Prognostic Utility of Heart-Type Fatty Acid Binding Protein in Patients With Acute Coronary Syndromes
Background— Heart-type fatty acid binding protein (H-FABP) is a cytosolic protein that is released rapidly from the cardiomyocyte in response to myocardial injury. Although it has been investigated as an early marker of acute myocardial infarction, its prognostic utility in acute coronary syndromes has not been established.
Methods and Results— We measured H-FABP in 2287 patients with acute coronary syndromes from the OPUS-TIMI 16 trial. H-FABP was elevated (>8 ng/mL) in 332 patients (14.5%). Patients with an elevated H-FABP were more likely to suffer death (hazard ratio [HR], 4.1; 95% CI, 2.6 to 6.5), recurrent myocardial infarction (HR, 1.6; 95% CI, 1.0 to 2.5), congestive heart failure (HR, 4.5; 95% CI, 2.6 to 7.8), or the composite of these end points (HR, 2.6; 95% CI, 1.9 to 3.5) through the 10-month follow-up period. H-FABP predicted the risk of the composite end point both in patients who were troponin I negative (HR, 2.1; 95% CI, 1.3 to 3.4) and in those who were troponin I positive (HR, 3.3; 95% CI, 2.0 to 5.3). In a Cox proportional-hazards model that adjusted for baseline variables, including demographics, clinical characteristics, creatinine clearance, ST deviation, index diagnosis, and troponin I, elevated H-FABP remained a significant predictor of the composite end point (HR, 1.9; 95% CI, 1.3 to 2.7), as well as the individual end points of death (HR, 2.7; 95% CI, 1.5 to 4.9) and CHF (HR, 2.4; 95% CI, 1.2 to 5.0). In a multimarker approach, H-FABP, troponin I, and B-type natriuretic peptide provided complementary information.
Conclusions— Elevation of H-FABP is associated with an increased risk of death and major cardiac events in patients presenting across the spectrum of acute coronary syndromes and is independent of other established clinical risk predictors and biomarkers.
Received April 26, 2006; revision received May 30, 2006; accepted June 8, 2006.
Heart-type fatty acid binding protein (H-FABP) is a small cytosolic protein that functions as the principal transporter of long-chain fatty acids in the cardiomyocyte.1–4 It is present in abundance in the myocardium and is released rapidly into the circulation in response to myocardial injury.1,2 As such, there are data documenting the diagnostic utility of H-FABP as an early marker of myocardial infarction (MI)5–7 and as a marker of reperfusion after ST-segment elevation MI (STEMI).8,9
Clinical Perspective 557
In contrast, the prognostic utility of H-FABP in acute coronary syndromes (ACS) has not been thoroughly evaluated. Risk stratification is an important objective in the evaluation of patients with ACS.10 To that end, biomarkers such as troponin,11–13 CRP,14,15 and B-type natriuretic peptide (BNP)16,17 have improved our ability to identify patients at increased risk for adverse outcomes in this setting. We therefore assessed the prognostic utility of H-FABP in a large cohort of patients presenting across the spectrum of ACS and examined its incremental prognostic value in addition to existing clinical risk factors and biomarkers.
Study Population and Design
The design and results of the Orbofiban in Patients with Unstable Coronary Syndromes (OPUS)-TIMI 16 trial have previously been reported.18 In brief, OPUS-TIMI 16 was a double-blind, randomized, multicenter clinical trial of long-term treatment with the oral glycoprotein IIb/IIIa inhibitor orbofiban in 10 288 patients with ACS. ACS was defined as chest pain at rest lasting ≥5 minutes within 72 hours of randomization associated with elevated cardiac biomarkers, ECG changes (new ST-segment deviation ≥0.5 mm, T-wave inversion ≥3 mm in 3 leads or left bundle-branch block), or prior cardiovascular (CV) disease. Exclusion criteria included age ≤18 years, recent coronary revascularization (other than for index event), creatinine >1.6 mg/dL, or a calculated creatinine clearance of <40 mL/min.
