Drug Metab. Pharmacokinet. 24 (4): 333–341 (2009).

Review
Ischemia Modified Albumin: A Novel Biomarker
for the Detection of Cardiac Ischemia
David C. GAZE*
Department of Chemical Pathology, Clinical Blood Scienses, St George's Hospital, London, United Kingdom

Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk

Summary: The diagnosis of cardiac ischemia remains a challenge in contemporary emergency medicine. A
blood-borne biomarker is an attractive alternative to cardiac imaging or stress testing as it would be cheaper
and logistically faster to obtain. A number of candidate biomarkers have been proposed for the detection of
cardiac ischemia; however, only Ischemia Modified Albumin (IMA) has been released for clinical use. IMA is a
good discriminator between ischemic and non-ischemic patients. Changes in IMA concentration have shown
to occur during coronary angioplasty-induced ischemia. Clinical studies indicate that IMA appears to offer on
admission an early test which can be combined with electrocardiographic findings and cardiac troponin meas-
urements for the early exclusion of acute coronary syndrome. IMA is an independent predictor of short and
long term adverse outcomes in patients with acute chest pain. However, this test is relatively new and uncer-
tainties remain. Elevations of IMA occur in conditions other than chest pain, thus questioning its specificity.
The mechanism of IMA formation and the precise entity being measured are not fully known. Nevertheless,
IMA measurement remains the only current clinical biomarker which may be used for the diagnosis of patients
suspected of cardiac ischemia.

Keywords: Ischemia; Albumin; Biomarker; Ischemia modified albumin; Cardiac ischemia; Clinial
study; Oxidative stress; Albumin cobalt binding assay

prompt revascularisation. The challenge is to use addi-

Introduction
Ischemia occurs when there is a supply demand mis-
match in cardiac blood flow. In unstable angina, this oc-
curs due to partial or total occlusion of a coronary artery
due to plaque rupture. In stable angina, there is progres-
sive vascular occlusion resulting ultimately in a stenosis
of more than 70%, impairing blood flow. If the ischemia
is reversible, no myocardial damage occurs. If the ische-
mia is prolonged, there will be cellular necrosis and my-
ocardial infarction. The interventional challenge for
medicine is to be able to identify acutely impaired my-
ocardial perfusion before necrosis has occurred. Current-
ly, the only strategy for this is to detect ST segment
changes on the electrocardiogram (ECG). Reperfusion
therapy can then be initiated and is life-saving and results
in myocardial salvage. Many patients who present with
chest pain do not have acute myocardial infarction
(AMI). The sensitivity of admission ECG is typically
around 50%. There is therefore a need for a strategy to
detect ischemia before necrosis occurs and conduct
tional quantitative risk stratification tools as potential
biomarkers for ischemia. Currently, three markers have
been proposed: choline, free fatty acids and ischemia mo-
dified albumin (IMA}).1) Of these, only ischemia modi-
fied albumin is currently available as a licensed test for
routine clinical application measured using the Albumin
Cobalt Binding (ACB}) assay.
Mechanism of IMA generation
The N-terminal portion of human serum albumin
(HSA) is a binding site for transition metal ions such as
cobalt, copper and nickel.2) It is currently not known if
there are significant changes in total human serum albu-
min between ischemic and non ischemic patients in the
general chest pain population. Many divalent metals bind
HSA in the circulation but in concentrations far lower
than that required to impact albumin directly. The N-ter-
minal portion of HSA is susceptible to biochemical degra-
dation and is less stable than the albumin of other spe-
cies.3) IMA is a form of HSA in which the N-terminal ami-

Received; March 30, 2009, Accepted; June 30, 2009

*To whom correspondence should be addressed: David C. GAZE, Department of Chemical Pathology, Clinical Blood Sciences, Level 0, Jenner
Wing, St George's Hospital, Blackshaw Road, London SW17 0QT, United Kingdom, Tel. ＋44(0)208 725 5878, Fax. ＋44(0)208 725 5868, E-mail:
david.gaze＠stgeorges.nhs.uk

