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Abstract

Background

Cystatin C is a cysteine protease inhibitor, synthesized by nucleated cells, and released into various body fluids. Lots of studies have reported an association between cystatin C and atherosclerotic cardiovascular disease. However, the association of cystatin C with high-risk patients with acute coronary syndrome(ACS) has not been well studied. In this study, we investigated potential association of cystatin C with high-risk patients with ACS, and assessed whether cystatin C provide discriminating power of clinical risk stratification in patients with ACS.

Methods

We enrolled 219 patients with ACS in the present study. The cystatin C concentration was measured in clinical laboratory. The global registry of acute coronary events (GRACE) scores was calculated to assess risk stratification. The high-risk patients with ACS were defined based on GRACE scores and killip classification.

Results

The cystatin C levels were significantly higher in high-risk patients compared to non-high-risk patients, both in the overall ACS group and its subtypes, including non-ST elevation ACS (NSTE-ACS) and ST elevation ACS (STE-ACS)(P < 0.05). The receiver operating characteristic (ROC) curve analysis showed that cystatin C had a discriminative performance for identifying high-risk patients across these groups(P < 0.05). After adjusting for potential confounders, multivariate logistic regression confirmed that the elevated cystatin C levels were independently associated with high-risk patients with ACS(P < 0.05).

Conclusions

The cystatin C was obviously elevated in high-risk group in the patients with ACS and its subgroups. Cystatin C appears to be a valuable biomarker for distinguishing and predicting high-risk patients with ACS, suggesting its relevance in clinical risk stratification.

Keywords

acute coronary syndrome cystatin c biomarker

Introduction

Acute coronary syndrome (ACS) represents a critical and potentially life-threatening group of conditions that are among the most severe cardiovascular diseases affecting humans today.¹ The severity of ACS can escalate to life-threatening complications such as cardiac arrest, ventricular tachycardia, ventricular fibrillation, or cardiogenic shock, primarily due to prolonged ischemia or severe mechanical complications.² Meanwhile, The global burden of ACS is substantial, with high rates of morbidity and mortality observed over recent decades across the world.^2,3 The spectrum of ACS includes non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and ST-segment elevation acute coronary syndrome (STE-ACS). Effective hazard stratification and accurate risk assessment are essential to ensure that patients receive timely and appropriate interventions, which can significantly impact their outcomes. The global registry of acute coronary events (GRACE) risk scores is one of the most widely used tools for this purpose.^4,5 It helps identify high-risk ACS patients who would benefit from early intervention to reduce the likelihood of major adverse cardiovascular events.²

Cystatin C, a member of the cysteine protease inhibitor family, is synthesized by all nucleated cells and is released into various body fluids. It is then metabolized by proximal tubular cells in the kidneys.^6,7,8 Traditionally used as a biomarker for assessing renal function, cystatin C has garnered increasing attention for its potential role in cardiovascular risk assessment. The potential mechanism of cystatin C relating to the cardiovascular disease have already been reported in previous literatures. It may be linked to inflammatory immunity, degradation of vascular matrix, insulin resistance.^8,9

Recent studies have highlighted its importance beyond renal function. For instance, a retrospective study conducted by Sai E et al demonstrated that elevated cystatin C levels were associated with major adverse cardiac and cerebrovascular events in patients with stable coronary artery disease undergoing percutaneous coronary intervention, with a follow-up period of 63 months.¹⁰ Similarly, Akgul O et al found that high cystatin C levels could predict short-term mortality in patients with STE-ACS receiving percutaneous coronary intervention.¹¹ Further evidence suggests that cystatin C may serve as a valuable predictor of cardiac events in the patients with ACS.^12,13 However, some studies have reported conflicting results. For example, the research by Obeid S et al indicated that cystatin C did not have predictive value for cardiovascular and cerebrovascular events or all-cause mortality in the patients with ACS, as determined by multivariate cox regression model analysis.¹⁴ This discrepancy underscores the need for further investigation into the role of cystatin C in cardiovascular risk assessment. Despite its potential, the ability of cystatin C to identify high-risk ACS patients has not been thoroughly explored. In this study, we aim to address this gap by comparing cystatin C levels between non-high-risk and high-risk ACS patients. We will investigate the potential association of cystatin C with high-risk profiles in the patients with ACS, and evaluate whether cystatin C provides significant discriminative power in clinical risk stratification for these patients. By clarifying these aspects, our research seeks to contribute to a better understanding of role of cystatin C in ACS and enhance strategies for risk assessment and management for ACS patients.

