With the ongoing global demographic aging and lifestyle modifications, the incidence of coronary atherosclerotic disease (CAD) continues to rise worldwide, solidifying its position as a leading cause of mortality and disability (1). As a multifactorial disorder, CAD profoundly impacts the quality of life of patients while imposing a substantial socioeconomic burden on families and healthcare systems. These realities underscore the critical importance of early diagnostic stratification and timely therapeutic intervention.

The atherogenic index of plasma (AIP), calculated from the logarithmic ratio of triglycerides (TG) to high-density lipoprotein cholesterol (TG/HDL-C), has emerged as a novel biomarker for assessing subclinical atherosclerosis and cardiovascular risk stratification (2). Accumulating evidence demonstrates significant correlations between elevated AIP and coronary atherosclerotic disease (CAD) severity, particularly in patients with normal glucose regulation (NGR) (3). Notably, AIP serves as an independent prognostic factor in CAD populations, with longitudinal studies linking cumulative AIP exposure to increased risks of major adverse cardiovascular events (MACE), stroke, and myocardial infarction, particularly among elderly cohorts (4, 5). Analysis of the National Health and Nutrition Examination Survey (NHANES) 20052018 data further corroborates AIP's predictive capacity for future MACE and cardiac mortality (6).

In contemporary CAD management, coronary computed tomography angiography (CCTA) has become indispensable for evaluating chronic coronary syndromes (7). The fat attenuation index (FAI) and pericoronary adipose tissue (PCAT) volumequantitative parameters derived from CCTAprovide non-invasive biomarkers of coronary inflammation and atherosclerotic burden (8, 9). Specifically, right coronary artery (RCA) FAI and total PCAT volume have been validated as independent predictors of CAD prevalence and progression (10). A recent multicenter longitudinal cohort study of 40,091 CCTA-examined patients [median follow-up: 2.7 years (IQR 1.4–5.3)] demonstrated significant associations between FAI scores and risks of cardiac mortality/MACE, highlighting its prognostic utility even in non-obstructive CAD (6).

Despite these advances, the mechanistic interplay between AIP, coronary inflammation (as quantified by FAI/PCAT), and CAD severity remains incompletely characterized. No prior study has systematically investigated whether coronary inflammatory activity mediates the relationship between atherogenic lipid profiles and multivessel CAD progression in aging populations. This study, therefore, aims to elucidate the association between AIP and CAD severity in middle-aged and elderly patients, with particular emphasis on the mediating role of RCA-FAI assessed coronary inflammation.

This study investigated the interplay between coronary arterial inflammation, AIP, and CAD severity across various glucose metabolism subtypes in middle-aged and elderly Chinese individuals. Mediation analysis revealed that the RCA-FAI played a partial mediating role (27.9%) in the association between AIP and CAD severity, highlighting the critical role of the “lipid-inflammation signaling pathway” in the development of CAD in middle-aged and older individuals. This result validates existing evidence supporting AIP as an independent predictor of CAD severity, which is consistent with the study by Wang and He (17).

Recent studies have shown that AIP can serve as an independent predictor of cardiovascular risk, and its ability to predict the progression of atherosclerotic plaques and the incidence of CAD is significantly superior to that of traditional risk factors, such as hypertension and diabetes (18). From a mechanistic perspective, AIP reflects the dynamic balance between small dense low-density lipoprotein cholesterol (sdLDL-C) and anti-atherosclerotic lipoproteins and serves as a practical surrogate marker for sdLDL-C levels (19). sdLDL-C is characterized by a smaller particle size and higher density and can accelerate atherosclerosis through the following pathways: (1) reduced particle size (18–22 nm vs. 22–25 nm for LDL-C) increases endothelial permeability; (2) lower sialic acid content promotes binding to proteoglycans, prolonging arterial retention time; (3) decreased affinity for LDL receptors leads to prolonged circulating half-life; (4) sdLDL-C is easily oxidized into pro-inflammatory oxidized low-density lipoprotein (oxLDL); (5) sdLDL-C stimulates macrophages to secrete cytokines and foam cells (20–23).

The 2023 “Chinese Guidelines for Blood Lipid Management” list small dense sdLDL-C as a key biomarker for risk stratification of atherosclerotic cardiovascular disease (ASCVD) (24). Multiple cohort studies have confirmed that sdLDL-C levels are significantly associated with the risk of developing coronary heart disease and its clinical outcomes (25–28). However, the detection of sdLDL-C has a high technical threshold and is costly, making it difficult to promote its application in routine clinical practice (29). In contrast, AIP is derived from routinely measured clinical lipid parameters. This approach incurs negligible additional costs when establishing AIP as a clinically reliable surrogate marker of sdLDL-C (19).

