IJCS | Volume 31, Nº3, May/ June 2018

304 Martucheli et al. Cystatin C and acute coronary syndromes International Journal of Cardiovascular Sciences. 2018;31(3)290-307 Review Article for its high sensitivity in detecting smaller immune aggregates, and monitoring an increase in light intensity against a low background signal, which gives the method a theoretical edge. 38 Although a lack of standardization of the methods may affect the results reported in different studies, the fact that most studies used immunonephelometry and immunoturbidimetry may indicate high reliability of the results. In addition, all studies included in themeta-analysis used thesemethods for cystatin C measurement. The predominant type of ACS was NSTEMI followed by STEMI and unstable angina. STEMI involves a total coronary obstruction and hence a more critical cardiovascular event thanNSTEMI and unstable angina. 39 A well-established diagnosis of AMI should take into consideration all recommended criteria, that consist in increased levels of myocardial necrosis markers (preferably troponin or CK-MB mass) combined with at least one of the following parameters: symptoms suggestive of ischemia (chest pain), pathological Q-wave in ECG, significant changes in ST segment or T-wave inversion, new left bundle branch block, loss of viable myocardium, changes in segmental ventricular contractility in imaging tests, and intracoronary thrombus in angiography. Unstable angina is diagnosed by the same criteria, except for myocardial necrosis markers, which are not increased. 14 Some studies (23.5%) did not report the criteria used (i.e., it was not possible to determine whether these criteria were used or not), and 7 studies (41.2%) did not use these criteria, which may yield an incorrect diagnosis of ACS, and variations in the groups of patients included in these studies. A study performed in 2009 demonstrated that STEMI is associated with increased short-term mortality risk, whereas NSTEMI is associated with increased long-term mortality risk. 40 All studies evaluated mortality, either alone or in combination with cardiovascular events, requiring a longer period of follow-up. Among the studies included in this systematic review, only one (5.9%) had a follow-up period shorter than six months; however, despite that, a significant association between increased levels of cystatin C and cardiovascular events or mortality was reported. Both studies included in the meta-analysis had a follow-up period longer than 12 months. Four studies (23.5%) had a sample size greater than 1,000, whichmay increase their statistical power. Although 5 studies (29.4%) had a sample size smaller than 200, these studies also reported a significant association of cystatin C and the outcomes. The only study that did not find any significant difference between the frequencies of patients who developed cardiovascular events or cardiovascular death and of those who did not develop these outcomes, found a significant association between the proportion of patients with and without congestive heart failure. Sample size of this study was smaller than 200; patients were followed for 6 months and classified by median cystatin C, which may have contributed for the results of cardiovascular events and cardiovascular mortality. Although this systematic review and meta-analysis has demonstrated a significant association between increased cystatin C levels and a worse prognosis of ACS, some limitations should be considered. First, the search was restricted to Medline via PubMed, Web of Science and Scielo databases; second, only articles published in English, Portuguese and Spanish were included in this study; finally the small number of articles included in the meta-analysis due to high variability of analyses between the studies. Conclusion Despite the limitations of the studies included in this systematic review, theydemonstrated, using aprospective design, a significant association between increased cystatin C and the development of cardiovascular events and mortality in patients with ACSs. Such association was confirmed by the meta-analysis, and shown to be independent of renal function evaluated by serum creatinine or GFR. Therefore, cystatin C is a useful marker in the prognosis assessment of ACSs and can be used in combination with currently available markers. Author contributions Conception and design of the research: Martucheli KFC, Domingueti CP. Acquisition of data: Martucheli KFC, Domingueti CP. Analysis and interpretation of the data: Martucheli KFC, Domingueti CP. Statistical analysis: Martucheli KFC, Domingueti CP. Writing of the manuscript: Martucheli KFC. Critical revision of the manuscript for intellectual content: Domingueti CP. Supervision / as the major investigador: Domingueti CP. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported.