119J Contemp Med Sci | Vol. 2, No. 8, Autumn 2016: 119–122 Research Prognostic value of cystatin C in acute coronary syndrome Mohammed Abdulwahid Shuaila,a Hassanain M Saeed Abdulamir,b Monem Makki Alshokb aMBChB, Merjan Teaching hospital Hilla Babylon, Ministry of Health, Babylon, Iraq. bDepartment of Medicine, College of Medicine, University of Babylon, Iraq. Correspondence to Professor Dr Monem Alshok (email: dr_monem_alshok@yahoo.com). (Submitted: 9 September 2016 - Revised version received: 2 October 2016 - Accepted: 7 October 2016 – Published online: 26 December 2016) Objective Coronary artery disease associated with an increment with a variety of markers, one of them Cystatin C, in this study we evaluate its role in a prospective study as prognostic marker, and evaluate the correlation between Cystatin C plasma level and variety of acute coronary syndrome (ACS) complications. Methods A total 51 patients who admitted for Merjan Teaching Hospital coronary care unit whom ACS was diagnosis was made depend on history, clinical examination and investigation, and then blood sample was taken to measure plasma level and follow up for 6 months of any new events including new ischemia, rehospitalization, electrical and mechanical complication. Results Patient who admitted with ACS with high level of cystatin C associated with more mortality (P value: 0.09) and more electrical complication (P value: 0.035) and more rehospitalization (P value: 0.01), but failed to show a correlation with mechanical complication. Conclusion Elevated level of Cystatin C in patient admitted to hospital with ACS associated with an increase in hospital mortality, electrical complication, and rehospitalization and lower ejection fraction than a patient with a normal Cystatin C level. Keywords cystatin C, prognostic value, acute coronary syndrome Introduction Cystatin C (cys-C) is a small protein molecule (120 amino acid peptide chain, approximately 13kDa) produced by virtually all nucleated cells in the human body. It belongs to the family of papain-like cysteine proteases and its main biological role is the extracellular inhibition of cathepsins. It’s near constant production rate, the fact that it is freely filtered from the glo- merular membrane and then completely reabsorbed without being secreted from the proximal tubular cells, made it an almost perfect candidate for estimating renal function. The strong correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) along with the growing under- standing of the role of cysteinyl cathepsins in the pathophysi- ology of CVD inspired researchers to explore the potential association of cys-C with CVD. A high level of cystatin C in the blood corresponds to a decreased glomerular filtration rate (GFR) and hence to kidney dysfunction, Recent studies sug- gest that increased levels of cystatin C may also indicate an increased risk of heart disease, heart failure, stroke, and mor- tality.1,2,3,4 There is a close relationship between cystatin C and acute ischemic stroke, independently of conventional risk fac- tors.5 Several studies mentioned that increased levels of cys- tatin C are found in patients with coronary artery disease.6,7,8,9,10 Cystatin C recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease. Also cys- tatin C may be an indicator of acute PTE (pulmonary throm- boembolism) in patients with normal renal function. Also elevated serum Cystatin C levels may predict venous throm- bosis beyond reflecting impaired kidney function. Cystatin C is known to modulate the neutrophil chemotactic activity and may inhibit prothrombotic activity of proteolytic substances secreted by activated neutrophils. Thus, it may be hypothe- sized that increased serum levels of cystatin C represent an inadequate counterbalancing mechanism to avoid thrombosis formation.11–17 A recent study conducted by Urbonaviciene et al. demonstrated that higher serum cystatin C levels inde- pendently predicted 5-year all-cause and CVS mortality in symptomatic peripheral arterial disease patients with normal renal function. In accordance with Urbonaviciene et al.18 Loew and colleagues19 have reported that only high plasma cystatin C levels(> 1.24 mg/l) were associated with risk of fatal and nonfatal cardiovascular events during the follow-up. Further- more, in a recent meta-analysis, higher cystatin C levels were strongly and independently associated with specific endpoints like stroke, myocardial infarction and heart failure.20,21 The aim of the present study was to evaluate whether the concentration of Cys C could predict the severity of coronary artery disease after myocardial infarction in patients with