AVAILABILITY OF ENERGETIC SUBSTRATES AND EXERCISE TOLERANCE IN HEART FAILURE WITH OR WITHOUT DIABETES

Aims: Due to reciprocal fuel flux regulation, elevated free fatty acids (FFA) may influence glucose utilization and efficiency of the failing heat. The goal was to address whether acute exercise-induced changes in plasma FFA and other metabolites can adversely impact cardiac performance and outcome in heart failure (HF) with or without diabetes mellitus (DM).
Methods and Results: 27 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 cardiac assessment, anthropometry and maximal spiroergometry with blood sampling to address the influence of exercise dynamics of etabolites on attained cardiac performance (peak VO2) and long-term outcome. HFDM+ patients had increased resting FFA and glucose, higher insulin resistance than HFDM-, and more elevated β-OH butyrate than controls. In all HF, baseline FFA correlated with adiposity, rather than neurohumoral activation. During exercise, FFA decreased both in HFDM-(28%) and HFDM+ (-39%), but not in controls. Peak VO2 was unrelated to post-exercise FFA, glucose, lactate or glycerol, but strongly correlated with post-exercise pyruvate (r=0.62, p<0.001). During next 17±10 months, 36% patients experienced an adverse event. Diabetes (HR 1.98, p=0.04), post-exercise glucose (HR 1.28, p=0.04) and total body fat (HR 0.58, p<0.001) but not FFA were predictive of outcome.
Conclusions: FFA-mediated effects on carbohydrate utilization do not play a role in exercise limitation in HF, regardless diabetes. Inhibition of body fat depletion or increasing dynamics of plasma pyruvate may represent a therapeutic target in advanced HF.