An herbal preparation ameliorates heart failure with preserved ejection fraction by alleviating microvascular endothelial inflammation and activating NO-cGMP-PKG pathway

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease presenting a substantial challenge to clinicians. Currently, there is no safe and efficacious HFpEF treatment. In this study, we reported a standardized herbal medicinal product, QiShenYiQi (QSYQ), that can be used in the treatment of HFpEF. HFpEF mice were established by infusing a combination of Nω-nitro-L-arginine methyl ester (L-NAME) and feeding them a high-fat diet for 14 weeks. In the 10th week, the HFpEF mice were given dapagliflozin or QSYQ via oral gavage for four weeks. The blood pressure, echocardiography, hemodynamics, leukocyte infiltration, and oxidative stress in HFpEF mice were evaluated. Besides, inflammatory factors, endothelial adhesion factors, and endothelial-mesenchymal transformation (EndMT) markers were investigated. QSYQ significantly attenuated concentric cardiac remodeling while improving diastolic function and left ventricular compliance in HFpEF mice. QSYQ also inhibited inflammation and immunocyte recruitment during HFpEF. The infiltration of CD8+, CD4+ T cells, and CD11b/c+ monocytes was substantially mitigated in the myocardium of QSYQ-treated mice. TNF-α, MCP-1, NF-κB, and NLRP3 levels also reduced after QSYQ treatment. Furthermore, QSYQ significantly reversed the elevated expression of endothelial adhesion factors and EndMT occurrence. These effects of QSYQ were demonstrated by the activation of NO-cGMP-PKG pathway and reduction of eNOS uncoupling in the HFpEF heart. These results provide novel evidence that QSYQ treatment improves HFpEF by inhibiting microvascular endothelial inflammation and activating NO-cGMP-PKG pathway.