Patients and Methods

Patients

This study included 219 patients diagnosed with ACS between January 2021 and October 2022. The diagnosis of ACS was based on the established guidelines for the management of ACS.² The diagnosis was determined by evaluating three key indicators: cardiac troponin I levels, clinical presentation, and electrocardiogram findings. ACS is marked by acute chest discomfort, which may manifest as pain, tightness, palpitation, throat discomfort or dyspnea at rest or on minimal exertion. These symptoms are often accompanied by new ischemic changes observed on an electrocardiogram and/or alterations in high-sensitivity cardiac troponin levels.² Patients were excluded if they had a history of cancer, severe liver or renal failure, sepsis, or mental disorders. In addition, the ACS patients with severe gastrointestinal hemorrhage were also excluded from the study. Ethical approval was granted by the Ethics Committee of the Clinical Medical College and Affiliated Hospital of Chengdu University, and informed consent was obtained from all participants. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki.

Data Collection

Clinical data was retrieved from the medical records of patients with ACS, including demographic and clinical characteristics such as age, gender, history of hypertension, diabetes mellitus, smoking status, and lipid profiles. The lipid profiles included total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol. A blood sample was taken and then transported to clinical laboratory after admission as soon as possible. Cystatin C was measured by an automatic biochemical analyzer using immunoturbidimetry assay in the clinical laboratory. NT-proBNP was measured by an automated immunoanalyzer using chemiluminescence method. Serum creatinine was measured by an automatic biochemical analyzer using creatine oxidase assay. Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol were measured by an automatic biochemical analyzer using direct method. Total cholesterol and triglycerides were measured by an automatic biochemical analyzer using oxidase assay.

Risk Assessment of ACS

These patients were stratified into high-risk and non-high-risk groups using either the GRACE risk scores or killip classification. The GRACE risk score was a validated tool used to estimated the risk of mortality in ACS patients. It incorporated clinical and laboratory data at presentation to stratify patients into risk categories, and included eight variables: age, heart rate, systolic blood pressure, killip class, creatine, cardiac arrest, ST deviation, and elevated cardiac enzymes. Each was assigned points, summed for a total score. For the specific calculation method of the GRACE score, please refer to the relevant literature and guidelines.^2,4 For these patients with NSTE-ACS, the high-risk group was defined as those with a GRACE scores greater than 140, while the non-high-risk group had a GRACE scores of 140 or below.¹⁵ Similarly, for those patients with STE-ACS, the high-risk group had a GRACE scores above 154, and the non-high-risk group had a GRACE scores of 154 or below.¹⁵ In addition to GRACE scores, the killip classification was used for further risk stratification. Patients in killip class III-IV were classified as high-risk, which included those with pulmonary edema and cardiogenic shock. In contrast, patients in killip class I-II were considered low-risk, characterized by rales affecting less than 50% of the lung area or the absence of pulmonary rales.^16,17

Statistical Analysis

Continuous variables with a normal distribution were expressed as mean ± standard deviation, while non-normally distributed data was presented as medians with interquartile ranges (25th to 75th percentiles). Categorical variables were reported as proportions. The t-test, Mann–Whitney U test, or χ² test were used to compare variables between groups, depending on the type of data. Receiver operating characteristic (ROC) curve analysis was performed to calculate the area under the curve (AUC) and determine the optimal cut-off value for cystatin C in identifying high-risk ACS patients. Univariate and multivariate logistic regression analyses were conducted to evaluate the association between cystatin C levels and high-risk ACS patients. Statistical analyses were performed using SPSS 26.0. A P-value of <0.05 was considered statistically significant.

Results

Baseline Characteristics of the Patients with ACS

The median age of the patients with ACS was 61 (52 to 72) years, with 79.0% being male, 50.2% having hypertension, 24.7% having diabetes mellitus, and 58.9% being smokers. Risk stratification of ACS patients was conducted using GRACE scores. Among the 219 patients, 126 were classified into the high-risk group, whereas 93 were categorized as non-high-risk. Patients in the high-risk group were older and had significantly higher serum creatinine levels compared to those in the non-high-risk group (P < 0.05). Additionally, the high-risk group exhibited lower triglyceride levels and a smaller proportion of male patients compared to the non-high-risk group (P < 0.05). Interestingly, the smoking prevalence was higher in the non-high-risk group than in the high-risk group (P < 0.05). However, no significant differences were observed between the two groups regarding hypertension, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, or low-density lipoprotein cholesterol levels (P > 0.05) (Table 1). When stratifying ACS patients using the killip classification, 88 patients were categorized as high-risk (killip class III-IV), and 131 patients as non-high-risk (killip class I-II). Similar to the GRACE score findings, the high-risk group in this classification also showed a higher mean age compared to the non-high-risk group (P < 0.05). Moreover, a significantly greater proportion of hypertensive individuals was observed in high-risk group compared to the non-high-risk group (P < 0.05). The serum creatinine and NT-proBNP levels were also higher in high-risk group than that in non-high-risk group (P < 0.05). Other baseline characteristics, including lipid profiles, diabetes mellitus prevalence, and the proportion of smoking and male, were similar between the two groups (P > 0.05) (Table 2).

