Metabolic therapy for the treatment of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a syndrome associated with high morbidity, mortality, and increasing prevalence. Development of HFpEF is driven by metabolic inflammation and alterations in energy metabolism with concomitant accumulation of lipotoxic metabolism intermediates. Long-chain acylcarnitines (LCAC) are fatty acid metabolism intermediates which at elevated levels impair mitochondrial bioenergetics and activate pro-inflammatory signaling pathways.

 

This project aims to assess the role of LCAC in HFpEF development and evaluate LCAC pool-lowering therapy as a potential treatment for HFpEF. HFpEF will be induced in mice by treating them with high fat diet and L-NAME in their drinking water. LCAC pool will be decreased by treatment with meldonium. To characterize HFpEF development, heart function, energy metabolism and physical performance in vivo, function of isolated skeletal muscle, mitochondrial bioenergetics will be assessed. Additionally, the effects of concomitant administration of an SGLT2 inhibitor with meldonium will be studied in the same experimental setup. The role of LCAC on the development of HFpEF will be studied in trimethyl-lysine hydroxylase knockout mice which do not express enzyme essential for the LCAC synthesis and have a very low LCAC levels.

 

Obtained results will provide new knowledge about the role of LCAC in the development of HFpEF as well as lay grounds for discovering novel drugs for treatment of HFpEF.