Publications by authors named "Arthur A M Wilde"

474 Publications

From a Polish 3 year old boy who visited Maastricht, to automatic detection using deep learning: Brugada syndrome is being revolutionized.

Can J Cardiol 2021 Sep 24. Epub 2021 Sep 24.

Amsterdam UMC, University of Amsterdam, Heart Center; department of Clinical Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.cjca.2021.09.016DOI Listing
September 2021

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

Eur Heart J 2021 Sep 24. Epub 2021 Sep 24.

Division of Cardiology, Toronto General Hospital, The Toronto General Hospital Research Institute, University Health Network, University of Toronto, 200 Elizabeth St, Toronto, ON M5G 2C4, Canada.

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.

Methods And Results: Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).

Conclusions: Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.
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http://dx.doi.org/10.1093/eurheartj/ehab687DOI Listing
September 2021

Human RyR2 (Ryanodine Receptor 2) Loss-of-Function Mutations: Clinical Phenotypes and In Vitro Characterization.

Circ Arrhythm Electrophysiol 2021 Sep 1;14(9):e010013. Epub 2021 Sep 1.

Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, AB, Canada (Y.L., J.W., W.G., B.S., J.P.E., R.W., S.R.W.C.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCEP.121.010013DOI Listing
September 2021

Optimal echocardiographic assessment of myocardial dysfunction for arrhythmic risk stratification in phospholamban mutation carriers.

Eur Heart J Cardiovasc Imaging 2021 Sep 13. Epub 2021 Sep 13.

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

Aims : Phospholamban (PLN) p.Arg14del mutation carriers are at risk of developing malignant ventricular arrhythmias (VAs) and/or heart failure. Currently, left ventricular ejection fraction (LVEF) plays an important role in risk assessment for VA in these individuals. We aimed to study the incremental prognostic value of left ventricular mechanical dispersion (LVMD) by echocardiographic deformation imaging for prediction of sustained VA in PLN p.Arg14del mutation carriers.

Methods And Results: We included 243 PLN p.Arg14del mutation carriers, which were classified into three groups according to the '45/45' rule: (i) normal left ventricular (LV) function, defined as preserved LVEF ≥45% with normal LVMD ≤45 ms (n = 139), (ii) mechanical LV dysfunction, defined as preserved LVEF ≥45% with abnormal LVMD >45 ms (n = 63), and (iii) overt LV dysfunction, defined as reduced LVEF <45% (n = 41). During a median follow-up of 3.3 (interquartile range 1.8-6.0) years, sustained VA occurred in 35 individuals. The negative predictive value of having normal LV function at baseline was 99% [95% confidence interval (CI): 92-100%] for developing sustained VA. The positive predictive value of mechanical LV dysfunction was 20% (95% CI: 15-27%). Mechanical LV dysfunction was an independent predictor of sustained VA in multivariable analysis [hazard ratio adjusted for VA history: 20.48 (95% CI: 2.57-162.84)].

Conclusion : LVMD has incremental prognostic value on top of LVEF in PLN p.Arg14del mutation carriers, particularly in those with preserved LVEF. The '45/45' rule is a practical approach to echocardiographic risk stratification in this challenging group of patients. This approach may also have added value in other diseases where LVEF deterioration is a relative late marker of myocardial dysfunction.
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http://dx.doi.org/10.1093/ehjci/jeab178DOI Listing
September 2021

Comparing clinical performance of current implantable cardioverter-defibrillator implantation recommendations in arrhythmogenic right ventricular cardiomyopathy.

Europace 2021 Sep 1. Epub 2021 Sep 1.

Netherlands Heart Institute, PO Box 19258, 3501 DG, Utrecht, The Netherlands.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have an increased risk of ventricular arrhythmias (VA). Four implantable cardioverter-defibrillator (ICD) recommendation algorithms are available The International Task Force Consensus ('ITFC'), an ITFC modification by Orgeron et al. ('mITFC'), the AHA/HRS/ACC guideline for VA management ('AHA'), and the HRS expert consensus statement ('HRS'). This study aims to validate and compare the performance of these algorithms in ARVC.

