Publications by authors named "Arthur A Wilde"

519 Publications

COVID-19 does not only disturb our social rhythm.

Heart Rhythm 2021 04;18(4):510-511

Department of Clinical and Experimental Cardiology, Amsterdam UMC, Heart Centre, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.hrthm.2021.02.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005660PMC
April 2021

Dutch Outcome in Implantable Cardioverter-Defibrillator Therapy: Implantable Cardioverter-Defibrillator-Related Complications in a Contemporary Primary Prevention Cohort.

J Am Heart Assoc 2021 Apr 31;10(7):e018063. Epub 2021 Mar 31.

Department of Epidemiology and Data Science Amsterdam UMC, University of Amsterdam the Netherlands.

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.
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http://dx.doi.org/10.1161/JAHA.120.018063DOI Listing
April 2021

Generation of iPSC lines from CPVT patient carrying heterozygous mutation p.A2254V in the ryanodine receptor 2 gene.

Stem Cell Res 2021 Feb 19;53:102259. Epub 2021 Feb 19.

Institute of Pharmacology and Toxicology, Technische Universität Dresden, Germany; Clinic for Cardiology and Pneumology, Universitätsmedizin Göttingen, Germany. Electronic address:

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inheritable cardiac disorder, which is characterized by life-threatening cardiac arrhythmias, syncope, seizures, or sudden cardiac death in response to physical exercise or emotional stress. This inherited disease is predominantly caused by mutations in the ryanodine receptor type 2 (RYR2). To minimize the cell line variations for disease modeling, we generated two induced pluripotency stem cell lines (hiPSCs: isCPVT1-2 and isCPVT1-3) from skin fibroblasts of one CPVT patient carrying the p.A2254V mutation using CytoTune2.0 Sendai virus cocktail for non-integration reprogramming. All generated iPSCs maintained pluripotency, normal karyotype, and spontaneous in vivo and in vitro differentiation capacity.
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http://dx.doi.org/10.1016/j.scr.2021.102259DOI Listing
February 2021

Improving electrocardiogram-based detection of rare genetic heart disease using transfer learning: An application to phospholamban p.Arg14del mutation carriers.

Comput Biol Med 2021 Apr 11;131:104262. Epub 2021 Feb 11.

Amsterdam UMC, University of Amsterdam, Department of Biomedical Engineering and Physics, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam, the Netherlands.

The pathogenic mutation p.Arg14del in the gene encoding Phospholamban (PLN) is known to cause cardiomyopathy and leads to increased risk of sudden cardiac death. Automatic tools might improve the detection of patients with this rare disease. Deep learning is currently the state-of-the-art in signal processing but requires large amounts of data to train the algorithms. In situations with relatively small amounts of data, like PLN, transfer learning may improve accuracy. We propose an ECG-based detection of the PLN mutation using transfer learning from a model originally trained for sex identification. The sex identification model was trained with 256,278 ECGs and subsequently finetuned for PLN detection (155 ECGs of patients with PLN) with two control groups: a balanced age/sex matched group and a randomly selected imbalanced population. The data was split in 10 folds and 20% of the training data was used for validation and early stopping. The models were evaluated with the area under the receiver operating characteristic curve (AUROC) of the testing data. We used gradient activation for explanation of the prediction models. The models trained with transfer learning outperformed the models trained from scratch for both the balanced (AUROC 0.87 vs AUROC 0.71) and imbalanced (AUROC 0.0.90 vs AUROC 0.65) population. The proposed approach was able to improve the accuracy of a rare disease detection model by transfer learning information from a non-manual annotated and abundant label with only limited data available.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104262DOI Listing
April 2021

Fractionated Epicardial Electrograms: Implication for Mechanism of the Brugada Pattern.

JACC Clin Electrophysiol 2021 02;7(2):258-270

Division of Electrophysiology, Department of Cardiology, University of California-San Francisco, San Francisco, California, USA.

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http://dx.doi.org/10.1016/j.jacep.2020.12.009DOI Listing
February 2021

Development and external validation of prediction models to predict implantable cardioverter-defibrillator efficacy in primary prevention of sudden cardiac death.

Europace 2021 Feb 14. Epub 2021 Feb 14.

Department of Cardiology, Flevo Hospital, Almere, the Netherlands.

Aims: This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation.

Methods And Results: We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1-2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0-3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality.

Conclusion: Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed.
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http://dx.doi.org/10.1093/europace/euab012DOI Listing
February 2021

Cardiac ryanodine receptor calcium release deficiency syndrome.

