Scandinavian Journal of Clinical & Laboratory Investigation, 2010; 70: 244251

ORIGINAL ARTICLE

Determinants of the release pattern of ischaemia-modified albumin

in acute ST-elevation myocardial infarction treated with primary PCI

SREN HJORTSHJ1, CLAUS DETHLEFSEN2, SREN RISOM KRISTENSEN3 &

JAN RAVKILDE1
1Department

of Cardiology, 2Department of Statistics, and 3Department of Clinical Biochemistry, Cardiovascular Research

Centre, Aalborg Hospital, Aarhus University Hospital, Denmark
Abstract
Background. Ischaemia-modified albumin (IMA) is proposed as a marker of cardiac ischaemia. Release kinetics of IMA
have not been investigated during ongoing acute coronary syndrome. We evaluated IMA kinetics in patients with ongoing
ST-segment elevation MI (STEMI) and revascularization by primary percutaneous coronary intervention (pPCI) as a
model. Methods. Twenty-five patients with STEMI undergoing successful pPCI (Age: median 65 y, range 4179 y; symptoms duration: median 4 h, range 17 h). Fourteen blood samples were collected (11 during the first 24 h following pPCI)
and analyzed for IMA, cardiac troponin T, CKMBmass, myoglobin, and heart-type fatty acid binding protein. Results.
Following pPCI, mean IMA increased to 16% above baseline, normalizing within less than 3 h. At the time of pPCI,
patients with TIMI 0 flow in the infarct artery had low levels of IMA and only exhibited a rise in IMA levels after pPCI,
whereas patients with TIMI 13 flow had high IMA levels on arrival with a subsequent decrease (p  0.036). There was
no statistically significant association between IMA and other variables, e.g. ECG, symptoms duration, sex, age, blood
pressure, and number of vessels affected. Relative concentrations of IMA were low compared with other cardiac biomarkers. Conclusions. Our results indicate that IMA release may depend on reperfusion-induced events rather than ischaemia
per se. Further, we find a narrow diagnostic time window and a low sensitivity of the IMA assay. Improved understanding
of the release mechanisms of IMA is needed before clinical application of the test.
Key Words: Acute coronary syndrome, cardiac biomarkers, cardiology, ischaemia, ischaemia-modified albumin, myocardial infarction,
troponins

Introduction
Biomarkers of myocardial necrosis are pivotal in
diagnosing acute coronary syndromes (ACS) with
cardiac troponins I and T (cTnI and cTnT) being
the preferred markers. Ischaemia-modified albumin
(IMA) has been proposed as a marker of ischaemia
and represents a new approach for the detection and
diagnosis of ACS [1,2]. IMA is measured by the
Albumin Cobalt Binding Test (ACB Test), which is
the first commercially available assay of ischaemia
approved by the United States Federal Drug Administration. The ACB Test relies on the observation by
Bar-Or et al. that human serum albumin (HSA)
exhibits a reduced in vitro binding to exogenous
cobalt in serum from ischaemic individuals [1,2].
Technical aspects of the assay have been described
previously [3,4].

The diagnostic performance of IMA has been

investigated in clinical trials involving chest pain
patients [2,510]. A high negative predictive value
(NPV) found in some studies have led to speculations that IMA may be a useful rule-out marker in
the emergency room [6,7,11]. In order to describe
release and modifying mechanisms for IMA, Bar-Or
et al. used percutaneous coronary intervention (PCI)
in patients with stable angina as a model of transient
ischaemia [12]. Levels of IMA showed a relative
increase following PCI but returned to baseline
within 6 h. Later studies have shown IMA to be
elevated after PCI and to correlate with the duration
of balloon inflation as well as the extent of collateral
circulation [13,14].
Despite recent investigations, the formation and
clearance of IMA are only partly understood [3].