Patients in OPUS-TIMI 16 were randomly assigned to receive 50 mg orbofiban twice daily, 50 mg orbofiban twice daily for 1 month, followed by 30 mg twice daily, or placebo. The present study included 2287 patients who were assigned to the group given 50 mg orbofiban twice daily and had baseline blood specimens available for analysis. Patients were followed for up to 10 months for major cardiac events. Clinical end points for this analysis included all-cause mortality, nonfatal MI, new or worsening congestive heart failure (CHF), and the composite of these end points. Additional end points included recurrent ischemia requiring either rehospitalization or urgent revascularization. End points were defined according to previously reported criteria.19,20 A clinical events committee adjudicated all cases of suspected infarction or recurrent ischemia leading to either hospitalization or urgent revascularization. Information on the development of new or worsening heart failure was collected from the case-record forms.
Blood Sampling and Analysis
A sample of venous blood was obtained in citrate-treated tubes from the subjects at the time of enrollment. The mean time from onset of chest pain to randomization was 41±20 hours. The plasma component was frozen and shipped to the TIMI Biomarker Laboratory (Boston, Mass), where samples were stored at −70°C. After trial completion, plasma samples were subsequently shipped to Biosite Diagnostics (San Diego, Calif) for analysis. Sequential sandwich immunoassays were used to measure H-FABP, troponin I, BNP, and myoglobin and were performed in 384-well microtiter plates with the use of an automated system (Tecan Genesis robotic sample processor 200/8, Durham, NC). The lower detection limit for the H-FABP assay was 8 ng/mL; this threshold was used to define H-FABP elevation. At this decision limit, the coefficient of variation for the assay was 16%.
The minimal detectable concentration for the Biosite troponin I assay was 0.05 ng/mL. Decision limits of 1.5 and 0.1 ng/mL were used for analysis on the basis of prior studies.13,21 In 622 patients, additional samples were measured at the TIMI Biomarker Laboratory for troponin I levels using the Bayer Diagnostics (Tarrytown, NY) 2-site sandwich immunoassay. The coefficients of variation and 99th percentile range for the troponin assays have previously been reported.22
Analyses that included BNP were performed using a threshold of 80 pg/mL, which has previously been established for risk stratification in patients with ACS.16,17 For myoglobin, the manufacturer’s recommended detection limit for MI is 107 μg/L; this threshold was used for the analyses in the present study.
Continuous variables were compared using Student’s t test, and categorical variables were compared using the χ2 test. Correlations between levels of H-FABP and other biomarkers were examined using Spearman’s correlation coefficient. Event rates over the 10-month follow-up period were estimated using the Kaplan-Meier method. Cumulative incidence curves were plotted and compared using the log-rank test. Cox proportional-hazard models were constructed to estimate the hazard ratios (HRs) and 95% CIs for clinical events associated with an elevated level of H-FABP.
H-FABP was modeled primarily as a binary variable, with values above the detection limit (8 ng/mL) of the assay defined as elevated. Among patients with an elevated level of H-FABP, medium and high were defined post hoc as below and above the new median (16 ng/mL), respectively. To evaluate the independent prognostic utility of H-FABP, a Cox proportional-hazards model was created that included the following variables: age, diabetes mellitus, history of CHF, history of hyperlipidemia, current tobacco use, time to randomization, systolic blood pressure at randomization, heart rate at randomization, Killip class II through IV, index diagnosis, creatinine clearance, new left bundle-branch block, ST deviation, and Biosite troponin I >1.5 ng/mL. Additional model permutations included Biosite troponin I >0.1 ng/mL, Biosite troponin I as a continuous variable, Bayer troponin I >0.1 ng/mL, and a model in which myoglobin (>107 μg/L) and/or BNP (>80 pg/mL) were included as covariates.