Table 1.

Baseline Characteristics of Patients with Acute Coronary Syndrome According to GRACE Risk Scores.

Variables	No-high risk goup (n = 93)	High risk group (n = 126)	P
Age (years)	53.20 ± 11.07	67.25 ± 10.57	<0.001
Male, n(%)	80(86.0)	93(73.8)	0.028
hypertension, n(%)	46(49.5)	64(50.8)	0.846
Diabetes mellitus, n(%)	23(24.7)	31(24.6）	0.983
Smoking, n (%)	63(67.7)	66(52.4)	0.022
Serum creatinine (umol/L)	68.19(56.61,79.11)	78.86(64.43,96.78)	<0.001
NST-ACS/ST-ACS	44/49	42/84	0.036
Triglycerides (mmol/L)	1.41(0.93,2.43)	1.24(0.79,1.79)	0.049
Total cholesterol (mmol/L)	4.37 ± 0.99	4.37 ± 1.02	0.977
High density lipoprotein cholesterol (mmol/L)	0.96(0.85,1.11)	1.01(0.88,1.19)	0.063
low density lipoprotein cholesterol (mmol/L)	2.92 ± 0.94	2.91 ± 0.95	0.931

Abbreviations: NST-ACS, non-ST segment elevation acute coronary artery syndrome; ST-ACS, ST segment elevation acute coronary artery syndrome; GRACE, global registry of acute coronary events. Lipids were available from 213 subjects.

Table 2.

Baseline Characteristics of Patients with Acute Coronary Syndrome According to Killip Classification.

Variables	Killip I/II (n = 131)	Killip III/IV (n = 88)	P
Age (years)	59.89 ± 12.30	63.36 ± 13.34	0.049
Male,n (%)	102 (77.9)	71 (80.7)	0.616
hypertension,n (%)	58 (44.3)	52 (59.1)	0.032
Diabetes mellitus,n (%)	36 (27.5)	18 (20.5)	0.237
Smoking,n (%)	76 (58.0）	53 (60.2)	0.744
Serum creatinine (umol/L)	66.47 (55.60,80.60)	83.80 (72.21,104.74)	<0.001
NST-ACS/ST-ACS	57/74	29/59	0.117
Triglycerides (mmol/L)	1.34 (0.80,2.15)	1.31 (0.84,1.92)	0.639
Total cholesterol (mmol/L)	4.28 ± 1.01	4.50 ± 0.98	0.116
High density lipoprotein cholesterol (mmol/L)	0.97 (0.85,1.11)	1.02 (0.89,1.22)	0.069
low density lipoprotein cholesterol (mmol/L)	2.88 ± 0.99	2.96 ± 0.86	0.510
NT-proBNP(pg/ml)	289.00 (104.80,1060.50)	974.65 (218.00,2773.00)	<0.001

Abbreviations: NST-ACS, non-ST segment elevation acute coronary artery syndrome; ST-ACS, ST segment elevation acute coronary artery syndrome;NT-proBNP, N-terminal proBNP. NT-proBNP and lipids were available from 215 and 213 subjects, respectively.

Elevated Cystatin C Levels in High-Risk ACS Patients Stratified by GRACE Scores

We assessed cystatin C levels in patients with ACS, including both NSTE-ACS and STE-ACS subtypes. As demonstrated in Figure 1A, there was no significant difference in cystatin C levels between the NSTE-ACS and STE-ACS groups. However, the cystatin C levels were markedly higher in the high-risk group compared to the non-high-risk group in these patients with ACS(Figure 1B). To further explore this, we conducted a sub-analysis. Among patients with NSTE-ACS, the cystatin C levels were significantly elevated in the high-risk group compared to the non-high-risk group (Figure 1C). A similar pattern was also observed in STE-ACS patients, with the high-risk group showing significantly higher cystatin C levels than the non-high-risk group (Figure 1D).

Figure 1.

