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Aims Indications and clinical impact of genetic testing for cardiac diseases have increased significantly over the past years. The aim of this physician-based European Heart Rhythm Association (EHRA) survey was to assess current clinical practice and access to genetic testing for cardiac diseases across European Society of Cardiology countries and to evaluate adherence to the 2022 EHRA/HRS/APHRS/LAHRS Expert Consensus Statement on genetic testing. Methods and results An online questionnaire composed of 28 questions was submitted to the EHRA Research Network and European Reference Network GUARD-Heart healthcare partners and promoted via dedicated social media channels. There were 357 respondents from 69 countries, 40% working in a hospital setting with a cardiac genetic service and/or a dedicated clinic focusing on inherited cardiac diseases and 27% with an onsite genetic laboratory. No genetic testing or low annual rate (<10/year) was declared by 39% of respondents. The majority of respondents (78%) declared issues or limitations to genetic testing access in their clinical practice. The main reasons for not providing or limited access to genetic testing were no availability of dedicated unit or genetic laboratory (35%) or reimbursement issues (25%). The most frequently reported indication for genetic testing was diagnostic purpose (55%). Most respondents (92%) declared offering genetic testing preceded by genetic counselling and 42% regular multidisciplinary evaluations for patients with cardiac genetic diseases. The perceived value of genetic testing in the diagnostic, prognostic, and therapeutic assessment was variable (67, 39, and 29%, respectively) and primarily based on the specific inherited disease. The majority of respondents recommended cascade genetic testing for the first-degree family members in case of pathogenic/likely pathogenic variant in the proband. Conclusion This survey highlights a significant heterogeneity of genetic testing access and provision and issues attributable to the availability of dedicated unit/genetic laboratory and reimbursement. However, adequate adherence to indications in the current recommendations for genetic testing in patients with cardiac diseases was observed. [ABSTRACT FROM AUTHOR]

Energy drinks potentially can trigger life-threatening cardiac arrhythmias. It has been postulated that the highly stimulating and unregulated ingredients alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a potentially proarrhythmic manner. The purpose of this study was to describe our experience regarding sudden cardiac arrest (SCA) occurring in proximity to energy drink consumption in patients with underlying genetic heart diseases. The electronic medical records of all SCA survivors with proven arrhythmias referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for evaluation were reviewed to identify those who consumed an energy drink before their event. Patient demographics, clinical characteristics, documented energy drink consumption, and temporal relationship of energy drink consumption to SCA were obtained. Among 144 SCA survivors, 7 (5%; 6 female; mean age at SCA 29 ± 8 years) experienced an unexplained SCA associated temporally with energy drink consumption. Of these individuals, 2 had long QT syndrome and 2 had catecholaminergic polymorphic ventricular tachycardia; the remaining 3 were diagnosed with idiopathic ventricular fibrillation. Three patients (43%) consumed energy drinks regularly. Six patients (86%) required a rescue shock, and 1 (14%) was resuscitated manually. All SCA survivors have quit consuming energy drinks and have been event-free since. Overall, 5% of SCA survivors experienced SCA in proximity to consuming an energy drink. Although larger cohort studies are needed to elucidate the incidence/prevalence and quantify its precise risk, it seems prudent to sound an early warning on this potential risk. [ABSTRACT FROM AUTHOR]

Cardiac tachyarrhythmia presents a significant health care challenge, causing notable morbidity and mortality. Conventional treatments have limitations and potential risks, resulting in an elevated disease burden. Adeno-associated virus (AAV)–mediated gene therapy holds promise as a potential future treatment option. Therefore, we aimed to provide a measured overview of the latest developments in this rapidly growing field. PubMed and Embase databases were searched up to January 2024. Studies that employed AAV as a vector for delivery of therapeutic agents to treat cardiac tachyarrhythmia were included. Of the 26 studies included, 20 published in the last 5 years. There were 22 novel molecular targets identified. More than 80% of the included studies employed small-animal models or used AAV9. In atrial fibrillation preclinical studies, AAV-mediated gene therapy reduced atrial fibrillation inducibility by 81% (odds ratio, 0.19 [0.08–0.45]; P <.01). Similarly, for acquired and inherited ventricular arrhythmia, animal models receiving gene therapy had less inducible ventricular arrhythmia (odds ratio, 0.06 [0.03–0.11]; P <.01). This review highlights the rapid progress of AAV-mediated gene therapy for cardiac tachyarrhythmia. Although these investigations are currently in the early stages of clinical application, they present promising prospects for gene therapy. (PROSPERO registry: CRD42023479448) [ABSTRACT FROM AUTHOR]

Right dominant arrhythmogenic cardiomyopathy, commonly known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), represents a formidable challenge in cardiovascular medicine, as conventional therapies are commonly ineffective in impeding disease progression and the development of end-stage heart failure. Recombinant adeno-associated virus (AAV)-mediated gene therapy presents a promising avenue for targeted therapeutic interventions, potentially revolutionising treatment approaches for ARVC patients. Encouraging results from preclinical studies have sparked optimism about the possibility of curing specific subtypes of ARVC in the near future. This narrative review delves into the dynamic landscape of genetic therapy for ARVC, elucidating its underlying mechanisms and developmental stages, and providing updates on forthcoming trials. Additionally, it examines the hurdles and complexities impeding the successful translation of ARVC genetic therapies into clinical practice. Despite notable scientific advancements, the journey towards implementing genetic therapies for ARVC patients in real-world clinical settings is still in its early phases. [ABSTRACT FROM AUTHOR]

Right dominant arrhythmogenic cardiomyopathy, commonly known as Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), represents a formidable challenge in cardiovascular medicine, as conventional therapies are commonly ineffective in impeding disease progression and the development of end-stage heart failure. Recombinant adeno-associated virus (AAV)-mediated gene therapy presents a promising avenue for targeted therapeutic interventions, potentially revolutionising treatment approaches for ARVC patients. Encouraging results from preclinical studies have sparked optimism about the possibility of curing specific subtypes of ARVC in the near future. This narrative review delves into the dynamic landscape of genetic therapy for ARVC, elucidating its underlying mechanisms and developmental stages, and providing updates on forthcoming trials. Additionally, it examines the hurdles and complexities impeding the successful translation of ARVC genetic therapies into clinical practice. Despite notable scientific advancements, the journey towards implementing genetic therapies for ARVC patients in real-world clinical settings is still in its early phases.

Competing Interests: Disclosures M.J.A. is a consultant for Abbott, BioMarin Pharmaceuticals, Boston Scientific, Bristol Myers Squibb, Illumina, Invitae, Medtronic, Solid Biosciences, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/intellectual property/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, Prolaio, and Thryv Therapeutics. However, none of these entities have contributed to this study in any manner.

