Q J Med 2004; 97: 187-198
QJM vol. 97 no. 4 (c) Association of Physicians 2004; all rights reserved.
Do we need additional markers of myocyte necrosis: the potential value of heart fatty-acid-binding protein
H.A. Alhadi and
K.A.A. Fox
From the Cardiovascular Research Unit, Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
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Summary
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Heart fatty-acid-binding protein (FABP) is a small cytosolic
protein that is abundant in the heart and has low concentrations
in the blood and in tissues outside the heart. It appears in
the blood as early as 1.5 h after onset of symptoms of infarction,
peaks around 6 h and returns to baseline values in 24 h. These
features of H-FABP make it an excellent potential candidate
for the detection of acute myocardial infarction (AMI). We review
the strengths and weaknesses of H-FABP as a clinically applicable
marker of myocyte necrosis in the context of acute coronary
syndromes.
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Introduction
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The fatty-acid-binding proteins (FABP) are a family of cytosolic
proteins that shows a large degree of structural homology. Discovered
by Ockner in 1972 in studies on the intestinal absorption of
fatty acids,
1 they are called FABP because they exhibit a high
affinity for the non-covalent binding of fatty acids. These
proteins are widely distributed and are present in the fatty-acid-metabolizing
tissues of many mammals. Their presence has also been reported
in various species, including birds, insects and fish.
2 There
are several types, and all have low molecular mass (12–15
kDa), but they differ markedly in tissue distribution, concentration
within tissue, isoelectric point (PI), binding capacity, and
binding specificity.
3–10 The FABP are relatively tissue-specific,
and are designated by a letter that refers to their tissue of
origin, e.g. L-FABP, H-FABP, I-FABP, referring to liver, heart
and intestine FABP, respectively;
11 tissue-specific FABP have
also been reported in muscle, adipose tissue, kidney, brain
and nerve cells. Tissue-specific FABP such as liver (L-FABP)
and intestinal (I-FABP) have been used to detect pathologies
in these tissues using specific antibodies raised against these
proteins.
12,13 Different FABP share between 30–80% amino
acid sequence homology. The heart and the liver contain the
highest concentrations of these proteins.
9
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Function
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Fatty acids are the major energy source of the heart.
14 They
are also important molecules for the synthesis of membrane lipids
and lipid mediators such as prostaglandins, leukotrienes and
thromboxanes.
15 In general, 50–80% of the heart's energy
is provided by lipid oxidation. The heart is a poor fatty acid
synthesizer, and contributes only 0.1% of total body fatty-acid
synthesis,
16 but accounts for 10% of the total body turnover
of fatty acids.
17 Fatty acids are insoluble in the intravascular
and extravascular space, and also in the intracellular space.
In plasma they are transported bound to albumin, or as part
of the lipoproteins complex.
14,18 Heart-FABP may constitute
the intracellular equivalent of albumin for the intracellular
transport of the insoluble fatty acids within the cells. These
proteins are truly cytoplasmic, in the sense that they do not
exist anywhere else (e.g. plasma or extracellular space) under
normal conditions.
19,20 Recent work has suggested more complex
regulatory functions for these proteins beyond lipid transport,
21–27 but the precise physiological functions of these abundant proteins
are not fully understood.
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Early diagnosis of acute coronary syndrome and its impact on patients’ care
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Early diagnosis of acute coronary syndrome based on multiple
samples would contribute to patients’ care in the following
ways.