A meta-analysis showed that elevated AIP levels were independently associated with CAD, regardless of whether continuous or categorical variables were used (4, 18). However, this association exhibited heterogeneity across different glucose metabolic states. Wu et al. (3) found a significant positive correlation between AIP and CAD severity in individuals with normal glucose tolerance (NGR), which is consistent with the results of this study; however, in subgroups with abnormal glucose metabolism (such as prediabetes and diabetes), this association was weakened. This heterogeneity may be related to pathways mediated by insulin resistance, which can intensify lipid metabolic disorders by increasing the release of free fatty acids and inhibiting lipoprotein lipase activity, thereby weakening the atherogenic effect of AIP (30, 31). In addition, this study found that even among patients with diabetes, in whom the association between AIP and CAD was weakened, RCA-FAI was still significantly associated with MVCAD, suggesting that inflammation may play a key role in severe CAD, independent of lipid dysregulation and DM.

This study found that RCA-FAI was significantly and positively correlated with CAD severity, consistent with previous studies (10). This result supports the view that “coronary artery inflammation is a core mechanism in the pathophysiology of CAD” (32). When the inflammatory cascade is activated, an elevated RCA-FAI indicates chronic low-grade inflammation, which promotes atherosclerosis progression through the following pathways: leukocyte infiltration, macrophage infiltration, and T-lymphocyte infiltration into the subendothelial layer, leading to lipid deposition and foam cell formation, vascular remodeling, activation of matrix metalloproteinases (MMP-2/9) that degrade the extracellular matrix resulting in vascular dilation or stenosis (33, 34), and release of pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1), accelerating plaque formation (35).

Although RCA-FAI was strongly associated with MVCAD severity, no significant association was observed between LAD-FAI, LCX-FAI, and MVCAD severity. This is consistent with the current consensus that “the RCA is the optimal anatomical site for assessing coronary artery inflammation” (36, 37). In addition, the anatomical stability of the RCA-FAI (located within the right atrioventricular groove with minimal cardiac movement) makes its measurement more reproducible than that of LAD-FAI and LCX-FAI (38). The purpose of including LAD-FAI and LCX-FAI in this study was to explore whether “multivessel FAI assessment can enhance risk stratification more than using RCA-FAI alone.” However, the results showed that LAD-FAI and LCX-FAI were not significantly associated with MVCAD, further confirming the primary role of RCA-FAI as a biomarker of coronary inflammation in the study population.

Stratified analysis of glucose metabolism showed that RCA-FAI was significantly associated with CAD severity in subgroups with normal blood glucose levels, prediabetes, and diabetes, consistent with the results of a cross-sectional cohort study involving 207 patients, which found that both RCA-FAI and total PCAT volume were independent predictors of coronary artery disease (10). In addition, among patients with stable angina, combining FAI with plaque burden indicators (such as plaque volume) can significantly improve the accuracy of ischemic lesion detection (AUC = 0.821) (39). Baseline quantification of perivascular inflammation by FAI is also significantly associated with the incidence of in-stent restenosis during follow-up (40). Unlike previous studies, which primarily used the “incidence of cardiovascular events” as the main endpoint, this study adopted validated threshold criteria (≥50% stenosis in two or more major coronary arteries) to quantify the severity of CAD, focusing on the anatomical severity of lesions. This design helped us directly explore the relationship between inflammation and CAD lesion progression.

AIP is a validated biomarker of sdLDL-C levels and is mechanistically linked to the activation of inflammatory cascades. We hypothesized that coronary inflammation mediates the association between AIP and CAD severity. This study used mediation analysis to investigate whether coronary inflammation (quantified by FAI) mediates the relationship between AIP (assessing lipoprotein abnormalities) and MVCAD. The analysis showed that the FAI mediated 27.9% of the association between AIP and MVCAD, suggesting that inflammation in the PCAT may be involved in the development of this pathological pathway. These results support the hypothesis proposed by Antonopoulos et al. (8) that inflammation of the perivascular adipose tissue is a key driver of metabolically related atherosclerotic disorders.