Unexplained sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in the young remains a critical issue for clinicians, researchers, patients and their family members. In this review, we explore the current status of SCA and SCD evaluation in the young, including recent monogenic and polygenic disease discoveries, advancements in cardiac imaging and our growing understanding of the role of the Purkinje system in triggering life threatening and even fatal ventricular arrhythmias. Yet, despite these advancements, over a third of SCA and SCD among individuals with seemingly structurally normal hearts remain unexplained. We explore the future role of artificial intelligence, novel biomarkers, multimodality cardiac imaging, genetic discoveries, as well as wearable devices and sensors in closing this current gap. With the overarching framework provided in this review, we envision a future in which collaboration among patients, clinicians, researchers, innovators, and policy makers culminates in our ability to diagnose, predict, and ultimately prevent SCA and SCD in the young., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose of Review: Heart failure is a syndrome with poor prognosis and no curative options for the majority of patients. The standard one-size-fits-all-treatment approach, targeting neurohormonal dysregulations, helps to modulate symptoms of heart failure, but fails to address the cause of the problem. Precision medicine aims to go beyond symptom modulation and targets pathophysiological mechanisms that underlie disease. In this review, an overview of how precision medicine can be approached as a treatment strategy for genetic heart disease will be discussed. PLN R14del, a genetic mutation known to cause cardiomyopathy, will be used as an example to describe the potential and pitfalls of precision medicine. Recent Findings: PLN R14del is characterized by several disease hallmarks including calcium dysregulation, metabolic dysfunction, and protein aggregation. The identification of disease-related biological pathways and the effective targeting using several modalities, including gene silencing and signal transduction modulation, may eventually provide novel treatments for genetic heart disease. Summary: We propose a workflow on how to approach precision medicine in heart disease. This workflow focuses on deep phenotyping of patient derived material, including in vitro disease modeling. This will allow identification of therapeutic targets and disease modifiers, to be used for the identification of novel biomarkers and the development of precision medicine approaches for genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) in young people is predominantly caused by genetic causes as cardiomyopathies. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disease and is responsible for the major proportion of SCD in the young. The purpose of this study was to identify the genetic variants present in young SCD victims with HCM characteristics. From the Portuguese records of autopsies performed at the National Institute of Legal Medicine and Forensic Sciences, North Delegation, 16 young (16–50 years) SCD victims whose death was suspected to be a manifestation of HCM were selected. Using next-generation sequencing, the coding regions of 40 genes associated with HCM, candidates, or strongly related to HCM-phenocopies were investigated. The victims included in this study were all males, with a mean age of 33.4 ± 11.7 years, left ventricle mean thickness of 21.5 ± 6.28 mm, and the majority of deaths occurred during sleep (36%). A pathogenic or likely pathogenic variant was identified in six out of 16 (37.5%) victims, in the most common HCM genes (MYBPC3 and MYH7). Our results indicate that molecular autopsy of SCD victims contributes to a more precise identification of a cause of death, and this can be used in the prevention of SCD cases through family screening of first relatives who may carry the same pathogenic variant. [ABSTRACT FROM AUTHOR]

Aims: Indications and clinical impact of genetic testing for cardiac diseases have increased significantly over the past years. The aim of this physician-based European Heart Rhythm Association (EHRA) survey was to assess current clinical practice and access to genetic testing for cardiac diseases across European Society of Cardiology countries and to evaluate adherence to the 2022 EHRA/HRS/APHRS/LAHRS Expert Consensus Statement on genetic testing., Methods and Results: An online questionnaire composed of 28 questions was submitted to the EHRA Research Network and European Reference Network GUARD-Heart healthcare partners and promoted via dedicated social media channels. There were 357 respondents from 69 countries, 40% working in a hospital setting with a cardiac genetic service and/or a dedicated clinic focusing on inherited cardiac diseases and 27% with an onsite genetic laboratory. No genetic testing or low annual rate (<10/year) was declared by 39% of respondents. The majority of respondents (78%) declared issues or limitations to genetic testing access in their clinical practice. The main reasons for not providing or limited access to genetic testing were no availability of dedicated unit or genetic laboratory (35%) or reimbursement issues (25%). The most frequently reported indication for genetic testing was diagnostic purpose (55%). Most respondents (92%) declared offering genetic testing preceded by genetic counselling and 42% regular multidisciplinary evaluations for patients with cardiac genetic diseases. The perceived value of genetic testing in the diagnostic, prognostic, and therapeutic assessment was variable (67, 39, and 29%, respectively) and primarily based on the specific inherited disease. The majority of respondents recommended cascade genetic testing for the first-degree family members in case of pathogenic/likely pathogenic variant in the proband., Conclusion: This survey highlights a significant heterogeneity of genetic testing access and provision and issues attributable to the availability of dedicated unit/genetic laboratory and reimbursement. However, adequate adherence to indications in the current recommendations for genetic testing in patients with cardiac diseases was observed., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Within the last 5 years, cardiac society guidelines have begun to acknowledge shared decision making (SDM) for the athlete with sudden cardiac death-predisposing genetic heart diseases (GHDs), such as long QT syndrome (LQTS), and the possibility for that athlete's return to play. Previously, international guidelines embraced a de facto disqualification for all such athletes including athletes with solely a positive genetic test in Europe.Objectives: This study sought to examine the prevalence and outcomes of athletes with sudden cardiac death-predisposing GHDs, particularly LQTS, after their return to play.Methods: A retrospective review of the electronic medical record was performed on all athletes with GHD, with a primary analysis for those with LQTS, who were evaluated, risk stratified, and treated in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic by a single genetic cardiologist between July 1, 2000, and July 31, 2020.Results: There were 672 athletes with GHD overall including 494 athletes with LQTS (231 female athletes [46.8%]; mean age at diagnosis 14.8 ± 10.5 years; mean follow-up 4.2 ± 4.8 years) who were given return-to-play approval. Overall, 79 of 494 athletes with LQTS (16.0%) were symptomatic before diagnosis, and 58 (11.7%) had an implantable cardioverter-defibrillator. In 2,056 combined years of follow-up, there was no GHD-sports associated mortality. Instead, 29 patients (5.9%) had ≥1 nonlethal, LQTS-associated breakthrough cardiac event. Of those, 15 (3.0%) were athletes at the time of the breakthrough cardiac event, with 3 (0.6%) experiencing a sports-related breakthrough cardiac event, and 12 (2.4%) a non-sports-related event. Overall, the event rate was 1.16 nonlethal events per 100 athlete-years of follow-up.Conclusions: This 20-year single center experience challenges the status quo of disqualification for all athletes with LQTS and provides additional observational evidence, albeit from a single center, in support of the more contemporary SDM approaches to this complex issue. [ABSTRACT FROM AUTHOR]

