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Ischaemia modified albumin in the diagnosis of acute coronary syndromes
Resuscitation 80 (2009) 306–310
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Review article
Ischaemia modified albumin in the diagnosis of acute coronary syndromes夽 Ioannis Pantazopoulos a , Lila Papadimitriou a , Ismene Dontas a , Theano Demestiha b , Nikoleta Iakovidou c , Theodoros Xanthos a,∗ a
University of Athens, Medical School, Department of Experimental Surgery and Surgical Research, Athens, Greece University of Athens, Medical School, Department of Anatomy, Athens, Greece c University of Athens, Medical School, Neonatal Division, 2nd Department of Obstetrics and Gynecology, Athens, Greece b
a r t i c l e
i n f o
Article history: Received 12 July 2008 Received in revised form 10 September 2008 Accepted 29 October 2008 Keywords: Ischaemia modified albumin Albumin cobalt binding test Acute coronary syndromes
a b s t r a c t The early diagnosis of acute coronary syndrome remains problematic, despite recent improvements. Traditionally, the diagnosis of acute cardiac ischaemia relies on the combination of chest pain, electrocardiographic changes and elevation of serum markers. Troponins are currently the “gold standard” test for the detection of myocardial necrosis, but they are unsuitable for early diagnosis, as nearly 50% of patients may present to the emergency department with non-diagnostic concentrations. Ischaemia modified albumin increases within minutes after the onset of ischaemia, remains elevated for 6 to 12 h, and returns to normal within 24 h. Thus, it may be a valuable aid for the clinician enabling early detection of ischaemia before the development of myocardial necrosis. Its high sensitivity comes at the expense of a lower specificity because its increase may be due to ischaemia of other tissues such as gastrointestinal tissues or skeletal muscles tissues. This paper has focuses on the cardiology aspect of this biomarker, underlying its potential value in the emergency department. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic difficulties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischaemia modified albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IMA and transient myocardial ischaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IMA, ECG, current biomarkers and the final diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischaemia modified albumin in non-coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction The triage and treatment of patients who present to emergency departments (EDs) with symptoms potentially indicative of acute cardiac ischaemia remain problematic and continue to challenge clinicians. More than 6 million patients present annually to US EDs with suspected acute coronary syndromes (ACS) of whom only 17% are finally diagnosed with coronary disease. Patients are hospitalised or held for observation and although ACS is often ruled out,
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2008.10.035. ∗ Corresponding author at: 15B Agiou Thoma Street, 11527 Athens, Greece. E-mail address: [email protected] (T. Xanthos). 0300-9572/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2008.10.035
this imposes a substantial financial burden and inconvenience to the patient and medical system.1–3 In the early 1980s, 3.8% of patients with acute myocardial infarction were sent home inappropriately. A more recent study showed that 2.1% of patients with acute myocardial infarction (AMI) and 2.3% of patients with unstable angina were erroneously discharged from the EDs. Non-hospitalised patients with AMI had a three times higher risk of death than those who were hospitalised.3,4 Failure to recognise ACS has unfavourable consequences not only for patients, but for physicians too. Missed acute cardiac ischaemia continues to be one of the major causes of malpractice litigation against emergency physicians. Twenty percent of ED-related malpractice compensation is expended to patients with complications because of myocardial ischaemia.1 The large number of patients
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Table 1 Cut-off values for IMA from five studies. Optimum IMA cut-off point 11
Anwarrudin et al. , 90 U/ml Christenson et al.30 , 75 U/ml Lee et al.46 , 85 U/ml Roy et al.2 , 93.5 U/ml Sinha et al.24 , 85 U/ml
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Area under the ROC curve
80 83 93 75 82
31 69 35.6 74.6 46
16 33 39.6 – 59
92 96 91.8 75.8 72
0.63 0.78 0.76 0.78 0.68
PPV, positive predictive value; NPV, negative predictive value; ROC, receiver operating characteristic.
