Acute decompensated heart failure (ADHF) refers to the abrupt deterioration of cardiac function, which may occur de novo or as a worsening of pre-existing chronic heart failure due to various underlying etiologies. Pathologically, it is characterized by volume overload and hemodynamic derangement, while clinically, it manifests with symptoms such as acute dyspnea, peripheral edema, and fatigue (1–4). Despite recent advancements in ADHF management, such as the utilization of mechanical circulatory support devices, heart transplantation, and the development of novel pharmacological agents, overall improvements in clinical outcomes remain modest (5, 6). Studies have shown that approximately 25% of ADHF patients are readmitted within 30 days after discharge, and the 30-day mortality rate approaches 10% (1, 7, 8). This imposes a significant economic and healthcare burden on patients, their families, and society. More critically, low- and middle-income countries face an even greater disease burden due to uneven regional distribution of healthcare resources (9). Therefore, early risk stratification using accessible and effective biomarkers may help improve short-term clinical outcomes in hospitalized patients with ADHF.

The pathophysiological manifestations of ADHF are pleiotropic, primarily influenced by multiple factors such as the type of cardiac dysfunction, extent of ventricular involvement, vascular tone regulation, neurohormonal/inflammatory activation status, and comorbid conditions (10). These factors also constitute key targets for assessment and monitoring in the clinical management of ADHF (6, 10). Investigations into ADHF pathophysiological progression reveal intimate linkages with dysregulated activation of the neurohormonal system and inflammatory pathways (11–13). Notably, elevated inflammatory marker levels in ADHF patients often precede elevations in neurohormonal biomarkers like N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) (14). This temporal pattern implies inflammation may act as an initial trigger for decompensation. To date, substantial clinical evidence has been collected confirming the involvement of inflammation in the pathogenesis and progression of ADHF (12, 13, 15). Additionally, various inflammatory biomarkers (including neutrophil, monocyte, and lymphocyte counts) have been investigated for their potential utility as diagnostic and prognostic indicators in ADHF (13, 15, 16). However, predictive models relying solely on blood cell counts have consistently shown limited prognostic value (13, 15–17). The Aggregate Index of Systemic Inflammation (AISI), a novel inflammatory marker developed recently using hematological parameters, provides a composite assessment of systemic inflammatory status through integration of neutrophil, monocyte, platelet (PLT), and lymphocyte counts (18). Accumulating evidence supports the clinical utility of AISI for risk stratification and prognosis prediction across multiple disease categories, including metabolic disorders (19–22), immune-mediated diseases (23–25), critical care scenarios (17, 26, 27), and psychiatric illnesses (28, 29), and its clinical utility generally surpasses that of traditional inflammatory markers. Additionally, the application of the AISI in cardiovascular diseases (CVD) has attracted growing attention. Emerging evidence indicates that elevated AISI levels are associated with an increased risk of various CVDs, including HF (30–34), and may serve as a predictor of poor prognosis in patients with hypertension and acute myocardial infarction (35, 36). However, the prognostic significance of the AISI in HF patients remains unclear. To address this gap, the present study aimed to investigate the association between AISI and 30-day mortality in ADHF patients, using data from the Jiangxi-ADHF II (JX-ADHF II) cohort.

The evaluation of novel inflammatory indices is essential for early risk stratification in ADHF. To the best of our knowledge, this study is the first to investigate the association between AISI and prognosis in ADHF among Chinese patients. Our findings demonstrate that both extremely low and elevated level of AISI are significantly associated with adverse outcomes in ADHF, exhibiting a U-shaped, curvilinear relationship. Furthermore, compared with traditional inflammatory markers, AISI showed superior predictive performance for short-term prognosis in ADHF patients and offered additional incremental predictive value when integrated with NT-proBNP or LVEF models for mortality assessment. These findings suggest that AISI may serve as a useful prognostic marker for early risk stratification in the management of ADHF.

ADHF refers to a clinical syndrome characterized by either rapid deterioration of cardiac function in patients with pre-existing chronic HF or de novo onset of cardiac dysfunction, typically precipitated by identifiable triggers. It manifests with severe symptoms and signs that require urgent medical intervention. The pathophysiological core of ADHF involves an abrupt decline in cardiac pumping capacity over a short period, during which compensatory mechanisms fail to sustain adequate circulatory function, leading to fluid retention and impaired tissue perfusion (1–3). Although the exact pathogenesis of ADHF has not been fully elucidated (10), current evidence indicates a strong association between ADHF onset and significant upregulation of inflammatory pathways (11–13). Notably, these inflammatory processes have been demonstrated to exacerbate disease progression in ADHF (10, 40, 41). During ADHF exacerbation, circulating levels of various pro-inflammatory cytokines and mediators are markedly elevated, contributing to further disease progression. This notion is supported by accumulating clinical evidence, which underscores the significant prognostic value of early inflammatory biomarker detection in predicting adverse outcomes associated with ADHF (42–45). Notably, dynamic changes in inflammatory markers often precede alterations in conventional biomarkers such as NT-proBNP (14), suggesting that early inflammatory monitoring may not only enhance prognostic stratification but also provide a critical window for timely clinical intervention.

