Cystatin C is a marker of renal dysfunction, and preliminary studies have suggested it might have a role as a prognostic marker in patients with coronary artery disease. The aim of the present study was to evaluate the usefulness of cystatin C for risk stratification of patients with ST-segment elevation myocardial infarction, regarding in-hospital and long-term outcomes. We included 153 consecutive patients with ST-segment elevation myocardial infarction treated by primary angioplasty. The baseline cystatin C level was measured at coronary angiography. The in-hospital outcome was determined as progression to cardiogenic shock or in-hospital death, and the long-term outcome was assessed, considering the following end points: (1) death and (2) death or reinfarction. Of the 153 patients evaluated (age 61 ± 12 years; 75.6% men), 15 (14.4%) progressed to cardiogenic shock and 4 (2.7%) died during hospitalization. The patients who progressed to cardiogenic shock or died during hospitalization had significantly greater cystatin C levels (1.02 ± 0.44 vs 0.69 ± 0.24 mg/L; p = 0.001). Long-term follow-up was available for 130 patients (583 ± 163 days). Among them, 11 patients died and 7 had reinfarction. A high baseline cystatin C level was associated with an increased risk of death (hazard ratio 8.5; p = 0.009) and death or reinfarction (hazard ratio 3.89; p = 0.021). Furthermore, only high baseline cystatin C levels and left ventricular ejection fraction ≤40% were independent predictors of the long-term risk of death, with synergistic interaction between the 2. In conclusion, cystatin C is a new biomarker with significant added prognostic value for patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, predicting both short- and long-term outcomes.
The risk stratification of patients with coronary artery disease, particularly progression to death and acute heart failure, has been the subject of research in recent years. Several biomarkers have been identified over the years, and the search for new ones with better and more accurate profiles has been very intense. Cystatin C is a cysteine protease inhibitor that is produced at a constant rate in all nucleated cells and freely filtered by the glomerulus, without secretion or subsequent tubular reabsorption. Several studies have shown that it is a good marker of renal dysfunction, particularly in patients with creatinine levels within normal limits. Cystatin C is also physiologically expressed in cardiomyocytes, and its production increases in conditions of ischemia or hypoxia. Furthermore, by regulating protease activity, cystatin C modulates the inflammatory response, extracellular matrix degradation, and phagocytic activity. That might explain its potential association with the progression of atherosclerosis and destabilization of the atheroma plaque. Therefore, we postulated that cystatin C might be a useful biomarker for prognostic stratification in patients with myocardial infarction. The prognostic value of cystatin C has been documented in patients with acute coronary syndrome without ST-segment elevation, with respect to in-hospital outcomes and long-term prognosis. However, its value in ST-segment elevation acute myocardial infarction (STEMI) remains unclear, probably because existing studies are of limited scope. Therefore, the aim of the present study was to evaluate the prognostic value of cystatin C, regarding in-hospital and long-term outcomes in patients with STEMI.
Methods
This was a prospective observational study of patients consecutively admitted with the diagnosis of STEMI who underwent urgent coronary angiography from June 2008 to June 2009. All patients met the following criteria: age ≥18 years; chest pain at rest lasting >30 minutes within the past 24 hours; ST-segment elevation of ≥1 mm in ≥2 consecutive leads that persisted for >30 minutes or was presumably new left bundle branch block; and admission to the hospital within the past 24 hours. Patients with chronic renal failure requiring dialysis were excluded from the analysis.
The hemodynamic status was evaluated on admission, including systemic blood pressure measurement and assessment of the Killip-Kimball class. At coronary angiography, a blood sample was taken for quantification of cystatin C (using automatic immunonephelometry methods), creatinine, glomerular filtration rate (GFR) (estimated using the Modification of Diet in Renal Disease formula), urea, uric acid, and N-terminal probrain natriuretic peptide (NT-proBNP). At 24 to 72 hours after revascularization, an echocardiographic study was performed, and the left ventricular ejection fraction (EF) was calculated using the biplane Simpson method. Significant left ventricular systolic dysfunction was defined as an EF of ≤40%. The maximum Killip-Kimball class during hospitalization was prospectively determined. During follow-up, the patients were evaluated in person at 12 months, and a structured questionnaire for the description of events was used. The circumstances of death were determined from the hospital records and/or interviews with the relatives. Participation in the study required informed consent. The study’s protocol complied with the Declaration of Helsinki and was approved by the ethics committee of the North Lisbon Hospital Center.
