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ImportanceIndividuals with schizophrenia have a reduced life-expectancy compared to the general population, largely due to an increased risk of cardiovascular disease (CVD). Clinical and epidemiological studies have been unable to fully unravel the nature of this relationship.ObjectiveInvestigate genetic correlations and potential bi-directional effects between liability to schizophrenia and CVD.Design, setting, and participantsWe obtained summary-data of genome-wide-association studies of schizophrenia (N=130,644), heart failure (N=977,323), coronary artery disease (N=332,477), systolic and diastolic blood pressure (N=757,601), heart rate variability (N=46,952), QT interval (N=103,331), early repolarization and dilated cardiomyopathy ECG patterns (N=63,700). We computed genetic correlations with linkage disequilibrium score regression and conducted bi-directional Mendelian randomization (MR). With multivariable MR, we investigated whether associations were mediated by smoking, body mass index, physical activity, lipid levels, or type 2 diabetes. To ensure robustness, we applied a range of sensitivity methods.Main outcomes and measuresSchizophrenia, heart failure, coronary artery disease, systolic blood pressure, diastolic blood pressure, heart rate variability, QT interval, early repolarization, dilated cardiomyopathy.ResultsGenetic correlations between liability to schizophrenia and CVD were close to zero (−0.02 to 0.04). With MR, we found robust evidence that liability to schizophrenia increases heart failure risk. This effect remained consistent with multivariable MR. There was also evidence that liability to schizophrenia increases early repolarization risk, largely mediated by BMI and lipid levels. Finally, there was evidence that liability to schizophrenia increases heart rate variability, a direction of effect contrasting previous studies. In the other direction, there was weak evidence that higher systolic, but not diastolic, blood pressure increases schizophrenia risk.Conclusions and relevanceOur findings indicate that liability to schizophrenia increases the risk of heart failure, and that this is not mediated by key health behaviours. This is consistent with the notion that schizophrenia is characterised by a systemic dysregulation of the body (including inflammation and oxidative stress) with detrimental effects on the heart. To decrease cardiovascular mortality among schizophrenia patients, priority should lie with optimal treatment and interventions in early stages of psychoses. We also identified early repolarization, currently understudied, as a potential CVD marker among patients with schizophrenia.

Hypertrophic cardiomyopathy (HCM) was traditionally described as an autosomal dominant Mendelian disease but is now increasingly recognized as having a complex genetic aetiology. Although eight core genes encoding sarcomeric proteins account for >90% of the pathogenic variants in patients with HCM, variants in several additional genes (ACTN2, ALPK3, CSRP3, FHOD3, FLNC, JPH2, KLHL24, PLN and TRIM63), encoding non-sarcomeric proteins with diverse functions, have been shown to be disease-causing in a small number of patients. Genome-wide association studies (GWAS) have identified numerous loci in cardiomyopathy case–control studies and biobank investigations of left ventricular functional traits. Genes associated with Mendelian cardiomyopathy are enriched in the putative causal gene lists at these loci. Intriguingly, many loci are associated with both HCM and dilated cardiomyopathy but with opposite directions of effect on left ventricular traits, highlighting a genetic basis underlying the contrasting pathophysiological effects observed in each condition. This overlap extends to rare Mendelian variants with distinct variant classes in several genes associated with HCM and dilated cardiomyopathy. In this Review, we appraise the complex contribution of the non-sarcomeric, HCM-associated genes to cardiomyopathies across a range of variant classes (from common non-coding variants of individually low effect size to complete gene knockouts), which provides insights into the genetic basis of cardiomyopathies, causal genes at GWAS loci and the application of clinical genetic testing. In this Review, Walsh et al. explore the complex contribution of genes encoding non-sarcomeric proteins that are robustly associated with non-syndromic or isolated hypertrophic cardiomyopathy to the genetics of cardiomyopathies across the full range of variant classes, from common regulatory variants to complete gene knockouts.

Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with apparently unexplained cardiac arrest (UCA) after varying degrees of evaluation. This is largely due to the lack of a standardized approach to UCA.We sought to develop an evidence-based diagnostic algorithm for IVF by systematically examining the yield of diagnostic testing in UCA probands.Studies reporting the yield of diagnostic testing in UCA were identified in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and conference abstracts. Their methodological quality was assessed by the National Institutes of Health quality assessment tool. Meta-analyses were performed using the random effects model.A total of 21 studies were included. The pooled comprehensive diagnostic testing yield was 43% (95% confidence interval 39%-48%). A lower yield was seen when only definite diagnoses based on the prespecified criteria were used (32% vs 47%; P = .15). Epinephrine challenge, Holter monitoring, and family screening were associated with low yield (5%), whereas cardiac magnetic resonance imaging, exercise treadmill test, and sodium-channel blocker challenge were associated with high yield (≥5%). Coronary spasm provocation, electrophysiology study, and systematic genetic testing were reported to be abnormal in a high proportion of UCA probands (10%).We developed a stepwise algorithm for UCA evaluation and criteria to assess the strength of IVF diagnosis on the basis of the diagnostic yield of UCA testing.

