Characterization of the electrophysiological substrate and the Purkinje system underlying sudden cardiac death with apparently normal hearts

La mort subite cardiaque est responsable d’environ 10% de la mortalité adulte en Europe et dans le monde. Dans la majorité des cas, le décès est lié à une arythmie ventriculaire par tachycardie ou fibrillation ventriculaire (FV). Les excitations initiales conduisant aux FV prennent souvent naissance dans le tissu spécialisé –le système de Purkinje (SP)- assurant l’activation ventriculaire physiologique. Quoique de taille réduite, le SP exerce une action pathogène majeure par son excitabilité et sa modulation du substrat environnant via son architecture arborescente unique. Toutefois les mécanismes et facteurs modulateurs de son arythmogénicité restent encore mal élucidés et il n’existe pas de marqueur diagnostique prédictif de sa pathogénicité potentielle, actuellement.Nous avons réalisé un total de six études cliniques et expérimentales (sur cœur entier et ventricule gauche de lapin). Les études expérimentales ont permis de montrer la capacité du SP à moduler l’arythmogénicité de son propre substrat par une modification hétérogène de la repolarisation ventriculaire. Cette dernière est un élément-clé des torsades de pointe comme on l’a montré sur un modèle de cœur perfusé sous clofilium. Les études cliniques ont mis en évidence l’importance du mécanisme de réentrée –favorisé par l’architecture arborescente du SP –dans les premiers battements initiant la FV et qu’il déterminait le succès de l’ablation. Certains éléments d’arythmogénicité tels que les extrasystoles ventriculaires à couplage long, considérés comme bénins, ont été montrés comme significativement associés à un risque rythmique des patients. Enfin, l’embryologie du SP, le sexe féminin/masculin et les hormones sexuelles étaient responsables de la variabilité phénotypique des arythmies ventriculaires liées au SP.Ce travail ouvre de nouvelles pistes de recherche sur les mécanismes électrophysiologiques impliqués dans les arythmies liées au Purkinje et les facteurs cliniques modulant son arythmogénicité.Sudden cardiac death is responsible for about 10% of adult mortality in Europe and the world. In the majority of cases, death is related to ventricular arrhythmia by tachycardia or ventricular fibrillation (VF). Initial excitations leading to VF often originate in the specialized tissue – the Purkinje system (PS)– providing physiological ventricular activation. Although small in size, PS exerts a major pathogenic action through its excitability and modulation of the surrounding substrate via its unique tree architecture. However, the mechanisms and modulating factors of its arrhythmogenicity remain unclear and there is currently no diagnostic marker predicting its potential pathogenicity.A total of six clinical and experimental studies (whole heart and left rabbit ventricle) were conducted. Experimental studies have shown the ability of PS to modulate the arrhythmogenicity of its own substrate by a heterogeneous modification of ventricular repolarization. The latter is a key element of advanced twists as shown on a model of heart perfused under clofilium. Clinical studies have highlighted the importance of the reentry mechanism – favoured by the PS tree architecture – in the early stages of VF initiation and that it determines the success of ablation. Some elements of arrhythmogenicity, such as long-coupled premature ventricular complexes, which are considered benign, have been shown to be significantly associated with patients' rhythmic risk. Finally, PS embryology, female/male sex, and sex hormones were responsible for phenotypic variability in PS-related ventricular arrhythmias.This work opens up new avenues of research on the electrophysiological mechanisms involved in Purkinje-related arrhythmias and the clinical factors modulating its arrhythmogenicity

Caractérisation du substrat électrophysiologique et du système de Purkinje dans les morts subites cardiaques sur cœur a priori sain

