Cardiology

Prognostic impact of serum chloride concentrations in acute heart failure patients: A systematic Rreview and meta-analysis

a b s t r a c t

Objective: Acute heart failure is a common disease in the emergency departments. Its occurrence is often accompanied by Electrolyte disorders, but little attention is paid to chloride ion. Recent studies have shown that hypochloremia was associated with poor prognosis of AHF. Therefore, this meta-analysis aimed to assess the in- cidence of hypochloremia and the impact of the reduction of serum chloride on the prognosis of AHF patients. Methods: We searched Cochrane Library, Web of science, PubMed, Embase databases and searched the relevant studies on chloride ion and AHF prognosis. The search time is from the establishment of the database to Decem- ber 29, 2021. Two researchers screened the literature and extracted data independently. The quality of the in- cluded literature was evaluated using Newcastle-Ottawa Scale (NOS) scale. The effect amount is expressed as hazard ratio (HR) or Relative risk and 95% confidence interval (CI). Review Manager 5.4.1 software for was used to perform the meta-analysis.

Results: Seven studies involving 6787 AHF patients were included in meta-analysis. Meta-analysis revealed that the incidence of hypochloremia in AHF patients at admission was 17% (95% CI: 0.11-0.22); One mmol /L decrease in serum chloride at admission was associated with 6% increased risk of All-cause death of AHF patients (HR = 1.06, 95% CI: 1.04-1.08, P < 0.00001); Compared with the non-hypochloremia group, the risk of all-cause death in the hypochloremia group increased by 1.71 times (RR = 1.71, 95% CI: 1.45-2.02, P < 0.00001), the risk of all-cause death in the progressive hypochloremia(development of hypochloremia after admission) group increased by 2.24 times (HR = 2.24, 95% CI: 1.72-2.92, P < 0.00001), and the risk of all-cause death in the persistent hypochloremia (hypochloremia both on admission and at discharge) group increased by 2.80 times (HR = 2.80, 95% CI: 2.10-3.72, P < 0.00001).

Conclusion: The available evidence shows that the decrease of chloride ion at admission is associated with poor prognosis of AHF patients, and the prognosis of persistent hypochloremia is worse.Some outcome indicators(pro- gressive hypochloremia, persistent hypochloremia, and composite of death + HF hospitalization)are as few as 2 studies in the literature, and the results should be interpreted carefully.

(C) 2023 Published by Elsevier Inc.

  1. Introduction

acute heart failure is a clinical syndrome with acute hemody- namic abnormalities caused by a variety of causes, which is often life-threatening and requires immediate hospitalization for medical intervention [1]. AHF is the main reason for hospitalization of patients over 65 years old. Although we have made great progress in the treat- ment of AHF, the prognosis of it is still poor [1,2]. The in-hospital

* Corresponding author at: No.256 Youyi West Road, Beilin District, Xi’an, Shannxi 730000, China.

E-mail address: [email protected] (L. Yan).

1 These authors contributed equally to this work.

mortality rate is from 4% to 7%. The mortality rate in three months after discharge is from 7% to 11%, and the Death rate in one year is about 22-27% [3-8]. The readmission rate after discharge from the hos- pital is also high, with a 25% readmission rate within 3 months and two- thirds of patients being readmitted within one year. [9]. AHF has placed a huge burden to the global health care system. High hospitalization rates and prevalence lead to high Total costs for HF, and the total costs of HF in the United States in 2012 were $30.7 billion, and it will increase to $69.7 billion in 2030 [10].

Electrolyte disorders often occur in HF [11], and affect clinical decision-making and treatment. Previous studies have shown that serum potassium ion and sodium ion are associated with poor prognosis of HF [12-14]. Therefore, the current clinical focus is on sodium ion and

https://doi.org/10.1016/j.ajem.2023.05.035 0735-6757/(C) 2023 Published by Elsevier Inc.

potassium ion, while the study of anionic chloride ion is less. However, more and more people began to pay attention to the role of chloride ions in HF. Chloride ion is the main strong anion in blood for about one-third of plasma tonicity, 97% to 98% of all strong anion charges and two-thirds of all negative charges in plasma [15]. In recent years, it has been found that serum chloride ion plays an important role in salt sensing, neuro- hormone activation, diuretic of target regulation, etc. [16-19]. This pathophysiological background supports its independent clinical and prognostic relevance in AHF.

