Predictive Value of Cardiac Troponin T in Pediatric Patients at Risk for Myocardial Injury
Background Biochemical markers have not been routinely used in children at risk for myocardial damage. Yet, because of somatic growth and the duration of survival, a low level of myocardial damage may ultimately be of more consequence in children than in adults.
Methods and Results We investigated the utility of cardiac troponin T (cTnT) blood levels (CARDIAC T ELISA Troponin T, Boehringer Mannheim Corp) in 51 consecutively sampled patients from 1 day to 34 years of age (median=5.7 years) undergoing cardiovascular (n=19) or noncardiovascular (n=17) surgery or who received doxorubicin for acute lymphoblastic leukemia (ALL) (n=15). Minimum detectable cTnT elevations were 0.03 ng/mL. cTnT was measurable in children of all ages with myocyte damage. In patients who underwent cardiovascular surgery, a correlation was noted between a score of increasing surgical severity and the mean level of postoperative cTnT (r=.79, P<.0001). Postoperative cTnT levels were elevated in children who completed cardiovascular surgery with an open chest compared with those with a closed chest (P=.0083). In addition, cTnT levels before cardiovascular surgery predicted postoperative survival (P=.007). cTnT elevations were observed after initial doxorubicin therapy for ALL. The magnitude of elevation predicted left ventricular dilatation (r=.80 when variables were treated as continuous, P=.003) and wall thinning (r=.61, P=.044) 9 months later.
Conclusions Elevations of blood cTnT in children relate to the severity of myocardial damage and predict subsequent subclinical and clinical cardiac morbidity and mortality.
Myocardial damage in children may be clinically occult in a variety of stressful settings. However, biochemical markers have not been routinely used in children at risk for myocardial damage due to a lack of sufficient specificity to unambiguously guide patient management.1
Children may have more deleterious consequences of low-level cardiomyocyte loss than adults due to both the length of subsequent survival and an insufficient potential for myocardial growth to compensate for both early damage and somatic development. In some doxorubicin-treated survivors of childhood ALL,2 an inadequate myocardial hypertrophic response to increasing somatic growth, possibly as a result of cell loss, results in thinner LV walls, increased afterload, and depressed contractility that is progressive and results in significant morbidity or related mortality. Early indications of cardiomyocyte damage in children receiving doxorubicin might allow for preventive measures that could limit cardiomyopathy in later life.
Some surgical techniques to repair congenital heart defects have also been associated with late depressed myocardial function, morbidity, or mortality.3 4 The ability to accurately detect myocardial risk in patients preoperatively or damage in the early postoperative period may direct management to attenuate further injury and promote the recovery of reversibly damaged myocardium.
cTnT, a thin-filament contractile protein present in high concentrations in the myocardium but usually not in other tissues, is released rapidly after myocardial injury in direct proportion to the extent of injury. It persists in the serum for several days, probably as a result of ongoing release from the heart, but is not present in the serum following nonmyocardial muscle or other tissue damage.5 In the evaluation of myocardial necrosis, cTnT, in contrast to CK-MB, is more cardiospecific,5 and persists longer and shows higher elevations relative to normal ranges.6 In adults, cTnT measurements can aid in risk stratification7 and prediction of adverse outcomes7 in patients with acute myocardial ischemia. The magnitude of cTnT release after myocardial infarction closely correlates with infarct size.8
Little has been published on the use of serum cTnT testing in children.9 10 11 12 13 14 15 Yet, since multiple protein isoforms of cTnT can be generated from a single gene in a developmentally regulated fashion,16 it would be important to determine whether the cTnT assay that has been FDA-approved for the detection of myocardial infarction can be accurately used in all pediatric age ranges.
To determine whether serum cTnT would specifically detect myocardial damage in children, we examined biochemical markers of myocardial damage in three groups of children: (1) those undergoing cardiovascular surgery, (2) those undergoing noncardiovascular surgery, and (3) those actively receiving chemotherapy. Follow-up echocardiographic studies of LV structure and function were measured in the doxorubicin-treated children to assess any prognostic value of serum cTnT.
Nineteen randomly selected patients undergoing cardiovascular surgery and 17 randomly selected patients undergoing noncardiac surgery at Boston Children’s Hospital between July 1994 and March 1995 had one or more blood samples before and 0 to 3 days after surgery assayed for cTnT. Patient information was obtained by medical record review after discharge. This protocol had institutional review board approval.
