Inflammation and Cardiovascular Disease in RA

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Cardiovascular (CV) disease is a major cause of morbidity and mortality in rheumatoid arthritis (RA). This increased CV risk is thought to be mediated through shared inflammatory pathways; however, this has been difficult to prove. This proposal is an application for renewal of an existing R01, "RA and Cardiovascular Disease" (AR050026-05) funded by NIAMS. We have been very productive in the current funding period. Some of our findings include a higher prevalence of subclinical coronary and carotid artery atherosclerosis, and significant reduction in left ventricular mass, in RA compared to nonRA subjects. In addition, we have noted that RA exerts its pro-atherogenic effect, in part, indirectly through "conventional" CV risk factor pathways. In this renewal, we propose to interrogate the role of inflammation in mediating accelerated atherosclerosis and myocardial dysfunction in RA by directly imaging the blood vessels and myocardia for characteristics of inflammation or its sequelae (fibrosis). Furthermore, we wish to confirm preliminary observations that RA susceptibility genes (the HLA-B1* "shared epitopes") are also risk factors for more severe subclinical atherosclerosis. Our overall hypothesis is that rheumatoid inflammation of blood vessels and myocardium predisposes to accelerated atherosclerosis and myocardial dysfunction, and that these effects are mediated in part by RA susceptibility genes. We propose the following aims: Specific Aim 1. In cross-sectional analyses, we will compare blood vessel wall and plaque characteristics of carotid arteries of RA vs nonRA subjects using carotid MRI. Specific Aim 2. In cross-sectional analyses of RA subjects, we will investigate the association of measures of LV structure and function with myocardial fibrosis and perfusion using cardiac MRI with delayed enhancement, first pass perfusion and tagging. Specific Aim 3. In cross-sectional analyses of several combined RA populations, we will evaluate the association of the RA-associated HLA-DRB1 "shared epitope" (SE) genes with the presence and severity of atherosclerosis. These studies will contribute important new information that will be useful in CV risk stratifying RA patients for earlier aggressive intervention, thus potentially reducing CV associated morbidity and mortality in RA.