In 1998, it was first reported that the reduction of serum chloride level was associated with Cardiovascular death risk of asymptomatic coronary heart disease [20]. In 2007, it was first reported that the reduc- tion of serum chloride was associated with risk of all-cause death of HF [21]. Recent studies have shown that serum chloride was associated with poor prognosis of AHF [22]. Therefore, this meta-analysis com- bined published research on the relationship between serum chloride ion and prognosis of AHF to evaluate the relationship between hypochlorhydria and prognosis of AHF, and further analyzes the inci- dence of hypochloremia in AHF patients.

  1. Methods
    1. Search strategy

The literature search was carried out by two researchers inde- pendently, and the differences were resolved through consultation with the third researcher. PubMed, Web of science, Embase and The Cochrane Library were searched to collect relevant studies on chloride concentration and HF prognosis. The search time limit was from the

Records excluded based on evaluation of title and abstracts(n=389)

Records screened (n =426)

Records after duplicates removal (n =426)

Additional records identified through other sources(n=0)

Records identified through database searching(n=544)

Identification

establishment of the database to December 29, 2021. There was no re- striction on language, publication type, region or sample size. The search terms are “Heart Failure”, “cardiac failure“, “Heart Failure, Left-Sided”, “Heart Failure, Left Sided”, “Myocardial Failure”, “Left-Sided Heart Fail- ure”, “Heart Failure, Right-Sided”, “Congestive Heart Failure”, “Heart Failure, Congestive”, “Heart Decompensation”, “Decompensation, Heart”, “Heart failure with reduced ejection fraction“, “heart failure with mildly reduced ejection fraction”,”heart failure with preserved ejection

fraction”,”Chloride”, “Chloride Ion Level”, “Ion Level, Chloride”, “Level, Chloride Ion”, “Hypochloraemia”,”Outcome”,”Prognosis”.

    1. Inclusion and exclusion criteria

Two researchers screened the literature and extracted the data ac- cording to the inclusion and exclusion criteria. Any differences were re- solved through consultation with a third party. The missing data should be supplemented by contacting the author as much as possible. When literature screening, first read the title and abstract, and then further read the full text after excluding the obviously irrelevant literature to determine whether it is included.

Inclusion criteria: (1) Cohort study; (2) Definition of AHF diagnosis;

(3) The exposure factor was serum chloride concentration; (4) The end point was the incidence of hypochloremia, all-cause death, composite endpoint (all-cause death or HF hospitalization); (5) The research re- port includes the Hazard Ratio (HR) or relative risk (RR) and 95% confi- dence interval (CI) of the Exposure factors adjusted by multifactor analysis, or the RR and 95% CI can be calculated according to the number and total number of endpoint events in the exposure group and non- exposure group;

Screening

Full-text articles assessed for eligibility(n = 37)

Full-text articles assessed for eligibility(n = 7)

Full-text articles excluded (n

= 30)?

Review articles?n=9? Insufficient?n=11? Duplicated?n=2? No AHF?n=6? Unavailable?n=2?

Fig. 1. Flow diagram of study searching and Selection process.

Studies included in qualitative synthesis(n = 7)

Included

Eligibility

Exclusion criteria: (1) Repeated publications; (2) Animal experi- ment, review, meta-analysis, case report; (3) Unable to obtain the outcome indicators of interest; (4) Incomplete or wrong data.

NOS

scores

1.47(0.51-2.68) years

1 year

30 days

180 days

3 months

180 days

1.86 +- 0.76 years

12 months

6

6

7

6

7

5

7

7

    1. Data extraction and quality evaluation

For each eligible study, the data were independently extracted by two researchers, and any differences were resolved through consulta- tion with the third researcher. The extracted contents include: (1) gen- eral information: title, first author, year of publication; (2) Clinical information: number, sex, age, serum chloride ion, definition of hypochloremia, length of follow-up; (3) Outcome: incidence of hypochloremia, all-cause death and composite endpoint (all-cause death or HF hospitalization).