333
334 David C. GAZE

Fig. 1. Postulated mechanism of IMA generation

Reduced blood flow due to ruptured atherosclerotic plaque results in insufficient oxygen to tissue (1) causing a lower pH (2). Copper (Cu＋＋)
is released from weak binding sites on plasma proteins (3). Metal bound at N-terminus. In the presence of ascorbic acid, Cu＋＋ is converted
to Cu＋ (4). Cu＋ reacts with oxygen to form superoxide radicals (O2－) (5). The enzyme superoxide dismutase (SOD) dismutates the O2－,
forming hydrogen peroxide (H2O2) (6). Normally, hydrogen peroxide is harmlessly degraded into water and oxygen by the action of a second
enzyme, catalase. However, in the presence of metals such as copper or iron, H2O2 undergoes a Fenton reaction, forming hydroxyl free rad-
icals (OH) (7). Free copper (Cu＋＋ ) is scavenged by HSA, on which it binds tightly to the N-terminus. OHis highlys reactive and capable of
damaging nucleic acids, lipids and proteins, including albumin. One site of damage is the N-terminus, where OHalters amino acids (8). Al-
tered albumin is incapable of binding to Cu＋＋. Bound copper is released from the albumin (9), where it may be taken up again by the N-termi-
nus of another albumin in a chain reaction so that the process of albumin binding and OH formation is repeated.