A value of P<0.05 was considered statistically significant. Statistical analyses were performed with Stata version 8 or above (StataCorp, College Station, Tex). The authors had full access to the data and take full responsibility for their integrity. All authors have read and agree to the manuscript as written.
Baseline Demographics and Clinical Presentation
H-FABP was elevated (>8 ng/mL) in 332 of the 2287 patients (14.5%). Among these patients, the median level of H-FABP was 16 ng/mL, with a range of 8 to 434 ng/mL. The baseline characteristics of the study population are displayed in Table 1. Patients with elevated levels of H-FABP were older and more likely to have a history of CHF and a lower creatinine clearance at the time of entry. Patients with elevated H-FABP more commonly presented with STEMI as their index diagnosis or had signs of CHF (Killip class II through IV) at randomization but were found to have a similar angiographic burden of disease. Patients with elevated levels of H-FABP were more likely to have ECG abnormalities and elevated biomarkers of necrosis. Although statistically significant, the correlations between levels of H-FABP and creatine kinase-MB (CK-MB; r=0.18, P<0.001) or troponin I (r=0.29, P<0.001) were not strong. The correlations between H-FABP and CK-MB or troponin I were not substantially changed when the analysis was restricted to only those patients with elevated levels of H-FABP (r=0.23, P<0.001 and r=0.31, P<0.001, respectively). Modest correlations were observed between H-FABP and serum myoglobin (r=0.46, P<0.001) and BNP (r=0.23, P<0.001). When analyses were restricted only to patients with elevated levels of H-FABP, the correlation between H-FABP and myoglobin was strengthened (r=0.58, P<0.001), whereas the correlation between H-FABP and BNP was attenuated (r=0.063, P=0.25).
Association of Baseline H-FABP With Clinical Outcomes
The cumulative incidence curves for the composite end point of death, MI, or CHF are displayed in Figure 1. Patients with an elevated level of H-FABP at baseline had a significantly higher clinical event rate over 10 months of follow-up than did patients with an undetectable level of H-FABP (23.5% versus 9.3%; HR, 2.6; 95% CI, 1.9 to 3.5; P<0.001). There was directional consistency across all the individual components of the composite end point, with an elevated level of H-FABP being a particularly powerful predictor of death (HR, 4.1; 95% CI, 2.6 to 6.5) and CHF (HR, 4.5; 95% CI, 2.6 to 7.8) (Table 2).
We further explored the relationship between the magnitude of H-FABP elevation and the risk of subsequent adverse clinical events by stratifying patients into 3 distinct categories based on levels of H-FABP defined as low (<8 ng/mL), medium (8 to 16 ng/mL), or high (>16 ng/mL). A strong graded relationship was observed between levels of H-FABP and the risk of death (P<0.001), recurrent MI (P=0.009), CHF (P<0.001), and the composite of these end points (P<0.001; Figure 2).
At the 30-day follow-up, elevated baseline levels of H-FABP (>8 ng/mL) were already associated with a significant increase in the risk of death, MI, or CHF (HR, 3.2; 95% CI, 2.2 to 4.8). Although relatively few patients experienced recurrent ischemia by 30 days (n=131), elevated levels of H-FABP were associated with an increased risk of recurrent ischemia leading to rehospitalization or urgent revascularization (HR, 1.6; 95% CI, 1.02 to 2.4). Moreover, elevated levels of H-FABP were associated with a significant increase in the early risk of recurrent MI (HR, 1.9; 95% CI, 1.04 to 3.4) and the composite end point of MI or recurrent ischemia (HR, 1.7; 95% CI, 1.2 to 2.4).
The prognostic utility of H-FABP was examined in several clinical subgroups (Figure 3). Importantly, H-FABP was associated with an increased risk of the composite end point for patients with time from onset of chest pain to randomization of ≤48 hours (HR, 2.5; 95% CI, 1.7 to 3.6) and >48 hours (HR, 2.8; 95% CI, 1.5 to 5.2). In the 171 patients who were enrolled within 12 hours after the onset of chest pain, the hazard ratio associated with an elevated level of H-FABP was 2.6 (95% CI, 0.91 to 7.4), consistent with the overall results.