Polygenic scores incorporating varying numbers of single nucleotide polymorphisms (SNPs) have been demonstrated to exert a prominent role in atrial fibrillation (AF). We sought to compare the relative discriminatory capacities of 2 previously validated polygenic scores in "lone" AF.A total of 186 lone AF cases of European ancestry underwent SNP genotyping. A genome-wide polygenic score (GPS) and polygenic risk score (PRS) involving 6,730,541 and 1168 SNPs, respectively, were calculated for 186 cases and 423 controls of European ancestry from the 1000 Genomes (1KG) Project. The distribution of the polygenic scores was compared between the cases and controls and their discriminatory capacities were evaluated using receiver operating characteristic (ROC) curves.A total of 34.4% of patients with lone AF had GPS scores greater than the top 10th percentile of 1KG controls, corresponding to a 4.64-fold increased odds (95% confidence interval [CI], 2.99-7.18;Our study evaluating 2 polygenic scores for AF suggests that the GPS, containing more than 6.7 million SNPs, exhibits an improved discriminatory capacity in lone AF compared with a PRS possessing 1168 SNPs. Our findings suggest that genetic risk scores for AF that maximally leverage genomic data may provide improved predictive power.Il a été démontré que des scores polygéniques intégrant un nombre variable de polymorphismes mononucléotidiques (PMN) jouent un rôle important en ce qui concerne la fibrillation auriculaire (FA). Nous avons comparé le potentiel discriminatoire relatif de deux scores polygéniques déjà validés dans la FA idiopathique.Au total, 186 sujets d’ascendance européenne atteints de FA idiopathique ont été soumis à un génotypage des PMN. Un score polygénique génomique (SPG) et un score de risque polygénique (SRP) comprenant respectivement 6 730 541 et 1 168 PMN ont été calculés pour les 186 sujets et pour 423 témoins d’ascendance européenne dont les données sont tirées du projet 1000 Genomes (1KG). Les distributions des scores polygéniques des sujets et des témoins ont été comparées, et leur potentiel discriminatoire a été évalué au moyen des courbes caractéristiques de la performance d’un test (courbes ROC, de l’anglaisAu total, 34,4 % des patients atteints de FA idiopathique avaient un SPG supérieur à celui des témoins du 10Les résultats de notre étude de deux scores polygéniques relatifs à la FA indiquent que le potentiel discriminatoire du SPG, qui comprend plus de 6,7 millions de PMN, pour prédire une FA idiopathique est supérieur à celui du SRP, qui comprend 1 168 PMN. Ces résultats indiquent que les scores de risque génétique de FA qui exploitent pleinement les données génomiques pourraient avoir un pouvoir prédictif supérieur.

BACKGROUND: Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model. OBJECTIVE: The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand. METHODS: We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants. RESULTS: Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10-10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10-10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10-9). Rare (minor allele frequency [MAF] 0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2-82.3). CONCLUSION: The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci.

Background: The Hearts in Rhythm Organization (HiRO) is a team of Canadian inherited heart rhythm and cardiomyopathy experts, genetic counsellors, nurses, researchers, patients, and families dedicated to the detection of inherited arrhythmias and cardiomyopathies, provision of best therapies, and protection from the tragedy of sudden cardiac arrest. Methods: Recently, existing disease-specific registries were merged into the expanded National HiRO Registry, creating a single common data set for patients and families with inherited conditions that put them at risk for sudden death in Canada. Eligible patients are invited to participate in the registry and optional biobank from 20 specialized cardiogenetics clinics across Canada. Results: Currently, there are 4700 participants enrolled in the National HiRO Registry, with an average of 593 participants enrolled annually over the past 5 years. The capacity to enable knowledge translation of research findings is built into HiRO’s organizational infrastructure, with 3 additional working groups (HiRO Clinical Care Committee, HiRO Active Communities Committee, and HiRO Annual Symposium Committee), supporting the organization’s current goals and priorities as set alongside patient partners. Conclusion: The National HiRO Registry aims to be an integrated research platform to which researchers can pose novel research questions leading to a better understanding, detection, and clinical care of those living with inherited heart rhythm and cardiomyopathy conditions and ultimately to prevent sudden cardiac death. Résumé: Contexte: La Hearts in Rhythm Organization (HiRO) est une équipe d’experts canadiens en matière de rythmes cardiaques et de cardiomyopathies héréditaires, de conseillers en génétique, d’infirmières, de chercheurs, de patients et de familles qui se consacrent à la détection des arythmies et des cardiomyopathies héréditaires, à la mise en place des meilleures thérapies et à la protection contre la tragédie que représente une mort subite d’origine cardiaque. Méthodes: Récemment, les registres existants relatifs à des maladies spécifiques ont été fusionnés en un registre national élargi de l’HiRO, créant ainsi un ensemble de données commun unique à destination des patients et leurs familles, atteints de maladies héréditaires, qui sont à risque de mort subite au Canada. Les patients admissibles sont invités à s’associer au registre et à la biobanque facultative regroupant 20 cliniques spécialisées en cardiogénétique au Canada. Résultats: Actuellement, 4 700 participants sont inscrits au registre national de l’HiRO, avec une moyenne de 593 participants inscrits chaque année au cours des cinq dernières années. La capacité à favoriser l’application des connaissances issues de la recherche fait partie de la structure organisationnelle de l’HiRO, avec trois groupes de travail supplémentaires (comité des soins cliniques de l’HiRO, comité des communautés cctives de l’HiRO et comité du symposium annuel de l’HiRO), soutenant les objectifs et les priorités actuels de l’organisation tels qu’ils ont été fixés en partenariat avec les patients. Conclusion: Le registre national de l’HiRO vise à devenir une plateforme de recherche intégrée au sein de laquelle les chercheurs peuvent exposer des questions de recherche inédites permettant de mieux comprendre, détecter et soigner les personnes atteintes de troubles du rythme cardiaque et de cardiomyopathie héréditaires et, à terme, de prévenir la mort subite d’origine cardiaque.

