Rationale Intracellular Na elevation is a hallmark of the ischaemic and failing heart – pathologies in which both acute and chronic metabolic remodelling occur.
Objective To assess whether acute (75 µM ouabain 100 nM blebbistatin) and chronic myocardial Nai load (PLM3SA mouse) are causally linked to metabolic remodelling and if the failing heart shares a common Na-mediated metabolic ‘fingerprint’.
Methods 23Na, 31P and 13C NMRS were performed in normal and hypertrophied (pressure overload) Langendorff perfused mouse hearts followed by 1 hour NMRS metabolomic profiling, mass spec and in silico modelling.
Results Na overload (acute, chronic (PLM3SA), and hypertrophy 2, 1.3 and 1.4-fold respectively) resulted in common metabolic perturbations: substrate switch (palmitate 35% reduction, glucose 58% increase), flux (TCA cycle, OXPHOS, glycolysis) and metabolomic profile (TCA cycle, glycolysis, anaplerosis) without energetic impairment (PCr/ATP 1.5±0.1 vs control 1.3±0.1). Inhibition of mitochondrial Na/Ca exchanger by CGP37157 during both acute and chronic Na load ameliorated the metabolic changes.
Conclusion Elevated Na leads to complex metabolic alterations preceding any energetic and functional impairment. Early prevention of Na overload and inhibition of Na/Camito could ameliorate metabolic dysregulation in hypertrophy and failure.
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