Regarding the in-hospital outcomes, the following end points were considered: (1) hemodynamic deterioration during hospitalization (defined as the occurrence of a final maximum Killip-Kimball class greater than that observed at urgent coronary angiography) and (2) progression to death or cardiogenic shock (composite end point). Regarding the long-term prognosis, the following composite end points were considered at any point after STEMI: death and death or reinfarction (composite end point).
Continuous variables are reported as the mean ± SD and were compared using t tests or the Wilcoxon rank sum test, as appropriate. Categorical variables are reported as the percentages of the cohort and were compared using Fisher’s exact tests. The correlation of baseline cystatin C with NT-proBNP was determined using Pearson’s coefficient. The accuracy for predicting each clinical end point was determined by the area under the receiver operating characteristic curve, for the significant continuous variables. Univariate and multivariate Cox regression analyses were conducted to identify and account for significant predictors of the clinical outcome. The quartile class associated with a greater risk on univariate analysis was considered as the testing class for continuous variables. Thus, the fourth quartile class was considered for laboratory variables, including cystatin C (cystatin C ≥0.84 mg/L
is referred to as high cystatin C), and the first quartile class was considered for blood pressure, GFR, and EF (EF of ≤40%; first quartile; referred to as left ventricular global systolic compromise). To avoid overfitting, nonsignificant predictor variables were removed from the regression model in a stepwise fashion. Additional analyses included Kaplan-Meier representations for the time-to-event data. Statistical analysis was performed using the Statistical Package for Social Sciences, version 17.0 (SPSS, Chicago, Illinois). All tests of significance were 2-sided, with p <0.05 considered statistically significant.Results
A total of 153 patients admitted with the diagnosis of STEMI and who underwent primary percutaneous coronary intervention were evaluated. Of these patients, 2 were excluded because of previous renal failure or dialysis. Of the remaining 151 patients, 115 were men (76.2%) and their mean age was 61 ± 12 years (range 36 to 91). Cardiovascular risk factors were very prevalent, but 11 patients (15.7%) had no identifiable conventional risk factors ( Table 1 ). On admission, 98 patients (94.2%) were hemodynamically stable and showed no signs of heart failure (Killip-Kimball class I). The baseline cystatin C level (0.74 ± 0.29 mg/L, range 0.04 to 2.24) did not differ according to the hemodynamic parameters recorded on admission (ie, blood pressure or Killip-Kimball class) but correlated with NT-proBNP (R = 0.41; p <0.001). The angiographic and procedural characteristics of the population are listed in Table 2 . Of the 151 patients, 141 underwent successful percutaneous coronary intervention (final Thrombolysis In Myocardial Infarction flow grade III), 8 had no reflow, and 2 required major dissections of the culprit vessel.
| Cardiovascular Risk Factors | Patients (n) |
|---|---|
| Hypertension | 91 (64%) |
| Hypercholesterolemia | 78 (55%) |
| Diabetes mellitus type 2 | 35 (25%) |
| Smoker | 66 (47%) |
| Former smoker (stopped ≥1 year previously) | 12 (9%) |
| Characteristic | Patients (n) |
|---|---|
| Vessels with significant lesions | |
| 1 Vessel | 81 (53%) |
| 2 Vessels | 47 (31%) |
| 3 Vessels | 23 (15%) |
| Left main disease | 2 (1%) |
| Infarct-related vessel | |
