Data on the ability of serum biomarkers to predict microvascular obstruction by ST-segment recovery after primary percutaneous coronary intervention (PCI) is largely absent. Therefore, we determined the association between 5 serum biomarkers, obtained before emergency coronary angiography, and immediate ST-segment recovery in patients who had undergone primary PCI for ST-segment elevation myocardial infarction. We measured N-terminal pro-brain natriuretic peptide (NT-pro-BNP), cardiac troponin T, creatinine kinase-MB fraction, high-sensitivity C-reactive protein, and serum creatinine from blood samples obtained through the arterial sheath at the start of primary PCI. Serial 12-lead electrocardiograms were recorded in the catheterization laboratory before arterial puncture and at the end of the PCI. ST-segment recovery was defined as incomplete if <50%. Of 662 included patients with ST-segment elevation myocardial infarction, 338 (51%) had incomplete ST-segment recovery. An elevated NT-pro-BNP level (≥608 ng/L) was the strongest predictor of incomplete ST-segment recovery (adjusted odds ratio 2.6, 95% confidence interval 1.6 to 4.1; p <0.001) compared to other serum biomarkers and clinical predictors. An elevated NT-pro-BNP level was more strongly predictive in patients without a history of coronary artery disease or hypertension (adjusted odds ratio 4.7, 95% confidence interval 2.4 to 9.2; p <0.001). NT-pro-BNP was the best contributor to both net reclassification (0.43; p <0.001) and integrated discrimination improvement (0.04; p <0.001) when added to a multivariate model with clinical predictors of incomplete ST-segment recovery. In conclusion, NT-pro-BNP was the strongest independent predictor of ST-segment recovery at the end of primary PCI for ST-segment elevation myocardial infarction compared to the other serum biomarkers reflecting myocardial cell damage, renal function, and inflammation.
Several studies have established the prognostic value of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) across the spectrum of patients with acute coronary syndrome. Other serum biomarkers, such as cardiac troponin T (cTnT), creatinine kinase-MB fraction, high-sensitivity C-reactive protein (hs-CRP), and serum creatinine have also been associated with prognosis in patients with acute coronary syndrome. Most studies have reported on the prognostic value of serum biomarker levels in the subacute or chronic phase after acute coronary syndrome. In patients with ST-segment elevation myocardial infarction, the efficacy of primary percutaneous coronary intervention (PCI) is limited when restoration of epicardial flow does not translate into reperfusion at the microvascular level. ST-segment recovery on the 12-lead electrocardiogram (ECG) is a marker of microvascular reperfusion and accurately predicts the final infarct size and clinical outcome. Serum biomarkers associated with incomplete ST-segment recovery might, at the start of PCI, identify patients who are at risk of suboptimal microvascular reperfusion. Such patients might particularly benefit from adjunctive measures aimed at improving tissue reperfusion. However, studies of serum biomarkers to predict microvascular reperfusion after primary PCI are largely absent. Therefore, we sought to investigate the association between 5 serum biomarkers, obtained immediately before emergency coronary angiography, and ST-segment recovery at the end of the procedure in patients who undergo primary PCI for ST-segment elevation myocardial infarction.
Methods
We analyzed the data obtained from patients with ST-segment elevation myocardial infarction who had undergone primary PCI at our institution from March 15, 2005 to January 1, 2007. Blood samples were obtained before primary PCI as a part of routine clinical care. Primary PCI was generally performed according to current guidelines. Patients received aspirin (500 mg), unfractionated heparin (5,000 IU), and clopidogrel (300 mg) during transportation to the catheterization laboratory. Glycoprotein IIb/IIIa inhibitors were not routinely used but were administered at the discretion of the operator during PCI.