Serum cystatin C levels in the patients with acute coronary syndrome(ACS). (A) The comparison of cystatin C levels between the non-ST elevation ACS (NSTE-ACS) patients and ST elevation ACS (STE-ACS) patients. (B) The comparison of cystatin C levels between the ACS patients with high-risk and those with non-high-risk group. (C) The comparison of cystatin C levels between the NSTE-ACS patients with high-risk and those with non-high-risk group. (D) The comparison of cystatin C levels between the STE-ACS patients with high-risk and those with non-high-risk group. Risk stratification was performed based on the global registry of acute coronary events (GRACE) scores. **P < 0.001, *P > 0.05.

Elevated Cystatin C Levels in High-Risk ACS Patients Stratified by Killip Classification

The patients with ACS were categorized into two groups based on the killip classification. As presented in Figure 2A, cystatin C levels were significantly higher in the high-risk group (killip class III-IV) compared to the non-high-risk group (killip class I-II). This trend was further observed in NSTE-ACS patients, where cystatin C levels were elevated in the high-risk group relative to the non-high-risk group (Figure 2B). Similarly, in STE-ACS patients, cystatin C levels remained consistently higher in the high-risk group compared to the non-high-risk group (Figure 2C).

Figure 2.

Serum cystatin C levels in the patients with acute coronary syndrome(ACS). (A) The comparison of cystatin C levels between the ACS patients with high-risk and those with non-high-risk group according to killip classification. (B) The comparison of cystatin C levels between the non-ST elevation ACS(NSTE-ACS) patients with high-risk and those with non-high group according to killip classification. (C) The comparison of cystatin C levels between the ST elevation ACS(STE-ACS) patients with high-risk and those with non-high group according to killip classification. *P < 0.001.

Value of Cystatin C to Discriminate High Risk ACS Patients Defined by GRACE Scores

ROC curve analysis was used to examined the ability of cystatin C to distinguish high-risk ACS patients from non-high-risk patients, as defined by GRACE scores. In all high-risk ACS patients, the area under the curve (AUC) for the levels of cystatin C to distinguish high-risk ACS patients was 0.749 [95% confidence interval (CI)= 0.684–0.814, P < 0.001], with a sensitivity and a specificity of 0.659 and 0.763(Figure 3A). The optimal cut-off value for cystatin C as a discriminative marker of high-risk ACS patients was 1.105. In the NSTE-ACS subgroup, the AUC was 0.779 (95% CI = 0.672–0.885, P < 0.001), with a sensitivity of 0.786 and a specificity of 0.773, and a cut-off value of 1.105 (Figure 3B). In the STE-ACS subgroup, the AUC was 0.752 (95% CI = 0.671–0.834, P < 0.001), with a sensitivity of 0.738, a specificity of 0.673, and a cut-off value of 1.045 (Figure 3C).

Figure 3.

Receiver operating characteristic (ROC) curve of cystatin C in acute coronary syndrome(ACS) patients. (A) ROC curve of cystatin C for identifying high-risk ACS patients according to GRACE scores (P < 0.001). (B) ROC curve of cystatin C for identifying high-risk non-ST elevation ACS(NSTE-ACS) patients according to GRACE scores(P < 0.001). (C) ROC curve of cystatin C for identifying high-risk ST elevation ACS(STE-ACS) patients according to GRACE scores (P < 0.001). ACS included NSTE-ACS and STE-ACS. GRACE: Global registry of acute coronary events.

Discriminatory Value of Cystatin C for Identifying High-Risk ACS Patients Based on Killip Classification

For all high-risk ACS patients based on the killip classification, the AUC for cystatin C levels was 0.844 (95% CI = 0.789–0.898, P < 0.001), with a sensitivity of 0.841 and a specificity of 0.763, and a cut-off value of 1.105 (Figure 4A). In the NSTE-ACS subgroup, the AUC was 0.845 (95% CI = 0.746–0.945, P < 0.001), with a sensitivity of 0.897, a specificity of 0.754, and a cut-off value of 1.135 (Figure 4B).

Figure 4.

Receiver operating characteristic (ROC) curve of cystatin C in acute coronary syndrome(ACS) patients. (A) ROC curve of cystatin C for identifying high-risk ACS patients (P < 0.001). (B) ROC curve of cystatin C for identifying high-risk non-ST elevation ACS(NSTE-ACS) patients(P < 0.001). (C) ROC curve of cystatin C for identifying high-risk ST elevation ACS(STE-ACS) patients(P < 0.001). ACS included NSTE-ACS and STE-ACS. Risk stratification was performed based on killip classification.

In the STE-ACS subgroup, the AUC was 0.859 (95% CI = 0.795–0.923, P < 0.001), with a sensitivity of 0.898, a specificity of 0.743, and a cut-off value of 1.065 (Figure 4C).