Sci Transl Med 2021 Feb;13(579)

Department of Cardiology, Aarhus University Hospital, and Department of Clinical Medicine, Health, Aarhus University, Palle Juul-Jensens Blv 99, DK-8200 Aarhus N, Denmark.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.
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http://dx.doi.org/10.1126/scitranslmed.aba7287DOI Listing
February 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
February 2021

Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway?

Eur Heart J 2021 Mar;42(11):1073-1081

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart (ERN GUARDHEART http://guardheart.ern-net.eu).

Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to the risk of sudden cardiac death and characterized by right precordial lead ST elevation. Early description of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. We propose that the final common pathway for BrS could be viewed as a disease of 'reduced RVOT conduction reserve'.
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http://dx.doi.org/10.1093/eurheartj/ehaa1051DOI Listing
March 2021

Left Axis Deviation in Brugada Syndrome: Vectorcardiographic Evaluation during Ajmaline Provocation Testing Reveals Additional Depolarization Abnormalities.

Int J Mol Sci 2021 Jan 6;22(2). Epub 2021 Jan 6.

Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing ( = 1430), we selected patients in whom a type-1 BrS-ECG was evoked ( = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a >30° leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 ± 14 ms versus +13 ± 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8;18] ms versus +8[4;12] ms, < 0.001 and 3rd QRS-loop quartile: +12 ± 10 ms versus +5 ± 7 ms, < 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59;147]° versus 44[25;91]°, < 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined.
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http://dx.doi.org/10.3390/ijms22020484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825029PMC
January 2021

Life-threatening arrhythmias with autosomal recessive TECRL variants.

Europace 2020 Dec 25. Epub 2020 Dec 25.

Unit of Cardiogenetics Research, Division of Genetic Medicine, University Hospital Lausanne (CHUV), Lausanne, Switzerland.

Aims : Sudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL. However, phenotypes have only begun to be described and no data are available on medical therapy after long-term follow-up.

Methods And Results : An international, multi-centre retrospective review was conducted. We report new cases associated with TECRL variants and long-term follow-up from previously published cases. We present 10 cases and 37 asymptomatic heterozygous carriers. Median age at onset of cardiac symptoms was 8 years (range 1-22 years) and cases were followed for an average of 10.3 years (standard deviation 8.3), right censored by death in three cases. All patients on metoprolol, bisoprolol, or atenolol were transitioned to nadolol or propranolol due to failure of therapy. Phenotypes typical of both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) were observed. We also observed divergent phenotypes in some cases despite identical homozygous variants. None of 37 heterozygous family members had a cardiac phenotype.

Conclusion : Patients with biallelic pathogenic TECRL variants present with variable cardiac arrhythmia phenotypes, including those typical of long QT syndrome and CPVT. Nadolol and propranolol may be superior beta-blockers in this setting. No cardiac disease or sudden death was present in patients with a heterozygous genotype.
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http://dx.doi.org/10.1093/europace/euaa376DOI Listing
December 2020

Two siblings with early repolarization syndrome: clinical and genetic characterization by whole-exome sequencing.

Europace 2020 Dec 16. Epub 2020 Dec 16.

Department of Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Heart Center, Amsterdam, The Netherlands.

Aims : The early repolarization syndrome (ERS) can cause ventricular fibrillation (VF) and sudden death in young, otherwise healthy individuals. There are limited data suggesting that ERS might be heritable. The aim of this study was to characterize the clinical phenotype and to identify a causal variant in an affected family using an exome-sequencing approach.

Methods And Results : Early repolarization syndrome was diagnosed according to the recently proposed Shanghai ERS Score. After sequencing of known ERS candidate genes, whole-exome sequencing (WES) was performed. The index patient (23 years, female) showed a dynamic inferolateral early repolarization (ER) pattern and electrical storm with intractable VF. Isoproterenol enabled successful termination of electrical storm with no recurrence on hydroquinidine therapy during 33 months of follow-up. The index patient's brother (25 years) had a persistent inferior ER pattern with malignant features and a history of syncope. Both parents were asymptomatic and showed no ER pattern. While there was no pathogenic variant in candidate genes, WES detected a novel missense variant affecting a highly conserved residue (p. H2245R) in the ANK3 gene encoding Ankyrin-G in the two siblings and the father.

Conclusion : We identified two siblings with a malignant ERS phenotype sharing a novel ANK3 variant. A potentially pathogenic role of the novel ANK3 variant is suggested by the direct interaction of Ankyrin-G with the cardiac sodium channel, however, more patients with ANK3 variants and ERS would be required to establish ANK3 as novel ERS susceptibility gene. Our study provides additional evidence that ERS might be a heritable condition.
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http://dx.doi.org/10.1093/europace/euaa357DOI Listing
December 2020

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration.