Background Access to pacemakers and defibrillators is problematic in places with limited resources. Resterilization and reuse of implantable cardiac devices obtained post mortem from patie...

Genetic testing is playing an ever-expanding role in cardiovascular care and is becoming part of the “toolkit” for the cardiovascular clinician. In patients with inherited arrhythmias, genetic testing can confirm a suspected diagnosis, establish a diagnosis in unexplained cases, and help facilitate cascade family screening. Many inherited arrhythmia syndromes are monogenic diseases arising from a single pathogenic variant involved in the structure and function of cardiac ion channels or structural proteins. As such, “arrhythmia gene panels” will often cast a wide net for such heritable diseases. However, challenges may arise when genetic testing results are ambiguous, or when genetic testing results (genotype) and clinical phenotypes do not match. In cases of “genotype-phenotype matching,” genetic results complement the clinical phenotype and genetic testing can be used in diagnosis, family screening, and occasionally prognostication. It becomes more challenging when genetic results are negative or noncontributory and “contradict” the clinical phenotype. “Genotype mismatches” can also occur when genotype-positive patients have no clinical phenotype, or when genetic testing results point towards a completely different disease than the clinical phenotype. We discuss an approach to genetic testing and review the challenges that may arise when interpreting genetic testing results. Genetic testing has opened a wealth of opportunities in the diagnosis, management, and cascade screening of inherited arrhythmia syndromes, but has also opened a “Pandora’s box” of challenges. Genetic results should be interpreted with caution and in a multidisciplinary clinic, with support from genetic counsellors and an expert with a focused interest in cardiovascular genetics.

Research teams developing biobanks and/or genomic databases must develop policies for the disclosure and reporting of potentially actionable genomic results to research participants. Currently, a broad range of approaches to the return of results exist, with some studies opting for non-disclosure of research results while others follow clinical guidelines for the return of potentially actionable findings from sequencing. In this review, we describe current practices and highlight decisions a research team must make when designing a return of results policy, from informed consent to disclosure practices and clinical validation options. The unique challenges of returning incidental findings in cardiac genes, including reduced penetrance and the lack of clinical screening standards for phenotype-negative individuals are discussed. Lastly, the National Hearts in Rhythm Organization (HiRO) Registry approach is described to provide a rationale for the selective return of field-specific variants to those participating in disease-specific research. Our goal is to provide researchers with a resource when developing a return of results policy tailored for their research program, based on unique factors related to study design, research team composition and availability of clinical resources.

AIMS: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. METHODS AND RESULTS: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P

Objectives: This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics.Background: Quinidine is an antiarrhythmic med...

Objectives This investigation was a retrospective study of catecholaminergic polymorphic ventricular tachycardia (CPVT) patients in Canada and the Netherlands to compare pregnancy, postpartum, and nonpregnant event rates. Background CPVT is characterized by life-threatening arrhythmias during exertion or emotional stress. The arrhythmic risk in CPVT patients during pregnancy is unknown. Methods Baseline demographics, genetics, treatment, and pregnancy complications were reviewed. Event rate calculations assumed a 40-week pregnancy and 24-week postpartum period. Results Ninety-six CPVT patients had 228 pregnancies (median 2 pregnancies per patient; range: 1 to 10; total: 175.4 pregnant patient-years). The median age of CPVT diagnosis was 40.7 years (range: 12 to 84 years), with a median follow-up of 2.9 years (range: 0 to 20 years; total 448.1 patient-years). Most patients had pregnancies before CPVT diagnosis (82%). Pregnancy and postpartum cardiac events included syncope (5%) and an aborted cardiac arrest (1%), which occurred in patients who were not taking beta-blockers. Other complications included miscarriages (13%) and intrauterine growth restriction (1 case). There were 6 cardiac events (6%) during the nonpregnant period. The pregnancy and postpartum event rates were 1.71 and 2.85 events per 100 patient-years, respectively, and the combined event rate during the pregnancy and postpartum period was 2.14 events per 100 patient-years. These rates were not different from the nonpregnant event rate (1.46 events per 100 patient-years). Conclusions The combined pregnancy and postpartum arrhythmic risk in CPVT patients was not elevated compared with the nonpregnant period. Most patients had pregnancies before diagnosis, and all patients with events were not taking beta-blockers at the time of the event.