Hypochloremia, n(%)

Follow-up period

NA NA NA

279(14)

25(16)

115(32)

26(13)

120(10)

Two researchers used the Newcastle Ottawa Scale (NOS) to evaluate the quality of the included studies independently. Any differences were resolved through consultation with the third researcher. The NOS con- sists of three domains: selection, comparability and outcomes. Scores ranging from 0 to 9, Studies that received a score of six or higher were considered high-quality studies [23,24].

Chloride ion concentration, mmol/l

100 +- 6

103 +- 6

NA

100.8 +- 5.0

104 (100-106)

100 +- 5

NA

99.4 +- 4.7

    1. Statistical methods

Review manager software (version 5.4.1) was used for statistical analysis. The main outcome indicators of this study were HR/RR and 95% CI. For univariate or multifactorial analyses, we used the results of the multifactorial analysis. For dichotomous variables, we used RR and 95% CI. P < 0.05 were considered statistically significant. Heterogeneity between included study outcomes was analysed using the ?2 test (test level ? = 0.1), while the magnitude of heterogeneity was determined quantitatively in conjunction with I2. If there is no statistical heteroge- neity among the results (I2 < 50%, P > 0.1), the fixed effect model is used for meta-analysis; If there is statistical heterogeneity among the research results (I2 >= 50%, P <= 0.1), then further analyze the source of heterogeneity. After excluding the influence of obvious clinical hetero- geneity, the random effect model is used for meta-analysis. Significant clinical heterogeneity was treated by subgroup analysis or sensitivity analysis, or descriptive analysis only. The funnel chart was used to eval- uate publication bias.

Male, n(%)

Study type

Definition of hypochloremia, mmol/l

NA NA NA

<96

NA

<98

<98

<96

923(70.0)

476(54.3)

345(51.2)

1308(66.7)

73 (48.0)

264 (73.7)

116(55.8)

649(52.3)

Retrospective cohort Retrospective cohort retrospective cohort Retrospective cohort Prospective cohort retrospective cohort Prospective cohort retrospective cohort

  1. Results

68.7(59.1-77.2)

62.9 (51.4-74.3)

65.3 +- 14.9

NA

77 (70-82)

70(62-79) NA

76.5 +- 13.0

    1. Literature search

Age, years

Using our pre-defined search strategy, we retrieved 544 relevant articles from EMbase, Cochrane, Web of science, and Pubmed databases, and excluded 118 articles after checking by Endnote. The full text of 37 articles were read after reading the titles and abstracts. Finally, 30 articles were excluded according to inclusion and exclusion criteria and 7 articles were included [22,25-30]. One article [22] includes two independent cohort studies, so it is considered as two independent studies for statistical analysis (Fig. 1).

Total number

Patient

1318

876

674

1960

152

358

208

1241

AHF AHF AHF AHF AHF AHF AHF AHF

    1. Study characteristics and quality assessment

Table 1

Baseline characteristics of the included studies.

Study and participant characteristics are summarized in Table 1.A total of 6787 AHF patients were included in 8 studies [22,25-30]. The in- cluded patients was predominately male (61.2%) with an average age of 62-67 years. The length of follow up ranged from 30 days to 2 years. The longest follow up time was 1.86 years [27], the shortest follow-up time was 30 days [26]. Five of the eight studies [22,25,26,28] were conducted in the United States and one each in Japan [27], Croatia [30], and the Netherlands [29].

Country

Grodin1 2015

Grodin2 2015 Khan2015

*Maaten2016

*Radulovic 2016

*Grodin 2017

*Kondo 2018

*Marchenko2020

American American American Netherlands Croatia American Japan American

The results of the quality evaluation of eight studies are shown in Table 1. According to the NOS scale, seven studies [22,26-30] were of high quality, scoring 6-8 points, and one study [25] was of low quality,

Study

Image of Fig. 2

Fig. 2. Forest plot for the meta-analysis of incidence of hypochloremia in AHF patients.

scoring 5 points. It indicates that the overall quality of the included stud- ies was high (Table 1).