Methods And Results: We classified 617 definite ARVC patients (38.5 ± 15.1 years, 52.4% male, 39.2% prior sustained VA) according to four algorithms. Clinical performance was evaluated by sensitivity, specificity, ROC-analysis, and decision curve analysis for any sustained VA and for fast VA (>250 b.p.m.). During 6.4 [2.8-11.5] years follow-up, 282 (45.7%) patients experienced any sustained VA, and 63 (10.2%) fast VA. For any sustained VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (94.0-97.8% vs. 76.7-83.5%), but lower specificity (15.9-32.0% vs. 42.7%-60.1%). Similarly, for fast VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (95.2-97.1% vs. 76.7-78.4%) but lower specificity (42.7-43.1 vs. 76.7-78.4%). Decision curve analysis showed ITFC and mITFC to be superior for a 5-year sustained VA risk ICD indication threshold between 5-25% or 2-9% for fast VA.

Conclusion: The ITFC and mITFC provide the highest protection rates, whereas AHA and HRS decrease unnecessary ICD placements. ITFC or mITFC should be used if we consider the 5-year threshold for ICD indication to lie within 5-25% for sustained VA or 2-9% for fast VA. These data will inform decision-making for ICD placement in ARVC.
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http://dx.doi.org/10.1093/europace/euab162DOI Listing
September 2021

Genotype-Phenotype Correlation of Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands.

Circ Genom Precis Med 2021 Oct 31;14(5):e003222. Epub 2021 Aug 31.

Division of Cardiology, Hospital of Peschiera del Garda, Veneto, Italy (G.A., P.D.).

Background: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to genotype in a large cohort of BrS probands with first arrhythmic event.

Methods: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed.

Results: The study group comprised 392 probands: 92 (23.5%) (44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with (11.4% versus 3%, =0.023). The proportion of females was higher among patients with P/LP compared with - (18.2% versus 6.3%, =0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with - (41.9% versus 16.8%, <0.001). A higher proportion of patients with P/LP were White compared with (87.5% versus 47%, <0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], <0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], =0.009) were independent variables associated with P/LP genotype following logistic regression.

Conclusions: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with . In addition, they were more likely to be White and to have family history of sudden cardiac death. Among females, a P/LP variant suggests an increased risk of being symptomatic. This association should be further studied on an ethnically specific basis in large prospectively collected international cohorts.
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http://dx.doi.org/10.1161/CIRCGEN.120.003222DOI Listing
October 2021

Tissues attached to retrieved leadless pacemakers: Histopathological evaluation of tissue composition in relation to implantation time and complications.

Heart Rhythm 2021 Aug 28. Epub 2021 Aug 28.

Department of Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Leadless pacemakers (LPs) have proven safe and effective, but device revisions remain necessary. Either replacing the LP or implanting a new adjacent LP is feasible. Replacement seems more appealing, but encapsulation and tissue adhesions may hamper the safety and efficacy of LP retrieval.

Objective: We determined the incidence and cellular characteristics of tissue adherent to retrieved LPs and the potential implications for end-of-life strategy.

Methods: All 15 consecutive successful Nanostim LP retrievals in a tertiary center were included. We assessed the histopathology of adherent tissue and obtained clinical characteristics.

Results: Adherent tissue was present in 14 of 15 retrievals (93%; median implantation duration 36 months; range 0-96 months). The tissue consisted of fibrosis (n = 2), fibrosis and thrombus (n = 9), or thrombus only (n = 3). In short-term retrievals (<1 year), mostly fresh thrombi without fibrosis were seen. In later retrievals, the tissue consisted of fibrosis often with organizing or lytic thrombi. Fibrosis showed different stages of organization, notably early fibrocellular and later fibrosclerotic tissue. Inflammatory cells were seen (n = 4) without signs of infection. Tricuspid valve material was retrieved in 1 patient after 36 months, resulting in increased tricuspid regurgitation.

