Metabolic fingerprinting in heart failure
Abstract
Heart failure (HF) remains a major global cause of morbidity and mortality. Despite improvements in treatments targeting neurohormonal and hemodynamic processes, the disease burden remains high. SGLT2 inhibitors offer new therapeutic opportunities, as they influence metabolic processes in addition to exerting diuretic effects. This thesis investigated metabolic changes in HF, with a particular focus on short-chain fatty acids (SCFAs) and ketone bodies (KBs) as biomarkers and potential therapeutic targets. SCFAs, such as acetate, propionate, and butyrate, are produced by gut bacteria and can serve as an alternative energy source for the failing heart. Furthermore, they influence fatty acid and glucose metabolism and may reduce fibrosis. HF patients exhibit alterations in the gut microbiome and lower concentrations of certain SCFAs, pointing to metabolic dysregulation. The role of ketone bodies was investigated in both experimental and clinical studies. In a mouse model, it was found that the beneficial effects of the SGLT2 inhibitor empagliflozin are partially dependent on cardiac ketone oxidation. In two HF cohorts, elevated KB levels were associated with a higher risk of death or hospitalization for HF. These elevated levels appeared to be persistently present and likely reflected a state of chronic metabolic stress, inflammation, and catabolism, rather than being a direct cause of adverse outcomes. Furthermore, it was demonstrated that KB concentrations correlate with…
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