A pediatric cardiologist (S.E.L.), who was blinded to cTnT status, classified cardiovascular surgical procedures into the following five categories on the basis of his impression of increasing risk of cardiomyocyte damage: (1) vascular surgery or intracardiac membrane resection, (2) atrial septal defect surgery, (3) atrioventricular valvular surgery, (4) ventricular septal defect surgery, and (5) resection of ventricular myocardium.
All newly diagnosed children with ALL treated at Dana-Farber Cancer Institute or Boston Children’s Hospital between July 1994 and September 1994 were included. Serum was obtained immediately before chemotherapy and 1 to 3 days after each dose of chemotherapy. All received doxorubicin as part of combination chemotherapy; other chemotherapeutic agents used included vincristine, methotrexate, prednisone, mercaptopurine, and asparaginase. No patients received amsacrine or cyclophosphamide, known cardiotoxic agents, or underwent mediastinal or spinal irradiation.
Echocardiograms were interpreted by echocardiographers unaware of the patient’s treatment protocol, cardiac marker status, individual and cumulative anthracycline doses, or other clinical information. The echocardiographic study consisted of a complete two-dimensional and Doppler evaluation with stress-velocity analysis. No patient had regional wall motion abnormalities. The combined M-mode echocardiogram, phonocardiogram, and pulse tracings were analyzed by computer, as previously described.17 For comparison we used data from 296 normal subjects who were studied according to the same protocol as the study population to create z scores.17 The z scores were determined relative to body surface area for LV dimension, wall thickness, and mass, and relative to age for wall stress and fractional shortening. Similarly, the stress-velocity index was calculated as the z score of LV heart rate corrected velocity of circumferential fiber shortening relative to LV end-systolic wall stress for each patient.
Serum or heparinized plasma samples were obtained from study patients. The study design included 335 samples obtained before and serially after cardiac surgery (median, 3 samples per patient; range, 2 to 9 samples per patient), noncardiac surgery (median, 2 samples per patient; range, 1 to 2 samples per patient), or administration of doxorubicin (median, 19 samples per patient; range, 3 to 33 samples per patient). In newly diagnosed patients, samples were obtained before and after doxorubicin administration. No patient had cardiogenic shock, renal failure, or rhabdomyolysis at the time of sampling. All samples were stored at −20°C for <60 days. cTnT was determined by an enzyme-linked one-step sandwich immunoassay with streptavidin technology18 on the ES-300 immunochemical analyzer (CARDIAC T ELISA Troponin T, a kind gift of Boehringer Mannheim Corp, Indianapolis, Ind). The sensitivity of the assay was determined. All the samples for cTnT measurement were batch assayed by a single operator who was unaware of the patient’s diagnosis, treatment, or outcome. No hemolyzed or EDTA-treated samples were measured. Whenever possible, all samples from a single patient were assayed on one run. All patient management decisions were made without knowledge of the patient’s cTnT results. Serum concentrations of CK (n=76), CK-MB (n=75), and myoglobin (n=65) were measured when sufficient serum was available. Plasma concentrations of CK were enzymatically determined on the Hitachi 911 autoanalyzer (Boehringer Mannheim Diagnostics) according to the manufacturer’s recommendations. The CK-MB concentration was determined by a fluorometric enzyme mass immunoassay on the Stratus analyzer (Dade International). Myoglobin concentrations were measured by immunonephelometric techniques using the Behring BN-100 analyzer (Behring Diagnostics).
The relationship between surgical severity and postoperative cardiac cTnT was characterized by Pearson’s correlation coefficient, looking specifically for a linear trend between cTnT (or log cTnT) and surgical severity. Because of the small sample size, we calculated exact P values for association between pairs of variables using the STAT XACT computer package. As shown in Table 1⇓, patient Nos. 18 and 19 had high postoperative cTnT levels of 17.7 ng/mL, which actually indicates 17.7 ng/mL or greater (sufficient serum was not available to permit sample dilution and remeasurement). Since patients with this value may not have the same level of elevation, and since the Pearson analysis can be influenced by high values, the Spearman analysis, which is based on the ranks of the two variables instead of their magnitude, was also used. Since the P values were practically identical using Spearman’s and Pearson’s correlation coefficients, we present the results of Pearson’s. Because only 2 of the 19 cardiac surgery patients had an open chest following cardiac surgery, an exact t test was used to compare the peak postoperative cTnT serum levels in patients leaving the operating room with a closed or an open chest. When analysis was done of precardiac surgery cTnT serum levels versus postoperative death, a 2×2 table was formed and Fisher’s exact test was used to test for association.