However, the 27.9% partial mediation result indicates that, in addition to FAI-mediated inflammation, other pathophysiological mechanisms are involved in the development of AIP-related MVCAD. This finding is consistent with the concept proposed by Wolf and Ley (41) that “atherosclerosis is a systemic disease. Although our mediation model statistically supports the inflammation-driven pathway of “AIP→RCA-FAI→MVCAD,” the possibility of bidirectional interactions is worth exploring based on established pathophysiological mechanisms. (1) Lipid-driven pathway: sdLDL-C retention and oxidation activate endothelial LOX-1 receptors, triggering NF-κB signalling and pro-inflammatory cytokine expression (35, 42–44). This cascade response is consistent with our observations, in which higher AIP quartiles were associated with progressively higher RCA-FAI. (2) Inflammation-driven pathway: Chronic vascular inflammation dysregulates lipid metabolism via pro-inflammatory cytokines (e.g., TNF-α and IL-6), suppresses lipoprotein lipase, inhibits HDL biosynthesis, and stimulates very low-density lipoprotein production, thereby elevating the TG/HDL-C ratio (45–47). Adipose tissue inflammation further aggravates lipid metabolic disorders by increasing free fatty acid flux and inducing insulin resistance (48). Studies have shown that chronic inflammatory states (such as chronic periodontitis and chronic hidradenitis suppurativa) are associated with an increase in AIP, supporting this pathway (49, 50). However, in our cohort, the consistent association between RCA-FAI and MVCAD across glucose metabolism strata, even among patients with diabetes in whom the association between AIP and CAD is weakened, suggests that inflammation may operate independently or precede lipid dysregulation in severe CAD cases.

Our mediation analysis (27.9% indirect effect) supports a partially lipid-driven pathway but cannot rule out reverse causality or feedback loops. Prospective studies with serial FAI/AIP measurements are required to clarify temporal precedence.

If AIP primarily contributes to inflammation through lipid-driven mechanisms, intensive lipid-lowering therapy (such as statins or PCSK9 inhibitors, which can specifically reduce sdLDL-C levels) may help alleviate coronary artery inflammation (51, 52). Inflammation is assumed to be the main driving factor of dyslipidemia. In such cases, anti-inflammatory treatments (e.g., colchicine or canakinumab) can be used to prevent atherosclerosis (53, 54). The data from this study highlight the need to develop individualized treatment strategies based on a patient's lipid profile and inflammation levels.

The core value of this study lies in the fact that AIP and RCA-FAI could serve as clinically accessible alternative biomarkers for MetS. Although the direct quantification of sdLDL-C can provide mechanistic insights, this technique is technically demanding and costly, making its routine application difficult in most clinical settings. Similarly, although vascular inflammation is a key mechanism of atherosclerosis, direct histological assessment is invasive and cannot be used for routine risk stratification. In contrast, the AIP is calculated based on standard lipid components (TG and HDL-C) routinely measured in clinical practice at minimal additional cost. The RCA-FAI is derived from routine CCTA scans and calculated using established standardized radiomics protocols without the need for additional specialized imaging sequences or contrast agents. This makes AIP and RCA-FAI readily accessible as assessment indicators within existing cardiovascular diagnostic systems.

We confirmed a significant association between AIP and CAD severity, which was partially mediated by RCA-FAI. This provides clinicians with valuable and easily accessible routine screening tools, such as the lipid profile and CCTA. The dose–response relationship between RCA-FAI and CAD risk further underscores its potential value in risk assessment. Integrating these biomarkers can enhance the ability to identify individuals at high risk of MVCAD, overcoming the limitations of traditional risk factors and standard CCTA stenosis assessment. This easy-to-implement risk stratification can be used to guide more intensive preventive strategies (such as adjusting lipid-lowering therapy) or more frequent monitoring (such as regular CCTA follow-up), ultimately improving the prognosis of patients with MVCAD.

Computed tomography-derived fractional flow reserve (CT-FFR) enables the non-invasive assessment of the hemodynamic significance of coronary stenosis (9, 55). However, this study specifically excluded CT-FFR-based functional ischemia evaluation, focusing instead on pericoronary inflammation quantified via the right coronary artery fat attenuation index (RCA-FAI), given the distinct pathophysiological correlates (anatomical inflammation vs. hemodynamic impairment) of these two conditions. While lifelong endurance exercise has cardioprotective effects, recent evidence indicates that it does not improve coronary plaque composition compared with a standard healthy lifestyle (56). Exercise-mediated anti-inflammatory effects were deliberately excluded to prioritize the investigation of metabolic pathways.

This study revealed a significant association between AIP and CAD severity in middle-aged and elderly Chinese populations, with RCA-FAI demonstrating a partial mediating effect on this relationship. These findings provide novel insights into the inflammatory mechanisms underlying CAD progression and highlight AIP's dual role of AIP as both a risk stratification tool and a potential therapeutic target. Future investigations should delineate the mechanistic interplay between sdLDL-C and CAD severity while validating AIP's clinical utility of AIP in personalized cardiovascular care.