Circ Arrhythm Electrophysiol 2021 Jan 9;14(1):e008509. Epub 2020 Dec 9.

Department of Medicine, Division of Cardiology (J.C.-T., W.W., A.B., C.T., B.M., S.C., J.E.C., D.P.J., H.T., H.C., C.A.J.), Johns Hopkins Hospital, Baltimore, MD.

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 (=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.
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http://dx.doi.org/10.1161/CIRCEP.120.008509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834666PMC
January 2021

Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms.

JACC Cardiovasc Imaging 2020 Nov 13. Epub 2020 Nov 13.

Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Objectives: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.

Background: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.

Methods: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.

Results: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).

Conclusions: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.
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http://dx.doi.org/10.1016/j.jcmg.2020.09.030DOI Listing
November 2020

Biomarkers in inherited arrhythmias: necessity for validation and collaboration.

Eur Heart J 2020 12;41(47):4523-4524

Department of Clinical and Experimental Cardiology, Academic University Medical Centre, location AMC, University of Amsterdam, Heart Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehaa708DOI Listing
December 2020

Complications related to elective generator replacement of the subcutaneous implantable defibrillator.

Europace 2021 Mar;23(3):395-399

Department of Clinical and Experimental Cardiology, Amsterdam UMC, AMC, PO Box 22700, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Aims: To guarantee uninterrupted function of the subcutaneous implantable cardioverter-defibrillator (S-ICD), the pulse generator needs to be surgically replaced before the battery is depleted. The risks related to this replacement substantially impact long-term outcome for S-ICD recipients, as the majority will undergo one or several of these procedures in their lifetime. We aim to describe the procedural characteristics of the replacement procedure and to provide an insight in the complications associated with these replacements.

Methods And Results: In this retrospective analysis, data from replacement procedures and follow-up visits were collected from all patients who underwent elective S-ICD generator replacement in our tertiary centre from June 2014 until November 2019. Original device position was assessed using the PRAETORIAN score. Complications were defined as those requiring surgical intervention, systemic antibiotic treatment, or device extraction. Seventy-two patients were included, with a median follow-up of 1.9 years (IQR 0.6-3.3 years) after replacement. Battery depletion occurred after 5.9 ± 0.7 years. The pulse generator was repositioned in patients with a PRAETORIAN score ≥90 to minimize the defibrillation threshold. Although there was an increase in impedance compared to the implant procedure, first shock conversion rate during defibrillation testing was 91.4% with a success rate of 100% after multiple attempts. Two patients developed a complication after, respectively, 9 and 21 months, resulting in a complication rate of 1.4% per year.

Conclusion: With a median follow-up of 1.9 years, this study shows a low complication rate after S-ICD replacement, with a first shock conversion rate of 91.4%.
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http://dx.doi.org/10.1093/europace/euaa263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947576PMC
March 2021

Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in Families.

Circ Genom Precis Med 2020 12 9;13(6):e002911. Epub 2020 Nov 9.

National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.).

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- is the most common mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and mutation type on BrS phenotype in BrS families with mutations.

Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring 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]; =0.0078). Among -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; =0.0846). In -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; =0.0146). Among E1784K- positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; =0.0011).

Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a mutation and severity of loss of function.
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http://dx.doi.org/10.1161/CIRCGEN.120.002911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748043PMC
December 2020

Importance of Validating Guideline Recommendations.

Authors:
Arthur A M Wilde

Circ J 2020 Nov 27;84(12):2136-2137. Epub 2020 Oct 27.

Heart Centre, Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centre, University of Amsterdam.

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http://dx.doi.org/10.1253/circj.CJ-20-1047DOI Listing
November 2020

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

Heart Rhythm 2021 Jan 19;18(1):e1-e50. Epub 2020 Oct 19.

The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

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.
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http://dx.doi.org/10.1016/j.hrthm.2020.10.010DOI Listing
January 2021

Computer versus cardiologist: Is a machine learning algorithm able to outperform an expert in diagnosing a phospholamban p.Arg14del mutation on the electrocardiogram?

Heart Rhythm 2021 Jan 8;18(1):79-87. Epub 2020 Sep 8.

Amsterdam UMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.

Background: Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists.

Objectives: We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist.

Methods: We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions.

Results: In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53-0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65-0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts.

Conclusion: This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis.
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http://dx.doi.org/10.1016/j.hrthm.2020.08.021DOI Listing
January 2021

Subcutaneous or Transvenous Defibrillator Therapy.

