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

https://doi.org/10.1016/j.yjmcc.2021.08.003Get rights and content

Highlights

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    Myocardial Na elevation is a hallmark of heart failure.

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    Na affects mitochondrial function.

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    Na elevation precedes myocardial metabolic remodelling.

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    Prevention of myocardial Nai elevation could alleviate metabolic remodelling in HF.

Abstract

Elevated intracellular Na (Nai) 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 (Camito) stimulates a variety of TCA cycle enzymes, thereby providing reducing equivalents to maintain ATP supply. Nai elevation has been shown to impact Camito; however, whether metabolic remodelling in HF is caused by increased Nai 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 Nai, and altered metabolic profile in the context of HF and their link to metabolic (in)flexibility and mitochondrial reprogramming.

Introduction

Heart failure (HF) imposes an enormous worldwide medical and economic burden. With few effective treatments available, heart failure (HF) affects over 64 million people worldwide carrying the annual death toll of 17.5 million lives [1]. Despite the advancements in diagnostic tools and therapies, with an ever-ageing population it's prevalence is on continuous rise. The current COVID-19 pandemic has added to this chronic disease burden as the patients with underlying cardiovascular disease face significantly poorer prognosis [[2], [3], [4], [5], [6]]. Thus, there is a clear and rapidly increasing requirement for improved understanding of fundamental cellular mechanisms in HF which can, in turn, help the development of improved treatments and innovative diagnostic techniques.

Numerous molecular mechanisms have been proposed that could contribute to the development of HF and these include an energy deficit following metabolic reprogramming. In a series of precisely regulated enzymatic reactions, heart muscle highly efficiently converts chemical into mechanical energy [7]. This fact is easily obscured by the complexities of myocardial anatomy, haemodynamics and coronary flow. Despite myocardial metabolism and function being inseparably linked, substrate metabolism as a paradigm for the development of novel HF therapies has been mostly overlooked [8]. In addition to the changes in cardiac metabolism, alterations in excitation–contraction (E-C) coupling including Nai elevation are characteristic features of pathological cardiac remodelling and underpin contractile dysfunction in HF.

Section snippets

Intracellular Na regulation

In the healthy mammalian heart, cytoplasmic Na, Ca, and H concentrations are lower than their electrochemical equilibrium values. In the myocardium of most large animals the intracellular Na concentration is typically around 8-10 mM [[9], [10], [11]] (Table 1). In the murine heart (rats and mice) Nai is reported to be significantly higher at 10-20 mM (reviewed in [9]) (Table 1). Due to differences in experimental methodologies, absolute values of measured Nai may vary (Table 1). This elevated

Energy metabolism in the healthy heart

The heart has an enormous energy demand—it burns through 6 kg of ATP daily, consuming 2% of its total energy reserves per beat and turning over its total ATP pool in <1 min [[23], [24], [25], [26]]. Despite this continuous dependence on ATP, its capacity to store ATP is miniscule: a 300 g human heart stores 30 mg ATP compared with the ATP utilization demand of 30 mg/s to sustain baseline cardiac function [27]. Therefore, it is predominantly reliant on aerobic metabolism for a continuous supply

Na pump and regulation of Nai in heart failure

Many studies of the failing myocardium report significantly elevated intracellular Na concentrations (reviewed in [9]) and, in part, this may be mediated by changes in NKA expression, activity and PLM phosphorylation [36]. The pathological consequences of elevation of intracellular Na include cellular Ca overload, a negative force–frequency relationship, impaired relaxation and arrhythmias [37]. While an increase in Na influx may be an important component of elevated Nai [11], each individual

Metabolic remodelling and myocardial Nai elevation: a causality dilemma

Despite the extensive evidence for the concomitance of remodelled metabolism and elevated Nai in HF, studies investigating their interaction are scarce and mostly limited to isolated organelles. Increase in cytosolic Na (12.5 mM to ≥25 mM) was shown to reduce state 3 respiration in isolated rat mitochondria potentially impacting ATP synthesis [64]. Other isolated mitochondria studies have shown that extramitochondrial Na addition (1–10 mM) led to a dose-dependent decrease in OXPHOS which was

Chronic and acute Nai overload reprogram cardiac metabolism

In order to ensure that ATP supply matches consumption during increased cardiac contractility, mitochondria readily respond to increases in the cytosolic Ca [73]. Resultant rise in mitochondrial matrix calcium (Camito) activates key Ca-sensitive TCA cycle regulatory enzymes (CaDHmito) including pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase and the NAD-linked isocitrate dehydrogenase (Fig. 2) as well as ETC complex V [74] [68].

CaDHmito activation leads to enhanced production of

Therapeutic potential

Since William Withering's recognition of the efficacy of cardiac glycosides, Nai has inadvertently been a HF therapeutic target for at least 200 years. Glycosides are not only present in plants such as the foxglove (digitalis purpurea), but are also endogenously found in animals under physiological conditions (e.g. ouabain, digoxin and bufalin) and are elevated in chronic kidney disease patients [83] and HF [84]. The positive inotropic effects of cardiac glycosides are well understood and

Funding

DA acknowledges British Heart Foundation Accelerator Award [AA/18/5/34222], Diabetes UK Grant (19/0005973), Barts Charity Grant (MRC 0215), Wellcome Trust [221604/Z/20/Z] for funding her work. MJS: British Heart Foundation Programme Grant [RG/12/4/29426].

Author contribution

D.A. and M.J.S drafted the manuscript. D.A. prepared the figures.

Disclosures

None.

Acknowledgements

Figures created with BioRender.com.

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