1. Triage of patients from accident and emergency department
Biochemical markers of early damage can help with the triage of patients from the emergency department. Those patients with positive results for ischaemia need to be admitted to the CCU or to a monitored bed. Those with ‘true negative’ results (i.e. after sufficient time for liberation of marker into the circulation) can be considered for early discharge if there is a low probability of ischaemia and of severe coronary artery disease, and the patient remains free of recurrence. These strategies will optimize the effective use of expensive resources in the CCU and other acute units for the appropriate groups of high and moderate risk patients.28–30
2. Acute myocardial infarction and non-diagnostic electrocardiogram
Early cardiac markers can be helpful in the diagnosis of AMI in the following situations when there is a high clinical suspicion of infarct. However the diagnostic value of the admission ECG may be limited: (i) when the ECG cannot be interpreted or has reduced diagnostic accuracy, e.g. the presence of conduction disorders including left bundle branch block (LBBB) or paced rhythm; (ii) if Q waves and ST-T changes are already present, e.g. old infarcts and digoxin effects, respectively; (iv) with ST-T changes of marked left ventricular hypertrophy (LVH); (iv) in posterior infarct or right ventricular infarct, which may produce no clear-cut diagnostic ECG changes on the standard 12-lead ECG; (v) when diagnostic changes of AMI are present in one lead only; and (vi) In the 30% of patients who have no diagnostic changes on their admission ECG.28–32 In clinical practice today reperfusion therapy, thrombolysis or percutaneous coronary intervention (PCI), is only given to patients with clinical evidence of ischaemia and ST segment elevation.
3. Unstable angina and non-Q-wave myocardial infarction
Clinical trials have shown most benefit from treatment in the unstable angina (UA) and non-Q-wave MI groups with positive biochemical marker evidence of ischaemia. Those patients with no biochemical marker evidence of ischaemia show least benefit (or no benefit) from treatment compared to placebo.33 Cardiac markers can help with risk stratification of patients early in the course of ischaemia.33,34 In those patients with UA and non-Q-wave MI, early diagnosis results in the admission of these patients to the CCU or to a monitored bed in a higher dependency area. Administration of antithrombotic agents (aspirin, clopidogrel, LMWH, and GPIIb/IIIa receptor antagonists) is associated with a significant reduction of subsequent complications (AMI and death).35,36 In addition to early identification and implementation of treatment, further risk stratification in these patients can guide the use of exercise tolerance testing, perfusion scans or angiography and, where appropriate, PCI or CABG (coronary artery bypass grafting).
4. Prevention of inappropriate discharge of patients
In the very early stages of AMI, some patients may present with atypical chest pain and non-diagnostic ECG changes. Without an appropriately timed biochemical marker to rule out AMI, these patients could be misdiagnosed and inappropriately discharged. Based on previous studies, between 2% and 10% of patients with AMI are discharged from A&E departments.37–39 This is more likely to happen in high-volume medical institutions where the turnover of patients is high and there is limited availability of beds. Common features of cases of missed AMI include factors such as age (young patients), sex (females), ethnic factors, atypical history of chest pain, absence of previous cardiac history, and being reviewed by inexperienced physicians.38,39
5. Financial implications
Previous studies estimated that less than 30% of patients admitted to the CCU with suspected AMI were eventually diagnosed with AMI.37 Conservative policies that opt for the safe admission of patients without clear-cut diagnosis of ischaemia, rather than risking inappropriate discharge, result in the admission of a large number of patients without ACS. The cost of caring for such patients is very substantial.37 Decisions based on cardiac markers for the triage of patients result in a considerable reduction of this financial burden without compromising the safety of patients.40
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Heart fatty-acid-binding protein
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Heart-FABP is a small (15 kDa) soluble non-enzyme protein. It
is composed of 132 amino acids.
41 It is one of the most abundant
proteins in the heart, and comprises 5–15% of the total
cytosolic protein pool in the aqueous cytoplasm. This is equal
to 0.5 mg/g wet weight of tissue.
42–45 Minor concentrations
of H-FABP specific to the mitochondrial function have also been
reported.
46 The gene is located on chromosome 1.
47 Heart-FABP
binds two molecules of fatty acids, and is involved with the
delivery of fatty acyl coenzyme A for oxidation with the generation
of energy in the mitochondria.
42 Myocardial ischaemia results
in a significantly higher level of fatty acids in the plasma
and the myocardial tissue, which can be harmful to the heart.
48–51 The presence of H-FABP may serve a protective function for the
myocardial cells against the oxidation of these fatty acids
while still having these substances readily available for the
metabolic needs of the cell. During ischaemia (e.g. AMI), H-FABP
leaks out of myocardial tissue and the concentration increases
in plasma.
