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Articles |
1
Department of Internal Medicine, Fujita Health University School of Medicine, 1–98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470–11, Japan.
2
Department of Clinical Chemistry, Fujita Health
University School of Health Sciences, Toyoake, Aichi, Japan
3
Third Division, Department of Internal Medicine, Osaka
Medical College, Takatsuki, Japan.
a Author for correspondence. Fax 81 562 93 2315; e-mail tkondo{at}fujita-hu.ac.jp
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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14. We conclude that H-FABPc is a more sensitive and
specific marker than myoglobin for the early diagnosis of AMI,
and that their ratio cannot give a clear advantage over the measurement
of H-FABPc alone.
Key Words: indexing terms: biochemical markers • myocardial injury
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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diagnosis of ami
The diagnosis of AMI was finally established at hospital discharge
by a cardiologist without knowing serum concentrations of H-FABPc and
myoglobin if a patient had at least two of the following three
findings: (a) clinical history of ischemic chest
discomfort of >30 min duration; (b) evolution of typical
changes in at least two leads of the electrocardiogram, appearance of
Q-waves of >0.04-s duration or an R wave increment leading to an R/S
ratio >1 in leads V1 and V2 (defined as Q-wave
infarctions), or ST segment depression of >0.1 mV 0.08 s after J
point or ST segment elevation >0.1 mV persisting for at least 24
h (defined as non-Q-wave infarctions); (c) time-dependent
changes in serum CKMB activity with an initial rise [to a peak value
exceeding twice the upper reference limit (24 U/L)] and subsequent
fall.
measurement of markers
Samples were obtained by venipuncture into a standard serum tube,
centrifuged at 1800g for 15 min, and stored at -80 °C.
The serum concentration of H-FABPc was determined by a recently
developed sandwich ELISA, the accuracy and reproducibility of which
have been described previously (9). This assay method can
also measure H-FABPc concentration in plasma. The lower detection limit
for H-FABPc was 1.25 µg/L. The value below the lower detection limit
of H-FABPc was defined as 1.0 µg/L. The concentration of myoglobin
was measured by turbidimetric latex agglutination method (Mb-latex
Seiken; Denka Seiken, Tokyo, Japan) with an automated chemical analyzer
(30R; Toshiba Medical, Tokyo, Japan) (10)(11)(12)(13). The
detection limit for myoglobin was 10 µg/L. The measurement of
myoglobin concentration required 10 min and that of H-FABPc
concentration required 90 min. Serum CKMB activity was determined by an
immunoinhibition assay (CKMB-NAC; Boehringer Mannheim, Tokyo, Japan)
with an automated chemical analyzer (30R). The ratio of myoglobin over
H-FABPc was obtained by dividing the serum concentration of myoglobin
with that of H-FABPc.
statistical analysis
Results are expressed either as mean ± SD or as median and
interquartile range. Differences in clinical characteristics between
groups were analyzed by Student's t-test, 
2
test, or Fisher's exact test, as appropriate. Differences in serum
H-FABPc concentration, serum myoglobin concentration, and the
concentration ratio of myoglobin over H-FABPc between groups were
compared by the nonparametric Mann–Whitney U-test,
Kruskal–Wallis H-test, or Scheffé type multiple
comparison, as appropriate. The 95% confidence intervals (CI) and ROC
curves (14) were used to assess the discriminatory ability
of indicators. A univariate Z-test was used to compare the
areas under the ROC curves of indicators, as described by Hanley and
McNeil (15). Differences in sensitivity, specificity, and
predictive accuracy between indicators were evaluated by the sign test.
P <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Patients in the AMI group were admitted earlier after the
onset of chest pain than those in the non-AMI group (P
<0.01). Forty-seven patients in the AMI group were admitted within
3 h (1.9 ± 0.6 h) and 52 from 3 to 6 h (4.4
± 0.9 h) after onset of chest pain. Coronary angiography was
performed in 90 patients of the AMI group at 22–32 days after onset of
chest pain (25 ± 4.1 days).
