The impact of dapagliflozin for the myocardial metabolomic profiles of mice with chronic heart failure induced by a high fat diet

Background The molecular mechanisms responsible for the clinical benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with heart failure and a reduced or preserved ejection fraction, both diabetic and non-diabetic, are still not fully understood. This study aimed to examine the myocardial metabolomic profiles of mice with chronic heart failure induced by high-fat diet (HDF) and assess the impact of dapagliflozin (DAPA) on these profiles. Methods An experimental model of chronic heart failure in mice was established by long-term HDF for six months, and verified using immunohistochemistry and echocardiography. Myocardial specimens were obtained from three groups: chow, HDF, and DAPA. Subsequently, all samples were subjected to non-targeted metabolomic analyses using untargeted liquid chromatography-mass spectrometry. Principal component analysis, partial least squares discriminant analysis, and orthogonal partial least squares discriminant analysis were used to identify differential metabolites or lipid molecules. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to determine the metabolic pathways associated with these identified metabolites. Results Echocardiography revealed that mice with chronic heart failure established through HDF exhibited systolic dysfunction compared to the control chow group. However, DAPA treatment partially restored these dysfunctions and protected against myocardial fibrosis and hypertrophy. Furthermore, a total of 72 upregulated and 34 downregulated differential metabolites were observed between the Chow and HDF groups, along with 40 upregulated and 25 downregulated differential metabolites between the HDF and DAPA groups. A total of 141 upregulated and 167 downregulated differential lipid metabolites were observed between the Chow group and HDF groups, along with 67 upregulated and 59 downregulated differential lipid metabolites between the HDF and DAPA groups, respectively. Dysregulated metabolites or lipids altered by DAPA treatment were found to significantly enrich several metabolic pathways, as identified by the KEGG database. Conclusions DAPA exhibited protective effects against myocardial fibrosis and hypertrophy, and enhanced systolic function in mice with chronic heart failure induced by HDF. Furthermore, we conducted a comprehensive analysis of myocardial profiles, focusing on various differential metabolites, including lipid molecules, as well as prominent metabolic pathways, in these mice. In addition, we assessed the impact of DAPA treatment on these profiles.