| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Proteomics and Protein Markers |
1 Division of Critical Care, Fujita Health University Graduate School of Health Sciences, Toyoake, Japan.
2 Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Japan.
3 Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University Hospital, Toyoake, Japan.
aAddress correspondence to this author at: Division of Critical Care, Fujita Health University Graduate School of Health Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan. Fax 81-562-93-2315; e-mail jishii{at}fujita-hu.ac.jp.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Methods: Serum concentrations of H-FABP and cTnT were measured on admission in 328 consecutive patients hospitalized for ACS within 6 h after the onset of chest pain [AMI, 241 (73.5%) patients; ST-segment elevation myocardial infarction, 154 (47.0%) patients; and emergent coronary angiography within 24 h after admission, 287 (87.5%) patients]. Cardiac events, which were defined as cardiac death or subsequent nonfatal AMI, were monitored for 6 months after admission.
Results: During the 6-month follow-up period, there were 25 cardiac events, including 15 cardiac deaths and 10 subsequent nonfatal AMIs. Stepwise multivariate analyses including clinical, electrocardiographic, and biochemical variables revealed that increased H-FABP (above the median of 9.8 µg/L), but not increased cTnT (above the median of 0.02 µg/L), was independently associated with cardiac events in all patients [relative risk (RR) = 8.96; P = 0.0004], the subgroup of patients with ST-segment elevation myocardial infarction (RR = 11.3; P = 0.02), and the subgroup of patients with unstable angina and non-ST-segment elevation myocardial infarction (RR = 8.31; P = 0.007). The area under the ROC curve was higher for H-FABP than for cTnT (0.711 vs 0.578; P = 0.08), suggesting that H-FABP concentrations have a greater predictive capacity for cardiac events than cTnT.
Conclusion: Serum H-FABP is a potential independent predictor of cardiac events within 6 months of patient admission and may provide prognostic information superior to cTnT in the early hours of ACS.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
6.2 µg/L (6). The prognostic value of serum H-FABP concentrations has not been established for acute coronary syndrome (ACS). The present study was designed to prospectively assess the prognostic value of serum concentrations of H-FABP relative to cardiac troponin T (cTnT) determined on admission for adverse cardiac outcomes within 6 months in patients presenting with ACS in the first 6 h after the onset of chest pain.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
All patients were treated according to routine clinical protocols. Early invasive management, including emergent coronary angiography within 24 h of admission followed by percutaneous coronary intervention, was routinely performed in our institution. Demographics and clinical data, including age, sex, diagnosis, revascularization, coronary risk factors, and Killip class (7) on admission, were collected from hospital medical records and patient interviews.
laboratory analyses
Venous whole blood samples were drawn and centrifuged within 30 min of collection, and the serum obtained was stored at –70 °C. H-FABP was measured by 2-step direct sandwich ELISA (Market-M H-FABP; Dainippon Pharmaceutical). The calibrators for the ELISA covered the range 0–250 µg/L. The lower limit of detection for the H-FABP assay was 1.25 µg/L, and a value of 6.2 µg/L has been used for an AMI cutoff (5)(8). The assay was linear within the range 0–220 µg/L. Myoglobin (200 mg/L) and myosin (84 mg/L) did not cross-react in the H-FABP assay. The total imprecision for the H-FABP assay was 8.2% at 6.2 µg/L, 7.9% at 12.0 µg/L, and 5.6% at 33.7 µg/L.
cTnT and creatine kinase MB (CK-MB) were determined routinely at admission, as well as 16 or 24 h after admission. For the cTnT measurements (Elecsys 2010 analyzer; Roche Diagnostics), the manufacturer-stated detection limit and cutoff for AMI were 0.01 and 0.1 µg/L, respectively. The total imprecision for the cTnT assay was 14% at 0.012 µg/L and 8.7% at 0.024 µg/L. For the CK-MB measurements (Dade Dimension RxL Max analyzer; Dimension Flex reagent cartridge MMB; Dade Behring), the detection limit and upper limit of the reference interval were 0.5 and 3.6 µg/L, respectively. The total imprecision for the CK-MB assay was 4.6% at 2.9 µg/L and 2.3% at 9.1 µg/L.