The 22q11.2 deletion syndrome is characterized by multiple congenital anomalies including conotruncal cardiac defects. Identifying the patient with a 22q11.2 deletion (22q11del) can be challenging because many extracardiac features become apparent later in life. We sought to better define the cardiac phenotype associated with a 22q11del to help direct genetic testing. 1,610 patients with conotruncal defects were sequentially tested for a 22q11del. The counts and frequencies of primary lesions and cardiac features were tabulated for those with and those without a 22q11del. Logistic regression models investigated cardiac features that predicted deletion status in tetralogy of Fallot (TOF). Deletion frequency varied by primary anatomic phenotype. Regardless of the cardiac diagnosis, a concurrent aortic arch anomaly (AAA) was strongly associated with deletion status [odds ratio (OR), 5.07; 95 % confidence interval (CI), 3.66-7.04]. In the TOF subset, the strongest predictor of deletion status was an AAA (OR, 3.14; 95 % CI 1.87-5.27; p < 0.001), followed by pulmonary valve atresia (OR, 2.03; 95 % CI 1.02-4.02; p = 0.04). Among those with double-outlet right ventricle and transposition of the great arteries, only those with an AAA had a 22q11del. However, 5 % of the patients with an isolated conoventricular ventricular septal defect and normal aortic arch anatomy had a 22q11del, whereas no one with an interrupted aortic arch type A had a 22q11del. A subset of patients with conotruncal defects are at risk for a 22q11del. A concurrent AAA increases the risk regardless of the intracardiac anatomy. These findings help to direct genetic screening for the 22q11.2 deletion syndrome in the cardiac patient.

The sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be "potentially informative." The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved. [ABSTRACT FROM AUTHOR]

Background: Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists.Objectives: We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist.Methods: We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions.Results: In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53-0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65-0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts.Conclusion: This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis. [ABSTRACT FROM AUTHOR]

Prior to the recognition of distinct clinical entities, such as Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome, all sudden cardiac arrest (SCA) survivors with ventricular fibrillation (VF) and apparently structurally normal hearts were labelled as idiopathic ventricular fibrillation (IVF). Over the last three decades, the definition of IVF has changed substantially, mostly as result of the identification of the spectrum of SCA-predisposing genetic heart diseases (GHDs), and the molecular evidence, by post-mortem genetic analysis (aka, the molecular autopsy), of cardiac channelopathies as the pathogenic basis for up to 35% of unexplained cases of sudden cardiac death (SCD) in the young. The evolution of the definition of IVF over time has led to a progressively greater awareness of the need for an extensive diagnostic assessment in unexplained SCA survivors. Nevertheless, GHDs are still underdiagnosed among SCA survivors, due to the underuse of pharmacological challenges (i.e. sodium channel blocker test), misrecognition of electrocardiogram (ECG) abnormalities/patterns (i.e. early repolarization pattern or exercise-induced ventricular bigeminy) or errors in the measurement of ECG parameters (e.g. the heart-rate corrected QT interval). In this review, we discuss the epidemiology, diagnostic approaches, and the controversies related to role of the genetic background in unexplained SCA survivors with a default diagnosis of IVF. [ABSTRACT FROM AUTHOR]

The spectrum of inherited arrhythmogenic diseases (IADs) includes disorders without overt structural abnormalities (i.e. primary inherited arrhythmia syndromes) and structural heart diseases (i.e. arrhythmogenic ventricular cardiomyopathy, hypertrophic cardiomyopathy). The aim of this European Heart Rhythm Association (EHRA) survey was to evaluate current clinical practice and adherence to 2015 European Society of Cardiology Guidelines regarding the management of patients with IADs. A 24-item centre-based online questionnaire was presented to the EHRA Research Network Centres and the European Cardiac Arrhythmia Genetics Focus Group members. There were 46 responses from 20 different countries. The survey revealed that 37% of centres did not have any dedicated unit focusing on patients with IADs. Provocative drug challenges were widely used to rule-out Brugada syndrome (BrS) (91% of centres), while they were used in a minority of centres during the diagnostic assessment of long-QT syndrome (11%), early repolarization syndrome (12%), or catecholaminergic polymorphic ventricular tachycardia (18%). While all centres advised family clinical screening with electrocardiograms for all first-degree family members of patients with IADs, genetic testing was advised in family members of probands with positive genetic testing by 33% of centres. Sudden cardiac death risk stratification was straightforward and in line with current guidelines for hypertrophic cardiomyopathy, while it was controversial for other diseases (i.e. BrS). Finally, indications for ventricular mapping and ablation procedures in BrS were variable and not in agreement with current guidelines in up to 54% of centres. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy, HoCM, Genetic heart disease, Myosin inhibitor, HFpEF Summary of interview Prof. van der Velden discusses a recent clinical trial which used a myosin inhibitor to treat patients with obstructive hypertrophic cardiomyopathy (HoCM). Keywords: Hypertrophic cardiomyopathy; HoCM; Genetic heart disease; HFpEF; Myosin inhibitor EN Hypertrophic cardiomyopathy HoCM Genetic heart disease HFpEF Myosin inhibitor e131 e132 2 05/25/23 20230501 NES 230501 Graph B Dr Monika M. Gladka, from Amsterdam University Medical Centre (The Netherlands), interviews Prof. Jolanda van der Velden, Director of the Amsterdam Cardiovascular Sciences Institute (The Netherlands). b B Highlight: b In this I Cardiovascular Research i On I Life i interview, Professor van der Velden discusses recent advancements that are crucial for treatment of inherited cardiomyopathies in the future, as well as the challenges in creating effective therapies. [Extracted from the article]

In the context of the current global COVID-19 pandemic, this Consensus Statement provides current recommendations for patients with, or at risk of developing, genetic heart disease, and for their health care management and service provision in Australia and New Zealand. Apart from general recommendations, there are specific recommendations for the following conditions: cardiomyopathy, Brugada syndrome (including in children), long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Other recommendations are relevant to patient self-care and primary health care. [ABSTRACT FROM AUTHOR]

The article discusses the application of next-generation sequencing (NGS) of the human genome in cardiovascular disease and its future in clinical practice. Topics mentioned include the use of the NGS in the diagnosis of Mendelian disease, the challenges associated with NGS in the clinical setting, and the need to expand genetic and clinical databases and develop precise disease taxonomy for the success of the application of clinical genomics.