The prognostic utility of H-FABP also was maintained in patients with either a reduced (<60 mL/min) (HR, 2.1; 95% CI, 1.2 to 4.0) or preserved (≥60 mL/min) (HR, 2.6; 95% CI, 1.8 to 3.8) creatinine clearance. Similarly, an elevated H-FABP was associated with an increased risk of the composite end point of death, MI, or CHF across the spectrum of ACS, including patients with unstable angina (HR, 2.9; 95% CI, 1.2 to 7.0), non-STEMI (HR, 2.2; 95% CI, 1.2 to 3.9), and STEMI (HR, 3.1; 95% CI, 1.9 to 5.2). Moreover, elevated levels of H-FABP were associated with an increased risk of MI or recurrent ischemia by 30 days, especially in those patients with unstable angina, either as their index diagnosis (HR, 2.5; 95% CI, 1.4 to 4.4) or with a negative core laboratory Biosite troponin I (HR, 1.7; 95% CI, 1.02 to 2.8).
Elevated H-FABP was associated with the composite of death, MI, or CHF through 10 months of follow-up in patients who were Biosite troponin I negative (≤1.5 ng/mL) (HR, 2.1; 95% CI, 1.3 to 3.4) and in those who were troponin I positive (>1.5 ng/mL) (HR, 3.3; 95% CI, 2.0 to 5.3; Table 3). Elevated H-FABP remained significantly associated with the risk of death, MI, or CHF when a lower troponin I threshold of ≤0.1 ng/mL (HR, 2.3; 95% CI, 1.1 to 4.9) and >0.1 ng/mL (HR, 2.9; 95% CI, 2.0 to 4.3) was selected. Furthermore, this trend remained consistent when a limited number of additional samples were analyzed with the Bayer troponin I assay at a threshold of ≤0.1 ng/mL (n=112; HR, 2.3; 95% CI, 0.5 to 10.6) and >0.1 ng/mL (n=510; HR, 2.1; 95% CI, 1.4 to 3.1).
Similarly, H-FABP elevation identified patients at increased risk of death, MI, or CHF in the presence of low plasma BNP (<80 pg/mL) (HR, 2.6; 95% CI, 1.3 to 5.1). In particular, patients with an elevated level of H-FABP but low plasma BNP were found to have a >6-fold-higher risk of death (HR, 6.9; 95% CI, 2.6 to 18.8) and a 5-fold-higher risk of developing CHF (HR, 5.1; 95% CI, 1.6 to 16.3). For patients with elevated plasma BNP (≥80 pg/mL), elevated H-FABP was associated with a >2-fold-higher risk of the composite end point (HR, 2.2; 95% CI, 1.5 to 3.1), including death (HR, 2.9; 95% CI, 1.7 to 4.9) or CHF (HR, 3.4; 95% CI, 1.8 to 6.6).
Importantly, when H-FABP, troponin I, and BNP were evaluated simultaneously, H-FABP provided incremental information for risk stratification regardless of baseline troponin or BNP status (Figure 4).
Simultaneous assessment of serum H-FABP and myoglobin was available in 1974 patients (86%). For patients with an elevated myoglobin level (>107 μg/L), elevation of H-FABP was associated with an increased risk of the composite end point (HR, 2.2; 95% CI, 1.4 to 3.3), including death (HR, 3.8; 95% CI, 1.9 to 7.4) and CHF (HR, 3.8; 95% CI, 1.8 to 7.9). A limited number of patients (n=43) were found to have elevated H-FABP in the presence of low serum myoglobin (≤107 μg/L). In this small subset of patients, an elevated H-FABP was not associated with a significant increase risk of death, MI, or CHF (HR, 1.1; 95% CI, 0.36 to 3.6).