Correspondence: Sren Hjortshj, MD, PhD, Department of Cardiology, Cardiovascular Research Centre, Aalborg Hospital, Aarhus University Hospital,
16-18 Hobrovej, DK-9000 Denmark. Tel: 45 9932 2178. E-mail: sph@dadlnet.dk
(Received 11 November 2009; accepted 16 February 2010)
ISSN 0036-5513 print/ISSN 1502-7686 online 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.3109/00365511003716990

Release of ischaemia-modified albumin in MI

There has, thus, been uncertainty whether IMA represented only ischaemia or also other manifestations
of disease, e.g. diffuse activity by Reactive Oxygen
Species (ROS) [15,16]. IMA has also been reported
to reflect conditions other than cardiac ischaemia
[1723]. Determinants of IMA elevations in cardiac
ischaemia, and especially its release kinetics, have
only been scarcely described and never in the context
of ongoing ACS.
The aim of our study was to evaluate the determinants of IMA kinetics in full-scale myocardial
infarction (MI). We therefore investigated patients
with ST-segment elevation MI (STEMI) undergoing
primary percutaneous intervention (pPCI), having a
model of severe ischaemia with angiographically
proven reperfusion

Materials and methods

Patient specimens
Twenty-five patients with STEMI undergoing pPCI
were included (male:female ratio 2.1:1; median age
65 y, range 4179 y). All patients had symptom duration below 7 h (median 4 h, range 17 h).

Blood sampling
Patients had 14 blood samples drawn (before and
after angiography, immediately after pPCI, and 15,
30, 45, 60, 90, 120 min as well as 6, 24, 48, 72, and
96 h after pPCI). Samples were drawn from a large
arm vein into serum tubes without any anticoagulant
and were centrifuged at 4000 g for 10 min. Serum
was stored at 80C before analysis. Frozen samples
were mixed after thawing and re-centrifuged before
analysis. Samples did not undergo repeat freeze-thaw
cycles. In order to evaluate sensitivity of the assays,
relative concentrations were calculated as measured
concentration divided by 99th percentile given the
lowest concentration with CV 10%. For IMA, relative concentrations were calculated as measured
concentrations divided by 95th percentile.

Cardiac biomarkers
Ischaemia-modified albumin (IMA) was determined
from serum with Albumin Cobalt Binding (ACB)
Test (Inverness Medical Innovations Inc. Stirling,
UK). The principle of the assay is described elsewhere
[3,4]. Analyses were performed on a Cobas MIRA
Plus instrument (Roche Diagnostics, Mannheim,
Germany). The within-series coefficient of variation
(CV) was 4.4% and the between-day imprecision was
6%. Previously, a reference interval was obtained from
258 healthy blood donors and analysed on a Hitachi
911 instrument (Roche Diagnostics, Mannheim,
Germany) [24]. The assay exhibited a CV 10% at

245

both the upper 95th and 99th percentile (88.2 and

111.8 U/mL, respectively). The 95th percentile has
been used in other studies [6,10], and 88.2 U/mL was
therefore defined as upper limit of normal (ULN).
Blood samples were handled and analyses performed
according to the manufacturers protocols.
Cardiac Troponin T (cTnT), creatine kinase MB
mass (CKMBmass), and myoglobin was determined
from serum at 37C on Elecsys 2010 (Roche Diagnostics, Germany). For cTnT (4th generation assay),
the lowest concentration exhibiting imprecision coefficient of variation (CV) 10% was 0.03 g/L
[25,26]. Upper reference value for CKMBmass was
4.0 (females) and 7.0 g/L (males), respectively [27],
and for myoglobin 51 g/L (females) and 72 g/L
(males), respectively [28].
Heart type fatty acid binding protein (H-FABP)
was analysed from dipotassium ethylenediamine tetraacetic acid (K-EDTA) plasma using enzyme linked
immunosorbent assay technique (HyCult Biotechnology, Uden, The Netherlands); upper reference
value is 6.0 g/L with CV 10% [28].
Electrocardiogram (ECG), invasive procedures, and
assessment of reperfusion
Patients were diagnosed by a 12 lead ECG showing
ST-segment elevation of  0.2 mV in at least two continuous leads and referred for emergency coronary
angiography (CAG). ECG-12 was performed in all
patients prior to admission, either in the ambulance
or the emergency room. Patients were pre-treated
with aspirin 300 mg, clopidogrel 300 mg, and unfractionated heparin 10,000 IU. All coronary arteries
were visualized by CAG before any decision on revascularization. All included patients had successful
pPCI according to guidelines [29]. All had stent
implantation of the culprit lesion. Mean balloon
inflation time during pPCI was 15 s (range 1025
sec). Following pPCI, patients with STEMI were
treated with a bolus of glycoprotein IIb/IIIa receptorblocker (ReoPro (abciximab)) and infusion for 12 h.
Flow in the coronary arteries was assessed using the
TIMI scale (Thrombolysis in Myocardial Infarction)
before and after revascularization [30]. All patients
had TIMI 3 flow in all vessels following pPCI and
were thus considered successfully reperfused.

