Publications by authors named "Vincent Probst"

157 Publications

Dose response to nadolol in congenital long QT syndrome.

Heart Rhythm 2021 Apr 24. Epub 2021 Apr 24.

L'institut du Thorax, Service de Cardiologie, CHU Nantes, Nantes, France; L'institut du Thorax, INSERM, CNRS, University of Nantes, CHU Nantes, Nantes, France. Electronic address:

Background: Beta-blocker therapy is the cornerstone of treatment for patients with long QT syndrome (LQTS). Few details on the dose to be used are available. As the response is variable between patients, we systematically evaluated the effect of treatment by performing an exercise test.

Objective: The purpose of this study was to explore dose response to nadolol on exercise test in LQTS patients in order to propose a more personalized therapeutic approach.

Methods: LQTS patients followed at the Reference Centre for Hereditary Arrhythmic Diseases of Nantes with at least 1 exercise test under nadolol were included retrospectively between 1993 and 2017. All patients underwent gradual cycle exercise tests. Doses adjusted to weight and response to treatment were recorded and evaluated by the percentage of age-predicted maximum heart rate reached on exercise test.

Results: Ninety-five patients were included in the study, and 337 stress tests under nadolol were analyzed. No correlation existed between dose and percentage of age-predicted maximum heart rate on exercise tests. Twenty-one patients were overresponders, mostly LQTS1, and 20 were underresponders, mainly LQTS2 (P = .0229). Forty-two patients had at least 3 stress tests under nadolol. We found a negative correlation between dose change and percentage of age-predicted maximum heart rate change (P <.0001). We then proposed a table to adapt dose according to exercise test response.

Conclusion: Our study demonstrated a major variability of dose response to nadolol in patients with LQTS, thus underlining the need for a tailored dosage for each patient. Intraindividual analysis showed a relatively constant dose-response relationship, allowing guided dose adaptation after the first exercise test.
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http://dx.doi.org/10.1016/j.hrthm.2021.04.021DOI Listing
April 2021

Device-related infection in de novo transvenous implantable cardioverter-defibrillator Medicare patients.

Heart Rhythm 2021 Apr 19. Epub 2021 Apr 19.

Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota; Department of Cardiovascular Disease, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

Background: Cardiac device infection is a serious complication of implantable cardioverter-defibrillator (ICD) placement and requires complete device removal with accompanying antimicrobial therapy for durable cure. Recent guidelines have highlighted the need to better identify patients at high risk of infection to assist in device selection.

Objective: To estimate the prevalence of infection in de novo transvenous (TV) ICD implants and assess factors associated with infection risk in a Medicare population.

Methods: A retrospective cohort study was conducted using 100% Medicare administrative and claims data to identify patients who underwent de novo TV-ICD implantation (July 2016-December 2017). Infection within 720 days of implantation was identified using ICD-10 codes. Baseline factors associated with infection were identified by univariable logistic regression analysis of all variables of interest, including conditions in Charlson and Elixhauser comorbidity indices, followed by stepwise selection criteria with a P ≤ .25 for inclusion in a multivariable model and a backwards, stepwise elimination process with P ≤ .1 to remain in the model. A time-to-event analysis was also conducted.

Results: Among 26,742 patients with de novo TV-ICD, 519 (1.9%) developed an infection within 720 days post implant. While more than half (54%) of infections occurred during the first 90 days, 16% of infections occurred after 365 days. Multivariable analysis revealed several significant predictors of infection: age <70 years, renal disease with dialysis, and complicated diabetes mellitus.

Conclusion: The rate of de novo TV-ICD infection was 1.9%, and identified risk factors associated with infection may be useful in device selection.
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http://dx.doi.org/10.1016/j.hrthm.2021.04.014DOI Listing
April 2021

Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features.

Circ Genom Precis Med 2021 Apr 10;14(2):e003097. Epub 2021 Feb 10.

Center for Cardiac Arrhythmias of Genetic Origin (A.G., M.-C.K., P.J.S., L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM.

Methods: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of -positive probands, and clinical evaluation was performed.

Results: Genetic screening of led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%).

Conclusions: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
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http://dx.doi.org/10.1161/CIRCGEN.120.003097DOI Listing
April 2021

Robustness and relevance of predictive score in sudden cardiac death for patients with Brugada syndrome.

