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Abstract The efficacy of an implantable cardioverter-defibrillator (ICD) in patients with a non-ischaemic cardiomyopathy for primary prevention of sudden cardiac death is increasingly debated. We developed a multimodal deep learning model for arrhythmic risk prediction that integrated late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI), electrocardiography (ECG) and clinical data. Short-axis LGE-MRI scans and 12-lead ECGs were retrospectively collected from a cohort of 289 patients prior to ICD implantation, across two tertiary hospitals. A residual variational autoencoder was developed to extract physiological features from LGE-MRI and ECG, and used as inputs for a machine learning model (DEEP RISK) to predict malignant ventricular arrhythmia onset. In the validation cohort, the multimodal DEEP RISK model predicted malignant ventricular arrhythmias with an area under the receiver operating characteristic curve (AUROC) of 0.84 (95% confidence interval (CI) 0.71–0.96), a sensitivity of 0.98 (95% CI 0.75–1.00) and a specificity of 0.73 (95% CI 0.58–0.97). The models trained on individual modalities exhibited lower AUROC values compared to DEEP RISK [MRI branch: 0.80 (95% CI 0.65–0.94), ECG branch: 0.54 (95% CI 0.26–0.82), Clinical branch: 0.64 (95% CI 0.39–0.87)]. These results suggest that a multimodal model achieves high prognostic accuracy in predicting ventricular arrhythmias in a cohort of patients with non-ischaemic systolic heart failure, using data collected prior to ICD implantation.

Background Chronic total coronary occlusions (CTO) substantially increase the risk for sudden cardiac death. Among patients with chronic ischemic heart disease at risk for sudden cardiac death, an implantable cardioverter defibrillator (ICD) is the favored therapy for primary prevention of sudden cardiac death. This study sought to investigate the impact of CTOs on the risk for appropriate ICD shocks and mortality within a nationwide prospective cohort. Methods and Results This is a subanalysis of the nationwide Dutch‐Outcome in ICD Therapy (DO‐IT) registry of primary prevention ICD recipients in The Netherlands between September 2014 and June 2016 (n=1442). We identified patients with chronic ischemic heart disease (n=663) and assessed available coronary angiograms for CTO presence (n=415). Patients with revascularized CTOs were excluded (n=79). The primary end point was the composite of all‐cause mortality and appropriate ICD shocks. Clinical follow‐up was conducted for at least 2 years. A total of 336 patients were included, with an average age of 67±9 years, and 20.5% was female (n=69). An unrevascularized CTO was identified in 110 patients (32.7%). During a median follow‐up period of 27 months (interquartile range, 24–32), the primary end point occurred in 21.1% of patients with CTO (n=23) compared with 11.9% in patients without CTO (n=27; P=0.034). Corrected for baseline characteristics including left ventricular ejection fraction, and the presence of a CTO was an independent predictor for the primary end point (hazard ratio, 1.82 [95% CI, 1.03–3.22]; P=0.038). Conclusions Within this nationwide prospective registry of primary prevention ICD recipients, the presence of an unrevascularized CTO was an independent predictor for the composite outcome of all‐cause mortality and appropriate ICD shocks.

Background An elegant bedside provocation test has been shown to aid the diagnosis of long‐QT syndrome (LQTS) in a retrospective cohort by evaluation of QT intervals and T‐wave morphology changes resulting from the brief tachycardia provoked by standing. We aimed to prospectively determine the potential diagnostic value of the standing test for LQTS. Methods and Results In adults suspected for LQTS who had a standing test, the QT interval was assessed manually and automated. In addition, T‐wave morphology changes were determined. A total of 167 controls and 131 genetically confirmed patients with LQTS were included. A prolonged heart rate–corrected QT interval (QTc) (men ≥430 ms, women ≥450 ms) at baseline before standing yielded a sensitivity of 61% (95% CI, 47–74) in men and 54% (95% CI, 42–66) in women, with a specificity of 90% (95% CI, 80–96) and 89% (95% CI, 81–95), respectively. In both men and women, QTc≥460 ms after standing increased sensitivity (89% [95% CI, 83–94]) but decreased specificity (49% [95% CI, 41–57]). Sensitivity further increased (P