44 The leakage of H-FABP from the myocardium may make
the myocardium more vulnerable to the harmful effects of fatty
acids during reperfusion, and may account for some of the complications
seen during reperfusion, e.g. arrhythmias. Some reports have
suggested another protective role for H-FABP, as scavengers
of free radicals that are present in the heart during ischaemia.
52,53 H-FABP exists in high concentrations in the heart only. However,
this protein is not totally cardiac-specific and occurs in other
tissues, although at much lower concentrations.
54,55 It occurs
in skeletal muscles in concentrations varying between 0.05 and
0.2 mg/g wet weight of tissue, depending on muscle fibre type
studied.
45 It has also been reported in very low concentrations
in tissues such as the kidney, aorta, testes, mammary glands,
placenta, brain, adrenal glands, adipose tissue, and stomach.
54–56 However, the detection of H-FABP in these tissues does not necessarily
means its presence in all cells of that tissue. Also, the evidence
was obtained in some of these studies by immunohistochemical
methods using antibodies to H-FABP. The different FABP from
heart, liver and intestine share between 20–35% amino
acid sequences homology, and heart, nerve, and adipose tissue
FABP share 60–80% amino acid sequence homology.
9 Antibodies
raised against heart, liver, or intestine in the earlier studies
may thus have up to 5% cross-reactivity with each other, and
have a detection limit of around 1 ng/ml. It is therefore possible
that cross-reactivity with other FABP, or other as yet unidentified
proteins, in these tissues is an alternative explanation for
the reported presence of H-FABP in these tissues.
57–61 The newer assays have a much improved sensitivity and can detect
H-FABP in concentrations as low as 0.25 ng/ml; the cross-reactivity
with other tissues FABP is < 0.005%.
62,63 The use of these
newer assays might show a more accurate picture of the true
distribution of H-FABP in the various tissues outside the heart.
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The rationale for the use of H-FABP as a marker for the early diagnosis of myocardial injury
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The rationale for the use of H-FABP as a marker for the early
diagnosis of myocardial injury is based on the following features:
(i) the presence of this soluble protein in the myocardium in
high concentration; (ii) virtual confinement to the cytoplasmic
space; (iii) small molecular size; (iv) relative tissue specificity,
with a relative distribution of H-FABP outside the heart similar
to that of creatine kinase muscle brain (CK-MB),
45 and (v) early
release into plasma and urine (within 2 h) after onset of myocardial
injury. Heart-FABP bears a considerable resemblance to myoglobin
(a well-accepted early marker of myocardial injury within 6
h) in terms of size, location within the cell, release and clearance
kinetics. However, when compared to myoglobin, H-FABP concentration
in the heart muscle is greater than that in skeletal muscle,
and its normal baseline concentration is several fold lower
than myoglobin. These advantages make H-FABP potentially a more
suitable cardiac marker than myoglobin.
64–66
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Measurement of H-FABP and normal range
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The method of measurement is based on sandwich enzyme-linked
immunosorbent assay (ELISA) using two monoclonal antibodies
specific for H-FABP.
22,55,63,67,68 The normal ranges reported
for H-FABP in plasma and serum are assay- and method-dependent.
Tanaka
et al. (1991) has reported the normal range for H-FABP
to be 0.0–2.8 µg/l;
69 Wodzig
et al. (1997) reported
0.3–5 µg/l as the normal limit;
63 and Tsuji
et al. (1993) used 3 µg/l (normal range 0.0–0.6 µg/l).
70 One study used a cut-off concentration of 19 µg/l (mean
± 2 SD of controls).
71 Heart-FABP is not likely to be
found in the blood stream under normal conditions. The normal
plasma H-FABP is likely to be due to the continuous release
of this protein from damaged skeletal muscle cells.
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Plasma H-FABP and acute myocardial infarction
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Heart-FABP was introduced by Glatz in 1988 as a potential novel
biochemical marker for the early diagnosis of AMI.
73 This assumption
was soon confirmed in several studies.
44,45,66,69,71,74,75 Under
normal conditions H-FABP is not present in plasma or interstitial
fluid, but is released into the blood upon cellular injury.
The cytoplasmic to vascular concentration of H-FABP is of the
order of 200 000:1.
