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

Future Directions

Emerging evidence indicates that chloride is a prognostic factor for HF outcomes, but it is not yet a therapeutic target. In patients with HF, the presence of hypochloremia may indicate a more generalized disturbance of cardiorenal homeostasis, in opposition to an isolated low serum sodium level.[19] In the Central Illustration, we suggested a management algorithm based on the existing data for patients with HF and different serum chloride levels, but there is a significant knowledge gap that needs to be addressed in future studies. For instance, whether the role of chloride is similar for the 2 HF subtypes remains unknown and requires further investigation.[30] The prognostic impact of chloride levels might differ between the normal and pathological conditions. The prognostic effect of serum chloride abnormalities in HF might be more striking in the presence of certain comorbidities such as chronic kidney disease, given its critical importance in HF and the kidney's role in electrolyte homeostasis.

Advice on routine monitoring of chloride concentration through testing blood and urine samples and preservation of chloride homeostasis in patients with HF could be useful in clinical practice especially in the future if interventions either targeting it or relating to it are proved useful. Sodium restriction and diuretic therapy might result in hypochloremia,[25] which is shown to be associated with worsening HF and poorer survival.[20] Patients with HF who have a lower urinary chloride concentration may benefit from the down-titration of loop diuretics; however, all previous studies exploring that have been underpowered. Targeting WNKs may be a potential therapeutic option in HF, as inhibition of WNK can decrease the activity of Na-K-2Cl and Na-Clsymporter. This could be more effective than targeting one of the cotransporters directly. Serial measurements can identify patients who are rapidly deteriorating and at risk for adverse outcomes and may provide insight on need for treatment alterations.[14,16]

Prospective studies, preferably randomized clinical trials with large numbers of patients are required to evaluate the effect of serum chloride manipulation as a prognostic factor in patients with HF. The prognostic value of serum chloride and its interaction with other electrolytes such as sodium in HF remains to be fully delineated and harnessed as a potential therapeutic target.