In a Cox proportional-hazards model that adjusted for multiple baseline variables, including demographics, clinical characteristics, time to randomization, index diagnosis, creatinine clearance, and Biosite troponin I (>1.5 ng/mL), H-FABP elevation remained independently associated with an increased risk of death, MI, or CHF (adjusted HR, 1.9; 95% CI, 1.3 to 2.7; P=0.001), as well as the individual end points of death (adjusted HR, 2.7; 95% CI, 1.5 to 4.9) and CHF (adjusted HR, 2.4; 95% CI, 1.2 to 5.0). Similarly, the association between H-FABP and early recurrent ischemic events, including MI or recurrent ischemia, was maintained after multivariable adjustment (adjusted HR, 1.6; 95% CI, 1.05 to 2.4).
In a series of sensitivity analyses, H-FABP was associated with the risk of death, MI, or CHF after 10 months of follow-up when troponin I was considered at a lower cut point of 0.1 ng/mL (adjusted HR, 2.1; 95% CI, 1.5 to 3.0), when troponin I was modeled as a continuous variable (adjusted HR, 1.9; 95% CI, 1.3 to 2.8), or when troponin I was replaced with the Bayer troponin I assay (adjusted HR, 2.1; 95% CI, 1.3 to 3.3). Moreover, elevated H-FABP was the strongest independent predictor of death, MI, or CHF when troponin I, BNP, and myoglobin were evaluated simultaneously in the model (adjusted HR, 1.7; 95% CI, 1.1 to 2.6). Of interest, an elevated myoglobin (>107 μg/L) was not independently associated with CV outcomes (P=0.32) when evaluated with H-FABP in the model.
We have demonstrated in a large cohort of patients that H-FABP is a strong and independent predictor of death and adverse cardiac events across the spectrum of ACS. H-FABP provided significant incremental information for risk stratification that was independent of traditional clinical risk factors and established cardiac biomarkers, including troponin I, BNP, and myoglobin. Importantly, an elevated H-FABP identified patients at risk for death and major cardiac events even when troponin and BNP were not elevated, suggesting that H-FABP, with its rapid-release kinetics, may offer a novel means by which to help identify patients with ongoing or recurrent myocardial ischemia who are at particular risk for adverse outcomes.
H-FABP is a small cytosolic protein (14 to 15 kDa) that is present in abundance in both skeletal and cardiac muscle.23 Because of its small size, H-FABP is released quickly into the circulation when membrane integrity is compromised in response to cardiac ischemia. Levels of H-FABP are detectable as early as 2 to 3 hours after injury, with a return to baseline levels typically within 12 to 24 hours of the initial insult.1,2 Although both myoglobin and H-FABP are present in cardiomyocytes, a much higher proportion of H-FABP is concentrated in myocardial tissue cells relative to myoglobin.24 In contrast, the concentration of myoglobin in skeletal muscle is approximately twice that of the myocardium.24–26 As such, H-FABP may offer improved specificity and sensitivity over myoglobin because of its relative predominance in myocardial tissue and lower normal reference range.6,27 For these reasons, a growing number of studies have shown that H-FABP is a sensitive early marker for the diagnosis of ACS1,5,26 and may be more sensitive than troponin, CK-MB, and myoglobin when measured in the early hours after symptom onset.6,7
In the present analysis, we found that elevated levels of H-FABP were associated with an increased risk of adverse CV events after ACS. In particular, elevated levels of H-FABP were associated with a >2.5-fold-higher risk of death and a >2-fold-higher risk of developing heart failure during the first 10 months after ACS. Furthermore, this association with risk was independent of several traditional risk predictors, including patient demographics, established cardiac risk factors, index diagnosis, creatinine clearance, and troponin I. Similarly, the prognostic utility of H-FABP was maintained in patients across the spectrum of ACS, regardless of age or sex. Although H-FABP may be elevated in patients with underlying renal dysfunction,24,28 H-FABP was equally useful for risk stratification in patients with normal (≥60 mL/min) or reduced (40 to 60 mL/min) creatinine clearance.