76 The plasma concentration of H-FABP under
normal conditions is < 5 µg/l. This makes the plasma
estimation of H-FABP suitable for the early detection and quantification
of myocardial tissue injury. The H-FABP is released into plasma
within 2 h after symptom onset and is reported to peak at about
4–6 h and return to normal base line value in 20 h.
75 Within the period of 30–210 min after symptom onset, H-FABP
has > 80% sensitivity for the diagnosis of AMI.
71 Within
the interval of 0–6 h after symptom onset, the other cardiac
markers such as creatine kinase, CK-MB mass or activity, cardiac
troponin I (cTnI) and cardiac troponin T (cTnT) will only be
starting to accumulate in the plasma, and their sensitivity
has been reported to be around 64%.
77
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Urinary H-FABP and acute myocardial infarction
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Urinary indicators of myocardial injury are almost unknown,
and only myoglobin has been tested as a urinary indicator of
myocardial injury.
78–80 Heart-FABP is eliminated from
the circulation by the kidney, but the precise mode of renal
handling of H-FABP is unknown. A rise in serum and urine H-FABP
concentration above normal values is seen in patients who present
with AMI as early as 1.5 h after symptom onset.
69 Studies in
animals have also shown decreased myocardial tissue content
and rising plasma and urine concentrations of H-FABP very early
after coronary artery ligation.
44,81 Measurement of plasma or
urine concentration of H-FABP was diagnostic of AMI as early
as 30 min after ligation. Assays that measure H-FABP in urine
samples were able to accurately diagnose patients with AMI and
provide reliable estimation of infarct size.
82 However, the
measurement of infarct size based upon urinary H-FABP may be
influenced by several factors, such as renal blood flow, perfusion
pressure, glomerular filtration rate, tubular absorption, and
diseases of the kidney. Measurement of urinary and plasma H-FABP
in the presence of kidney diseases may lead to underestimation
and overestimation, respectively, of the size of infarct due
to impairment of excretion of H-FABP.
83 Heart-FABP circulates
for longer (> 25 h) after AMI in the presence of renal failure.
71 Several sensitive assays that can measure H-FABP in urine samples
are available.
67,69,70,82
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Limitations of H-FABP assays
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The human skeletal muscle FABP has been reported to be identical
to that of H-FABP.
56 The H-FABP content of skeletal muscle is
variable, and is reported to range between 0.05 and 0.2 mg/g
wet weight of tissue, depending on muscle type.
72,84 Skeletal
muscle damage during the course of AMI (e.g. intramuscular injections,
electric cardioversion, traumatic cardiopulmonary resuscitation)
may result in the leakage of H-FABP, and this could interfere
with the results of the assays.
84 Diagnosis of AMI in these
groups of patients using H-FABP alone can be difficult. H-FABP
is increased in the plasma of healthy volunteers after strenuous
exercise as a result of release from skeletal muscle, but in
these patients the ratio of myoglobin to H-FABP is below the
6% cut-off value considered specific for skeletal muscle injury.
85 One study however did not report any increase of H-FABP in urine
or serum in a patient with crush injury, whereas myoglobin was
markedly elevated.
69
Surgery (both cardiac and non-cardiac) causes elevation of H-FABP concentration. H-FABP is excreted by the kidney, and renal insufficiency results in decreased clearance of H-FABP, thereby elevating the concentration and prolonging the circulation time.86 In situations of AMI and renal failure, measurement of plasma H-FABP could lead to overestimation of myocardial infarct size, and could interfere with its use for the detection of re-infarction.83 However, renal failure is readily detectable in standard biochemical analysis and should not confound the diagnostic specificity of H-FABP, (as distinct from infarct size measurements) for the vast majority of patients.
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Isoforms of H-FABP
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Heart-FABP could be an ideal early marker of myocyte injury
in ACS, if there is an isoform of this protein that is 100%
specific to the heart. Several investigators have addressed
the possibility for the existence of possible isoforms of H-FABP.
87 Glatz
et al. (1985) isolated FABP from the human heart. This
protein had a molecular mass of 15 kDa and an isoelectric point
of 7.5.
88 Unterberg
et al. (1986) reported the isolation of
H-FABP with a molecular mass of 15.5 kDa, pI of 5.3, and a an
amino acid sequence that included two cysteine residues.