    1. Meta-analysis results
      1. The incidence of hypochloremia in AHF patients

Five studies [25,27-30] reported the incidence of hypochloremia in AHF patients at admission, and there was significant heterogeneity be- tween the studies (I2 = 95% > 50%). Therefore, a random effect model was used for meta-analysis. The results showed that the incidence of hypochloremia was 17% (95% CI: 0.11-0.22). We conducted subgroup analysis according to different regions, and we found that the incidence of hypochloremia in the different regions ranged from 13% to 21%: North America (21%, 95% CI: -0.01-0.43), Europe (14%, 95% CI:

0.13-0.16), and Asia (13%, 95%CI: 0.08-0.17). However, the incidence of hypochloremia in different regions was not statistically significant (P = 0.62> 0.05) (Fig. 2).

      1. All-cause death of AHF patients with one unit reduction in chloride ion

Five studies [22,25,26,29] reported that there was no significant het- erogeneity (I2 = 0% < 50%) among studies in the risk of all-cause death of AHF patients with one unit reduction of chloride ion at admission, so the fixed effect model was used for meta-analysis. The results showed that the risk of all-cause death in AHF patients increased by 6% (HR = 1.06, 95% CI: 1.04-1.08, P < 0.00001) (Fig. 3) with one mmol /L reduc- tion of chloride ion.

      1. Composite endpoint of AHF patients with one unit reduction of chloride ion

Two studies [25,26] reported the risk of Composite end point with reduction in one unit of chloride ion in patients with AHF at admission. No significant heterogeneity between studies (I2 = 19% < 50%), so the fixed effect model was used for meta-analysis. The results showed that the risk of composite end point in AHF patients increased with one mmol /L reduction in chloride ion, but there was no statistical significance (HR = 1.04, 95% CI: 0.99-1.09, P = 0.14) (Fig. 4).

      1. All-cause death of hospitalized patients with hypochloremia and AHF Three studies [28-30] reported the incidence of all-cause death of AHF patients with hypochlorism at admission, and there was no signif- icant heterogeneity among the studies (I2 = 0% < 50%), so the fixed effect model was used for meta-analysis. The results showed that the risk of all-cause death in the hypochloremia group was 1.71 times that in the non-hypochloremia group (RR = 1.71, 95% CI: 1.45-2.02,

P < 0.00001)(Fig. 5).

      1. All-cause mortality in patients with progressive hypochloremia and AHF

Two studies [27,29] reported the occurrence of all-cause death in AHF patients with progressive hypochloremia(development of hypochloremia after admission), and there was no significant heteroge- neity between the studies (I2 = 0% < 50%), so the fixed effect model was used for meta-analysis. The results showed that the risk of all-cause death in patients with progressive hypochloremia was 2.24 times that

Image of Fig. 3

Fig. 3. Forest plot for the meta-analysis of all-cause death of AHF patients with one unit reduction in chloride ion.

Image of Fig. 4

Fig. 4. Forest plot for the meta-analysis of composite endpoint of AHF patients with one unit reduction in chloride ion.

Image of Fig. 5

Fig. 5. Forest plot for the meta-analysis of all-cause death of hospitalized patients with hypochloremia.

Image of Fig. 6

Fig. 6. Forest plot for the meta-analysis of all-cause mortality in patients with progressive hypochloremia.

in patients with non-hypochloremia (HR = 2.24, 95% CI: 1.72-2.92,

P < 0.00001)(Fig. 6).

      1. Persistent hypochloremia and all-cause death of AHF patients

Two studies [27,29] reported the occurrence of all-cause death in AHF patients with persistent hypochloremia(hypochloremia both on admission and at discharge), and there was no significant heterogeneity between the studies (I2 = 0% < 50%), so the fixed effect model was used for meta-analysis. The results showed that the risk of all-cause death in patients with persistent hypochloremia was 2.80 times that in patients with non-hypochloremia (HR = 2.80, 95% CI: 2.10-3.72, P < 0.00001)

(Fig. 7).

    1. Publication bias analysis

In this study, publication bias of all cause death was evaluated by funnel chart. Results All the studies were concentrated and distributed in the “funnel”, symmetrically distributed on both sides of the axis, which showed that the overall publication bias was small(Fig. 8).

  1. Discussion

We evaluated the incidence of hypochloremia in AHF patients and the impact of chloride ion on the prognosis of AHF patients from all- cause death, composite endpoint (all-cause death or HF hospitaliza- tion). This study found that: (1)The incidence of hypochloremia in AHF patients was 17%, and there was no significant difference among North America, Europe and Asia; (2)The decrease of chloride ion at ad- mission is associated with poor prognosis of AHF patients, but it has no statistical significance for composite endpoint. (3)The risk of all- cause death in AHF patients and persistent hypochloremia is higher than that in patients with progressive hypochloremia and hospitalized hypochloremia.