Precision of Low-Level Measurements of Serum cTnT
Since there are no published studies validating the performance of the cTnT assay in the submyocardial infarction range of 0 to 0.1 ng/mL, we first established the analytical limit of sensitivity and performance of this assay at low levels. We performed a precision study using serial dilutions of serum with elevated cTnT. Fig 1⇓ shows the linearity of the serum cTnT assay in the low range of 0.01 to 0.1 ng/mL. The coefficient of variance of each dilution was small, demonstrating excellent reproducibility, as well as a statistically significant ability to distinguish between values differing in this range by 0.01 ng/mL. Although the sensitivity of this assay has been reported by others to be 0.015 ng/mL,25 in our hands the detection limit was 0.02 ng/mL. When serum from a healthy person with no history of cardiovascular disease was examined for cTnT, the mean value of 20 replicate measurements was 0.0053 ng/mL. The lower limit of detection of this cTnT assay, by definition, is a value exceeding three standard deviations above the mean value of a cTnT-free serum. This value, measured on the same instrument that we used to measure study samples, was 0.02 ng/mL. In addition, the reproducibility of the assay at this cTnT level of 0.03 ng/mL was shown to be 7%. Therefore, the determination of a concentration of cTnT of ≥0.03 ng/mL was deemed analytically valid and was taken to represent an elevated serum cTnT.
Thirty-six patients had no detectable cTnT before doxorubicin treatment or surgery; 4 patients with detectable cTnT were severely ill and required intensive medical support. All patients, ranging in age from 1 day to 34 years, had high-level elevations of cTnT after cardiovascular surgery (median, 1.78 ng/mL; range, 0.17 to ≥17.7 ng/mL, the upper limit of the range of linearity of the assay).
The peak postoperative cTnT level was correlated with a subjective five-part surgical severity scale. The Pearson correlation coefficient was .7896, with a P value of .0000, indicating that there was a significant positive association between increasing surgical intervention and higher postoperative cTnT concentration (Fig 2⇓). The linear relationship between log cTnT and surgical severity was even stronger (Pearson correlation=.92, P<.0001). For cardiac surgery patients, the peak postoperative serum cTnT level was elevated in patients whether they left the operating room with their chest closed or open; the median peak levels were 1.73 and ≥17.7 ng/mL, respectively. The exact P value for the t test is .0083, indicating that patients who had open chests had greater cardiac injury.
Fifteen of 18 patients who underwent cardiac surgery had undetectable cTnT serum levels before surgery (Table 1⇑) and were discharged alive from the hospital. In contrast, among the 3 of 19 patients who had elevated cTnT levels before cardiovascular surgery, 2 died after the operation. These 2 patients had the highest preoperative serum cTnT levels (0.11 and 4.54 ng/mL). Fisher’s exact P value was .029 when the death rate (0 of 14) in the patients with serum cTnT level of 0 before cardiac surgery was compared with the death rate (2 of 3) in patients with elevated preoperative cTnT. We did not include the 1 child with a borderline cTnT level of 0.02 ng/mL in this analysis. If we had included this patient in the nonelevated group, the results would have been more significant.
Seventeen children undergoing noncardiac surgery had postoperative cTnT levels measured (Table 2⇓). All children had normal cTnT levels before and after surgery, with the exception of 2 patients who had elevated postoperative cTnT levels (patient 16, who underwent a thoracic noncardiac procedure, and patient 17, who had recently had cardiovascular surgery).
All 15 eligible children treated for ALL during the study were evaluated for cTnT levels, 14 had a pre-doxorubicin echocardiogram, and 15 had post-doxorubicin echocardiograms at a median interval of 0.67 year (mean, 0.69 year; range, 0.12 to 1.33 years) after their peak measured cTnT level. Ten children were male, and the median age at which cTnT was measured was 4.4 years (mean, 5.9 years). All 15 patients had received doxorubicin chemotherapy at a median cumulative dose of 60 mg/m2 (range, 45 to 222 mg/m2) by either bolus infusion (n=7) or 48-hour continuous infusion (n=8). No patient had symptomatic cardiovascular disease, or echocardiographic evidence of structural cardiovascular malformations, ischemic heart disease, or cardiomyopathy before receiving doxorubicin.
