Relationship Between Syntax Score and Cystatin C in Patients with Acute Coronary Syndrome

Kenan Toprak

Department of Cardiology, Harran University Faculty of Medicine, Şanlıurfa, Türkiye

Keywords: Syntax score; cystatin C; ST-elevation myocardial infarction

Abstract

Introduction: The SYNTAX (SYNergy between PCI with TAXUS and Cardiac Surgery) score (SS) is an angiographic scoring system to determine the severity of coronary artery disease (CAD). As far as we know, studies examining the relationship between SYNTAX Score and Cystatin C (Cys-C) are limited in the literature. In this study, we aimed to investigate the relationship between Cys-C level and SS in patients presenting with ST-elevation myocardial infarction (STEMI).

Patients and Methods: One hundred ninety-two patients who underwent coronary angiography for STEMI between June 2021 and December 2021 in our center were included in the study. The patients were divided into two groups according to their SS values: Group 1 included patients with SS<22, and Group 2 included patients with SS≥ 22. The two groups were compared in terms of baseline characteristics and serum Cys-C levels.

Results: Patients in Group 2 had significantly higher Cys-C levels than those in Group 1 (1.7 ± 0.53 vs 1.3 ± 0.29; p= 0.006). In the correlation analysis, SS showed a positive correlation with the Cys-C level (r= 0.189, p= 0.015). Multivariate logistic regression analysis showed that Cys-C level was an independent predictor of high SS (β=0.306, p= 0.006). When receiver operating characteristic (ROC) curve analysis was performed, the optimal cut-off value of Cys-C to predict severe coronary artery disease (indicating high SS) was Cys-C≥ 1.56, which was predictive for severe coronary artery disease with 74% sensitivity and 72% specificity [area under the curve (AUC)= 0.745, 95% confidence interval (CI)= 0.624-0.835, p<0.001).

Conclusion: Cystatin C levels are independently associated with high SS in STEMI patients. In summary, our findings show that Cys-C is a promising clinical biomarker that can be used to assess the severity of coronary artery lesions, potentially providing additional information to established risk markers.

Introduction

Coronary artery disease (CAD), a major cause of morbidity and mortality worldwide, remains one of the most pressing public health issues among cardiovascular diseases(1). Cystatin C or Cystatin 3 (formerly gamma trace, post-gamma-globulin, or neuroendocrine basic polypeptide), a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function(2). Epidemiological studies show that high circulating Cys-C is associated with a risk of cardiovascular disease (CVD), independent of creatinine-based renal function(3,4).

With the advancement of technology, intravascular ultrasound (IVUS) has become another accurate tool for assessing atherosclerotic burden(5,6). The limitations of IVUS are cost and availability, as most CAD registries continue to use angiography to assess atherosclerosis severity. SYNTAX (SYNergy between PCI with TAXUS and Cardiac Surgery) score (SS) is used as an angiographic scoring system to evaluate the severity and extent of CAD(7). Coronary angiography has potential consequences such as radiocontrast nephropathy, vascular rupture, and hematoma, and it is not cost-effective to perform on every patient. This emphasizes the importance of noninvasive detectors (such as biomarkers) in predicting the risk and burden of CAD and taking appropriate protective measures. Although studies suggest that Cys-C may be a promising marker in this regard, the data in the literature are insufficient. Therefore, in this study, we tried to reveal the relationship of Cys-C with atherosclerotic extensivity and severity, as verified by the SYNTAX score.

Materials and Methods

Trial Design and Study Population

The study had a single center and a cross-sectional design. A total of 192 patients who underwent coronary angiography for STEMI between June 2021 and December 2021 in our center were included. Patients were divided into two groups according to their SS: Group 1 (SS< 22, mild CAD) and Group 2 (SS≥ 22, severe CAD). Patients with known CAD, severe heart valve disease, heart failure, malignancy, acute infection, severe liver disease, and renal failure and patients without written consent were excluded from the study. Type 2 diabetes mellitus was defined as a fasting blood glucose level of ≥126 mg/dL and/or previous diagnosis and treatment of diabetes (8). Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or using antihypertensive therapy and/or having known hypertension(9). STEMI diagnosis and treatment were made according to current guidelines(10).

The study was approved by the ethics committee of XXX Faculty of Medicine and was performed in accordance with the guidelines of the Declaration of Helsinki. Informed consent was obtained from all patients.

Biochemical Analysis

After the patients were admitted for coronary angiography, venous blood samples were taken into biochemistry tubes to study the serum Cys-C levels before the procedure. Samples were centrifuged at 4000 rpm for 15 minutes and serum were stored at -80°C until the day of analysis. Then, the Cys-C levels of all participants were studied simultaneously using the same serum samples. The enzyme-linked immunosorbent assay (ELISA) was used to measure serum Cys-C.

