Inflammatory Responses, Fibrotic Mediators, and Comorbidity Burden as Determinants of Myocardial Dysfunction and Heart Failure in Rheumatoid Arthritis - Project Summary Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint inflammation and damage as well as systemic manifestations including cardiovascular disease that lead to premature mortality. People with RA suffer up to a 2-fold increased risk of heart failure (HF), among the most burdensome chronic conditions and the most common cause of hospitalization in the U.S. This heightened risk of HF in RA, including HF subtypes with preserved and reduced left ventricular ejection fraction, has not improved despite substantial RA treatment advances over the last two decades. The mechanisms propagating HF risk in RA are poorly understood, prohibiting the development of effective strategies to improve HF-related outcomes in RA. Given the rising prevalence of HF in an aging population and the concerning persistence in RA-related HF risk, a critical need exists to identify unique drivers of HF development in RA to serve as priority targets for the design of HF prevention and management strategies in this high-risk patient population. The overall objective of this study is to identify molecular determinants and epidemiologic mediators of early myocardial dysfunction and clinical HF in RA, while completing a robust training program in prospective cohort development, cardiac phenotyping, and causal inference methodology. The central hypothesis is that RA-related dysregulation in cytokines, adipokines, and matrix metalloproteinases (MMPs) contributes to early myocardial dysfunction and potentiates the impact of comorbidity development on clinical HF onset. In Specific Aim 1, the PI will initiate a new, prospective RA cohort with comprehensive cardiac risk stratification, biospecimen collection, and deep cardiac phenotyping using speckle-tracking trans-thoracic echocardiogram and paired cardiac magnetic resonance imaging to investigate RA-related biomolecular alterations underlying subclinical myocardial dysfunction. The hypothesis in Aim 1 is that disproportionate increases in circulating interleukin (IL)-1, IL-6, adiponectin, and MMPs in RA will associate with subclinical myocardial dysfunction as indicated by worsened systolic and diastolic dysfunction, valvular heart disease, and myocardial infiltration. In Specific Aim 2, the mediating effect of comorbidity development on clinical HF and HF subtypes will be quantified through causal mediation analyses in a national cohort of RA patients and matched non-RA controls. Further, the independent and combined effects of comorbidity with RA-related risk factors on HF risk will be examined in an ongoing, multicenter, prospective cohort of >3,500 RA patients. The hypotheses in Aim 2 are that 1) obesity, diabetes, hypertension, chronic lung disease, and valvular heart disease will mediate excess HF risk in RA, and 2) RA-specific factors interact with these comorbidities to potentiate HF risk in patients with RA. Impact: Successful completion of this study will identify high-priority, modifiable risk-factors for myocardial dysfunction in RA and inform the development of personalized HF prevention and management strategies in RA. Moreover, this mentored research will develop the PI into an independent, patient-oriented investigator focused on improving CVD outcomes in RA.