Eur Heart J 2021 05;42(17):1687-1695

l'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.

Aims: Risk stratification of sudden cardiac arrest (SCA) in Brugada syndrome (Brs) remains the main challenge for physicians. Several scores have been suggested to improve risk stratification but never replicated. We aim to investigate the accuracy of the Brs risk scores.

Methods And Results: A total of 1613 patients [mean age 45 ± 15 years, 69% male, 323 (20%) symptomatic] were prospectively enrolled from 1993 to 2016 in a multicentric database. All data described in the risk score were double reviewed for the study. Among them, all patients were evaluated with Shanghai score and 461 (29%) with Sieira score. After a mean follow-up of 6.5 ± 4.7 years, an arrhythmic event occurred in 75 (5%) patients including 16 SCA, 11 symptomatic ventricular arrhythmia, and 48 appropriate therapies. Predictive capacity of the Shanghai score (n = 1613) and the Sieira (n = 461) score was, respectively, estimated by an area under the curve of 0.73 (0.67-0.79) and 0.71 (0.61-0.81). Considering Sieira score, the event rate at 10 years was significantly higher with a score of 5 (26.4%) than with a score of 0 (0.9%) or 1 (1.1%) (P < 0.01). No statistical difference was found in intermediate-risk patients (score 2-4). The Shanghai score does not allow to better stratify the risk of SCA.

Conclusions: In the largest cohort of Brs patient ever described, risk scores do not allow stratifying the risk of arrhythmic event in intermediate-risk patient.
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http://dx.doi.org/10.1093/eurheartj/ehaa763DOI Listing
May 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

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194370PMC
January 2021

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Implantable cardiac defibrillator leads dysfunction after LVAD implantation.

Pacing Clin Electrophysiol 2020 11 24;43(11):1309-1317. Epub 2020 Jul 24.

Department of Cardiology and Cardiac Surgery, AP-HP CHU Henri Mondor, Créteil, France.

Background: Implantable cardioverter-defibrillator (ICD) lead dysfunction has been reported after left ventricular assist device (LVAD) implantation in limited single-center studies. We aimed at describing and characterizing the incidence of ICD lead parameters dysfunction after LVAD implantation.

Methods: Among the 652 patients enrolled in the ASSIST-ICD study, only patients with an ICD prior to LVAD were included (n = 401). ICD lead parameters dysfunction following LVAD implantation is defined as follows: (a) >50% decrease in sensing threshold, (b) pacing lead impedance increase/decrease by >100Ω, and (c) >50% increase in pacing threshold.

Results: One hundred twenty-two patients with an ICD prior to LVAD had available ICD interrogation reports prior and after LVAD. A total of 67 (55%) patients exhibited at least one significant lead dysfunction: 17 (15%) exhibited >50% decrease in right ventricular (RV) sensing, 51 (42%) had >100 Ω increase/decrease in RV pacing impedance, and 24 (20%) experienced >50% increase in RV pacing threshold. A total of 52 patients experienced ventricular arrhythmia during follow-up and all were successfully detected and treated by the device. All lead dysfunction could be managed conservatively.

Conclusion: More than 50% of LVAD-recipients may experience >1 significant change in lead parameters but none had severe clinical consequences.
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http://dx.doi.org/10.1111/pace.14004DOI Listing
November 2020

Idiopathic Ventricular Fibrillation: Role of Purkinje System and Microstructural Myocardial Abnormalities.

JACC Clin Electrophysiol 2020 06;6(6):591-608

Institut Hospitalo-Universitaire Electrophysiology and Heart Modeling Institute, Centre Hospitalier Universitaire de Bordeaux, France; Cardiothoracic Research Center Bordeaux, Université de Bordeaux, Bordeaux, France.