89 Offner
e
t al. (1988) also reported the isolation of H-FABP, with a
molecular mass 14 768 Da; pI 5.25, and an amino acid sequence
that contained no cysteine residues.
41 These results suggest
that isoforms of H-FABP may exist in the human heart. Similarly,
in some studies in rats, the nucleotide sequence of two rat
H-FABP cDNAs differed in the 5' and 3' untranslated regions.
The existence of H-FABP isoforms has also been reported in bovine
species.
92–95 Further studies using more sensitive techniques
are needed to resolve this matter.
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H-FABP and myoglobin
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Myoglobin has been introduced as a marker for early diagnosis
of AMI (within 3 h after symptom onset).
96–101 In a 1994
study, myoglobin was superior to CK-MB mass and cTnT for ruling
out AMI within the period of 3–6 h after symptom onset.
102 Myoglobinuria has long been known to be useful in the diagnosis
of AMI.
78,103 Myoglobin and H-FABP share many key features:
104 (i) low molecular mass (17 and 15 kDa, respectively); (ii) found
in abundant concentrations in the cytosol of myocardial cells;
(iii) provide substrates for mitochondrial oxidation (oxygen
and fatty acids, respectively); and (iv) released within 2 h
after symptom onset, peak early (6 h) and return to normal baseline
concentration within 24 h. Both are present in the heart and
skeletal muscle. However, concentration of myoglobin is approximately
two-fold lower in cardiac than skeletal muscle (2.5 and 4.0
mg/g wet weight of tissue, respectively). In contrast, H-FABP
concentrations are 2–10-fold higher in heart than in skeletal
muscle (0.5 vs. 0.05–0.2 mg/g wet weight).
84,104 In addition,
the normal plasma concentration of H-FABP (< 5 µg/l)
is 10–15-fold lower than that of myoglobin (20–80
µg/l). H-FABP is therefore more cardiospecific than myoglobin
and because of this superior specificity, the use of H-FABP
as a marker may be preferable for the early diagnosis of AMI.
65,66,104
The main disadvantage of myoglobin or H-FABP as early markers of myocardial injury is lack of complete specificity, due to the presence of both in skeletal muscle. Severe skeletal muscle injury may result in the release of both proteins in sufficient quantity to interfere with the specificity of the assay. Both proteins are released into plasma after injury at about the same time and in a ratio similar to the concentration of the proteins in the tissue of origin, therefore the measurement of the myoglobin: H-FABP ratio could be useful for discriminating between cardiac and skeletal muscle damage. A myoglobin:H-FABP ratio 
5 is considered to be specific for the heart; a ratio 21–70 is more indicative of skeletal muscle damage.84 The combination of the two markers in a ratio has been reported by some investigators to increase the diagnostic specificity for the diagnosis of AMI more than relying on either marker alone. However, the use of this ratio should not be a rigid criterion, as overlaps do occur. Some investigators did not find any additional value in myoglobin:H-FABP ratio over the measurement of H-FABP alone.66,84,105
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H-FABP and unstable angina
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H-FABP may be useful for the identification of patients with
UA based upon detection of myocyte injury. However, there have
been no detailed studies evaluating its usefulness for the diagnosis,
or risk stratification in patients with UA. In a study by Tsuji
(1993) using H-FABP with a normal range of 0.0–0.6 µg/l
and an upper limit of normal of 3 µg/l, in patients suspected
with a diagnosis of UA, the concentration of H-FABP was 3.5
± 1.7 µg/l. In patients with AMI, the range was
12.3 ± 9.6 µg/l.
70 Other investigators have also
observed an increase in H-FABP serum concentration in UA patients.
66 One study reported that H-FABP was normal in a patient diagnosed
with UA.
71 In this study, a relatively high upper limit of normal
concentration was used (19 µg/l), and this high cut-off
concentration may have affected the sensitivity, or could be
due to UA without myocardial necrosis. At present we have limited
information on the ischaemic threshold for leakage of H-FABP
from myocytes. Preliminary results from our pilot study have
suggested a possible role for H-FABP in the diagnosis of UA
(
Figure 1). There is a need for larger-scale studies designed
to look specifically at the role of H-FABP for the diagnosis
of patients with UA.
