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The role of the perinexus in Long QT Syndrome Type 3

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dc.contributor.authorWu, Xiaoboen
dc.contributor.committeechairPoelzing, Stevenen
dc.contributor.committeememberSane, David C.en
dc.contributor.committeememberSmyth, Jamesen
dc.contributor.committeememberGourdie, Robert G.en
dc.contributor.departmentGraduate Schoolen
dc.date.accessioned2023-02-14T09:00:19Zen
dc.date.available2023-02-14T09:00:19Zen
dc.date.issued2023-02-13en
dc.description.abstractGain of function of cardiac voltage-gated sodium channel (Nav1.5) leads to Long QT Syndrome Type 3 (LQT3). LQT3 phenotype can be exacerbated by expanding the perinexus, which is an intercellular nanodomain with high density of Nav1.5 in the intercalated disc. Following this finding, we found that elevating extracellular sodium and widening the perinexus synergistically exacerbated LQT3 phenotype, Importantly, we also found that perinexal expansion increases the susceptibility to cardiac arrest in aged LQT3, which demonstrated that perinexal expansion is an arrhythmogenic risk especially in aged LQT3 patients. Furthermore, we observed that the perinexus narrows with aging and conceals LQT3 phenotype, which suggests that perinexal narrowing may have a cardio-protective role during aging in LQT3. Surprisingly, following the finding of the synergistic effect of extracellular sodium elevation and perinexal widening on LQT3 phenotype in drug-induced LQT3 guinea pig hearts, we found that this synergistic effect was not observed in genetically-modified LQT3 mouse hearts, which is due to high sodium also increasing transient outward potassium current (Ito). In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts which functionally express Ito channels. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose.en
dc.description.abstractgeneralLong QT Syndrome Type 3 (LQT3) is an inherited heart disease with the phenotype of long QT interval in ECG. It has been found that LQT3 phenotype gets worse when a very tiny space in the heart, termed as the perinexus, is wide due to cardiac edema. Following this finding, we also found that increasing sodium concentration together with wide perinexus can further exacerbate LQT3 phenotype in guinea pig hearts. Furthermore, we found that widening the perinexus in aged LQT3 hearts causes cardiac death but not in adult, which suggests that perinexal widening worsens LQT3 phenotype and even leads to cardiac death in aged hearts. Besides, we found that the perinexus narrows with aging and there is no difference in LQT3 phenotype between adult and aged hearts, which suggests that the narrow perinexus during aging may protect the hearts from cardiac death in LQT3. Surprisingly, we discovered that increasing sodium and widening the perinexus together fails to exacerbate LQT3 phenotype when compared with widening the perinexus alone in LQT3 mouse hearts, which is due to high sodium increasing transient outward potassium current (Ito). Notably, Ito channels are not functionally expressed in guinea pig hearts. In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:36074en
dc.identifier.urihttp://hdl.handle.net/10919/113826en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectLong QT Syndrome Type 3en
dc.subjectperinexusen
dc.subjectaction potential durationen
dc.subjectconduction velocityen
dc.subjectsynergisticen
dc.subjecttransient outward potassium channelen
dc.titleThe role of the perinexus in Long QT Syndrome Type 3en
dc.typeDissertationen
thesis.degree.disciplineTranslational Biology, Medicine and Healthen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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