study end point and follow-up
Cardiac events were defined as cardiac death or subsequent nonfatal AMI. Cardiac death was defined as any death for which there was no clearly documented noncardiac cause. Sudden death occurring outside the hospital for which no other cause was assigned was also regarded as cardiac death. Patients were defined as having admission AMI when serum cTnT concentrations were 0.1 µg/L in blood samples collected within 24 h of admission. Only a new AMI occurring >24 h after admission was considered a subsequent AMI. Patients were defined as having a subsequent AMI if they presented with symptoms suggestive of ACS and typical increased concentrations of biochemical markers with CK-MB greater than the upper reference limit (and a CK-MB increase 50% from the previous concentration in the case of an AMI occurring soon after the admission AMI).
The study endpoint was a cardiac event at 6 months after admission. A review of medical records and follow-up telephone interviews were conducted to survey for patient cardiac events. The review of case notes for follow-up was performed by 2 of the authors (J.L. and H.N.), who were blinded to H-FABP concentrations.
statistical analysis
Continuous variables were analyzed (Ver. 11.0, Statistical Package for the Social Sciences) with the Mann–Whitney U-test, Wilcoxon paired sign-rank test, or linear regression analysis, and data were expressed as mean (SD) or median (25th–75th percentiles). Values below the detection limit of the assay were defined as zero. Categorical variables were compared by the 
2 test. The relative risk with the 95% confidence interval (CI) is presented. Univariate and stepwise multivariate Cox regression analyses were used to evaluate the prognostic value of variables. The log-rank test was performed for the Kaplan–Meier probability estimates. The ROC curve was used to assess the discriminatory ability of biomarkers (9). A univariate Z-test was used to compare the area under the ROC curve of biomarkers, as described by Hanley and McNeil (10). P <0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
), 241 (73.5%) were diagnosed with AMI at admission. On the basis of electrocardiographic findings on admission, 154 patients who had a persistent (>30 min) ST-segment elevation of at least 0.05 mV in at least 2 contiguous leads or presumed new left-bundle branch block were assigned to the ST-segment elevation myocardial infarction (STEMI) group, and the other 174 patients were placed in the unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) group. Mean (SD) serum concentrations of both H-FABP [63.8 (92.4) µg/L vs 25.2 (46.4) µg/L; P <0.0001] and cTnT [0.552 (1.77) µg/L vs 0.093 (0.211) µg/L; P <0.0001] on admission in the STEMI group were significantly higher than those in the UA/NSTEMI group. Of the patients with STEMI, 139 (90.3%) underwent emergent coronary angiography within 24 h after admission [median of 0.8 (0.4–1.1) h after admission], with 123 (79.9%) of these subsequently undergoing coronary revascularization. Of the patients with UA/NSTEMI, 148 (85.1%) underwent emergent coronary angiography within 24 h after admission [median of 3.2 (1.0–17.5) h], with 76 (43.7%) of these subsequently undergoing coronary revascularization.
|
The serum concentration of H-FABP on admission was <1.25 µg/L in 3 patients (0.9%), 1.25–6.2 µg/L in 113 (34.5%), and 6.2 µg/L in 212 (64.6%). The cTnT concentration on admission was <0.01 µg/L in 136 patients (41.5%), 0.01–0.1 µg/L in 95 (29.0%), and 0.1 µg/L in 97 (29.6%). A significantly higher percentage of patients had H-FABP concentrations 6.2 µg/L (64.6%) than cTnT concentrations 0.01 µg/L (58.5%; P = 0.02) or 0.1 µg/L (29.6%; P <0.0001), suggesting that H-FABP concentration is a more sensitive indication than cTnT of myocardial damage in patients with ACS within 6 h after the onset of chest pain.
The time from the onset of chest pain to admission correlated significantly with H-FABP concentration (r = 0.197; P = 0.0003), but not with cTnT concentration. There was a weak but significant correlation between H-FABP and cTnT concentrations at admission (r = 0.17; P = 0.002).
