Front Pharmacol. 2026 Jun 3;17:1781866. doi: 10.3389/fphar.2026.1781866. eCollection 2026.
ABSTRACT
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure cases and is associated with substantial morbidity and mortality. Although sodium-glucose cotransporter-2 inhibitors (SGLT2is) have shown efficacy in reducing HFpEF hospitalizations, the disease's multi-pathway pathogenesis often limits the effectiveness of single-target interventions. This study examines whether the cardiovascular benefits of empagliflozin (EMPA) can be synergistically enhanced by co-administration with the targeted anti-fibrotic agent pirfenidone (PFD).
AIMS: We hypothesized that simultaneous modulation of metabolic stress and pro-fibrotic signaling would lead to synergistic structural and functional recovery in a severe HFpEF phenotype.
METHODS: HFpEF was induced in Sprague-Dawley rats (n = 16/group) using a two-hit model [NG-nitro-L-arginine methyl ester (L-NAME) and a high-fat diet (HFD)] over 5 weeks. The rats subsequently received daily oral EMPA (0.35 g/kg/d), PFD (0.3 g/kg/d), or combination therapy (EMPA + PFD) for 4 weeks. Treatment efficacy was evaluated via echocardiography, histopathology, and exercise tolerance testing. Further insights into the underlying transcriptional mechanisms were gained through RNA sequencing and semi-quantitative Western blotting. Bliss independence analysis was used to analyze pharmacological synergy.
RESULTS: Co-treatment with EMPA + PFD significantly enhanced diastolic indices, left ventricular ejection fraction (LVEF), fractional shortening (FS), and cardiac output (CO) compared with controls and monotherapy groups (p < 0.05). Histological analysis revealed reduced cardiomyocyte hypertrophy and lower collagen deposition, particularly in the endocardium. Although additive improvement in systemic hemodynamics was observed, EMPA + PFD co-treatment exerted compartmentalized synergy within the myocardium. The combination reversed cellular hypertrophy and deep fibrosis, restoring diastolic and systolic function (p < 0.05). Transcriptomic profiling revealed that local myocardial rescue was mediated by gene networks linked to protein kinase C-activating G-protein-coupled receptor signaling, which blocked the downstream PKC/NF-κB inflammatory pathway and transforming growth factor-beta (TGF-β)-driven fibrosis, thereby explaining the molecular basis of functional improvement.
CONCLUSION: Dual therapy with EMPA and PFD achieves compartmentalized synergy, effectively eliminating cellular hypertrophy and deep fibrosis, thereby restoring cardiac mechanics. These findings provide mechanistic proof of concept that multi-axis metabolic and antifibrotic combinations can disrupt the complex pathological cycle of HFpEF.
PMID:42318351 | PMC:PMC13272355 | DOI:10.3389/fphar.2026.1781866