Blood was collected in heparin-coated or plain glass tubes (4.5 ml) through the arterial sheath before primary PCI for assessment of the NT-pro-BNP, cTnT, creatinine kinase-MB fraction, hs-CRP, and serum creatinine levels. The blood samples were centrifuged without undue delay and stored at −70°C until additional, off-line analysis. Both NT-pro-BNP and cTnT were measured using a Hitachi modular E-170 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). For NT-pro-BNP, the coefficient of variation was 12.5% at 45 pg/ml, 4.9% at 270 pg/ml, 3.6% at 464 pg/ml, and 3.4% at 1,930 pg/ml. The analytic range extended from 5 to 35,000 pg/L. The manufacturer reported the 97.5th percentile in healthy blood donors aged <50 years was 84 pg/ml for men and 155 pg/ml for women. For patients >50 years old, the reported 97.5th percentile for men and women was 194 and 222 pg/ml, respectively. The creatinine kinase-MB fraction and hs-CRP serum levels were measured using an immunoassay and immunoturbidimetric assay (Roche Diagnostics GmbH), respectively. The estimated creatinine clearance rate was calculated according to the Cockcroft and Gault formula.
For the purposes of the present study, we divided the cohort into subgroups according to quartiles of NT-pro-BNP, hs-CRP, and creatinine clearance and defined a serum concentration in the upper quartile as elevated and a concentration in the lower 3 quartiles as nonelevated. For cTnT, a prospectively defined upper reference limit of 0.10 μg/L was used. For values less than the limit of detection, the lower limit (0.04 μg/L) was used for statistical analysis. The upper limit of normal for the creatinine kinase-MB fraction was 6.5 μg/L.
From the local electronic database at the catheterization laboratory we abstracted the baseline demographic variables and the procedural and angiographic information that had been prospectively collected and entered by specialized nurses and interventional cardiologists concurrently with routine patient care. We retrospectively sought to collect the 12-lead ECGs recorded at the start of the procedure before arterial access at the catheterization laboratory for all patients with ST-segment elevation myocardial infarction who had undergone primary PCI at our institution. These preprocedural ECGs were compared with the 12-lead ECGs recorded at the end of the procedure (postprocedural ECGs) before the patients were transferred to the coronary or intensive care unit.
The ECGs of the included patients were analyzed by one investigator (NV), who was unaware of the angiographic and biomarker data. ST-segment deviation was measured using a handheld caliper and magnifying glass at 80 ms after the J-point in all available leads. ST-segment deviation was measured to the nearest 0.05 mV, with the TP segment as the preferred isoelectric baseline. We defined ST-segment recovery as the percentage of change in the cumulative ST-segment deviation between the preprocedural and immediately postprocedural ECG. The primary outcome of the present analysis was the occurrence of incomplete ST-segment recovery, which we defined as ST-segment recovery of <50%.
All consecutive patients with ST-segment elevation myocardial infarction who had undergone primary PCI at our institution according to our digital database were evaluated. Patients with a missing preprocedural ECG, postprocedural ECG, or blood sample were excluded from the present analysis. Furthermore, patients in whom ST-segment recovery could not be assessed, such as those patients with ECG recordings showing complete left bundle branch block, an accelerated idioventricular rhythm, a paced rhythm, severe artifacts, or left main or bypass graft occlusions and severely widened QRS complexes, were excluded. Patients who had been referred for primary PCI in whom ST-segment elevation had disappeared on arrival at the catheterization laboratory were also excluded. To exclude patients with overt inflammatory conditions or infections, we reviewed the reports of the included patients who had an admission hs-CRP level >20 mg/L. Patients with an unambiguous explanation for an elevated admission hs-CRP serum level (eg, acute or chronic systemic infection, autoimmune disease, or recent [<1 month] surgical procedure) were excluded from the analyses for hs-CRP.
In a subgroup analysis, we studied the association between NT-pro-BNP and ST-segment recovery in the included patients without hypertension or a history of coronary artery disease. We defined a history of coronary artery disease as the occurrence of previous myocardial infarction, coronary artery bypass grafting, or PCI. With this subgroup analysis, we sought to investigate the association between NT-pro-BNP and ST-segment recovery for patients in whom we assumed a nonelevated NT-pro-BNP concentration before the index event.
The association between serum biomarkers (both as categorical and continuous variables) and incomplete ST-segment recovery was investigated using logistic regression analysis in 3 sets of models: univariate models, models with the serum biomarkers (ie, NT-pro-BNP, cTnT, creatinine kinase-MB fraction, hs-CRP, and creatinine clearance), and overall models with the serum biomarkers adjusting for the baseline characteristics that showed a univariate association (p <0.05) with ST-segment recovery (eg, age, current smoking, diabetes mellitus, and anterior wall ST-segment elevation myocardial infarction). The variables were entered en bloc to identify independent predictors of incomplete ST-segment recovery.
