Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Lawrence H. Young

Abstract

Atrial fibrillation (AF) is the most common arrhythmia worldwide with about 1 in 4 adults expected to develop the condition in their lifetime. AMP-activated kinase (AMPK) is a critical energy sensor and regulates tissue energy and substrate metabolism. Our lab has previously shown that atrial cardiomyocyte-specific cardiac AMPK deletion induces electrophysiologic changes, left atria structural remodeling and spontaneous AF. The mechanism by which loss of AMPK and consequent metabolic stress leads to AF has not yet been elucidated. Using single nuclear RNA sequencing (snRNA sequencing) of mouse heart atria from mice with atrial cardiomyocyte AMPK deletion, we begin to investigate the primary changes in atrial cardiomyocytes and secondary alterations in the atrial cellular landscape that are associated with left atrial remodeling and arrhythmogenesis, in this model of metabolic stress. The heart contains multiple cell types in addition to cardiomyocytes, including fibroblasts, endothelial cells, macrophages and other immune cells. Interactions between these cells is critical to maintaining physiological homeostasis and when altered contributes to pathological remodeling in disease. Our findings reveal a distinct cell population of endothelial cells (ECs) that shows an upregulation of genes involved in the uptake and oxidation and fatty acids, in response to the knock-out of AMPK in the atrial cardiomyocytes. We also show that cardiomyocytes upregulate a cohort of secreted autocrine/paracrine factors, including neuregulin, angiopoietin, and fibroblast growth factors. Metabolic stress induced by the loss of AMPK alters cardiomyocyte phenotype and secretome, triggering paracrine effects that remodel endothelial cell metabolism, angiogenesis and fibrosis.

Comments

This is an Open Access Thesis.

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