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Elevated C-reactive protein levels are associated with an increased risk of subsequent cardiovascular events in patients with unstable angina. However, limited information is available concerning the value of C-reactive protein levels in patients with acute myocardial infarction.
Methods
We prospectively studied 448 consecutive patients (mean [± SD] age, 60 ± 12 years) with acute myocardial infarction. Serum C-reactive protein levels were measured within 12 to 24 hours of symptom onset, and divided into tertiles. Infarct size was determined by echocardiographic examination that was performed on day 2 or 3. Patients were followed for 30 days for mortality and subsequent cardiac events.
Results
At 30 days, 4 deaths (3%) occurred in patients in the lowest C-reactive protein tertile, 15 (10%) in patients in the middle tertile (P = 0.02 vs. the lowest tertile), and 33 (22%) in patients in the highest tertile (P <0.001 vs. the lowest tertile). In a multivariate analysis, C-reactive protein in the upper tertile was associated with 30-day mortality (relative risk = 3.0; 95% confidence interval [CI]: 1.3 to 7.2; P = 0.01) and the development of heart failure (odds ratio = 2.6; 95% CI: 1.5 to 4.6; P = 0.0006). C-reactive protein levels were not associated with the development of postinfarction angina, recurrent myocardial infarction, or the need for revascularization.
Conclusion
Plasma C-reactive protein level obtained within 12 to 24 hours of symptom onset is an independent marker of 30-day mortality and the development of heart failure in patients with acute myocardial infarction. These findings suggest that C-reactive protein levels may be related to inflammatory processes associated with infarct expansion and postinfarction ventricular remodeling.
High-sensitivity C-reactive protein, a marker of systemic inflammation, has been evaluated as a risk predictor in apparently healthy subjects (
Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes a TIMI 11A substudy. Thrombolysis in Myocardial Infarction.
Predictive value of C-reactive protein and troponin T in patients with unstable angina a comparative analysis. CAPTURE Investigators. Chimeric c7E3 AntiPlatelet Therapy in Unstable angina REfractory to standard treatment trial.
Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.
). In patients with unstable angina, small elevations in C-reactive protein levels predict future cardiovascular events, independent of other markers of risk such as troponin T (
Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.
The predictive value of elevated C-reactive protein levels in acute coronary syndromes has been attributed to several factors, including their association with a more diffuse process of coronary atherosclerosis with a higher total plaque burden, and plaque properties (i.e., inflammation and instability). In addition, inflammatory reactions associated with myocardial necrosis may account, at least in part, for the elevation in C-reactive protein levels in these patients (
However, limited information is available concerning the clinical importance of C-reactive protein in acute myocardial infarction, when there is overt myocardial necrosis. Several small studies suggest that elevated levels in these patients are associated with worse prognosis (
Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy.
Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction.
Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy.
Therefore, we evaluated the associations between admission C-reactive protein levels and 30-day mortality, heart failure, postinfarction angina, and the need for revascularization in patients with acute myocardial infarction. In addition, we determined the relation between C-reactive protein and echocardiographic infarct size.
Methods
Patients
All patients who presented to the intensive coronary care unit with acute myocardial infarction from July 2001 until August 2002 were eligible for the study. The investigational review committee on human research approved the study protocol.
Myocardial infarction was diagnosed if a patient had chest pain lasting >20 minutes, diagnostic serial electrocardiographic (ECG) changes consisting of new pathological Q wave or ST-segment and T-wave changes, and a plasma creatine kinase-MB elevation greater than twice normal or cardiac troponin T level >0.1 ng/mL (
Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.
). Exclusion criteria were known malignancy, inflammatory disease, surgery, or trauma in the previous month. Patients admitted more than 24 hours from the onset of symptoms were also excluded. Patients with ST-segment elevation of ≥0.1 mV in two contiguous ECG leads received thrombolytic therapy (tissue plasminogen activator or streptokinase) or underwent primary angioplasty.
Blood sampling procedure and C-reactive protein assay
Venous blood samples for C-reactive protein were obtained within 12 to 24 hours of symptom onset. Blood samples were collected in citrate-treated tubes, centrifuged for at least 5 minutes, and stored at –70°C. Plasma C-reactive protein levels were measured in a single batch at the end of the study using high-sensitivity latex-enhanced immunonephelometry on a Behring BN-ProSpec Nephelometer (Dade Behring, Marburg, Germany). In this assay, polystyrene beads coated with mouse monoclonal antibodies bind C-reactive protein in the serum sample to form aggregates. The intensity of the scattered light is proportional to the size of the aggregates. The assay has a detection limit of 0.175 mg/L. The intra-assay coefficient of variation was 3.3% and the interassay coefficient of variation was 3.2%.
