Impacts of Aging and Hypertension on Fibrosis and Electrical Conduction in the Sinoatrial Node and Atria

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dc.contributor.advisorRose, Robert Alan
dc.contributor.authorMackasey, Martin
dc.contributor.committeememberFedak, Paul
dc.contributor.committeememberNygren, Anders
dc.date2020-11
dc.date.accessioned2020-07-17T16:35:33Z
dc.date.available2020-07-17T16:35:33Z
dc.date.issued2020-07-14
dc.description.abstractSinoatrial node (SAN) and atrial fibrosis are major mediators of sinus node dysfunction (SND) and atrial fibrillation (AF), respectively. Both frequently co-exist in pathological states involving enhanced fibrotic remodeling. Aging and hypertension are characterized by electrical and structural remodeling and have been identified as important risk factors for the development of SND and AF. However, the underlying mechanisms facilitating these processes are incompletely understood. Natriuretic peptides (NPs) are a family of cardioprotective hormones that act partially through activation of the natriuretic peptide receptor type-C (NPR-C); although, its capacity to regulate cardiac remodeling is poorly understood. The studies presented examine the role of SAN and atrial fibrosis in regulating electrical conduction using two models associated with adverse remodeling: aging and Ang II-mediated hypertension. Aging studies also investigated the utility of assessing frailty to gain further insight into age-associated mechanisms of structural remodeling and arrhythmogenesis. Accordingly, aged and hypertensive mice exhibited enhanced SAN and atrial fibrosis as assessed by picrosirius red staining. This impacted electrical conduction as assessed by optical mapping experiments and promoted arrhythmogenesis. Frailty scores were correlated with several aspects of the remodeling process, including gene expression changes, indicating the potential for frailty score to provide additional insight into cellular and sub-cellular mechanisms. Aged and hypertensive mice exhibited distinct gene expression alterations in regulators of the cardiac extracellular matrix including collagens, transforming growth factor β1 (TGFβ1), lysyl oxidase (LOX), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs). In studies examining the role of NPR-C in Ang II-mediated hypertension, NPR-C-/- mice displayed substantially worse outcomes with respect to SAN and atrial fibrosis as well as electrical impairments. These alterations were associated with changes in ECM-related gene expression. Conversely, a selective NPR-C agonist cANF potently prevented Ang II-mediated fibrosis and electrical impairments. However, these changes were generally not accompanied by ECM-related gene expression alterations. Taken together, these results demonstrate a crucial role for adverse fibrotic remodeling in influencing electrical conduction and arrhythmogenesis in the SAN and atria. Additionally, these studies show that NPR-C signaling exhibits potent anti-fibrotic effects that could be utilized for future therapeutic approaches in hypertension.en_US
dc.identifier.citationMackasey, M. (2020). Impacts of Aging and Hypertension on Fibrosis and Electrical Conduction in the Sinoatrial Node and Atria (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/38026
dc.identifier.urihttp://hdl.handle.net/1880/112308
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectCardiac Scienceen_US
dc.subjectSinoatrial Nodeen_US
dc.subjectCardiac Fibrosisen_US
dc.subjectNatriuretic Peptidesen_US
dc.subjectAtrial Fibrillationen_US
dc.subjectHypertensionen_US
dc.subjectAgingen_US
dc.subjectFrailtyen_US
dc.subjectNatriuretic Peptide Receptorsen_US
dc.subjectNatriuretic Peptide Receptor Type-Cen_US
dc.subjectCardiac Extracellular Matrixen_US
dc.subjectAngiotensin IIen_US
dc.subjectSinus Node Dysfunctionen_US
dc.subjectSick Sinus Syndromeen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationPhysiologyen_US
dc.titleImpacts of Aging and Hypertension on Fibrosis and Electrical Conduction in the Sinoatrial Node and Atriaen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Cardiovascular/Respiratory Scienceen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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