Idiopathic ventricular fibrillation is diagnosed in patients who survived a ventricular fibrillation episode without any identifiable structural or electrical cause after extensive investigations. It is a common cause of sudden death in young adults. The study reviews the diagnostic value of systematic investigations and the new insights provided by detailed electrophysiological mapping. Recent studies have shown the high incidence of microstructural cardiomyopathic areas, which act as the substrate of ventricular fibrillation re-entries. These subclinical alterations require high-density endo- and epicardial mapping to be identified using electrogram criteria. Small areas are involved and located individually in various sites (mostly epicardial). Their characteristics suggest a variety of genetic or acquired pathological processes affecting cellular connectivity or tissue structure, such as cardiomyopathies, myocarditis, or fatty infiltration. Purkinje abnormalities manifesting as triggering ectopy or providing a substrate for re-entry represent a second important cause. The documentation of ephemeral Purkinje ectopy requires continuous electrocardiography monitoring for diagnosis. A variety of diseases affecting Purkinje cell function or conduction are potentially at play in their pathogenesis. Comprehensive investigations can therefore allow the great majority of idiopathic ventricular fibrillation to ultimately receive diagnoses of a cardiac disease, likely underlain by a mosaic of pathologies. Precise phenotypic characterization has significant implications for interpretation of genetic variants, the risk assessment, and individual therapy. Future improvements in imaging or electrophysiological methods may hopefully allow the identification of the subjects at risk and the development of primary prevention strategies.
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http://dx.doi.org/10.1016/j.jacep.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308805PMC
June 2020

Predictors of Subcutaneous Implantable Cardioverter-Defibrillator Shocks and Prognostic Impact in Patients With Structural Heart Disease.

Can J Cardiol 2021 Mar 28;37(3):400-406. Epub 2020 May 28.

CHRU Lille, Institut Cœur-Poumon - Bd du Professeur Jules Leclercq - CHU Lille, F59000-Lille, France.

Background: In this study we aimed to assess long-term outcomes in subcutaneous implantable cardioverter-defibrillator (S-ICD) recipients with structural heart disease by focussing especially on shock incidence, predictors, and associated prognoses.

Methods: In this multicenter registry‒based study, we retrospectively included all patients who underwent S-ICD implantation at 3 tertiary centers. The prognostic impact of S-ICD shock was assessed with a composite outcome that included all-cause death and hospitalisation for heart failure.

Results: A total of 351 patients with underlying cardiomyopathy were included in the investigation. Using multivariable Fine and Gray regression models, secondary prevention, left ventricular ejection fraction (LVEF), conditional shock threshold, and QRS duration appeared to be independent predictors of appropriate S-ICD shock occurrence. In the multivariate Cox regression model adjusted for age, baseline LVEF, underlying cardiomyopathy subtype, New York Heart Association class, and appropriate shocks were significantly associated with increased composite prognostic outcome risk (hazard ratio [HR], 2.61; 95% confidence interval [CI], 1.21-5.65; P = 0.014), whereas inappropriate shocks were not (HR, 1.35; 95% CI, 0.75-4.48; P = 0.18). The analysis of each component of the composite prognostic outcome highlighted that the occurrence of appropriate shocks was associated with an increased risk of hospitalisation for heart failure (HR, 3.10; 95% CI, 1.26-7.58; P = 0.013) and a trend for mortality (HR, 2.19; 95% CI, 0.78-6.16; P = 0.14).

Conclusions: Appropriate S-ICD shocks were associated with a 3-fold increase in acute heart failure admission, whereas inappropriate shocks were not. Conditional shock threshold programming is an independent predictor of S-ICD shock, and its prognostic impact should be investigated further in patients with structural heart disease.
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http://dx.doi.org/10.1016/j.cjca.2020.05.032DOI Listing
March 2021

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

Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies.

ESC Heart Fail 2020 08 1;7(4):1520-1533. Epub 2020 May 1.

l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.

Aims: Several data suggest that acute myocarditis could be related to genetic variants involved in familial cardiomyopathies, particularly arrhythmogenic cardiomyopathy, but the management of patients with acute myocarditis and their families regarding their risk for having an associated inherited cardiomyopathy is unclear.

Methods And Results: Families with at least one individual with a documented episode of acute myocarditis and at least one individual with a cardiomyopathy or a history of sudden death were included in the study. Comprehensive pedigree, including genetic testing, and history of these families were analysed. Six families were included. Genetic analysis revealed a variant in desmosomal proteins genes in all the probands [five in desmoplakin (DSP) gene and one in desmoglein 2 gene]. In the five families identified with a DSP variant, genetic testing was triggered by the association of an acute myocarditis with a single case of apparently isolated dilated cardiomyopathy or sudden death. Familial screening identified 28 DSP variant carriers; 39% had an arrhythmogenic left ventricular (LV) cardiomyopathy phenotype. Familial histories of sudden death were frequent, and a remarkable phenotype of isolated LV late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance without any other structural abnormality was found in 38% of asymptomatic mutation carriers. None of the DSP variant carriers had imaging characteristics of right ventricle involvement meeting current Task Force criteria for arrhythmogenic right ventricular cardiomyopathy.

Conclusions: Comprehensive familial screening including genetic testing in case of acute myocarditis associated with a family history of cardiomyopathy or sudden death revealed unknown or misdiagnosed arrhythmogenic variant carriers with left-dominant phenotypes that frequently evade arrhythmogenic right ventricular cardiomyopathy Task Force criteria. In view of our results, acute myocarditis should be considered as an additional criterion for arrhythmogenic cardiomyopathy, and genetic testing should be advised in patients who experience acute myocarditis and have a family history of cardiomyopathy or sudden death.
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http://dx.doi.org/10.1002/ehf2.12686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373927PMC
August 2020

Subcutaneous implantable cardioverter defibrillator indication in prevention of sudden cardiac death in difficult clinical situations: A French expert position paper.

Arch Cardiovasc Dis 2020 May 22;113(5):359-366. Epub 2020 Apr 22.

Service de cardiologie, CHU de Rouen, 76000 Rouen, France.

The introduction of a new technology always raises questions about its place compared with the reference technology. The use of an implantable cardioverter defibrillator to prevent sudden cardiac death is now a widely proven technique, with a clear statement of its indication in the guidelines. More recently, a subcutaneous implantable cardioverter defibrillator has been introduced, and appears to be an attractive technique as it removes the need to implant a lead inside the right ventricle to treat the patient, which should dramatically decrease the risk of complications over time. Currently, only one model of subcutaneous implantable cardioverter defibrillator is available on the market; its indications are the same as for transvenous implantable cardioverter defibrillators, except for patients who need stimulation because of conduction disorders or ventricular tachycardias that can potentially be treated effectively by antitachycardia pacing. The different technical characteristics of transvenous versus subcutaneous implantable cardioverter defibrillators therefore raise the question of which to choose in different clinical settings. The experts who participated in the preparation of this manuscript had three meetings, organized by the company Boston Scientific. Each expert prepared the draft of a section corresponding to a clinical situation. The choice between transvenous versus subcutaneous implantable cardioverter defibrillator was then voted on by all the experts. The results of the votes are presented in this manuscript, as it seemed important to us to show the disparities of opinion that can exist in certain situations. The votes were cast independently and anonymously.
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http://dx.doi.org/10.1016/j.acvd.2020.03.011DOI Listing
May 2020

Diagnosis and management of subcutaneous implantable cardioverter-defibrillator infections based on process mapping.

Pacing Clin Electrophysiol 2020 09 23;43(9):958-965. Epub 2020 Apr 23.

Center for Heart Rhythm Disorders Bluhm Cardiovascular Institute, Northwestern Memorial Hospital, Chicago, Illinois.

Background: Infection is a well-recognized complication of cardiovascular implantable electronic device (CIED) implantation, including the more recently available subcutaneous implantable cardioverter-defibrillator (S-ICD). Although the AHA/ACC/HRS guidelines include recommendations for S-ICD use, currently there are no clinical trial data that address the diagnosis and management of S-ICD infections. Therefore, an expert panel was convened to develop consensus on these topics.

Methods: A process mapping methodology was used to achieve a primary goal - the development of consensus on the diagnosis and management of S-ICD infections. Two face-to-face meetings of panel experts were conducted to recommend useful information to clinicians in individual patient management of S-ICD infections.

Results: Panel consensus of a stepwise approach in the diagnosis and management was developed to provide guidance in individual patient management.

Conclusion: Achieving expert panel consensus by process mapping methodology in S-ICD infection diagnosis and management was attainable, and the results should be helpful in individual patient management.
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http://dx.doi.org/10.1111/pace.13902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607386PMC
September 2020

High Risk of Sustained Ventricular Arrhythmia Recurrence After Acute Myocarditis.

J Clin Med 2020 Mar 20;9(3). Epub 2020 Mar 20.

Cardiology Department, Dijon Bourgogne University Hospital, 21000 Dijon, France.

