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dc.contributor.author | Moreno-Manuel, Ana I | |
dc.contributor.author | Macias, Alvaro | |
dc.contributor.author | Cruz, Francisco Miguel | |
dc.contributor.author | Gutiérrez, Lilian K | |
dc.contributor.author | Martínez, Fernando | |
dc.contributor.author | González-Guerra, Andrés | |
dc.contributor.author | Martinez-Carrascoso, Isabel | |
dc.contributor.author | Bermúdez-Jimenez, Francisco José | |
dc.contributor.author | Sánchez-Pérez, Patricia | |
dc.contributor.author | Vera-Pedrosa, María Linarejos | |
dc.contributor.author | Ruiz, Juan Manuel | |
dc.contributor.author | Bernal, Juan Antonio | |
dc.contributor.author | Jalife, Jose | |
dc.date.accessioned | 2024-05-06T11:29:05Z | |
dc.date.available | 2024-05-06T11:29:05Z | |
dc.date.issued | 2024-01-23 | |
dc.identifier.citation | Cardiovasc Res. 2024 Jan 23:cvae019. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/19244 | |
dc.description.abstract | AIMS Short QT Syndrome Type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. METHODS AND RESULTS We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to lack of inward-going rectification and increased IK1 at voltages positive to -80 mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80 mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. CONCLUSIONS The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer. | es_ES |
dc.description.sponsorship | This work was supported by ‘La Caixa’ Foundation [project code LCF/PR/ HR19/52160013]; grant PI20/01220 of the public call ‘Proyectos de Investigación en Salud 2020’ [PI-FIS-2020] funded by Instituto de Salud Carlos III (ISCIII); MCIU grant BFU2016-75144-R and PID2020-116935RB-I00, and co-funded by Fondo Europeo de Desarrollo Regional (FEDER); and Fundació La Marató de TV3 [736/C/ 2020]. We also receive support from the European Union’s ‘Horizon 2020 Research and Innovation Framework Programme’ [grant agreement GA-965286]; the Dynamic Microscopy and Imaging Unit—ICTS-ReDib Grant ICTS-2018-04-CNIC-16 funded by MCIN/AEI/10.13039/ 501100011033 and ERDF ‘A way of making Europe’; project EQC2018-005070-P funded by MCIN/AEI/10.13039/501100011033 and FEDER ‘Una manera de hacer Europa’. CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence [grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033]. A.I.M.M. holds a FPU contract [FPU20/01569] from Ministerio de Universidades. L.K.G. holds a FPI contract [PRE2018-083530], Ministerio de Economía y Competitividad de España co-funded by Fondo Social Europeo ‘El Fondo Social Europeo invierte en tu futuro’, attached to Project SEV-2015-0505-18-2. I.M.C. holds a PFIS contract [FI21/00243] funded by Instituto de Salud Carlos III and Fondo Social Europeo Plus (FSE+), ‘co-funded by the European Union’. M.L.V.P. held contract PEJD-2019-PRE/BMD-15982 funded by Consejería de Educación e Investigación de la Comunidad de Madrid ‘El FSE invierte en tu futuro’ | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Oxford University Press | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.title | The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of Short QT Syndrome type 3. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 38261726 | es_ES |
dc.identifier.doi | 10.1093/cvr/cvae019 | es_ES |
dc.contributor.funder | Fundación La Caixa | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.contributor.funder | Fundación La Marató TV3 | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea. H2020 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.contributor.funder | Ministerio de Universidades (España) | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1755-3245 | es_ES |
dc.relation.publisherversion | 10.1093/cvr/cvae019 | es_ES |
dc.identifier.journal | Cardiovascular research | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Arritmias Cardíacas | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/LCF/PR/HR19/52160013 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PI20/01220 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BFU2016-75144-R | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2020-116935RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/736/C/2020 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MCIN/AEI/10.13039/501100011033 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/EQC2018-005070-P | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MICIN/AEI/10.13039/501100011033/CEX2020-001041-S | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/FPU20/01569 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PRE2018-083530 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/FI21/00243 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PEJD-2019-PRE/BMD-15982 | es_ES |