no acids are unable to bind to transition metals. My-
ocardial ischemia to generates free radicals;4,5) acidosis
develops6) and release of free iron and copper ions oc-
curs.7,8) HSA is a scavenger for divalent metal ions. It may
thus be postulated that in ischemia, these processes may
result in change in the ability of the N-terminus to bind
to transition metal ions (Fig. 1). The release of these ions
likely initiates one potential pathway for IMA generation
and thus need not be considered an interference to nega-
tively affect IMA. In support of this suggestion, decreased
albumin cobalt binding was reported in patients with
chest pain and myocardial ischemia9) and following coro-
nary artery angioplasty the baseline was resumed after six
hours.10) Using nuclear magnetic resonance spec-
troscopy, high-performance and liquid chromatography
combined with mass spectrometry, it was confirmed that
the N-terminal aspartate-alanine-histidine-lysine se-
quence binds to cobalt. Modification of this site by N-ter-
minal acetylation or deletion of one or more residues
abolishes this cobalt binding.11)
The postulated mechanism is that localised ischemia
results in acidosis and the release of copper II from weak
binding sites on circulating proteins. In the presence of a
reducing agent such as ascorbic acid, free copper II is
converted to copper I which reacts with oxygen to form
copper II and generate superoxide free radicals. Su-
peroxide dismutase converts the superoxide free radicals
to hydrogen peroxide which is then degraded by catalase.
Copper II ions released are immediately scavenged by al-
bumin but are tightly bound to the N terminus. Copper
bound albumin is then damaged by hydroxyl free radi-
cals, causing removal of the three N terminal amino acids
and release of copper II ions to repeat the process in a
chain reaction.12) This postulated mechanism, although
theoretically attractive, has not been borne out in prac-
tice. In a study of patients with increased IMA, the N-ter-
minal portion of albumin was sequenced in 8 cases. No
evidence of N-terminal degradation or truncation was
found.13) Recent physicochemical studies of cobalt bind-
ing to HSA suggest a different explanation. Three binding
sites for cobalt were identified, two of which showed
greater avidity than the N-terminal binding site.14) Fatty
acid binding to albumin occurs at one of the additional
cobalt binding sites with negative allosteric interaction.
Possibly, in myocardial ischemia the release of fatty acids
results in binding of fatty acids to albumin. This should
 IMA: A Novel Ischemia Marker
reduce the ability of albumin to take up cobalt and thus
account for the presence of IMA.14) If this produces a
conformational change in the albumin affecting the N
terminal site, reduced cobalt binding should occur.
IMA - A Marker, a Cause of Oxidative Stress?
There is a wealth of candidate biomarkers used to de-
termine the extent of oxidative stress, including lactate,
myeloperoxidase, nitric oxide, free fatty acids,
glutathione and thiobarbituric acid reactive substances
(TBARS). There is a lack of direct comparison between
IMA and oxidative stress markers. Senes and colleagues15)
have demonstrated a positive correlation between IMA
and TBARS (r＝0.276, p＝0.029) in patients with acute
ischaemic stroke. In the percutaneous coronary artery
angioplasty model, IMA is not correlated to lactate con-
centrations.16)
Advanced oxidation protein products (AOPP) are
generated by the oxidation of plasma proteins and along
with carbonyl residues are markers of oxidative protein
damage. Correlation of IMA to AOPP and carbonyl
residues has been performed in patients with scleroder-
ma.17) In patients with scleroderma, oxidative stress mar-
kers were elevated, but carbonyl residues and not AOPP
were correlated with IMA. AOPP is generated via a pro-
inflammatory mechanism in neurodegenerative diseases,
vascular calcification and renal failure. IMA, however, is
not a signal protein and not generated in a pro-inflamma-
tory state alone but is rather an end product of oxidative
stress. The association of AOPP and carbonyl residues
with respect to cardiovascular disease has not been inves-
tigated.
In normal human serum, neither H2O2 nor superoxide
anions produced change in IMA in vitro.18) Conversely
hydroxyl radicals generated by the Fenton reaction were
associated with a rapid rise in IMA. The addition of mer-
captopropionylglycine, a hydroxyl radical scavenger
resulted in attenuation of IMA. Furthermore, as Co2＋
may interfere in ACB assay; Co2＋ in the absence of
hydroxyl radicals does not alter the concentration of
IMA.18)
Like IMA, oxidative stress markers lack tissue specific-
ity and therefore their utility as diagnostic markers in the
general chest pain population is questionable. Although
IMA is implicated in oxidative stress mechanisms, it is
further downstream in the pathological process than
traditional markers such as those mentioned above and
may confer qreater cardiac specificity.
Kinetic Release of Ischemia Modified Albumin
Studies on patients receiving angioplasty where ische-
mia is induced in a controlled manner, have indicated the
kinetics of IMA production. There is rapid rise in IMA af-
ter balloon inflation with subsequent fall at 6 hours and
return to normal values by 24 hours.10,16) The rise in IMA
335