Acute myocarditis is associated with cardiac arrhythmia in 25% of cases; a third of these arrhythmias are ventricular tachycardia (VT) or ventricular fibrillation (VF). The implantation of a cardiac defibrillator (ICD) following sustained ventricular arrhythmia remains controversial in these patients. We sought to assess the risk of major arrhythmic ventricular events (MAEs) over time in patients implanted with an ICD following sustained VT/VF in the acute phase of myocarditis compared to those implanted for VT/VF occurring on myocarditis sequelae. Our retrospective observational study included patients implanted with an ICD following VT/VF during acute myocarditis or VT/VF on myocarditis sequelae, from 2007 to 2017, in 15 French university hospitals. Over a median follow-up period of 3 years, MAE occurred in 11 (39%) patients of the acute myocarditis group and 24 (60%) patients of the myocarditis sequelae group. Kaplan-Meier MAE rate estimates at one and three years of follow-up were 19% and 45% in the acute group, and 43% and 64% in the sequelae group. Patients who experienced sustained ventricular arrhythmias during acute myocarditis had a very high risk of VT/VF recurrence during follow-up. These results show that the risk of MAE recurrence remains high after resolution of the acute episode.
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http://dx.doi.org/10.3390/jcm9030848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141537PMC
March 2020

SARS-CoV-2, COVID-19, and inherited arrhythmia syndromes.

Heart Rhythm 2020 09 31;17(9):1456-1462. Epub 2020 Mar 31.

Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Heart Center, Amsterdam, The Netherlands; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart). Electronic address:

Ever since the first case was reported at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) has become a serious threat to public health globally in short time. At this point in time, there is no proven effective therapy. The interactions with concomitant disease are largely unknown, and that may be particularly pertinent to inherited arrhythmia syndrome. An arrhythmogenic effect of COVID-19 can be expected, potentially contributing to disease outcome. This may be of importance for patients with an increased risk of cardiac arrhythmias, either secondary to acquired conditions or comorbidities or consequent to inherited syndromes. Management of patients with inherited arrhythmia syndromes such as long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia in the setting of the COVID-19 pandemic may prove particularly challenging. Depending on the inherited defect involved, these patients may be susceptible to proarrhythmic effects of COVID-19-related issues such as fever, stress, electrolyte disturbances, and use of antiviral drugs. Here, we describe the potential COVID-19-associated risks and therapeutic considerations for patients with distinct inherited arrhythmia syndromes and provide recommendations, pending local possibilities, for their monitoring and management during this pandemic.
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http://dx.doi.org/10.1016/j.hrthm.2020.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156157PMC
September 2020

Adult-onset Still's disease revealed by a complete atrioventricular block, totally regressive under corticosteroid therapy.

J Cardiol Cases 2020 Mar 27;21(3):110-113. Epub 2019 Nov 27.

Department of Internal Medicine, Nantes University Hospital, Nantes, France.

We report the case of a 40-year-old veterinary surgeon who was admitted for spiking fevers, arthralgia, and a complete atrioventricular block. Tests revealed an inflammatory syndrome, hepatic cytolysis, neutrophilic leukocytosis, and increased troponin levels. Cardiac magnetic resonance imaging showed a small myocarditis but no tissue abnormality on the conduction pathways. In the absence of evidence-based infection and favorable evolution under broad spectrum antibiotherapy, an adult-onset Still's disease was suspected and corticosteroid therapy administered. Evolution was then impressively favorable, with a persistent sinus heart rhythm 3 days later. Febrile conductive disorders occurring during a systemic disorder with negative infection and auto-immunity work-up should lead to consider an adult-onset Still's disease, which can be treated and cured, especially with steroids. Moreover, fever, polyarthritis, neutrophilic leukocytosis, pericarditis, and myocarditis should lead to consideration of adult-onset Still's disease.
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http://dx.doi.org/10.1016/j.jccase.2019.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054654PMC
March 2020

Genetic Association Analyses Highlight , , and As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

Circ Genom Precis Med 2019 10 15;12(10):e002617. Epub 2019 Oct 15.

l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France (C.D., S.L.S., R.C., S.R., F.S., A.-S.B., S.L., E.B., S.B., M.K., E.C., I.F., J.-C.R., V.P., R. Redon, T.L.T., J.-J.S.).

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, and , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS.

Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits.

Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: (interleukin 6) on 7p15.3 and (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the locus. The signal identified colocalizes with the expression of the RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors.

Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
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http://dx.doi.org/10.1161/CIRCGEN.119.002617DOI Listing
October 2019

Dynamic changes in ventricular depolarization during exercise in patients with Brugada syndrome.

PLoS One 2020 3;15(3):e0229078. Epub 2020 Mar 3.

Univ Rennes, CHU Rennes, Inserm, LTSI - UMR 1099, Rennes, France.

Brugada syndrome (BS) is a genetic pathological condition associated with a high risk for sudden cardiac death (SCD). Ventricular depolarization disorders have been suggested as a potential electrophysiological mechanism associated with high SCD risk on patients with BS. This paper aims to characterize the dynamic changes of ventricular depolarization observed during physical exercise in symptomatic and asymptomatic BS patients. To this end, cardiac ventricular depolarization features were automatically extracted from 12-lead ECG recordings acquired during standardized exercise stress test in 110 BS patients, of whom 25 were symptomatic. Conventional parameters were evaluated, including QRS duration, R and S wave amplitudes ([Formula: see text], [Formula: see text]), as well as QRS morphological features, such as up-stroke and down-stroke slopes of the R and S waves ([Formula: see text], [Formula: see text] and [Formula: see text]). The effects of physical exercise and recovery on the dynamics of these markers were assessed in both BS populations. Features showing significantly different dynamics between the studied groups were used alone and in combination with the clinical characteristics of the patients in a logistic regression analysis. Results show larger changes in the second half of the QRS complex through [Formula: see text] and [Formula: see text] measured in the right precordial leads for asymptomatic patients, especially during recovery, when the vagal tone is more pronounced. Multivariate analysis involving both types of features resulted in a reduced model of three relevant features ([Formula: see text] in lead V2, Sex and heart rate recovery, HRR), which achieved a suitable discrimination performance between groups; sensitivity = 80% and specificity = 75% (AUC = 83%). However, after controlling the model for possible confounding factors, only one feature ([Formula: see text]) remained meaningful. This adjusted model significantly improved the overall discrimination performance by up to: sensitivity = 84% and specificity = 100% (AUC = 94%). The study highlights the importance of physical exercise test to unmask differentiated behaviors between symptomatic and asymptomatic BS patients through depolarization dynamic analysis. This analysis together with the obtained model may help to identify asymptomatic patients at low or high risk of future cardiac events, but it should be confirmed by further prospective studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053736PMC
June 2020

Heart Rate Recovery After Exercise Is Associated With Arrhythmic Events in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

Circ Arrhythm Electrophysiol 2020 03 16;13(3):e007471. Epub 2020 Feb 16.

Department of Pediatrics, Children's Heart Centre, Division of Cardiology, British Columbia Children's Hospital, Vancouver, BC, Canada (T.M.R., S.S.).

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias.

Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1').

Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; =0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (=0.045).

Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.
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http://dx.doi.org/10.1161/CIRCEP.119.007471DOI Listing
March 2020

Age at diagnosis of Brugada syndrome: Influence on clinical characteristics and risk of arrhythmia.

Heart Rhythm 2020 05 29;17(5 Pt A):743-749. Epub 2019 Nov 29.

l'Institut du Thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France. Electronic address:

Background: Despite a strong genetic background, Brugada syndrome (BrS) mainly affects middle-age patients. Data are scarce in the youngest and oldest age groups.

Objective: The purpose of this study was to describe the clinical characteristics and variations in rhythmic risk in BrS patients according to age.

Methods: Consecutive BrS patients diagnosed in 15 French tertiary centers in France were enrolled from 1993 to 2016 and followed up prospectively. All of the clinical and ECG data were double reviewed.

Results: Among the 1613 patients enrolled (age 45 ± 15 years; 69% male), 3 groups were defined according to age (52 patients <17 years; 1285 between 17 and 59 years; and 276 >60 years). In the youngest patients, we identified more female gender (42%), diagnosis by familial screening (63%), previous sudden cardiac death (15%), SCN5A mutation (62%) sinus dysfunction (8%) and aVR sign (37%) (P <.001). The oldest patients had the same clinical characteristics except for gender (40% women; P <.001). During median follow-up of 5.5 [2.1, 10.0] years, 91 patients experienced an arrhythmic event, including 7 (13%) in the youngest patients, 80 (6%) in middle-age patients, and 4 (1%) in the oldest patients. Annual event rates were 2.1%, 1%, and 0.3%, respectively (P <.01).