Study endpoints and definitions
The primary endpoint was all-cause mortality within 30 days. Secondary endpoints included development of heart failure (defined as rales in more than half of the lung field and pulmonary congestion on chest radiograph), reinfarction (defined as the coincidence of typical chest pain, new ST-segment changes, and re-elevation of the creatine kinase-MB level to at least three times normal and >50% above the previous value); postinfarction angina (defined as recurrence of ischemic chest pain at rest or during exercise); and need for revascularization with either angioplasty or bypass surgery because of recurrent ischemia. Following hospital discharge, endpoints were obtained by reviewing the National Death Registry, and by contacting each patient and reviewing the hospital course if the patient had been rehospitalized.
Echocardiographic examination
Assessment of left ventricular systolic function by echocardiography was performed in each patient on day 2 or 3 of hospitalization. Parasternal long- and short-axis and apical four- and two-chamber views were obtained. For analysis of left ventricular function and wall motion abnormalities, we used the segmentation model according to the American Society of Echocardiography (
Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms.
). The left ventricle was divided into 16 segments and a regional wall motion score for each segment was calculated using the following grading system: 1 = normal (≥5 mm excursion); 2 = hypokinesis (<5 mm excursion); 3 = akinesis (defined as no systolic myocardial thickening); and 4 = dyskinesis (defined as systolic thinning or paradoxic endocardial excursion away from the left ventricular lumen). The sum of the scores for the individual regions divided by 16 yielded the left ventricular wall motion score index.
Statistical analysis
C-reactive protein cutpoints were chosen prospectively based on tertiles in the overall sample. Additional analyses were performed using a published cutpoint of 10 mg/L (
Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.
Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients.
). The baseline characteristics of the groups were compared using analysis of variance for independent samples for continuous variables and the chi-squared statistic for categorical variables. Correlations were determined with the Spearman rank correlation test. The relation between tertiles of C-reactive protein and echocardiographic wall motion score index, adjusted for other important covariates, was determined by analysis of covariance followed by the Bonferroni correction for multiple comparisons.
Cox proportional hazard analyses were used to determine the relation between tertiles of C-reactive protein level and 30-day mortality. Survival curves were estimated by the Kaplan-Meier method, and curves were compared with the log-rank test. In addition, a multivariate logistic regression model was used to assess the risk of developing heart failure during the follow-up period. All hypothesis testing was two-tailed. Statistical analyses were performed using SPSS statistical software, version 10.1 (Chicago, Illinois).
Results
A total of 448 consecutive patients who presented with acute myocardial infarction were enrolled. The median C-reactive protein level was 13.1 mg/L (interquartile range, 5.0 to 32.3 mg/L). All patients had C-reactive protein levels above the upper limit of normal (0.3 mg/L). Patients with levels in the upper tertile (>22.3 mg/L) were older, had higher serum creatinine levels and Killip class, and were more likely to have diabetes than the other patients (Table 1).
Table 1Characteristics of the Patients at Enrollment, by Tertile of C-Reactive Protein Level
Relation between C-reactive protein and infarct size
The mean wall motion score index was 1.52 (95% confidence interval [CI]: 1.45 to 1.58) among patients in the lowest tertile of C-reactive protein level, 1.63 (95% CI: 1.56 to 1.69) in the middle tertile, and 1.78 (95% CI: 1.71 to 1.85) in the highest tertile. After adjustment for other covariates that affected infarct size, wall motion score index increased continuously from the lowest to the highest tertile of C-reactive protein (Figure 1, P <0.0001). Similar results were obtained when the analysis was restricted to patients with first myocardial infarction (P <0.0001) and to patients with or without reperfusion therapy (P<0.0001).
Figure 1Adjusted means of echocardiographic wall motion score index and 95% confidence intervals (error bars) by tertile of C-reactive protein level. Wall motion score index was adjusted for age, sex, diabetes, hypertension, smoking, prior aspirin therapy, previous myocardial infarction, ST-elevation infarction, anterior infarction, and reperfusion therapy. Adjusted means were calculated by analysis of covariance followed by the Bonferroni correction for multiple comparisons. The asterisk (*) indicates P <0.0001 for the highest tertile compared with the lowest tertile; the dagger (†) indicates P = 0.004 for the highest tertile compared with the middle tertile.
