Cardiovascular diseases are an important global public health problem with incidences rising annually [1]. Acute coronary syndrome (ACS), one of the most severe subtypes, presents a wide range of prognoses depending on the various pathophysiological elements. Early risk stratification is crucial for determining appropriate treatment strategies, which can prevent overtreatment, reduce healthcare costs, and improve patient outcomes [2, 3, 4]. The global registry of acute coronary events (GRACE) score is a widely utilized tool for predicting short- and long-term outcomes in ACS patients, including major adverse cardiovascular events (MACE) [5, 6]. While sphingolipid metabolism has been shown to play a critical role in ACS progression and prognosis [7], the GRACE score does not account for biological markers related to this pathway, limiting its predictive accuracy.

Ceramide plays a pivotal role in sphingolipid metabolism, particularly in the context of cardiovascular disease. It tends to accumulate in areas where low-density lipoprotein (LDL) deposits in vivo, facilitating the penetration of lipoproteins through the vascular wall, contributing to the destabilization of atherosclerotic plaques [8, 9]. Recent studies have demonstrated the critical role of ceramide in predicting MACE in individuals with ACS [10, 11]. However, the potential application of ceramide as a key biomarker to enhance the predictive accuracy of the GRACE score, specifically for long-term outcomes in ACS patients undergoing percutaneous coronary intervention (PCI), is still under investigation.

In this study, we combined the ceramide and GRACE risk scores into a novel metric to test its capacity to predict the occurrence of MACE in patients with ACS undergoing PCI. Furthermore, we assessed whether this integration enhances the prognosis assessment following patient discharge.

Our results demonstrate that the combination of the CERT1 score and the GRACE score leads to a novel metric with the ability to independently predict clinical outcomes in patients with ACS undergoing PCI. This integrated approach enhances the predictive power of the GRACE score more effectively than traditional lipid markers (LDL) and imaging techniques (QFR). This improvement is expected to help clinicians identify personalized therapeutic strategies for their patients, thereby optimizing treatment outcomes.

Increasing evidence supports the notion that timely and comprehensive individual risk stratification for patients with ACS undergoing PCI can facilitate personalized treatments. This approach not only promises to improve outcomes for the high-risk patients but also aims to reduce the financial burden on those at low risk. According to current clinical practice guidelines, the use of the GRACE score is recommended for predicting short term and long-term prognostic outcomes of ACS patients undergoing PCI. However, when analyzed using the ROC curve, the AUC for the GRACE score alone stands at 0.733. This limited predictive power may be attributed to the omission of certain underlying risk factors in the existing model. Many researchers have sought to find new biomarkers to improve prognostic accuracy by adding C-reactive protein [15], HbA1C [16], TyG index [17], triglyceride-glucose index [18], pro-brain natriuretic peptide (pro-BNP) [19], and nutritional risk index [20] to the GRACE score. These efforts reflect the ongoing quest to refine risk assessment tools for better management of ACS patients.

A study has shown that hyperlipidemia is a major determinant of clinical prognosis in patients with ACS [21]. It is now widely accepted that strategies aimed at lowering lipid levels improve long-term cardiovascular outcomes and stabilize atherosclerotic plaques in ACS subjects [22, 23, 24, 25]. LDL is a standard indicator for blood lipids in clinical practice, and is a simple manifestation of lipid metabolism. This traditional lipid marker, however, is still not sufficient to completely represent the complexity of lipid metabolism. Findings from a large-scale cohort study indicated that higher CERT1 scores correlate with increased cardiovascular mortality rates among individuals with ACS, outperforming LDL levels as a prediction metric [10]. In our study, the addition of the CERT1 score to the GRACE score not only surpassed LDL in predictive ability but also significantly enhanced the capability to identify long-term significant cardiovascular complications in individuals with ACS following PCI. This underscores the value of incorporating the CERT1 score into existing prognostic frameworks to improve outcome predictions.