| Anterior descending artery | 68 (45%) |
| Right coronary artery | 67 (44%) |
| Circumflex artery | 3 (2%) |
| Stent type | |
| Bare metal stent | 83 (54%) |
| Drug-eluting stent | 67 (44%) |
| Both | 3 (2%) |
During hospitalization, hemodynamic deterioration occurred in 15 patients (14.4%), the maximum Killip-Kimball class reached was II, III, and IV in 6 (4.1%), 7 (4.8%), and 15 patients (10.2%), respectively. The patients who progressed with deterioration of Killip-Kimball class had a greater baseline cystatin C (0.94 ± 0.45 vs 0.69 ± 0.24 mg/L, p = 0.006). Furthermore, the cystatin C levels were greater in the patients who progressed to cardiogenic shock ( Figure 1 ). Overall, the EF was 51 ± 12%. Despite percutaneous revascularization, left ventricular global systolic impairment persisted 24 to 72 hours after catheterization in 25 patients (17.1%). In those patients, a trend was seen for the baseline cystatin C levels to be greater (0.86 ± 0.41 vs 0.74 ± 0.30 mg/L; p = 0.08). A total of 19 patients (11.6%) progressed to death or cardiogenic shock during hospitalization (composite end point). Cystatin C and the associated parameters of renal function were significantly greater in these patients (cystatin C, 1.02 ± 0.44 vs 0.69 ± 0.24 mg/L, p = 0.001; creatinine, 1.25 ± 0.46 vs 0.91 ± 0.61 mg/dl, p <0.001; urea, 53 ± 14 vs 44 ± 15 mg/dl, p = 0.006; uric acid, 6.25 ± 1.36 vs 5.42 ± 3.4 mg/dl, p <0.001), with a lower GFR (67.8 ± 30.5 vs 98.0 ± 35.1 ml/min/1.73 m 2 , p = 0.001). The accuracy of these parameters in predicting unfavorable in-hospital outcomes, evaluated using the area under the receiver operating characteristic curve, was only moderate ( Table 3 ). In addition, patients belonging to the highest quartile (fourth quartile) of each parameter (except for urea) were a group at particularly high risk ( Table 3 ). However, on multivariate analysis, only GFR of ≤71.1 ml/min/1.73 m 2 constituted an independent risk factor for death or cardiogenic shock (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.27 to 21.37; p = 0.022). It should be highlighted that among patients with a baseline creatinine of <1.5 mg/dl, those with high cystatin C levels presented with a greater risk of subsequent hemodynamic deterioration (OR 3.96, 95% CI 1.19 to 13.20; p = 0.018) and progression to cardiogenic shock or death (OR 3.36, 95% CI 1.04 to 10.86; p = 0.034).
| Variable | Receiver Operating Characteristic Curve | Univariate Analysis | |||||
|---|---|---|---|---|---|---|---|
| Area | 95% CI | p Value | Fourth Quartile | OR | 95% CI | p Value | |
| Systolic blood pressure (mm Hg) | 0.75 ⁎ | 0.59–0.92 | 0.006 | ≤125.5 † | 4.40 | 1.22–15.84 | 0.026 |
| Diastolic blood pressure (mm Hg) | 0.72 ⁎ | 0.56–0.89 | 0.015 | ≤71.5 † | 4.40 | 1.22–15.84 | 0.026 |
| Mean blood pressure (mm Hg) | 0.76 ⁎ | 0.59–0.93 | 0.005 | ≤90.3 † | 5.78 | 1.47–22.44 | 0.013 |
| Cystatin C (mg/L) | 0.75 | 0.62–0.89 | 0.001 | ≥0.84 | 5.40 | 1.88–15.50 | 0.002 |
| Creatinine (mg/dl) | 0.79 | 0.76–0.92 | <0.001 | ≥1.10 | 6.93 | 2.35–20.42 | <0.001 |
| Glomerular filtration rate (ml/min/1.73 m 2 ) | 0.77 ⁎ | 0.64–0.89 | 0.001 | ≤71.1 † | 4.91 | 1.67–14.37 | 0.004 |
| Urea (mg/dl) | 0.71 | 0.61–0.81 | 0.005 | ≥52.25 | 1.72 | 0.59–5.05 | NS |
| Uric acid (mg/dl) | 0.77 | 0.67–0.87 | <0.001 | ≥6.3 | 5.15 | 1.80–14.76 | 0.002 |
| N-terminal probrain natriuretic peptide (pg/ml) | 0.68 | 0.55–0.81 | 0.016 | ≥688.5 | 3.19 | 1.13–9.07 | 0.035 |
| Ejection fraction (%) ‡ | 0.72 ⁎ | 0.54–0.89 | 0.015 | ≤40% † | 3.44 | 1.12–10.58 | 0.036 |
⁎ Prediction of nonprogression to death or cardiogenic shock.
