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Dive into the research topics where Solena Le Scouarnec is active.

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Featured researches published by Solena Le Scouarnec.


The New England Journal of Medicine | 2008

Sudden Cardiac Arrest Associated with Early Repolarization

Michel Haïssaguerre; Nicolas Derval; Frederic Sacher; Laurence Jesel; Isabel Deisenhofer; Luc De Roy; Jean-Luc Pasquié; Akihiko Nogami; Dominique Babuty; Sinikka Yli-Mayry; Christian de Chillou; Patrice Scanu; Philippe Mabo; Seiichiro Matsuo; Vincent Probst; Solena Le Scouarnec; Pascal Defaye; Juerg Schlaepfer; Thomas Rostock; Dominique Lacroix; Dominique Lamaison; Thomas Lavergne; Yoshifusa Aizawa; Anders Englund; Frederic Anselme; Mark O'Neill; Mélèze Hocini; Kang-Teng Lim; Sébastien Knecht; George D. Veenhuyzen

BACKGROUND Early repolarization is a common electrocardiographic finding that is generally considered to be benign. Its potential to cause cardiac arrhythmias has been hypothesized from experimental studies, but it is not known whether there is a clinical association with sudden cardiac arrest. METHODS We reviewed data from 206 case subjects at 22 centers who were resuscitated after cardiac arrest due to idiopathic ventricular fibrillation and assessed the prevalence of electrocardiographic early repolarization. The latter was defined as an elevation of the QRS-ST junction of at least 0.1 mV from baseline in the inferior or lateral lead, manifested as QRS slurring or notching. The control group comprised 412 subjects without heart disease who were matched for age, sex, race, and level of physical activity. Follow-up data that included the results of monitoring with an implantable defibrillator were obtained for all case subjects. RESULTS Early repolarization was more frequent in case subjects with idiopathic ventricular fibrillation than in control subjects (31% vs. 5%, P<0.001). Among case subjects, those with early repolarization were more likely to be male and to have a history of syncope or sudden cardiac arrest during sleep than those without early repolarization. In eight subjects, the origin of ectopy that initiated ventricular arrhythmias was mapped to sites concordant with the localization of repolarization abnormalities. During a mean (+/-SD) follow-up of 61+/-50 months, defibrillator monitoring showed a higher incidence of recurrent ventricular fibrillation in case subjects with a repolarization abnormality than in those without such an abnormality (hazard ratio, 2.1; 95% confidence interval, 1.2 to 3.5; P=0.008). CONCLUSIONS Among patients with a history of idiopathic ventricular fibrillation, there is an increased prevalence of early repolarization.


Journal of Clinical Investigation | 2008

Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans

Hiroshi Watanabe; Tamara T. Koopmann; Solena Le Scouarnec; Tao Yang; Christiana R. Ingram; Jean-Jacques Schott; Sophie Demolombe; Vincent Probst; Frédeéric Anselme; Denis Escande; Ans C.P. Wiesfeld; Arne Pfeufer; Stefan Kääb; H.-Erich Wichmann; Can Hasdemir; Yoshifusa Aizawa; Arthur A.M. Wilde; Dan M. Roden; Connie R. Bezzina

Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel alpha subunit NaV1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel beta1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, beta1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when NaV1.5 was coexpressed with mutant beta1 or beta1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.


Circulation-cardiovascular Genetics | 2009

SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome

Vincent Probst; Arthur A.M. Wilde; Julien Barc; Frederic Sacher; Dominique Babuty; Philippe Mabo; Jacques Mansourati; Solena Le Scouarnec; Florence Kyndt; Cédric Le Caignec; Pascale Guicheney; Laetitia Gouas; Juliette Albuisson; Paola G. Meregalli; Hervé Le Marec; Hanno L. Tan; Jean-Jacques Schott

Background— Mutations in SCN5A are identified in ≈20% to 30% of probands affected by Brugada syndrome (BrS). However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families. Methods and Results— Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects. Conclusions— Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels.


Circulation | 2007

Defining the Cellular Phenotype of “Ankyrin-B Syndrome” Variants: Human ANK2 Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes

Peter J. Mohler; Solena Le Scouarnec; Isabelle Denjoy; John S. Lowe; Pascale Guicheney; Lise Caron; Iwona M. Driskell; Jean-Jacques Schott; Kris Norris; Antoine Leenhardt; Richard B. Kim; Denis Escande; Dan M. Roden

Background— Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. Methods and Results— We performed a comprehensive screen of ANK2 in populations (control, congenital arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a spectrum of cellular phenotypes. We then characterized the relative severity of loss-of-function properties of all 9 nonsynonymous ANK2 variants identified to date in primary cardiomyocytes and identified a range of in vitro phenotypes, including wild-type, simple loss-of-function, and severe loss-of-function activity, seen with the variants causing severe human phenotypes. Conclusions— We present the first description of differences in cellular phenotypes conferred by specific ANK2 variants. We propose that the various degrees of ankyrin-B loss of function contribute to the range of severity of cardiac dysfunction. These data identify ANK2 variants as modulators of human arrhythmias, provide the first insight into the clinical spectrum of “ankyrin-B syndrome,” and reinforce the role of ankyrin-B–dependent protein interactions in regulating cardiac electrogenesis.


