Yang Mai Tong Luo formula ameliorates heart failure with preserved ejection fraction by alleviating microvascular endothelial inflammation

<x>Abstract</x> Objectives: The study aimed to investigate the efficacy and underlying mechanisms of Yang Mai Tong Luo formula (YMTLF) in the treatment of heart failure with preserved ejection fraction (HFpEF) by focusing on its ability to alleviate microvascular endothelial inflammation. Methods: We analyzed the main components of YMTLF using ultra performance liquid chromatography tandemmass spectrometry (UPLC-MS/MS). HFpEF mouse model was established by High fat diet and N-nitro-L-arginine methyl ester (L-NAME) stimulation and then treated with YMTLF for 10 weeks. The cardiac function of mice was assessed by echocardiography. The myocardial cross-sectional area was evaluated by wheat germ agglutinin (WGA) staining. The blood perfusion of hindlimb was analyzed by laser speckle. Network pharmacology and transcriptome analysis were employed to explore the potential mechanisms of YMTLF in addressing HFpEF. Immunofluorescence staining was used to analyze the expression levels of proteins related to microvascular inflammation. Results: A total of 27 principal components of YMTLF were characterized by UPLC-MS/MS. YMTLF reversed the weight gain, improved heart functions and myocardial hypertrophy of HFpEF mice. Specifically, YMTLF treatment reduced serum N-terminal probrain natriuretic peptide (NT-proBNP) levels from 622 to 319 pg/mL and decreased left ventricular posterior wall thickness in diastole (LVPWD) from 0.794 to 0.604 mm (P < 0.05). Furthermore, it improved hindlimb blood perfusion (perfusion unit value increased from 156 to 226). It ameliorated the microvascular endothelial dysfunction (zonula occludens-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) and downregulated the expression levels of microvascular inflammation related proteins (interleukin-1 β, F4/80, high mobility group box 1, transforming growth factor β1 and thrombospondin-1) (P < 0.05). Conclusions: YMTLF exerted therapeutic effect on HFpEF by ameliorating microvascular inflammation.