Systemic inflammation induces a myocardial inflammatory transcriptional signature without cardiac dysfunction in murine arthritis

Patients with rheumatoid arthritis (RA) face an elevated risk of developing heart failure, but the underlying mechanisms remain incompletely understood. Plausible causes include cardiac structural and molecular alterations attributable to sustained chronic inflammation. The present study investigates such putative cardiac alterations in a modified delayed-type hypersensitivity arthritis (DTHA) mouse model of sustained, RA-like inflammation. An RA-like inflammatory phenotype was induced in male BALB/c mice (n = 13) using a modified DTHA protocol, while control mice received vehicle injections (n = 13). The standard DTHA protocol consists of (1) immunization towards methylated bovine serum albumin (mBSA), (2) intravenous administration of a mixture of anti-collagen II antibodies, and (3) induction of arthritis via subcutaneous hind-leg injection of mBSA. In the modified DTHA protocol, steps 2 and 3 were repeated weekly for eight consecutive weeks to sustain inflammation. Analyses included serial cardiac magnetic resonance imaging (MRI, days 15 and 57), plasma inflammatory markers, the left ventricular (LV) myocardial transcriptome, and assessment of hypertrophic and fibrotic remodelling. Fluctuating, yet sustained local and systemic inflammation was demonstrated. Despite this, no structural or functional differences were detected by cardiac MRI, and no gross fibrotic or hypertrophic alterations were observed. However, RNA-sequencing of bulk LV myocardial tissue revealed a distinct transcriptional profile with marked enrichment of inflammatory signalling pathways. Despite preserved cardiac structure and function, mice subjected to sustained DTHA-driven systemic inflammation displayed a pronounced myocardial inflammatory transcriptional signature. Whether this observation represents an early state of cardiac vulnerability preceding overt dysfunction, possibly requiring additional cardiac stressors, remains a hypothesis to be tested.