Both in-stent restenosis and residual stenosis may lead to MACE following PCI in patients with ACS. QFR is highly accurate in predicting whether coronary artery stenosis will lead to ischemia, and several studies have validated its ability to predict the risk of MACE [26, 27, 28]. Our study adds to this body of knowledge by demonstrating that the integrating the CERT1 score with the GRACE score not only provides a superior predictive ability for long-term MACE among ACS patients undergoing PCI, but also surpasses the predictive accuracy of the imaging biomarker QFR. This finding highlights the potential of combining biochemical and clinical risk scores to enhance prognostic assessments in this patient population.

Disrupted sphingolipid metabolism is closely related to the occurrence and development of ACS [29, 30]. Ceramide is a key component of sphingolipid metabolism [31, 32]. Ceramide stimulates the aggregation of LDL-C, facilitating the infiltration of lipoproteins into the vascular wall, increasing the transendothelial permeability for lipoproteins [33, 34, 35]. A key consequence is an increased risk of vascular occlusion reoccurring in patients with ACS that have had PCI. Under these circumstances, ceramide acts as a second messenger for cytokine induction, leading inflammatory immune cells to the plaque [31, 36]. This in turn can cause the plaque to rupture and ultimately produce an acute myocardial infarction along with related complications. Consequently, we propose that integrating the CERT1 score with the GRACE score can improve risk stratification and provide an important additional prognostic inform in patients with ACS undergoing PCI.

There are several important limitations of the study that must be considered. First, the research was conducted using a single-center, small-sample cohort, which may limit the generalizability of our results to more diverse patient populations. Future research should aim to incorporate multiple centers with heterogeneous patient groups for further validation. Second, our study only enrolled ACS patients undergoing PCI, thus the results may not be applicable to ACS patients undergoing alternative therapies or who are on medication. Third, measuring serum ceramide concentrations requires specialized laboratory equipment and technology, which can be costly and limit its clinical applicability. However, as diagnostic techniques improve and technologies such as mass spectrometry become more commonplace, it is expected that the costs associated with ceramide testing will decrease. Additionally, as our understanding of ceramide’s role in the pathophysiology of cardiovascular diseases deepens, routine testing for ceramide levels in clinical settings is anticipated to become more commonplace. Fourth, the addition of the CERT1 score to the GRACE score significantly enhanced prediction of MACE over the 1-year follow-up period. However, this integration slightly reduced the model’s specificity, potentially leading to an increase in false positive rates, potentially resulting in wrongly classifying patients as high risk and receiving unnecessary medical interventions. Fifth, the CERT1 score was initially measured at the time of patient admission, and its scores during the follow-up period may be influenced by lipid-lowering and blood glucose lowering medications. Further research is necessary to determine whether changes to the CERT1 score due to these interventions influence its predictive power for patients with ACS undergoing PCI.

The CERT1 score is currently utilized as a standalone predictor of long-term MACE in individuals with ACS undergoing PCI. However, when combined with the GRACE score, the CERT1 score forms a novel metric that enhances incremental risk-stratification and prognostic value for these patients. This integrative approach not only improves the accuracy of prognostic predictions but also facilitates more informed clinical decision-making, potentially leading to improved outcomes for patients with ACS who have undergone PCI.

The data supporting the findings of this study are not publicly available to protect patient privacy. However, access to the raw data can be requested from the corresponding author as part of reasonable request regulations.

XFW, CZL, and FY made significant contributions to the design, data analysis, and manuscript writing of this study; ZZZ, JLW, and XYS collected the data required for the research; TYX and QD provided assistance in data analysis; LPZ and WYS participated in data analysis and the revision of the manuscript; LLY and HJ provided financial support for the research and participated in the conception and design of the study, as well as critical review of the manuscript. All authors contributed to 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 Ethics Committee of Renmin Hospital of Wuhan University (Protocol No.WDRY2022-K257). All of the participants provided signed informed consent.

Not applicable.

The research was supported by the National Natural Science Foundation of China (Grant Numbers: 82270532, 81970287, and 82370286).

The authors declare no conflict of interest.