Association of Cystatin C with High-Risk ACS Patients

The ACS patients were classified into two group accordding to the cystatin C cut-off value. In those patients classified as high-risk according to GRACE scores, univariate logistic regression revealed that elevated cystatin C levels were significantly associated with high-risk ACS(OR = 6.229, 95%CI = 3.406–11.392, P < 0.001). To further assess whether cystatin C is an independent predictor of high-risk ACS, multivariate logistic regression was performed, after adjusting for other variables including age, gender, hypertesion, diabetes mellitus, smoking, types of ACS, lipid levels. cystatin C remained an independent predictor with an adjusted OR of 5.637 (95% CI =2.699–11.774, P < 0.001). Similarly, in high-risk patients based on the killip classification, the association between cystatin C and high-risk ACS persisted, the OR for the univariate analysis was 17.051(95% CI =8.475–34.302, P < 0.001), while the OR for the multivariate analysis was 20.003(95% CI =9.445–42.361, P < 0.001).

Discussion

Our study had provided robust evidence that elevated cystatin C levels were significantly associated with high-risk ACS patients. Notably, we observed that cystatin C exhibits a substantial degree of accuracy in identifying these high-risk individuals with ACS. These findings align with a growing body of literature, further reinforcing the potential utility of cystatin C as a prognostic biomarker in the patients with ACS.

As a low-molecular-weight endogenous protein composed of 122 amino acids, cystatin C concentrations were less influenced by factors such as sex, physical activity, diet, or muscle mass,⁶ suggesting that cystatin C may be an ideal biomarker for certain diseases. Previous studies have also reported an association between cystatin C and atherosclerotic cardiovascular disease. The elevated levels of cystatin C in diseases involving vascular endothelial cell damage, such as atherosclerosis, are well-documented. In elderly hypertensive patients, cystatin C levels were significantly higher in those with two-vessel or three-vessel disease compared to those with single-vessel disease, suggesting that cystatin C levels were positively correlated with the degree of coronary stenosis.¹⁸ similar associations between cystatin C levels and degree of coronary stenosis were found by another study,¹⁹ which demonstrated that cystatin C was positively correlated with the gensini score, a measure of plaque burden in coronary lesions. Further studies have also reported that serum cystatin C levels in ACS patients increased in accordance with the severity of coronary lesion.^9,20 This relationship extends to carotid artery disease, where elevated cystatin C concentrations have been associated with intima-media thickness and plaque burden of the common carotid.²¹ Additional analysis showed the high concentrations of cystatin C were linked to stenosis in both the common and extracranial internal carotid arteries.²¹ Furthermore, cystatin C levels have also been shown to correlate with intima-media thickness and plaque thickness in the carotid arteries.^22–24 In addition, An increasing number of studies have found that cystatin C levels were significantly elevated in patients with coronary artery disease or ACS compared to those without these conditions.^18,25,26 Therefore, the above literatures mentioned suggested that cystatin C might play a role in the atherosclerotic process and contribute to the progression of atherosclerotic cardiovascular disease. Moreover, the study by Gu FF et al demonstrated that cystatin C was notably higher in unstable angina group compared to stable angina group, and positively associated with area and burden of plaque in patients with unstable angina.²⁵ In addition, Huang et al reported that cystatin C levels was increased in ACS patients aged over 60 years compared to those without ACS.²⁶ High cystatin C concentration was more likely to promote unstable atherosclerotic plaques in cases of acute cerebral infarction.²¹ Taken together, this body of evidence supported the role of cystatin C as a marker of plaque instability, which is a crucial factor in the pathogenesis of ACS. Thus, cystatin C should be viewed not merely as a biomarker for vascular damage but as an indicator of ACS-related pathological processes, including plaque destabilization, rupture, and systemic inflammation.⁸

Beyond its association with atherosclerotic disease, cystatin C had also been linked to traditional cardiovascular risk factors such as age, blood pressure, HbA1c, and metabolic syndrome.^9,18,27 The associations between cystatin C levels and both arteriosclerotic cardiovascular disease and its associated risk factors revealed the complex relationship between cystatin C and the pathophysiological processes leading to ACS. Thus, cystatin C may reflect not only the direct effects of vascular injury but also the cumulative burden of cardiovascular risk factors that predispose individuals to ACS. Elevated cystatin C levels, therefore, may serve as an integrative biomarker that encapsulates both endothelial dysfunction and the systemic metabolic disturbances characteristic of high-risk ACS patients.

