Current coronary artery revascularization techniques primarily involve coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) [1]. CABG serves as the primary treatment for patients with triple-vessel coronary artery disease and/or left main coronary artery disease, particularly in diabetic patients. However, graft vessel (GV) failure, particularly in saphenous vein grafts (SVGs), is common post-CABG, with failure rates of SVGs reaching 15%–20% at 1 year and approximately 50% at 10 years post-surgery [2]. Patients with a history of CABG often experience rapid progression of atherosclerotic lesions in native coronary artery vessels (NVs) and GVs, leading to recurrent angina or acute coronary syndrome (ACS) events [3, 4]. Despite optimal medical therapy, satisfactory clinical outcomes are often elusive, necessitating repeat coronary artery revascularization to ameliorate symptoms [5]. However, compared to primary CABG, patients undergoing repeat CABG face higher mortality rates and poorer prognoses, particularly due to advanced age and comorbidities [6]. Consequently, PCI emerges as the preferred revascularization strategy for patients with a history of CABG [7].

Recent research has increasingly focused on novel biomarkers such as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and direct bilirubin (DBIL) [8, 9, 10]. LDL-C contributes to the development of atherosclerotic plaques, vascular inflammation, and endothelial cell damage, thereby elevating the risk of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with coronary artery disease (CAD) [11]. Conversely, HDL-C exerts diverse beneficial effects by facilitating cholesterol efflux and diminishing cholesterol accumulation in arterial walls [12]. Moreover, HDL-C suppresses inflammation, enhances endothelial function, and displays antioxidant properties, collectively safeguarding endothelial cell integrity and decreasing the risk of plaque rupture [13, 14, 15]. DBIL inhibits oxidative stress and inflammation, reducing free radical production and protecting endothelial cell integrity, thereby lowering plaque rupture and thrombosis risk [16]. Furthermore, DBIL possesses antiplatelet and anticoagulant properties, further mitigating MACCE risk in CAD patients [17].

To enhance assessment accuracy, researchers have proposed the concept of LDL-C/(HDL-C+DBIL) ratio. This ratio integrates the risk factor LDL-C with the protective factors HDL-C and DBIL, accounting for the integrated effects of various potential mechanisms, including cholesterol metabolism, oxidative stress, and inflammation [18]. A retrospective analysis of data from Chinese CAD patients published in 2020 found a significant correlation between LDL-C/(HDL-C+DBIL) ratio and MACCE incidence, with higher ratios associated with increased MACCE risk and lower ratios correlated with reduced risk [19]. This study provided initial evidence for further exploring the relationship between LDL-C/(HDL-C+DBIL) ratio and MACCE and analyzing its role in pre-PCI risk assessment. Additionally, it offers valuable insights into repeat PCI treatment for patients with a history of CABG and explores the potential clinical application of LDL-C/(HDL-C+DBIL) ratio.

This study employed a large-sample, single-center, observational, retrospective design to investigate the relationship between LDL-C/(HDL-C+DBIL) levels and the incidence of MACCE among patients with prior history of CABG undergoing PCI. LDL-C/(HDL-C+DBIL) level emerged as a significant risk factor, with higher levels correlating with increased incidence of MACCE. Although LDL-C/(HDL-C+DBIL) levels in the native PCI group were significantly lower than those in the graft PCI group, the effect of LDL-C/(HDL-C+DBIL) on MACCE is consistent whether the target vessels are native arteries or grafts.