Sudden cardiac death is responsible for about 10% of adult mortality in Europe and the world. In the majority of cases, death is related to ventricular arrhythmia by tachycardia or ventricular fibrillation (VF). Initial excitations leading to VF often originate in the specialized tissue – the Purkinje system (PS)– providing physiological ventricular activation. Although small in size, PS exerts a major pathogenic action through its excitability and modulation of the surrounding substrate via its unique tree architecture. However, the mechanisms and modulating factors of its arrhythmogenicity remain unclear and there is currently no diagnostic marker predicting its potential pathogenicity.A total of six clinical and experimental studies (whole heart and left rabbit ventricle) were conducted. Experimental studies have shown the ability of PS to modulate the arrhythmogenicity of its own substrate by a heterogeneous modification of ventricular repolarization. The latter is a key element of advanced twists as shown on a model of heart perfused under clofilium. Clinical studies have highlighted the importance of the reentry mechanism – favoured by the PS tree architecture – in the early stages of VF initiation and that it determines the success of ablation. Some elements of arrhythmogenicity, such as long-coupled premature ventricular complexes, which are considered benign, have been shown to be significantly associated with patients' rhythmic risk. Finally, PS embryology, female/male sex, and sex hormones were responsible for phenotypic variability in PS-related ventricular arrhythmias.This work opens up new avenues of research on the electrophysiological mechanisms involved in Purkinje-related arrhythmias and the clinical factors modulating its arrhythmogenicity.La mort subite cardiaque est responsable d’environ 10% de la mortalité adulte en Europe et dans le monde. Dans la majorité des cas, le décès est lié à une arythmie ventriculaire par tachycardie ou fibrillation ventriculaire (FV). Les excitations initiales conduisant aux FV prennent souvent naissance dans le tissu spécialisé –le système de Purkinje (SP)- assurant l’activation ventriculaire physiologique. Quoique de taille réduite, le SP exerce une action pathogène majeure par son excitabilité et sa modulation du substrat environnant via son architecture arborescente unique. Toutefois les mécanismes et facteurs modulateurs de son arythmogénicité restent encore mal élucidés et il n’existe pas de marqueur diagnostique prédictif de sa pathogénicité potentielle, actuellement.Nous avons réalisé un total de six études cliniques et expérimentales (sur cœur entier et ventricule gauche de lapin). Les études expérimentales ont permis de montrer la capacité du SP à moduler l’arythmogénicité de son propre substrat par une modification hétérogène de la repolarisation ventriculaire. Cette dernière est un élément-clé des torsades de pointe comme on l’a montré sur un modèle de cœur perfusé sous clofilium. Les études cliniques ont mis en évidence l’importance du mécanisme de réentrée –favorisé par l’architecture arborescente du SP –dans les premiers battements initiant la FV et qu’il déterminait le succès de l’ablation. Certains éléments d’arythmogénicité tels que les extrasystoles ventriculaires à couplage long, considérés comme bénins, ont été montrés comme significativement associés à un risque rythmique des patients. Enfin, l’embryologie du SP, le sexe féminin/masculin et les hormones sexuelles étaient responsables de la variabilité phénotypique des arythmies ventriculaires liées au SP.Ce travail ouvre de nouvelles pistes de recherche sur les mécanismes électrophysiologiques impliqués dans les arythmies liées au Purkinje et les facteurs cliniques modulant son arythmogénicité

Characterization of the electrophysiological substrate and the Purkinje system underlying sudden cardiac death with apparently normal hearts

La mort subite cardiaque est responsable d’environ 10% de la mortalité adulte en Europe et dans le monde. Dans la majorité des cas, le décès est lié à une arythmie ventriculaire par tachycardie ou fibrillation ventriculaire (FV). Les excitations initiales conduisant aux FV prennent souvent naissance dans le tissu spécialisé –le système de Purkinje (SP)- assurant l’activation ventriculaire physiologique. Quoique de taille réduite, le SP exerce une action pathogène majeure par son excitabilité et sa modulation du substrat environnant via son architecture arborescente unique. Toutefois les mécanismes et facteurs modulateurs de son arythmogénicité restent encore mal élucidés et il n’existe pas de marqueur diagnostique prédictif de sa pathogénicité potentielle, actuellement.Nous avons réalisé un total de six études cliniques et expérimentales (sur cœur entier et ventricule gauche de lapin). Les études expérimentales ont permis de montrer la capacité du SP à moduler l’arythmogénicité de son propre substrat par une modification hétérogène de la repolarisation ventriculaire. Cette dernière est un élément-clé des torsades de pointe comme on l’a montré sur un modèle de cœur perfusé sous clofilium. Les études cliniques ont mis en évidence l’importance du mécanisme de réentrée –favorisé par l’architecture arborescente du SP –dans les premiers battements initiant la FV et qu’il déterminait le succès de l’ablation. Certains éléments d’arythmogénicité tels que les extrasystoles ventriculaires à couplage long, considérés comme bénins, ont été montrés comme significativement associés à un risque rythmique des patients. Enfin, l’embryologie du SP, le sexe féminin/masculin et les hormones sexuelles étaient responsables de la variabilité phénotypique des arythmies ventriculaires liées au SP.Ce travail ouvre de nouvelles pistes de recherche sur les mécanismes électrophysiologiques impliqués dans les arythmies liées au Purkinje et les facteurs cliniques modulant son arythmogénicité.Sudden cardiac death is responsible for about 10% of adult mortality in Europe and the world. In the majority of cases, death is related to ventricular arrhythmia by tachycardia or ventricular fibrillation (VF). Initial excitations leading to VF often originate in the specialized tissue – the Purkinje system (PS)– providing physiological ventricular activation. Although small in size, PS exerts a major pathogenic action through its excitability and modulation of the surrounding substrate via its unique tree architecture. However, the mechanisms and modulating factors of its arrhythmogenicity remain unclear and there is currently no diagnostic marker predicting its potential pathogenicity.A total of six clinical and experimental studies (whole heart and left rabbit ventricle) were conducted. Experimental studies have shown the ability of PS to modulate the arrhythmogenicity of its own substrate by a heterogeneous modification of ventricular repolarization. The latter is a key element of advanced twists as shown on a model of heart perfused under clofilium. Clinical studies have highlighted the importance of the reentry mechanism – favoured by the PS tree architecture – in the early stages of VF initiation and that it determines the success of ablation. Some elements of arrhythmogenicity, such as long-coupled premature ventricular complexes, which are considered benign, have been shown to be significantly associated with patients' rhythmic risk. Finally, PS embryology, female/male sex, and sex hormones were responsible for phenotypic variability in PS-related ventricular arrhythmias.This work opens up new avenues of research on the electrophysiological mechanisms involved in Purkinje-related arrhythmias and the clinical factors modulating its arrhythmogenicity