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In the non-AMI group, 24 patients complained of unstable angina with
the clinical classes being III B in 18 and I B in 6 (16).
Coronary angiography was performed within the interval from 4 h to
1 week after admission (4.2 ± 2.6 days) in all patients with
unstable angina. Significant obstruction (
75% stenosis in vessel
diameter) of a major coronary artery was found in 22 patients (91.7%)
and not in two. In these two patients, the clinical diagnosis was
variant angina.
Serum concentrations of H-FABPc and myoglobin in the AMI group were
significantly (P <0.01) higher than the respective
concentrations in the non-AMI group and in the healthy volunteers
(Table 2
). The serum concentration of myoglobin in the non-AMI group was
significantly (P <0.01) higher than that in the healthy
volunteers, whereas no significant difference of H-FABPc concentration
was found between the non-AMI group and healthy volunteers. The normal
serum H-FABPc concentration was low with a narrow range similar to that
reported by Kleine et al. (9 ± 5 µg/L) (2). Serum
H-FABPc concentration ranged between 1.0 and 11.4 µg/L, and myoglobin
concentration between 24 and 94 µg/L. The upper normal values,
defined as the 97.5% percentile in healthy volunteers, were 10.5
µg/L for H-FABPc and 92 µg/L for myoglobin.
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The concentration ratio of myoglobin over H-FABPc in the AMI group was
significantly (P <0.01) lower than the ratio in the non-AMI
group and in the healthy volunteers (Table 2
, Fig. 1
). There was no significant difference of the ratio between the
non-AMI group and healthy volunteers. In the AMI group, 72 patients
with H-FABPc concentration >12 µg/L had a significantly
(P <0.01) lower ratio (median 6, interquartile range
5.1–7.0) than 17 patients with H-FABPc concentration 12 µg/L
(median 8.6, interquartile range 6.1–12.7). The upward and leftward
shift in the ROC curve of the ratio between AMI group and healthy
volunteers was markedly less than the shift in H-FABPc and myoglobin
concentration (Fig. 2
), indicating that it is difficult to discriminate healthy
subjects from patients with AMI by the ratio alone. The area under the
ROC curve of the ratio (0.823, 95% CI = 0.765–0.881) between AMI
group and healthy volunteers was significantly (P <0.01 and
P <0.05, respectively) smaller than the area under the
H-FABPc (0.946, 95% CI = 0.913–0.979) and the myoglobin curves
(0.895, 95% CI = 0.846–0.944).
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For the detection of AMI within 6 h of onset of chest pain, the
upward and leftward shift in the ROC curve between the AMI group and
the non-AMI group was greater for H-FABPc concentration than for
myoglobin concentration and the ratio of myoglobin over H-FABPc (Fig. 3
). The area under the ROC curve of H-FABPc (0.898, 95% CI
= 0.849–0.946) was significantly (P <0.01) greater than
the area under the myoglobin curve (0.782, 95% CI =
0.713–0.852), whereas no significant difference was found between the
area under the ROC curve of H-FABPc and that of the ratio of myoglobin
over H-FABPc (0.831, 95% CI = 0.764–0.898).
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The value that offered the maximal predictive accuracy in patients was
taken as the cutoff value for the diagnosis of AMI. The cutoff values
were 12 µg/L for H-FABPc and 105 µg/L for myoglobin and exhibited a
100% specificity in healthy volunteers. The sensitivity, specificity,
and predictive accuracy of H-FABPc concentration beyond the cutoff
value were 81.8%, 86.4%, and 83.6%, respectively, for detection of
AMI within 6 h of onset of chest pain, and were significantly
(P <0.05, P <0.05 and P <0.01,
respectively) higher than those of myoglobin (Table 3
). The sensitivities of H-FABPc concentration for the detection
of AMI were 72.3% within 3 h, and 90.4% from 3 to 6 h after
the onset of chest pain. The sensitivity of H-FABPc concentration
within 3 h of onset was significantly (P <0.05) higher
than that of myoglobin, but was similar to myoglobin from 3 to 6 h
of onset.