Coronary angiography

The Judkins technique was used to perform coronary angiography via the radial or femoral route. Two independent cardiologists reviewed all angiographic images. The SYNTAX score was calculated as follows: According to the American Heart Association (AHA) classification, the coronary tree was divided into 16 segments. Scores assigned to each lesion identified in the coronary tree with >50% diameter narrowing in vessels >1.5 mm in diameter were added. Each segment was given 1 or 2 points according to the presence of the disease. This score was then weighted according to values ranging from 3.5 for the proximal left anterior descending artery (LAD) to 5.0 for the left main and 0.5 for the smaller branches (11).

Statistical Analysis

Statistical Program for Social Sciences 20 (IBM SPSS, Chicago, IL, USA) was used for all statistical calculations. The Kolmogorov-Smirnov test was used to test the normal distribution of the data. Continuous variables were expressed as mean ± SD or median (interquartile range) and compared with Student’s t or Mann-Whitney U tests according to distribution. Categorical variables were expressed as percentages and numbers, and compared with the Chi-square test. Spearman’s correlation analysis was performed to determine the correlation of SS with other continuous variables. In addition, multivariate logistic regression analysis was performed to identify independent predictors of high SS. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimum cut-off value of the Cys-C level for predicting a high SYNTAX score. The statistical significance level was accepted as p< 0.05.

Results

A total of 192 patients were included in the study. The demographic and clinical characteristics of the patients are given in Table 1. There was no significant difference between the two groups in terms of baseline demographic characteristics. However, Cys-C levels in Group 2 were significantly higher than in Group 1 (p= 0.006). In the correlation analysis, there was a positive correlation between the SYNTAX score and Cystatin C (r= 0.189, p= 0.015) (Table 2). Multivariate logistic regression analysis was performed to identify independent predictors of high SS. Cys-C and smoking were found to independently predict high SS in multivariate logistic regression analysis (β= 0.310, t= 2.759, p= 0.006; β= 0.230, t= 2.019, p= 0.045; respectively) (Table 3). The best cut-off value of Cystatin C in predicting high SS was determined by receiver operating characteristic (ROC) analysis (Figure 1). When ROC curve analysis was performed, the optimal cut-off value of Cys-C to predict severe CAD (indicating high SS) was ≥1.56; which was predictive for severe CAD with 74% sensitivity and 72% specificity [area under the curve (AUC)= 0.745, 95% confidence interval (CI)= 0.624-0.835, p< 0.001].

Table 1. Demographic and characteristic features of patients

Table 2. Correlation analysis between SYNTAX score, cystatin C, and other parameters

Table 3. Multivariate linear regression analysis showing independent predictor of high SYNTAX score

Figure 1. ROC curve analysis of Cystatin C predicting high SYNTAX score. AUC: Area under the curve.

Discussion

In this study, the aim was to examine the relationship between Cys-C and the presence of severe CAD. The main finding of our study was that serum Cys-C levels were independently associated with high SYNTAX scores, which indicate severe CAD in STEMI patients. The findings of our study suggest that there may be a possible relationship between Cys-C level and the severity of CAD. The higher the levels of Cys-C, the higher the SYNTAX score, indicating greater severity of atherosclerotic burden in the coronary arteries. Our findings suggest that the serum level of Cys-C could be a promising biomarker for detecting the extent and severity of atherosclerotic vessel disease.

Coronary angiography is used as the gold standard diagnostic method in determining the severity of CAD(12). For this reason, some scoring systems based on angiographic imaging have been developed. SS is a scoring system used angiographically to determine the severity and extent of CAD. The number, location, and functional significance of the lesions are all evaluated in this scoring system(12,13). Studies have shown a relationship between high SS and adverse cardiac events(14). Therefore, this scoring system is accepted as an independent prognostic marker widely used in CAD patients.

Atherosclerosis is a complex disease of the arteries characterized by endothelial dysfunction, vascular inflammation, and subintimal lipid deposition. Although the underlying mechanisms are controversial, many cardiometabolic risk factors facilitate the development of atherosclerosis. As the disease progresses, the formation of an atherosclerotic plaque causes the development of acute coronary syndrome, which results in platelet activation and thrombus formation after plaque erosion or rupture(15). Previous studies have found a strong link between high Cys-C serum levels and stable CAD, acute coronary syndrome (ACS), non-ST-elevation acute coronary syndrome (NSTEMI), and ST-elevated myocardial infarction (STEMI)(16-20). When the relationships between Cys-C and CAD severity were evaluated, we found a positive correlation between Cys-C serum levels and SYNTAX score. The results of our study are consistent with some past studies proving that elevated Cys-C levels are associated with the severity of CAD(18-20).