Proceedings of the National Academy of Sciences of the United States of America | 2008

Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease.

Solena Le Scouarnec; Naina Bhasin; Claude Vieyres; Thomas J. Hund; Shane R. Cunha; Olha M. Koval; Céline Marionneau; Biyi Chen; Yuejin Wu; Sophie Demolombe; Long-Sheng Song; Hervé Le Marec; Vincent Probst; Jean-Jacques Schott; Mark E. Anderson; Peter J. Mohler

The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases. In contrast, very little is known about the genetic and molecular mechanisms underlying human sinus node dysfunction (SND). Here, we report a genetic and molecular mechanism for human SND. We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing. Finally, dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and SND. Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability.


Journal of the American College of Cardiology | 2014

HCN4 Mutations in Multiple Families With Bradycardia and Left Ventricular Noncompaction Cardiomyopathy

Annalisa Milano; Alexa M.C. Vermeer; Elisabeth M. Lodder; Julien Barc; Arie O. Verkerk; Alex V. Postma; Ivo van der Bilt; Marieke J.H. Baars; Paul L. van Haelst; Kadir Caliskan; Yvonne M. Hoedemaekers; Solena Le Scouarnec; Richard Redon; Yigal M. Pinto; Imke Christiaans; Arthur A.M. Wilde; Connie R. Bezzina

BACKGROUND Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause. OBJECTIVES This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause. METHODS Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis. RESULTS The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia. CONCLUSIONS Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium.


Human Molecular Genetics | 2015

Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome

Solena Le Scouarnec; Matilde Karakachoff; Jean-Baptiste Gourraud; Pierre Lindenbaum; Stéphanie Bonnaud; Vincent Portero; Laetitia Duboscq-Bidot; Xavier Daumy; Floriane Simonet; Raluca Teusan; Estelle Baron; Jade Violleau; Elodie Persyn; Lise Bellanger; Julien Barc; Stéphanie Chatel; Raphaël P. Martins; Philippe Mabo; Frederic Sacher; Michel Haïssaguerre; Florence Kyndt; Sébastien Schmitt; Stéphane Bézieau; Hervé Le Marec; Christian Dina; Jean-Jacques Schott; Vincent Probst; Richard Redon

The Brugada syndrome (BrS) is a rare heritable cardiac arrhythmia disorder associated with ventricular fibrillation and sudden cardiac death. Mutations in the SCN5A gene have been causally related to BrS in 20-30% of cases. Twenty other genes have been described as involved in BrS, but their overall contribution to disease prevalence is still unclear. This study aims to estimate the burden of rare coding variation in arrhythmia-susceptibility genes among a large group of patients with BrS. We have developed a custom kit to capture and sequence the coding regions of 45 previously reported arrhythmia-susceptibility genes and applied this kit to 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-year old and showing no history of cardiac arrhythmia. By applying burden tests, a significant enrichment in rare coding variation (with a minor allele frequency below 0.1%) was observed only for SCN5A, with rare coding variants carried by 20.4% of cases with BrS versus 2.4% of control individuals (P = 1.4 × 10(-7)). No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C. These results indicate that, except for SCN5A, rare coding variation in previously reported arrhythmia-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry. Extreme caution should thus be taken when interpreting genetic variation in molecular diagnostic setting, since rare coding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes.


Journal of the American College of Cardiology | 2013

Identification of Large Families in Early Repolarization Syndrome

Jean-Baptiste Gourraud; Solena Le Scouarnec; Frederic Sacher; Stéphanie Chatel; Nicolas Derval; Vincent Portero; Pascal Chavernac; Juan E. Sandoval; Philippe Mabo; Richard Redon; Jean-Jacques Schott; Hervé Le Marec; Michel Haïssaguerre; Vincent Probst