During the 6 months after admission, there was 1 (0.3%) noncardiac death (gastric cancer) and 25 (7.6%) cardiac events, including 15 (4.6%) cardiac deaths and 10 (3.0%) subsequent nonfatal AMIs. The causes of cardiac death were fatal AMI in 10 patients, heart failure in 3 patients, and sudden death occurring outside hospital in 2 patients.
A comparison of patients who had subsequent cardiac events with those who did not revealed that cardiac events were associated with patient age (mean age, 69.8 vs 64.5 years; P = 0.02), higher serum concentrations of H-FABP (119 vs 46.6 µg/L; P = 0.0004) and cTnT (1.72 vs 0.45 µg/L; P = 0.01), AMI (96% vs 71.6%; P = 0.008) or anterior AMI (56% vs 30%; P = 0.01), hypertension (72% vs 53.5%; P = 0.09), and a tendency not to receive emergent coronary angiography within 24 h after admission (64% vs 89.4%; P = 0.001; Table 1
). A comparison of patients who experienced a cardiac event and those who did not revealed that there was no difference in the number of patients who had diabetes or hyperlipidemia, currently smoked, or had received early coronary revascularization.
Kaplan–Meier analyses showed that patients with H-FABP concentrations above the median value of 9.8 µg/L on admission had a significantly higher risk of cardiac mortality (P = 0.0006) and cardiac events (P <0.0001) within 6 months after admission compared with those who did not (Fig. 1
). Although weaker (P = 0.018 and 0.012, respectively), a similar relationship was observed for H-FABP 6.2 µg/L; we therefore used the median H-FABP value of 9.8 µg/L as the cutoff for predicting cardiac death and cardiac events.
|
Patients with increased H-FABP (above the median value of 9.8 µg/L) on admission had a significantly higher risk of cardiac death and cardiac events within 30 days (P = 0.002 and 0.006, respectively) and 6 months (P = 0.0008 and P <0.0001, respectively) after admission compared with those who did not (Table 2
). Although weaker, a similar relationship was observed for increased cTnT (above the median value of 0.02 µg/L; Table 3
).
|
|
The relationship between increased H-FABP and cardiac death or cardiac events within 6 months after admission in patients with or without increased cTnT is shown in Fig. 2
. Increased H-FABP was significantly associated with an increased risk of cardiac events within 6 months after admission in patients with or without increased cTnT concentrations (P = 0.0001 and 0.003, respectively). There was a greater tendency for cardiac death within 6 months after admission among patients with increased cTnT and H-FABP concentrations compared with those patients with only increased cTnT concentrations (P = 0.07).
|
In the subgroup of patients with STEMI or UA/NSTEMI, patients with increased H-FABP also had a higher risk of cardiac events within 6 months after admission compared with those who did not (P = 0.04 and 0.005, respectively; Table 2
). There was no significant difference in the tendency for cardiac event risk within 6 months after admission between patients with and without increased cTnT (Table 3
).
The relationship between early invasive management and incidence of cardiac events within 6 months after admission for UA/NSTEMI patients with or without increased H-FABP or cTnT is shown in Fig. 3
. Patients with increased H-FABP who received early invasive management had a significantly lower risk of cardiac events within 6 months after admission compared with those who did not (P = 0.015). However, the risk of cardiac events within 6 months after admission did not differ significantly between patients without increased H-FABP who received early invasive management and those who did not. Similar results were observed for increased cTnT.
|
Univariate Cox proportional regression analyses revealed that increased H-FABP and cTnT were signifi-cantly associated with cardiac death (P = 0.009 and 0.01, respectively) and cardiac events (P = 0.0009 and 0.03, respectively; Table 4
). Stepwise multivariate analyses including age, gender, time from the onset of chest pain, STEMI, increased H-FABP, increased cTnT, creatinine concentration, Killip class >1, anterior AMI, and previous history of myocardial infarction revealed that increased H-FABP, but not increased cTnT, was independently associated with cardiac death (P = 0.04) and cardiac events (P = 0.0004) within 6 months after admission (Table 5
). Similar to all patients, for patients with STEMI stepwise multivariate analyses including age, gender, time from the onset of chest pain, increased H-FABP, increased cTnT, creatinine concentration, Killip class >1, anterior AMI, and previous history of myocardial infarction revealed that increased H-FABP (P = 0.02), age (P = 0.004), and a history of myocardial infarction (P = 0.006) were independent predictors of cardiac events within 6 months after admission (Table 5
). For patients with UA/NSTEMI, only increased H-FABP was independently associated with cardiac events within 6 months after admission (P = 0.007).