Of the 15 doxorubicin-treated children, 10 had cTnT measured while receiving doxorubicin. Six of these 10 children showed low-level cTnT elevations (5 of 10 ≥0.04 ng/mL and 1 of 10=0.03 ng/mL), with the single highest level of all patients of 0.06±0.02 ng/mL (median); range, 0.03 to 0.09 ng/mL (Fig 3⇓). In contrast, there were no cTnT increases in 5 children who had completed doxorubicin but continued to receive other chemotherapy (Fig 3⇓). The level of cTnT was elevated in 4 of 7 children after initial doxorubicin therapy and in 2 of 3 patients who received higher cumulative doses beyond initial therapy. The level of cTnT was elevated in patients who received doxorubicin by either a continuous or a bolus infusion, suggesting that the lower peak doxorubicin serum concentrations in continuous infusion did not prevent cardiac damage. No significant elevations in CK, CK-MB, or myoglobin levels were noted for any of the doxorubicin-treated patients as measured in the same samples.
Correlation Between Peak Post-Doxorubicin cTnT and Echocardiographic Parameters on Late Follow-up of Doxorubicin-Treated Patients
Pre-doxorubicin LV wall thickness, dimension, afterload, and fractional shortening z scores were not significantly different from normal. LV contractility was elevated (mean, 1.39 SD; 95% confidence interval, 0.26 to 2.51). Post-doxorubicin LV wall thickness, dimension, afterload, contractility, and fractional shortening were not significantly different from normal. The peak cTnT in each doxorubicin-treated patient was compared with the echocardiographically determined z scores for LV fractional shortening, dimension, wall thickness, contractility, and afterload (Table 3⇑). Significant correlations were found between the highest cTnT level after doxorubicin treatment and the LV end-diastolic dimension z score at late follow-up (Table 3⇑). The Pearson correlation coefficient was .794 with a P value of .0032. The correlation coefficient was largely unchanged when a Spearman correlation coefficient was used. In addition, the correlation between the highest cTnT level after doxorubicin treatment and the LV end-diastolic posterior wall thickness z score was also significant (Pearson correlation coefficient, .612; P=.0437). The cTnT–wall thickness relation was also significant using a Spearman correlation analysis.
The measurement of elevated blood cTnT can be accurately made in children of all ages despite developmentally regulated cTnT isoform diversity. The significant correlation of the extent of myocardial damage due to cardiac surgery with peak elevations of cTnT, as well as the lack of cTnT elevation following noncardiac surgery without cardiovascular complications, firmly demonstrates that cTnT elevation in children reliably reflects myocardial damage. Furthermore, the precision of the cTnT assay at levels much lower than those used to detect acute myocardial infarction in adults has been established and is important because it allows a clear demonstration of cardiac injury after doxorubicin chemotherapy. The clinical significance of these doxorubicin-related low-level cTnT elevations is attested to by their significant correlations with persistent abnormalities of LV structure by echocardiography 9 months later. The potential predictive ability of elevations of cTnT in children is further supported by the significant correlations between cTnT levels before cardiac surgery and postoperative mortality, and between postoperative levels of cTnT and postoperative open versus closed chest. These very-low-level elevations of cTnT may be even more important in children than in adults because of somatic growth and the duration of survival.
This study confirms earlier work9 indicating that in children without myocardial damage, serum cTnT is below the analytical limit of detection. Patients undergoing noncardiovascular surgery had cTnT elevations only when there was cardiac damage, indicating that in children cTnT can be used to detect cardiac injury in a postsurgical situation.