OBJECTIVES The aim of this study was to identify families affected by early repolarization syndrome (ERS) and to determine the mode of transmission of the disease. BACKGROUND Early repolarization (ER) has recently been linked to idiopathic ventricular fibrillation. Familial inheritance of the disease has been suggested but not demonstrated. METHODS We screened relatives of 4 families affected by ERS. ER was defined as a distinct J-wave in at least 2 consecutive leads and a 1-mm amplitude above baseline. The Valsalva maneuver was performed in affected and unaffected family members to decrease heart rate and thus increase or reveal an ER pattern. RESULTS Twenty-two sudden cardiac deaths occurred in the 4 families including 10 before 35 years of age. In the 4 families, the prevalence of ER was 56%, 34%, 61%, and 33% of, respectively, 30, 82, 29, and 30 screened relatives. In these families, transmission of an ER pattern is compatible with an autosomal dominant mode of inheritance. All probands were screened for genes identified in ERS, and no mutation was found. The Valsalva maneuver was performed in 80 relatives, resulting in increased J-wave amplitude for 17 of 20 affected patients and revealing an ER pattern in 17 relatives in whom 5 are obligate transmitters of an ER pattern. CONCLUSIONS ERS can be inherited through autosomal dominant transmission and should be considered a real inherited arrhythmia syndrome. Familial investigation can be facilitated by using the Valsalva maneuver to reveal the electrocardiographic pattern in family members. The prognosis value of this test remains to be assessed.


Circulation | 2006

Familial Aggregation of Calcific Aortic Valve Stenosis in the Western Part of France

Vincent Probst; Solena Le Scouarnec; Antoine Legendre; Valérie Jousseaume; Philippe Jaafar; Jean-Michel Nguyen M.D.; André Chaventré; Hervé Le Marec; Jean-Jacques Schott

Background— Calcific aortic valve stenosis (CAVS) is the most common valvular defect in developed countries. Unlike mitral valve prolapse, there is no demonstration that a familial factor could play a role in the occurrence of this disease. The aim of this study was to demonstrate a familial aggregation for CAVS. Methods and Results— We used the files of 2527 consecutive patients operated on for CAVS in our institution between 1992 and 2002 to map the distribution of operated CAVS in the western part of France. In a second step, we investigated clinically and genealogically the clusters with the highest rates of operated CAVS to detect familial forms of the disease. The geographic distribution of CAVS is highly heterogeneous, with an average frequency of operated CAVS of 1.13 per 1000 inhabitants but up to 9.38 per 1000 in specific parishes. A screening of the population from the parishes with the highest rate of operated CAVS allowed us to identify 5 families with ≥3 sibs affected by CAVS. A large genealogical analysis performed in one of these families allowed us to link 48 patients who derived from 34 nuclear families. Genealogical information could be traced to a common ancestor within 13 generations. Conclusions— Identification of clusters and large families affected by a classic form of CAVS demonstrates a familial aggregation for this disease.


PLOS ONE | 2010

Variable Na(v)1.5 protein expression from the wild-type allele correlates with the penetrance of cardiac conduction disease in the Scn5a(+/-) mouse model.

Anne-Laure Leoni; Bruno Gavillet; Jean-Sébastien Rougier; Céline Marionneau; Vincent Probst; Solena Le Scouarnec; Jean-Jacques Schott; Sophie Demolombe; Patrick Bruneval; Christopher L.-H. Huang; William H. Colledge; Andrew A. Grace; Hervé Le Marec; Arthur A.M. Wilde; Peter J. Mohler; Denis Escande; Hugues Abriel; Flavien Charpentier

Background Loss-of-function mutations in SCN5A, the gene encoding Nav1.5 Na+ channel, are associated with inherited cardiac conduction defects and Brugada syndrome, which both exhibit variable phenotypic penetrance of conduction defects. We investigated the mechanisms of this heterogeneity in a mouse model with heterozygous targeted disruption of Scn5a (Scn5a +/− mice) and compared our results to those obtained in patients with loss-of-function mutations in SCN5A. Methodology/Principal Findings Based on ECG, 10-week-old Scn5a +/− mice were divided into 2 subgroups, one displaying severe ventricular conduction defects (QRS interval>18 ms) and one a mild phenotype (QRS≤18 ms; QRS in wild-type littermates: 10–18 ms). Phenotypic difference persisted with aging. At 10 weeks, the Na+ channel blocker ajmaline prolonged QRS interval similarly in both groups of Scn5a +/− mice. In contrast, in old mice (>53 weeks), ajmaline effect was larger in the severely affected subgroup. These data matched the clinical observations on patients with SCN5A loss-of-function mutations with either severe or mild conduction defects. Ventricular tachycardia developed in 5/10 old severely affected Scn5a +/− mice but not in mildly affected ones. Correspondingly, symptomatic SCN5A–mutated Brugada patients had more severe conduction defects than asymptomatic patients. Old severely affected Scn5a +/− mice but not mildly affected ones showed extensive cardiac fibrosis. Mildly affected Scn5a +/− mice had similar Nav1.5 mRNA but higher Nav1.5 protein expression, and moderately larger INa current than severely affected Scn5a +/− mice. As a consequence, action potential upstroke velocity was more decreased in severely affected Scn5a +/− mice than in mildly affected ones. Conclusions Scn5a +/− mice show similar phenotypic heterogeneity as SCN5A-mutated patients. In Scn5a +/− mice, phenotype severity correlates with wild-type Nav1.5 protein expression.

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