Étudier des numérations orales en classe : quels savoirs mathématiques et langagiers ?

International audienceThis paper deals with a multilingual approach of language awareness to teach and learn mathematics. The analysis of oral number systems in four languages (French, English, Breton, Maori) shows linguistic particularities to "say numbers". Numbers decompositions (additive and multiplicative) are proposed in the four languages regarding to place-value system with the usual polynomial decomposition. The notion of regular oral system number is as well presented. Cultural and linguistic aspects concern in particular written comprehension and the notion of translation. The multilingual approach allows to look beyond the language and culture of school and to consider mathematics through linguistic particularities.Cet article propose une approche plurilingue d'éveil aux langues pour enseigner et apprendre les mathématiques. L'analyse des numérations orales en quatre langues (français, anglais, breton et maori) montre des spécificités linguistiques pour « dire les nombres ». Des décompositions de nombres (additives et multiplicatives) sont proposées dans les quatre langues et mises au regard de la numération décimale de position avec la décomposition polynomiale usuelle. La notion de numération orale régulière est également présentée. Les aspects culturels et langagiers concernent en particulier la compréhension écrite et la notion de traduction. L'approche plurilingue permet de se décentrer de la langue et de la culture de l'école et d'envisager les mathématiques au regard de spécificités linguistiques

Clinical Presentation and Heart Failure in Children With Arrhythmogenic Cardiomyopathy

International audienceBackground: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, and sudden cardiac death represents an important mode of death in these patients. Data evaluating the implantable cardioverter defibrillator (ICD) in this patient population remain scarce. Methods: A Nationwide French Registry including all patients with tetralogy of Fallot with an ICD was initiated in 2010 by the French Institute of Health and Medical Research. The primary time to event end point was the time from ICD implantation to first appropriate ICD therapy. Secondary outcomes included ICD-related complications, heart transplantation, and death. Clinical events were centrally adjudicated by a blinded committee. Results: A total of 165 patients (mean age, 42.2±13.3 years, 70.1% males) were included from 40 centers, including 104 (63.0%) in secondary prevention. During a median (interquartile range) follow-up of 6.8 (2.5–11.4) years, 78 (47.3%) patients received at least 1 appropriate ICD therapy. The annual incidence of the primary outcome was 10.5% (7.1% and 12.5% in primary and secondary prevention, respectively; P =0.03). Overall, 71 (43.0%) patients presented with at least 1 ICD complication, including inappropriate shocks in 42 (25.5%) patients and lead dysfunction in 36 (21.8%) patients. Among 61 (37.0%) patients in primary prevention, the annual rate of appropriate ICD therapies was 4.1%, 5.3%, 9.5%, and 13.3% in patients with, respectively, 0, 1, 2, or ≥3 guidelines-recommended risk factors. QRS fragmentation was the only independent predictor of appropriate ICD therapies (hazard ratio, 3.47 [95% CI, 1.19–10.11]), and its integration in a model with current criteria increased the 5-year time-dependent area under the curve from 0.68 to 0.81 ( P =0.006). Patients with congestive heart failure or reduced left ventricular ejection fraction had a higher risk of nonarrhythmic death or heart transplantation (hazard ratio, 11.01 [95% CI, 2.96–40.95]). Conclusions: Patients with tetralogy of Fallot and an ICD experience high rates of appropriate therapies, including those implanted in primary prevention. The considerable long-term burden of ICD-related complications, however, underlines the need for careful candidate selection. A combination of easy-to-use criteria including QRS fragmentation might improve risk stratification. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03837574

