Targeting Sodium in Heart Failure

Abstract

A dominant event determining the course of heart failure (HF) includes the disruption of the delicate sodium (Na⁺) and water balance leading to (Na⁺) and water retention and edema formation. Although incomplete decongestion adversely affects outcomes, it is unknown whether interventions directly targeting (Na⁺), such as strict dietary (Na⁺) restriction, intravenous hypertonic saline, and diuretics, reverse this effect. As a result, it is imperative to implement (Na⁺)-targeting interventions in selected HF patients with established congestion on top of quadruple therapy with angiotensin receptor neprilysin inhibitor, β-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor, which dramatically improves outcomes. The limited effectiveness of (Na⁺)-targeting treatments may be partly due to the fact that the current metrics of HF severity have a limited capacity of foreseeing and averting episodes of congestion and guiding (Na⁺)-targeting treatments, which often leads to dysnatremias, adversely affecting outcomes. Recent evidence suggests that spot urinary sodium measurements may be used as a guide to monitor (Na⁺)-targeting interventions both in chronic and acute HF. Further, the classical (2)-compartment model of (Na⁺) storage has been displaced by the (3)-compartment model emphasizing the non-osmotic accumulation of (Na⁺), chiefly in the skin. 23(Na⁺) magnetic resonance imaging (MRI) enables the accurate and reliable quantification of tissue (Na⁺). Another promising approach enabling tissue (Na⁺) monitoring is based on wearable devices employing ion-selective electrodes for electrolyte detection, including (Na⁺) and (Cl^-). Undoubtably, further studies using 23(Na⁺)-MRI technology and wearable sensors are required to learn more about the clinical significance of tissue (Na⁺) storage and (Na⁺)-related mechanisms of morbidity and mortality in HF.

Keywords: congestion; hypertonic saline; sensors; sodium; urinary spot.

Figure 1

The (3)-compartment model. Sodium is stored in tissues (e.g., skin or muscles) in addition to the intravascular and interstitial compartments. The third compartment sodium is osmotically inactive and can be either returned to the intravascular compartment through lymphatic vessels or excreted through the sweat. (This figure is adapted from Ref. [30]. Polychronopoulou E, Braconnier P, and Burnier M (2019) New Insights on the Role of Sodium in the Physiological Regulation of Blood Pressure and Development of Hypertension. Front. Cardiovasc. Med. 6:136.)

Figure 2

Mechanisms of damage to the glycocalyx induced by salt, resulting in hypertension and cardiovascular disease. High salt intake impairs glycocalyx and induces inflammation, oxidative stress, and immune activation, leading to the development of hypertension and cardiovascular disease. ROS, reactive oxygen species; ENaC, epithelial sodium channel; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NLRP3, NLR Family Pyrin Domain Containing 3; NF-Kb, Nuclear factor kappa-light-chain-enhancer of activated B cells; IsoLGs, Islovuglandins; TNF-α, tumor necrosis factor alpha; IFN-γ, Interferon gamma. (This figure is adapted from Ref. [42]. Sembajwe, L.F.; Ssekandi, A.M.; Namaganda, A.; Muwonge, H.; Kasolo, J.N.; Kalyesubula, R.; Nakimuli, A.; Naome, M.; Patel, K.P.; Masenga, S.K.; et al. Glycocalyx–Sodium Interaction in Vascular Endothelium. Nutrients 2023, 15, 2873).

Figure 3

Mechanisms of diuretic resistance and hypertonic saline (HS). The lower panel depicts the apical membrane of the tubular cells of the thick ascending limb of the Henle loop (A) under physiological conditions, the Na⁺/K⁺/Cl⁻ cotransporter 2 (NKCC2), which is blocked by loop diuretics, contributes to the reabsorption of up to 25% of filtered sodium. (B) In cases with diuretic resistance, sodium reabsorption increases in the different segments of the nephron, resulting in lower concentration of sodium in the tubular lumen of the Henle loop and, therefore, less sodium excretion in urine and less diuresis. (C) With the use of HS, sodium concentration increases in the tubular lumen, potentiating the action of loop diuretics and attenuating diuretic resistance. HS: hypertonic saline. (This figure is adapted from Ref. [58]. Hypertonic Saline Solution: How, Why, and for Whom? Ciro Mancilha Murad1 and Fabiana Goulart Marcondes-Braga. ABC Heart Fail Cardiomyop. 2023; 3(2):e20230078).

Figure 4

Disease-modifying treatment with renin–angiotensin–aldosterone inhibitors (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor–neprilysin inhibitors/mineralocorticoid receptor antagonists), B-adrenergic blockers, and especially sodium–glucose transporter 2 inhibitors, which additionally inhibit proximal tubule sodium (Na⁺) reabsorption, is the cornerstone for the prevention and treatment of (Na⁺) retention leading to congestion in HF. Interventions directly targeting (Na⁺) such as strict dietary sodium restriction, intravenous hypertonic saline (IV saline), and diuretics should be additionally implemented in selected patients with florid congestion to alleviate symptoms as they are not devoid of adverse effects and their effect on outcome is doubtful.