Several previous studies have demonstrated a link between SYNTAX score and CAD prognosis, such as mortality and disease progression(14,21,22). However, few studies have highlighted the role of Cys-C in predicting the severity of atherosclerotic vessel prevalence(19,20). The association of high Cys-C with mortality and morbidity has also been demonstrated in several cohort studies(23-27). Furthermore, previous research has shown an independent relationship between Cys-C and the number of narrowed vessels(28). These observations confirmed that Cys-C levels may not be merely an indicator of renal dysfunction and thus may represent more than just a marker of renal function. Thus, Cys-C may be a more potent biomarker for predicting the severity and adverse outcomes of CAD.

Cystatin C is expressed in nucleated cells, regulates the activity of cysteine protease, and plays a role in the dynamic balance of production and degradation of the extracellular matrix (ECM). Cys-C and its fragments can also affect the phagocytic and chemotactic ability of neutrophils, participate in the inflammatory process and modulate inflammatory responses(29). Inflammation plays an important role in the development of atherosclerosis(30,31). Several studies have shown that an imbalance in cysteine protease and its inhibitor leads to the degradation of the extracellular matrix and the development of atherosclerosis by directing monocytes, macrophages, and vascular smooth muscle cells to the intima(32,33). Cysteine proteinase, the major enzyme in ECM degradation, and its inhibitor as Cys-C is expressed in the plaque. An excess of cysteine proteinase over Cys-C may contribute significantly to ECM destruction rendering the plaque more prone to rupture. ECM disruption and positive arterial remodeling are closely associated with plaque destabilization, suggesting that cysteine proteinase-Cys-C imbalance may facilitate plaque sensitivity as a result of ACS(34). Several studies found that in patients with NSTE-ACS and increased cardiac troponin T concentrations, high plasma Cys-C concentrations are associated with a higher risk of death and spontaneous MI and there is evidence that both elastolytic cysteine proteases and their inhibitors, such as Cys-C, are involved in the pathogenesis of atherosclerosis(35,36). Therefore, protease-antiprotease imbalance may be the main factor underlying the close relationship between Cys-C and acute coronary syndrome. As we found in our study, the high Cys-C levels in patients with high SYNTAX scores can be explained by the fact that as the atherosclerotic load increases, the protease-antiprotease balance in the atherosclerotic plaque deteriorates and the protective mechanisms are upregulated at that rate in the acute period. A previous experimental study showed that the absence of the protease inhibitor Cys-C in inflammatory cells resulted in a larger area of atherosclerotic plaque and induced atherosclerosis in an atherosclerotic mouse model(32). This can be explained by counterregulatory upregulation so a negative feedback loop in the upregulation of Cys-C to counteract the increased elastolysis activity.

In addition, a renal mechanism might be another potential link between increased Cys-C and CAD and its severity. Several studies have demonstrated that early renal dysfunction is a strong and independent risk for CAD(37,38). Systemic microinflammation response would accelerate the progression of atherosclerosis in CAD patients with early renal impairment. The systemic microinflammatory response has been found to accelerate the progression of atherosclerosis in CAD patients with early renal failure(39).

In this study, high serum Cys-C levels were found to be consistent with a high SYNTAX score. This suggests that Cys-C has an active role in the biological process that leads to the instability and formation of atherosclerotic plaque and therefore, Cys-C level may be a promising clinical biomarker to predict the severity and prognosis of CAD.

The most significant limitation of our study was that it was a cross-sectional study with a small number of patients. Secondly, only patients with a diagnosis of STEMI were included in the study, and other patients with acute coronary syndrome were not evaluated. Finally, there was no control group with normal coronary arteries in our study. We believe that prospective studies with larger populations are needed to confirm our findings.

Conclusion

Our findings show that Cys-C levels are higher in those with severe CAD than in those with mild CAD and are significantly related to CAD severity. This implies that Cys-C may be an independent predictor of CAD severity, as verified by the SYNTAX score. Further research is needed to clarify the pathophysiological mechanisms responsible for this association.

Cite this article as: Toprak K. Relationship between syntax score and cystatin C in patients with acute coronary syndrome. Koşuyolu Heart J 2022;25(3):219-225.

Ethics Committee Approval

The study was approved by the ethics committee of Harran University Clinical Research Ethics Committee (Decision no: 22/03/02, Date: 07.02.2022). and was performed in accordance with the guidelines of the Declaration of Helsinki.

Peer Review

Externally peer-reviewed.

Author Contributions

Concept/Design - KT; Analysis/Interpretation - KT; Data Collection - KT; Writing - KT; Critical Revision - KT; Final Approval - KT; Statistical Analysis - KT; Overall Responsibility - KT.

Conflict of Interest

The author declares no conflict of interest

Financial Disclosure

The author declared that this study has received no financial support.

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Figure and Tables

Figure 1. ROC curve analysis of Cystatin C predicting high SYNTAX score. AUC: Area under the curve.
Table 1. Demographic and characteristic features of patients
Table 2. Correlation analysis between SYNTAX score, cystatin C, and other parameters
Table 3. Multivariate linear regression analysis showing independent predictor of high SYNTAX score