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Figure 1. Concentrations of H-FABP in patients with unstable angina and non-cardiac chest pain. Data from our pilot study in patients with acute chest pain.
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H-FABP and acute myocardial infarction after surgery
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H-FABP peaks early, and may be useful for the early detection
of myocardial injury after surgery. The plasma concentration
of H-FABP is increased relatively early, compared to CK-MB and
cTnT, after aortic declamping in CABG surgery. The time to peak
concentration was significantly shorter for plasma H-FABP (1.4
± 0.5 h) than for CK-MB (2.5 ± 0.5 h) or cTnT
(6.6 ± 1.3 h).
106 Similar findings were reported in other
studies.
107 H-FABP was not increased in low-risk patients after
CABG surgery without cardiopulmonary bypass.
108 The myoglobin
to H-FABP ratio (see ‘H-FABP and myoglobin’ above)
was useful in the diagnosis of AMI after non-cardiac surgery.
However, the sensitivity of this ratio for the diagnosis of
AMI in patients after cardiac surgery was less clear, and ranged
from 11.3 ± 4.7 to 32.1 ± 13.6.
84
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H-FABP and detection of reperfusion
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Establishment of reperfusion in the infarct-related artery is
associated with significant reduction in morbidity and mortality.
However, thrombolytic treatment is associated with successful
reperfusion in only 50–80%.
109,110 New or alternative
treatment options are being examined to try to see the best
way to deal with patients who do not reperfuse after the first
course of thrombolytic treatment.
111–113 Clinical trials
are now underway randomizing patients who do not reperfuse to
either another course of thrombolytic treatment, PCI, or conservative
treatment. In clinical practice, reperfusion is ascertained
indirectly by the reliance on clinical features such as disappearance
of chest pain, resolution of ST segment elevation, and occurrence
of reperfusion arrhythmias (e.g. accelerated idioventricular
rhythm).
114 Reliance on clinical features alone is not sensitive
for the detection of reperfusion, but H-FABP has been reported
to be a sensitive marker for the detection of reperfusion after
thrombolytic treatment. Abe
et al. (1996) demonstrated that
a rise of H-FABP ratio of
1.5 (compared to pre-treatment
concentration), 30 min after thrombolytic treatment, was associated
with 100% accuracy for the detection of reperfusion. This accuracy
dropped to 94% at 60 min after thrombolytic treatment.
74 The
advantage of using H-FABP is that reperfusion is ascertained
very quickly, in some studies as early as 15 min. In a study
by Ishii
et al. (1995), the predictive accuracy of H-FABP ratio
> 1.8 for the detection of reperfusion within 60 min of initiation
of treatment was 93% at 15 min, 98% at 30 min, and 100% at 60
min after reperfusion.
115 The few additional studies that have
examined the role of H-FABP for the detection of reperfusion
also support this view.
64
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H-FABP and detection of re-infarction
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Re-infarction is a well-recognized complication following AMI,
but one which may be difficult to detect clinically. This may
be attributable to re-occlusion of the infarct-related artery
after an initial successful reperfusion or to a vessel occlusion
at another site. Re-infarction can manifest as a recurrence
of chest pain, or haemodynamic deterioration such as hypotension,
acute pulmonary oedema, and arrhythmia with or without new ST
segment changes. In the presence of AMI, recurrence of chest
pain with or without ST segment changes could be misinterpreted
and without a confirmatory test, the diagnosis of re-infarction
could be missed. Re-infarction carries a worse prognosis, and
may necessitate further pharmacological, supportive (e.g. balloon
pump) or intervention treatment with PCI, or (rarely) urgent
CABG. It is vital that this complication is recognized and appropriate
interventions implemented. The most definitive method for the
confirmation of re-infarction is coronary angiography, but the
diagnosis of re-infarction may be possible using cardiac markers.
The high sensitivity, simplicity, cost and safety profile make
cardiac markers a practical option for the detection of re-infarction.
