Date of Award

2026

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology

First Advisor

David Barefield

Abstract

Atrial fibrillation (AFib) is the most common cardiac arrythmia worldwide and is characterized by hallmarks including electrical, fibrotic, and hemodynamic remodeling, each of which can cause or be caused by alterations in the contractile apparatus. However, there is little known about contractile remodeling in AFib. While our current understanding of AFib lacks contractile remodeling, it also largely ignores the contribution of aging-induced remodeling. Aging is the strongest risk factor for AFib development, with most patients diagnosed with AFib over the age of 70, and aging also involves the three molecular hallmarks of AFib, which could explain increased susceptibility of AFib development in the aged population. We hypothesize that in AFib, atrial cardiomyocytes have primary contractile impairments, and that aging worsens the pathophysiology. To test this hypothesis, we have developed two specific aims. Aim 1 investigated atrial contractile remodeling in a canine model of induced AFib. Aim 2 investigated the role of aging in AFib pathophysiological and molecular remodeling using a mouse model of atrial myopathy by treating mice with Angiotensin II. From this work, we have found that the sarcomere is fundamentally degraded in AFib, associated with calpain proteolysis, resulting in reduced contractile force and resting tension and increased calcium sensitivity of force development. We found that Angiotensin II-induced atrial remodeling is most severe in aged mice and proteomic remodeling is both age and sex dependent. Overall, this work has characterized contractile dysfunction as a novel hallmark of AFib.

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