|
|
Comparison of the areas under the ROC curves for H-FABP and cTnT revealed that H-FABP (0.711; 95% CI, 0.810–0.612) was a better predictor of cardiac events within 6 months after admission than cTnT (0.578; 95% CI, 0.695–0.462; P = 0.08; Fig. 4A
). The area under the H-FABP ROC curve for patients with STEMI was 0.684 (95% CI, 0.814–0.553), and the H-FABP concentration associated with maximum sensitivity (60%) and specificity (65%) was 35 µg/L (Fig. 4B
). For patients with UA/NSTEMI, the area under the H-FABP ROC curve was 0.730 (95% CI, 0.893–0.567), and the H-FABP concentration associated with maximum sensitivity (80.0%) and specificity (71%) was 10.4 µg/L.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Although there was a relationship between increased serum cTnT concentrations and adverse outcomes within 6 months after admission, the predictive ability of H-FABP concentration was higher. Increased H-FABP concentrations, but not cTnT concentrations, retained independent significance based on a stepwise Cox regression analysis. Supporting these findings, ROC curve analyses revealed that H-FABP concentrations tended to have a higher predictive ability than cTnT concentrations. Furthermore, increased H-FABP was associated with an increased risk of cardiac events within 6 months after admission independent of increased cTnT (Fig. 2
). These findings show that serum H-FABP concentrations provide prognostic information superior to that provided by cTnT concentrations for patients presenting with ACS in the first 6 h after the onset of chest pain. The superiority of H-FABP over cTnT may result from its higher sensitivity for the detection of myocardial damage in the early hours of ACS.
A recent report on 134 patients with suspected ACS, including 74 (55%) patients presenting within 6 h after symptom onset, showed that H-FABP 6.2 µg/L had higher sensitivities than cTnT 0.1 µg/L for identifying patients requiring emergency hospitalization (64% vs 43%; P <0.05), emergency angiography (63% vs 41%; P <0.05), and early coronary intervention within 7 days after admission (78% vs 58%; P <0.05) (11). This study, however, showed no correlation of H-FABP and subsequent AMI or death because the authors reported no subsequent AMI and death during the 1-month follow-up period. These differences between the 2 studies might result from differences in population sizes (larger in our study) and the severity of patient condition (more severe in our study).
Given the diagnostic and prognostic properties of cTnT for patients with ACS during the first 6 h after the onset of chest symptoms (12)(13)(14), our findings clearly demonstrate the need to consider either serum H-FABP or cTnT for diagnosis of AMI and risk stratification, depending on the ischemic interval at presentation. Our findings indicate that if patients present within 6 h after the onset of chest pain, measurement of serum H-FABP concentrations provides a more appropriate platform for diagnosis and prognosis than measurement of cTnT concentrations; conversely, if patients present later than the first 6 h after the onset of chest pain, measurement of serum cTnT concentrations is appropriate. Because accurately predicting the ischemic interval in ACS is difficult (15)(16), a combination of serum H-FABP and cTnT measurements would provide a better early risk assessment for patients with ACS than would measurement of either of these markers alone. Larger prospective studies would allow the effectiveness of combined H-FABP and cTnT serum measurements for patients presenting with ACS to be ascertained.
Recent multicenter studies demonstrated the use of cTnT concentrations to identify UA/NSTEMI patients, who particularly benefit from early invasive management (17)(18). By comparing the serum H-FABP concentrations of UA/NSTEMI patients, the present study showed that early invasive management reduced cardiac event rates within 6 months after admission in patients with increased serum H-FABP on admission but had no significant effect when H-FABP concentrations were not increased (Fig. 3
). These results provide evidence that measurement of serum H-FABP concentrations on admission would allow identification of high-risk patients presenting in the early hours of ACS, who would benefit greatly from an early invasive strategy. A disadvantage of this study is that because the population of patients who did not receive early invasive management was small, the treatments were not randomized. Larger prospective studies would confirm the results from this study and clarify the utility of H-FABP for identifying appropriate therapeutic options.