Preoperative cTnT elevations appear to identify high-risk patients with myocardial damage and to correlate with postoperative mortality. This may affect plans for the timing of surgery, for palliative versus complete repair, or for the use of cardioprotectants with bypass. The importance of preoperative elevations of cTnT is similar to the results from patients who have received heart transplants in the first year of life, in whom the preoperative donor cardiac troponin I levels were significantly related to posttransplant problems10 as well as preoperative donor cTnT having been also predictive of postoperative inotropic requirements.18 Cardiac troponin I is a genetically distinct component of the troponin complex that is also a protein marker of myocardial damage. Although one pediatric study simultaneously measured cTnT and cardiac troponin I after cardiac surgery and found similar high-level elevations of both troponins,4 we have found that this cTnT assay may be more sensitive for the detection of low-level damage than some of the FDA-approved cTnI assays (unpublished data).
The level of blood cTnT may also be a successful monitor of perioperative myocardial cell damage in patients at pediatric hospitals. The findings of this study demonstrated myocardial damage in all patients after heart surgery, suggesting a means of monitoring and improving myocardial protection or support perioperatively. In children undergoing cardiovascular surgery, less central nervous system perturbation was noted postoperatively when low-flow cardiopulmonary bypass was used instead of hypothermic circulatory arrest,20 and cardiac damage may be influenced by these same factors. Our findings with childhood cardiovascular surgery relate closely to preliminary observations,21 suggesting that children with congenital heart disease have low baseline CK-MB levels. After cardiac surgery, children whose CK-MB levels peaked 3.5 hours or less postoperatively did well, but those with peak levels more than 3.5 hours postoperatively had evidence of myocardial infarction, even though it was not suspected clinically. There was no relationship between peak CK-MB and aortic cross-clamp time or cardiopulmonary bypass time. However, in echocardiographically controlled adult studies, cTnT was superior to CK-MB for the detection of perioperative infarcts.22 The peak postoperative cTnT levels were higher in patients who left the operating room with an open chest, suggesting that the inability to close a child’s chest after cardiovascular surgery is associated with more myocardial damage. A tremendous potential exists to identify children at high risk for later problems or for surgical procedures of high concern.
Other recent work examining blood troponin levels in children after cardiovascular surgery has shown that cTnT elevations occur early and peak within 48 hours.13 14 15 Similar to our study, peak postoperative troponin levels were lesion-specific but the patterns of rise and fall were similar.13 14 15 One study found that the peak postoperative troponin level correlated with cardiopulmonary bypass time and aortic cross-clamp time but not bypass temperature.14 All three other studies found, similar to our study, that serum troponin had potentially important prognostic information.13 14 15 One study found that peak cTnT levels greater than 7.5 ng/mL or the failure of troponin levels to decline within 72 hours were associated with complicated postoperative courses.15 Another found that levels at 12 to 24 hours postoperatively correlated with inotropic support, duration of intubation, and duration of intensive care and hospital stays.14 The third study suggested that high levels 3 to 6 hours after surgery were related to reduced survival.13
In our study, low-level cTnT elevations were noted in children after their first dose of cardiotoxic doxorubicin chemotherapy and at any point in treatment with doxorubicin but not after noncardiotoxic chemotherapy. The importance of low-level cTnT elevations after doxorubicin therapy in children is suggested by the significant correlation of low-level cTnT elevations with LVs that had thinner walls and were more dilated by echocardiography 9 months later. In contrast to the significant correlation between the post-doxorubicin cTnT levels and the late echocardiographic results, the lack of correlation between the pre-doxorubicin echocardiograms and post-doxorubicin cTnT levels decreases the probability of a preexisting or spurious association. Furthermore, the fact that cTnT was not elevated either after non-doxorubicin chemotherapy or before doxorubicin therapy also indicates that doxorubicin is responsible for the myocardial damage. Although the severity of cardiotoxicity is known to be related to higher cumulative doxorubicin doses, our results suggest that even the initial dose may be cardiotoxic, indicating a potentially much wider window of vulnerability. This damage associated with the first dose occurs at a time when the patient is frequently most ill and the heart is therefore most vulnerable. The cumulative doses may compound the initial injury and further decrease the ability to recover. Preliminary reports suggest that low-level elevations of blood troponin after anthracycline chemotherapy also occur in adults even with normal LV ejection fractions23 24 and continue weeks later.25 Another pediatric study measured cTnT after anthracycline chemotherapy and found no elevation;11 however, that study used a high cutoff for defining abnormally elevated cTnT (the European cutoff for defining myocardial infarction, cTnT ≥0.2 ng/mL) and would have missed all the low-level doxorubicin-associated cTnT elevations we have noted in this report.12
