Heart failure (HF) is defined as a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality that is confirmed by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion [1]. It is estimated that 64.3 million people worldwide suffered from HF in 2017 [2]. A survey based on medical insurance data from 0.5 billion Chinese urban workers found that the nationally standardized prevalence of HF among people aged 25 years and older in China was 1.1%, with an incidence rate of 275/100,000 person-years. Moreover, the survey estimated that there were 12.05 million existing HF patients and 2.97 million new cases of HF each year. In China, HF patients face alarmingly high rates of mortality and hospital readmission, creating a substantial public health burden that strains healthcare resources and impacts both the quality of life of patients and the national healthcare system. The growing prevalence of HF, particularly among the aging population, has made this condition a critical challenge for healthcare policymakers in China, requiring urgent interventions to improve disease management, optimize treatment protocols, and enhance post-discharge care coordination to reduce the socioeconomic impact on families and the healthcare system [3]. The European Society of Cardiology (ESC) classifies HF into three distinct subtypes according to left ventricular ejection fraction (LVEF), namely, HF with reduced ejection fraction (HFrEF, LVEF $\le$40%), mildly reduced ejection fraction (HFmrEF, LVEF 41–49%), and preserved ejection fraction (HFpEF, LVEF $\ge$50%) [1].

Electrolyte derangements are frequently present in patients with HF. Meanwhile, serum chloride has been recognized as a critical anion with significant implications for understanding the pathophysiological mechanisms of HF. Research indicates that serum chloride plays a pivotal role in maintaining the acid–base balance, modulating neurohormonal activation, and influencing diuretic resistance [4, 5, 6, 7]. Notably, studies have demonstrated that low serum chloride levels are independently associated with adverse clinical outcomes, including increased mortality and hospitalization rates, in HF patients. These findings underscore the potential of serum chloride as both a prognostic biomarker and a therapeutic target in HF management. Although chlorine as a therapeutic target seems reasonable in terms of mechanism, key knowledge gaps remain, and further research is needed to elucidate potential mechanisms and explore chlorine-guided treatment strategies [8, 9, 10, 11, 12, 13, 14].

Malnutrition refers to insufficiencies, surpluses, or imbalances in the intake of energy or nutrients by an individual [15]. Malnutrition is frequently observed in HF patients due to multiple contributing factors, including anorexia, impaired intestinal absorption from gut mucosal edema, systemic inflammation, and the catabolic state induced by HF. These pathological processes collectively drive a progressive nutritional deficit that further exacerbates disease progression and worsens clinical outcomes. This underscores the critical need for comprehensive dietary assessment and targeted interventions in HF management protocols [16]. Serum albumin concentration and body mass index (BMI) values are well-established, clinically accessible markers of nutritional status that have demonstrated strong prognostic value in HF populations. These biomarkers may reflect nutritional depletion and potential disease severity in patients with HF. Meanwhile, these findings emphasize the importance of incorporating routine nutritional assessments into a comprehensive HF risk stratification program [17, 18, 19, 20]. The advanced lung cancer inflammation index (ALI), calculated as BMI $\times$ serum albumin/neutrophil-to-lymphocyte ratio (NLR), was originally developed as an integrated biomarker to assess systemic inflammation in oncology patients [21]. Emerging evidence has also demonstrated the significant prognostic utility of this index in HF populations. The ALI may reflect the levels of malnutrition and inflammation in patients with HF. Moreover, the ALI has a significantly higher prognostic stratification ability than single-component indicators, as it synchronously evaluates the multidimensional characteristics of malnutrition and systemic inflammation status. This synergistic effect makes the ALI an ideal tool for identifying high-risk HF patients, providing more reliable risk predictions [22, 23].

Both serum chloride levels and the ALI score have been established as independent prognostic factors in HF patients; however, their potential interaction and combined predictive value for all-cause mortality risk remain poorly understood. Thus, further investigations are needed to determine whether these markers have additive or synergistic effects in risk stratification, which could enhance prognostic accuracy and guide personalized therapeutic strategies for HF management. Further, this study hypothesized a risk interaction between serum chloride levels and the ALI score, proposing that patients with concurrently lower ALI scores and reduced serum chloride levels would exhibit poorer outcomes. Therefore, this study aimed to investigate the predictive value of combining the ALI score and serum chloride levels for all-cause mortality in HF patients.