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For the maximal predictive accuracy in patients and a 100% specificity
in healthy volunteers, H-FABPc concentration >12 µg/L combined with
the ratio 14 was defined as the diagnostic criterion for AMI. The
sensitivity, specificity, and predictive accuracy of this criterion for
the detection of AMI within 6 h of chest pain were 79.8%, 90.9%,
and 84.2%, respectively (Table 3
). These values were similar to the
single criterion of H-FABPc concentration >12 µg/L.
In the non-AMI group, H-FABPc was increased at admission in nine
patients (Table 4
), and myoglobin in 16. In patients with unstable angina,
H-FABPc concentration exceeded the cutoff concentration in two patients
(8.3%), and myoglobin in three (12.5%). There was no significant
difference in the frequency of increased concentration of H-FABPc and
myoglobin in patients with unstable angina. The frequency of increased
concentration of H-FABPc was significantly (P <0.05) lower
than that of myoglobin in patients without unstable angina in the
non-AMI group. Three patients of non-AMI group with increased H-FABPc
concentration had a ratio >14, and the ratio was helpful in
differentiating AMI from skeletal muscle injury. In two patients with
AMI, serum concentrations of both H-FABPc and myoglobin were increased,
with a ratio >14. The increased ratio may reflect an injury to both
myocardial and skeletal muscle because the chest pain appeared while
the patients were playing golf or jogging.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, Van Nieuwenhoven et al. reported that the ratio of the increase in the plasma concentrations of myoglobin and H-FABPc above basal concentrations could be an index to discriminate myocardial injury from skeletal muscle injury (8). For the calculation of the ratio of the increased plasma concentrations, it is necessary to obtain the basal plasma concentrations. This is too complicated and time consuming to use in an emergency situation. We therefore calculated the ratio of the serum concentrations on admission.
In healthy volunteers, one expects that the concentration ratio of myoglobin to H-FABPc in serum corresponds to the content ratio found in skeletal muscle, the major source of these proteins in normal circulation. However, for skeletal muscle the content ratio of myoglobin to H-FABPc was reported to be 20–70 (7)(8), which was considerably higher than the concentration ratio in healthy volunteers. The relatively low ratio of serum concentrations of myoglobin to H-FABPc in healthy subjects may be due to the difference in renal clearance of these proteins. The isoelectric points of H-FABPc (pI 5.1) and myoglobin (pI 7.0) were different, and this makes H-FABPc more negatively charged, causing H-FABPc to be cleared less rapidly by the kidneys and hence to stay longer in circulation than myoglobin (17). In animal studies, the disappearance half-time for H-FABPc (27.5 min) is approximately four times as long as that of myoglobin (5.5–8.9 min) (18)(19)(20). Under normal conditions, because only a small amount of these proteins is continuously released into the bloodstream, the effect of the difference in renal clearance of proteins is much more than in conditions under which a great deal of these proteins is released into bloodstream abruptly because of myocardial or skeletal muscle damage. Therefore, the concentration ratio in healthy subjects shows a lower concentration than the content ratio for skeletal muscle.
There was a considerable overlap in the ratio distribution in healthy
volunteers and patients with AMI within 6 h after onset (Fig. 1
),
indicating that it is difficult to use the ratio alone for early
detection of AMI. There are several possible explanations for the
overlap of the ratio between the healthy subjects and the patients with
AMI within 6 h after onset. Healthy subjects have relatively low
concentration ratios of myoglobin over H-FABPc, as mentioned above.