normal renal function estimated from the concentration of serum creatinine, and to determine the prognostic value of Cys C in predicting cardiovascular mortality during the follow up of patients with acute coronary syndrome (ACS). Methods A short-term prospective study was conducted on 51 patients with ACS admitted to Merjan teaching hospital from the first of March 2015 to first of July 2015. Patients were excluded from the study if there is any neoplasia in any organ, preg- nancy, thyroid dysfunction, altered mental state, renal impair- ment on admission, suspected dissected aortic aneurysm, recent MI (6 month ago), patients with eGFR less than 60 ml/ kg/min, patient received steroid and any patient refuse partic- ipation. The diagnosis of ACS was established by symptoms, electrocardiography and cardiac biomarkers. Detailed history was taken from the patients, and physical examination was performed on admission. Echocardiography was done usually in the next day of admission, but bed-side echocardiography was done if there is a strong indication to assess hemodynam- ically unstable patients and to rule out mechanical complica- tion in STEMI patients. Potential risk factors for ACS including hypertension (HPT), diabetes (DM), smoking, as well as age of patients, and other information were reviewed by direct ques- tionnaire to the patients or their relatives. Risk factors were defined according to the protocol. The patients with a history of HPT or without history but compatible with JNC9 defini- tion of hypertension mm Hg were defined hypertensive. ISSN 2413-0516 120 J Contemp Med Sci | Vol. 2, No. 8, Autumn 2016: 119–122 Prognostic value of cystatin c in acute coronary syndrome Research Mohammed Abdulwahid Shuaila et al. The patients who have the history of DM, being on glu- cose-lowering medication prior to ACS onset or without a his- tory but who had fasting blood sugar more than 126 mg/dl or random blood sugar > 200 mg/dl on two occasions were defined diabetics. The patients were regarded as current smokers if they smoked until admission or stopped smoking within the last 3 months. GFR measured using MDRD equa- tion (modification of diet in renal disease) as follows: eGFR ml/min. 73m² = 175 × S.(S.Cr) ¹ ־¹⁴⁵ × (Age)־ º²º³× (0742 if female) × (1.212 if black) We followed the patients daily during the period of hospi- talization. Clinical assessment and echocardiography was done to the patients who discharged from hospital, on average of 6 to 8 weeks after discharge. The patients were followed up by telephone or outpatient clinic visits for up to 3 months. Blood sampling and Laboratory methods Blood was drawn on admission at the time of inserting an intravenous line. The sample was collected into a plain tube, allowed to clot and then separate the serum by centrifuge using {Hettich Rotofix22} (A German 2005), centrifuge at a rate of 3000 rpm for 5 minutes. 0.5–1.0 ml of serum is stored at 2–8 Celsius for a few days for the measurement of Cystatin C level. Serum Cystatin C is measured by using (Nephlometric- immunoterbidimetric method). The other laboratory investi- gation included a complete blood count, and random blood glucose, urea and creatinine. Cardiac enzymes, including tro- ponin, if indicated we perform a thyroid function test. Statistical Analysis Statistical analysis was performed using statistical package for social science version 20 “SPSS 20”. Categorical variable such as sex, diabetes, hypertension, smoking, occurrence of death was expressed as a percentage. The correlations between cate- gorical variables were assessed using Chi square or Fisher exact test as appropriate. Continuous variables that were nor- mally distributed such as the age of the patient, serum Cystatin C, duration of hospitalization were expressed as mean ± Standard deviation. The correlation between continuous vari- ables were assessed using annova test. P value of 0.05 or less considered to be significant. Results In this study, 51 patients were enrolled. The age ranged from 45 to 65 (mean ± SD 52.12 ± 8.93), 32 of them were male, 19 were female, 12 patients (23.5%) were diabetes, 15 patients (29.4%) were hypertensive, 13 patients (25.4%) were current smokers. Of those patients, 36 patients (71%) were admitted with the diag- nosis of STEMI, 15 patients (29%) admitted with the diagnosis of non-STEMI/UA, among patients with STEMI 20(28%) had anterior STEMI, 16(22%) had Inferior STEMI. In the UA/ NSTEMI group 13(86%) of them have ST depression/T inver- sion, and 2(14%) have normal ECG findings. 