As an emerging tool for systemic inflammation assessment, the AISI has gained significant research attention in recent years by integrating multi-dimensional inflammatory parameters. Furthermore, growing evidence-based medical research highlights its unique advantages in risk stratification and prognostic evaluation across diverse disease contexts spanning multiple disciplines, offering a novel biomarker option for clinical decision-making (19–29). Given the involvement of inflammatory mechanisms in the pathogenesis of multiple CVDs, the potential applications of AISI in this field have generated considerable research enthusiasm (30–36). Emerging evidence indicates a strong association between this biomarker and both CVD risk and prognostic outcomes. To date, multiple international studies have reported associations between AISI and HF (30, 46). Furthermore, growing evidence supports the critical prognostic value of AISI in the management of CVDs (35, 36). In the current study, we evaluated the association between AISI and 30-day mortality outcomes among ADHF patients in Jiangxi, China. Our analysis revealed that ADHF patients in the highest AISI quartile (Q4) had a 3.1-fold increased risk of all-cause death within 30 days compared to those in the lowest quartile (Q1). Building upon previous research on HF risk assessment (30, 46), the present study provides further evidence supporting the prognostic utility of AISI in HF patients. Compared to its application in assessing HF incidence risk, AISI appears to offer more substantial predictive value for HF prognosis. Moreover, these results expand the clinical applications of AISI in CVD prognosis assessment. In light of existing evidence demonstrating the prognostic value of AISI in patients with hypertension and acute myocardial infarction (35, 36), our findings suggest that AISI may be particularly well-suited for short-term risk assessment in CVD management.

Our findings highlighted that the association between AISI and 30-day mortality in ADHF patients may be nonlinear. Notably, we observed a U-shaped relationship between AISI and 30-day mortality in this population: both extremely low and excessively high AISI levels act as risk factors for elevated 30-day mortality. Similar nonlinear associations have been reported in several recent AISI-related studies (19, 24, 29, 31), several of which specifically evaluated the inflection point for LnAISI-clinical outcome associations: Yin et al. identified a special “U-shaped” association between LnAISI and RA risk, calculating a curve inflection point at 5.70, while Huang et al. calculated an inflection point of 5.20 for the LnAISI-CKD association (19, 24). In the current study, a recursive algorithm was applied to identify the inflection points in the association between the LnAISI and 30-day mortality among ADHF patients, revealing a threshold at 5.06. Below this value, LnAISI was inversely associated with mortality, whereas a positive association was observed above 5.06. This threshold demonstrates remarkable consistency with previous reports by Yin et al. and Huang et al. (19, 24), collectively indicating that maintaining LnAISI values within the 5.0–6.0 range may facilitate risk control for both disease severity and adverse prognosis. The association between elevated AISI levels and increased mortality risk is readily understandable, primarily attributable to direct inflammatory storm-mediated damage. Regarding the increased mortality observed at low AISI levels, we postulate that it may be attributed to mechanisms including lymphocyte depletion, immunosuppression, advanced cachexia, and iatrogenic factors: (i) While low AISI may indicate a relative predominance of lymphocytes, however, in advanced HF this could signify an “immune exhaustion” state, where persistent inflammatory stimulation leads to T-cell exhaustion and impaired capacity to regulate inflammatory responses (47, 48). (ii) In end-stage HF patients, intestinal congestion-induced malabsorption and reduced hepatic synthetic function contribute to muscle wasting and lipolysis (49–52); meanwhile, the body may catabolize immunoglobulins and lymphocyte proteins for energy, further exacerbating immune exhaustion (53, 54). (iii) Intracellular ion homeostasis is crucial for maintaining normal cellular function. In end-stage HF patients, prolonged use of diuretics and digoxin may lead to chronic hypokalemia, which causes suppression of T-cell function (55, 56). In addition, prolonged use of β-blockers may lead to partial suppression of immune function: Theoretically, β-adrenergic receptors are expressed on both innate immune cells (e.g., neutrophils, macrophages) and adaptive immune cells (e.g., T lymphocytes, B lymphocytes, natural killer cells); these receptors may exert inhibitory effects on immune cells, and chronic stimulation of these receptors could result in immune dysfunction (57). Overall, the RCS-based findings in this study carry dual clinical significance: First, the dose-response relationship curves visually demonstrate the nonlinear association patterns between AISI/LnAISI and 30-day mortality risk in ADHF patients, revealing both overall associations and stage-specific dynamic changes. Second, the nadir of this U-shaped curve (LnAISI = 5.06) has significant clinical value: At the risk prognostic level, this threshold may serve as the optimal cutoff for minimal short-term mortality risk in ADHF risk stratification.

