Empagliflozin's Cardioenergetic Protective Effects through PPARα Pathway Modulation in Heart Failure

Hua Wei^1*Menghua Yin¹Junshun Chang¹Bo Feng¹Qin Zhou¹Xirong Li¹Ping Wu¹Xiaoshan Guo¹Siyuan Chen¹Bao Li^2*Sijin Li^1*

• ¹First Hospital of Shanxi Medical University, Taiyuan, China
• ²Second Hospital of Shanxi Medical University, Taiyuan, China

Background Heart Failure (HF) pathology is complex and seriously life-threatening. SGLT2 inhibitor, as one of the new quadruple drugs for HF treatment, have a complex mechanism for improving. Energy metabolism is one of the important aspect of HF pathology, and the PPARα signaling pathway plays an important role in energy metabolism. Therefore, this study aims to observe changes in the PPARα signal transduction pathway in chronic heart failure by 18F-FDG MicroPET/CT imaging. Based on the myocardial metabolic imaging of 18F-FDG MicroPET/CT, this study aims to verify the mechanism of SGLT2 inhibitor treatment in heart failure rats through the PPARα signal transduction pathway of energy metabolism, and provide an imaging diagnostic basis. Results In 18F-FDG PET/CT myocardial metabolic imaging, pre-treatment MRGlu levels in the HC group of heart failure rats were significantly higher than in the other three groups. Post-treatment, MRGlu and glucose uptake decreased markedly in the EMPG group, while no significant changes were observed in the FF group. Compared with normal healthy rats, HF model rats showed a significant increase in Myocardial Glucose Metabolism Rate (MRGlu), and the expression of lipid metabolism pathway proteins (PPARα, RXRα, CPT1α, CD36) and energy metabolism pathway proteins (AMPKα, sirt 1) was significantly inhibited, while the expression of glycolytic pathway protein (GLUT4) was enhanced. After 4 weeks of drug treatment in HF model rats, empagliflozin showed the same lipid metabolism pathway (PPARα, RXRα, CPT1α) and energy metabolism pathway proteins (AMPKα, sirt1) as fenofibrate; but only empagliflozin showed significant decrease in MRGlu, inhibition of glycolytic pathway protein (GLUT 4) expression, and decreased cardiac fibrosis in HF rats. Conclusion 1 HF rats showed a significant increase in myocardial glucose metabolism rate compared with healthy rats. 2 Empagliflozin can improve the energy supply efficiency of the heart in rats with chronic heart failure by inhibiting glucose metabolism and promoting lipid metabolism, thereby ameliorating energy metabolism in chronic heart failure. 3 18F-FDG microPET/CT can observe the energy metabolism changes of HF, and the myocardial glucose metabolism rate can provide quantitative data for the changes of HF energy metabolism.