Individuals with rheumatoid arthritis (RA) are at 50% greater risk for developing heart failure (HF) and HF- associated morbidity and mortality than non-RA controls. This risk persists even after adjustment for coronary artery disease, implying that immunologic and inflammatory factors intrinsic to RA contribute to the increased risk of HF. Our overall hypothesis is that myocardial inflammation and microvascular ischemia are prevalent in RA patients, are mediated by antibodies to myocardial citrullinated proteins, promote impairment of left ventricular (LV) structure/function, and are attenuated with RA therapies. Indeed, in 128 RA patients without clinical CVD who underwent [18fluoro-deoxyglucose] positron emission-computed tomography (FDG PET-CT) (the RHYTHM study), we observed FDG uptake (inflammation) in 35% and impaired myocardial blood flow reserve (MFR) in 29%. Both myocardial inflammation and impaired MFR were strongly associated with clinical and laboratory measures of RA disease activity; impaired MFR was also associated with higher LV mass, a known precursor of HF. These data suggest that myocardial inflammation and impaired MFR mediate, in part, early changes in LV structure/function that predate clinical HF; but it is critical to confirm these relationships in longitudinal studies. Proximal events that mediate myocardial pathology in RA are unknown. We hypothesize that antibodies against citrullinated myocardial proteins (APCAs) mediate, in part, this abnormal myocardial phenotype (inflammation and impaired MFR), leading to myocardial remodeling and ultimately to functional decline. Our preliminary data demonstrating seroreactivity in 30% of RHYTHM sera in a novel myocardial protein array support this hypothesis. A related question is whether tumor necrosis inhibitors (TNFi?s) affect myocardial inflammation. This is a far from insignificant question as TNFi?s were associated with increased HF hospitalizations and death in non-RA HF patients and their risk for HF in RA is still unclear despite widespread use. In the next funding period, we seek to extend the study period for the RHYTHM cohort for aims 1 and 3, and to utilize an independently funded study (TARGET) for aim 2, in order to investigate the following aims: 1) To determine if imaging indicators of myocardial pathology at baseline (inflammation, impaired MFR) are predictive of longitudinal (adverse) change in measures of LV structure and function over 4-6 years in RA patients without clinical cardiovascular disease (CVD) at baseline. 2) To determine, in a currently enrolling NIH-NIAMS funded randomized clinical trial (the TARGET study), if RA therapies reduce myocardial inflammation. 3) To determine if seroreactivity to citrullinated myocardial antigens in RHYTHM participants is associated with baseline myocardial inflammation and impaired MFR and/or with change over time in parameters of LV structure/function. These investigations will advance understanding of mechanisms that contribute to and mitigate increased risk of myocardial dysfunction in RA.

Public Health Relevance

In the proposed studies, we will investigate several hypotheses that might help to explain why individuals with rheumatoid arthritis (RA) develop and die from heart failure at a higher rate than individuals without RA. We propose that particular features on PET/CT imaging (inflammation and decreased blood flow in the heart) and antibodies against certain proteins make them susceptible to developing stiffness and muscle weakness in the heart that eventually can lead to heart failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050026-14
Application #
9762580
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Washabaugh, Charles H
Project Start
2004-05-01
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
14
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Amigues, Isabelle; Tugcu, Aylin; Russo, Cesare et al. (2018) Myocardial Inflammation, Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography (FDG PET-CT) is Associated with Disease Activity in Rheumatoid Arthritis. Arthritis Rheumatol :
Darrah, Erika; Giles, Jon T; Davis, Ryan L et al. (2018) Autoantibodies to Peptidylarginine Deiminase 2 Are Associated With Less Severe Disease in Rheumatoid Arthritis. Front Immunol 9:2696
Bathon, Joan M; Giles, Jon T; Solomon, Daniel H (2018) Editorial: Tumor Necrosis Factor Antagonists: Killing Two Birds With One Biologic Stone. Arthritis Rheumatol 70:326-329
Geraldino-Pardilla, Laura; Zartoshti, Afshin; Ozbek, Ayse Bag et al. (2018) Arterial Inflammation Detected With 18 F-Fluorodeoxyglucose-Positron Emission Tomography in Rheumatoid Arthritis. Arthritis Rheumatol 70:30-39
Konig, Maximilian F; Giles, Jon T; Teles, Ricardo P et al. (2018) Response to comment on ""Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis"". Sci Transl Med 10:
Tedeschi, Sara K; Bathon, Joan M; Giles, Jon T et al. (2018) Relationship Between Fish Consumption and Disease Activity in Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 70:327-332
Giles, Jon T; Ferrante, Antony W; Broderick, Rachel et al. (2018) Adipose Tissue Macrophages in Rheumatoid Arthritis: Prevalence, Disease-Related Indicators, and Associations With Cardiometabolic Risk Factors. Arthritis Care Res (Hoboken) 70:175-184
Geraldino-Pardilla, Laura; Russo, Cesare; Sokolove, Jeremy et al. (2017) Association of anti-citrullinated protein or peptide antibodies with left ventricular structure and function in rheumatoid arthritis. Rheumatology (Oxford) 56:534-540
Morgenstern, Rachelle; Amigues, Isabelle; Giles, Jon T et al. (2017) Coronary Artery Inflammation in Rheumatoid Arthritis Using Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography. J Clin Rheumatol 23:454-455
Sammut, Amanda; Shea, Steven; Blumenthal, Roger S et al. (2017) Albuminuria in Rheumatoid Arthritis: Associations With Rheumatoid Arthritis Characteristics and Subclinical Atherosclerosis. Arthritis Care Res (Hoboken) 69:1799-1808

Showing the most recent 10 out of 42 publications