To estimate the discriminative value of the 5 serum biomarkers, we calculated the C statistic (area under the receiver operating characteristic curve). To further quantify this discriminative power, we used the method previously described by Pencina et al. We analyzed the differences in a patient’s individual estimated probability of incomplete ST-segment recovery after the addition of a serum biomarker as categorical variable to a referent model containing the baseline characteristics with a significant association with incomplete ST-segment recovery. Each probability increase in a patient with incomplete ST-segment recovery and probability decrease in a patient with complete ST-segment recovery would imply improved prediction ability, and the opposite would imply worse prediction ability. We combined the numbers of improved and worsened probabilities for patients with incomplete and complete ST-segment recovery in the net reclassification improvement. We also calculated the integrated discrimination improvement, which directly compared the mean difference in probability between the models with and without each serum biomarker.
Normally distributed continuous variables are expressed as the mean ± SD and were compared using Student’s t test. Other continuous data, expressed as the median and interquartile range, were compared using the Mann-Whitney U test. All categorical variables are depicted using relative frequency distributions and Fischer’s exact test was used to make a comparison. All probability values are 2-sided and considered significant at p <0.05. Statistical analyses were performed using the Statistical Package for Social Sciences, version 16.0 (SPSS, Chicago, Illinois).
Results
A total of 1,182 consecutive patients with ST-segment elevation myocardial infarction underwent primary PCI at our institution from March 15, 2005 to January 1, 2007. We excluded 27 patients with left main coronary artery or bypass graft occlusion, 281 patients with missing ECGs, and 50 patients with missing biomarker results. Of 824 patients with a complete set of ECGs and blood sample data, 36 were excluded on the basis of the electrocardiographic criteria and 126 because of preprocedural ST-segment normalization. The remaining 662 patients constituted the study cohort for the present analysis. The NT-pro-BNP, creatinine kinase-MB fraction, and hs-CRP levels were available for all 662 patients, cTnT for 659 patients (>99%), and creatinine clearance for 629 patients (95%). The analyses of hs-CRP were restricted to 645 patients without evidence of concomitant overt inflammatory disease at primary PCI.
The baseline and procedural characteristics of the included and nonincluded patients are listed in Table 1 . The patients who were not included in the present study were older, more often had a history of coronary artery disease, and more often needed circulatory support. They also had a higher NT-pro-BNP concentration (192 vs 142 ng/L) and lower creatinine clearance (96 vs 104 ml/min) than the included patients. Otherwise, the 2 groups had comparable serum biomarker concentrations ( Table 1 ).
| Variable | Patients Included (n = 662) | Patients Not Included (n = 520) | p Value |
|---|---|---|---|
| Age (years) | 62 ± 13 | 64 ± 13 | 0.02 |
| Men | 484 (73%) | 368 (71%) | 0.40 |
| Current smoker | 292 (44%) | 200 (39%) | 0.06 |
| Diabetes mellitus | 81 (12%) | 72 (14%) | 0.44 |
| Body mass index (kg/m 2 ) | 27 ± 4 | 27 ± 4 | 0.20 |
| Hypertension | 188 (28%) | 168 (32%) | 0.16 |
| Hypercholesterolemia | 139 (21%) | 118 (23%) | 0.52 |
| Previous myocardial infarction | 83 (13%) | 102 (20%) | 0.001 |
| Previous coronary bypass | 6 (1%) | 23 (4%) | <0.001 |
| Previous percutaneous coronary intervention | 63 (10%) | 72 (14%) | 0.02 |
| Anterior myocardial infarction | 298 (45%) | 200 (39%) | 0.02 |
| Intra-aortic balloon counterpulsation used | 43 (7%) | 62 (12%) | 0.001 |
| Glycoprotein IIb/IIIa inhibitors used | 209 (32%) | 144 (28%) | 0.16 |
| Postprocedural Thrombolysis In Myocardial Infarction-3 flow | 594 (90%) | 463 (89%) | 0.78 |
| Total ischemic time (min) ⁎ | 185 (128–268) | 186 (135–275) | 0.35 |
| Biomarker concentrations † | |||
| N-terminal pro-brain natriuretic peptide (ng/L) | 142 (60–608) | 196 (66–805) | 0.02 |
| Cardiac troponin T (μg/L) | 0.04 (0.04–0.24) | 0.07 (0.04–0.26) | 0.20 |
| Elevated (>0.10 μg/L) | 275 (42%) | 187 (45%) | 0.34 |
| Creatinine kinase-MB fraction (μg/L) | 6.4 (3.7–19.6) | 7.0 (3.8–18.0) | 0.84 |
| Elevated (>6.5 μg/L) | 325 (49%) | 218 (52%) | 0.35 |
| High-sensitivity C-reactive protein (mg/L) | 3.3 (1.4–7.6) | 3.0 (1.4–7.3) | 0.74 |
| Elevated (>7.0 mg/L) | 162 (25%) | 106 (20%) | 0.06 |
| Creatinine clearance (ml/min) | 104 (78–132) | 96 (70–123) | 0.002 |
| Decreased (<78 ml/min) | 158 (24%) | 132 (25%) | 0.59 |
⁎ Data available for 979 patients.
