Introduction: We hypothesize that acute heart failure (AHF) de novo and worsening of pre‑existing disease (WHF) reflect distinct underlying metabolic states.

Objectives: To compare circulating metabolomic and lipidomic profiles between AHF de novo and WHF.

Patients and methods: We performed metabolomic and lipidomic analyses in venous blood collected from 274 patients admitted for AHF to a single tertiary referral cardiology center between 2021 and 2023.

Results: WHF patients (67%) were older, more often had coronary artery disease, and presented with slightly higher left ventricular ejection fraction. De novo AHF was characterized by higher levels of sphingolipids, angiotensin (1–7), and purine‑related metabolites, indicating a pro‑inflammatory and pro‑apoptotic state and oxidative stress, with metabolomic signals of neurohormonal activation despite no differences in conventional neurohormonal biomarkers. WHF was associated with elevated levels of amino acid derivatives, glucuronidated compounds, and organic acids, which reflect altered energy metabolism and detoxification adaptations. Lipidomic analysis revealed higher levels of glycerophospholipids (GPEtn, GPGro, GPA, SQDG) and lower levels of sphingomyelins and selected GPEtn species in WHF, which may be related to impaired cellular membrane integrity or cellular injury. Biomarkers of catabolism and inflammation were also associated with pre‑existing disease. In exploratory Cox modeling, several metabolites demonstrated reproducible associations with 12‑month all‑cause mortality independent of clinical covariates.

Conclusions: De novo AHF was characterized by a metabolomic profile indicative of a pro‑inflammatory state and neurohormonal activation, while patients hospitalized for exacerbated pre‑existing disease presented with metabo‑lipidomic signatures of abnormal energy metabolism, catabolic state, and cellular injury.