The persistent low-level cTnT elevations are reminiscent of chronic inflammatory changes, rather than the higher and more transient elevations seen with ischemia or infarction. This may be the mechanism of doxorubicin cardiotoxicity,26 27 similar to those noted after cardiac transplantation.28 Support for these ideas comes from studies of In-111–labeled antimyosin antibody uptake in doxorubicin-treated patients. Antimyosin cardiac uptake related to persistent sarcolemmal damage was shown in 92% of patients who had received doxorubicin chemotherapy.29 Adults with decreased LV ejection fractions or who received doxorubicin instead of the less-cardiotoxic mitoxantrone showed more intense antimyosin uptake, indicating more severe myocardial damage. The antimyosin uptake in the myocardium preceded ejection fraction deterioration. Similarly, in rats treated for 5 weeks with doxorubicin, myocardial antimyosin uptake 3 weeks later was more prominent than in controls and progressively increased with the severity of myocardial damage.30 There was a strong positive correlation between the intensity of myocardial uptake and the loss of contractile function. Immunohistochemical staining demonstrated that antimyosin was localized exclusively to injured myocytes. Doxorubicin cardiotoxicity in the rat can be monitored by serum cTnT levels, and these cTnT elevations relate to the loss of cTnT from damaged myocytes, as demonstrated by immunohistochemical localization.31 Doxorubicin cardiotoxicity in the rat, as assessed by serum cTnT, was significantly prevented by the administration of an ACE inhibitor in conjunction with doxorubicin.32 Adult rat cardiomyocytes exposed to doxorubicin dosages similar to those used to treat childhood malignancy show intracellular oxidation close to the mitochondria after only 20 minutes,33 further supporting our findings of myocardial damage after the initial exposure to doxorubicin. This suggests that myocyte damage begins early, and the window for diagnosis and treatment may be relatively brief.
This study was designed as a pilot to assess cTnT in blood from children receiving doxorubicin and to compare these with cTnT in excess blood remaining after the measurement of clinically-ordered blood chemistries from cardiovascular surgical patients (a positive control group) and noncardiovascular surgical patients (a negative control group). Other indices of ischemia or infarction in children were not uniformly captured. We present significant associations noted in our positive control group, but our exploratory study design limits our ability to assess the impact of other factors on cTnT elevations in this population. Nevertheless, our findings are consistent with other recent reports.13 14 15 Larger prospective studies specifically exploring these factors will determine the relative contribution of surgery itself and associated perioperative conditions on myocardial damage.
The cTnT values in pediatric patients appear more sensitive than CK, CK-MB, or myoglobin for the measurement of myocardial damage and provide independent and important prognostic information. This supports another pediatric study13 that found that elevations of CK-MB and myoglobin occur after cardiac surgery but that those elevations also occurred after noncardiac surgery, even when blood troponin levels did not increase, suggesting that elevation of CK-MB or myoglobin were not as specific for myocardiocyte damage as blood cTnT levels. The advantages of cTnT are high specificity and sensitivity for myocyte damage and a wide diagnostic time frame. The relatively low cost, low level of invasiveness, ease of serial monitoring, and lack of need to visit the hospital make the cTnT assay potentially more appealing for monitoring cardiac injury in children than other more-conventional techniques such as echocardiography or radionuclide scans. The greatest utility of assays for cTnT may be for risk stratification of patients with heart disease and possibly for prognostic information. In certain situations, an increased cTnT may be the only indicator of myocardial damage and can be used to define a new diagnostic group with low-level, possibly focal, myocardial damage. It appears that myocardial damage in children is more common than has been supposed.
Selected Abbreviations and Acronyms
|ALL||=||acute lymphoblastic leukemia|
|CK-MB||=||creatine kinase myocardial band isoenzyme|
|cTnT||=||cardiac troponin T|
This work was supported in part by grants CA68484, CA34183, HR96041, and HL53392 from the National Institutes of Health, Bethesda, Md, the David B. Perini, Jr, Quality of Life Program. The authors acknowledge Boehringer Mannheim Corp, Indianapolis, Ind, for supplying the instrument and reagent kits for the cTnT assays for this study.
- Received March 12, 1997.
- Revision received May 27, 1997.
- Accepted June 1, 1997.
- Copyright © 1997 by American Heart Association
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