Chloride ion is the main anion in plasma and extracellular fluid, ac- counting for two thirds of all negative charges in plasma [15]. It plays an important role in maintaining plasma osmotic pressure, regulating body fluid, acid-base balance and renin secretion [15,31,32]. The main source of chloride ion is from the intake of dietary sodium chloride and the excretion of chloride ion is mainly through the kidney. The

Image of Fig. 7

Fig. 7. Forest plot for the meta-analysis of all-cause death in patients with persistent hypochloremia.

Image of Fig. 8

Fig. 8. Funnel plot.

concentration of chloride ion in urine is regulated by the chloride ion fil- tered by the glomerulus and the balance of reabsorption and secretion of nephron, usually ranging from 110 to 250 mmol/L [15,33]. In the gen- eral population, the amount of chloride ion excreted through urine is roughly equal to the intake [33]. HF patients often have hypochloremia. The article shows that the incidence of hypochloremia in AHF is 17%. We consider the following three reasons: first, the activation of neurohu- moral mechanisms in AHF patients regulates the level of chloride ion, for example, the increase of arginine vasopressin secretion makes the reab- sorption of free water, leading to dilution hypochloremia; Second, patients with AHF often use Loop diuretics or Thiazide diuretics to inhibit the reabsorption of chloride ion, leading to consumptive hypochloremia; Third, AHF patients are often accompanied by gastrointestinal congestion, resulting in reduced intake and absorption of chloride ion resulting in hypochloremia [33].

Our study shows that the decrease of chloride ion at admission is as- sociated with poor prognosis of AHF patients, but it has no statistical significance for composite endpoint. However, because we have included fewer studies, it needs to be further verified by a large prospec- tive cohort study. The mechanism of the effect of chloride ion on HF is still unclear. In 2017, Kataoka put forward the “chloride theory” based on his own observations and others’ research, and believed that the changes in plasma volumn, vasopressin secretion and renin- angiotensin-aldosterone system (RAAS) during the deterioration of HF were mainly mediated by serum chloride ion [34]. Previous studies based on rat models have shown that chlorine in renal tubules can affect the release of renin [35]. Hanberg et al. showed that the renin level in HF patients with hypochloremia was higher [36]. Hypochloremia can lead to the decrease of chloride concentration in the macular densa. The macula densa can sense a decrease in chloride concentration, which causes an increased release of renin from the granular cells of the paraglomerular organs, thus increasing the reabsorption of renal tu- bules, aggravating the fluid retention, and further worsening the HF. In addition, the dosage of loop diuretics in HF patients with

hypochloremia increased significantly [37]. Considering that serine- threonine kinase (WNK kinase) is the main target for regulating the Na+-K+-2Cl cotransporter in the thick segment of the ascending branch of the loop and the Na+-Cl symporter in the distal tubule, the reduction of serum chloride ion activates WNK to produce cascade reactions. It increases the activity of the Na+-K+-2Cl cotransporter in the thick segment of the ascending branch of the loop and the Na+-Cl symporter in the distal convoluted tubule, promotes the reabsorption of chloride ion, thus weakening the inhibition of loop diuretics and thiazide diuretics [38], reducing the efficiency of diuretics, allowing clinicians to further increase the dosage of diuretics, further reducing chloride ions, and forming a vicious circle. Testani et al. [39] showed that diuretic resistance was associated with poor prognosis of HF. The decrease of chloride ion can also cause the acid-base imbalance of cardiomyocytes, which has been proved to be an arrhythmogenic fac- tor [40]. In a word, the activation of neurohormones, diuretic resistance and acid-base imbalance are the reasons for the poor prognosis of AHF patients with hypochloremia, but the specific mechanisms need to be further studied.