Background: Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as reinterpretation can change the diagnosis, prognosis, and management of patients and their relatives. Methods: This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American College of Medical Genetics and Association for Molecular Pathology guidelines for the interpretation of genetic variants. The algorithm was applied to genetic results in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry, to assess the rate of variant reclassification over time. Variant classifications were then compared with the classifications of 2 commercial laboratories to determine the rate and identify sources of variant interpretation discordance. Results: Thirty-one percent of participants (40 of 131) had at least 1 genetic variant with a clinically significant reclassification over time. Variants of uncertain significance were more likely to be downgraded (73%) to benign than upgraded to pathogenic (27%; P =0.03). For the second part of the study, 50% (70 of 139) of variants had discrepant interpretations (excluding benign variants), provided by at least 1 team. Conclusions: Periodic review of genetic variant classification is a key component of follow-up care given rapidly changing information in the field. There is potential for clinical care gaps with discrepant variant interpretations, based on the interpretation and application of current guidelines. The development of gene- and disease-specific guidelines and algorithms may provide an opportunity to further standardize variant interpretation reporting in the future. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00292032.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Aim. Cardiac arrhythmias comprise a major health and economic burden and are associated with significant morbidity and mortality, including cardiac failure, stroke and sudden cardiac death (SCD). Development of efficient preventive and therapeutic strategies is hampered by incomplete knowledge of disease mechanisms and pathways. Our aim is to identify novel mechanisms underlying cardiac arrhythmia and SCD using an unbiased approach. Methods and Results. We employed a phenotype-driven N-ethyl-N-nitrosourea (ENU) mutagenesis screen and identified a mouse line with a high incidence of sudden death at young age (6-9 weeks) in the absence of prior symptoms. Affected mice were found to be homozygous for the nonsense mutation Bcat2p.Q300*/p.Q300* in the Bcat2 gene encoding branched chain amino acid transaminase 2. At the age of 4-5 weeks, Bcat2p.Q300*/p.Q300* mice displayed drastic increase of plasma levels of branch chain amino acids (BCAAs – leucine, isoleucine, valine) due to the incomplete catabolism of BCAAs, in addition to inducible arrhythmias ex vivo as well as cardiac conduction and repolarization disturbances. In line with these findings, plasma BCAA levels were positively correlated to ECG indices of conduction and repolarization in the German community-based KORA F4 Study. Isolated cardiomyocytes from Bcat2p.Q300*/p.Q300* mice revealed action potential (AP) prolongation, pro-arrhythmic events (early and late afterdepolarizations, triggered APs) and dysregulated calcium homeostasis. Incubation of human pluripotent stem cell-derived cardiomyocytes with elevated concentration of BCAAs induced similar calcium dysregulation and pro-arrhythmic events which were prevented by rapamycin, demonstrating the crucial involvement of mTOR pathway activation. Conclusions. Our findings identify for the first time a causative link between elevated BCAAs and arrhythmia, which has implications for arrhythmogenesis in conditions associated with BCAA metabolism dysregulation such as diabetes, metabolic syndrome and heart failure. Translational perspectives. Development of efficient anti-arrhythmic strategies is hampered by incomplete knowledge of disease mechanisms. Using an unbiased approach, we here identified for the first time a pro-arrhythmic effect of increased levels of branched chain amino acids (BCAAs). This is of particular relevance for conditions associated with BCAA dysregulation and increased arrhythmia risk, including heart failure, obesity and diabetes, as well as for athletes supplementing their diet with BCAAs. Such metabolic dysregulation is potentially modifiable through dietary interventions, paving the way for novel preventive strategies. Our findings furthermore identify mTOR inhibition as a potential anti-arrhythmic strategy in patients with metabolic syndrome.

Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77–10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69–0.80) and calibration slope of 0.95 (95% CI, 0.94–0.98) indicating minimal over-optimism. Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.

Supplemental Digital Content is available in the text., Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P=0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Introduction: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure requiring transplantation in young individuals. While some cases have a monogenic underlying cause, the majority remain unexplained. Objective: To better understand the contribution of common genetic variants in susceptibility and severity of cardiomyopathy. Methods: We conducted three genome-wide association studies (GWAS) and multi-trait analyses in European-ancestry individuals, including a HCM (1,733 cases) and DCM meta-analyses (5,521 cases), and a GWAS of 9 left ventricular (LV) traits in 19,260 healthy participants from the UK Biobank that underwent cardiac magnetic resonance imaging. We investigated genetic correlations between LV traits, HCM and DCM using LD score regression. We used two-sample mendelian randomization (MR) to assess the causal relationship of increased LV contractility with HCM risk. Lastly, we derived a polygenic risk score and assessed whether it modulates maximal LV wall thickness (maxLVWT) and clinical events in 368 sarcomeric mutation carriers, using linear and Cox mixed effects models, respectively. Results: We identified 16 genetic loci (15 novel) associated with HCM, 13 loci (7 novel) associated with DCM, and 23 loci associated with LV traits. We showed strong genetic correlations between LV volumes and contractility traits in the general population and cardiomyopathies, with opposing effects in HCM and DCM. Using MR, we demonstrated a causal association linking increased LV contractility with HCM risk and estimated that each unit (1%) increase in LV ejection fraction increases the risk of HCM by 37% (95% CI 10%-69%, P=0.004). Lastly, a polygenic risk score (PRS HCM ) derived from the HCM GWAS was associated with maxLVWT (P=0.0001) and clinical events (P=0.009) in carriers of HCM-causing rare variants. Conclusion: Our findings highlight the contribution of common genetic variants in susceptibility for HCM and DCM, and in severity in sarcomeric mutation carriers. Our data also point to increased LV contractility as an important mechanism of HCM independently of sarcomere activating rare variants, and highlight the potential clinical relevance of PRS for risk stratification in HCM.