presenting to EDs with symptoms suggestive of ACS, and the medical and legal consequences of an erroneous discharge from the ED, demand that clinicians pursue new diagnostic approaches to ACS.5 Diagnostic difficulties The diagnostic approach to ACS remains one of the most difficult and controversial medical challenges. Traditionally, the diagnosis of acute cardiac ischaemia relies on the combination of chest pain, electrocardiographic (ECG) changes and serum markers’ elevation. Clinical symptoms and characteristic ECG alterations have been useful tools in the diagnosis of AMI.6 However, symptoms may be non-specific in up to one-third of chest pain patients, and the ECG misses up to 50% of the patients who have had an AMI.7–9 Hence, the diagnosis of ACS has become increasingly dependent on serum markers of myocardial injury.10 The first markers of AMI such as creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) have a low specificity and their detection in the blood stream cannot guarantee myocardial involvement. The discovery of assays that could measure the CK-MB isoenzyme improved specificity and sensitivity, but values may be normal at presentation in up to one half of patients with AMI.11 Since an early and accurate diagnosis can improve outcome, researchers reported on biochemical markers that are rapidly released after myocardial injury. Myoglobin, a muscle protein, appeared promising as an early marker of myocardial injury, as it increases 3–4 h after the appearance of symptoms, but it is less cardiospecific than CK-MB and disappears rapidly from the blood stream.10 Troponins are nowadays the “gold standard” test for the detection of myocardial necrosis. They have greater sensitivity and specificity than any other biomarker for the diagnosis of myocardial infarction. Very low concentrations of troponins can be detected and this means that even very small myocardial injuries can be recognised. Although troponins have great sensitivity, they are unsuitable for early diagnosis, as nearly 50% of patients may present at EDs with non-diagnostic concentrations. This happens either because patients present early after the onset of AMI and troponin is not yet detectable or because patients present with acute myocardial ischaemia without necrosis.12 Patients with myocardial ischaemia pose a greater challenge than patients with AMI because the patient may have acute chest pain, a non-diagnostic ECG and normal levels of all the aforementioned biomarkers. Thus, despite the fact that patients with myocardial ischaemia are at high risk for subsequent coronary events, they often get discharged because there is not enough evidence to justify hospital admission. Furthermore, the sensitivity of necrosis markers is time dependent and they often give false negative results at presentation to the ED. Hence, the usefulness of the standard biomarkers of myocardial necrosis for the early and confident exclusion of the diagnosis of myocardial ischaemia is limited. New markers capable of identifying early myocardial ischaemia before it progresses to the irreparable myocardial cell damage might play an important role in the clinical setting because they will give the emergency physician the opportunity to intervene and prevent progression to infarction.10,13,14
Therefore, the ideal biochemical marker of myocardial ischaemia should be released solely from the myocardium and should achieve high concentrations and rapid release into the blood stream at the time of ischaemia. Furthermore, its concentrations should be related to the extent of injury and should be detectable in the blood for long enough to be measured even in late-presenting patients. Another feature of the ideal biochemical marker is a steep decrease after a period of 24 h, so that recurrent ischaemia can easily be detected. The test should also be rapid, easy and cheap.12 Ischaemia modified albumin A modification of human serum albumin (HSA) caused by ischaemia has been recently proposed as a serum biomarker of myocardial ischaemia. Under physiological conditions, the amino terminal end (N-terminal) of HSA binds transitional metals such as cobalt, copper and nickel. During ischaemia several changes occur in the amino terminal end (N-terminus) of HSA, possibly caused by oxidative free radicals, which reduces its capacity to bind transition metals, notably cobalt. This new, chemically changed albumin is called ischaemia modified albumin (IMA).14,15 A recent study that correlated IMA with levels of melatonin in ST segment elevation infarction (STEMI) patients supports the suspicion that reactive oxygen species may be responsible for the creation of IMA.16 Approximately 1–2% of the total albumin concentration in the normal population is IMA compared to 6–8% in patients experiencing ischaemia. IMA is detected by the albumin cobalt binding (ACB) test. The test provides results in about 30 min.17 Investigations are ongoing for the discovery of an immunoassay.18,19 Various studies have shown that IMA increases