Background:
Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular syndrome with rising incidence and persistently poor prognosis due to limited therapeutic options. It is closely associated with obesity, hypertension, and metabolic dysregulation, which promote chronic inflammation. Although inflammatory processes have been implicated in HFpEF, the role of the complement system, a key component of innate immunity, remains unclear. This study investigates whether complement activation contributes to HFpEF pathogenesis and whether C3aR blockade can ameliorate its features in a metabolic mouse model.
Methods:
Plasma complement levels, including C3c, were analyzed in a large patient cohort with or without HFpEF using the TriNetX database. C57BL/6J wild-type (WT) mice were fed a high-fat diet (n = 9) for 18 weeks to induce cardiometabolic syndrome with HFpEF-like features and were then randomized to receive the C3aR antagonist JR14a or vehicle for an additional 10 weeks. Chow-fed mice (n=6) served as controls. Echocardiography was performed to assess left ventricular (LV) diastolic function and wall thickness, and plasma NT-proBNP levels were measured by ELISA to evaluate cardiac stress and ventricular dysfunction. Myocardial fibrosis, collagen deposition, and inflammation were quantified by PCR analysis and Picrosirius Red staining of cardiac tissue.
Key Results:
Plasma C3c levels were elevated in patients with HFpEF compared to individuals without HFpEF, indicating systemic complement activation. In the mouse model, cardiac expression of complement components C1q, C3, and C3aR was markedly increased in obese HFpEF mice compared with lean controls. Pharmacological C3aR blockade with JR14a improved diastolic function and reduced LV wall thickness despite HFD, indicating beneficial effects on cardiac remodeling. Treatment also significantly decreased NT-proBNP levels, reflecting reduced cardiac wall stress and ventricular dysfunction. Moreover, C3aR inhibition significantly reduced myocardial expression of TNF-α and IL-6, demonstrating anti-inflammatory effects, and downregulated fibrotic markers Col1a1, Col3a1, and TGF-β. These anti-fibrotic effects were confirmed by Picrosirius Red staining.
Conclusion:
This study demonstrates for the first time that complement C3aR activation contributes to myocardial fibrosis, ventricular remodeling, and cardiac dysfunction in HFpEF. Pharmacological inhibition with JR14a attenuates inflammation and fibrosis, improves diastolic function, reduces cardiac wall stress, and mitigates adverse remodeling, highlighting C3aR as a promising therapeutic target in HFpEF.
