AbstractIntracellular Na elevation in the heart is a hallmark of pathologies where both acute and chronic metabolic remodelling occurs. Here, we assess whether acute (75 μM ouabain 100 nM blebbistatin) or chronic myocardial Na_i load (PLM^3SA mouse) are causally linked to metabolic remodelling and whether the failing heart shares a common Na-mediated metabolic ‘fingerprint’. Control (PLM^WT), transgenic (PLM^3SA), ouabain-treated and hypertrophied Langendorff-perfused mouse hearts are studied by ²³Na, ³¹P, ¹³C NMR followed by ¹H-NMR metabolomic profiling. Elevated Na_i leads to common adaptive metabolic alterations preceding energetic impairment: a switch from fatty acid to carbohydrate metabolism and changes in steady-state metabolite concentrations (glycolytic, anaplerotic, Krebs cycle intermediates). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 ameliorates the metabolic changes. In silico modelling indicates altered metabolic fluxes (Krebs cycle, fatty acid, carbohydrate, amino acid metabolism). Prevention of Na_i overload or inhibition of Na/Ca_mito may be a new approach to ameliorate metabolic dysregulation in heart failure.