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

Abstract and Introduction


The increasing burden of heart failure (HF) and emerging knowledge regarding chloride as a prognostic marker in HF have increased the interest in the pathophysiology and interactions of chloride abnormalities with HF-related factors and treatments. Chloride is among the major electrolytes that play a unique role in fluid homeostasis and is associated with cardiorenal and neurohormonal systems. This review elucidates the role of chloride in the pathophysiology of HF, evaluates the effects of treatment on chloride (eg, diuretic agents cause higher urinary chloride excretion and consequently serum hypochloremia), and discusses recent evidence for the association between chloride levels and mortality.


Heart failure (HF) is a highly prevalent disease with a substantial risk of morbidity and mortality worldwide.[1] It is a prominent and growing health problem, with a 5-year mortality rate of ~50% after diagnosis. Electrolyte imbalances, especially potassium and sodium, are of interest in the clinical course of HF because their alterations may require intervention or adaptation of HF therapies and they appear to be associated with prognosis.[2] In the last several decades, practice guidelines and clinicians predominantly focused on sodium, given its role in preserving fluid homeostasis and influence on progression of HF. However, sodium's often unnoticed counterion in salt, chloride, was recently discovered to also play an important role in the pathophysiology of HF and to be associated with neurohormonal system activity,[3,4] replacing the long-standing view that it merely balances the other components of the metabolic profile.

Chloride and sodium are both major potent ions in extracellular fluid. A multitude of studies have purported the serum sodium abnormalities to be a predictor of poorer outcomes in patients with acute or chronic HF, but almost no studies have accounted for chloride levels in their analyses (Supplemental Table 1). Chloride has been shown to be a stronger predictor of outcomes than sodium in HF, and the existing controversy about the favorable versus detrimental effects of salt restriction in patients with HF may be related, in part, to its effect on chloride homeostasis. Changes in the plasma volume, vasopressin secretion, and renin-angiotensin-aldosterone (RAAS) systems that occur under worsening HF are purported to be primarily mediated by serum chloride, not by serum sodium levels.[5] Also, several studies in patients with worsening HF have reported serum chloride to be inversely associated with mortality independent of serum sodium levels, and hence they have suggested its potential use as a prognostic marker in HF.[6,7]

Although some evidence has emerged from these studies, many questions remain unanswered. Can chloride be used as a prognostic factor for HF? If so, what is the underlying pathogenesis that links chloride levels with outcomes? How does it interplay with sodium homeostasis in patients with HF? What HF-related factors (eg, pathophysiology, treatments) can affect the plasma chloride levels? Can chloride abnormality affect the patient's response to HF therapies? This review will examine existing evidence on chloride and its role in HF.