Ethics
The study was approved by the ethical committee of
North Jutland and Viborg Counties, Denmark. All
participants gave informed consent.
Statistics
Categorical variables were compared between groups
with the Chi-square test. Continuous data were

246

S. Hjortshj et al.

analysed by the t test and presented as means and

95% CI of the mean (95% CI). The level of significance chosen was 0.05. Unless otherwise specified,
data are given as mean  2 standard deviations (2
SD). Students paired t test was used in comparison
of time to maximum between serum markers. When
comparing release kinetics for different patient
groups, a mixed linear effect model was applied. Correlations were tested using Spearmans correlation
test. The statistical analyses were performed using
STATA statistical software package (StataCorp,
Texas, USA).

Results
Baseline characteristics of enrolled patients are shown
in Table I. The majority of patients (88%) were
asymptomatic with respect to CAD prior to the
index MI. Individual curves of IMA in all patients
following pPCI through the first 6 h are shown in
Figure 1.
The peak value was above ULN in 23 patients
(92%). There was substantial variation between the
patients. Thirteen patients (52%) had cTnT above
ULN on admission. There was a non-significant relationship between cTnT on admission and symptoms
duration (r2  0.57, p  0.67).
Figure 2, panel A shows mean  2SD of IMA
from angiography and pPCI throughout the sampling period, while panel B focuses on the first 6 h

following revascularization. On admission, mean

IMA was 94  12.6 U/mL. Thirteen patients (52%)
had IMA above ULN (88.2 U/mL) on admission.
Mean IMA levels increased sharply with a peak
IMA occurring between 1545 min after pPCI in
almost all patients. The mean peak level was
106.4  9.6 U/mL (range: 72125) reached 40 min
after pPCI, which is 16% above ULN. The mean
increase in IMA levels was 15.1  11.4 U/mL equivalent to a mean relative change in IMA on 12.9%.
Peak IMA was independent of age, sex, previous
hypertension and hypercholesterolaemia, and diabetes mellitus. Nineteen patients (76%) had ST
segment elevations  0.2 mV in the ECG, whereas
six patients (24%) had ST segment elevations in
regression (0.2 mV) on arrival. There was no significant association between duration of symptoms
and peak IMA (p  0.82). Nor was there any association between the presence of ST segment elevations in the ECG on arrival and higher IMA levels
(p  0.81).
After the peak mean IMA subsequently decreased
at a very steep rate and levels were nearly normalized
after 2.5 h (p  0.001 compared with peak values).
After 7 h, mean IMA was normalized remaining constant for the duration of the study for most of the
patients, although a few patients had an unexplained
smaller, prolonged secondary increase.
Some patients (n  10) already exhibited elevated
levels of IMA on arrival, whereas others (n  15)
exhibited a later rise in levels of IMA (p  0.036).

Table I. Baseline characteristics of patients with STEMI (N  25).