33 patients (91%) had successful reperfusion therapy, 25 patients (69%) had PCI primary or rescue, and 8(22%) patients had thrombolysis as a sole reperfusion therapy. One patient developed acute ischemic stroke with slurred speech and dysphagia on the second day of hospitalization after primary PCI (with normal brain CT scan done immediately after the event) with the resolution of the neurological deficit during the follow up. The duration of hospitalization was 4 ± 1.82 days and mortality was 4 patients (7.5%). Table 2 shows the correlation between mortality and the patients’ clinical characteristics. The mean age of patients who died (55 ± 6.272), 3(75%) of them where males and 1(25%) where females, 2 (50%) were hypertensive with (0.22 P value), and 3(75%) were diabetics (0.036 P value), 3 (75%) were smokers (0.046 P value). Table 3 shows the correlation between cystatin Table 1. Baseline characteristics of the patients Variables No./percent No. 51 patients Age (52.12 ± 8.93) Sex 32 males/19 females DM 12 patients (23.5%) Hypertension 15 patients (29.4%) Smoking 13 patients (25.4%) STEMI 36 patients 70.5%) NonSTEMI\UA 15 patients (28.3%) Reperfusion in STEMI 33 patients (62.2%) Thorombolysis 8 patients (15%) PCI 25 patients (47.1%) ECG findings Anterior STEMI 20(39.2%) Inferior STEMIs 16(30.1%) ST depression\T inversion 13(24.5%) Normal ECG 2(3.7%) Mortality 4 patients (7.5%) s. cystatin Duration of hospitalization (4 days ± 1.82) Table 2. correlation between mortality and patients’ clinical characteristics Variables In hospital mortality P value Yes (4) No (49) Age 55 ± 6.272 51.87 ± 9.138 NS Sex 3 (5.6%) males 1 (1.8%) 0.22 Hypertension 2(3.7%) 2(3.7%) 0.22 DM 3(5.6%) 1(1.8%) 0.036 Smoking 3(5.6%) 1(1.8%) 0.046 Table 3. Correlation among cystatin level, mortality electrical complications and mechanical complications variables No. Mean Cystatin C ± SD P values Mortality died 4 0.8538 0.48531 0.009 no 47 1.5250 0.30838 Electrical complications yes 4 1.4150 0.61016 0.035 no 47 0.8632 0.47869 Rehospitalization yes 9 1.3833 0.40159 0.01 No 42 0.8043 0.46864 Mechanical complications yes 1 1.7000 0.1 no 50 0.8906 0.49770 Mohammed Abdulwahid Shuaila et al. 121J Contemp Med Sci | Vol. 2, No. 8, Autumn 2016: 119–122 Research Prognostic value of cystatin c in acute coronary syndrome level and mortality, re hospitalization, electrical and mechanical complications. In patients who died during the hospital course were 1.5250 ± 0.30838, while the mean cystatin c level in patients who were discharged alive from the hospital were between 0.8538 and 0.8531. The correlation was statistically significant (P value 0.009). 4 patients (19%) developed electrical complica- tions in hospital. Two patients developed primary ventricular fibrillation (VF) were successfully resuscitated, one patient developed atrial fibrillation in which rate controls done with intravenous amiodarone infusion, and one patient developed sustained ventricular tachycardia (VT) was successfully resusci- tated with mean cystatin C (1.4150 ± 61016) SD developed elec- trical (P value 0.035 significant). Also our results showed correlation between Cystatin C level and ejection fraction (EF) using Spearman’s correlation coefficient, which showed a nega- tive correlation coefficient (–154). Nine patients (17.6%) read- mitted to hospital, of those patient 4 patients admitted with decompensated heart failure, 2 patients admitted due to post MI angina, 2 patients due to acute pulmonary edema, and 1 patient due to VSR. With mean 1.3833 and std. deviation 0.40159. VSR in which 1 patient (1.9%) developed VSR. This patient devel- oped clinical deterioration with hemodynamic instability and developed a new murmur with auscultation, ECHO approves the presence of acquired VSD and the patient referred for urgent surgical intervention (P value 0.1 non-significant) Discussion In this study, we have found that an increase in Cystatin-C level is associated with an increase in hospital mortality. This result has agreed with Osama Tayeh et al.23 Their study was a non-randomised controlled trial took place in Egypt, prospec- tively has conducted on 75 patients with (ACS) and also an equal number of controls. Patients who have included in this study are presented with ACS and evaluated the prognostic value of it as a predictor for the major acute coronary event). Our concern study has shown that group with a high Cystatin C level is associated with significant in hospital mortality (P value 0.025), and also it is going with Leila Abid et al.,24 Which showed (P value 0.01 clinically significant). And another study where Cystatin C was used as a prognostic biomarker in STEMI and Shlipak et al.25 Eriksson et al. have asserted that an increase in cholesterol or LDL-cholesterol levels