within minutes after the onset of ischaemia, remains elevated for 6–12 h, and returns to normal within 24 h.10,15 Thus, it may be a valuable aid for the clinician because it enables early detection of ischaemia before the development of myocardial necrosis. The optimum IMA cut-off value for ruling out ACS differs from study to study. Table 1 shows the sensitivity, specificity, positive and negative predictive value (NPV) as well as the area under the receiver operating characteristic curves at various cut-off points. IMA and transient myocardial ischaemia Many reports have demonstrated that percutaneous transluminal coronary angioplasty (PTCA) can be a useful in vivo model of mild transient myocardial ischaemia in humans.20–22 Therefore, Bar-or et al. measured IMA, CK-MB, myoglobin, and cardiac troponin I (cTnI) before, immediately after and 6 and 24 h after elective PTCA in 41 patients. The control group consisted of 13 patients that underwent diagnostic coronary angiography without PTCA. Albumin cobalt binding test results demonstrated a significant mean percent difference of 10.1% compared with baseline immediately after PTCA. At the same time, ACB assay values were also significantly higher than in the control group (10.1% versus −0.9%, p < 0.001). Mean CK-MB, myoglobin, and cTnI were not significantly increased immediately after PTCA, when compared with baseline levels, but were significantly elevated at 6 and 24 h later. This study demonstrated that IMA is an early marker of myocardial ischaemia
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in contrast with CK-MB, myoglobin and cTnI, which increase later after the onset of ischaemia.23 Ischaemia modified albumin concentrations were higher in patients with more balloon inflations, higher pressure inflations, and longer inflation duration, so IMA may also indicate the severity of ischaemia.24 Ischaemia modified albumin concentrations were also significantly lower in patients with collateral circulation compared with those without collateral circulation. The IMA concentration is extremely sensitive and reflects even the protective effect of the collateral circulation against PCI-induced ischaemia.25 In patients that underwent intracoronary ergonovine spasm provocation tests for the diagnosis of variant angina, IMA levels were elevated.26 IMA, ECG, current biomarkers and the final diagnosis Several studies have compared IMA values with ECG changes and current biomarkers in patients with myocardial ischaemia. Sinha et al. recorded a 12 lead ECG and collected blood for IMA and cardiac troponin T within 2 h of arrival in 208 patients that presented to the ED within 3 h of acute chest pain. A cardiologist determined that all patients had high initial clinical risk. The final diagnosis of non-ischaemic chest pain, unstable angina, STEMI and NSTEMI, was based on the history, clinical examination, serial cTnT results and data from medical records. These included results of ECG, exercise stress testing, perfusion scans, and coronary angiography, as available. The sensitivity of IMA at presentation (with a cut-off point of 85 U/ml) for the diagnosis of myocardial ischaemia was 82%, compared with 45% for the ECG and only 20% for cTnT. The combination of IMA and cTnT increased sensitivity to 90%, while combination of IMA and ECG raised sensitivity to 92%. When all three tests were combined, 95% of the patients with myocardial ischaemia were recognised.27 The role of IMA has been compared with standard biomarkers (myoglobin, CK-MB, TnI) in the assessment of 200 patients with ACS symptoms within 3 h of ED presentation.14 The clinical history, physical examination, ECG, cardiac biomarker values (other than IMA), and hospital course (including results of diagnostic studies such as cardiac catheterisation) were presented to a clinical cardiologist who was blinded to the values of IMA. A clinical diagnosis of ischaemia was assigned and correlated with biomarker test results. The albumin cobalt binding test proved to have 80% sensitivity for the diagnosis of myocardial ischaemia (with a cut-off point of 90 U/ml), while the combination of myoglobin, CK-MB and TnI had a sensitivity of 57%. When IMA was added to the diagnostic algorithm, sensitivity increased to 97%, with a NPV of 92%. A comparison of IMA levels with ECG changes in the same patient group showed that IMA was positive in four of five patients with ECG evidence of ischaemia (ST segment depression or elevation or a new LBBB) and 16 of 20 patients with coronary ischaemia, but negative ECG.14 These findings were confirmed by other investigators who correlated clinical diagnoses of myocardial ischaemia or non-myocardial ischaemia with results of IMA.28 Clinical assessment of myocardial ischaemia included several objective clinical indices, imaging studies, ECG studies, and serum cardiac biochemical markers (CK-MB, cTnI). The sensitivity and specificity of the ACB test for the detection of ischaemia were 88% and 94%, respectively, while positive and negative predictive values were 92% and 91%.28 Roy et al. studied 131 patients presenting to the ED with symptoms suggestive of ACS but with normal or non-diagnostic ECGs. All patients arrived to the ED within 3 h of the last episode of chest pain and had negative cTn results on admission to the ED. Cardiologists, unaware of IMA results, reviewed all the patients’ notes and hospital test results (ECG exercise stress testing, dobutamine stress echo and coronary angiography) to establish a final diagnosis of ACS or non-ischaemic chest pain. Ischaemia modified albumin
