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.

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-Cl⁻symporter. 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.

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Abbreviations and Acronyms
BNP = B-type natriuretic peptide; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; RAAS = renin-angiotensin-aldosterone system; WNK = with-no-lysine protein kinases

Funding Support and Author Disclosures
The Canadian VIGOUR Centre provided in-kind support via data management and statistical analysis. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Table 1. Studies Exploring the Link Between Chloride Abnormalities and Outcome in Patients With HF
First Author, Year, Country (Ref. #)	Design	Participants	N	Single or Serial Measurement	Dichotomous/Continuous (Cutoff)	Primary Endpoint	Key Findings
Cuthbert et al, 2018, United Kingdom (6)	Registry-based cohort	Outpatients with HF	4,705	Single	Categorical and continuousHypochloremia: <96 mmol/L Hyperchloremia: >105 mmol/L	All-cause mortality, composite endpoint of mortality/HFH	Every unit decrease in chloride was associated with 4% and 3% increase in death alone and composite of death/HFH, respectively. Lowest quartile associated with 2-fold increased risk of mortality.
Ferreira et al, 2017, France (10)	EPHESUS and CAPRICORN RCT	In- or outpatients, post-AMI (HFrEF)	7,195	Single	Continuous (tertiles)	All-cause mortality, CV mortality, and HFH	Chloride levels <100 mmol/L were associated with higher risk of mortality, but not HFH, in the context of sodium ≤138 but not in sodium >141 mmol/L.
Grodin et al, 2015, USA (7)	Population-based cohort	Hospitalized patients with AHF	Main cohort: 1,318Validation cohort: 876	Serial (admission and discharge)	Categorical and continuous (tertiles)Hypochloremia: <96 mmol/L	All-cause mortality	Chloride <96 mmol/L associated with higher mortality. Mortality of <1 y decreased by 6% for every unit increase in admission chloride level. Similar findings in validation cohort.
Grodin et al, 2016, USA (12)	Registry-based cohort	Outpatients with HF	1,664	Single	Continuous (quartiles)	5-y all-cause mortality	For each 4.1-mmol/L decrease in serum chloride concentration, 5-y all-cause mortality risk increased by 29%.
Grodin et al, 2017, USA (11)	ROSE-AHF RCT	Hospitalized patients with AHF	358	Serial (at randomization and during hospital stay)	Continuous (tertiles)	Diuretic response, renal function at 72 h, death, and rehospitalization at 60 and 180 d	For each mmol/L increase in serum chloride, the risk of 60-d death, 60-d death/rehospitalization, and 180-d death decreased with 14%, 10%, and 9%, respectively. Lower serum chloride levels at baseline were associated with less diuretic efficiency.
Grodin et al, 2018, USA (19)	TOPCAT RCT	Outpatients with HFpEF (LVEF ≥45)	942	Serial measurements, baseline used for evaluating association with outcomes	Continuous (tertiles)Hypochloremia: ≤96 mmol/L	Composite of CV death, HFH, or aborted cardiac arrest	5-y all-cause death and CV death increased with 29% and 51%, respectively, for each 4.05-mmol/L decrease in serum chloride level. No association with HFH.
Grodin et al, 2018, USA (18)	Registry-based cohort	Outpatients with HF	438	Single	Continuous (tertiles)	Composite endpoint of death, heart transplant, or LVAD placement	Each mmol/L reduction in chloride level was associated with 6% increase in composite endpoint, after adjustment for sodium and bicarbonate.
Hanberg et al, 2016, USA (9)	Registry-based cohort	Outpatients with HF	162	Single	DichotomousHypochloremia: ≤96 mmol/L	Diuretic efficiency, plasma renin activity, all-cause mortality	Hypochloremia was associated with reduced survival (HR: 5.7) and impaired diuretic efficiency (OR: 7.3).
Kataoka, 2018, Japan (17)	Registry-based cohort	Outpatients with HF	47	Serial		Change in chloride concentration	During HF therapy with conventional diuretics, the chloride changes were greater than the changes in sodium levels. Chloride levels increased during worsening HF.