occurs earlier than rise in cardiac troponin and natriuret-
ic peptides (Fig. 2) The magnitude of IMA elevation has
been found correlated with the number and frequency of
balloon inflations during PCI,19) the number of collaterals
present,20) the need for subsequent revascularisation21)
and to parallel the transmyocardial lactate gradient.16)
Elevation has been recorded following coronary
vasospasm.22) Other studies involving invasive cardiac
procedures show rise in IMA where ischemia might oc-
cur, occurring concurrently to ECG changes in cardi-
oversion,23) but show variation when there is non-ischae-
mic myocardial damage such as cardiac ablation.24,25)
Half-life and Clearance of
Ischemia Modified Albumin
The half life of human serum albumin is 19–20 days. If
a slightly truncated form is responsible for generating
IMA, it would presumably have similar stability proper-
ties. IMA however returns to the baseline rapidly after an
ischaemic cardiac event. This indicates that alteration in
albumin is possibly transient and reversible, rather than a
definitive chemical alteration. However IMA may possi-
bly undergo preferential proteolytic degradation. There
are no data that focus specifically on IMA clearance apart
from in vivo kinetic studies in models of ischemia. This
warrants further investigation.
Clinical Studies using Ischemia Modified Albumin
Clinical validation of any test for ischemia is difficult
as there is no accepted diagnostic gold standard. In addi-
tion, there is no predicate test which can be used against
which initial validations can be performed. Initial studies
on IMA were based on the ability of early measurements
to predict a final diagnosis of AMI as defined by cardiac
troponin. Two studies utilized the pre-release ACB test,
the third an in-house method. The first study examined
acute coronary syndrome (ACS) patients and utilized seri-
al sampling on admission and two subsequent samples.26)
Diagnostic sensitivity of the admission sample for a final
diagnosis of AMI was 23.9% for cardiac troponin I (cTnI)
alone, 39.1% for IMA alone and 55.9% for the two com-
bined. The second study examined 256 ACS patients.27)
The area under the curve (AUC) of the receiver operator
characteristic (ROC) curve for the ACB test was 0.78
with a sensitivity and specificity of 83% and 69% respec-
tively at the optimised decision threshold for AMI. The
third study was conducted on 75 patients with ischemia
and 92 non-ischaemic patients.13) IMA had poor predic-
tive power in discriminating between AMI and non-AMI
in patients with underlying ischaemic heart disease (AUC
of 0.66). However, the test gave good discrimination be-
tween patients with or without ischemia. AUC for the
ROC curve for diagnosis of ischemia was 0.95 with a sen-
sitivity of 94% and specificity of 88%. In these initial stu-
dies, there were significant problems with sample stabili-
336
Fig. 2. Release kinetics of IMA in relation to standard cardiac biomarkers of necrosis (cardiac troponin, cTn) and dysfunction (B-
type natriuretic peptide, BNP)
Elevation of markers in relation to concentration not to scale.
ty and the assay involved the use of calcium chloride and
centrifugation as part of the routine. This made the
method unsuitable for routine analysis and the assay was
reformulated.
Most patients brought to the hospital with chest pain
and suspected of ACS are eventually ruled out for acute
myocardial infarction and active unstable coronary dis-
ease. The ideal role of an ischemia marker would thus be
as a rule out test. The most logical place to use such a test
is in the Emergency Department (ED). A study on ED
presentations examined 208 patients and the diagnostic
sensitivity of IMA measurement alone was 82% at 46%
specificity in samples taken within the first 3 hours. A
combination of ECG, cardiac troponin T (cTnT) and IMA
showed 95% sensitivity for diagnosis of ACS at presenta-
tion.28) One year follow up on this population demon-
strated a survival disadvantage in patients with IMA
greater than the median concentration of the study group
(Fig. 3).29) In a subsequent study on 538 patients admit-
ted for chest pain evaluation admission measurement of
IMA plus cTnT indicated 100% sensitivity for prediction
of a final diagnosis of AMI.30) The presence of elevated
IMA and elevated cTnT on admission predicted 21% risk
of major adverse cardiac events (MACE) compared to
patients for whom both were not elevated, even in
patients where the final diagnosis excluded AMI by
troponin based criteria. IMA measurement appears to
work best as part of other tests or a test sequence.31) Ad-
David C. GAZE
mission measurement of IMA has been found superior to
biomarkers of necrosis and to show 97% sensitivity when
combined with them. Not all investigators consider the
diagnostic performance of IMA either alone or in combi-
nation with cardiac troponin, or other biomarkers of
necrosis, to be adequate. A prospective ED study on 277
patients using a positive IMA or troponin as the index
test and 8 hour troponin as the definitive test found only
a 97.6% sensitivity with 97% negative predictive value.
This was not considered adequate compared to troponin
but no follow-up data were provided.32) A second large
study prospectively on 189 patients presenting ED with
chest pain indicated elevated IMA to be a poor predictor
of cardiac events within the next 72 hours.33) Conversely,