Background--Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. Methods and Results--We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41). Conclusions--FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDLlowering therapy, and comprehensive management of traditional coronary heart disease risk factors. [ABSTRACT FROM AUTHOR]

The article focuses on the treatment of genetic heart diseases among athletes. Topics discussed include 2005 guidelines of European Society of Cardiology on disqualification of athletes surrounding from genetic heart diseases from competitive sports for preventing sudden cardiac death; take of American Heart Association/American College of Cardiology on the same; and an account of athletes elected return-to-play affected for the same.

The article discusses a study which aims to provide a basis for the importance of assessing benefits and harms of new technologies and outline evidence for the application of hypertrophic cardiomyopathy (HCM) genetic testing as a predictive tool for asymptomatic family members.

Summary Many factors have been implicated in SIDS cases including environmental influences such as sleeping arrangements and smoking. Most recently, cardiac abnormalities have been hypothesised to play a role in some cases, particularly the primary genetic arrhythmogenic disorders such as familial long QT syndrome (LQTS). Both post-mortem and clinical studies of SIDS cases have provided supporting evidence for the involvement of cardiac genetic disorders in SIDS. This review provides a summary of this evidence focussing particularly on the primary hypothesis related to underlying familial LQTS. In addition, the current literature relating to other cardiac genetic conditions such as Brugada syndrome (BrS) and structural heart diseases such as hypertrophic cardiomyopathy (HCM) is briefly presented. Finally, the implications of a possible cardiac genetic cause of SIDS is discussed with reference to the need for genetic testing in SIDS cases and subsequent clinical and genetic testing in family members. [ABSTRACT FROM AUTHOR]

Genetic biomarkers are crucial for diagnosis, guiding of treatments and estimation of prognosis. In the past, clinical genetic diagnostics was limited by the sequencing information gained from selected exons and single genes. For genetically heterogeneous diseases, such as cardiomyopathies, where underlying mutations in more than 1000 exons are known, a Sanger-based comprehensive test would have been extremely expensive and labor intensive. Next-generation sequencing has overcome these problems in terms of costs, speed and throughput. In this review we discuss available methods for targeted next-generation sequencing that ease the introduction of this technology into routine clinical application. We further provide results of a study we have performed to compare two state-of-the-art methods for their enrichment efficiency and detection accuracy of variants in a clinical setting. [ABSTRACT FROM AUTHOR]

The evolution of genetic testing in the past few years has been astounding. In a matter of only a few years, we now have comprehensive gene tests comprising vast panels of “cardiac” genes, whole exome sequencing (the entire coding region) and even whole genome sequencing (the entire genome). Making the call as to whether a DNA variant is causative or benign is difficult and the focus of intense research efforts. In most cases, the final answer will not be a simple yes/no outcome but rather a graded continuum of pathogenicity. This allows classification of variants in a more probabilistic way. How we convey this to a patient is the challenge, and certainly shines a spotlight on the important skills of the cardiac genetic counselor. This is an exciting step forward, but the overwhelming complexity of the information generated from these tests means our current practices of conveying genetic information to the family must be carefully considered. Despite the challenges, a genetic diagnosis in a family has great benefit both in reassuring unaffected family members and removing the need for lifetime clinical surveillance. The multidisciplinary specialized clinic model, incorporating genetic counselors, cardiologists and geneticists, provides the ideal framework for ensuring the best possible care for genetic heart disease families. [Copyright &y& Elsevier]