Conclusion: Our results suggest that fibrosis and thrombus adherent to LPs are common and encapsulate the LP as seen in transvenous pacemakers. LPs may adhere to the tricuspid valve or subvalvular apparatus affecting retrieval safety. The end-of-life strategy should be optimized by incorporating risk stratification for excessive fibrotic encapsulation and adhesions.
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http://dx.doi.org/10.1016/j.hrthm.2021.08.025DOI Listing
August 2021

Oral contraceptives and their effect on arrhythmogenesis in long QT syndrome: Does it matter?

Heart Rhythm 2021 Aug 10. Epub 2021 Aug 10.

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

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http://dx.doi.org/10.1016/j.hrthm.2021.08.007DOI Listing
August 2021

Investigation on Sudden Unexpected Death in the Young (SUDY) in Europe: results of the European Heart Rhythm Association Survey.

Europace 2021 Aug 5. Epub 2021 Aug 5.

Division of Cardiology, Cardiocentro Ticino Institute, Lugano, Switzerland.

The aims of this centre-based survey, promoted and disseminated by the European Heart Rhythm Association (EHRA) was to investigate the current practice for the investigation of Sudden Unexplained Death in the Young (SUDY) amongst European countries. An online questionnaire composed of 21 questions was submitted to the EHRA Research Network, European Cardiac Arrhythmia Genetics (ECGen) Focus Group members, and European Reference Network GUARD-Heart healthcare partners. There were 81 respondents from 24 European countries. The majority (78%) worked in a dedicated clinic focusing on families with inherited cardiac conditions and/or SUDY or had easy access to a nearby one. On average, an autopsy was performed in 43% of SUDY cases. Macroscopic examination of the body and all organs were completed in 71% of cases undergoing autopsy, and expert cardiac examination in 32%. Post-mortem genetic testing was requested on average in 37% of Sudden Arrhythmic Death Syndrome (SADS) cases, but not at all by 20% of survey respondents. Psychological support and bereavement counselling for SADS/SUDY families were available for ≤50% of participants. Whilst electrocardiogram (ECG) and echocardiography were largely employed to investigate SADS relatives, there was an inconsistent approach to the use of provocative testing with exercise ECG, sodium channel blocking drugs, and/or epinephrine and genetic testing. The survey highlighted a significant heterogeneity of service provision and variable adherence to current recommendations for the investigation of SUDY, partly attributable to the availability of dedicated units and specialist tests, genetic evaluation, and post-mortem examination.
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http://dx.doi.org/10.1093/europace/euab176DOI Listing
August 2021

Does function trump bioinformatics in Brugada syndrome-associated SCN5A mutation calling? Patients, computers, and patches.

Eur Heart J 2021 07;42(29):2864-2865

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

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http://dx.doi.org/10.1093/eurheartj/ehab292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325777PMC
July 2021

Evaluation of age at symptom onset, proband status, and sex as predictors of disease severity in pediatric catecholaminergic polymorphic ventricular tachycardia.

Heart Rhythm 2021 Jul 29. Epub 2021 Jul 29.

Amsterdam University Medical Center, Amsterdam, Netherlands; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart.

Background: Children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for sudden death, and a risk stratification tool does not exist.

Objective: The purpose of this study was to determine whether proband status, age at symptom onset, and/or sex are independent predictors of cardiac events.

Methods: A multicenter, ambispective, cohort of pediatric CPVT patients was categorized by sex, proband status, and age at symptom onset (D1: first decade of life [symptom onset <10 years] or D2: second decade of life [symptom onset 10-18 years, inclusive]). Demographics, therapy, genetics, and outcomes were compared between groups.

Results: A total of 133 patients were included and stratified into 58 D1 and 75 D2 patients (68 female and 65 male; 106 probands and 27 relatives). Localization of RYR2 variants to hotspots differed based on proband status and age at symptom onset. The cardiac event rate was 33% (n = 44/133), inclusive of a 3% (n = 4/133) mortality rate, over a median of 6 years (interquartile range 3-11) after time of symptom onset. Proband status, rather than age at of symptom onset or sex, was an independent predictor of time to first cardiac event (P = .008; hazard ratio = 4.4). The 5-, 10- and 15-year event-free survival rates for probands were 77%, 56%, and 46%, respectively, and for relatives were 96%, 91%, and 86%, respectively. Event risk after diagnosis was 48% (32/67) in patients on β-blocker or flecainide alone vs 10% (5/48) in patients on β-blocker plus flecainide and/or left cardiac sympathetic denervation (P <.001).