STEMI patients (N  25)
Clinical characteristics
Age, median; range, years
Sex, male/female, n
Weight, median; range (kg)
Systolic/diastolic blood pressure on arrival, median; range (mm Hg)
Prior known coronary artery disease, n (%)
Hypertension, n (%)
Diabetes, n (%)
Duration from onset of symptoms to pPCI, median; range (hours)
Medication prior to hospitalization
Beta-blockers, n (%)
Calcium antagonists, n (%)
ACE-inhibitors/A-II receptor blockers, n (%)
Statins, n (%)
Biochemical variables on arrival
Creatinine, median; range (mol/L)
Albumin, median; range (g/L)
Other variables
Infarct related artery, n (%)
Left anterior descendent artery
Left circumflex artery
Right coronary artery
No. of vessels affected, n (%)
1-vessel/2-vessels/3-vessels
TIMI flow on arrival, n (%)
TIMI 0/1/2/3
ECG on arrival
ST elevations  0.2 mV/0.2 mV

58; 4193
17/8
79; 55119
120; 105180/80; 60109
3 (12)
11 (44%)
2 (8)
4; 17
7
5
5
3

(28)
(20)
(20)
(12)

97.5; 67139
36; 2550

6 (24)
9 (36)
10 (40)
13 (52)/5 (20)/7 (28)
15 (60)/3 (12)/5 (20)/2 (8)
19 (76)/6 (24)

Release of ischaemia-modified albumin in MI

247

Discussion
IMA following revascularization

Figure 1. Individual curves of IMA in patients with STEMI

(N  25) through the first 6 h following pPCI. Blood sampling
continued up to 96 hours after pPCI, but IMA remained constant
during this time.

Neither duration of symptoms nor the presence of

ST-elevations on arrival or absolute ST-elevations
(measured in mV) was associated with this
phenomenon (p  0.84, 0.71, and p  0.57,
respectively).
The flow in the coronary artery was graded
according to the TIMI scale. Patients with no flow
(TIMI 0) had lower levels of IMA on arrival as compared to patients with the TIMI 13 flow (p  0.042)
(Figure 3). There was no statistical significant association between the course of IMA and other variables, e.g. sex, age, blood pressure, number of vessels
affected, and infarct related artery.
Levels of cTnT, CKMBmass, myoglobin, and
H-FABP increased markedly following STEMI and
revascularization consistent with significant myocardial necrosis (p  0.0001 for all markers). Mean
relative concentrations of these markers are shown in
Figure 4. IMA relative concentrations remained low
compared to other markers (p  0.001 for cTnT,
CKMB mass, myoglobin, and H-FABP), indicating
a low sensitivity of the ACB assay. Peak levels of IMA
were not correlated to peak levels of necrosis
markers.

This is the first study to describe determinants of

IMA release and clearance during ongoing ACS. We
used STEMI patients undergoing pPCI as a model
of severe cardiac ischaemia and found an increase in
mean levels to 16% above ULN. The mean relative
increase from admission was 12.9%. Previously,
Bar-Or et al. found 10% relative increase in IMA
levels in patients with stable angina undergoing PCI
with prolonged balloon inflations [12]. Our study
population had ongoing MI, and it may be questionable to compare the present study with previous
studies in patients with stable angina. In our study,
levels of IMA increased abruptly following pPCI,
peaked after 40 min, and returned to almost normal
levels within less than 23 h, whereas Bar-Or et al.
described normalization over 68 hours. However,
Bar-Or et al. took only four blood samples against
our 10 samples from baseline to 6 h following PCI
and it may well be that we are simply able to describe
the kinetics more precisely. Notably, only 13 patients
(52%) had IMA above ULN on admission in the
setting of severe myocardial ischaemia. This observation suggests that in the clinical setting, one has to
rely on at least two samples before ruling out a patient
with an IMA value below ULN.
IMA and coronary flow
Some patients showed signs of normalization of flow
in the infarct artery on admission, possibly due to
pre-treatment with antithrombotic drugs and inherent spontaneous fibrinolysis. It is thus possible to
divide patients into those who were partly reperfused
on arrival and those who were not. Patients who had
TIMI 13 flow in the infarct artery had significantly
lower and falling IMA levels that seemed to have
peaked before arrival (Figure 3). On the other hand,
an initial rise and peak of IMA was seen in patients
who had their infarct artery opened only during

Figure 2. Mean IMA levels with 2 SD in patients with STEMI (N  25) undergoing angiography and primary pPCI. Panel A: Mean IMA
in entire sampling period (96 h). Panel B: First 6 h following pPCI.