Serum biochemical factors are considered auxiliary indicators for assessing the presence of atherosclerotic plaques [20]. In 1994, Schwertner et al. [21] first reported an inverse relationship between total bilirubin (TBIL) levels and the prevalence of CAD in a cross-sectional study. Subsequent epidemiological studies have consistently demonstrated that low serum bilirubin concentrations are independently associated with an increased risk of CAD, suggesting that bilirubin may have protective cardiovascular effects [22]. The relationship between bilirubin and lipoproteins, particularly in the context of lipid metabolism, remains of great interest in understanding the pathophysiology of atherosclerosis. Bilirubin, a byproduct of hemoglobin degradation, plays a multifaceted role in lipid metabolism. On one hand, bilirubin has been shown to facilitate the dissolution and excretion of TC, thereby reducing LDL levels and increasing HDL content [23]. Elevated levels of small, dense LDL particles and oxidized LDL are known to penetrate the arterial wall, promoting cholesterol crystallization and plaque formation, which are key mechanisms in the development of atherosclerosis and cardiovascular disease [24]. On the other hand, bilirubin serves as a potent endogenous antioxidant, exerting protective effects by reducing the oxidative modification of LDL. The oxidation of LDL is a pivotal process in atherogenesis, as oxidized LDL (oxLDL) triggers endothelial dysfunction, promotes foam cell formation, and induces inflammatory responses in the arterial wall, all of which accelerate the development of atherosclerotic plaques. Bilirubin, through its antioxidant properties, scavenges reactive oxygen species (ROS) and other free radicals that initiate LDL oxidation. By preventing LDL oxidation, bilirubin reduces the formation of oxLDL, thus mitigating its atherogenic potential and the downstream inflammatory cascade [25]. Additionally, HDL, commonly referred to as “good cholesterol”, is recognized for its role in reverse cholesterol transport, antioxidant properties, and anti-inflammatory effects. HDL not only facilitates the removal of excess cholesterol from the arterial wall but also mitigates oxidative stress and inflammation in the vascular endothelium, further protecting against atherosclerotic disease [26]. The combined effects of HDL and bilirubin, particularly when expressed in a composite ratio such as LDL/(HDL+DBIL), may offer a more comprehensive reflection of cardiovascular risk. This ratio could represent the synergistic interplay between HDL’s anti-atherogenic properties and bilirubin’s antioxidant and anti-inflammatory functions, potentially providing a more robust predictor of cardiovascular health.

The majority of patients in this cohort were treated with statins (99.1%), which are known to effectively lower LDL-C and TC levels [27]. Moreover, lipid metabolism and bilirubin metabolism are closely interconnected, as both processes are primarily regulated by the liver. Lipid-lowering therapies, particularly statins, have been shown to elevate bilirubin levels, which in turn may contribute to a reduced incidence of MACCE in patients [28].

In patients with a history of combined CABG, early graft failure, particularly in SVGs, is primarily attributed to surgical factors, including anastomotic stenosis and vascular endothelial injury, which can lead to acute thrombosis, intimal hyperplasia, and fibrosis. Late graft failure is predominantly due to the progression of atherosclerotic lesions, resulting in luminal narrowing or complete occlusion [29, 30]. Furthermore, underlying patient conditions, such as diabetes, hypertension, and hyperlipidemia, accelerate the process of atherosclerosis and create a more unfavorable environment for the grafts. Diabetes, in particular, is associated with an increased risk of graft failure, largely due to its adverse effects on endothelial function and microvascular circulation [31]. Additionally, the choice of graft material—whether arterial or venous—can significantly influence graft patency, with arterial grafts typically exhibiting superior long-term outcomes compared to venous grafts [32]. The duration of surgery can also affect liver function, which plays a key role in processing medications and recovery. Prolonged surgery may lead to hepatic stress, altering drug metabolism and impacting patient recovery [33]. Additionally, medications such as anticoagulants and antiplatelets, used during and after CABG, can affect graft patency and liver function [34]. Chronic medication use may contribute to hepatic dysfunction, influencing cardiovascular disease progression. Therefore, evaluating liver function before and after CABG is crucial when assessing PCI outcomes and making treatment decisions.