values were significantly higher in 64 patients with myocardial ischaemia compared with 67 patients with non-ischaemic cardiac pain (98.3 ± 11 versus 85.5 ± 15, p < 0.0001). At the optimum cut-off point of 93.5 U/ml, IMA had a sensitivity of 75% for the diagnosis of myocardial ischaemia. The combination of IMA (measured at presentation to the ED) and serial cTnT (6–12 h) increased sensitivity to 82.8%.2 Lee et al. studied 413 patients who had visited the ED for symptoms suspicious of ACS.29 The diagnosis of ACS or non-ACS was made by emergency medicine specialists and cardiologists and was based on the combination of clinical manifestation, ECG, cardiac markers, coronary angiography and echocardiography. The IMA results were unknown at the time of diagnosis. The IMA concentrations in the ACS group were significantly higher than those of the non-ACS group. Sensitivity and specificity of IMA for identifying ACS were 93% and 35.6%, respectively, and the negative and positive predictive values were 91.8% and 39.6%, respectively. The combination of myoglobin, CK-MB, and troponin T had a sensitivity of 80.2% and specificity 57% for the diagnosis of ACS. When IMA was included in the cardiac marker panel, sensitivity increased to 94.5% while specificity fell to 45.1%.29 Finally, Christenson et al., in an attempt to discover if IMA could be an early predictor of troponin I results, compared the results of IMA in the presentation sample of 224 patients with the results of a troponin test 6–24 h later. All patients arrived at the ED within 3 h of clinical signs and symptoms of ACS and had negative cTn at presentation. Patients were considered troponin positive if one or more cTnI values were above the upper reference limit within 6–24 h. With a cut-off point of 75 U/ml, ACB test had a sensitivity of 83%, specificity 69%, NPV 96% and PPV 33%. There were only six false negatives and 131 true negatives results. Christenson et al. suggested that IMA has a high NPV and sensitivity in the presentation sample for predicting troponin results 6–24 h later.30 A meta-analysis of more than 1800 patients concluded that in a large ED cohort with suspected myocardial ischaemia, the combination of ECG, troponin and IMA has 94.4% sensitivity and 97.1% negative predictive value for the final diagnosis.3 Ischaemia modified albumin in non-coronary syndromes Recognition that IMA is an early and sensitive marker of myocardial ischaemia gave clinicians the opportunity of new cardiology research. Measurements of cTnT have been used in the past to indicate that direct-current cardioversion (DCCV) does not cause cardiac damage.31 Roy et al. measured IMA concentrations in 24 patients before and at 1 and 6 h after DCCV for atrial fibrillation, to determine whether transient myocardial ischaemia occurs. Fourteen patients developed ECG changes (ST depression and/or T wave inversion). IMA results were elevated in all patients after DCCV from baseline and were significantly higher in patients who developed ST-T ECG changes. There was no significant increase in CK and cTnT after cardioversion. Roy et al. claimed that ECG changes and an increase in IMA levels suggest that DCCV may cause transient myocardial ischaemia.32 The extent of any myocardial injury that occurs during transvenous lead implantation for permanent pacemakers or implantable cardioverter defibrillators has been investigated.33–35 In 64 patients, compared with baseline, IMA values increased at 6 and 48 h after pacemaker insertion or defibrillator implantation. It was concluded that the myocardial injury was caused by ischaemia and not acute coronary events. 35 Discussion The ACB test can bring a new dimension to the care of patients with ACS. It may reduce the 6–24 h delay for a reliable
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Table 2 Test characteristics of IMA in combination with traditional diagnostic markers of ACS. Study 24
Sinha et al. Anwaruddin et al.11 Roy et al.2 Peacock et al.3 (meta-analysis) Lee et al.46
n
Combination of tests
Sensitivity (%)
Specificity (%)
NPV (%)
PPV (%)
208 200 131 1800 413
IMA, cTnT, ECG, IMA, cTnI, Myo, CK-MB IMA, cTnT IMA, cTn, ECG IMA, cTnT, Myo, CK-MB
95 97 82.8 94.4 94.5
42 – 74.6 – 45.1
84 92 82 97.1 94.6
74 – – – 44.6
PPV, positive predicted value; NPV, negative predictive value; ECG, electrocardiogram; cTnT, cardiac troponin T; cTnI, cardiac troponin I; IMA, ischaemia modified albumin; myo, myoglobin.