N Engl J Med 2020 08;383(6):526-536

From the Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam (R.E.K., L.R.A.O.N., L.V.A.B., T.F.B., A.-F.B.E.Q., L.S., W.S., A.W., K.C.W., J.R.G., K.M.K., M.C.B., J.G.P.T., A.A.M.W.), ERN GUARD-Heart (E.R.B., P.D.L., A.A.M.W.), and the Department of Cardiology, OLVG (J.S.S.G.J.), Amsterdam, the Department of Cardiology, Isala Heart Centre, Zwolle (P.-P.H.M.D.), the Department of Cardiology, St. Antonius Hospital, Nieuwegein (L.V.A.B.), the Department of Cardiology, Flevoziekenhuis, Almere (N.R.B.), the Department of Cardiology, Radboud University Medical Center, Nijmegen (M.A.B.), the Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht (K.V.), the Department of Cardiology, Amphia Hospital, Breda (M.A.), Werkgroep Cardiologische Centra Nederland, Utrecht (M.A.), and the Department of Electrophysiology, Catharina Hospital, Eindhoven (F.A.L.E.B.) - all in the Netherlands; the First Department of Medicine-Cardiology, University Medical Center Mannheim, and the German Center for Cardiovascular Research Partner Site Heidelberg-Mannheim, Mannheim (J.K.), Klinik für Innere Medizin III, Schwerpunkt Kardiologie und Angiologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel (H.B.), the Department of Medicine I, Ludwig-Maximilians University Hospital, and the German Center for Cardiovascular Research, Munich Heart Alliance, Munich (S.K.), and the Department of Electrophysiology, Heart Center at University of Leipzig, Leipzig (S.R.) - all in Germany; the Division of Cardiology Section of Electrophysiology, Emory University, Atlanta (M.F.E.-C.); the Cardiology Clinical Academic Group, St. George's, University of London and St. George's University Hospitals NHS Foundation Trust London (E.R.B.), and Office of the Director of Clinical Electrophysiology Research and Lead for Inherited Arrhythmia Specialist Services, University College London and Barts Heart Centre (P.D.L.), London, the Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford (T.R.B.), and Liverpool Heart and Chest Hospital, Liverpool (D.J.W.) - all in the United Kingdom; Valley Health System, Ridgewood, NJ (S.M.); the Department of Cardiology, Homolka Hospital, Prague, Czech Republic (P.N.); and CorVita Science Foundation, Chicago (M.C.B.).

Background: The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing these systems has been based primarily on observational studies.

Methods: We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks.

Results: A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12).

Conclusions: In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).
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http://dx.doi.org/10.1056/NEJMoa1915932DOI Listing
August 2020

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of -Catecholaminergic Polymorphic Ventricular Tachycardia.

Circulation 2020 Sep 22;142(10):932-947. Epub 2020 Jul 22.

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (K.N., J.W., A.S.T., A.C.S., J.M., J.D.R.).

Background: Genetic variants in calsequestrin-2 () cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of -CPVT was sought through an international multicenter collaboration.

Methods: Genotype-phenotype segregation in -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.

Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic variant, were identified. Among homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to heterozygotes, homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers.

Conclusions: This international multicenter study of -CPVT redefines its heritability and confirms that pathogenic heterozygous variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484339PMC
September 2020

Inherited cardiac arrhythmias.

Nat Rev Dis Primers 2020 07 16;6(1):58. Epub 2020 Jul 16.

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Bruxelles, Belgium.

The main inherited cardiac arrhythmias are long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. These rare diseases are often the underlying cause of sudden cardiac death in young individuals and result from mutations in several genes encoding ion channels or proteins involved in their regulation. The genetic defects lead to alterations in the ionic currents that determine the morphology and duration of the cardiac action potential, and individuals with these disorders often present with syncope or a life-threatening arrhythmic episode. The diagnosis is based on clinical presentation and history, the characteristics of the electrocardiographic recording at rest and during exercise and genetic analyses. Management relies on pharmacological therapy, mostly β-adrenergic receptor blockers (specifically, propranolol and nadolol) and sodium and transient outward current blockers (such as quinidine), or surgical interventions, including left cardiac sympathetic denervation and implantation of a cardioverter-defibrillator. All these arrhythmias are potentially life-threatening and have substantial negative effects on the quality of life of patients. Future research should focus on the identification of genes associated with the diseases and other risk factors, improved risk stratification and, in particular for Brugada syndrome, effective therapies.
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http://dx.doi.org/10.1038/s41572-020-0188-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935690PMC
July 2020

In Children and Adolescents From Brugada Syndrome-Families, Only Mutation Carriers Develop a Type-1 ECG Pattern Induced By Fever.

