Chloride in Heart Failure: The Neglected Electrolyte

Arietje J.L. Zandijk, BSC; Margje R. van Norel, BSC; Florine E.C. Julius, BSC; Nariman Sepehrvand, MD, PHD; Neesh Pannu, MD, SM; Finlay A. McAlister, MD, MSC; Adriaan A. Voors, MD; Justin A. Ezekowitz, MBBCH, MSC

Disclosures

JACC Heart Fail. 2022;9(12):904-915. 

In This Article

Potential Mechanisms of the Effect of Chloride Level in HF

Chloride and the Gastrointestinal Tract

Prominent causes of hypochloremia are related to the loss of chloride anions in the gastrointestinal tract or kidneys. Dietary intake, intestinal absorption, and excretion are important aspects that need to be considered in the gastrointestinal tract. Adequate intake of chloride is set at a level equivalent to the molar basis of sodium, because almost all dietary chloride comes with sodium and thus deficiencies are rare, except in the context of salt restriction.[22] On a daily basis, the gastrointestinal tract is responsible for handling 8 to 10 L of fluid containing 800 mmol of sodium and 700 mmol of chloride. Salivary gland acinar cells secrete chloride and sodium as an isotonic fluid. Parietal cells secrete HCl in response to the release of gastrin caused by the presence of peptides (ie, meal) in the gastric lumen. About 98% of the chloride intake will be absorbed.[22] There are 3 distinct mechanisms responsible for chloride absorption from the intestinal lumen. The main pathway is the electroneutral coupled Na/H and Cl/HCO3 exchange, which results in Na+ and Cl absorption in exchange for H+ and HCO3− excretion. The other 2 mechanisms are paracellular pathway and bicarbonate-dependent chloride absorption. Intestinal absorption can be impaired in HF through the congestion of the splanchnic circulation and the subsequent intestinal wall edema and barrier dysfunction.[23] Eventually, only 100 mL fluid is lost through the stools per day and this contains 10 to 15 mmol/L chloride, which can exceed 90 mmol/L in case of malabsorption.

Chloride and the Kidney

Kidney has a central role in the body's electrolyte homeostasis. The urinary concentration of chloride is regulated by the amount of chloride filtered by the glomeruli and the balance of resorption and secretion along the nephron (Figure 1) and normally ranges between 110 and 250 mmol/L. In the general population, the amount of excreted urinary chloride roughly equals the intake. However, renal dysfunction is prevalent in patients with HF and related to a worse prognosis. In patients with HF, renal blood flow is often impaired because of a decrease in cardiac output and an increase in central venous congestion. Chloride is the main modulator of the tubuloglomerular feedback in the kidney, and hypochloremia in HF would interfere with the kidney's regulatory role in electrolyte homeostasis and diuresis.

Figure 1.

Renal Regulation of the Chloride Homeostasis
Sixty percent of chloride is reabsorbed in the proximal convoluted tubule. In step 1A, sodium, bicarbonate, and other nonchloride anions are reabsorbed. In step 1B, most of the secreted Cl is reabsorbed passively through the concentration gradient generated by step 1A, and carbon anhydrase increases serum HCO3 levels. In step 2, there is only passive water transport, whereas the thick ascending limb (step 3) is impermeable for water and the sodium-potassium-2 chloride (Na-K-2Cl) cotransporter is active. In step 4, sodium and chloride are reabsorbed via the sodium-chloride cotransporter. The basolateral Na-K–adenosine triphosphatase (ATPase) pump creates a low sodium gradient, so direct coupled sodium/chloride transport can be facilitated. Chloride is passively and indirectly reabsorbed in this step, because of the negative potential caused by the transport of sodium via the apical epithelial sodium channels. Serine-threonine kinases (with-no-lysine protein kinases [WNKs]) play an important role as chloride sensors and are in control of Na+-K+-2Cl and Na+-Cl cotransporters. In step 5, the final urinary chloride concentration is regulated via paracellular transport. If chloride is low on the serum electrolyte balance, there will be maximal reabsorption in the collecting duct to conserve normal chloride levels. ACE = angiotensin converting enzyme; ARBs = angiotensin receptor blocker; CA = carbon anhydrase; MR = mineralocorticoid receptor; MRA = mineralocorticoid receptor antagonist; SGLT2 = sodium-glucose cotransporter 2; VR = vasopressin receptor 2 antagonists.

Chloride and Neurohormonal Activation

Chloride has a unique role in homeostasis that is distinct from sodium. As demonstrated in Figure 2, hypochloremia leads to decreased chloride delivery to the macula densa in nephrons, resulting in an increase in the secretion of renin from the juxtaglomerular apparatus caused by tubuloglomerular feedback in the kidney.[3] This salt-sensing and physiological feedback is dependent on chloride rather than sodium.[9] There is also activation of the sympathetic nervous system, which particularly results in renal afferent vasoconstriction causing a decrease in renal blood flow and therefore less natriuresis and diuresis, leading to more congestion. Serine-threonine kinases (with-no-lysine protein kinases [WNK]) play an important role as chloride sensors for changes in intracellular chloride concentration, cell volume, and extracellular osmolarity. Lower serum chloride activates a cascade, in which the WNK family increases the activity of Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle, as well as the Na-Cl symporters in the distal convoluted tubule to facilitate the chloride reabsorption.[3] Up-regulation of these transporters can lead to potassium wastage and arrhythmias.[8] Changes in plasma potassium can affect the Na-Cl symporter because they alter the intracellular chloride concentration and thereby modulate WNK activity. When plasma potassium is high and consequently aldosterone is secreted, the WNK activity is inhibited.[24] Recent studies show that chloride appears to bind directly to a catalytic site of WNK, phosphorylating sodium regulatory pathways, and thereby regulating blood pressure and electrolyte homeostasis.[20] This represents a plausible mechanistic link between HF pathology and chloride imbalances.[9]

Figure 2.