troponin-negative classification and it has an important role, alone or in combination with markers of necrosis, in reducing the inappropriate admission of low-risk patients.30 Table 2 shows test characteristics of IMA in combination with traditional diagnostic markers of ACS. Combining IMA with ECG and cTn has the highest NPV. A very high NPV is important because IMA would be able to help the emergency physician to identify the non-cardiac chest pain cases, which can then be shifted to low-risk areas.36 Concentrations of IMA are related significantly to left ventricular ejection function and represent an early marker of left ventricular dysfunction in patients with STEMI undergoing PCI.37 The IMA concentration can also be used for identifying the patient who has a high risk of subsequent cardiac events. In a study by Aparci et al., 50 ACS patients were followed for 1 year after the ischaemic event.38 In patients with IMA values above 477 U/ml, mortality was significantly higher than in those with values below 477 U/ml. The sensitivity and specificity for 1-year mortality at the cut-off point of 477 U/ml were 70% and 82%, respectively.38 The IMA concentration may also be useful as a discriminative marker to exclude pulmonary embolism and acute mesenteric ischaemia.39,40 It may also have a place in the early identification of acute stroke.41 There are limitations to the use of IMA values. It is not specific for cardiac ischaemia and there is anecdotal evidence which suggests that IMA increases in most patients with cirrhosis, bacterial and viral infections, advanced cancers, stroke, and end-stage renal disease.18 Furthermore, a decrease in IMA values has been documented after muscle ischaemia.42,43 It has been demonstrated (in vivo and in vitro) that an increase in lactate concentration, which occurs after a forearm ischaemia test (skeletal muscle ischaemia), decreases true IMA values and therefore the diagnostic sensitivity. Clinicians must be careful when interpreting IMA negative values in patients with uncontrolled diabetes, sepsis and renal failure, all of which are associated with increased lactate concentrations.42,43 Apple et al. found that in a group of 19 marathon runners, IMA values did not increase immediately after the race but increased significantly 24–48 h later. The ACB test results 24–48 h after the race were significantly higher than the values at baseline and immediately after the race. This was attributed to gastrointestinal ischaemia or a delayed response to skeletal muscle ischaemia.44 In patients with peripheral vascular disease, compared with baseline, IMA concentrations are significantly lower immediately after exercise-induced leg ischaemia.42 This decrease in IMA values or latent increase (that occurred in marathon runners) may potentially complicate use of the test in clinical practice. The relationship between IMA levels and exercise stress testing was investigated in 40 patients with established coronary artery disease. The IMA concentrations decreased significantly at peak exercise compared with baseline and returned to initial values after 60 min. This occurred similarly in both positive and negative exercise tests and it was concluded that IMA does not increase the diagnostic value of exercise stress testing.45 The ACB test is an indirect method of measurement. It is expected that the amount of cobalt able to bind to albumin
would be low at low serum albumin concentration (<20 g/l) and high at high albumin concentration (>55 g/l). An albumin adjusted marker, which includes the serum albumin concentration in the interpretation of IMA measurement, has been described.29,46 The albumin adjusted IMA marker = serum albumin concentration (g/dl) × 23 + IMA (U/ml) − 100. It has been suggested that an albumin-adjustment index should be established in each laboratory. Conclusion Failure to recognise ACS often has unfavourable consequences for patients and physicians. During ischaemia, the capability of HSA to bind transitional metals is modified and this can be used for the early detection of ischaemia in patients with chest pain. The IMA value may predict the onset of irreversible cardiac damage before irreversible injury.10 Many questions about IMA remain unanswered. The test is likely to be most valuable for ruling out ACS in low to moderate pre-test probability conditions with negative necrosis markers and a negative ECG. However, it is unclear if IMA testing will actually reduce the number of inappropriate admissions of low-risk patients. Its higher sensitivity comes at the expense of a lower specificity. Thus, although more patients with possible ischaemia may be identified, many will be admitted that do not have ischaemia. Thus, it might increase the number of patients admitted, in the same way that d-dimer testing increased the number of CT scans performed for pulmonary embolism.47–49 Further studies are required to investigate the role of IMA in cardiac and non-cardiac ischaemic diseases in the ED setting. An example is the international multicentre IMAGINE trial, which will evaluate IMA values in 1200 patients across five sites.3 Conflict of interest statement The authors of this manuscript have no conflict of interest to declare. References 1. Duseja R, Feldman JA. Missed acute cardiac ischemia in the ED: limitations of diagnostic testing. Am J Emerg Med 2004;22:219–25. 