Conclusion: Proband status, but not age at symptom onset or male sex, independently predicted an earlier onset of cardiac events. A larger sample size would enable a comprehensive investigation of other risk factors.
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http://dx.doi.org/10.1016/j.hrthm.2021.07.061DOI Listing
July 2021

Management of Congenital Long-QT Syndrome: Commentary From the Experts.

Circ Arrhythm Electrophysiol 2021 Jul 9;14(7):e009726. Epub 2021 Jul 9.

Clinical Cardiovascular Research Center, University of Rochester Medical Center, NY (W.Z.).

While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of β-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.
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http://dx.doi.org/10.1161/CIRCEP.120.009726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301722PMC
July 2021

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.

J Arrhythm 2021 Jun 8;37(3):481-534. Epub 2021 Apr 8.

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/10.1002/joa3.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207384PMC
June 2021

The β-angle can help guide clinical decisions in the diagnostic work-up of patients suspected of Brugada syndrome: a validation study of the β-angle in determining the outcome of a sodium channel provocation test.

Europace 2021 Jun 14. Epub 2021 Jun 14.

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

Aims: In patients with Brugada syndrome (BrS) but without spontaneous Type-1 electrocardiogram, several electrocardiographic characteristics have been studied, including the β-angle. Previous studies suggested that the β-angle might be useful in distinguishing BrS-patients from patients with only suggestive repolarization patterns without performing sodium channel blocker provocation testing. In this study, we aimed to determine the diagnostic value of the β-angle in patients suspected of BrS.

Methods And Results: A large cohort (n = 1430) of consecutive patients who underwent provocation testing was evaluated. β-angles were measured in leads V1, V2, and their corresponding positions over the second and third intercostal space. Receiver-operating characteristic curves were constructed and the diagnostic accuracy of previously reported β-angle cut-offs were calculated and evaluated. The importance of the β-angle for predicting the provocation test outcome was determined using a prediction model constructed with logistic regression. The optimum β-angle cut-off in our cohort for ruling out a positive provocation test was 15°; sensitivities were 80-98% and negative predictive values were 79-96% among the right precordial leads. Previously reported β-angle cut-offs performed less well, indicated by lower Youden indices. In the optimism-corrected prediction model [C-statistic: 0.78 (95% CI: 0.75-0.81)], the β-angle had large value (Z-score: 2.1-10.3) and aided construction of a nomogram to predict test outcome.

Conclusion: To predict the outcome of provocation testing for BrS, the β-angle alone does not demonstrate strong diagnostic characteristics. However, the β-angle is an important variable to predict provocation test outcome and thus has added value.
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http://dx.doi.org/10.1093/europace/euab128DOI Listing
June 2021

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction.

Eur Heart J 2021 07;42(29):2842-2850

Heart Center, Department of Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands.

Aims: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model.

Methods And Results: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75).

Conclusion: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.
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http://dx.doi.org/10.1093/eurheartj/ehab294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325776PMC
July 2021

Diagnostic accuracy of the response to the brief tachycardia provoked by standing in children suspected for long QT syndrome.

Heart Rhythm O2 2021 Apr 13;2(2):149-159. Epub 2021 Mar 13.

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

Background: Adult long QT syndrome (LQTS) patients have inadequate corrected QT interval (QTc) shortening and an abnormal T-wave response to the sudden heart rate acceleration provoked by standing. In adults, this knowledge can be used to aid an LQTS diagnosis and, possibly, for risk stratification. However, data on the diagnostic value of the standing test in children are currently limited.

Objective: To determine the potential value of the standing test to aid LQTS diagnostics in children.

Methods: In a prospective cohort including children (≤18 years) who had a standing test, comprehensive analyses were performed including manual and automated QT interval assessments and determination of T-wave morphology changes.

