Objective To evaluate the pharmacodynamics of astragaloside Ⅳ derivatives for chronic heart failure,screen the candidate compounds and preliminarily explore the mechanism of the candidate compound HHQ16 against heart failure.Methods Chronic heart failure was induced by left anterior descending artery ligation in C57BL/6 mice for 4 weeks,and the mice were divided into 4 groups,including sham group,model group,positive control captopril group,and astragaloside Ⅳ derivatives group.After continuous intragastric administration for four weeks,the cardiac function was detected by echocardiography,and the optimal astragaloside Ⅳ derivative HHQ16 was selected for the treatment of heart failure.The preliminary mechanism for HHQ16 was further explored.The size of heart was observed by gross morphology;pathological changes were observed by HE staining;collagen deposition in the myocardium was observed by Masson staining;protein levels of myocardial fibrosis indexes COL1,COL3,and αSMA were detected by immunohistochemical staining,and mRNA levels of myocardial fibrosis indexes COL1,COL3,αSMA,and TGF-β1 were determined by qPCR technique.Results All astragaloside Ⅳ derivatives significantly improved cardiac function with increasing LVEF and LVFS,of which HHQ16 was the optimal compound.Compared with the model group,the heart volume of HHQ16 group was significantly reduced;myocardial hypertrophy was reduced;collagen deposition in myocardial tissues was reduced;and myocardial fibrosis indexes,COL1,COL3,αSMA and TGF-β1 mRNA levels,as well as the protein levels of COL1,COL3 and αSMA were significantly reduced.Conclusion HHQ16 is an optimal astragaloside Ⅳ derivatives for the treatment of chronic heart failure in mice,which could improve cardiac function by improving myocardial remodeling,and inhibit myocardial hypertrophy and myocardial fibrosis.