Abstract Background Congenital long QT syndrome (LQTS) is a rare heart disease caused by various underlying mutations. Most general cardiologists do not routinely see patients with congenital LQTS and may not always recognize the accompanying ECG features. In addition, a proportion of disease carriers do not display obvious abnormalities on their ECG. Combined, this can cause underdiagnosing of this potentially life-threatening disease. Methods This study presents 1D convolutional neural network models trained to identify genotype positive LQTS patients from electrocardiogram as input. The deep learning (DL) models were trained with a large 10-s 12-lead ECGs dataset provided by Amsterdam UMC and externally validated with a dataset provided by University Hospital Leuven. The Amsterdam dataset included ECGs from 10000 controls, 172 LQTS1, 214 LQTS2, and 72 LQTS3 patients. The Leuven dataset included ECGs from 2200 controls, 32 LQTS1, and 80 LQTS2 patients. The performance of the DL models was compared with conventional QTc measurement and with that of an international expert in congenital LQTS (A.A.M.W). Lastly, an explainable artificial intelligence (AI) technique was used to better understand the prediction models. Results Overall, the best performing DL models, across 5-fold cross-validation, achieved on average a sensitivity of 84 ± 2%, 90 ± 2% and 87 ± 6%, specificity of 96 ± 2%, 95 ± 1%, and 92 ± 4%, and AUC of 0.90 ± 0.01, 0.92 ± 0.02, and 0.89 ± 0.03, for LQTS 1, 2, and 3 respectively. The DL models were also shown to perform better than conventional QTc measurements in detecting LQTS patients. Furthermore, the performances held up when the DL models were validated on a novel external cohort and outperformed the expert cardiologist in terms of specificity, while in terms of sensitivity, the DL models and the expert cardiologist in LQTS performed the same. Finally, the explainable AI technique identified the onset of the QRS complex as the most informative region to classify LQTS from non-LQTS patients, a feature previously not associated with this disease. Conclusions This study suggests that DL models can potentially be used to aid cardiologists in diagnosing LQTS. Furthermore, explainable DL models can be used to possibly identify new features for LQTS on the ECG, thus increasing our understanding of this syndrome.

Background: Congenital heart diseases (CHD) are the most common congenital malformations in newborns and remain the leading cause of mortality among infants under one year old. Molecular diagnosis is crucial to evaluate the recurrence risk and to address future prenatal diagnosis. Here, we describe two families with various forms of inherited non-syndromic CHD and the genetic work-up and resultant findings. Methods: Next-generation sequencing (NGS) was employed in both families to uncover the genetic cause. In addition, we performed functional analysis to investigate the consequences of the identified variants in vitro. Results: NGS identified possible causative variants in both families in the protein kinase domain of the TGFBR1 gene. These variants occurred on the same amino acid, but resulted in differently substituted amino acids (p.R398C/p.R398H). Both variants co-segregate with the disease, are extremely rare or unique, and occur in an evolutionary highly conserved domain of the protein. Furthermore, both variants demonstrated a significantly altered TGFBR1-smad signaling activity. Clinical investigation revealed that none of the carriers had (signs of) aortopathy. Conclusion: In conclusion, we describe two families, with various forms of inherited non-syndromic CHD without aortopathies, associated with unique/rare variants in TGFBR1 that display altered TGF-beta signaling. These findings highlight involvement of TGFBR1 in CHD, and warrant consideration of potential causative TGFBR1 variants also in CHD patients without aortopathies.

Abstract This international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

Background Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with ventricular fibrillation of which the origin is not identified after extensive evaluations. Recent studies suggest an association between mitral annulus disjunction (MAD), mitral valve prolapse (MVP), and ventricular arrhythmias. The prevalence of MAD and MVP in patients with IVF in this regard is not well established. We aimed to explore the prevalence of MAD and MVP in a consecutive cohort of patients with IVF compared with matched controls. Methods and Results In this retrospective, multicenter cohort study, cardiac magnetic resonance images from patients with IVF (ie, negative for ischemia, cardiomyopathy, and channelopathies) and age‐ and sex‐matched control subjects were analyzed for the presence of MAD (≥2 mm) and MVP (>2 mm). In total, 72 patients (mean age 39±14 years, 42% women) and 72 control subjects (mean age 41±11 years, 42% women) were included. MAD in the inferolateral wall was more prevalent in patients with IVF versus healthy controls (7 [11%] versus 1 [1%], P=0.024). MVP was only seen in patients with IVF and not in controls (5 [7%] versus 0 [0%], P=0.016). MAD was observed in both patients with (n=4) and without (n=3) MVP. Conclusions Inferolateral MAD and MVP were significantly more prevalent in patients with IVF compared with healthy controls. The authors advocate that evaluation of the mitral valve region deserves extra attention in the extensive screening of patients with unexplained cardiac arrest. These findings support further exploration of the pathophysiological mechanisms underlying a subset of IVF that associates with MAD and MVP.