248

S. Hjortshj et al.

Figure 3. IMA with 2 SD in STEMI patients grouped according to TIMI flow in the infarct artery on arrival. Panel A: TIMI 0 flow. Panel
B: TIMI 1, 2, and 3 flow. Patients with TIMI 0 flow exhibit lower IMA values on arrival and later peak values (p  0.042).

pPCI, thus being exposed to the immediate effects

of reperfusion. IMA thus seems to reflect the response
to reperfusion at a time, where ischaemia supposedly
should be relieved. This poses the question whether
IMA is solely an ischaemia marker or may also be a
marker of diffuse reperfusion-induced events by
reactive oxygen species (ROS). ROS activity has also
been proposed as the cause of IMA elevation following DC cardioversion and ablation [19,20]. Others,
however, have found IMA levels directly correlating
to the extent of ischaemia [13,14,31]. In this study,
we did not have access to measures of ROS activity,
e.g. isoprostanes, but future studies may address this
particular issue.
The release pattern of IMA resembles that of
myoglobin, and it may also be that we are observing
the same phenomenon as in a study by Jurlander
et al. where patients with STEMI receiving thrombolytic therapy were investigated with CAG and classified as reperfused or non-reperfused [32], i.e. that
opening the artery releases IMA entrapped distal to

the coronary occlusion of blood with very high IMA

levels although the total volume of trapped blood in
the microvascular bed of the heart is likely to be very
small relatively to the systemic intravascular volume.
In that study [32] the time to peak for myoglobin
was significantly shorter in the reperfusion group
compared with the non-reperfusion group, i.e. a
short time to peak is a marker of reperfusion. However, Haastrup et al. investigated non-invasive methods for assessment of reperfusion and found that
biochemical markers were very dependent of infarct
size and thus not very useful in the assessment of
reperfusion status [33].
Another less possible explanation for the observed
phenomenon could be dislodgement of thrombus
material from the site of occlusion and subsequent
blockage of the microvasculature with resulting
ischaemia. However, ischaemia should be expected
to be at its maximum before opening the artery, and
is therefore unlikely to see yet another increase as a
result of thrombus material in parts of the microvascular bed.
IMA and ECG

Figure 4. Release of biomarkers of myocardial necrosis, i.e. cTnT

and myoglobin. Data are shown as mean relative concentrations.
Please note that the scale on the left y-axis is of much smaller
magnitude. Necrosis markers exhibit significant release following
pPCI, consistent with full-scale myocardial infarction. Relative
concentrations of IMA are plotted against the left y-axis remaining
at a low amplitude compared with necrosis markers.

Regression of ST elevations are used when assessing

the efficacy of revascularization therapy [34], and
one may therefore have expected an association
between the presence of ST elevations and IMA on
admission. The majority of patients (76%) had ST
elevations  0.2 mV in the ECG on arrival, but this
was not associated with an elevated arrival IMA. Neither was there any relationship between absolute ST
elevations and IMA. In this case, it was not possible
to link different release patterns of IMA to the ECG,
possibly due to the size of the study. To explain this,
one may again draw on experiences from the thrombolytic era showing a possible connection between
the rapid release of a marker and regression of
ST-changes. Thus, Jurlander et al. found an inverse
relationship between a rapid peak of myoglobin and

Release of ischaemia-modified albumin in MI

a high rate of ST-segment resolution in the ECG
using continuous ST-segment monitoring and a validated assessment of myocardial salvage [35]. It is
possible that in patients who were partly reperfused
before admission, IMA peaked early with concomitant ST-segment regression.

IMA and symptoms duration

ST-elevations in the ECG and an occluded epicardial
artery definitely represent a full-scale MI as can also
be seen from the elevated necrosis markers (Figure
3). As IMA levels in stable patients undergoing PCI
depend on the magnitude and duration of myocardial ischaemia (balloon inflation) [14], one could
expect that IMA levels were higher in those patients
with the longest symptoms duration. However, we
found no relationship between IMA on arrival, peak
IMA, and symptoms duration. Neither was there any
statistical significant relationship between cTnT and
symptoms duration. Further, there seems to be a
finite upper level for IMA formation, where only a
certain proportion of circulating albumin can be converted into IMA regardless of the magnitude or duration of ischaemia, cf. the small relative changes of
IMA compared to the necrosis markers. This warrants further investigation.

