Graduation Date

Summer 8-15-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Bryant R. England, MD, PhD

Second Advisor

Ted R. Mikuls, MD, MSPH

Third Advisor

Rebekah L. Gundry, PhD

Fourth Advisor

Cheng Zheng, PhD

MeSH Headings

Rheumatoid arthritis, Heart Failure, Epidemiology

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease with its primary manifestation as a small joint, symmetric inflammatory arthritis. RA is associated with substantial morbidity and premature mortality, owed to systemic inflammation causing extra-articular manifestations such as cardiovascular disease (CVD). CVD is the most common cause of death in RA; however, the specific burden, mechanisms, and ability to predict heart failure (HF) development, a leading cause of hospitalization and death in the U.S., remain poorly characterized in RA populations. In this dissertation, I examine the epidemiology and determinants of HF in RA and identify key gaps in HF risk stratification through three, large-scale studies. First, leveraging a national cohort enriched with echocardiographic data derived from validated natural language processing algorithms, I demonstrate that patients with RA experience a significantly increased risk of both HF with preserved (HFpEF) and reduced ejection fraction (HFrEF), with HFpEF being the more frequent, over-represented, and severe manifestation. Notably, this heightened risk has not improved over the last two decades despite advances in RA treatment. Second, I address the underexplored contribution of valvular heart disease (VHD, an established HF risk factor) to CVD risk in RA. Using national data, I show that RA is associated with a nearly 50% increased risk of incident aortic stenosis (AS), the most common cause of VHD-related death in the U.S., as well as an increased risk of aortic valve intervention and AS-related mortality. Finally, I evaluate the performance of the Predicting Risk of cardiovascular EVENTs (PREVENT) CVD risk calculator, the first to include a model for HF prediction, in a national-level RA cohort. I find that the calculator underestimates both atherosclerotic CVD and HF risk in RA, which may be driven in part by paradoxical effects of obesity and serum lipids on CVD risk in RA, as well as indicators of risk severity such as hemoglobin A1c. Together, these studies establish HF as high-burden and inadequately predicted complication of RA. These findings underscore the need for RA-specific strategies to improve HF risk prediction, prevention, and management, and lay a foundation for future research to improve CVD-related outcomes in RA.

Comments

2025 Copyright, the authors

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Available for download on Tuesday, July 27, 2027

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