Impacts of Aging and Hypertension on Fibrosis and Electrical Conduction in the Sinoatrial Node and Atria
Date
2020-07-14
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Sinoatrial 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.
Description
Keywords
Cardiac Science, Sinoatrial Node, Cardiac Fibrosis, Natriuretic Peptides, Atrial Fibrillation, Hypertension, Aging, Frailty, Natriuretic Peptide Receptors, Natriuretic Peptide Receptor Type-C, Cardiac Extracellular Matrix, Angiotensin II, Sinus Node Dysfunction, Sick Sinus Syndrome
Citation
Mackasey, 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.