2. Roy D, Quiles J, Aldama G, et al. Ischemia modified albumin for the assessment of patients presenting to the emergency department with acute chest pain but normal or non-diagnostic 12-lead electrocardiograms and negative cardiac troponin T. Int J Cardiol 2004;97:297–301. 3. Peacock F, Morris DL, Anwaruddin S, et al. Meta-analysis of ischemia-modified albumin to rule out acute coronary syndromes in the emergency department. Am Heart J 2006;152:253–62. 4. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342:1163–70. 5. Montagnana M, Lippi G, Guidi GC. New perspectives in the diagnostic approach to acute coronary syndrome. Recenti Prog Med 2005;96:171–7. 6. Rajappa M, Sharma A. Biomarkers of cardiac injury: an update. Angiology 2005;56:677–91. 7. Green GB. Green SF markers of myocardial injury in the evaluation of the emergency department patient with chest pain. In: Wu AHB, editor. Cardiac markers. Totawa, NJ: Humana Press; 1998. p. 75–89. 8. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
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I. Pantazopoulos et al. / Resuscitation 80 (2009) 306–310 (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1996;28:1328–428. Christenson RH, Azzazy HME. Biochemical markers of the acute coronary syndromes. Clin Chem 1998;44:1855–64. Lippi G, Montagnana M, Salvagno GL, Guidi GC. Potential value for new diagnostic markers in the early recognition of acute coronary syndromes. CJEM 2006;8:27–31. Karras DJ, Kane DL. Serum markers in the emergency department diagnosis of acute myocardial infarction. Emerg Med Clin North Am 2001;19:321–37. Morrow DA, de Lemos JA, Sabatine MS, Antman EM. The search for a biomarker of cardiac ischemia. Clin Chem 2003;49:537–9. Lippi G, Montagnana M, Guidi GC. Albumin cobalt binding and ischemia modified albumin generation: an endogenous response to ischemia? Int J Cardiol 2006;108:410–1. Anwaruddin S, Januzzi Jr JL, Baggish AL, Lewandrowski EL, Lewandrowski KB. Ischemia modified albumin improves the usefulness of standard cardiac biomarkers for the diagnosis of myocardial ischemia in the emergency department setting. Am J Clin Pathol 2005;123:140–5. Worster A, Devereaux PJ, Heels-Ansdell D, et al. Capability of ischemia modified albumin to predict serious cardiac outcomes in the short term among patients with potential acute coronary syndrome. CMAJ 2005;172:1685–90. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Samimi-Fard S, Reiter RJ, Kaski JC. Association of ischemia-modified albumin and melatonin in patients with ST-elevation myocardial infarction. Atherosclerosis 2008;199:73–8. Kumar A, Sivakanesan R, Gunasekera S. Ischemia modified albumin: a potent marker in acute myocardial infarction in normolipidaemic. Pak J Med Sci 2008;24:364–7. Carreiro-Lewandowski E. Update on cardiac biomarkers. Lab Med 2006;37: 598–605. Apple FS, Wu AH, Mair J, et al. Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clin Chem 2005;51:810–24. Bush HS, Ferguson 3rd JJ, Angelini P, Willerson JT. Twelve-lead electrocardiographic evaluation of ischemia during percutaneous transluminal coronary angioplasty and its correlation with acute reocclusion. Am Heart J 1991;121:1591–9. Dellborg M, Emanuelsson H, Swedberg K. Silent myocardial ischemia during coronary angioplasty. Cardiology 1993;82:325–34. Bertinchant JP, Polge A, Ledermann B, et al. Relation of minor cardiac troponin I elevation to late cardiac events after uncomplicated elective successful percutaneous transluminal coronary angioplasty for angina pectoris. Am J Cardiol 1999;84:51–7. Bar-or D, Winkler JV, Vanbenthuysen K, Harris L, Lau E, Hetzel FW. Reduced albumin-cobalt binding with transient myocardial ischemia after elective percutaneous transluminal coronary angioplasty: a preliminary comparison to creatine kinase-MB, myoglobin, and troponin I. Am Heart J 2001;141:985–91. Quiles J, Roy D, Gaze D, et al. Relation of ischemia-modified albumin (IMA) levels following elective angioplasty for stable angina pectoris to duration of ballooninduced myocardial ischemia. Am J Cardiol 2003;92:322–4. Garrido IP, Roy D, Calvino R, et al. Comparison of ischemia modified albumin levels in patients undergoing percutaneous coronary intervention for unstable angina pectoris with versus without coronary collaterals. Am J Cardiol 2004;93:88–90. Cho DK, Choi JO, Kim SH, et al. Ischemia-modified albumin is a highly sensitive serum marker of transient myocardial ischemia induced by coronary vasospasm. Coron Artery Dis 2007;18:83–7. Sinha MK, Roy D, Gaze DC, Collinson PO, Kaski JC. Role of “Ischemia Modified Albumin”, a new biochemical marker of myocardial ischaemia, in the early diagnosis of acute coronary syndromes. Emerg Med J 2004;21:29–34. Bhagavan NV, Lai EM, Rios PA, et al. Evaluation of human serum albumin cobalt binding assay for the assessment of myocardial ischemia and myocardial infarction. Clin Chem 2003;49:581–5.
