Patients with rheumatoid arthritis (RA) are at 1.5x risk for heart disease risk compared to the general population. Effective RA therapies which reduce inflammation such as tumor necrosis factor antagonists (anti- TNF), increase levels of low density lipoprotein cholesterol (LDL-C) suggesting that treatment may increase the burden of heart disease. However, large observational studies suggest the opposite: anti-TNF therapies are independently associated with reduced heart disease risk. While inflammation may explain these seemingly paradoxical findings, the exact mechanisms are poorly understood. A gap in knowledge exists regarding how rheumatologists should weigh changes in lipid levels with treatment and level of inflammation when assessing for risk of heart disease in RA. The objective of this proposal is to determine the clinical significance of increased LDL-C levels in associated with reduction in inflammation by anti-TNF therapy, and directly test the association of changes in inflammation with changes in lipid levels and risk of heart disease. The central hypothesis of this study is that reducing inflammation will be associated with reduced heart disease risk in RA. We will further determine whether advanced lipoprotein measures, including apolipoprotein B and A1 levels, LDL particle size and HDL function may be better markers of heart disease risk in RA patients.
The Aims of this project are to: (1) study the longitudinal association between changes in inflammation with changes in advanced lipoprotein measures, (2) determine the effect of reducing inflammation with anti-TNF therapy on markers of injury and vascular function in the heart, (3) examine the effect of reducing inflammation on changes in advanced lipoprotein measures, and association with heart disease risk in RA.
Aim 1 will be conducted using data and blood samples collected annually from a prospective longitudinal RA cohort. Subjects (N=200) with significant changes in inflammation between two consecutive years will be identified and their blood samples measured for inflammatory markers, lipids and advanced lipoprotein tests.
In Aims 2 and 3, RA patients (N=75) about to initiate anti-TNF therapy will be recruited, and prospectively studied for changes in inflammatory markers, routine lipids and advanced lipoprotein measures before and at 6, 12, and 24 weeks after starting anti-TNF. Subjects will undergo cardiac PET imaging to calculate coronary flow reserve (CFR) at baseline and 24 weeks. CFR measures coronary vascular function and is a validated surrogate marker for heart disease risk. This approach is innovative because it leverages RA as a human model of inflammation. In this experiment anti-TNF is repurposed as an intervention to reduce inflammation in order to study associated changes in lipids and risk for heart disease. The study is significant because it may transform the way heart disease risk is assessed in RA, by informing development of an integrated approach using comprehensive lipid measurements and level of inflammation. Results from this study may also have implications for the general population where inflammation has a smaller but significant role in the risk of heart disease.

Public Health Relevance

The proposed research is relevant to public health because both inflammation and lipids are key factors to consider when assessing risk of heart disease in rheumatoid arthritis (RA) patients as well as the general population. Advancing understanding of the association between inflammation and lipids may lead to new effective strategies to prevent and treat heart disease. This project is relevant to the missions of NHLBI and NIAMS as highlighted by our objective to study the clinical mechanisms behind the burden of inflammation on heart disease and utilization of advanced imaging techniques to provide insight into anatomic and physiologic changes associated with the rheumatic diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Kirby, Ruth
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Brigham and Women's Hospital
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