Targeting Sodium in Heart Failure

Figures

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  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.)

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  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).

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  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).

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  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.