IJCS | Volume 31, Nº3, May/ June 2018

297 García Acuña et al., 2009 28 NSTEMI, STEMI At least two of these criteria: chest pain: signs of ischemia in ECG; increased cardiac markers 203/ 59.21 ± 12.26 (cystatin C ≤ 0.95 mg/L) 72.49 ± 10.69 (cystatin C > 0.95 mg/L) Approximately 6 months/ Heart failure, no-fatal infarction, cardiovascular death Immunonephelometry No Patients with cystatin C > 0.95 mg/L had a higher frequency of GFR < 60 and a lower frequency of GFR > 90 in comparison with patients with cystatin C levels ≤ 0,95 mg/L p = 0,001 Windhausen et al., 2009 5 NSTEMI Chest pain with increasing intensity or at rest, increased levels of cardiac troponin, and one of these criteria: signs of ischemia in ECG; CAD 1128/ 57 ± 10 (1 st tertile) 62 ± 10 (2 nd tertile) 67 ± 9 (3 rd tertile) 3 years (infarction) and 4 years (death)/ All-cause mortality, non-fatal infarction Immunonephelometry No GFR = 102 (87- 118) (1 st tertile) GFR = 87 (75-103) (2 nd tertile) GFR = 68 (56-82) (3 rd tertile) p < 0,001 CK-MB: Creatine kinase isoenzyme MB; CAD: Coronary artery disease; ECG: Electrocardiogram; AMI: acute myocardial infarction; CHF: congestive heart failure; NI: not informed; NSTEMI: non-ST segment elevation myocardial infarction, PCI: percutaneous coronary intervention; STEMI: ST segment elevation myocardial infarction; GFR: glomerular filtration rate. Martucheli et al. Cystatin C and acute coronary syndromes International Journal of Cardiovascular Sciences. 2018;31(3)290-307 Review Article Discussion The current study aimed to assess the association between increased levels of cystatin C and the development of cardiovascular events and mortality in patients with ACS by a systematic review and meta- analysis. All studies included in the systematic review found a significant association between increased cystatin C levels and the outcome measures by odds ratio or relative risk, which was confirmed in the meta-analysis. Some studies also compared the proportion of patients with increased cystatin C levels who developed or not outcomes, and only one study showed no statistically significant difference. Therefore, results of the studies included in this systematic review and meta-analysis indicate a significant association between increased cystatin C levels and the development of cardiovascular events and mortality in ACS patients. Themechanism responsible for this association has not been fully elucidated. However, a possible mechanism is based on the fact that cystatin C is a more sensitive marker for kidney dysfunction, capable to detect small reductions in GFR, 4 and a pre-clinical status of kidney dysfunction, which cannot be detected by serum creatinine or creatinine-based GFR. 29 Some studies have shown that the presence of mild-to-moderate kidney failure is an important risk factor for the development of cardiovascular events andmortality. 30-32 Thus, patients with increased cystatin C levels could have a mild kidney dysfunction, which could contribute to increased risk of cardiovascular events and worse prognosis. Another possiblemechanismis related to inflammation associated with the atherogenic process, since some studies have suggested that increased cystatin C levels are associated with inflammation and atherosclerosis. 32 Inflammatory cytokines and atherosclerosis stimulate the production of lysosomal cathepsins, 32 such as cathepsin S that seems to contribute to disruption of atherosclerotic plaque. 33 Since cystatin C is a cathepsin inhibitor, 32 increased cystatin C levels may be associated with inhibition of these cathepsins involved in atherosclerotic plaque disruption, contributing to the development of cardiovascular events. Although all studies included in this review had good or excellent methodological quality, evaluated by the NOS, 13 they also showed some limitations. Only two studies (11.8%) included exclusively patients with normal kidney function. Nevertheless, most studies (88.2%, n = 15) performed a multivariate analysis, and more than half (58.8%, n = 10) included GFR or serum creatinine, which gives greater credibility to results. After adjustment for these and other risk factors, a