Kir2.1 mutations differentially increase the risk of flecainide proarrhythmia in Andersen Tawil Syndrome
Notice bibliographique
Résumé
Abstract Background Flecainide and other class-Ic antiarrhythmic drugs (AADs) are widely used in Andersen-Tawil syndrome type 1 (ATS1) patients. However, class-Ic drugs might be proarrhythmic in some cases. We investigated the molecular mechanisms of class-I AADs proarrhythmia and whether they might increase the risk of death in ATS1 patients with structurally normal hearts. Methods and Results Of 53 ATS1 patients reviewed from the literature, 54% responded partially to flecainide, with ventricular arrhythmia (VA) reduction in only 23%. Of the latter patients, VA persisted in 20-50%. Flecainide was ineffective in 23%, and surprisingly, 13.5% suffered a non-fatal cardiac arrest. In five cardiac-specific ATS1 mouse models (Kir2.1 Δ314–315 , Kir2.1 C122Y , Kir2.1 G215D and Kir2.1 R67W and Kir2.1 S136F ), flecainide or propafenone (40 mg/Kg i.p.) differentially prolonged the P wave, and the PR, QRS and QTc intervals compared to Kir2.1 WT ; Kir2.1 S136F had milder effects. Flecainide increased VA inducibility in all mutant mice except Kir2.1 S136F , which exhibited significant VA reduction. At baseline, Kir2.1 G215D cardiomyocytes had the lowest inward rectifier K+ channel (I K1 ) reduction, followed by Kir2.1 C122Y , Kir2.1 R67W and Kir2.1 S136F . Kir2.1 C122Y cardiomyocytes had a significant decrease in sodium inward current (I Na ). Flecainide (10 µM) slightly increased I K1 density in Kir2.1 WT and Kir2.1 S136F , while it decreased both I K1 and I Na in Kir2.1 C122Y and Kir2.1 R67W , despite normal trafficking of mutant channels. Optical mapping in ATS1 patient-specific iPSC-CM monolayers expressing Kir2.1 C122Y , Kir2.1 G215D and Kir2.1 R67W showed an increase in rotor incidence at baseline and under flecainide, confirming the druǵs proarrhythmic effect. Lastly, in-silico molecular docking predicts that the Kir2.1-Cys 311 pharmacophore-binding site is altered in Kir2.1 C122Y heterotetramers, reducing flecainide accessibility and leading to channel closure and arrhythmias. Conclusions Class-Ic AADs are only partially effective and might be proarrhythmic in some ATS1 patients. Kir2.1 mutations impacting the resting membrane potential and cellular excitability create a substrate for life-threatening arrhythmias, raising significant concern about using these drugs in some ATS1 patients. CLINICAL PERSPECTIVE NOVELTY AND SIGNIFICANCE What is known? Andersen-Tawil syndrome type 1 (ATS1) is a rare autosomal dominant disease caused by loss-of-function mutations in the KCNJ2 gene, which encodes the Kir2.1 channel responsible for the repolarizing, strong inwardly rectifying current I K1 . ATS1 treatment is empirical and subject to clinical judgment. It includes the use of class-Ic antiarrhythmic drugs (AADs), mainly flecainide, alone or in combination with β-adrenergic blocking drugs. However, pharmacological treatment is partial and might fail, leading to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD) in some ATS1 patients. Some ATS1 mutations are known to disrupt the Kir2.1-Nav1.5 channelosome in mice and human iPSC-CMs, with consequent reductions in cardiac excitability and conduction velocity (CV), leading to VA, which may be exacerbated by flecainide. What new information does this article contribute? In our analysis of 53 ATS1 patients, flecainide showed partial effectiveness. While a few patients experienced complete disappearance of VA, others had persistent arrhythmias and even suffered non-fatal cardiac arrest while on medication. In murine models expressing five relevant ATS1 mutations, flecainide or propafenone produced differential alteration in the P wave, PR, QRS and QTc intervals, and increased VA inducibility compared with Kir2.1 WT mice. Additionally, flecainide differentially affected I K1 and the Na + inward current (I Na ) current densities despite normal trafficking of mutant channels. In patient-specific induced pluripotent stem cell derived cardiomyocyte (iPSC-CM) monolayers flecainide reduced CV and increased rotor incidence, confirming the drugś proarrhythmic effect. In-silico molecular docking studies predicted that the Cys 311 pharmacophore binding site and flecainide accessibility are altered in mutated Kir2.1 channels, leading to premature channel closure and arrhythmias. We conclude that class-Ic AADs are only partially effective and might be proarrhythmic in some ATS1 patients. These findings raise concern about the use of class-Ic AADs in ATS1 patients and highlight the need for further studies to guide personalized therapy.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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) | 0,002 | 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 source (Gemma direct ou Codex distillé), 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 ».