The 2018 European Society of Cardiology (ESC) myocardial revascularization guidelines recommend native vessels as the preferred target for intervention in patients with failed grafts [35]. However, there remains controversy regarding the comparative outcomes of PCI using native vessels versus graft vessels. The ARTS-II trial, a randomized controlled study in post-CABG patients, aimed to compare the efficacy of PCI using native vessels versus graft vessels [36]. Over a 5-year follow-up period, there was no significant difference in MACCE between the native vessel PCI group and the graft vessel PCI group, with rates of 36% and 31% respectively. Furthermore, the native vessel PCI group had a slightly higher mortality rate than the graft vessel PCI group, but lower rates of myocardial infarction and repeat revascularization. Similarly, the 2019 EXCEL trial published in the Lancet demonstrated comparable MACCE rates for patients undergoing PCI using native vessels or graft vessels following left main coronary artery stenosis [37]. With 1905 patients enrolled, comprising 948 receiving native vessel PCI and 957 receiving graft vessel PCI, there was no statistically significant difference in MACCE rates between the two groups over a three-year follow-up period (15.4% vs. 14.7% respectively). Additionally, the native vessel PCI group exhibited a slightly higher mortality rate compared to the graft vessel PCI group (5.3% vs. 3.0%), but lower rates of myocardial infarction and stroke. These findings provide valuable insights suggesting that while there may be no significant difference in reducing MACCE between native vessel PCI and graft vessel PCI in post-CABG patients, each approach may offer advantages in specific outcomes. Some studies have begun exploring potential biomarkers such as high-sensitivity C-reactive protein (hs-CRP), cardiac troponin T (cTnT), and B-type natriuretic peptide (BNP) [38, 39, 40, 41]. These biomarkers are closely associated with the development and progression of cardiovascular disease and may guide the choice of intervention. Alternatively, imaging modalities like computed tomography and magnetic resonance imaging can provide specific parameters to assist in treatment decision-making [42]. However, there is currently no definitive biomarker to guide the choice between native vessel PCI and graft vessel PCI in post-CABG patients. The LDL-C/(HDL-C+DBIL) ratio has shown potential in assessing the risk and prognosis of cardiovascular disease, suggesting it as a possible biomarker. This study investigated the differences in LDL-C/(HDL-C+DBIL) ratio between patients undergoing native vessel PCI and graft vessel PCI, and analyzed its relationship with MACCE rates. Results showed a significant difference in LDL-C/(HDL-C+DBIL) ratio between the two groups, with the graft vessel PCI group exhibiting higher ratios, indicating higher cardiovascular risk factors prior to PCI. Further univariate Cox regression analysis and subgroup analysis revealed a positive correlation between LDL-C/(HDL-C+DBIL) ratio and MACCE rates in the native vessel PCI group, suggesting an increase in the ratio was associated with higher MACCE rates. However, in the graft vessel PCI group, an increase in LDL-C/(HDL-C+DBIL) ratio did not show a significant association with cardiovascular MACCE rates. This indicates that the LDL-C/(HDL-C+DBIL) ratio may have different effects on MACCE rates between native vessel treatment and graft vessel treatment. These findings are consistent with previous studies suggesting that MACCE rates may not significantly differ between different treatment groups. We also highlight the potential role of LDL-C/(HDL-C+DBIL) levels in guiding treatment selection and assessing patient prognosis.