Aims The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors. Methods and results We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of Conclusion Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes.

Background/Introduction Guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false positive rate over test sensitivity and diagnostic yield, and require customisation for the specific genetic characteristics of gene-disease dyads. Inherited arrhythmias like long QT syndrome (LQTS) and Brugada syndrome (BrS) are genetically heterogeneous, with missense variants constituting the preponderance of disease-causing variants. Evidence from family segregation or functional assays to confirm pathogenicity are often unavailable or impractical in clinical genetic testing, leading to high rates of variants of uncertain significance and false negative test results. Methods We compared rare variant frequencies from 1847 LQTS (KCNQ1, KCNH2, SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data. We propose disease-specific criteria for ACMG/AMP evidence classes – rarity (PM2/BS1 rules) and enrichment of individual (PS4) and domain-specific (PM1) variants in cases over controls. Results Rare SCN5A variant prevalence differed between BrS cases with spontaneous (28.7%) versus induced (15.8%) type 1 Brugada ECG (p=1.3x10–13) and between European (20.8%) and Japanese (8.9%) patients (p=8.8x10–18). Transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterised by high enrichment of case variants and >95% probability of pathogenicity. Applying the customised rules, 17.5% of European BrS cases and 73.7% of European LQTS cases had variants classified as (likely) pathogenic, compared to estimated diagnostic yields (case excess over gnomAD) of 19.3%/82.6%. Conclusions Large case/control datasets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing. Classification of Brugada/LQTS variants Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Heart Foundation, Netherlands Organisation for Scientific Research

BACKGROUND: Pulmonary vein (PV) stenosis is a complication of atrial fibrillation (AF) ablation. The incidence of PV stenosis after routine post-ablation imaging remains unclear and is limited to single-centre studies. Our objective was to determine the incidence and predictors of PV stenosis following circumferential radiofrequency ablation in the multicentre Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination (ADVICE) trial. METHODS: Patients with symptomatic AF underwent circumferential radiofrequency ablation in one of 13 trial centres. Computed tomographic (CTA) or magnetic resonance (MRA) angiography was performed before ablation and 90 days after ablation. Two blinded reviewers measured PV diameters and areas. PVs with stenosis were classified as severe (> 70%), moderate (50%-70%), or mild (< 50%). Predictors of PV stenosis were identified by means of multivariable logistic regression. RESULTS: A total of 197 patients (median age 59.5 years, 29.4% women) were included in this substudy. PV stenosis was identified in 41 patients (20.8%) and 47 (8.2%) of 573 ablated PVs. PV stenosis was classified as mild in 42 PVs (7.3%) and moderate in 5 PVs (0.9%). No PVs had severe stenosis. Both cross-sectional area and diameter yielded similar classifications for severity of PV stenosis. Diabetes was associated with a statistically significant increased risk of PV stenosis (OR 4.91, 95% CI 1.45-16.66). CONCLUSIONS: In the first systematic multicentre evaluation of post-ablation PV stenosis, no patient acquired severe PV stenosis. Although the results are encouraging for the safety of AF ablation, 20.8% of patients had mild or moderate PV stenosis, in which the long-term effects are unknown.

Summary Engaging patients—defined broadly as individuals with lived experience of a given condition, family members, caregivers, and the organisations that represent them—as partners in research is a priority for policymakers, funders, and the public. Nonetheless, formal efforts to engage patients are absent from most studies, and models to support meaningful patient engagement in clinical anaesthesia research have not been previously described. Here, we review our experience in developing and implementing a multifaceted patient engagement strategy within the Regional Versus General Anesthesia for Promoting Independence After Hip Fracture (REGAIN) surgery trial, an ongoing randomised trial comparing spinal vs general anaesthesia for hip fracture surgery in 1600 older adults across 45 hospitals in the USA and Canada. This strategy engaged patients and their representatives at both the level of overall trial oversight and at the level of individual recruiting sites. Activities spanned a continuum ranging from events designed to elicit patients' input on key decisions to longitudinal collaborations that empowered patients to actively participate in decision-making related to trial design and management. Engagement activities were highly acceptable to participants and led to concrete changes in the design and conduct of the REGAIN trial. The REGAIN experience offers a model for future efforts to engage patients as partners in clinical anaesthesia research, and highlights potential opportunities for investigators to increase the relevance of anaesthesia studies by incorporating patient voices and perspectives into the research process.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

Polygenic risk scores, or PRS, are a tool to estimate individuals’ liabilities to a disease or trait measurement based solely on genetic information. One commonly discussed potential use is in the clinic to identify people who are at greater risk of developing a disease. In this paper, we investigate the suitability of three large PRS for coronary artery disease (CAD) for clinical use. In the UK Biobank, the cohort which was used in the creation of each score, we calculated the association between CAD, the scores, and population structure for the white British subset. After adjustment for geographic and socioeconomic factors, CAD was not associated with population structure; however all three scores were confounded by genetic ancestry, raising questions about how these biases would impact clinical application. Furthermore, we investigated the differences in risk stratification using four different UK Biobank assessment centers as separate cohorts and tested how missing genetic data affected risk stratification through simulation and comparisons to scores calculated in French Canadians. We show that missing data impact classification for extreme individuals for high- and low-risk, and quantiles of risk is sensitive to individual-level genotype missingness. Distributions of scores varied between assessment centers, revealing that thresholding based on quantiles can be problematic for consistency across centers and populations. We highlight three criteria that a genetic risk score must fulfill in order to be used to stratify patients in the clinic: 1) it must be robust to population structure 2) scores must provide absolute thresholds for risk levels, and 3) there must be an approach to compensate for missing genetic data. Finally, we propose potential avenues of improvements for determining individual’s genetic liability to a complex trait such as CAD.

