Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation

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dc.contributor.authorRaisch, Tristan B.en
dc.contributor.authorYanoff, Matthew S.en
dc.contributor.authorLarsen, Timothy R.en
dc.contributor.authorFarooqui, Mohammed A.en
dc.contributor.authorKing, D. Ryanen
dc.contributor.authorVeeraraghavan, Rengasayeeen
dc.contributor.authorGourdie, Robert G.en
dc.contributor.authorBaker, Joseph W.en
dc.contributor.authorArnold, William S.en
dc.contributor.authorAlMahameed, Soufian T.en
dc.contributor.authorPoelzing, Stevenen
dc.contributor.departmentBiomedical Engineering and Mechanicsen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentVirginia Tech Carilion School of Medicineen
dc.date.accessioned2019-10-29T17:26:58Zen
dc.date.available2019-10-29T17:26:58Zen
dc.date.issued2018-05-04en
dc.description.abstractAims: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous evidence in animal models suggests that the gap junction (GJ) adjacent nanodomain - perinexus - is a site capable of independent intercellular communication via ephaptic transmission. Perinexal expansion is associated with slowed conduction and increased ventricular arrhythmias in animal models, but has not been studied in human tissue. The purpose of this study was to characterize the perinexus in humans and determine if perinexal expansion associates with AF. Methods: Atrial appendages from 39 patients (pts) undergoing cardiac surgery were fixed for immunofluorescence and transmission electron microscopy (TEM). Intercalated disk distribution of the cardiac sodium channel Nav1.5, its beta 1 subunit, and connexin43 (C x 43) was determined by confocal immunofluorescence. Perinexal width (Wp) from TEM was manually segmented by two blinded observers using ImageJ software. Results: Nav1.5, beta 1, and C x 43 are co-adjacent within intercalated disks of human atria, consistent with perinexal protein distributions in ventricular tissue of other species. TEM revealed that the GJ adjacent intermembrane separation in an individual perinexus does not change at distances greater than 30 nm from the GJ edge. Importantly, Wp is significantly wider in patients with a history of AF than in patients with no history of AF by approximately 3 nm, and Wp correlates with age (R = 0.7, p < 0.05). Conclusion: Human atrial myocytes have voltage-gated sodium channels in a dynamic intercellular cleft adjacent to GJs that is consistent with previous descriptions of the perinexus. Further, perinexal width is greater in patients with AF undergoing cardiac surgery than in those without.en
dc.description.notesThis work was supported by a Carilion Clinic Research Acceleration Program Grant to SA and SP, National Institutes of Health R01-HL56728 awarded to RG, National Institutes of Health R01-HL102298 awarded to SP, and National Institutes of Health F31-HL140873 awarded to TR.en
dc.description.sponsorshipCarilion Clinic Research Acceleration Program Grant; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-HL56728, R01-HL102298, F31-HL140873]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fphys.2018.00398en
dc.identifier.issn1664-042Xen
dc.identifier.other398en
dc.identifier.pmid29780324en
dc.identifier.urihttp://hdl.handle.net/10919/95199en
dc.identifier.volume9en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectatrial fibrillationen
dc.subjectgap junctionsen
dc.subjectconnexin43en
dc.subjectperinexusen
dc.subjecthumanen
dc.titleIntercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillationen
dc.title.serialFrontiers in Physiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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Scholarly Works, Virginia Tech Carilion School of Medicine (VTCSOM)