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.
The proposed studies, we hypothesize that enhanced systemic and/or local inflammation contributes significantly to the increased risk for cardiovascular events in individuals with rheumatoid arthritis. We will utilize state-of-the art imaging techniques that highlight inflammation both within blood vessels and in the myocardium. In addition, we will examine a genetic risk factor, associated with susceptibility to developing rheumatoid arthritis, to determine whether it also conveys risk for accelerated heart disease.
|Lusa, Amanda L; Amigues, Isabelle; Kramer, Henry R et al. (2015) Indicators of walking speed in rheumatoid arthritis: relative influence of articular, psychosocial, and body composition characteristics. Arthritis Care Res (Hoboken) 67:21-31|
|Giles, Jon T; Danoff, Sonye K; Sokolove, Jeremy et al. (2014) Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease. Ann Rheum Dis 73:1487-94|
|Giles, Jon T; Allison, Matthew; Bingham 3rd, Clifton O et al. (2009) Adiponectin is a mediator of the inverse association of adiposity with radiographic damage in rheumatoid arthritis. Arthritis Rheum 61:1248-56|
|Giles, Jon T; Ling, Shari M; Ferrucci, Luigi et al. (2008) Abnormal body composition phenotypes in older rheumatoid arthritis patients: association with disease characteristics and pharmacotherapies. Arthritis Rheum 59:807-15|
|Giles, Jon T; Bartlett, Susan J; Andersen, Ross E et al. (2008) Association of body composition with disability in rheumatoid arthritis: impact of appendicular fat and lean tissue mass. Arthritis Rheum 59:1407-15|
|Malayeri, Ashkan Akhavan; Johnson, W Craig; Macedo, Robson et al. (2008) Cardiac cine MRI: Quantification of the relationship between fast gradient echo and steady-state free precession for determination of myocardial mass and volumes. J Magn Reson Imaging 28:60-6|
|Harris, Michelle L; Darrah, Erika; Lam, Gordon K et al. (2008) Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis. Arthritis Rheum 58:1958-67|
|Giles, Jon T; Bartlett, Susan J; Andersen, Ross et al. (2008) Association of body fat with C-reactive protein in rheumatoid arthritis. Arthritis Rheum 58:2632-41|