IMA compared with other biomarkers

It is readily seen from Figure 3 that other necrosis
markers are significantly above discriminatory limits.
The shape of the IMA curve shape is similar to that
of myoglobin and to a lesser extent H-FABP
(cf. Figure 2), but the latter markers decreased to
normal levels at a slower rate. IMA has been found
to have a high negative predictive value in patients
presenting with symptoms of ACS [6,11]. However,
the very sharp rise and decline in IMA levels following severe ischaemia means that the negative predictive value decreases if the patient presents in the
emergency room just a few hours beyond the ischaemic event where IMA may have returned to normal
levels. On the other hand, the release characteristics
with rapid normalization could indicate a role for
IMA as a marker of re-infarction. There are, however,
no available clinical data to support this. A role as a
marker of re-infarction would also be on the expense
of a very narrow diagnostic time window meaning
that the test can be applied only in those patients
with very short symptoms duration. Thus, it is not
clear to what extent IMA offers any advantages over
cardiac necrosis markers in a clinical setting.

IMA and specificity

From a cardiologists perspective, biomarkers of
ischaemia have an important inherent problem from

249

the clinicians point of view, as they are not heart

specific [1618,2123]. If indeed originating from
the heart, the marker may not reflect coronary artery
disease but possibly other processes, e.g. stunning
after electrical cardioversion [19,20]. In the case of
IMA, there are indications that this marker may
reflect ischaemic processes throughout the organism
[18,3640], and thus an elevated IMA may not guide
the clinician sufficiently. Further, if ROS activity during reperfusion plays a major role in IMA formation,
there may be numerous non-cardiac conditions where
IMA may be elevated due to diffuse ROS activity.

Limitations
The number of included patients is small which does
not allow for robust conclusions in some areas, e.g.
regarding influence of gender on IMA levels.
A previous report questioned the use of frozen
IMA samples [41]. However, the study investigated
IMA results from samples frozen at 20C, whereas
the present study investigated samples stored at 80C
which complies with the manufacturers adjusted
recommendations.
Ideally, the results from the present study should
have been compared with data from individuals who
did not obtain reperfusion. However, it is not possible
to include patients with STEMI who were not revascularized, as this is unethical or would demand a very
large screening population in order to obtain a reasonable study group, as among STEMI patients, it
can be expected that approximately 3% of patients
have TIMI 0 or 1 flow following primary PCI [42].
At present, no animal model has been validated with
the concept of IMA. It is still unknown whether the
decreased cobalt/albumin binding in ischaemia is
confined to humans or also present in other species.
In this study, we found that the main changes in
IMA occur during the first 23 hours. Therefore, the
inclusion of patients with up to 7 h of symptoms
duration may be problematic, as some patients may
present with already decreased levels of IMA. Future
studies may focus exclusively on the first hours to
obtain an even more homogenous population.

Conclusions
We conclude that the release pattern of IMA in
STEMI patients undergoing pPCI was significantly
associated with the degree of flow in the infarct artery
on arrival. Patients with no flow in the artery (TIMI
0) had lower levels on arrival and accordingly later
peaks in IMA. Our findings suggest that increases
in IMA beyond baseline levels could have other
causes than ischaemia, i.e. reperfusion-induced
events, possibly by reactive oxygen species (ROS),
possibly in addition to indicating successful reperfusion. Further, the very fast clearance of IMA may

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S. Hjortshj et al.

suggest a role for IMA in the detection of re-infarction,

although not supported by available clinical data.
Until questions regarding IMA formation and clearance have been resolved, there seems to be limited
benefit of IMA sampling in a clinical context.

Acknowledgements
We are grateful to the staff at the departments of
Cardiology and Clinical Chemistry, Aalborg Hospital, Aarhus University Hospital for their help and
support during sampling and analysis of samples.
Funding
The study was financially supported by The Danish
Heart Foundation and the County of North Jutland
Research Foundation. Also, we would like to thank
Inverness Medical Innovations, Inc. for providing
assays and technical support.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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