The features of an ideal marker for early re-infarction are early release and clearance from the circulation, thus permitting a prompt return to pre-infarction concentrations. H-FABP fulfils these features, appearing within 3 h after infarction, peaking early at about 5 h, and returning to baseline concentrations about 20 h after symptom onset.71 Re-infarction is shown by a rapid rise in H-FABP concentration in serum compared to the previous value. Heart-FABP can detect re-infarction when it occurs 10 h after symptom onset (Figure 2).84 Other cardiac markers such as CK-MB, cTnI, cTnT, and LDH take several days to return to the pre-infarction levels, and thus are not sufficiently sensitive for the detection of re-infarction.
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H-FABP and estimation of infarct size
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The measurement of infarct size after AMI can have important
prognostic implications.
116–118 It may also have therapeutic
applications in the selection of patients for ACE inhibitor
or anticoagulation treatment. Those patients with large infarcts
who are deemed at higher risk for complications such as congestive
cardiac failure, adverse remodelling of the ventricles or intramural
thrombosis may be selected for higher intensity treatment options.
However, the measurement of infarct size is not performed routinely.
This may be partly due to the complicated blood sampling protocol,
which is both prolonged (several days) and time-consuming, but
is necessary to establish a complete time-concentration curve
profile necessary for this type of measurement. In clinical
practice, infarct size is estimated indirectly (or qualitatively)
by methods such as nuclear perfusion imaging, echocardiography
(wall motion abnormalities, measurement of ejection fraction),
ECG changes (e.g. number of leads involved; conduction abnormalities
in anterior infarction), the presence of heart failure, and
by reference to the maximum rise of cardiac marker concentrations
after infarction. Accurate measurement of infarct size is possible
using nuclear studies, but is not practical for routine use
because it is expensive, requires high technology, and exposes
patients to additional radiation.
Cardiac markers offer an alternative for the estimation of infarct size. The rapid and quantitatively robust release of H-FABP into plasma after symptom onset and its rapid clearance from the circulation within 24 h, make it potentially suitable for the early estimation of infarct size, provided that blood is sampled sufficiently frequently.83 Sohmiya et al. (1993) showed good correlation between myocardial infarct size measured from plasma H-FABP and infarcted myocardium estimated from triphenyl tetrazolium chloride (TTC) staining.82 A study by Glatz et al. (1994) using H-FABP for the early estimation of infarct size, showed a good correlation between H-FABP, CK-MB and 
-hydroxybutyrate dehydrogenase (-HBDH) for the estimation of infarct size. The advantage of H-FABP is that this measurement is completed much earlier than with the other two markers: 24 h, 48 h, and 72 h for H-FABP, CK-MB, and -HBDH, respectively.76
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Excretion of heart fatty acid binding protein
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It is not clear at present whether H-FABP reaches the circulation
trans-endothelially, or via the lymphatic system, or both, after
its release from the cell into the intercellular space. The
rapid appearance from blood may suggest the first route. The
route of elimination from the circulation is assumed to be the
kidney, based on direct and indirect evidence.
The indirect evidence comes from observations in clinical studies. Patients presenting with AMI demonstrate rising levels of plasma and urine H-FABP within 1.5 h after symptom onset.70 Patients with renal insufficiency have raised levels of H-FABP, and circulation time is prolonged compared to those with normal renal function.71,83
The direct evidence comes from radioactive iodine-H-FABP excretion studies in animals. The compound is concentrated within the kidney and appears in the bladder within very short period after intravenous injection.82 However, the reported amount of radioactive H-FABP excreted in the urine is variable. One study reported that only 14–29% of the total intravenous dose injected was excreted in the urine. The total clearance was 0.33 ml/min and the half-life value of total elimination was estimated to be 270 min.81 A study by Sohmiya (1993) reported only 6.5 ± 1.0% recovery of the radioactive H-FABP in the urine, and its disappearance half-time was 27.5 ± 8.4 min. They suggested that the administered H-FABP might be degraded elsewhere in the body and the undegraded H-FABP is excreted in the urine. The authors concluded that their results were comparable to the excretion studies of myoglobin (known to be excreted by the kidney).119
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Pathological confirmation of acute myocardial infarction using anti-H-FABP antibodies on autopsy materials
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Summary
Introduction