Importantly, the association between H-FABP and outcomes was not limited to samples measured in the earliest hours of ACS. Instead, we observed that H-FABP continued to be useful for risk stratification beyond the first 48 hours after the onset of chest pain. One consideration is that elevated levels of H-FABP in these patients reflect continuing ischemia and myocyte injury and thus identify a population at particular risk for death and recurrent CV events. To that end, elevated levels of H-FABP were associated with an increased risk of reinfarction or recurrent ischemic events in patients with unstable angina or a negative serum troponin who would otherwise not be deemed to be at increased risk based on traditional risk markers. This theory is further supported by prior reports that have shown a bimodal plasma curve for H-FABP in patients with recurrent MI.3 Thus, the modest correlation observed between H-FABP and established biomarkers of necrosis such as CK-MB and troponin may reflect important differences in the thresholds for release and the kinetics of circulating levels. Specifically, slower plasma clearance and a slower rise of troponin and CK-MB may reduce their sensitivity for detecting early reinfarction or low-grade ischemia. In contrast, H-FABP, a smaller molecule that is highly concentrated in the cytoplasm of cardiomyocytes and is cleared rapidly, may be better suited to detect subtle recurrent myocardial injury.
Our findings build on smaller studies that have shown an association between H-FABP and clinical outcomes when drawn during the early hours of ACS. Nakata and colleagues29 found that elevated H-FABP at presentation was associated with an increased need for emergent hospitalization, coronary angiography, and interventional therapy in 133 patients with suspected ACS. Similarly, a retrospective study of 90 patients with ACS found that H-FABP measured at presentation was independently associated with an increased risk of death or recurrent ischemic events during follow-up.30 However, both studies were relatively small and had periods of follow-up lasting only 1 week and 30 days, respectively. More recently, Ishii and colleagues31 evaluated the prognostic utility of H-FABP and troponin in 328 consecutive patients hospitalized with ACS. When drawn during the first 6 hours after the onset of chest pain, serum H-FABP was independently associated with an increased risk of death and recurrent MI during 6 months of follow-up. Of interest, H-FABP was a stronger predictor of outcomes than troponin, although simultaneous assessment of BNP and myoglobin was unavailable.
In the present study, we were able to conduct a multimarker analysis and found that H-FABP may provide incremental information for risk stratification beyond that seen with existing risk markers, including troponin, BNP, or myoglobin. Importantly, H-FABP may be useful for identifying patients at increased risk of death or CV events despite having a negative serum troponin or BNP. In particular, elevated H-FABP was associated with an increased risk of recurrent MI in patients who otherwise had a negative troponin. These findings are particularly relevant because troponin is commonly used by physicians to help guide appropriate in-hospital and postdischarge care.
Several potential limitations to the present study warrant consideration. First, we evaluated the prognostic utility of H-FABP in a population of patients exclusively with ACS. As such, the value of H-FABP testing in the setting of chest pain but a lower probability of ACS remains unknown. In addition, the present study was conducted in a single treatment arm of the OPUS-TIMI 16 trial. Because the clinical outcomes in this arm did not significantly differ from those in the placebo arm, we believe that our results should be applicable to all patients presenting with ACS. In addition, we are unable to ascertain the relative prognostic utility of H-FABP in patients with severe renal insufficiency (creatinine clearance <40 mL/min) because these patients were excluded from the OPUS-TIMI 16 trial.
Future investigation is required to establish the optimal timing of sampling for H-FABP and the optimal cut points for use, including whether minor elevations in H-FABP (<8 ng/mL) will be of similar prognostic value. Since we analyzed our samples, new assays have been developed to measure troponin with lower detection limits. Determining the utility of H-FABP in the setting of these newer assays is required before clinical use of this marker can be recommended. Future study also is required to ascertain whether H-FABP will be useful for helping to direct treatment strategies in ACS.
