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The goal of the study was to examine whether resting or post-exercise metabolic substrate levels are associated with differential exercise performance and long-term outcome in control subjects or heart failure (HF) patients with or without type 2 diabetes mellitus (DM).Twenty five healthy controls matched with 97 patients with stable advanced HF were prospectively enrolled. Exercise capacity, age, gender, and HF aetiology were balanced between HFDM– and HFDM+ groups. Subjects underwent maximal bicycle spiroergometry with blood sampling to measure metabolites and neurohormones before and immediately after the exercise. HFDM+ patients had increased free fatty acids, glucose, and β-hydroxybutyrate compared with controls. HFDM+ patients had higher baseline copeptin (24 ± 16 vs. 17 ± 13 pmol/L, P < 0.05) but otherwise showed similar neurohumoral activation and exercise response to HFDM– patients. Peak oxygen consumption (VO2) was unrelated to post-exercise free fatty acids, glucose, lactate, or glycerol, but strongly correlated with post-exercise pyruvate (in all: r = 0.62, P < 0.001). During the next 17 ± 10 months, 36% of HF patients experienced an adverse event (death, urgent transplantation, or assist device insertion). From metabolic factors, only post-exercise glucose [hazard ratio (HR) 1.28, P = 0.04), total body fat (HR 0.58, P < 0.001), and the presence of DM (HR 1.98, P = 0.04) were predictive of the outcome.With the exception of pyruvate, acute changes of metabolic substrates are not related to cardiac performance in HF, regardless of diabetic status. Inhibition of body fat depletion, attenuation of stress-related hyperglycaemia, or increasing dynamics of plasma pyruvate may represent therapeutic targets in advanced HF.