Besides, cystatin C had also shown potential in predicting cardiovascular outcomes, particularly in identifying individuals at heightened risk for ACS. For instance, the study showed that cystatin C have great prognostic value of risk of heart failure.²⁸ Further evidence suggested that cystatin C was associated with long-term mortality of patients with acute chest pain, and remained statistically significant even after adjusting for other variables such as the GRACE scores.²⁹ our study revealed that cystatin C levels were notably higher in patients classified as high-risk according to GRACE scores, a well-established tool for predicting mortality risk in ACS patients. Meanwhile, multivariate logistic regression analysis showed that elevated cystatin C levels were significantly associated with an increased ischemic risk of ACS. Our findings were consistent with those of previous studies,^29,30 which suggested that higher cystatin C concentrations were linked to an increased risk of mortality in ACS patients. In addition, we also found that cystatin C levels were significantly higher in patients classified as high-risk (killip class III or IV) compared to those in the non-high-risk group (killip class I or II), further supporting its role in predicting the severity of acute coronary symdrome and adverse outcomes.

The elevation of cystatin C concentrations may be linked to multiple factors, such as inflammatory stimuli and immune response related to atherosclerosis.^8,9 Moreover, high risk patients, such as those with killip classifications III and IV are often characterized by conditions like pulmonary edema, low blood pressure, poor tissue perfusion, or multi-organ failure, all of which might impair renal function and contribute to elevated cystatin C levels. Furthermore, cystatin C levels in the blood can also be influenced by chronic renal dysfunction.⁶ It is important to understand that some ACS patients may have underlying chronic renal dysfunction even prior to the onset of acute coronary events. In this study, we excluded patients with severe renal dysfunction. However, serum creatinine levels indicated that some of the enrolled patients had mild renal dysfunction, as shown in Tables 1 and 2. The elevation of cystatin C could be at least partly attributed to acute kidney injury or chronic kidney disease, but we coluld not differentiate the specific cause of cystatin C elevation. Renal dysfunction, whether acute or chronic, is more likely to be associated with high-risk ACS patients, this was also supported by literature.² The future studies should explore the association between cystatin C and high-risk ACS patients, based on the presence or absence of chronic kidney disease. Moreover, our findings indicated that cystatin C was a relatively sensitive biomarker for identifying individuals predisposed to the high-risk states associated with ACS. The elevation of cystatin C also contributed to increase ischemic risk of ACS. This was comfirmed by ROC analysis in current study. Collectively, cystatin C may be an overall indicator of pathophysiological abnormalities in patients with ACS.

The precise mechanisms linking cystatin C to ischemic risk of ACS warranted further investigation. Cystatin C plays an important physiological role, particularly as an inhibitor of cysteine proteinases, which affected the production of extracellular and intracellular proteins, cell metabolism processes, lipid metabolism, and immune response.⁶ The onset of ACS is typically triggered by plaque destabilization, rupture, and increased coagulation activity. Inflammation and immune responses play a central role in driving the plaque phenotypic changes. Given this context, the probable mechanisms of action of cystatin C throughout the cardiovascular system are as follows: firstly, by inhibiting cathepsins, cystatin C helps regulate extracellular matrix degradation and prevent excessive remodeling. In the context of ACS, where tissue remodeling is elevated, maintaining a dynamic balance between cystatin C and cysteine proteases may act as a protective mechanism against pathological vascular and myocardial remodeling by limiting protease activity.^20,31,32 Secondly, cystatin C is expressed in the vascular wall and can impact endothelial cell function by modulating protease activity, which influences cell migration, proliferation, and barrier function. It helps maintain endothelial cell integrity, thereby protecting against damage to the vascular wall and endothelial cells.^6,31 Thirdly, cystatin C can modulate inflammatory processes by inhibiting proteases that activate pro-inflammatory cytokines, and regulate monocyte or macrophage function, both of which play key roles in atherosclerosis, plaque instability, and thrombus formation.^8,33,34 The observed correlation between cystatin C and other inflammatory markers such as C-reactive protein (CRP), fibrinogen, and the neutrophil-to-lymphocyte ratio further supports the hypothesis that cystatin C plays a significant role in the inflammatory pathways that drive atherosclerosis and ACS.⁹ Further research is needed to elucidate the biological pathways through which cystatin C influences ACS risk, potentially uncovering novel therapeutic targets and preventive strategies.

Several limitations should be acknowledged in the study. Firstly, the cross-sectional observational nature of our study design and potential confounding factors may limit the generalizability of results across diverse patient populations. Secondly, being a single-center study, it is subject to potential biases that could affect the robustness of our findings. To address these issues, future multicenter and prospective studies are necessary to validate the prognostic utility of cystatin C and refine ACS risk prediction models. Furthermore, although we evaluated the risk of ACS using widely accepted clinical scoring systems such as the GRACE score and killip classification, our study did not include coronary angiography, which is considered the gold standard for diagnosing ACS. This limitation may impact the accuracy of our findings and should be addressed in future studies.