Aims Mutations in the Lamin A/C gene may cause atrioventricular block, supraventricular arrhythmias, ventricular arrhythmias (VA), and dilated cardiomyopathy. We aimed to explore the predictors and the mechanisms of VA in Lamin A/C mutation-positive subjects. Methods and results We included 41 Lamin A/C mutation-positive subjects. PR-interval and occurrence of VA were recorded. Left ventricular (LV) myocardial function was assessed as ejection fraction and speckle tracking longitudinal strain by echocardiography. Magnetic resonance imaging was performed to assess fibrosis in a selection of subjects. Ventricular arrhythmias were documented in 21 patients (51%). Prolonged PR-interval was the best predictor of VA (P < 0.001). Myocardial function by strain was reduced in the interventricular septum compared with the rest of the LV segments (−16.7% vs. −18.7%, P = 0.001) and correlated to PR-interval (R = 0.41, P = 0.03). Myocardial fibrosis was found exclusively in the interventricular septum and only in patients with VA (P = 0.007). PR-interval was longer in patients with septal fibrosis compared with those without (320 ± 66 vs. 177 ± 40 ms, P < 0.001). Conclusion Prolonged PR-interval was the best predictor of VA in Lamin A/C mutation-positive subjects. Electrical, mechanical, and structural cardiac properties were related in these subjects. Myocardial function was most reduced in the interventricular septum and correlated to prolonged PR-interval. Myocardial septal fibrosis was associated with prolonged PR-interval and VA. Localized fibrosis in the interventricular septum may be the mechanism behind reduced septal function, atrioventricular block and VA in Lamin A/C mutation-positive subjects. [ABSTRACT FROM PUBLISHER]

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal, rare hereditary disease with an estimated prevalence of 1:10 000. The genetic variants that cause CPVT are usually highly penetrant. To date, about 189 variants in 5 genes (RYR2, CASQ2, CALM1, TRND, and KCNJ2) have been associated with CPVT pathogenesis.The Exome Sequencing Project database (ESP; n= 6503) was systematically searched for previously published missense and nonsense CPVT-associated variants reported in several comprehensive reviews and in 2 databases: The Human Gene Mutation Database and The Inherited Arrhythmias Database. We used 4 different prediction tools to assess all missense variants previously associated with CPVT and compared the prediction of protein damage between CPVT-associated variants identified in the ESP and those variants not identified in the ESP. We identified 11% of the variants previously associated with CPVT in the ESP population. In the literature, 57% of these variants were reported as novel disease-causing variants absent in the healthy control subjects. These putative CPVT variants were identified in 41 out of 6131 subjects in the ESP population, corresponding to a prevalence of CPVT of up to 1:150. Using an agreement of ≥3, in silico prediction tools showed a significantly higher frequency of damaging variants among the CPVT-associated variants not identified in the ESP database (83%) compared with those variants identified in the ESP (50%; P=0.021).We identified a substantial overrepresentation of CPVT-associated variants in a large exome database, suggesting that these variants are not necessarily the monogenic cause of CPVT. [ABSTRACT FROM AUTHOR]

Whole exome sequencing is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied whole exome sequencing to identify the causal variant in a large family with familial dilated cardiomyopathy of unknown pathogenesis.A large family with autosomal dominant, familial dilated cardiomyopathy was identified. Exome capture and sequencing were performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool. Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency 0.001 or not reported) in 2 public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with Variant Annotation Analysis and Search Tool supported this result.Whole exome sequencing of remotely related dilated cardiomyopathy subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis. [ABSTRACT FROM AUTHOR]

The article evaluates the efficacy and harm rate of implantable cardioverter defibrillator (ICD) therapy for primary prevention versus secondary prevention in inherited cardiac diseases. Findings showed that for Brugada Syndrome, long QT and DPP6, ICD do not relate to the occurrence of appropriate shocks. Higher discharge rates in arrhythmogenic right ventricular cardiomyopathy and hypertrophic cardiomyopathy may result from more advanced stratification in the inherited cardiomyopathies.