Abstract Background We aimed to determine the mutation yield and clinical applicability of “molecular autopsy” following sudden arrhythmic death syndrome (SADS) by validating and utilizing low-cost high-throughput technologies: Fluidigm Access Array PCR-enrichment with Illumina HiSeq 2000 next generation sequencing (NGS). Methods We validated and optimized the NGS platform with a subset of 46 patients by comparison with Sanger sequencing of coding exons of major arrhythmia risk-genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2). A combined large multi-ethnic international SADS cohort was sequenced utilizing the NGS platform to determine overall molecular yield; rare variants identified by NGS were subsequently reconfirmed by Sanger sequencing. Results The NGS platform demonstrated 100% sensitivity for pathogenic variants as well as 87.20% sensitivity and 99.99% specificity for all substitutions (optimization subset, n = 46). The positive predictive value (PPV) for NGS for rare substitutions was 16.0% (27 confirmed rare variants of 169 positive NGS calls in 151 additional cases). The overall molecular yield in 197 multi-ethnic SADS cases (mean age 22.6 ± 14.4 years, 68% male) was 5.1% (95% confidence interval 2.0–8.1%), representing 10 cases carrying pathogenic or likely pathogenic risk-mutations. Conclusions Molecular autopsy with Fluidigm Access Array and Illumina HiSeq NGS utilizing a selected panel of LQTS/BrS and CPVT risk-genes offers moderate diagnostic yield, albeit requiring confirmatory Sanger-sequencing of mutational variants.

Background One third of primary prevention implantable cardioverter‐defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter‐defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter‐defibrillator. During a follow‐up of 2.2 years (interquartile range, 2.0–2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead‐related (n=47) and pocket‐related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter‐defibrillator–related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits.

BackgroundPrevious studies report conflicting results about a higher incidence of ventricular arrhythmias in patients with a chronic total coronary occlusion (CTO). We aimed to investigate this association in a large cohort of implantable cardioverter defibrillator patients with long‐term follow‐up. Methods and ResultsAll consecutive patients from 1992 onwards who underwent implantable cardioverter defibrillator implantation for ischemic cardiomyopathy at the Leiden University Medical Center were evaluated. Coronary angiograms were reviewed for the presence of a CTO. The occurrence of ventricular arrhythmias and survival status at follow‐up were compared between patients with and patients without a CTO. A total of 722 patients constitute the study cohort (age 66±11 years; 84% males; 74% primary prevention, median left ventricular ejection fraction 30% [first–third quartile: 25–37], 44% received a cardiac resynchronization therapy defibrillator). At baseline, 240 patients (33%) had a CTO, and the CTOs were present for at least 44 (2–127) months. The median follow‐up duration was 4 (2–6) years. On long‐term follow‐up, CTO patients had a higher crude appropriate device therapy rate (37% versus 27%, P=0.010) and a lower crude survival rate (51% versus 67%, P

BackgroundHuman induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) can recapitulate features of ion channel mutations causing inherited rhythm disease. However, the lack of maturity of these cells is considered a significant limitation of the model. Prolonged culture of hiPSC‐CMs promotes maturation of these cells. We studied the electrophysiological effects of the I230T mutation in the sodium channel gene SCN5A in hiPSC‐CMs generated from a homozygous (I230Thomo) and a heterozygous (I230Thet) individual from a family with recessive cardiac conduction disease. Since the I230T mutation occurs in the developmentally regulated “adult” isoform of SCN5A, we investigated the relationship between the expression fraction of the adult SCN5A isoform and the electrophysiological phenotype at different time points in culture. Methods and ResultsAfter a culture period of 20 days, sodium current (INa) was mildly reduced in I230Thomo hiPSC‐CMs compared with control hiPSC‐CMs, while I230Thet hiPSC‐CMs displayed no reduction in INa. This coincided with a relatively high expression fraction of the “fetal” SCN5A isoform compared with the adult isoform as measured by quantitative polymerase chain reaction. Following prolonged culture to 66 days, the fraction of adult SCN5A isoform increased; this was paralleled by a marked decrease in INa in I230Thomo hiPSC‐CMs, in line with the severe clinical phenotype in homozygous patients. At this time in culture, I230Thet hiPSC‐CMs displayed an intermediate loss of INa, compatible with a gene dosage effect. ConclusionsProlonged culture of hiPSC‐CMs leads to an increased expression fraction of the adult sodium channel isoform. This new aspect of electrophysiological immaturity should be taken into account in studies that focus on the effects of SCN5A mutations in hiPSC‐CMs.

