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


JACC Heart Fail. 2022;9(12):904-915. 

In This Article

The Effect of Chloride Abnormality on Response to HF Treatments

Diuretic Resistance

Adaptive renal mechanisms to maintain volume status may be initiated by chloride depletion and may eventually lead to diuretic resistance.[9,11] A significant association was shown between chloride and diuretic response, even after adjustment for sodium and bicarbonate levels.[16] The reduced quantity of diuretic reaching the tubular site of action and an inadequate tubular response to the delivered diuretic could explain the reduced diuretic efficiency. Also, as mentioned, a family of chloride-sensitive kinases known as WNK were recently identified to have a vital role in regulating Na-K-2Cl cotransporters in the thick ascending limb of the loop of Henle and the Na-Cl symporters in the distal convoluted tubule on which loop and thiazide diuretic agents operate. Hypochloremia activates these transporters to reabsorb chloride, unlike loop and thiazide diuretic agents that work by inhibiting these transporters. These opposing effects link hypochloremia to diuretic resistance. A change of diuretic drug (switching from a loop to a nonloop diuretic), a dose increase, or alternatively, chloride supplementation are some measures suggested for overcoming diuretic resistance.[9,11] It is noteworthy that the above-mentioned loop diuretic dose increase that occurs frequently in current practice to address the diuretic resistance induces even lower serum chloride levels and possibly creates a vicious cycle.[9]

Dilution and Depletion

Patients with HF seem to have 2 distinct biochemical profiles. In patients with HF, a greater relative wasting of chloride versus sodium can suggest that depletion rather than dilution is the underlying mechanism.[9] Even though the urinary chloride concentrations can be used to differentiate between depletion and dilution phenotypes, these are less frequently tested.[6,11]

The fraction of serum chloride versus sodium can be used to distinguish these 2 phenotypes. In the first patient group, with both hypochloremia and hyponatremia, hemodilution appears to be the main contributor[6] with limited tubular chloride resorption, higher arginine vasopressin secretion, and overstimulation of vasopressin receptor 2, which results in increased water retention by the kidneys (Figure 2).[12,25] Whereas increasing the dose of loop diuretic may be appropriate to treat a patient with severe congestion and hemodilution, it may worsen hypochloremia.[11] This patient group can be treated with fluid restriction and electrolyte supplementation,[28] as well as with mineralocorticoid receptor antagonists that can counteract the potassium loss that is observed in these patients.[33]

The second phenotype are patients with hypochloremia and normal sodium levels, which may be caused by chloride depletion as a consequence of diuretic therapy.[6] A metabolic alkalosis is often present, which can be treated with aggressive potassium and chloride repletion.

Current Therapies for Hypochloremia

Hypochloremia can be a consequence of salt and water handling along the nephron in patients with HF. Some studies have explored possible therapies for hypochloremia, which are summarized in the Central Illustration. A change of the diuretic regimen might be an option. In a post hoc analysis from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial; NCT00094302) lower serum chloride levels were not associated with spironolactone use, in contrast to treatment with loop diuretic agents.[19] Another study reported that coadministration of acetazolamide with loop diuretic agents can reduce the chloride loss by approximately 5%. More insights on the efficacy of the combined therapy with acetazolamide and loop diuretic agents in patients with HF are expected to be provided through the ongoing ADVOR (Acetazolamide in Decompensated Heart Failure With Volume Overload; NCT03505788) trial. Administration of adjuvant thiazides may theoretically reduce chloride wastage.[20]

Central Illustration.

Management of Patients With Heart Failure Based on Their Serum Chloride Status
This algorithm depicts the several key parameters used in the assessment of patients with heart failure with regard to their serum chloride status, various phenotypes involved, and the suggested therapeutic approaches for each phenotype.

Manipulation of the serum chloride concentration could become an attractive novel therapeutic target for HF treatment.[33] Therapies may directly or indirectly affect serum chloride level. Recently, there have been small studies on newer agents, sometimes with conflicting results. Sodium glucose cotransporter 2 inhibitors seem to maintain or increase serum levels of chloride, without any change in serum Na and K levels, but with a decrease in HCO3 concentrations.[34] This effect on serum chloride levels may be mediated in early treatment stages by RAAS activation caused by vessel contraction, and decreased blood pressure resulted from osmotic diuresis in sodium glucose cotransporter 2 inhibitor treatment, inhibition of NaHCO3 reabsorption caused by the buffering effect of increased organic acid metabolites such as ketone bodies, and inhibition of Na-H exchanger 3 in the proximal convoluted tubule.[34] Vasopressin receptor 2 antagonists ("vaptans") increase free water clearance by antagonizing the vasopressin receptors 2 and result in improvement of hyponatremia and presumably low serum chloride levels.[25] The use of vaptans would be expected to change sodium and chloride equally in a 1:1 molar ratio in a hemodilution state,[20] meaning that they have potentially equal ameliorating effects on hyponatremia and hypochloremia. Hypertonic saline may be a possible treatment intervention in acute decompensated HF, as this was shown to improve serum chloride abnormalities,[35] but this requires further testing in adequately powered and well-designed randomized controlled trials.

Supplementation of lysine chloride directly increases chloride levels approximately by 2.2 to 2.3 mmol/L, but its longer-term pharmacological impact is not fully investigated yet.[25] Hence, a randomized controlled trial is underway (expected completion: March 2023) on the effects of sodium-free chloride supplementation in patients with decompensated HF concomitantly treated with intravenous diuretic agents (Mechanism and Effects of Manipulating Chloride Homeostasis in Stable Heart Failure [NCT03440970]).