Also, a significant change in the ratio requires the release of
significant amounts of proteins from injured muscle, which makes the
ratio difficult to use in patients without sufficiently increased
concentrations of these proteins. Finally, a wide variation in the
ratio in healthy individuals may exist, resulting from a wide variation
in the distribution of both proteins in the type of skeletal muscle
(7)(8). In the AMI group, patients with
H-FABPc concentration >12 µg/L had a significantly lower ratio than
patients with concentration 12 µg/L, suggesting that the more
proteins are released, the more useful the ratio may become in
differentiating myocardial injury from skeletal muscle injury. In the
present study, the sensitivity, specificity, and predictive accuracy
for the combination of H-FABPc concentration above the cutoff value and
the ratio 14 were similar to H-FABPc alone for early diagnosis of
AMI. Thus, the ratio was not more useful than the measurement of
H-FABPc alone for the detection of AMI within 6 h after the onset
of chest pain.
When evaluating the diagnostic value of the concentration ratio of myoglobin to H-FABPc, one must use a sensitive method for both determinations. In the present study, the concentration of H-FABPc was determined by a recently developed and considerably sensitive sandwich ELISA (9). For the measurement of myoglobin, the turbidimetric latex agglutination method was used because it is the most practical method in an emergency situation for its rapid and easy assay and has been proved to be sensitive, accurate, and precise (10)(11). The detection limit for myoglobin is 10 µg/L (10). In none of the 104 healthy volunteers and 165 patients was serum concentration of myoglobin lower than the detection limit. Thus, we believe if we measure myoglobin concentration with a more sensitive assay such as RIA, we can get the same results for the diagnostic utility of the ratio of myoglobin to H-FABPc.
Application of H-FABPc as an early marker of AMI requires a rapid assay procedure with high diagnostic accuracy. The sandwich ELISA applied in the present study requires an analysis time of ~90 min, too long to be practical in emergency situations. However, a rapid assay system is being developed to facilitate H-FABPc analysis in clinical practice (8)(21).
There are limitations to clinical application of the H-FABPc concentration for early detection of AMI. Serum H-FABPc concentration increased beyond the cutoff concentration in two patients with unstable angina. Both patients had severe chest pain, electrocardiographic changes, and abnormal angiographic findings, suggesting that the increase of biochemical markers may be attributed to minor myocardial injury. One of the patients developed AMI on the second day after admission and died. Thus, H-FABPc concentration may increase in patients with minor myocardial injury. However, this limitation is not necessarily serious. Patients with H-FABPc concentration >12 µg/L who had unstable angina may be at increased risk of cardiac events and may require further therapy.
Serum H-FABPc concentration exceeded the cutoff concentration in four patients with skeletal muscle injury due to exercise, dissection of aneurysm, or frequent intramuscular injections. Three of these four patients had a ratio >14. Skeletal muscle injuries have less effect on the serum concentration of H-FABPc than the myoglobin concentration. However, the false-positive findings for H-FABPc resulting from these skeletal muscle injuries should be considered. The ratio of myoglobin over H-FABPc may be helpful in discriminating myocardial injury from skeletal muscle injury in patients with sufficiently increased concentrations of H-FABPc and myoglobin, as suggested by Yoshimoto et al. and Van Nieuwenhoven et al. (7)(8).
Serum H-FABPc concentration exceeded the cutoff concentration in three
patients with shock, severe hypoxemia, or renal failure. These three
patients had a ratio 14. Thus, the H-FABPc concentration may exceed
the cutoff value and lead to a false-positive result in such
complicated cases. It may be also difficult to interpret the meaning of
the ratio of myoglobin over H-FABPc in complicated cases. In such
cases, markers such as troponin I and T that become increased later
than H-FABPc or myoglobin may be useful in the diagnosis of myocardial
injury (22)(23).
In conclusion, H-FABPc is a more sensitive and specific marker than myoglobin for the detection of AMI within 6 h, particularly within 3 h, after the onset of chest pain; the ratio of myoglobin over H-FABPc cannot give a clear advantage over the measurement of H-FABPc alone. Serum H-FABPc concentration at admission can provide a tool for early triage of patients.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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