We have shown that elevated levels of H-FABP are associated with an increased risk of death and adverse CV events when measured during the first days after hospitalization for ACS. In addition to evidence that supports its use as an early diagnostic marker, H-FABP appears to provide incremental information for risk assessment that is independent of established clinical predictors and biomarkers of risk. These findings lend further support to the idea of a multimarker approach in the evaluation of patients with ACS32,33 to optimize risk stratification.
Sources of Funding
Drs O’Donoghue, Morrow, and Sabatine are supported by NIH grant U01 HL083-1341. Biosite provided grant funding for the present analysis. Reagents for the Bayer troponin assay were supplied by Bayer. All data analysis and interpretation were conducted at the TIMI Study Group. The OPUS-TIMI 16 study was supported through grant funding from Searle.
Dr de Lemos has received grant support and honoraria from Biosite. Dr Morrow has received research grants from Bayer, Beckman-Coulter, Biosite, Dade-Behring, GlaxoSmithKline, and Roche; has served on the speakers’ bureau for Bayer Beckman-Coulter; and has served as a consultant/advisory board member for OrthoClinical Diagnostics and Beckman-Coulter. Dr Cannon has received research grants from Merck, AstraZeneca, and Merck/Schering-Plough; has received research support from GlaxoSmithKline and Pfizer; has received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Sanofi-Aventis, and Schering Plough; and has served as a consultant/advisory board member for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Merck/Schering-Plough, Pfizer, Sanofi-Aventis, and Schering-Plough. Dr Sabatine has received research support from Roche and Biosite. Drs O’Donoghue, Murphy, and Buros report no disclosures.
Glatz JF, Kleine AH, van Nieuwenhoven FA, Hermens WT, van Dieijen-Visser MP, van der Vusse GJ. Fatty-acid-binding protein as a plasma marker for the estimation of myocardial infarct size in humans. Br Heart J. 1994; 71: 135–140.
Okamoto F, Sohmiya K, Ohkaru Y, Kawamura K, Asayama K, Kimura H, Nishimura S, Ishii H, Sunahara N, Tanaka T. Human heart-type cytoplasmic fatty acid-binding protein (H-FABP) for the diagnosis of acute myocardial infarction: clinical evaluation of H- FABP in comparison with myoglobin and creatine kinase isoenzyme MB. Clin Chem Lab Med. 2000; 38: 231–238.
Seino Y, Ogata K, Takano T, Ishii J, Hishida H, Morita H, Takeshita H, Takagi Y, Sugiyama H, Tanaka T, Kitaura Y. Use of a whole blood rapid panel test for heart-type fatty acid-binding protein in patients with acute chest pain: comparison with rapid troponin T and myoglobin tests. Am J Med. 2003; 115: 185–190.
de Groot MJ, Muijtjens AM, Simoons ML, Hermens WT, Glatz JF. Assessment of coronary reperfusion in patients with myocardial infarction using fatty acid binding protein concentrations in plasma. Heart. 2001; 85: 278–285.
Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE, 3rd, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC Jr. ACC/AHA guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction–2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation. 2002; 106: 1893–1900.
Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA, Hamm CW, O’Hanesian MA, Wagner GS, Kleiman NS, Harrell FE Jr, Califf RM, Topol EJ. Cardiac troponin T levels for risk stratification in acute myocardial ischemia: GUSTO IIA Investigators. N Engl J Med. 1996; 335: 1333–1341.
Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub WS, Braunwald E, for the TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction. JAMA. 2001; 286: 2405–2412.
Morrow DA, Rifai N, Antman EM, Weiner DL, McCabe CH, Cannon CP, Braunwald E. 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. J Am Coll Cardiol. 1998; 31: 1460–1465.
Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin 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. N Engl J Med. 2000; 343: 1139–1147.
Morrow DA, de Lemos JA, Sabatine MS, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Gibson CM, Cannon CP, Braunwald E. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol. 2003; 41: 1264–1272.