The increasing proportion of CABG procedures observed in recent years raises important questions about the underlying causes of this trend. While some of this increase can be attributed to the growing prevalence of CAD and the aging population, advancements in surgical techniques and patient selection criteria also play a key role. With the improvement in grafting methods, such as the widespread adoption of ITA and the development of hybrid procedures, more patients are eligible for CABG who may have previously been considered inoperable or at high risk for complications [43, 44]. These technical advancements contribute to the expanding role of CABG as a primary intervention for coronary artery disease, thus explaining the increased proportion of cases in clinical settings. The statistical findings presented in this study reflect the expanding indications for CABG and its growing acceptance as a viable treatment option. However, to ensure that these findings are not merely statistical artifacts, it is crucial to evaluate whether the increase in CABG procedures truly translates into improved patient outcomes, particularly in terms of post-operative recovery and long-term survival. This evaluation requires integrating several key factors, including the technical aspects of CABG, surgical duration, the use of specific medications, and the rationale behind the increasing number of CABG procedures. By considering these elements, a more comprehensive understanding of the impact of CABG on patient outcomes can be achieved. The data was collected from past records without randomization. This design may introduce selection bias, which could impact the generalizability of the findings. While the study establishes an association between LDL-C/(HDL-C+DBIL) and MACCE, it does not explore the underlying biological mechanisms or modes of action, making it difficult to draw definitive conclusions about the cause-and-effect relationship between these biomarkers and MACCE. Therefore, the study’s design prevents a deeper insight into how LDL-C/(HDL-C+DBIL) levels influence cardiovascular outcomes, highlighting the need for further research to investigate these mechanisms and validate the observed association. Additionally, an important limitation is the absence of a control group. All participants in this study underwent coronary revascularization (PCI), and there was no comparison with a group of patients who did not undergo the procedure. The lack of a control group makes it difficult to assess whether LDL-C/(HDL-C+DBIL) levels independently contribute to MACCE, or if the observed association is confounded by the effects of coronary revascularization. Including a control group, such as patients who did not undergo revascularization, would allow for a more robust comparison and provide a clearer understanding of the role of these biomarkers, independent of the treatment received. Finally, this study focused on a single-center cohort, which may limit the generalizability of the findings to different populations. To confirm the robustness of the results, future studies should adopt a longer-term, more diverse research design with larger sample sizes and additional control groups, which will help provide a more comprehensive understanding of the role of LDL-C/(HDL-C+DBIL) in cardiovascular disease and MACCE.

This study found that the levels of LDL-C/(HDL-C+DBIL) were positively correlated with the occurrence of MACCE events in the population, with increasing age and diabetes being closely associated with MACCE event rates. When undergoing PCI again after CABG surgery, the LDL-C/(HDL-C+DBIL) levels had different effects on cardiovascular MACCE event rates depending on the target vessel. In the native vessel PCI group, LDL-C/(HDL-C+DBIL) levels were positively correlated with MACCE event rates, whereas in the graft vessel PCI group, an increase in LDL-C/(HDL-C+DBIL) did not show a significant association with cardiovascular MACCE event rates. LDL-C/(HDL-C+DBIL) levels serve as an important indicator for predicting cardiovascular event risk, particularly in risk assessment prior to PCI treatment, holding significant clinical relevance. These findings offer new directions for the prevention and management of cardiovascular diseases, providing valuable reference for clinical practice and further research endeavors.

ACS, acute coronary syndrome; BMI, body mass index; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CRP, C-reactive protein; DBIL, direct bilirubin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MACCE, major adverse cardiac and cerebrovascular events; MACE, major adverse cardiac events; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; SVGs, saphenous vein grafts; SCAD, stable coronary artery disease; STEMI, ST-elevation myocardial infarction; TC, total cholesterol; TVR, target vessel revascularization; UA, unstable angina.

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Additionally, any materials used in the study are available upon request.

XY wrote the entire manuscript. MR was responsible for organizing the data. QL and ZY conducted the statistical analysis. LY contributed to the revision of the manuscript. ZW ensured that the research direction was correctly guided. YZ designed the study and revised the manuscript critically for important intellectual content. All authors contributed to the conception and 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.

The study was carried out in accordance with the guidelines of the Declaration of Helsinki and approved by the institutional review board of Beijing Anzhen Hospital, Capital Medical University (No. 2022084X) and informed consent was waived due to the retrospective nature of this study. All personal information regarding patient identity was removed.

This work was supported by Beijing Municipal Natural Science Foundation, General Program (7232039).

The authors declare no conflict of interest. Yujie Zhou is serving as Editor-in-Chief of this journal, and Zhijian Wang is serving as one of the Editorial Board members of this journal. We declare that Yujie Zhou and Zhijian Wang had no involvement in the peer review of this article and have no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Lloyd W. Klein.