In the present study, we demonstrated that in asymptomatic MetS patients without prior diagnosed CAD and with normal creatinine-based eGFR, elevated serum cystatin C was independently associated with the presence of asymptomatic CAD, even in an adjusted model. Serum cystatin C levels were positively and significantly correlated with the Gensini score. Furthermore, a positive association was also illustrated between serum cystatin C concentrations and the number of coronary arteries with luminal stenosis vessels. To the best of our knowledge, the study is the first to identify cystatin C as an independent risk factor for the development and severity of asymptomatic CAD in subjects with MetS and normal creatinine-based eGFR.
It is well recognized that patients with impaired renal function are at significantly higher risk for cardiovascular disease, congestive heart failure, all-cause mortality and adverse long-term outcomes in contrast to patients without renal disease [25
]. Cystatin C has been regarded as a novel sensitive marker for the assessment of renal function, and the role of cystatin C as a predictor of cardiovascular events in patients with impaired renal function has been confirmed in clinical studies. In this study we assessed the association between cystatin C and asymptomatic CAD in a consecutive series of MetS patients with normal kidney function in order to avoid the well-known effect of overt renal insufficiency on coronary atherosclerosis, and evaluate whether cystatin C has an ability to identify individuals at a higher risk for CAD among patients belonging to a low-risk category according to eGFR. The current study demonstrated that serum levels of cystatin C, but not sCr and eGFR, were independently associated with the development of asymptomatic CAD, even after a variety of potential confounders were controlled. In accordance with our study, Wang et al. demonstrated elevated cystatin C was associated with the presence of CAD in subjects with mild renal impairment, while creatinine and eGFR were not able to predict CAD occurrence [28
]. Similar findings were also observed by Koenig and his colleagues [29
], who reported that cystatin C was superior to creatinine or eGFR for predicting cardiovascular events in a cohort of 1033 patients with CAD. Recently, the close relationship between cystatin C and all-cause cardiovascular mortality has been illustrated in subjects with normal eGFR [30
], which further confirmed that cystatin C may not simply be regarded as an indicator of the association between renal dysfunction and an increased risk of CAD, the information contained by cystatin C represents more than just a marker of renal function.
Although cystatin C was independently associated with the presence of asymptomatic CAD,in the ROC analysis, the AUC for cystatin C falls into the range 0.6–0.7, which indicates the predictive value of cystatin as a sole marker was only moderate, and the cut-off value of 0.825
mg/L can not be categorized as ideal value to identify asymptomatic CAD effectively. Nevertheless, the addition of cystatin C may compensate for the inadequacy of. other classical parameters such as FRS for asymptomatic CAD. Future studies should investigate the feasibility of combined use of cystatin C and other parameters to improve the predictive value the presence of asymptomatic CAD.
In addition, when the associations between cystatin C and severity of asymptomatic CAD were evaluated, we found a positive relationship between serum levels of cystatin C and the number of diseased vessels. A positive association was also found between serum cystatin C levels and the Gensini score independent of eGFR, even after adjustment for established risk factors associated with cardiovascular disease and cystatin C. Similar results were also reported by Niccoli et al. [31
], who demonstrated that the independent association between cystatin C and CAD severity was superior to that of creatinine or eGFR. In contrast, Kim et al. [32
] failed to demonstrate an association between serum cystatin C and CAD in a retrospective study which included 64 diabetic patients, although they found an association between cystatin C and renal dysfunction. The small sample size might explain these discrepancies.
Detailed mechanisms underlying link between cystatin C and asymptomatic CAD have not been fully elucidated. Renal mechanism seems to be a plausible link between increased cystatin C and asymptomatic CAD. Serum cystatin C was assumed to be a sensitive indicator of“pre-clinical” renal disease which can not be detected by eGFR based on serum creatinine [33
]. Cystatin C may thus help to identify individuals who are at increased risk for the development of asymptomatic CAD among patients with MetS and normal creatinine-based eGFR.
Besides renal mechanism, another possible explanation for the close relationship between cystatin C and. asymptomatic CAD is that cystatin C is associated with inflammation regardless of renal function Inflammation is a critical step in the development of atherosclerosis. Inflammatory cytokines associated with atherosclerosis may alter the relationship between cysteine protease and their endogenous inhibitors like cystatin C. The imbalance of cysteine protease and its inhibitor may increase the degradation of extracellular matrix and migration of monocytes, macrophages and vascular smooth muscle cells into the intima, thus leading to the development of atherosclerosis [34
]. In the Heart and Soul Study, data from 990 patients with CAD indicated significant associations between cystatin C and proinflammatory parameters like C-reactive protein (CRP) or fibrinogen [36
]. Similar results were shown in the Cardiovascular Health Study, which demonstrated cystatin C was correlated with CRP and fibrinogen in patients with mild to moderate renal dysfunction [37
]. Consistent with these studies, we found a significant correlation between cystatin C and fibrinogen, whereas the correlations between fibrinogen and other renal markers such as serum Cr and eGFR were weak and insignificant. This may at least partly explain the complicated underlying link between cystatin C and asymptomatic CAD.
Uric acid has been shown to be related with increased production of oxygen free radicals, to promote the oxygenation of LDL-c and to facilitate lipid peroxidation[38
]. Studies have shown increased uric acid levels are associated with atherosclerosis [39
]. Apart from the strong correlation with creatinine and eGFR as expected, our data from MetS patients demonstrated that cystatin C was significantly positively correlated with uric acid. These findings are in accordance with previous reports about cystatin C and uric acid in patients with type 2 diabetes [40
] and in a hypertensive population [41
There were some limitations in our study which should be considered. First, we did not collect 24-hour urine for direct measurements of GFR because of its difficulty in daily practice. Instead, we assessed renal function with the commonly used Cockcroft-Gault formula which has some minor flaws that may lead to substantial bias in the assessment. However, numerous studies have demonstrated that the creatinine-based eGFR provides a good approximation. Second, to avoid confounding, we adjusted for well-known confounders such as gender, age, smoking status, and BMI. However, residual confounding may have occurred. Third, our results are derived from a cross-sectional study. Further studies, especially larger, population-based prospective studies are required to validate the findings suggested by the current study.