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P P Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Introduction Left ventricle (LV) substrate can be characterized by imaging modalities providing physiological variables (tissue perfusion, ischemia, etc.) grouped in a complex dataset. Principal Component Analysis (PCA) can identify the dataset variables that best explain its variance. Variables linked to substrate arrhythmogenicity will lead PCA to identify LV regions most influenced by the variables on a LV 3D geometry. Purpose To evaluate whether regions identified by PCA correspond to regions targeted by physicians in a ventricular tachycardia (VT) ablation procedure. Methods Ischemic VT subjects underwent SPECT/CT perfusion imaging (rest and stress) prior to LV voltage mapping with the cardiac mapping system. Co-registration allowed projection of ablation sites onto SPECT/CT geometries. PCA retrospectively analyzed the following dataset: tissue perfusion (rest and stress), tissue ischemia and the local (1cm2 sub-regions) stress-rest difference for: 1) standard deviation (STD) and 2) skewness (Skew). PCA components (PCAc) explaining ≥85% of the total variance were plotted on the LV 3D geometry to display regions highly influenced by the dataset variables (see figure below). Results Ten subjects (9 males, 66 ± 8 years old, LVEF 37 ± 11%) underwent co-registration. In 7/10 subjects, tissue perfusion (in PCAc#1) and ischemia (in PCAc#2) were most influential on LV regions variance. Ischemia and low perfusion (≤40%) areas equaled 32 ± 19 % of the LV with 21 ± 23% of these areas highly involved in the arrhythmogenic substrate (≥75% of explained LV variance). The location of 63 ± 18% of ablation sites were Conclusion Preliminary results showed that PCA can synthesize the influence of different perfusion derived variables, like tissue perfusion and ischemia, used in SPECT/CT imaging of the LV. Further analysis is needed to confirm whether this could be used to select VT ablation targets. Abstract Figure.

Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular cardiomyopathies. We present a family with arrhythmogenic cardiomyopathy associated with a novel missense variant in DSP (NM_004415.4): c.877G>A, p.(Glu293Lys). The phenotype is characterized by predominant involvement of the left ventricle with systolic dysfunction, fibrosis, and life-threatening arrhythmias. We performed a systematic review of literature collecting all cardiomyopathy cases with rare missense variants in DSP. We demonstrate that the distribution of missense variants across the protein domains in cardiomyopathy cases differs from that in gnomAD (p = .04), with a case enrichment of rare missense variants in the spectrin repeat domain (36/78 [46%] in cases vs. 449/1495 [30%] in gnomAD; p = .004). Our findings highlight the predominance of cardiac arrhythmia and left ventricular involvement in desmoplakin cardiomyopathy and pinpoint to a potential mutation hotspot in DSP thereby facilitating missense variant interpretation in the diagnostic setting.

The COVID-19 pandemic has led to efforts at rapid investigation and application of drugs which may improve prognosis but for which safety and efficacy are not yet established. This document attempts to provide reasonable guidance for the use of antimicrobials which have uncertain benefit but may increase risk of QT interval prolongation and ventricular proarrhythmia, notably, chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. During the pandemic, efforts to reduce spread and minimize effects on health care resources mandate minimization of unnecessary medical procedures and testing. We recommend that the risk of drug proarrhythmia be minimized by 1) discontinuing unnecessary medications that may also increase the QT interval, 2) identifying outpatients who are likely to be at low risk and do not need further testing (no history of prolonged QT interval, unexplained syncope, or family history of premature sudden cardiac death, no medications that may prolong the QT interval, and/or a previous known normal corrected QT interval [QTc]), and 3) performing baseline testing in hospitalized patients or those who may be at higher risk. If baseline electrocardiographic testing reveals a moderately prolonged QTc, optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged, drugs that further prolong it should be avoided, or expert consultation may permit administration with mitigating precautions. These recommendations are made while there are no known effective treatments for COVID-19 and should be revisited when further data on efficacy and safety become available.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Arrhythmia-induced cardiomyopathy (AIC) is characterized by left ventricular systolic dysfunction for which the primary cause is arrhythmia. The hallmark of AIC is its reversibility once the arrhythmia is properly controlled. Any tachyarrhythmia can potentially cause AIC (often called "tachycardiomyopathy"), with atrial fibrillation (AF) being by far the most common in clinical practice. The pathophysiological mechanisms underlying AIC need further clarification, but the available evidence, principally from animal models, implicates metabolic dysfunction due to increased oxygen requirements, neurohormonal adaptive mechanisms, and cellular Ca2+ mishandling as important contributors. Tachycardia is a common denominator of most cases of AIC, but other components specific to the patient and the arrhythmia have been implicated. The diagnosis of AIC requires the exclusion of a primary causative role of other conditions such as hypertension, primary cardiomyopathies, and valve disease, which may require specific pharmacological and invasive therapies. Catheter ablation is emerging as a safe and effective alternative to antiarrhythmic medication and has an established role in the management of AIC. Recent studies showing improved cardiac function and mortality rates in patients with heart failure and concomitant AF dramatically illustrate the often-unrecognized scope of AIC and the potential benefits of interventional therapy. Major AF trials do not otherwise focus specifically on AIC, and careful analysis of the literature is necessary to appreciate the clinical characteristics and therapeutic implications. This contemporary review summarizes the current understanding of pathophysiological mechanisms underlying AIC, discusses the clinical implications, and offers a general approach to management, with a particular focus on AF-induced cardiomyopathy.

