Sex-Specific Characterization of a Novel Osteoarthritis-Induced Heart Failure Model in Mice

Chronic low-grade inflammation is increasingly recognized as a key driver of heart failure (HF) progression; however, the direct contribution of systemic inflammatory disorders such as osteoarthritis (OA) remains unclear. Here, we establish a murine model of OA-induced HF using destabilization of the medial meniscus (DMM) to induce systemic inflammation and sex-specific cardiac remodeling. Longitudinal echocardiography revealed that females develop diastolic dysfunction with preserved ejection fraction, resembling HFpEF, whereas males exhibit progressive systolic impairment, consistent with a transitional HFmrEF-to-HFrEF phenotype. Morphometric and histological analyses confirmed concentric hypertrophy in females and eccentric remodeling in males. Transcriptomic profiling identified distinct molecular programs: females upregulated extracellular matrix, cytoskeletal, and calcium-handling genes, while males showed enrichment of inflammatory and immune signaling pathways. Immunoblot analyses further validated these sex-specific molecular signatures: females displayed increased ANP, BNP, Sirt1, and AMPK expression, consistent with metabolic resilience and fibrotic remodeling, whereas males exhibited elevated p38 MAPK, NF-κB, LC3B, and cleaved caspase-3, reflecting heightened inflammation, autophagy, and apoptosis. Both sexes demonstrated downregulation of mitochondrial and lipid metabolic proteins, indicating convergent energetic stress. Collectively, these findings identify OA as a systemic inflammatory driver of heart failure, delineate the molecular and proteomic basis of sex-dependent cardiac remodeling, and introduce a translational preclinical model that recapitulates the clinical heterogeneity of HFpEF and HFmrEF/HFrEF, providing a foundation for mechanistic and therapeutic exploration.