Background Mutations in the coding sequence of SCN5A, which encodes the cardiac Na+ channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias. Methods and Results We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild‐type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity. Conclusions Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.

Introduction The cardiovascular benefits of physical exercise are well-known. However, vigorous exercise has also been associated with adverse cardiac effects. To improve our understanding of cardiovascular adaptation to exercise versus maladaptation and pathology, the limits of adaptation should be firmly established using state-of-the-art diagnostic modalities. We therefore initiated the Evaluation of Lifetime participation in Intensive Top-level sports and Exercise (ELITE) cohort to investigate the longitudinal (beneficial and pathological) cardiovascular effects of intensive elite sports and exercise.Methods and analysis ELITE is a prospective, multicentre, longitudinal cohort study. Elite athletes, from the age of sixteen, are recruited in The Netherlands. The primary objective is to determine the association between elite sports and exercise-induced cardiac remodelling, cardiac pathology, and health benefits over time. Secondary objectives include determining and identifying genetic profiles of elite athletes, and how these are associated with cardiac indices. ELITE will collect data from consultations, electrocardiography, echocardiography and cardiac magnetic resonance imaging, and training- and injury data. ELITE will also collect blood for biobanking and cardiogenetics. Follow-up will take place at intervals of two to five years, and after the elite athletes’ professional careers have ended. In addition, a subcohort of ELITE has been established to investigate cardiac sequelae following infections associated with myocardial involvement, including SARS-CoV-2. ELITE is a prospective observational study; therefore, analyses will be primarily explorative.Ethics and dissemination This study has been approved by the Medical Ethics Review Board of the Amsterdam University Medical Centers (NL71682.018.19). The results of the study will be disseminated by publication in peer-reviewed journals (Netherlands Trial Register number: NL9328).

Objectives Quantification of pericardial/myocardial involvement and risks of sudden cardiac arrest/sudden cardiac death (SCA/SCD) after SARS-CoV-2 infection in athletes who return to sports.Design Systematic review on post-SARS-CoV-2 infection pericardial/myocardial manifestations in athletes.Data sources Combinations of key terms in Medline, Embase and Scopus (through 2 June 2021).Eligibility criteria for selecting studies Inclusion: athletes, with cardiovascular magnetic resonance (CMR) or echocardiography after recovery from SARS-CoV-2 infection, including arrhythmia outcomes. Exclusion: study population ≥1 individual comorbidity and mean age 64 years. Quality assessment was performed using Joanna Briggs Institute Critical Appraisal tools checklists.Results In total, 12 manuscripts (1650 papers reviewed) comprising 3131 athletes (2198 college/student athletes, 879 professional athletes and 54 elite athletes) were included. The prevalence of myocarditis on echocardiography and/or CMR was 0%–15%, pericardial effusion 0%–58% and late gadolinium enhancement (LGE) 0%–46%. Weighted means of diagnosed myocarditis were 2.1% in college/student athletes and 0% in elite athletes. The prevalence of LGE was markedly lower in studies with high-quality assessment scores (3%–4%) versus low scores (38%–42%). A single study reported reversibility of myocardial involvement in 40.7%. No important arrhythmias were reported. Ten studies (n=4171) reporting postrecovery troponin T/I found no clear relationship with cardiac abnormalities.Summary/conclusion Athletes have an overall low risk of SARS-CoV-2 pericardial/myocardial involvement, arrhythmias and SCA/SCD. Rates of pericardial/myocardial abnormalities in athletes are highly variable and dependent on study quality. Troponin screenings seem unreliable to identify athletes at risk for myocardial involvement. Prospective athlete studies, with pre-SARS-CoV-2 imaging (CMR), including structured follow-up and arrhythmia monitoring, are urgently needed.