Our study confirmed that the decrease of chloride ion is associated with poor prognosis of HF, and the prognosis of persistent hypo- chloremia is worse, but chloride ion is an indicator that can be intervened. A study published in 2018 showed that the prognosis of AHF patients with improved serum chloride ion at discharge was signif- icantly better than that of patients with persistent and progressive hypochloremia during hospitalization [27]. However, there is no consensus on the critical value of hypochloremia at present, and hypochloremia is generally defined as<96 mmol/L. A number of studies have shown a U-shaped relationship between chloride concentration and poor prognosis of HF [40,41]. In the study of Cubbert et al. [40], the concentration of chloride ion is 106-108 mmol/L. After one year of follow-up, it was found that chloride ion was associated with HF sudden death. Therefore, this problem should be considered to correct hypochloremia and avoid excessive chloride ion.

At present, some studies have explored the treatment of hypochloremia. In a small-scale study of lysine chloride supplementa- tion in patients with HF (n = 10) was associated with an increase in serum Chloride levels of 2.2 +- 2.3 mmol/L and the majority of partici- pants experienced weight loss and reduction in NT-proBNP [36]. Acetazolamide is another method to increase serum chloride ion. It can increase serum chloride ion level by inhibiting Carbonic anhydrase activity in proximal convoluted tubules, and promoting chloride ion re- absorption by reducing the secretion of hydrogen ion and the formation of HCO3- [42]. In a clinical observation of 30 patients with HF who were treated with low-dose acetazolamide, it was found that its effect of in- creasing serum chloride ion occurred within 10 days and lasted at least 60 days [42]. Recent studies have found that sodium glucose cotransporter 2 inhibitor (SGLT2i) also has a certain role in increasing the serum chloride concentration. When Kataoka et al. [43] explored the effect of SGLT2i on the chloride concentration of Diabetic patients without HF, they found that the serum chloride concentration increased from 104 +- 3.23 to 106 +- 2.80 mEq/L, but the concentrations of sodium and potassium did not change. Therefore, SGLT2i is expected to be used in HF patients with hypochloremia, but there is no research in HF pa- tients at present. It is hoped that future research can be conducted in HF patients to determine the impact of SGLT2i on chloride ions in HF pa- tients. Tovaptan may have some effect on correcting hypochloremia. Tovaptan is a selective vasopressin V2 receptor antagonist, which can improve the clearance of free water and urine excretion, reduce the osmotic pressure of urine, and promote the increase of serum chloride concentration [44]. However, there is no relevant research at present, so further exploration is needed in the future. For the treatment of hypochloremia, further research on the treatment of hypochloremia and the optimal chloride ion range is needed in the future.

  1. Limitations

This meta-analysis provides evidence that the reduction of serum chloride concentration is associated with poor prognosis of HF, but it still has the following limitations: (1) The follow-up time varies from 30 days to 2 years, which may affect the comparison of outcome indica- tors, and may be one of the reasons for heterogeneity; (2) The included studies are mainly retrospective studies, which need to be further veri- fied by a large number of prospective studies in the future; (3) The different standards of hypochloremia may be one of the main reasons for the formation of heterogeneity; (4) Some outcome indicators(pro- gressive hypochloremia, persistent hypochloremia, and composite of death + HF hospitalization)are as few as 2 studies in the literature, and the results should be interpreted carefully.

  1. Conclusion

The decrease of chloride ion at admission is associated with poor prog- nosis of AHF patients, and the prognosis of persistent hypochloremia is worse. There is insufficient research on the treatment of hypochloremia. In the future, more prospective studies are needed to evaluate whether the intervention of serum chloride level can improve the prognosis of AHF.

Funding

The project number of Shaanxi Natural Science Foundation is 2022JQ-891.

Author contributions statement

WFC and LQS conceived the research and set standards; WFC and LQS performed the research; WFC and LQS performed the statistical analysis; WFC and LQS wrote the manuscript; YL provided professional knowledge of treatment and made a final revision of the manuscript; all

authors read and approved the final manuscript. WFC and LQS are the

first authors of this paper.

CRediT authorship contribution statement

Fengchao Wu: Writing – review & editing, Writing – original draft, Software, Resources, Methodology, Formal analysis, Data curation, Conceptualization. Qingsu Lan: Writing – review & editing. Li Yan: Writing – review & editing, Supervision.

Declaration of Competing Interest

The authors declared that they have no conflicts of interest to this work.We declare that we do not have any commercial or associative in- terest that represents a conflict of interest in connection with the work submitted.

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