Objectives This study evaluated the yield of ajmaline testing and assessed the occurrence of confounding responses in a large cohort of families with unexplained cardiac arrest (UCA) or sudden unexplained death (SUD). Background Ajmaline testing to diagnose Brugada syndrome (BrS) is routinely used in the evaluation of SUD and UCA, but its yield, limitations, and appropriate dosing have not been studied in a large cohort. Methods We assessed ajmaline test response and genetic testing results in 637 individuals from 482 families who underwent ajmaline testing for SUD or UCA. Results Overall, 89 individuals (14%) from 88 families (18%) had a positive ajmaline test result. SCN5A mutations were identified in 9 of 86 ajmaline-positive cases (10%). SCN5A mutation carriers had positive test results at significantly lower ajmaline doses than noncarriers (0.75 [0.64 to 0.98] mg/kg vs. 1.03 [0.95 to 1.14] mg/kg, respectively; p 1mg/kg than in those obtained at ≤1mg/kg (7 of 48 vs. 0 of 41 individuals; Fisher’s exact test: p = 0.014). Conclusions In line with previous, smaller studies, a positive ajmaline response was observed in a large proportion of UCA/SUD families. Importantly, our data emphasize the potential for confounding possibly false-positive ajmaline responses in this population, particularly at high doses, which could possibly lead to a misdiagnosis. Clinicians should consider all alternative causes in UCA/SUD and avoid ajmaline doses >1 mg/kg.

Objectives The impact of beta-blockers on mortality and hospitalizations was assessed in the largest randomized trial of patients with both atrial fibrillation (AF) and heart failure with a reduced ejection fraction (HFrEF): the Atrial Fibrillation-Congestive Heart Failure trial. Background Although beta-blockers are the cornerstone of therapy for HFrEF, a recent patient-level meta-analysis cast doubt on their efficacy in patients with coexisting AF. Methods From a total of 1,376 subjects randomized in the AF-CHF trial, those without beta-blockers at baseline were propensity matched to a maximum of 2 exposed patients. All absolute standardized differences after matching were ≤10%. Primary analyses respected the intention-to-treat principle. In on-treatment sensitivity analyses, beta-blocker status was modeled as a time-dependent covariate. Results Baseline characteristics were comparable among the matched cohorts (mean age 70 ± 11 years, 81% male, and mean left ventricular ejection fraction 27 ± 6%). During a median follow-up of 37 months, beta-blockers were associated with significantly lower all-cause mortality (hazard ratio [HR]: 0.721, 95% confidence interval [CI]: 0.549 to 0.945; p = 0.0180) but not hospitalizations (HR: 0.886; 95% CI: 0.715 to 1.100; p = 0.2232). Similar results were obtained in sensitivity analyses that modeled beta-blockers as a time-dependent variable (HR: 0.668 for all-cause mortality; 95% CI: 0.511 to 0.874; p = 0.0032; HR: 0.814 for hospitalizations; 95% CI: 0.653 to 1.014; p = 0.0658). There were no significant interactions between beta-blockers and patterns (i.e., persistent vs. paroxysmal) or burden of AF with respect to mortality or hospitalizations. Conclusions In propensity-matched analyses, beta-blockers were associated with significantly lower mortality but not hospitalizations in patients with HFrEF and AF, irrespective of the pattern or burden of AF. These results support current evidence-based recommendations for beta-blockers in patients with HFrEF, whether or not they have associated AF.

Rationale: Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near HEY2 ) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved. Objective: We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in Hey2 +/− ( Hey2 heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome. Methods and Results: We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for cis -expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and HEY2 expression (β=+0.159; P =0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for HEY2 , which uncovered KCNIP2 , encoding the β-subunit of the channel underlying the transient outward current ( I to ), as the transcript most robustly correlating with HEY2 expression (β=+1.47; P =2×10 −34 ). Transcript abundance of Hey2 and the I to subunits Kcnip2 and Kcnd2 , assessed by quantitative reverse transcription–polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in Hey2 +/− mice compared with wild type. Surface ECG measurements showed less prominent J waves in Hey2 +/− mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower V max in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher I to and a lower sodium current ( I Na ) density in subepicardium versus subendocardium. These transmural differences were diminished in Hey2 +/− mice because of changes in subepicardial cardiomyocytes. Conclusions: This study uncovers a role of HEY2 in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a HEY2 -dependent alteration of ion channel expression across the cardiac ventricular wall.