A total of 52 deaths (12%) occurred at 30 days. Both mortality and new heart failure were more common among patients with greater C-reactive protein levels (Table 2), but C-reactive protein levels were not associated with the development of postinfarction angina or recurrent myocardial infarction, or the need for revascularization.
Table 2Risk of Adverse Cardiac Events at 30 Days, by Tertile of C-Reactive Protein Level
Similar results were obtained using a >10 mg/L cutpoint for the C-reactive protein level. Patients with levels >10 mg/L had higher 30-day mortality (18% [46/256] vs. 3% [6/192], P <0.0001) and rates of heart failure (34% [n = 86] vs. 19% [n = 36], P = 0.001), but there was no significant difference in rates of postinfarction angina or recurrent myocardial infarction (21% [n = 59] vs. 25% [n = 48], P = 0.6) and the need for revascularization (21% [n = 55] vs. 29% [n = 55], P = 0.1).
Patients with C-reactive protein levels in the middle and highest tertiles had significantly higher 30-day mortality than patients in the lowest tertile (Figure 2). Adjustment for other predictors of mortality (Table 3) had only a modest effect on the association between C-reactive protein level in the highest tertile and 30-day mortality (Table 4). In patients with a level >10 mg/L, the adjusted relative risk for 30-day mortality was 5.6 (95% CI: 2.0 to 16; P = 0.001).
Figure 2Kaplan-Meier survival curves by tertile of C-reactive protein level. P = 0.02 for comparison of the lowest and middle tertiles; P <0.0001 for comparison of the lowest and highest tertiles; and P = 0.003 for comparison of the middle and highest tertiles.
C-reactive protein level in the upper tertile was also an independent predictor of the development of heart failure during 30-day follow-up (odds ratio [OR] = 2.6; 95% CI: 1.5 to 4.6; P = 0.0006). Other predictors of heart failure were wall motion score index >1.5 (OR = 3.5; 95% CI: 1.9 to 6.6; P <0.0001), anterior infarction (OR = 2.6; 95% CI: 1.5 to 4.6; P = 0.0004), peak creatine kinase (OR = 1.2 per increase of 1000 IU; 95% CI: 1.1 to 1.4; P = 0.004), and age >65 years (OR = 3.1; 95% CI: 1.7 to 5.6; P = 0.0002). Using a C-reactive protein level cutpoint of >10 mg/L, the adjusted odds of developing heart failure was 1.7 (95% CI: 1.1 to 3.0; P = 0.04).
Discussion
We found that elevated C-reactive protein levels on admission are associated with significantly higher rates of 30-day mortality and heart failure in patients with acute myocardial infarction. Our results confirm those of smaller studies and extend them in several important ways. First, we used C-reactive protein level cutpoints based on tertiles in the overall sample, rather than arbitrary cutpoints chosen according to the best fit with a specific outcome. Second, the prognostic value of a single blood sample obtained soon after admission was determined, rather than that of the peak C-reactive protein level which requires serial measurements. This approach simplifies the use of C-reactive protein levels for risk stratification. Finally, we determined the adjusted relation between C-reactive protein level and echocardiographic infarct size.
Previous studies have mainly investigated the relation between C-reactive protein level and infarct size determined by peak creatine kinase level. In a small study, C-reactive protein levels on admission were not related to measures of infarct size (
). In another study, peak levels of C-reactive protein correlated substantially with concentration–time integrals of creatine kinase levels, especially in patients without successful reperfusion (
Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy.
). In our study, infarct size measured echocardiographically was greater with increasing tertiles of C-reactive protein level on admission, regardless of whether patients received reperfusion therapy. Furthermore, adjustments for other important variables that determine infarct size had little effect.
The levels of circulating markers of inflammation, such as C-reactive protein and amyloid A protein, are higher in patients with unstable coronary disease than in those with stable coronary disease (
). Patients with myocardial infarction have higher C-reactive protein levels than patients with unstable angina, despite comparable angiographic coronary disease (
Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction.
). However, data on the prognostic value of elevated C-reactive protein levels in myocardial infarction and their relation to specific outcomes are sparse. Zebrack et al reported that C-reactive protein level was not associated with death or recurrent coronary events in patients with acute myocardial infarction (
Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction.