Khan et al, 2015, USA (13)	Population-based cohort	Hospitalized patients with AHF	674	Serial (admission and discharge)	DichotomousCDA: change in serum bicarbonate ≥3 mmol/LNon-CDA: change <3 mmol/L	In-hospital mortality and composite endpoint of 30-d all-cause mortality and HFH	In-hospital mortality was lower in the group with CDA (OR: 0.11). No difference in 30-d composite endpoint.
Kondo et al, 2018, Japan (14)	Registry-based cohort	Hospitalized patients with AHF	208	Serial (admission and discharge)	Dichotomous and changeHypochloremia: <98 mmol/L	HF death, non-CV death, all-cause death	Lower admission and discharge chloride levels were associated with increased HF mortality. Persistent and progressive hypochloremia during hospitalization were associated with increased risk of HF death (HR: 9.13 and 4.65, respectively) and all-cause death (HR: 3.63 and 2.10, respectively) compared to the groups without hypochloremia.
Marchenko et al, 2020, USA (21)	Population-based cohort	Hospitalized patients with AHF	1,241	Serial (admission and discharge)	DichotomousHypochloremia: <96 mmol/L	30-d hospital readmission	Hypochloremia either on admission or discharge was independently associated with a higher 30-d rehospitalization rates (adjusted OR: 1.35), but only explained 4% of the variability of the rehospitalization outcome.
Radulovic et al, 2016, Croatia (15)	Registry-based cohort	Hospitalized patients with AHF	152	Single	DichotomousHypochloremia: <98 mmol/L	In-hospital and 3-mo mortality, hyponatremia at follow-up	Hypochloremia at admission was associated with higher in-hospital and 90-d death in univariate analysis, but not after adjustment for age, sodium and cholesterol levels, and statin therapy. Hypochloremia associated with higher risk of hyponatremia at 90 d (OR: 27.1)
Ter Maaten et al, 2016, the Netherlands (16)	PROTECT RCT	Hospitalized patients with AHF (HFrEF)	1,960	Serial (baseline, 7th and 14th d)	Continuous (quintile)Hypochloremia: <96 mmol/L	Diuretic responsiveness, decongestion, and 180-d all-cause mortality	With each unit decrease in serum chloride level, the risk of 180-d mortality increased in patients with hypochloremia by 4% and 7% at 7th and 14th d, respectively. Progressive and persistent hypochloremia within 2 wk from baseline were associated with higher mortality rates than those for patients who were nonhypochloremic (HR: 3.11).
Testani et al, 2016, USA (20)	BEST RCT	In- and outpatients with HF (HFrEF)	2,699	Serial (baseline, 3 and 12 mo)	DichotomousHypochloremia:≤96 mmol/L	All-cause mortality	Low serum chloride independently associated with increased mortality. Each 4.5-mmol/L decrease in baseline serum chloride increased the adjusted mortality risk by 30%.
Zhang et al, 2018, China (1)	Registry-based cohort	Hospitalized patients with HF	905	Single	Continuous (quartiles)	All-cause death	8% higher adjusted risk of mortality for every unit decrease in serum chloride. Mortality risk increased for hypochloremia in the context of hyponatremia (HR: 4.30).

AHF = acute heart failure; AMI = acute myocardial infarction; BEST = Beta-Blocker Evaluation of Survival Trial; CAPRICORN = Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left-Ventricular Dysfunction; CDA = chloride depletion alkalosis; CV = cardiovascular; EPHESUS = Eplerone, a Selective Aldosterone Blocker, in Patients With Left Ventricular Dysfunction After Myocardial Infarction; HF = heart failure; HFH = heart failure (re)hospitalization; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; OR = odds ratio; PROTECT = Placebo-controlled Randomized Study of the Selective A1 Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; RCT = randomized controlled trial; ROSE-AHF = Renal Optimization Strategies Evaluation in Acute Heart Failure; TOPCAT = Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial.

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Chloride in Heart Failure: The Neglected Electrolyte

Future Directions

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