Daily exposure to chlordecone, an organochlorine pesticide, increases cardiac fibrosis and atrial fibrillation vulnerability
Notice bibliographique
Résumé
Chlordecone (CLD) is a carcinogenic organochlorine pesticide. CLD was shown to disturb the activity of cardiac Na + -K + -ATPase and Ca 2+ -Mg 2+ -ATPase. Conditions affecting these transmembrane pumps are often associated with cardiac arrhythmias (CA). However, little is known about the role of CLD on atrial fibrillation (AF) incidence, the most common type of CA. 1) Daily ingestion of CLD induces arrhythmogenic cardiac remodeling. 2) A phase of CLD withdrawal can reduce CLD-induced AF susceptibility. Adult male Wistar rats (250 g-275 g) ingested daily-doses of CLD (0 μg/L, 0.1 μg/L, or 1 μg/L) diluted in their quotidian water for 4 weeks. From day (D)29 to D56, all rats received CLD-free water. Vulnerability to AF and cardiac function were evaluated at D28 and D56 by electrophysiological study, echocardiography, and optical-mapping. Levels of genes and proteins related to inflammation, fibrosis, and senescence were quantified by qPCR and immunoassays. Twenty-eight days of CLD exposure were associated with significantly increased AF vulnerability compared to CLD-free rats. Contamination with 1 μg/L CLD significantly reduced atrial conduction velocity (ERP, APD). CLD-weaning normalized food consumption and weight intake. However, after the CLD-withdrawal period of 28 days, AF inducibility, atrial inflammation (IL6, IL1β), and atrial fibrosis (Masson’s trichrome staining) remained significantly higher in rats exposed to 1 μg/L CLD compared to 0 μg/L. Prolonged CLD ingestion provokes atrial conduction slowing and increased risk of AF. Although CLD-weaning, some persistent damages occurred in the atrium like atrial fibrosis and atrial senescence signals, which are accompanied by atrial inflammation and arrhythmogenicity. Arrhythmogenic remodeling from prolonged CLD-poisoning to AF. Daily ingestion of concentrations of CLD above 0.1 µg/L is associated with increased atrial inflammation characterized by enhanced expression of pyroptosis promotor GSDMD (via pore-forming activity) and proinflammatory biomarkers such as NLRP3, IL1b, and IL6. Senescence markers p16 and p21 are also overexpressed in the heart. Atrial inflammation and senescence are accompanied by increased production of fibrous content and fibrosis biomarkers such as ACTA2, COL3A1, and TGFβ1. CLD-induced damaged atrial tissue also shows a reduction of key ion channels such as KCNQ1 and SCN5A involved in the cardiomyocytes’ action potential. Convergence of CLD-induced atrial toxicity via inflammation, senescence, fibrosis, and deregulated circulation of ions provoke reduction of conduction velocity, decreased ERP, and reduced APD. Altogether, these phenomena contribute to increasing the risk of atrial arrhythmias and AF. Abbreviations ACTA2 : alpha 2 smooth muscle actin , AF : atrial fibrillation, APD : action potential duration, CLD : chlordecone, COL : collagen, ERP : effective refractory period, GSDMD : gasdermin-D, IL : interleukin, KCNQ1 : potassium voltage-gated channel subfamily Q member 1, NLRP3 : NACHT, LRR, and PYD domain-containing protein 3, p16 : cyclin-dependent kinase inhibitor 2 A, p21 : cyclin-dependent kinase inhibitor 1, SCN5A : sodium voltage-gated channel alpha subunit 5, TGFβ1 : transforming growth factor beta 1. • CLD poisoning provokes atrial inflammation (IL1β and IL6). • CLD-induced atrial inflammation is accompanied by atrial fibrosis. • CLD-associated atrial fibrosis leads to conduction slowing and AF susceptibility. • CLD weaning might not be sufficient to reverse CLD-induced arrhythmogenic damages. • AF management might involve CLD-weaning combined with anti-inflammation strategies.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».