Key Teaching Points • Atrial arrhythmias are common in patients with Brugada syndrome. • Many medications commonly used to treat atrial arrhythmias are contraindicated in patients with Brugada syndrome. • Quinidine has been shown to be an effective antiarrhythmic drug for some patients with Brugada syndrome who suffer from ventricular arrhythmias and may be beneficial to patients with Brugada syndrome who suffer from atrial arrhythmias as well.

Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.

Introduction: Ventricular arrhythmias are often seen in association with structural heart disease. However, approximately a tenth of affected patients have apparently normal hearts, where such arrhythmias typically occur in young patients, are sometimes inherited and can occasionally lead to sudden cardiac death (SCD). Over the past two decades, increased understanding of the underlying pathophysiology resulted in improved targeted pharmacological therapy.Areas covered: This article reviews current knowledge regarding drug therapy for inherited arrhythmia syndromes (Brugada, early repolarization, long QT and short QT syndromes, and catecholaminergic polymorphic ventricular tachycardia), and acquired arrhythmias (idiopathic ventricular fibrillation, short-coupled torsade de pointes, outflow tract ventricular tachycardia, idiopathic left, papillary muscle and annular ventricular tachycardias).Expert opinion: In inherited arrhythmia syndromes, appropriate clinical and genetic diagnoses followed by proper selection and dosing of antiarrhythmic drugs are of utmost importance to prevent SCD, most often without the need of implantable cardioverter-defibrillators. In acquired arrhythmias, appropriate pharmacotherapy in selected patients can also provide symptomatic relief and avoid the need for invasive therapy. Further research is needed to develop novel antiarrhythmic drugs or targeted therapy to increase efficacy and limit side effects.

Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined disease associated with a significant risk of ventricular arrhythmias and sudden cardiac death (SCD)...

Inheritable cardiac disorders, which may be associated with cardiomyopathic changes, are often associated with increased risk of sudden death in the young. Early linkage analysis studies in Mendelian forms of these diseases, such as hypertrophic cardiomyopathy and long-QT syndrome, uncovered large-effect genetic variants that contribute to the phenotype. In more recent years, through genotype-phenotype studies and methodological advances in genetics, it has become evident that most inheritable cardiac disorders are not monogenic but, rather, have a complex genetic basis wherein multiple genetic variants contribute (oligogenic or polygenic inheritance). Conversely, studies on genes underlying these disorders uncovered pleiotropic effects, with a single gene affecting multiple and apparently unrelated phenotypes. In this review, we explore these 2 phenomena: on the one hand, the evidence that variants in multiple genes converge to generate one clinical phenotype, and, on the other, the evidence that variants in one gene can lead to apparently unrelated phenotypes. Although multiple conditions are addressed to illustrate these concepts, the experience obtained in the study of long-QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, and in the study of functions related to SCN5A (the gene coding for the α-subunit of the most abundant sodium channel in the heart) and PKP2 (the gene coding for the desmosomal protein plakophilin-2), as well, is discussed in more detail.

Background Compelling evidence showing a link between atrial fibrillation (AF) and cognitive decline and dementia is accumulating. Methods Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) is a prospective, multicentric, double-blind, randomized-controlled trial, recruiting patients with nonvalvular AF and a low risk of stroke. Patients with a high risk of bleeding will be excluded from the study. Participants will be randomized to receive either rivaroxaban (15 mg daily) or standard of care (placebo in patients without vascular disease or acetylsalicylic acid 100 mg daily in patients with vascular disease). Results The primary outcome is the composite of stroke, transient ischemic attack, and cognitive decline (defined by a decrease in the Montreal Cognitive Assessment score ≥ 3 at any follow-up visit after baseline). Approximately 3250 patients will be enrolled in approximately 130 clinical sites until 609 adjudicated primary outcome events have occurred. Conclusions BRAIN-AF determines whether oral anticoagulation therapy with rivaroxaban compared with standard of care reduces the risk of stroke, transient ischemic attack, or cognitive decline in patients with nonvalvular AF and a low risk of stroke.

Aims Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG). Methods and results In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose–response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P Conclusion We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.

The atrioventricular (AV) node generates half of the AV delay needed for blood pumping and filters atrial impulses that could otherwise induce life-threatening ventricular arrhythmias. It is also a pacemaker and a key target in the treatment of cardiac arrhythmias. The special roles of the AV node primarily arise from its slow conduction, long refractory period, and cellular automaticity. However, efforts to establish the dynamics of these properties and their interaction led to many controversies. In fact, the AV node's behavior is so complex that it seems to escape broadly applicable rules. This review summarizes progresses made in resolving these issues and in integrating the multiple roles of the AV node within a common functional model. Presented evidence shows that the rate-dependent conduction and refractory properties of the AV node can be reliably characterized and reconciled from nodal responses to S1 S2 S3 protocols. It also supports the concept that dual pathways constitute a feature of the normal AV node and account for its overall conduction and refractory properties. In this model, the posterior extension and compact node provide the core of the slow and fast pathway, respectively. The transitional tissues and lower nodal bundle provide a common proximal and distal pathway, respectively. These pathways would also support bidirectional conduction. The dual pathway involvement can also be extended to widely variable AV nodal responses, such as Wenckebach cycles, hysteresis, and ventricular response to atrial fibrillation. In brief, the intricate AV nodal behavior may obey a limited set of accessible and definable rules.