The article focuses on treatment and diagnosis of cardiac channelopathies. It states that genetic testing ideally identifies patients at risk through optimal therapy and identifies those patients who are not carriers. It further states that the paradigm of inherited arrhythmias was changed by the seminal discovery of genetic linkage for long-QT syndrome (LQTS). Studies reveal that KCNQ1, KCNH2, and SCN5A genes were the cause for the clinical disorder of LQTS.

The article presents a study which analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of individuals from the National Heart, Lung, and Blood Institute's Exome Sequencing Project and the rates of structural variation from the Database of Genomic Variants. Cardiomyopathy-associated genes showed a rate of nonsense variants. It was concluded that genes associated with cardiomyopathy have very low rates of population variation.

The article assesses cardiac myosin binding protein-C (MYBPC3) mutations in families with hypertrophic cardiomyopathy (HCM). It is indicated that HCM typified by marked variation in clinical phenotype, is inherited as autosomal dominant trait caused by mutations in cardiac sarcomeric protein genes in about 60% of patients. Study results showed marked heterogeneity with incomplete, age-related and gender specific penetrance in disease expression in families with HCM related to MYBPC3 mutations.

Abstract: Over the last decade the genetic etiology of many heritable diseases could be resolved. For heart muscle diseases, so called cardiomyopathies, mutations in more than 40 different genes have been identified. Due to this large genetic heterogeneity and missing of adequate gene-diagnostic tools, most patients are not genetically characterized, which would be important for individualized patient care. Currently, next-generation sequencing technologies are revolutionizing genetic and epigenetic research, since they are capable to produce billions of bases of sequence information in a single experiment. Accordingly, this powerful technology can now also open avenues for genetic diagnostics. The scope of this article is to illustrate technical approaches, clinical applications, and yet unsolved problems of next-generation sequencing entering the clinical arena. [Copyright &y& Elsevier]

The article presents information on the role of multiple mutations in patients with genetic cardiovascular disease. A brief overview is given on inherited cardiomyopathies, such as hypertrophic cardiomyopathy (HCM). It explains the clinical and genetic heterogeneity in genetic cardiovascular disease. It also explores multiple mutations in other genetic cardiovascular disorders.

A National Genetic Heart Disease Registry has recently been established, with the aim to enrol every family in Australia with a genetically determined cardiomyopathy or primary arrhythmic disorder. The Registry seeks to further our understanding of the impact and burden of disease in this population; increase awareness and provide education to health professionals and families; and establish a large cardiac genetic cohort as a resource for approved research studies. The Registry is currently recruiting families with inherited cardiomyopathies (e.g. hypertrophic cardiomyopathy) and primary arrhythmogenic disorders (e.g. long QT syndrome), with scope to expand this in the future. Affected individuals, as well as their first-degree (at-risk) family members are eligible to enrol. Participants are currently being recruited from cardiac genetics clinics in approved recruitment sites and hope to expand to other Australian centres including general cardiology practice in the future. A significant focus of the Registry is to improve understanding and create awareness of inherited heart diseases, which includes ensuring families are aware of genetic testing options and current clinical screening recommendations for at-risk family members. A Registry Advisory Committee has been established under the NHMRC Guidelines, and includes a representative from each major recruitment centre. This committee approves all decisions relating to the Registry including approval of research studies. A National Genetic Heart Disease Registry will provide a valuable resource to further our knowledge of the clinical and genetic aspects of these diseases. Since most of the current data about the prevalence, natural history and outcomes of genetic heart diseases has emanated from the United States and Europe, characterising these Australian populations will be of significant benefit, allowing for more informed and specific health care planning and resource provision. [Copyright &y& Elsevier]

The author reflects on a study by C.A. James et al on the psychosocial adjustment, anxiety and depression in 86 adult with arrhythmogenic right ventricular cardiomyopathy (ARVC) and implantable cardioverter defibrillator (ICDs). Four questionnaires were used to assess ICD-specific anxiety, device acceptance and functional capacity. He finds the study timely and meaningful and commends James for bringing to attention the risk for poor psychosocial adjustment in patients with ARVC and ICDs.