Conclusion

In this study, the increased cystatin C was associated with high-risk patients with ACS. Cystatin C emerges as a promising biomarker for identifying individuals at high risk for ACS with a reliable accuracy. Our findings support the incorporation of cystatin C into clinical practice to improve cardiovascular risk assessment and clinical management. Continued research efforts are essential to validate the clinical utility of cystatin C, and elucidate its mechanistic role in ACS pathogenesis.

Footnotes

Acknowledgements

Not applicable

Authors’ Contributions

XXL designed the study, and drafted the main manuscript. XXL,YL, LXB, HS, LL and AMS collected the relevant data. XXL,YL,HS,AMS,LXB,LL analyzed the relevant data. XXL reviewed and edited the writing. All authors read and approved the final manuscript.

Availability of Data and Materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Consent for Publication

Not applicable

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics Approval and Consent to Participate

The study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Ethical approval was granted by the Ethics Committee of the Clinical Medical College and Affiliated Hospital of Chengdu University, and informed consent was obtained from all participants.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Xinlin Xiong

References

Ralapanawa

Sivakanesan

. Epidemiology and the magnitude of coronary artery disease and acute coronary syndrome: A narrative review. J Epidemiol Glob Health. 2021;11(2):169–177.

Byrne

Rossello

Coughlan

, et al. 2023 ESC guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720–3826.

Safiri

Karamzad

Singh

, et al. Burden of ischemic heart disease and its attributable risk factors in 204 countries and territories,1990-2019. Eur J Prev Cardiol. 2022;29(2):420–431.

Fox

Eagle

Gore

Steg

Anderson

, GRACE And GRACE2 investigators. The global registry of acute coronary events, 1999 to 2009–GRACE. Heart. 2010;96(14):1095–1101.

Martha

Sihite

Listina

. The difference in accuracy between global registry of acute coronary events score and thrombolysis in myocardial infarction score in predicting in-hospital mortality of acute ST-elevation myocardial infarction patients. Cardiol Res. 2021;12(3):177–185.

Spencer

Desborough

Bhandari

. Should cystatin C eGFR become routine clinical practice? Biomolecules. 2023;13(7):1075.

Malmgren

Öberg

den Bakker

, et al. The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation. J Intern Med. 2023;293(3):293–308.

Taglieri

Koenig

Kaski

JC.

Cystatin C and cardiovascular risk. Clin Chem. 2009;55(11):1932–1943.

Mao

Zhao

Wang

, et al. Association of cystatin C with metabolic syndrome and its prognostic performance in non-ST-segment elevation acute coronary syndrome with preserved renal function. Biomed Res Int. 2019;2019:8541402.

10.

Sai

Shimada

Miyauchi

, et al. Increased cystatin C levels as a risk factor of cardiovascular events in patients with preserved estimated glomerular filtration rate after elective percutaneous coronary intervention with drug-eluting stents. Heart Vessels. 2016;31(5):694–701.

11.

Akgul

Uyarel

Ergelen

, et al. Predictive value of elevated cystatin C in patients undergoing primary angioplasty for ST-elevation myocardial infarction. J Crit Care. 2013;28(5):882.e13–20.

12.

Brankovic

Kardys

van den Berg

, et al. Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome: BIOMArCS study. Int J Cardiol. 2020;299:12–19.

13.

Taglieri

Fernandez-Berges

Koenig

, et al. Plasma cystatin C for prediction of 1-year cardiac events in Mediterranean patients with non-ST elevation acute coronary syndrome. Atherosclerosis. 2010;209(1):300–305.

14.

Obeid

Yousif

Davies

, et al. Prognostic role of plasma galectin-3 levels in acute coronary syndrome. Eur Heart J Acute Cardiovasc Care. 2020;9(8):869–878.

15.

https://www.outcomes-umassmed.org/grace/grace_risk_table.aspx .

16.

Armillotta

Amicone

Bergamaschi

, et al. Predictive value of Killip classification in MINOCA patients. Eur J Intern Med. 2023;117:57–65.

17.

El-Menyar

Zubaid

AlMahmeed

, et al. Killip classification in patients with acute coronary syndrome: Insight from a multicenter registry. Am J Emerg Med. 2012;30(1):97–103.

18.