another study found elevated IMA to predict long-term
cardiac events.34) The most consistent finding in all stu-
dies of IMA was a high negative predictive value. This has
been highlighted in a recently published meta-analysis
specifically examining the role of IMA as a rule out
test.35)
Measuring Ischemia Modified Albumin
Measurement of IMA is done by albumin cobalt bind-
ing (ACB}) assay (Inverness Medical, Stockport, UK).
The assay measures cobalt binding capacity of albumin in
a sample. A known amount of cobalt is added to a patient
serum sample. Dithiothreitol (DTT) is added which binds
to any remaining unbound cobalt and colorimetric
 IMA: A Novel Ischemia Marker
Fig. 3. Kaplan-Meier survival analysis of all-cause mortality in chest pain patients stratified by IMA above and below the median
concentration
Adapted from ref. with permission from ref. 29.
change is measured spectrophotometrically. In serum
from non-ischaemic patients, cobalt binds to the N-termi-
nus of HSA, leaving little cobalt to react with DTT to
form a colored product. Conversely, in serum of patients
with ischemia, cobalt does not bind to the N-terminus of
modified HSA, leaving more free cobalt to react with
DTT to produce a darker colour. As normal albumin
binds to cobalt, the amount of free cobalt and hence ab-
sorbance will be proportional to IMA present.
The stability of IMA has been shown to be two hours
at 4oC or 209C, but values increase significantly after
four hours irrespective of storage temperature.36) It is
likely that change is due to in vitro pH change that would
alter the metal binding capacity of albumin. Samples
frozen at －209 C are stable although values have been
reported slightly higher compared to freshly analysed
samples.37)
A reference range study on 109 subjects (55 men and
54 women; age range, 20–85 years) to determine the
95th percentile reference range for IMA has been per-
formed27) based on the first generation of the assay. Fur-
ther studies on healthy subjects report higher IMA
ranges.31,38) The biological variation of IMA has been stu-
died.39) Gender differences in IMA amongst healthy in-
dividuals do not occur but IMA is statistically different
between Caucasian and Black populations.
Albumin values may be expected to affect IMA meas-
urement. There is a relationship between IMA and serum
albumin levels although this is much less marked across
the reference interval for albumin.40) The use of an albu-
min adjusted correction has been proposed38,41) although
a reference interval study found albumin correction to
337
have little impact compared to other analytical factors.38)
Changes in IMA observed in patients with chest pain may
be attributable only to changes in the albumin concentra-
tion.42)
Assessment of the Cardiospecificity of
Ischemia Modified Albumin
The specificity of IMA has been studied in clinical situ-
ations (Table 1). Studies of patients with skeletal muscle
ischemia have produced contradictory results. In healthy
subjects undergoing arduous physical exertion, IMA has
been reported to fall immediately post exercise and then
subsequently rise43–45) or return to normal.46) Subjects un-
dergoing a forearm ischemia test (forearm muscles are
exercised for 1 minute with blood supply interrupted by
external compression) showed a fall in IMA, maximal at
3 minutes from the test, returning to baseline by 30
minutes.47) Similar rise in serum lactate occurred. Con-
versely, during calf muscle ischemia, a rise in IMA, peak-
ing at 30 minutes occurred.48) Peri-operative skeletal
muscle ischemia induced by a tourniquet was followed by
rise in IMA.49) Patients with peripheral vascular disease
(PVD) undergoing a treadmill walk test demonstrate
decrease in IMA immediately post test,50,51) as do patients
undergoing exercise electrocardiography with a fall at
peak exercise and then subsequent rise.52) However,
revascularisation for PVD is accompanied by post
procedural rise in IMA.50,51,53) In skeletal muscle ische-
mia, an initial fall with subsequent rise appears a consis-
tent finding without adequate explanation. Smooth mus-
cle ischemia does not appear associated with rise in
IMA.54) The effects of skeletal muscle on ischemia limit
338 David C. GAZE

Table 1. IMA elevations under conditions other than cardiac which should be researched. The mechanism for genera-
ischemia tion should be the subject of future research. The assay
% with IMA Median IMA needs to be studied combined with recently developed
Disease group N À85 KU/L* KU/L ultra-sensitivity cardiac troponins but the lack of
PVD 11 9.1 73.6 cardiospecificity remains the biggest barrier for clinical
GERD, Crohn's disease 37 18.9 74.9 use. IMA may be enormously valuable to the emergency
CHF and valve disease 52 19 74.7 physician assessing chest pain patients but we require a
Trauma 15 20.0 76.35 better understanding on this marker before it is ready for
Autoimmune disease 72 34.7 79.0 prime time use.
Hypoxia 22 36.4 79.7
Hemorrhagic or ischemic stroke 44 54.5 85.4 Acknowledgments: The author expresses sincere
End-stage renal disease 21 57.1 86.0 thanks to Dr. Hollie Huff, Inverness Medical for valuable
Infection 31 64.5 89.1 advice and discussion regarding Ischemia Modified Albu-
Cancer 31 71.0 91.9 min.
Cirrhosis of the liver 12 75.0 106.15 References
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