Is there a causal link between intracellular Na elevation and metabolic remodelling in cardiac hypertrophy?

Alterations in excitation-contraction coupling and elevated intracellular sodium (Na_i) are hallmarks of pathological cardiac remodelling that underline contractile dysfunction. In addition, changes in cardiac metabolism are observed in cardiac hypertrophy and heart failure (HF) that lead to a mismatch in ATP supply and demand, contributing to poor prognosis. A link between Na_i and altered metabolism has been proposed but is not well understood. Many mitochondrial enzymes are stimulated by mitochondrial calcium (Ca_mito) during contraction, thereby sustaining production of reducing equivalents to maintain ATP supply. This stimulation is thought to be perturbed when cytosolic Na_i is high due to increased Ca_mito efflux, potentially compromising ATP_mito production and leading to metabolic dysregulation. Increased Na_i has been previously shown to affect Ca_mito; however, whether Na_i elevation plays a causative role in energetic mismatching in the hypertrophied and failing heart remains unknown. In this review, we discuss the relationship between elevated Na_i, NaK ATPase dysregulation and the metabolic phenotype in the contexts of pathological hypertrophy and HF and their link to metabolic flexibility, capacity (reserve) and efficiency that are governed by intracellular ion homeostasis. The development of non-invasive analytical techniques using nuclear magnetic resonance able to probe metabolism in situ in the functioning heart will enable a better understanding of the underlying mechanisms of Na_i overload in cardiac pathophysiology. They will lead to novel insights that help to explain the metabolic contribution towards these diseases, the incomplete rescue observed with current therapies and a rationale for future energy-targeted therapies.