Conclusion: Age on diagnosis changes the clinical presentation of BrS. Although children are identified more during familial screening, they present the highest risk of sudden cardiac death, which is an argument for early and extensive familial screening. The oldest patients present the lowest risk of SCD.
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http://dx.doi.org/10.1016/j.hrthm.2019.11.027DOI Listing
May 2020

Number of electrocardiogram leads in the diagnosis of spontaneous Brugada syndrome.

Arch Cardiovasc Dis 2020 Mar 29;113(3):152-158. Epub 2019 Nov 29.

L'Institut du thorax, Inserm, CNRS, université de Nantes, CHU de Nantes, 44093 Nantes, France. Electronic address:

Background: The recently recommended single lead-based criterion for the diagnosis of Brugada syndrome may lead to overdiagnosis of this disorder and overestimation of the risk of sudden cardiac death.

Aim: To investigate the value of a single-lead diagnosis in patients with Brugada syndrome and a spontaneous type 1 electrocardiogram.

Methods: Consecutive patients with Brugada syndrome were included in a multicentre prospective registry; only those with a spontaneous type 1 electrocardiogram were enrolled. Clinical and electrocardiogram data were reviewed by two physicians blinded to the patients' clinical and genetic status.

Results: Among 1613 patients, 505 (31%) were enrolled (79% male; mean age 46±15 years). A spontaneous type 1 electrocardiogram pattern was found in one lead in 250 patients (group 1), in two leads in 227 patients (group 2) and in three leads in 27 patients (group 3). Groups were similar except for individuals in group 3, who presented more frequently a fragmented QRS complex, an early repolarization pattern and a prolonged T-T interval. After a mean follow-up of 6.4±4.7 years, ventricular arrhythmia, sudden cardiac death or implantable cardiac defibrillator shock occurred in 46 (9%) patients, without differences between groups.

Conclusion: The prognosis of Brugada syndrome with a spontaneous type 1 electrocardiogram pattern does not appear to be affected by the number of leads required for the diagnosis.
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http://dx.doi.org/10.1016/j.acvd.2019.10.007DOI Listing
March 2020

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome.

Heart Rhythm 2019 10 5;16(10):1468-1474. Epub 2019 Jul 5.

Quebec Heart and Lung Institute, Quebec City, Quebec, Canada.

Background: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs).

Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs.

Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group.

Results: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility.

Conclusion: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.
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http://dx.doi.org/10.1016/j.hrthm.2019.07.003DOI Listing
October 2019

Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest.

Eur Heart J 2019 09;40(35):2953-2961

Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, Oslo, Norway.

Aims: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated.

Methods And Results: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%).

Conclusion: In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.
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http://dx.doi.org/10.1093/eurheartj/ehz309DOI Listing
September 2019

RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome.

Eur Heart J 2019 10;40(37):3081-3094

Division of Cardiovascular Medicine, Department of Medicine, Stanford Cardiovascular Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Aims: The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias. Despite considerable efforts, its genetic basis and cellular mechanisms remain largely unknown. The objective of this study was to identify a new susceptibility gene for BrS through familial investigation.

Methods And Results: Whole-exome sequencing performed in a three-generation pedigree with five affected members allowed the identification of one rare non-synonymous substitution (p.R211H) in RRAD, the gene encoding the RAD GTPase, carried by all affected members of the family. Three additional rare missense variants were found in 3/186 unrelated index cases. We detected higher levels of RRAD transcripts in subepicardium than in subendocardium in human heart, and in the right ventricle outflow tract compared to the other cardiac compartments in mice. The p.R211H variant was then subjected to electrophysiological and structural investigations in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). Cardiomyocytes derived from induced pluripotent stem cells from two affected family members exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations, with decreased Na+ peak current amplitude and increased Na+ persistent current amplitude, as well as abnormal distribution of actin and less focal adhesions, compared with intra-familial control iPSC-CMs Insertion of p.R211H-RRAD variant in control iPSCs by genome editing confirmed these results. In addition, iPSC-CMs from affected patients exhibited a decreased L-type Ca2+ current amplitude.