The underlying mechanisms linking AISI to short-term adverse outcomes in ADHF remain unclear, though preliminary insights may be gleaned through analysis of the immune cell components that comprise AISI: (1) Activated neutrophils mediate the degranulation-dependent release of large quantities of proteolytic enzymes, which directly degrade the cardiac extracellular matrix and induce cardiomyocyte apoptosis/necrosis. This pathological process not only exacerbates cardiac systolic dysfunction but also amplifies inflammatory cascades through the release of damage-associated molecular patterns, ultimately contributing to poor prognosis in ADHF (58, 59). Notably, neutrophil-derived inflammatory factors can also induce lymphocyte apoptosis (60). Furthermore, the concurrent presence of persistent neutrophilia and lymphopenia often serves as a clinical indicator of extensive myocardial injury and elevated short-term mortality risk in HF patients (17, 61). (2) Monocytes play a significant role in myocardial injury, through the following mechanisms (62):: (i) Direct participation in inflammatory infiltration and immune activation; (ii) Promotion of myocardial remodeling, including hypertrophy and fibrosis; (iii)Induction of cell death programs. Additionally, the inflammatory mediators they secrete may further accelerate lymphocyte apoptosis, and this “cross-talk” between immune cells significantly exacerbates the progression of HF (60, 63, 64). (3) In addition to being influenced by inflammatory mediators mediated by other immune cells (60, 63, 64), lymphocytes are also affected by the clinical symptoms of HF. Studies have shown that visceral congestion in HF can trigger a bidirectional vicious cycle of “lymphocyte loss-myocardial injury” (65, 66): On one hand, intestinal congestion leads to abnormal lymphocyte loss via the mesenteric lymphatic system; on the other hand, this immunocyte depletion accelerates myocardial remodeling by weakening anti-inflammatory defenses, forming a self-amplifying pathophysiological loop. (4) Although PLTs are not typical immune cells, their activation is closely associated with poor prognosis in HF (67). They primarily exert their effects through the following pathways (68, 69): (i) hemodynamic disturbances; (ii) vascular dysfunction; and (iii) regulation of chemokine networks, collectively serving as key drivers of HF progression. (4) Another critical consideration is the crosstalk between neurohormonal pathways and the immune system during acute HF exacerbation. Studies indicate that activated neurohumoral mechanisms modulate immune cells in HF (70, 71): From an AISI perspective, evidence shows that Renin-Angiotensin-Aldosterone System activation in HF patients leads to angiotensin II-mediated regulation of macrophage phenotypes by promoting M2 macrophage polarization; this stimulation may influence Th1/Th2 lymphocyte balance, induce lymphocyte apoptosis, and ultimately reduce lymphocyte counts (70, 72). Moreover, neurohormonal activation can trigger inflammatory responses by activating the nuclear factor-κB inflammatory pathway and upregulating pro-inflammatory mediators, including tumor necrosis factor-α and monocyte chemoattractant protein-1 (73, 74). On the other hand, neurohormonal activation increases plasma cortisol levels and catecholamine release, leading to downregulated lymphocyte differentiation and proliferation, followed by enhanced lymphocyte apoptosis (75, 76). Based on these findings, we recommend that early risk stratification of ADHF patients using AISI should also account for the promoting effects of neurohormonal pathways.

The strengths of this study include the novelty of the research topic, the ease of obtaining study variables, and the support from a large-scale cohort study, which collectively confer innovative clinical significance and generalizability to the AISI in short-term prognostic assessment for ADHF patients. Furthermore, through multi-faceted validation analyses, including subgroup analysis, temporal sensitivity analysis, and data integrity tests, we systematically validated the robustness of our findings across diverse clinical scenarios.

This study also has several limitations that warrant consideration: (1) As a non-interventional observational study, its design inherently precludes evaluation of post-admission treatment benefits for ADHF patients (77) and causal inferences about therapeutic efficacy. Consequently, conclusions are limited to disease natural history and biomarker associations. (2) This study focuses on the predictive value of AISI levels at admission for short-term mortality prognosis in ADHF patients, without exploring the association between in-hospital AISI changes and clinical outcomes. Future research needs to employ continuous biomarker monitoring to further clarify the incremental prognostic value of temporal AISI evolution patterns. (3) Although this study employed multivariable adjustment and sensitivity analyses to rigorously control for known confounders, the inherent limitations of observational research preclude the complete exclusion of residual confounding effects. (4) Given that participants were primarily recruited from Jiangxi Province in southern China, the generalizability of our findings to northern China and different ethnic populations requires further validation.

This population-based retrospective cohort study is the first to evaluate the predictive value of AISI for short-term prognosis in ADHF patients within the Chinese population. Compared with conventional inflammatory markers, AISI demonstrates superior predictive performance for 30-day mortality. These findings have important clinical implications, as they may facilitate optimized prevention strategies for adverse outcomes in ADHF and enable early risk stratification through personalized assessment of individual ADHF patients.