Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Often, CAD is complicated with heart failure (HF), hypertension, and chronic kidney disease (CKD) (1, 2), and the mortality of patients with CAD is increased markedly if they also have HF (3). Congestive heart failure (CHF) describes an inadequacy of the pumping function of the heart (4), which is tightly linked to CAD (5).

Li and colleagues indicated that hypochloremia is associated with an increased risk of all-cause mortality (ACM) among patients in the Cardiac Care Unit (those with severe CAD) (6). Several studies have shown that hypochloremia is independently associated with mortality among patients with cardiovascular disease, especially those with acute HF or CHF even after taking the use of diuretics into account (7–10). Often, patients with CHF and CAD have electrolyte disorders, such as hypochloremia, which may be related to diuretic use, insufficient intake of fluids, or a complex association between diseases.

However, it is not clear if the same connection exists among CAD patients complicated with CHF after full consideration of diuretic use. The loss of gastrointestinal digestive juices, derangement of secretion of adrenal hormones, the inflammatory response, and the critical role of chloride ions (Cl⁻) in several regulatory pathways central to HF have been postulated (11–14).

In this context, we aimed to assess the prevalence and mortality (short- and long-term) of hypochloremia among CAD patients with CHF.

Our study is the first systematic exploration of the prevalence and mortality of hypochloremia among CAD patients with CHF in two databases. Our study indicated that ~10% of CAD patients with CHF were complicated with hypochloremia in the CIN-I database and ~20% in the relatively high-risk MIMIC-III database. Among those patients, hypochloremia was independently associated with higher short- and long-term ACM. The impact of hypochloremia was consistent and independent of the presence of AMI or use of diuretics. In addition, the association of hypochloremia with long-term ACM was attenuated slightly in the women of the two databases.

Epidemiological data have demonstrated that HF is a global disease (20). The most common reason for HF is CAD (21). Physicians need to use indices to evaluate the outcome among CAD patients with CHF. Chloride is the most plentiful anion in the extracellular fluid (12). Some studies have suggested that regulation of renin secretion from the macula densa in the kidneys may be reliant on Cl⁻ (22). The latter is crucial in acid–base balance, muscle activity, and immune regulation (23). Non-potassium-sparing diuretics are used widely (particularly among patients with HF). These agents primarily inhibit the Na⁺-potassium ion–Cl⁻ cotransporter, which leads inevitably to the excessive wastage of Cl⁻. The prognostic value of Cl⁻ on HF was reported by Grodin and colleagues, who stated that hypochloremia upon hospital admission was associated with poor long-term survival (8). Li et al. studied the relationship of Cl⁻ and short-term mortality in all CCU patients who have complex conditions and many confounding factors (6). However, evidence of the prognostic value of Cl⁻ for CAD patients with CHF is lacking. We revealed that the Cl⁻ concentration is an independent factor of short- and long-term mortality for CAD patients with CHF in two databases.

The exact mechanisms underlying the relationship between hypochloremia and CAD with CHF are not known, but three hypotheses have been proposed. First, the reason why hypochloremia is associated with short- and long-term mortality is that a low concentration of Cl⁻ might upregulate the expression of proinflammatory cytokines. This action may accelerate inflammation (24), which is a well-known predictor of poor outcomes and mortality for CAD (25–27) and HF (28). Second, Cl⁻ has a critical role in regulatory pathways central to physiological stability. For example, a low concentration of Cl⁻ means a high anion gap and high renin level (29–31), which is related to higher blood pressure (32) and stimulates HF directly (33). Additionally, several Cl⁻ channels with important regulatory functions have been identified or characterized further recently (23, 34). Third, according to our results, hypochloremia could be considered a marker of clinical complexity because hypochloremia is observed more often in older patients with DM, CKD, or AMI, which eventually leads to a significantly increased mortality risk (35–39).

In addition, a study had reported that hypochloremia results in hyponatremia and that they are significantly associated with each other and increased mortality risk (9). The increase in the prevalence of hyponatremia reported in that study was consistent with our findings, but we did not find that hyponatremia affected death. This may have been because our study population had CHD with CHF. Furthermore, long-term ACM was attenuated slightly in the women of the two databases. However, it seems that this phenomenon is not reported previously. More randomized controlled trials and basic research are needed to validate these phenomena.

Two databases were selected for our study. There were certain differences between the two databases. A higher prevalence of hypochloremia and mortality was observed in the relatively high-risk MIMIC-III database, which was in line with clinical concepts. The same connection exists even in relatively high-risk groups, which indicates that our conclusion was applicable to a wider range of people. Interestingly, in the MIMIC database, hypochloremia seemed to have a more substantial effect on long-term ACM than short-term ACM.

Our study had three main limitations. First, our population was from two single-center retrospective cohort studies with a selection bias. However, the MIMIC-III database has been used widely and shown to be of high quality. In addition, we added a large sample database from China. Therefore, our study included sufficient samples to make it representative. Second, information on cause-specific death was not presented here, and it was difficult to examine a significant correlation between hypochloremia and cause-specific death. ACM is an important endpoint that clinicians concentrate upon commonly. Third, Cl⁻ levels were extracted only upon hospital admission without assessment of their changes after hospital discharge.

Our results suggested that hypochloremia could be a risk-assessment tool for primary-care clinicians. The serum Cl⁻ level may represent a therapeutic target rather than being a marker of disease severity. Early adequate assessment of hypochloremia and active supplementation with Cl⁻ (such as oral and intravenous supplements of concentrated sodium chloride) may help to improve the prognosis of patients with CAD and CHF. Hence, evaluation of the mechanism of the association between hypochloremia and mortality in CAD patients with CHF, and whether the mortality risk decreases after treating hypochloremia, merit investigation. Also, more emphasis should be laid on female patients suffering from CAD with CHF. Large-scale multi-center prospective studies are needed to verify our conclusions.

The original contributions presented in the study are included in the article/Supplementary Materials, further inquiries can be directed to the corresponding authors.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

YLiu, NT, DH, and JC designed the study, reviewed, interpreted, and checked clinical data. YLia, CC, JL, and XH collected and reviewed clinical and laboratory data. SC, HH, LQ, QL, and WL analyzed data. SC, HH, YLiu, LQ, and BW performed the statistical analysis. JL, HH, YLiu, KB, QL, and JLL drafting or revising of the manuscript. All authors contributed to the article and approved the submitted version.

This research was funded and supported by the Beijing Lisheng Cardiovascular Health Foundation Pilot Fund (No. LHJJ20141751); The National Science Foundation of China (No. 81970311 and No. 82070360); Study on the function and mechanism of the potential target for early warning of cardiorenal syndrome after acute myocardial infarction based on transformism (DFJH201919); Clinical Medicine Research Fund of Guangdong Province (2019ZX01)

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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