Conclusion: This study identified a potential new BrS-susceptibility gene, RRAD. Cardiomyocytes derived from induced pluripotent stem cells expressing RRAD variant recapitulated single-cell electrophysiological features of BrS, including altered Na+ current, as well as cytoskeleton disturbances.
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http://dx.doi.org/10.1093/eurheartj/ehz308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769825PMC
October 2019

Characterization and Management of Arrhythmic Events in Young Patients With Brugada Syndrome.

J Am Coll Cardiol 2019 04;73(14):1756-1765

Quebec Heart and Lung Institute, Quebec City, Quebec, Canada.

Background: Information on young patients with Brugada syndrome (BrS) and arrhythmic events (AEs) is limited.

Objectives: The purpose of this study was to describe their characteristics and management as well as risk factors for AE recurrence.

Methods: A total of 57 patients (age ≤20 years), all with BrS and AEs, were divided into pediatric (age ≤12 years; n = 26) and adolescents (age 13 to 20 years; n = 31).

Results: Patients' median age at time of first AE was 14 years, with a majority of males (74%), Caucasians (70%), and probands (79%) who presented as aborted cardiac arrest (84%). A significant proportion of patients (28%) exhibited fever-related AE. Family history of sudden cardiac death (SCD), prior syncope, spontaneous type 1 Brugada electrocardiogram (ECG), inducible ventricular fibrillation at electrophysiological study, and SCN5A mutations were present in 26%, 49%, 65%, 28%, and 58% of patients, respectively. The pediatric group differed from the adolescents, with a greater proportion of females, Caucasians, fever-related AEs, and spontaneous type-1 ECG. During follow-up, 68% of pediatric and 64% of adolescents had recurrent AE, with median time of 9.9 and 27.0 months, respectively. Approximately one-third of recurrent AEs occurred on quinidine therapy, and among the pediatric group, 60% of recurrent AEs were fever-related. Risk factors for recurrent AE included sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, or large S-wave on ECG lead I in the pediatric group and the presence of SCN5A mutation among adolescents.

Conclusions: Young BrS patients with AE represent a very arrhythmogenic group. Current management after first arrhythmia episode is associated with high recurrence rate. Alternative therapies, besides defibrillator implantation, should be considered.
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http://dx.doi.org/10.1016/j.jacc.2019.01.048DOI Listing
April 2019

High risk of heart failure associated with desmoglein-2 mutations compared to plakophilin-2 mutations in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Eur J Heart Fail 2019 06 21;21(6):792-800. Epub 2019 Feb 21.

Centre de Référence Pour les Maladies Cardiaques Héréditaires, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.

Background: Previous studies suggested that genetic status affects the clinical course of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients. The aim of this study was to compare the outcome of desmoglein-2 (DSG2) mutation carriers to those who carry the plakophilin-2 (PKP2) mutation, the most common ARVC/D-associated gene.

Methods And Results: Consecutive ARVC/D patients carrying a pathogenic mutation in PKP2 or DSG2 were selected from a national ARVC/D registry. The cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (HF) during follow-up was assessed, compared between PKP2 and DSG2, and predictors for ventricular arrhythmia and HF events determined. Overall, 118 patients from 78 families were included: 27 (23%) carried a DSG2 mutation and 91 (77%) a PKP2 mutation. There were no significant differences between DSG2 and PKP2 mutation carriers concerning gender, proband status, age at diagnosis, T-wave inversion, or right ventricular dysfunction at baseline. DSG2 patients displayed more frequent epsilon wave (37% vs. 17%, P = 0.048) and left ventricular dysfunction at diagnosis (54% vs. 10%, P < 0.001). During a median follow-up of 5.6 years (2.5-16), DSG2 and PKP2 mutation carriers displayed a similar risk of sustained ventricular arrhythmia (log-rank P = 0.20), but DSG2 mutation carriers were at higher risk of transplantation/HF-related death (log-rank P < 0.001). The presence of a DSG2 mutation vs. PKP2 mutation was a predictor of transplantation/HF-related death in univariate Cox analysis (P = 0.0005).

Conclusions: In this multicentre cohort, DSG2 mutation carriers were found to be at high risk of end-stage HF compared to PKP2 mutation carriers, supporting careful haemodynamic monitoring of these patients. The benefit of early HF treatment needs to be assessed in DSG2 carriers.
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http://dx.doi.org/10.1002/ejhf.1423DOI Listing
June 2019