Wang

Zhang

Yang

Wang

. Correlation between serum cystatin C level and elderly hypertensive patients combined coronary heart disease. Int J Clin Exp Med. 2015;8(4):6287–6290.

19.

Zhang

Gao

Yan

. Correlations of serum cystatin C and glomerular filtration rate with vascular lesions and severity in acute coronary syndrome. BMC Cardiovasc Disord. 2017;17(1):47.

20.

Chen

Shen

Pan

, et al. Association of serum cystatin C level with coronary atherosclerotic plaque burden: A comprehensive analysis of observational studies and genetic study. BMC Cardiovasc Disord. 2023;23(1):499.

21.

Ren

Dong

Nao

. Serum cystatin C is associated with carotid atherosclerosis in patients with acute ischemic stroke. Neurol Sci. 2020;41(10):2793–2800.

22.

Huang

Yao

. Carotid artery color Doppler ultrasonography and plasma levels of lipoprotein-associated phospholipase A2 and cystatin C in arteriosclerotic cerebral infarction. J Int Med Res. 2019;47(9):4389–4396.

23.

Kobayashi

Yokokawa

Fujibayashi

, et al. Association between high cystatin C levels and carotid atherosclerosis. World J Cardiol. 2017;9(2):174–181.

24.

Zhu

Zhang

Wang

, et al. Serum cystatin C level is associated with carotid intima-media thickening and plaque. Scand J Clin Lab Invest. 2015;75(3):265–272.

25.

Lü

Chen

, et al. Relationship between plasma cathepsin S and cystatin C levels and coronary plaque morphology of mild to moderate lesions: An in vivo study using intravascular ultrasound. Chin Med J (Engl). 2009;122(23):2820–2826.

26.

Huang

Shen

, et al. Association of serum cystatin C levels with acute coronary syndrome in patients of advanced age. J Int Med Res. 2019;47(5):1987–1997.

27.

Peralta

Whooley

, et al. Kidney function and systolic blood pressure new insights from cystatin C: data from the Heart and Soul Study. Am J Hypertens. 2006;19(9):939–946.

28.

Shlipak

Anderson

, et al. Risk factors for heart failure in patients with chronic kidney disease: The CRIC (chronic renal insufficiency cohort). Study J Am Heart Assoc. 2017;6(5):e005336.

29.

Eggers

Kempf

Venge

Wallentin

Wollert

Lindahl

Improving long-term risk prediction in patients with acute chest pain: The G

lobal Registry of Acute Coronary Events (GRACE) risk score is enhanced by selected nonnecrosis biomarkers. Am Heart J. 2010;160(1):88–94.

30.

Saito

Arashi

Yamaguchi

Mori

Ogawa

Hagiwara

. Elevated cystatin-C levels are associated with increased mortality in acute coronary syndrome patients: An HIJ-PROPER sub-analysis. Cardiorenal Med. 2022;12(1):20–28.

31.

Sawada

. Cystatin C as a promising biomarker of atherosclerotic plaque. J Atheroscler Thromb. 2021;28(5):474–476.

32.

Xie

Terrand

Tsaprailis

Boyer

Chen

. Cystatin C increases in cardiac injury: A role in extracellular matrix protein modulation. Cardiovasc Res. 2010;87(4):628–635.

33.

Nishimura

Honda

Yuzaki

, et al. Serum cystatin C level as a biomarker of aortic plaque in patients with an aortic arch aneurysm. J Atheroscler Thromb. 2021;28(5):506–513.

34.

Ganda

Magnusson

Yvan-Charvet

, et al. Mild renal dysfunction and metabolites tied to low HDL cholesterol are associated with monocytosis and atherosclerosis. Circulation. 2013;127(9):988–996.

Cystatin C as a Biomarker for Identifying High-Risk Patients with Acute Coronary Syndrome: An Observational Study

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Patients and Methods

Patients

Data Collection

Risk Assessment of ACS

Statistical Analysis

Results

Baseline Characteristics of the Patients with ACS

Elevated Cystatin C Levels in High-Risk ACS Patients Stratified by GRACE Scores

Elevated Cystatin C Levels in High-Risk ACS Patients Stratified by Killip Classification

Value of Cystatin C to Discriminate High Risk ACS Patients Defined by GRACE Scores

Discriminatory Value of Cystatin C for Identifying High-Risk ACS Patients Based on Killip Classification

Association of Cystatin C with High-Risk ACS Patients

Discussion

Conclusion

Footnotes

Acknowledgements

Authors’ Contributions

Availability of Data and Materials

Consent for Publication

Declaration of Conflicting Interests

Ethics Approval and Consent to Participate

Funding

ORCID iD

References