Abstract Body: Introduction: Heart failure with preserved ejection fraction (HFpEF) is an increasing clinical challenge with few disease-modifying treatments. Soluble urokinase plasminogen activator receptor (suPAR), a circulating marker of chronic inflammation and immune activation, is linked to worse outcomes in patients with cardiometabolic and renal comorbidities common in HFpEF. We hypothesized that suPAR promotes HFpEF development via inflammation-related mechanisms and investigated its effects on cardiac function, remodeling, metabolism, and immune pathways in a metabolic HFpEF model.
Methods: We studied msuPAR1-Tg mice (adipose aP2-driven full-length murine suPAR overexpression, raising circulating suPAR) versus WT littermates exposed to a 2-hit HFpEF regimen high-fat diet (HFD, 60% fat) + Nω-Nitro-L-arginine methyl ester (L-NAME, 0.75 g/L). Cardiac function was performed using echocardiography. Immune cell populations in the heart, spleen, and blood were analyzed by flow cytometry, and transcriptomic profiling was performed by RNA sequencing. Mac-2 (galectin-3) staining on cardiac sections was performed to demonstrate cardiac macrophage infiltration.
Results: After 15 weeks of HFD+L-NAME, suPAR-Tg mice developed more severe diastolic dysfunction than wild-type controls (Fig. 1A). Cardiac gene-expression analyses revealed upregulation of heart failure and inflammatory markers (Fig. 1B). Flow cytometry showed significantly increased immune cell populations in suPAR-Tg hearts (Fig. 1C), spleen, and peripheral blood. RNA sequencing identified distinct transcriptional signatures enriched for immune-related gene expression (Fig. 1D). Mac-2 staining in suPAR-Tg hearts demonstrated increased cardiac macrophage infiltration (Fig. 1E).
Conclusion: These findings demonstrate that elevated suPAR exacerbates diastolic dysfunction and immune-mediated cardiac remodeling in a metabolic HFpEF model, establishing suPAR as a causal driver of HFpEF pathogenesis through inflammation and encouraging evaluation of suPAR-directed therapeutic strategies.