Detection and Modulation of Olfactory Sensing Receptors in Carnivorous Rainbow Trout (Oncorhynchus mykiss) Fed from First Feeding with Plant-Based Diet

International audienceSense of smell is mediated by diverse families of olfactory sensing receptors, conveying important dietary information, fundamental for growth and survival. The aim of this study was to elucidate the role of the sensory olfactory pathways in the regulation of feeding behavior of carnivorous rainbow trout (RT, Oncorhynchus mykiss), from first feeding until 8 months. Compared to a commercial diet, RT fed with a total plant-based diet showed drastically altered growth performance associated with feed intake from an early stage. Exhaustive examination of an RT genome database identified three vomeronasal type 1 receptor-like (ORA), 10 vomeronasal type 2 receptor-like (OLFC) and 14 main olfactory receptor (MOR) genes, all highly expressed in sensory organs, indicating their potential functionality. Gene expression after feeding demonstrated the importance in olfactory sensing perception of some OLFC (olfcg6) and MOR (mor103, -107, -112, -113, -133) receptor family genes in RT. The gene ora1a showed evidence of involvement in olfactory sensing perception for fish fed with a commercial-like diet, while ora5b, mor118, mor124 and olfch1 showed evidence of involvement in fish fed with a plant-based diet. Results indicated an impact of a plant-based diet on the regulation of olfactory sensing pathways as well as influence on monoaminergic neurotransmission in brain areas related to olfactory-driven behaviors. The overall findings suggest that feeding behavior is mediated through olfactory sensing detection and olfactory-driven behavior pathways in RT

Involvement of taste receptors in the oro-sensory perception of nutrients in rainbow trout (Oncorhynchus Mikyss) fed diets with different fatty acid profiles

International audienceTaste perception plays an important role in an animal's detection of nutrients, conveying key dietary information, fundamental for its growth and survival. Because alternative terrestrial ingredients are known to affect the feeding of rainbow trout (RT, Oncorhynchus mikyss), we aimed to assess the importance of taste receptors in detection. Using self-feeders, we examined the feeding behavior (30 days of a feeding trial followed by 10 days of a preference trial) of RT fed with a commercial diet (C), vegetable diets supplemented with linseed oil (V1) or algal oil (V2). During the feeding trial those fed V2 decreased their food intake. The preference trial revealed that fish preferred V2 v. C and V1 v. V2 for fish which had consumed V1 and C during their feeding trial. Mechanistically, taste receptors were mainly expressed in taste organs and regulated by diet, which indicated the function of the taste receptors. Some taste receptors for fatty acids (such as the ffar receptor) and amino acids (such as the tasr receptor) were highly expressed in the RT tongue. While ffar2a transcripts were upregulated by vegetal diets in the tongue, ffar1 and ffar4, known for important roles in mammals, were very low expressed and not found in the RT genome, respectively. Overall findings show that RT displayed the fundamental mechanisms for oro-gustatory perception of nutrients related to different diet composition

Inherited Cardiomyopathies Revealed by Clinically Suspected Myocarditis

International audienceNo abstract availabl

Contribution of exome sequencing for genetic diagnostic in arrhythmogenic right ventricular cardiomyopathy/dysplasia

International audienceBackground: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing.Methods: WES was performed in 22 patients, all without a mutation identified in desmosomal genes. Putative pathogenic variants were screened in 96 candidate genes associated with other cardiomyopathies/channelopathies. The sequencing coverage depth of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 exons was compared to the mean coverage distribution to detect large insertions/deletions. All suspected deletions were verified by real-time qPCR, Multiplex-Ligation-dependent-Probe-Amplification (MLPA) and cGH-Array. MLPA was performed in 50 additional gene-negative probands.Results: Coverage-depth analysis from the 22 WES data identified two large heterozygous PKP2 deletions: one from exon 1 to 14 and one restricted to exon 4, confirmed by qPCR and MLPA. MLPA identified 2 additional PKP2 deletions (exon 1–7 and exon 1–14) in 50 additional probands confirming a significant frequency of large PKP2 deletions (5.7%) in gene-negative ARVC/D. Putative pathogenic heterozygous variants in EYA4, RBM20, PSEN1, and COX15 were identified in 4 unrelated probands.Conclusion: A rather high frequency (5.7%) of large PKP2 deletions, undetectable by Sanger sequencing, was detected as the cause of ARVC/D. Coverage-depth analysis through next-generation sequencing appears accurate to detect large deletions at the same time than conventional putative mutations in desmosomal and cardiomyopathy-associated genes

Detailed list and characteristics of putative mutations.

<p>Detailed list and characteristics of putative mutations.</p