† Blood samples available for 419 nonincluded patients (81%).
Of the 662 patients, 338 (51%) had incomplete ST-segment recovery. Table 2 lists the association between the 5 serum biomarkers and incomplete ST-segment recovery. Incomplete ST-segment recovery occurred in 121 (73%) of 165 patients with elevated NT-pro-BNP (≥608 ng/L) and in 217 (44%) of 497 patients with nonelevated NT-pro-BNP (odds ratio [OR] 3.5, 95% confidence interval [CI] 2.4 to 5.2; p <0.001). Elevated cTnT (OR 2.2, 95% CI 1.6 to 3.0; p <0.001), creatinine kinase-MB fraction (OR 1.9, 95% CI 1.4 to 2.6; p <0.001), hs-CRP (OR 1.5, 95% CI 1.1 to 2.2; p = 0.03), and decreased creatinine clearance (OR 2.2, 95% CI 1.5 to 3.2; p <0.001) had a significant, but weaker, univariate relation with incomplete ST-segment recovery.
| Marker | Incomplete ST-Segment Recovery | Univariate Analysis | Model With Serum Biomarkers ⁎ | Overall Model † | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| % | n/n | OR | 95% CI | p Value | OR | 95% CI | p Value | OR | 95% CI | p Value | |
| N-terminal pro-brain natriuretic peptide (ng/L) | 3.5 | 2.4–5.2 | <0.001 | 2.6 | 1.7–4.1 | <0.001 | 2.6 | 1.6–4.1 | <0.001 | ||
| ≥608 | 73 | 121/165 | |||||||||
| <608 | 44 | 217/497 | |||||||||
| Cardiac troponin T (μg/L) | 2.2 | 1.6–3.0 | <0.001 | 1.2 | 0.8–1.9 | 0.44 | 1.1 | 0.7–1.6 | 0.79 | ||
| >0.10 | 63 | 172/275 | |||||||||
| ≤0.10 | 43 | 165/384 | |||||||||
| Creatinine kinase-MB fraction (μg/L) | 1.9 | 1.4–2.6 | <0.001 | 1.3 | 0.9–2.1 | 0.19 | 1.3 | 0.8–2.0 | 0.23 | ||
| >6.5 | 59 | 193/325 | |||||||||
| ≤6.5 | 43 | 145/337 | |||||||||
| High-sensitivity C-reactive protein (mg/L) | 1.5 | 1.1–2.2 | 0.03 | 1.1 | 0.7–1.6 | 0.72 | 1.1 | 0.7–1.6 | 0.79 | ||
| >7.0 | 58 | 94/162 | |||||||||
| ≤7.0 | 48 | 231/483 | |||||||||
| Creatinine clearance (ml/min) | 2.2 | 1.5–3.2 | <0.001 | 1.8 | 1.2–2.7 | 0.003 | 1.9 | 1.2–3.1 | 0.009 | ||
| <78 | 66 | 104/158 | |||||||||
| ≥78 | 47 | 222/471 | |||||||||
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