Cannon CP, McCabe CH, Wilcox RG, Langer A, Caspi A, Berink P, Lopez-Sendon J, Toman J, Charlesworth A, Anders RJ, Alexander JC, Skene A, Braunwald E. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation. 2000; 102: 149–156.
Antman EM, for the TIMI 9A Investigators. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A trial. Circulation. 1994; 90: 1624–1630.
Antman EM, McCabe CH, Gurfinkel EP, Turpie AGG, Bernink PJLM, Salein D, Bayes de Luna A, Fox K, Lablanche J-M, Radley D, Premmereur J, Braunwald E, for the TIMI 11B Investigators. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 11B trial. Circulation. 1999; 100: 1593–1601.
Morrow DA, Rifai N, Tanasijevic MJ, Wybenga DR, de Lemos JA, Antman EM. Clinical efficacy of three assays for cardiac troponin I for risk stratification in acute coronary syndromes: a Thrombolysis in Myocardial Infarction (TIMI) 11B Substudy. Clin Chem. 2000; 46: 453–460.
Van Nieuwenhoven FA, Kleine AH, Wodzig WH, Hermens WT, Kragten HA, Maessen JG, Punt CD, Van Dieijen MP, Van der Vusse GJ, Glatz JF. Discrimination between myocardial and skeletal muscle injury by assessment of the plasma ratio of myoglobin over fatty acid-binding protein. Circulation. 1995; 92: 2848–2854.
Lin L, Sylven C, Sotonyi P, Somogyi E, Kaijser L, Jansson E. Myoglobin content and citrate synthase activity in different parts of the normal human heart. J Appl Physiol. 1990; 69: 899–901.
Ishii J, Wang JH, Naruse H, Taga S, Kinoshita M, Kurokawa H, Iwase M, Kondo T, Nomura M, Nagamura Y, Watanabe Y, Hishida H, Tanaka T, Kawamura K. Serum concentrations of myoglobin vs human heart-type cytoplasmic fatty acid-binding protein in early detection of acute myocardial infarction. Clin Chem. 1997; 43: 1372–1378.
Ishii J, Ozaki Y, Lu J, Kitagawa F, Kuno T, Nakano T, Nakamura Y, Naruse H, Mori Y, Matsui S, Oshima H, Nomura M, Ezaki K, Hishida H. Prognostic value of serum concentration of heart-type fatty acid-binding protein relative to cardiac troponin T on admission in the early hours of acute coronary syndrome. Clin Chem. 2005; 51: 1397–1404.
Morrow DA, Braunwald E. Future of biomarkers in acute coronary syndromes: moving toward a multimarker strategy. Circulation. 2003; 108: 250–252.
Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA, Rifai N, McCabe C, Antman EM, Cannon CP, Braunwald E. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation. 2002; 105: 1760–1763.
Heart-type fatty acid binding protein (H-FABP) is a small cytosolic protein that is present in abundance in the myocardium and rapidly released into the circulation in response to myocardial injury. We evaluated the prognostic utility of H-FABP in 2287 patients with an acute coronary syndrome enrolled in OPUS-TIMI 16. Patients were followed up for 10 months for major cardiovascular events. After adjustment for differences in baseline characteristics, patients with an elevated level of H-FABP (>8 ng/mL) had a significantly higher risk of death, myocardial infarction, or congestive heart failure over 10 months of follow-up (adjusted hazard ratio, 1.9; 95% CI, 1.3 to 2.7; P=0.001). Moreover, H-FABP provided incremental information for risk stratification that was independent of traditional risk factors and biomarkers, including troponin I, myoglobin, and B-type natriuretic peptide. In addition, H-FABP identified patients at increased risk of recurrent cardiovascular events in the presence of a negative serum troponin I. H-FABP, with its rapid-release kinetics, may offer a novel means to help identify patients with ongoing or recurrent myocardial ischemia who are at particular risk of adverse outcomes. Further investigation will be useful to help to establish the clinical utility of this marker in the context of new biomarker assays.