Results: We included 47 LQTS children and 86 control children. At baseline, the QTc that identified LQTS children with a 90% sensitivity was 435 ms, which yielded a 65% specificity. A QTc ≥ 490 ms after standing only slightly increased sensitivity (91%, 95% confidence interval [CI]: 80%-98%) and slightly decreased specificity (58%, 95% CI: 47%-70%). Sensitivity increased slightly more when T-wave abnormalities were present (94%, 95% CI: 82%-99%; specificity 53%, 95% CI: 42%-65%). When a baseline QTc ≥ 440 ms was accompanied by a QTc ≥ 490 ms and T-wave abnormalities after standing, sensitivity further increased (96%, 95% CI: 85%-99%) at the expense of a further specificity decrease (41%, 95% CI: 30%-52%). Beat-to-beat analysis showed that 30 seconds after standing, LQTS children had a greater increase in heart rate compared to controls, which was more evidently present in LQTS boys and LQTS type 1 children.

Conclusion: In children, the standing test has limited additive diagnostic value for LQTS over a baseline electrocardiogram, while T-wave abnormalities after standing also have limited additional value. The standing test for LQTS should only be used with caution in children.
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http://dx.doi.org/10.1016/j.hroo.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183857PMC
April 2021

Echocardiographic deformation imaging unmasks global and regional mechanical dysfunction in patients with idiopathic ventricular fibrillation: A multicenter case-control study.

Heart Rhythm 2021 Oct 28;18(10):1666-1672. Epub 2021 May 28.

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

Background: Idiopathic ventricular fibrillation (IVF) is diagnosed in patients with sudden onset of ventricular fibrillation of unidentified origin. New diagnostic tools that can detect subtle abnormalities are needed to diagnose and treat patients with an underlying substrate.

Objective: The purpose of this study was to explore echocardiographic deformation characteristics in IVF patients.

Methods: Echocardiograms were analyzed with deformation imaging by 2-dimensional speckle tracking. Global and regional measurements of the left ventricle (LV) and right ventricle (RV) were performed. Regional LV deformation patterns were evaluated for the presence of postsystolic shortening. Regional RV deformation patterns were classified as type I (normal) or type II/III (abnormal).

Results: In total, 47 IVF patients (mean age 45 years; left ventricular ejection fraction [LVEF] 56%) and 47 healthy controls (mean age 41 years; LVEF 60%) were included. IVF patients showed more global deformation abnormalities as indicated by lower LV global longitudinal strain (18.5% ± 2.6% vs 21.6% ± 1.8%; P <.001) and higher LV mechanical dispersion (41 ± 12 ms vs 26 ± 6 ms; P <.001). In addition, IVF patients showed more regional LV postsystolic shortening compared to healthy controls (50% vs 11%; P <.001). Abnormal RV deformation patterns were observed in 16% of IVF patients and in none of the control subjects (P <.001).

Conclusion: We were able to show both regional and global echocardiographic deformation abnormalities in IVF patients. This study provides evidence that localized myocardial disease is present in a subset of IVF patients.
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http://dx.doi.org/10.1016/j.hrthm.2021.05.030DOI Listing
October 2021

Diagnosis, management and therapeutic strategies for congenital long QT syndrome.

Heart 2021 May 26. Epub 2021 May 26.

Heart Centre, Department of Cardiology, Amsterdam Universitair Medische Centra, Amsterdam, The Netherlands.

Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype-phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.
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http://dx.doi.org/10.1136/heartjnl-2020-318259DOI Listing
May 2021

Clinical utility gene card for: Long-QT syndrome.

Eur J Hum Genet 2021 May 24. Epub 2021 May 24.

Department of Legal Medicine, University Hospital Frankfurt, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1038/s41431-021-00904-yDOI Listing
May 2021

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 04 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174382PMC
April 2021

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

Stem Cell Res 2021 05 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
May 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 04 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 06;23(6):887-897

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184225PMC
June 2021

Cardiac ryanodine receptor calcium release deficiency syndrome.

Sci Transl Med 2021 02;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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611259PMC
February 2021

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

Eur Heart J 2021 03;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 2021 05;23(5):781-788

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139815PMC
May 2021
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