are considered as risk factors of IHD, but CYS-C may reflect precisely the presence or absence of CAD.26 We found in this study that diabetes and smoking are associated with increasing mortality that agrees with Osama Tayehetal. and presenting significant correlation with smoking and disagree with Leila Abidetal. (non-signifi- cant). While in a multivariate regression analysis between the prevalence of high CYS-C and other common traditional risk factors, including: hypertension, diabetes, and smoking if all risk factors are present, the patient had a high CYS-C level. Meanwhile hypertensive was clinical regarded as nonsignifi- cant (P value 0.22). The reasonable explanation for our results is that serum cystatin C has regarded as the most sensitive marker of early renal dysfunction, due to that it may be involved in the process of coronary heart disease. Despite the uncertainty of the exact mechanisms underlying the predictive role of cystatin C in CHD, evidence suggests that elevated serum cystatin C is associated with worse prognosis in patients with CHD. A study by Zethelius et al. have declared whether a combination of biomarkers, including N-terminal pro-brain natriuretic peptide, cystatin C, troponin, and hs-CRP, have improved patient stratification of risk compared with estab- lished cardiovascular risk factors. Those researchers have dis- covered that adding cystatin C to the system significantly will improve predictive efficacy.27 Also, we found that higher patient with higher level of Cystatin C levels have associated with increased incidence in hospital electrical complications (P value 0.035), and this agrees with Osama Tayah et al. who have confirmed that higher level of Cystatin C is associated with a higher chance of electrical complications (P value 0.029). And we also found that high level of Cystatin C associ- ated with higher rehospitalization due to various causes (decompensated heart failure, post MI angina, pulmonary edema, etc.) that agreed with Ichimoto et al.,28 whom investi- gated the Cystatin level of 71 patients with STEMI, had also suggested the prognostic value of Cys C, high concentrations of this marker were associated with greater frequency of rehos- pitalization and acute heart failure episodes. Association of Cystatin C with greater mortality rate during follow-up. Kilic et al.29 have investigated 160 patients hospitalized with ACS and demonstrated that the admission of the serum CYSC level was significantly associated with future cardiovascular complications and rehospitalization and mortality during 12 months of follow-up. It also agrees with Osama Tayeh and Axel Akerblom et al.30 Higher level of Cystatin C is associated with lower ejection fraction (Spearman’s correlation coeffi- cient which showed a negative correlation coefficient (–0.154). This also has agreed with Moran et al. who have concluded that CYS-C can be a marker of heart failure, and its combina- tion with N-terminal pro-B-type natriuretic peptide (Nt– Pro-BNP) considered to be as good marker than CYS-C alone for predicting cardiovascular mortality, especially in elderly patients with heart failure.31 Our study agrees with Garcıa Acuna et al. who indicated that an elevated serum CYS-C level will predict the development of myocardial infarction, heart failure and cardiovascular death in 203 patients hospitalized with high-risk ACS, independent of other classical risk factors either in-hospital or during a 6-month follow-up period.32 The results of our study also have agreed with Silva et al.33 who have suggested that patients admitted for ST elevation myo- cardial infarction and who presented elevated Cys C levels (P 0.84 mg/L) on admission, had greater risk of progression to cardiogenic shock or death during hospitalization. In this same study, only Cys C levels P 0.84 mg/L and impaired LVEF < 40% were the predictors of the risk of death during the fol- low-up. And also agreed with Ichimoto et al. and Osama et al. Mechanical complications have shown non-significant results (P value 0.1), which had disagreed with Osama Tayeh et al. (P value 0.002), and this might be due to small a number of data that we have used in our study. Conclusion Elevated level of Cystatin C in patients admitted to the hos- pital with ACS associated with an increase in hospital mor- tality, electrical complication, and re hospitalization and lower ejection fraction than a patient with a normal Cystatin C level. We recommend measuring the Cystain C level with early hours of admission for any patient of ACS for risk stratifica- tion and early possible intervention. 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