This study evaluated the association between the admission ALI score and prognostic outcomes in patients with ADHF. We found that the risk of all-cause mortality was higher in patients in the lowest ALI quartile group compared to the higher ALI quartile groups and that the combination of the ALI score and serum chloride levels contributed to risk stratification. To our knowledge, this represents the first investigation to integrate the inflammatory–nutritional spectrum captured by the ALI with pathophysiological pathways for chloride in mortality risk stratification for ADHF. This synergistic approach addresses both metabolic derangements and systemic inflammation simultaneously. Our results demonstrate that this novel biomarker combination provides superior risk stratification compared to either marker alone, addressing critical gaps in existing prognostic models.

The ALI is a simple, reproducible, and cost-effective prognostic tool used to evaluate new prognostic indicators for diseases such as cancer. The ALI integrates three commonly measured clinical parameters: NLR, BMI, and serum albumin, all of which are associated with poor prognosis and may reflect malnutrition and inflammation levels in HF patients. Prior studies have established the independent prognostic value of the ALI in HF, including the demonstration by Maeda et al. [23] of its association with mortality and readmission in ADHF and the application by Kurkiewicz et al. [24] for risk stratification in advanced HF.

Patients with HF are frequently malnourished due to gastrointestinal oedema, anorexia leading to reduced nutrient intake or inadequate absorption, inflammatory cytokine-induced hypercatabolic syndrome, abnormal liver function due to hepatic congestion, and insulin resistance [25, 26, 27]. The BMI is a predictor of poor prognosis in HF patients, and it is easy to measure BMI clinically; however, it is not an ideal indicator of the nutritional status of patients with HF since these patients usually suffer from water and sodium retention, which leads to short-term changes in body weight; therefore, the BMI is unable to differentiate between weight due to excess fluids and fat. In patients with HF, low BMI is associated with poor prognosis, a phenomenon known as the “obesity paradox” [28, 29]. In our study, patients with HF in the low ALI quartile (Group 1: 22.17 $\pm$ 3.18 kg/m²) had a lower BMI than those in the other two groups (Group 2: 22.92 $\pm$ 3.95 kg/m²; Group 3: 23.98 $\pm$ 4.13 kg/m²; p 0.0001). Hepatic congestion reduces albumin synthesis and lipid transport and synthesis, leading to metabolic disorders [30]. In our study, we found that serum albumin levels were lower in the low ALI quartile group than in the other two groups (p 0.0001). In contrast, the causes of reduced albumin synthesis in the liver include malnutrition, inflammation, and liver dysfunction due to congestion and hypoperfusion [18, 31]. Inflammation also plays a pivotal role in the pathogenesis and progression of HF. NLR, a well-established marker of systemic inflammation, is associated with adverse clinical outcomes in HF patients [32, 33]. The proinflammatory environment in HF accelerates the catabolic process, leading to hypoalbuminemia due to protein breakdown, and induces insulin resistance, anorexia, and impaired nutrient absorption, collectively driving weight loss and cardiac cachexia [34]. Given the multifactorial nature of HF progression, reliance on a single inflammatory marker may provide an incomplete risk assessment. The ALI score is calculated as BMI $\times$ serum albumin level/NLR, and a comprehensive evaluation combining these parameters provides an improved prediction of long-term prognosis in patients.

This study demonstrated that the combination of the ALI score and serum chloride levels was valuable for risk stratification in HF patients. Our findings showed that lower chloride levels upon admission were associated with an elevated mortality risk and provided substantial insights into the interpretation of electrolyte disturbance in ADHF. To commence with, our multivariate analyses revealed that serum chloride levels were independently and inversely correlated with mortality, even after adjusting for other prognostic determinants. Secondly, a significant association was observed between serum sodium levels and serum chloride levels (r = 0.577; p 0.0001) (Table 4). Notably, our study found no significant correlation between serum sodium levels and mortality when serum chloride levels were added to the multivariate model (Table 2). These outcomes emphasize the prognostic significance of serum chloride levels in ADHF, suggesting that serum chloride levels provide more robust prognostic evidence than serum sodium levels. These findings also reveal that serum chloride levels may provide important prognostic information for patients with ADHF, highlighting the need for a better understanding of the potential benefits of strategies that can maintain electrolyte homeostasis, particularly long-term diuretic strategies. Low serum chloride levels are a commonly presented electrolyte disturbance in HF patients. The main contributing factors to decreased serum chloride levels are related to the loss of chloride anions in the gastrointestinal tract or kidneys. The chloride absorption in patients with HF may be compromised due to visceral circulation congestion and ensuing intestinal wall edema and barrier dysfunction [35]. In addition, chloride plays a vital role in fluid homeostasis, neurohormonal activation, and diuretic resistance [4], which are commonly acknowledged as key factors in the genesis and progression of HF. Chloride serves as the principal regulator of renin release and tubuloglomerular feedback within the kidneys, while also playing a central role in modulating sodium transport mechanisms in both the thick ascending limb of the loop of Henle and the distal convoluted tubule. A reduction in serum chloride levels stimulates renin secretion and enhances the activity of the sodium–potassium–chloride cotransporter in the thick ascending limb, as well as the thiazide-sensitive sodium–chloride symporter in the distal tubule. Consequently, low serum chloride concentrations may disrupt regulatory pathways essential for efficient renal excretion of sodium and water. Furthermore, hypochloremia is strongly associated with neurohormonal activation and diuretic resistance, which collectively impair fluid clearance in patients with HF.

Therefore, patients with diminished ALI scores and low serum chloride levels are likely to require nutritional supplementation, adjunctive pharmacotherapy, and meticulous follow-up. Electrolyte derangements and malnutrition should be considered as a crucial therapeutic focus in patients with HF. While evaluating the nutritional status of HF patients, emphasis should also be placed on the treatment modalities for those with abnormal serum chloride levels. Pharmacological intervention should be applied to recover digestive and absorptive functions, particularly in patients with gastrointestinal congestion, which may afford an opportunity to ameliorate the prognosis of HF patients and could potentially have a favorable impact on the long-term prognosis.

Firstly, this study was a single-center, retrospective, and observational study. Hence, there may be some unmeasured variables that could potentially impact the interpretation of the research results. Secondly, this study mainly focuses on patients with a NYHA classification III or IV, moderate and severe HF. Therefore, these findings might not be applicable to a cohort with mild or moderate HF symptoms. Thirdly, we only collected data about the ALI score and serum chloride concentrations upon admission. Consequently, we were unable to examine the relationship between the dynamic changes of these two variables and the prognosis. Fourthly, notwithstanding that several covariates were taken into consideration within the regression model, it remains likely that some confounding variables are either unknown or inaccessible. Finally, we used all-cause mortality as an endpoint and did not follow up on other major cardiovascular adverse events. Prospective studies with more detailed cardiovascular endpoints could be designed in the future.

This study suggests that low ALI scores and low serum chloride levels are independent predictors of all-cause mortality in patients with ADHF. It is worth noting that the prognostic evaluation value of the combination of the two factors is significantly better than that of a single biomarker. Thus, the risk stratification of ADHF patients can be optimized by jointly evaluating the ALI and serum chloride levels, which helps to identify high-risk populations that require enhanced anti-inflammatory treatment and metabolic support in the early stages, ultimately improving patient prognosis.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

WYG: investigation, data collection and analysis, writing - original draft, writing - review & editing. FZY and ZJL: data analysis, data curation, investigation. DX, YS, AYX, XNM and YJP: data collection, software, investigation. LXC, WYG and FZY: investigation, writing - review & editing, methodology, project administration. All authors contributed to the editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This is an observational study. The study protocol was approved by the Medical Ethics Committee of the First Affiliated Hospital of Kunming Medical University and was in line with the guidelines of the World Medical Association Declaration of Helsinki. All patients gave written informed consent for their data to be electronically stored and used for research. The ethics number of the study was (2022) Ethics L No.173.

This study was supported by the Applied Basic Research Program of the Science and Technology Hall of Yunnan Province and Kunming Medical University (Project No.202301AY070001-130), the Yunnan health training project of high level talents (H2019052).

The authors declare no conflict of interest.