With a grain of salt: Sodium elevation and metabolic remodelling in heart failure

Elevated intracellular Na (Na_i) and metabolic impairment are interrelated pathophysiological features of the failing heart (HF). There have been a number of studies showing that myocardial sodium elevation subtly affects mitochondrial function. During contraction, mitochondrial calcium (Ca_mito) stimulates a variety of TCA cycle enzymes, thereby providing reducing equivalents to maintain ATP supply. Na_i elevation has been shown to impact Ca_mito; however, whether metabolic remodelling in HF is caused by increased Na_i has only been recently demonstrated. This novel insight may help to elucidate the contribution of metabolic remodelling in the pathophysiology of HF, the lack of efficacy of current HF therapies and a rationale for the development of future metabolism-targeting treatments. Here we review the relationship between Na pump inhibition, elevated Na_i, and altered metabolic profile in the context of HF and their link to metabolic (in)flexibility and mitochondrial reprogramming.