This study highlights the advantages of using serum H-FABP concentrations for risk assessment of patients only with a high clinical probability of ACS. Further investigations are required to explore the application of this approach to a broad spectrum of patients presenting with chest pain and a low to intermediate probability of ACS. Because H-FABP has a very low molecular mass, its elimination rate is partly determined by the patient’s kidney function (19). It would be interesting to determine whether our findings might apply to patients with chronic renal failure. To minimize the effects of renal clearance, however, we excluded patients with serum creatinine concentrations >15 mg/L. In addition, it would be useful to calculate the H-FABP/creatinine concentration ratio in serum. Further studies are needed to clarify the usefulness of this ratio in patients with ACS. A further limitation of this study is the potential increase in H-FABP concentrations in patients with skeletal muscle damage (3)(4) or heart failure (20). Recent studies have also suggested that H-FABP concentrations may be increased in patients with minor brain injuries (21) or neurodegenerative disease (22). It is important to ascertain whether the prognostic and diagnostic value of serum H-FABP concentrations also applies to ACS patients with these complications. Further investigations using larger cohorts are necessary to address these issues.
The cutoff values derived from ROC curves are highly dependent on the study population and may not provide optimal prognostic cutoff values for small studies. In addition, the H-FABP cutoff concentration for predicting cardiac events within 6 months after admission was 3-fold higher for patients with STEMI than the cutoff for patients with UA/NSTEMI, indicating that prognostic cutoffs may differ according to admission diagnoses. We used the median value of 9.8 µg/L, therefore, as the prognostic cutoff value of H-FABP because of the relatively small number of cardiac events (n = 25).
The time required to perform the quantitative H-FABP assay is 90 min, which limits its value as a rapid diagnostic or prognostic tool. The qualitative whole-blood rapid panel test for H-FABP is currently available for the diagnosis of AMI in Japan (6). The established H-FABP cutoff value for this test is 6.2 µg/L. Our results suggest, however, that an H-FABP concentration 6.2 µg/L may have a lower prognostic value than an H-FABP concentration above the median value of 9.8 µg/L for predicting cardiac death and cardiac events. Larger studies would allow the optimum prognostic cutoff value of H-FABP to be determined.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The following articles in journals at HighWire Press have cited this article:
|
|
 |
|
  M. Lankeit, C. Dellas, A. Panzenbock, N. Skoro-Sajer, D. Bonderman, M. Olschewski, K. Schafer, M. Puls, S. Konstantinides, and I. M. Lang Heart-type fatty acid-binding protein for risk assessment of chronic thromboembolic pulmonary hypertension Eur. Respir. J., May 1, 2008; 31(5): 1024 - 1029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. de Lemos and M. O'Donoghue The Skinny on Fatty Acid-Binding Protein J. Am. Coll. Cardiol., November 20, 2007; 50(21): 2068 - 2070. [Full Text] [PDF]
|
|
|
|
|
|
N. Kilcullen, K. Viswanathan, R. Das, C. Morrell, A. Farrin, J. H. Barth, A. S. Hall, and for the EMMACE-2 Investigators Heart-Type Fatty Acid-Binding Protein Predicts Long-Term Mortality After Acute Coronary Syndrome and Identifies High-Risk Patients Across the Range of Troponin Values J. Am. Coll. Cardiol., November 20, 2007; 50(21): 2061 - 2067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Puls, C. Dellas, M. Lankeit, M. Olschewski, L. Binder, A. Geibel, C. Reiner, K. Schafer, G. Hasenfuss, and S. Konstantinides Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism Eur. Heart J., January 2, 2007; 28(2): 224 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O'Donoghue, J. A. de Lemos, D. A. Morrow, S. A. Murphy, J. L. Buros, C. P. Cannon, and M. S. Sabatine Prognostic Utility of Heart-Type Fatty Acid Binding Protein in Patients With Acute Coronary Syndromes Circulation, August 8, 2006; 114(6): 550 - 557. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