29. Lee YW, Kim HJ, Cho YH, Shin HB, Choi TY, Lee YK. Application of albuminadjusted ischemia modified albumin index as an early screening marker for acute coronary syndrome. Clin Chim Acta 2007;384:24–7. 30. Christenson RH, Duh SH, Sanhai WR, et al. Characteristics of an Albumin Cobalt Binding Test for assessment of acute coronary syndrome patients: a multicenter study. Clin Chem 2001;47:464–70. 31. Rao AC, Naeem N, John C, Collinson PO, Canepa-Anson R, Joseph SP. Direct current cardioversion does not cause cardiac damage: evidence from cardiac troponin T estimation. Heart 1998;80:229–30. 32. Roy D, Quiles J, Sinha M, Aldama G, Gaze D, Kaski JC. Effect of direct-current cardioversion on ischemia-modified albumin levels in patients with atrial fibrillation. Am J Cardiol 2004;93:366–8. 33. Dworschak M, Franz M, Khazen C, Czerny M, Haisjackl M, Hiesmayr M. Mechanical trauma as the major cause of troponin T release after transvenous implantation of cardioverter/defibrillators. Cardiology 2001;95:212–4. 34. Nikolaou N, Spanodimos S, Tsaglis E, et al. Biochemical evidence of cardiac damage following transvenous implantation of a permanent antibradycardia pacemaker lead. Pacing Clin Electrophysiol 2005;28:1174–81. 35. Sbarouni E, Georgiadou P, Panagiotakos D, Livanis E, Theodorakis GN, Kremastinos DT. The ischemia modified albumin in relation to pacemaker and defibrillator implantation. Pacing Clin Electrophysiol 2008;31:83–7. 36. Chawla R, Navendu G, Rajneesh C, Shweta G. Ischemia modified albumin: a novel marker for acute coronary syndrome. Ind J Clin Biochem 2006;21:77–82. 37. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Samimi-Fard S, Kaski JC. Relation of ischemia-modified albumin levels and left ventricular systolic function in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Clin Chim Acta 2008;388:196–9. 38. Aparci M, Kardesoglu E, Ozmen N, et al. Prognostic significance of ischemiamodified albumin in patients with acute coronary syndrome. Coron Artery Dis 2007;18:367–73. 39. Turedi S, Gunduz A, Mentese A, et al. Value of ischemia modified albumin in the diagnosis of pulmonary embolism. Am J Emerg Med 2007;25:770–3. 40. Gunduz A, Turedi S, Mentese A, et al. Ischemia-modified albumin in the diagnosis of acute mesenteric ischemia: a preliminary study. Am J Emerg Med 2008;26:202–5. 41. Abboud H, Labreuche J, Meseguer E, et al. Ischemia-modified albumin in acute stroke. Cerebrovasc Dis 2007;23:216–20. 42. Roy D, Quiles J, Sharma R, et al. Ischemia-modified albumin concentrations in patients with peripheral vascular disease and exercise-induced skeletal muscle ischemia. Clin Chem 2004;50:1656–60. 43. Zapico-Muniz E, Santalo-Bel M, Merce-Muntanola J, Montiel JA, MartinezRubio A, Ordonez-Llanos J. Ischemia-modified albumin during skeletal muscle ischemia. Clin Chem 2004;50:1063–5. 44. Apple FS, Quist HE, Otto AP, Mathews WE, Murakami MM. Release characteristics of cardiac biomarkers and ischemia-modified albumin as measured by the albumin cobalt-binding test after a marathon race. Clin Chem 2002;48:1097–100. 45. Sbarouni E, Georgiadou P, Theodorakis GN, Kremastinos DT. Ischemia modified albumin in relation to exercise stress testing. J Am Coll Cardiol 2006;48: 2482–4. 46. Lippi G, Montagnana M, Salvagno GL, Guidi GC. Standardization of ischemiamodified albumin testing: adjustment for serum albumin. Clin Chem Lab Med 2007;45:261–2. 47. Lebrun E, Maitre B, Grenier-Sennelier C, et al. Effect of D-dimer testing on the diagnostic strategy of suspected pulmonary embolism: an observational study of practice patterns and costs. Eur Radiol 2000;10:433–4. 48. Kabrhel C, Matts C, Mc Namara M, Katz J, Ptak T. A highly sensitive ELISA D-dimer increases testing but not diagnosis of pulmonary embolism. Acad Emerg Med 2006;13:519–24. 49. Goldstein NM, Kollef MH, Ward S, Gage BF. The impact of the introduction of a rapid D-dimer assay on the diagnostic evaluation of suspected pulmonary embolism. Arch Intern Med 2001;161:567–71.
