P1 Causal link between intracellular sodium overload and metabolic remodelling in the heart: uncoupling ATP supply and demand?

Aksentijević, Dunja; Karlstädt, Anja; Basalay, Marina; O'Brien, BA; Thakker, Alpesh; Tennant, Daniel A.; Fuller, William; Taegtmayer, H; Eykyn, TR; Shattock, M. J.

doi:10.1136/heartjnl-2018-bscr.6

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“…To elucidate concomitant changes in substrate metabolism or energetics, it is also necessary to be able to quantify a wide range of metabolites involved in energy homeostasis in these models. We have previously applied and validated techniques able to measure intracellular Na i in the Langendorff perfused mouse [ 51 , 52 ] or rat heart preparations [ 53 ] using NMR.…”

Section: Measuring Na I Overload In the Beating Hementioning

confidence: 99%

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

Aksentijević

O’Brien

Eykyn

et al. 2018

Biochemical Society Transactions

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Alterations in excitation–contraction coupling and elevated intracellular sodium (Nai) 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 Nai and altered metabolism has been proposed but is not well understood. Many mitochondrial enzymes are stimulated by mitochondrial calcium (Camito) during contraction, thereby sustaining production of reducing equivalents to maintain ATP supply. This stimulation is thought to be perturbed when cytosolic Nai is high due to increased Camito efflux, potentially compromising ATPmito production and leading to metabolic dysregulation. Increased Nai has been previously shown to affect Camito; however, whether Nai 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 Nai, 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 Nai 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.

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Section: Measuring Na I Overload In the Beating Hementioning

confidence: 99%