Pathophysiological Relations Between HF and Hypochloremia
The upper half of this schematic figure depicts the mechanisms with which heart failure (HF) could lead to hypochloremia and the lower half covers the pathways that connect hypochloremia with contractile dysfunction and heart failure decompensation. GI = gastrointestinal; JGA = juxtaglomerular apparatus; RAAS = renin-angiotensin-aldosterone system; SA = sinoatrial; TAL = thick ascending limb of the loop of Henle; WNK = with-no-lysine protein kinases.

Neurohormonal activation is modulated by the HF medications, ventricular dysfunction, and renal dysfunction.[25] Maladaptive neurohormonal activation and acid-base changes during the chronic HF progression can affect the serum chloride concentration by activating the neural thirst center and impairing the vasopressin secretion.[1] According to the "chloride theory," changes in serum chloride levels are the primary determinants of changes in RAAS and plasma volume.[26] For example, total renin levels were shown to be higher in patients with hypochloremia than in patients without hypochloremia, and this inverse correlation remained significant even after adjustment for serum sodium.[9] The B-type natriuretic peptide (BNP) is secreted by ventricular myocytes caused by elevated ventricular filling pressure, and it counteracts the effects of RAAS and sympathetic activity. Chloride and BNP both seem to be predictors of outcome in HF, but it is unclear how and whether BNP modulates the prognostic value of chloride. In a United Kingdom study, hypochloremia was associated with adverse outcome independent of BNP.[6] In the VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial, after adjustment for clinical covariates including natriuretic peptides, there was a 12% decrease in the risk of cardiovascular death and HF hospitalization per each 5 mmol/L increase in serum chloride level.[27]

Acid Base Imbalances

The interdependence among serum chloride, sodium, potassium, and bicarbonate is shown in the anion gap formula: Anion Gap = SNa + SK – SHCO3− − SCl. This equation highlights why hypochloremia occurs frequently with metabolic alkalosis. These 2 combined are called "chloride depletion alkalosis," which is a state of volume contraction in the extracellular fluid caused mainly by diuretic-induced natriuresis and diuresis. In laboratory results, this can be seen as a rise in pH and serum bicarbonate level, as well as low serum chloride concentrations. The exact role of pH as prognostication marker has not been fully explored, but pH has been shown to be affected by chloride level in the forms of chloride depletion alkalosis or hyperchloremic metabolic acidosis.[3] Chloride depletion alkalosis is shown to be an independent predictor of in-hospital mortality in patients with decompensated HF.[13] In HF, electrolyte depletion occurs mostly as a result of salt restriction and loop and thiazide diuretic therapy and metabolic alkalosis is often seen as a consequence of diuretic usage.[28]

Hyperchloremia

As mentioned, several studies suggested a U-shaped correlation between serum chloride levels and adverse outcomes in patients with HF.[6,10,19,20] Hyperchloremia occurs when the plasma concentration of chloride is elevated in excess of 105 to 115 mmol/L; although, there is no universal definition and the criteria may differ between laboratories. Mechanisms leading to hyperchloremia include excessive electrolyte-free or hypotonic fluid loss and disproportionate chloride administration (eg, excessive intravenous saline administration). Hyperchloremia is distinct from hyperchloremic metabolic acidosis where elevated serum chloride is accompanied by a decrease in serum bicarbonate concentration and a drop in blood pH. Hyperchloremic metabolic acidosis can be of renal or extrarenal origin. Proximal or distal renal tubular acidosis should be considered when a patient presents with hyperchloremic metabolic acidosis. In proximal renal tubular acidosis, the filtered bicarbonate is lost by kidney wasting.[29] This will lead to the reabsorption of chloride by the kidney for maintaining volume. In distal renal tubular acidosis, there is insufficient bicarbonate production/regeneration in the kidneys to compensate and buffer for the endogenous acid.[29] Secretory diarrhea is the common extrarenal cause of hyperchloremic metabolic acidosis that stimulates chloride resorption in exchange of bicarbonate secreted into the intestinal lumen with diarrhea.

HFrEF and HFpEF

As shown in Table 1, only 3 studies enrolled only patients with heart failure with reduced ejection fraction (HFrEF), 1 included only patients with heart failure with preserved ejection fraction (HFpEF), and the others represented a mix consisting mainly of patients with HFrEF. Whether the role of chloride is similar for the 2 HF phenotypes remains unknown;[30] although, at least 1 study demonstrated that hypochloremia was more common in HFrEF.[6]

Comorbidities

Patients with HF and hypochloremia were more likely to have diabetes mellitus than were patients with normal or higher chloride levels.[6,10,18] In the study of Grodin et al,[12] the association between hypochloremia and mortality was unchanged after adjustment for diabetes mellitus, chronic obstructive pulmonary disorder, and coronary artery disease. Low serum chloride is of prognostic value in both patients with chronic kidney disease[31] and those with hypertension.[32] However, the question of whether patients with HF and certain comorbidities are more prone to hypochloremia remains to be investigated in future studies.

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