). However, levels were obtained predischarge during coronary angiography. Tommasi et al reported that C-reactive protein levels measured 8 hours after acute myocardial infarction predicted cardiac events at 1 year in 64 patients with an uncomplicated in-hospital course and normal ejection fraction (
). Pietila at al found that patients who died during the first 6 months after the onset of infarction had higher peak C-reactive protein levels than those who survived (
Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment.
), whereas Anzai and associates reported that peak C-reactive protein level was an independent predictor of cardiac rupture, ventricular aneurysmal formation, and 1-year cardiac death (
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes a TIMI 11A substudy. Thrombolysis in Myocardial Infarction.
Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients.
), suggest that the interpretation of elevated C-reactive protein levels in patients with acute coronary syndromes depends on the clinical setting. Levels of C-reactive protein, and proinflammatory cytokines such as interleukin 6, are elevated in 70% of patients with severe unstable angina on admission, and are associated with recurrent instability and acute infarction (
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes a TIMI 11A substudy. Thrombolysis in Myocardial Infarction.
). In contrast, elevated C-reactive protein levels in patients with myocardial infarction are predictors of short-term mortality and the development of heart failure, but do not predict recurrent infarction, unstable angina, or the need for revascularization.
The relation between C-reactive protein levels and the degree of myocardial necrosis, as assessed by echocardiography, suggests that these levels may reflect the inflammatory response to myocardial necrosis (
). However, the increased risk of 30-day mortality and heart failure associated with elevated C-reactive protein levels was independent of markers of infarct size, such as peak creatine kinase level and echocardiographic wall motion score index. These findings support the hypothesis that C-reactive protein is not merely a marker of myocardial necrosis, but may be related to the inflammatory processes associated with infarct healing or expansion and postinfarction ventricular remodeling. Inflammation around the zone of hypoxic necrosis affects the final infarct size, remodeling, and clinical outcomes (
). In an experimental model of acute myocardial infarction, parenteral injection of human C-reactive protein enhanced tissue damage via a complement-dependent mechanism (
). Furthermore, inhibition of complement activation attenuates the infiltration of neutrophils into the jeopardized myocardium and reduces infarct size (
The absence of a relation between elevated C-reactive protein levels and the risk of recurrent infarction, unstable angina, or the need for revascularization suggest that elevated levels do not reflect a more unstable coronary lesion in patients with acute myocardial infarction. Among patients with acute coronary syndromes, the risk of myocardial infarction (or reinfarction) or unstable angina, in relation to C-reactive protein levels, may follow an inverted U-shaped curve, as described for troponin T (
). Thus, the adverse prognosis associated with elevated C-reactive protein levels in patients with unstable angina with or without minor myocardial damage is a marker of plaque instability (
Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes a TIMI 11A substudy. Thrombolysis in Myocardial Infarction.
Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients.
). By contrast, in patients with overt myocardial infarction, elevated levels appear to reflect an inflammatory response due to myocardial necrosis, infarct expansion, and ventricular remodeling, and thus are associated with heart failure and death rather than recurrent ischemia.
Several limitations of our study must be acknowledged. The production of C-reactive protein increases in all patients with myocardial infarction within 4 to 6 hours of the onset of symptoms, and reaches a peak in about 48 to 72 hours (
). Thus, because we did not measure C-reactive protein repeatedly (our only measurement was obtained during the first 24 hours), our results do not exclude the possibility that peak levels can provide additional prognostic information. In addition, our study included a mixed group of patients with regard to eligibility for reperfusion therapies, and various types of reperfusion were used. Therefore, we were unable to examine the effect of reperfusion therapies on the interaction between C-reactive protein levels and prognosis.
In conclusion, our results suggest that plasma C-reactive protein levels obtained within 12 to 24 hours of symptoms onset are an independent marker of 30-day mortality and the development of heart failure in patients with acute myocardial infarction. These findings suggest that in patients with acute myocardial infarction, C-reactive protein levels may be related to inflammatory processes associated with infarct expansion and postinfarction ventricular remodeling.
References
Ridker P.M.
Cushman M.
Stampfer M.J.
et al.
Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.
Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.
Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy.
Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction.
Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.
Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms.
Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive patients.
Serum C-reactive protein concentration in acute myocardial infarction and its relationship to mortality during 24 months of follow-up in patients under thrombolytic treatment.
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