Identifying Inflammatory Mechanisms in Calcific Aortic Valve Disease

Abstract

Aortic stenosis is a common and insidious disease that can lead to heart failure and death. Calcific aortic valve disease, the leading cause of aortic stenosis, has no pharmacologic therapy due to a limited understanding of pathophysiology, but characterization studies have shown increased immune infiltrate and activation of inflammatory pathways. This thesis presents work testing hypotheses regarding two inflammatory pathways (cyclooxygenase-2 and STAT3) and one infiltrating cell type (macrophages) and their roles in valvular calcification. The thesis begins with a thorough background of calcific aortic valve disease, known inflammatory phenomena, and how these phenomena may impact clinical care. It continues with a translational study of cyclooxygenase-2 inhibitor celecoxib, a study of the mechanobiology of myeloid cell activation, and a comprehensive study of macrophage involvement in aortic valve calcification using the Notch1+/- model of disease found in both mice and humans. The body of work concludes with an analysis of clinical diagnostic patterns in aortic stenosis that may be impacted by inflammation, and how they might enact health inequity. A concluding section summarizes the results and their impact, and offers areas of continued investigation. Most impactfully, these studies reveal that celecoxib treatment is associated with aortic stenosis and that the Notch1+/- model of valve disease promotes macrophage infiltration, leading to calcification in part through altered STAT3 splicing. The clinical diagnostics study reveals a pattern of under-diagnosis in those with atypical aortic stenosis, especially female patients. The objective of this thesis is to integrate broad-ranging fields of expertise to highlight novel areas of exploration, specifically immunology and inflammation, that could spark further scientific investigation in this transformational time. Through the body of work described, the author hopes to have moved the field forward and contributed to continued improving care for patients with aortic stenosis.