Circulation 2020 Jul 6;142(1):89-91. Epub 2020 Jul 6.

Department of Pediatric Cardiology, Emma Children's Hospital (P.J.P, N.A.B., A.S.V., S.-A.B.C.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045720DOI Listing
July 2020

Prophylactic (hydroxy)chloroquine in COVID-19: Potential relevance for cardiac arrhythmia risk.

Heart Rhythm 2020 Sep 3;17(9):1480-1486. Epub 2020 Jul 3.

Amsterdam UMC, location AMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; European Cardiac Arrhythmia Genetics Focus Group (ECGen) of the European Heart Rhythm Association (EHRA). Electronic address:

(Hydroxy)chloroquine ((H)CQ) is being investigated as a treatment for COVID-19, but studies have so far demonstrated either no or a small benefit. However, these studies have been mostly performed in patients admitted to the hospital and hence likely already (severely) affected. Another suggested approach uses prophylactic (H)CQ treatment aimed at preventing either severe acute respiratory syndrome coronavirus 2 infection or the development of disease. A substantial number of clinical trials are planned or underway aimed at assessing the prophylactic benefit of (H)CQ. However, (H)CQ may lead to QT prolongation and potentially induce life-threatening arrhythmias. This may be of particular relevance to patients with preexisting cardiovascular disease and those taking other QT-prolonging drugs. In addition, it is known that a certain percentage of the population carries genetic variant(s) that reduces their repolarization reserve, predisposing them to (H)CQ-induced QT prolongation, and this may be more relevant to female patients who already have a longer QT interval to start with. This review provides an overview of the current evidence on (H)CQ therapy in patients with COVID-19 and discusses different strategies for prophylactic (H)CQ therapy (ie, preinfection, postexposure, and postinfection). In particular, the potential cardiac effects, including QT prolongation and arrhythmias, will be addressed. Based on these insights, recommendations will be presented as to which preventive measures should be taken when giving (H)CQ prophylactically, including electrocardiographic monitoring.
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http://dx.doi.org/10.1016/j.hrthm.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332460PMC
September 2020

Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand.

Heart Rhythm 2020 12 30;17(12):2145-2153. Epub 2020 Jun 30.

Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Pacific Rim Electrophysiology Research Institute, Bumrungrad Hospital, Bangkok, Thailand.

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). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0-11.1), but an enrichment of low-frequency (MAF<0.001 and >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.
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http://dx.doi.org/10.1016/j.hrthm.2020.06.027DOI Listing
December 2020

A highly specific biomarker for Brugada syndrome. Also too good to be true?

Eur Heart J 2020 08;41(30):2891-2893

Heart Centre, Department of Clinical and Experimental Cardiology, Academic University Medical Centre, location AMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehaa468DOI Listing
August 2020

Improving the care for female subcutaneous ICD patients: A qualitative study of gender-specific issues.

Int J Cardiol 2020 Oct 5;317:91-95. Epub 2020 Jun 5.

Amsterdam UMC, University of Amsterdam, Heart Center: Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) consists of a large generator and is implanted near the left breast. This might lead to discomfort and problems with self-perception and sexuality, especially in the female population. We aimed to assess the issues that female S-ICD patients experience and to provide practical guidance for cardiologists and implanters on minimizing these issues.

Methods: For this retrospective single-center study, we conducted semi-structured interviews with four female S-ICD patients and processed their experiences into a questionnaire. This consisted of three open questions and 17 statements that participants could answer through a five-point Likert scale. The questionnaire was subsequently sent to all female adult patients who received an S-ICD between February 2009 and November 2018 in our tertiary centre in Amsterdam, the Netherlands.

Results: The response rate of the questionnaire was 73%, with 52 female respondents (mean age 47.4 ± 12.5 years, mean time since implant 4.6 ± 3.1 years). Postoperative pain exceeded the expectation of 54% of the respondents. Furthermore, 14 out of 49 respondents (29%) expressed an unpleasant feeling during intimate contact with their sexual partner since the implant. Many women (44%) reported daily discomfort caused by their bra and preferred a more cranial and posterior position of the S-ICD generator. Finally, a smaller design of the generator is desired by a great majority (63%) of female S-ICD patients CONCLUSION: Female S-ICD patients experience a variety of issues with a substantial impact on their daily life. Most issues that we identified would benefit from adequate counseling and implanter awareness.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.091DOI Listing
October 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 Jul 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

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 (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). 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 (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Genetic susceptibility for COVID-19-associated sudden cardiac death in African Americans.

Heart Rhythm 2020 09 5;17(9):1487-1492. Epub 2020 May 5.

Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2020.04.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198426PMC
September 2020