BackgroundTo evaluate QT-interval dynamics in patients and in drug safety analysis, beat-to-beat QT-interval measurements are increasingly used. However, interobserver differences, aberrant T-wave morphologies and changes in heart axis might hamper accurate QT-interval measurements.ObjectiveTo develop and validate a QT-interval algorithm robust to heart axis orientation and T-wave morphology that can be applied on a beat-to-beat basis.MethodsAdditionally to standard ECG leads, the root mean square (ECGRMS), standard deviation and vectorcardiogram were used. QRS-onset was defined from the ECGRMS. T-wave end was defined per individual lead and scalar ECG using an automated tangent method. A median of all T-wave ends was used as the general T-wave end per beat. Supine-standing tests of 73 patients with Long-QT syndrome (LQTS) and 54 controls were used because they have wide ranges of RR and QT-intervals as well as changes in T-wave morphology and heart axis orientation. For each subject, automatically estimated QT-intervals in three random complexes chosen from the low, middle and high RR range, were compared with manually measured QT-intervals by three observers.ResultsAfter visual inspection of the randomly selected complexes, 21 complexes were excluded because of evident noise, too flat T-waves or premature ventricular beats. Bland-Altman analyses of automatically and manually determined QT-intervals showed a bias of 0.9) between the algorithm and all observers individually as well as between the algorithm and the mean QT-interval of the observers.ConclusionOur automated algorithm provides reliable beat-to-beat QT-interval assessment, robust to heart axis and T-wave morphology.

BackgroundVentricular fibrillation (VF) in the setting of acute ST elevation myocardial infarction (STEMI) is a leading cause of mortality. Although the risk of VF has a genetic component, the underlying genetic factors are largely unknown. Since heart rate and ECG intervals of conduction and repolarization during acute STEMI differ between patients who do and patients who do not develop VF, we investigated whether SNPs known to modulate these ECG indices in the general population also impact on the respective ECG indices during STEMI and on the risk of VF.Methods and resultsThe study population consisted of participants of the Arrhythmia Genetics in the NEtherlandS (AGNES) study, which enrols patients with a first STEMI that develop VF (cases) and patients that do not develop VF (controls). SNPs known to impact on RR interval, PR interval, QRS duration or QTc interval in the general population were tested for effects on the respective STEMI ECG indices (stage 1). Only those showing a (suggestive) significant association were tested for association with VF (stage 2). On average, VF cases had a shorter RR and a longer QTc interval compared to non-VF controls. Eight SNPs showed a trend for association with the respective STEMI ECG indices. Of these, three were also suggestively associated with VF.ConclusionsRR interval and ECG indices of conduction and repolarization during acute STEMI differ between patients who develop VF and patients who do not. Although the effects of the SNPs on ECG indices during an acute STEMI seem to be similar in magnitude and direction as those found in the general population, the effects, at least in isolation, are too small to explain the differences in ECGs between cases and controls and to determine risk of VF.

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p = 3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

BACKGROUND: The cardiac sodium channel (Na(v)1.5) controls cardiac excitability. Accordingly, SCN5A mutations that result in loss-of-function of Na(v)1.5 are associated with various inherited arrhythmia syndromes that revolve around reduced cardiac excitability, most notably Brugada syndrome (BrS). Experimental studies have indicated that Na(v)1.5 interacts with the cytoskeleton and may also be involved in maintaining structural integrity of the heart. We aimed to determine whether clinical evidence may be obtained that Na(v)1.5 is involved in maintaining cardiac structural integrity. METHODS: Using cardiac magnetic resonance (CMR) imaging, we compared right ventricular (RV) and left ventricular (LV) dimensions and ejection fractions between 40 BrS patients with SCN5A mutations (SCN5a-mut-positive) and 98 BrS patients without SCN5A mutations (SCN5a-mut-negative). We also studied 18 age/sex-matched healthy volunteers. RESULTS: SCN5a-mut-positive patients had significantly larger end-diastolic and end-systolic RV and LV volumes, and lower LV ejection fractions, than SCN5a-mut-negative patients or volunteers. CONCLUSIONS: Loss-of-function SCN5A mutations are associated with dilatation and impairment in contractile function of both ventricles that can be detected by CMR analysis.

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10(-10)). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).