and the ethical and legal framework related to postmortem testing. We propose an algorithm that narrows the diagnostic possibilities in apparently healthy relatives of young SCD victims. Molecular autopsy may play an important role. [ABSTRACT FROM AUTHOR]

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Background: Ventricular arrhythmias (VA) and sudden death are inherited in German Shepherd Dogs (GSDs). Objectives: To estimate the genetic parameters (heritabilities and correlations) of 3 traits of VA (single premature ventricular complexes (PVCs), 2 consecutive PVCs (couplets), and 3 or more consecutive PVCs—ventricular tachycardia [VT]). Animals: Three hundred and ninety-eight GSDs. Methods: Prospective, observational, case control study. Dogs were phenotyped by 24-hour ambulatory ECG from 6 to 45 weeks of age. Edited ECG records included the number of incidents of (1) single PVCs, (2) couplets, and (3) VT. Results: A data set of 1,239 Holter records from 398 GSDs was used to estimate genetic variables. Phenotypic correlations for affectedness (binarily coded 0/1) of the 3 traits ranged from 0.55 to 0.74, whereas correlations for severity (continuous values of 24-hour VA counts) ranged from 0.26 to 0.39. Estimates of genetic correlation among the severity traits were 0.06 to 0.27. Estimated heritabilities were 0.54, 0.54, and 0.46 for affectedness and 0.33, 0.69, and 0.69 for severity of PVCs, couplets, and VT, respectively. Month and year of birth and age at ECG recording had significant effects on all 3 traits. Season of ECG recording had a significant effect on the number of single PVCs, but not couplets or incidents of VT. Age of onset differed, with single PVCs appearing an average of 4 days earlier than couplets and VT. Conclusion: These results imply a strong genetic component for this disease but suggest that differences in the 3 traits should be taken into consideration in studies to identify the underlying genes. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study was to assess the value of genetic testing in addition to a comprehensive clinical evaluation, as part of the diagnostic work-up of elite and/or amateur Italian athletes referred for suspicion of inherited cardiac disease, following a pre-participation screening programme., Methods: Between January 2009-December 2018, of 5892 consecutive participants, 61 athletes were investigated: 30 elite and 31 amateur athletes. Elite and amateur athletes were selected, on the basis of clinical suspicion for inherited cardiac disease, from two experienced centres for a comprehensive cardiovascular evaluation. Furthermore, the elite and amateur athletes were investigated for variants at DNA level up to 138 genes suspected to bear predisposition for possible cardiac arrest or even sudden cardiac death., Results: Of these 61 selected subjects, six (10%) had diagnosis made possible by a deeper clinical evaluation, while genetic testing allowed a definite diagnosis in eight (13%). The presence of >3 clinical markers (i.e. family history, electrocardiogram and/or echocardiographic abnormalities, exercise-induced ventricular arrhythmias) was associated with a higher probability of positive genetic diagnosis (75%), compared with the presence of two or one clinical markers (14.2%, 8.1%, respectively, p-value = 0.004)., Conclusion: A combined clinical and genetic evaluation, based on the subtle evidence of clinical markers for inherited disease, was able to identify an inherited cardiac disease in about one-quarter of the examined athletes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Implantable cardioverter-defibrillators (ICDs) are an effective treatment in some patients with inherited heart disease, including inherited channelopathies, yet they have also been shown to impact patients' psychological health., Objective: We sought to improve understanding of the level of anxiety and depression as well as device acceptance among inherited channelopathy patients with an ICD., Methods: Eligible patients seen at Johns Hopkins Hospital were sent a survey, which included the Hospital Anxiety and Depression Scale (HADS), Cardiac Anxiety Questionnaire (CAQ), and the Florida Patient Acceptance Survey (FPAS). Student t tests and χ 2 tests were used to identify associations with abnormal anxiety and depression scores., Results: Among eligible patients (n = 65), 32 individuals (49%) completed the survey. The rate of device-related complications was 34%, and 41% of patients experienced 1 or more ICD shocks. Twelve patients (38%) had an abnormal HADS anxiety subscore and 5 patients (16%) had an abnormal HADS depression subscore (score ≥ 8). Secondary-prevention ICDs were associated with an abnormal HADS anxiety subscore ( P = .03). Experiencing ICD shock(s), device complications, age, sex, and family history of sudden cardiac death were not statistically associated with anxiety or depression. Overall, respondents demonstrated high device acceptance by FPAS (79.9 ± 2.9, maximum total score 100) and moderately high cardiac-specific anxiety by CAQ total score (1.53 ± 0.12)., Conclusion: A high prevalence of generalized anxiety was identified among inherited channelopathy patients with ICDs. High device acceptance and lack of association with ICD shocks or complications indicate that further research is necessary to understand this increased incidence., (© 2021 Heart Rhythm Society. Published by Elsevier Inc.)

Purpose: Copy-number variant (CNV) analysis is increasingly performed in genetic diagnostics. We leveraged recent gene curation efforts and technical standards for interpretation and reporting of CNVs to characterize clinically relevant CNVs in patients with inherited heart disease and sudden cardiac death., Methods: Exome sequencing data were analyzed for CNVs using eXome-Hidden Markov Model tool in 48 established disease genes. CNV breakpoint junctions were characterized. CNVs were classified using the American College of Medical Genetics and Genomics technical standards., Results: We identified eight CNVs in 690 unrelated probands (1.2%). Characterization of breakpoint junctions revealed nonhomologous end joining was responsible for four deletions, whereas one duplication was caused by nonallelic homologous recombination between duplicated sequences in MYH6 and MYH7. Identifying the precise breakpoint junctions determined the genomic involvement and proved useful for interpreting the clinical relevance of CNVs. Three large deletions involving TTN, MYBPC3, and KCNH2 were classified as pathogenic in three patients. Haplotype analysis of a deletion in ACTN2, found in two families, suggests the deletion was caused by an ancestral event., Conclusion: CNVs infrequently cause inherited heart diseases and should be investigated when standard genetic testing does not reveal a genetic diagnosis.

Objective: The sudden cardiac death (SCD) of a young person is a devastating event for any parent. Inherited heart disease is often either identified or assumed to be the cause. Few studies have explored the psychosocial impact to the surviving at-risk family members. We sought to investigate the needs of parents who have experienced the SCD of their child (≤45 years)., Methods: A quantitative needs analysis questionnaire was developed based on semistructured interviews, including one focus group and a review of relevant literature. Eligible participants were invited to participate in this cross-sectional survey study., Results: There were 38 parents who completed a quantitative survey. Parents' perceived needs for information and support spanned medical, psychosocial, spiritual and financial domains. Of the support and information needs assessed, medical needs were identified as the most important domain, followed by psychosocial, spiritual and financial. Importantly, psychosocial information and support needs were reported as the most unmet need, endorsed by 54% of parents. Medical information and support needs were reported as unmet by almost one third of parents. The two most endorsed needs were 'To have the option of whether or not you would pursue genetic testing for yourself or family members' and 'To understand what happened'., Conclusions: This work demonstrates for the first time, the multifactorial needs of parents after SCD in the young. With the greatest unmet need reported as psychosocial needs, there is clear necessity to find ways of integrating psychological support in to the care of families after SCD in the young., Competing Interests: Competing interests: JI receives research grant support from Myokardia, Inc., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)