Long-term follow-up data were available for 130 patients (62 ± 12 years; 74% men). During the follow-up period (583 ± 163 days), 11 patients (8%) died and 7 (5%) experienced reinfarction. The patients who died were older (73 ± 7 vs 60 ± 12 years; p = 0.002) and had greater baseline cystatin C (0.94 ± 0.23 vs 0.71 ± 0.29 mg/L, p = 0.002), creatinine (1.11 ± 0.34 vs 0.89 ± 0.29 mg/dl, p = 0.034), urea (55 ± 19 vs 44 ± 14 mg/dl, p = 0.032), and NT-proBNP (2,207 ± 3,668 vs 814 ± 1,954 pg/ml, p = 0.008) levels and lower EF (39 ± 11% vs 52 ± 11%, p = 0.008). The prognostic accuracy of these parameters in predicting death during follow-up, evaluated by the area under the receiver operating characteristic curve, was moderate (cystatin C, OR 0.77, 95% CI 0.63 to 0.92, p = 0.003; creatinine, OR 0.89, 95% CI 0.52 to 0.85, p = 0.042; urea, OR 0.69, 95% CI 0.52 to 0.87, p = 0.034; NT-proBNP, OR 0.74, 95% CI 0.63 to 0.85, p = 0.008; EF, OR 0.80, 95% CI 0.64 to 0.97, p = 0.008). On univariate analysis, cystatin C, urea, and EF were predictors of long-term mortality. However, only the presence of elevated cystatin C and impaired EF were independent predictors, increasing the risk of death by 8 times (hazard ratio [HR] 8.5, 95% CI 1.71 to 42.15, p = 0.009) and 4 times (HR 4.73, 95% CI 1.18 to 19.0, p = 0.028), respectively. Thus, the cumulative survival of patients with high cystatin C levels was significantly lower in the long term (p = 0.001; Figure 2 ). In addition, to evaluate the interaction of the 2 risk factors, the Kaplan-Meier survival curve was determined for cystatin C, with stratification for EF. The risk of death was significantly greater in patients presenting with both elevated cystatin C levels and impaired EF (p = 0.003). Remarkably, the risk of death tended to be greater in patients with elevated cystatin C and EF >40% than in those with impaired EF and nonelevated cystatin C, although statistical significance was not reached ( Figure 3 ).
During follow-up, 15 patients (8.5%) progressed to death or reinfarction. These patients had higher cystatin C and creatinine levels and a lower EF ( Table 4 ). The prognostic accuracy of these parameters in predicting the progression to death or reinfarction was moderate ( Table 4 ). On univariate analysis, elevated cystatin C and an EF of ≤40% correlated with the risk of death or reinfarction, and both constituted independent predictors of this outcome ( Table 5 ). Thus, the risk of death or reinfarction more than tripled for patients with elevated cystatin C levels ( Figure 4 ).
| Admission | Favorable Outcome | Death or Reinfarction | p Value | Receiver Operating Characteristic Curve | ||
|---|---|---|---|---|---|---|
| Area | 95% CI | p Value | ||||
| Systolic blood pressure (mm Hg) | 139 ± 31 | 141 ± 22 | NS | — | — | NS |
| Diastolic blood pressure (mm Hg) | 81 ± 19 | 80 ± 15 | NS | — | — | NS |
| Mean blood pressure (mm Hg) | 102 ± 21 | 104 ± 16 | NS | — | — | NS |
| Cystatin C (mg/L) | 0.73 ± 0.30 | 0.86 ± 0.23 | 0.016 | 0.69 | 0.56–0.82 | 0.016 |
| Creatinine (mg/dL) | 0.89 ± 0.30 | 1.05 ± 0.31 | 0.042 | 0.66 | 0.52–0.79 | 0.044 |
| Glomerular filtration rate (ml/min/1.73 m 2 ) | 96.9 ± 37.1 | 80.9 ± 25.3 | NS | — | — | NS |
| Urea (mg/dl) | 44 ± 14 | 50 ± 19 | NS | — | — | NS |
| Uric acid (mg/dl) | 5.64 ± 3.55 | 5.69 ± 1.64 | NS | — | — | NS |
| N-terminal probrain natriuretic peptide (pg/ml) | 865 ± 2,019 | 1,691 ± 3,228 | NS | — | — | NS |
| Ejection fraction (%) ⁎ | 53 ± 11 | 41 ± 10 | 0.003 | 0.77 † | 0.65–0.89 | 0.003 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
