Attenuation of Cardiac Dysfunction in the Collagen-Induced Arthritis Mouse Model Mediated by a Reactive Aldehyde Species Inhibitor

Individuals with rheumatoid arthritis (RA) experience increased risk of heart failure. Malondialdehyde–acetaldehyde (MAA) adducts are overexpressed and co-localize with citrullinated (CIT) proteins in RA myocardium. This study investigated whether reactive aldehyde species (RASP) inhibitors prevent MAA formation in vitro and attenuate cardiac dysfunction in a collagen-induced arthritis (CIA) mouse model. Among eight RASP inhibitors screened, ADX-246 demonstrated the greatest inhibition of MAA formation in vitro. Mice with early CIA (week 5) exhibited elevated levels of myocardial MAA adducts, myocardial inflammation, and reduced ejection fraction, but normal cardiac collagen deposition and diastolic function vs. control. By weeks 10–12, mice with chronic CIA demonstrated increased levels of myocardial MAA and CIT adducts, perivascular collagen deposition, and diastolic dysfunction. ADX-246 treatment reduced myocardial levels of MAA and CIT adducts, inflammation, fibrosis, and cardiac dysfunction in CIA. While ADX-246 reduced weight loss and attenuated arthritis severity, it did not reduce serum autoantibody levels or serum markers of inflammation or fibrosis. Indices of diastolic dysfunction significantly correlated with myocardial MAA and CIT levels, collagen deposition, arthritis severity, and weight loss. These findings support the hypothesis that targeting myocardial RASP and MAA formation may represent a novel therapeutic approach for preventing cardiac dysfunction in RA.