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Review article
Ischaemia modified albumin in the diagnosis of acute coronary syndromes夽 Ioannis Pantazopoulos a , Lila Papadimitriou a , Ismene Dontas a , Theano Demestiha b , Nikoleta Iakovidou c , Theodoros Xanthos a,∗ a
University of Athens, Medical School, Department of Experimental Surgery and Surgical Research, Athens, Greece University of Athens, Medical School, Department of Anatomy, Athens, Greece c University of Athens, Medical School, Neonatal Division, 2nd Department of Obstetrics and Gynecology, Athens, Greece b
a r t i c l e
i n f o
Article history: Received 12 July 2008 Received in revised form 10 September 2008 Accepted 29 October 2008 Keywords: Ischaemia modified albumin Albumin cobalt binding test Acute coronary syndromes
a b s t r a c t The early diagnosis of acute coronary syndrome remains problematic, despite recent improvements. Traditionally, the diagnosis of acute cardiac ischaemia relies on the combination of chest pain, electrocardiographic changes and elevation of serum markers. Troponins are currently the “gold standard” test for the detection of myocardial necrosis, but they are unsuitable for early diagnosis, as nearly 50% of patients may present to the emergency department with non-diagnostic concentrations. Ischaemia modified albumin increases within minutes after the onset of ischaemia, remains elevated for 6 to 12 h, and returns to normal within 24 h. Thus, it may be a valuable aid for the clinician enabling early detection of ischaemia before the development of myocardial necrosis. Its high sensitivity comes at the expense of a lower specificity because its increase may be due to ischaemia of other tissues such as gastrointestinal tissues or skeletal muscles tissues. This paper has focuses on the cardiology aspect of this biomarker, underlying its potential value in the emergency department. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic difficulties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischaemia modified albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IMA and transient myocardial ischaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IMA, ECG, current biomarkers and the final diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischaemia modified albumin in non-coronary syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction The triage and treatment of patients who present to emergency departments (EDs) with symptoms potentially indicative of acute cardiac ischaemia remain problematic and continue to challenge clinicians. More than 6 million patients present annually to US EDs with suspected acute coronary syndromes (ACS) of whom only 17% are finally diagnosed with coronary disease. Patients are hospitalised or held for observation and although ACS is often ruled out,
夽 A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2008.10.035. ∗ Corresponding author at: 15B Agiou Thoma Street, 11527 Athens, Greece. E-mail address: [email protected] (T. Xanthos). 0300-9572/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.resuscitation.2008.10.035
this imposes a substantial financial burden and inconvenience to the patient and medical system.1–3 In the early 1980s, 3.8% of patients with acute myocardial infarction were sent home inappropriately. A more recent study showed that 2.1% of patients with acute myocardial infarction (AMI) and 2.3% of patients with unstable angina were erroneously discharged from the EDs. Non-hospitalised patients with AMI had a three times higher risk of death than those who were hospitalised.3,4 Failure to recognise ACS has unfavourable consequences not only for patients, but for physicians too. Missed acute cardiac ischaemia continues to be one of the major causes of malpractice litigation against emergency physicians. Twenty percent of ED-related malpractice compensation is expended to patients with complications because of myocardial ischaemia.1 The large number of patients
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Table 1 Cut-off values for IMA from five studies. Optimum IMA cut-off point 11
Anwarrudin et al. , 90 U/ml Christenson et al.30 , 75 U/ml Lee et al.46 , 85 U/ml Roy et al.2 , 93.5 U/ml Sinha et al.24 , 85 U/ml
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Area under the ROC curve
80 83 93 75 82
31 69 35.6 74.6 46
16 33 39.6 – 59
92 96 91.8 75.8 72
0.63 0.78 0.76 0.78 0.68
PPV, positive predictive value; NPV, negative predictive value; ROC, receiver operating characteristic.
presenting to EDs with symptoms suggestive of ACS, and the medical and legal consequences of an erroneous discharge from the ED, demand that clinicians pursue new diagnostic approaches to ACS.5 Diagnostic difficulties The diagnostic approach to ACS remains one of the most difficult and controversial medical challenges. Traditionally, the diagnosis of acute cardiac ischaemia relies on the combination of chest pain, electrocardiographic (ECG) changes and serum markers’ elevation. Clinical symptoms and characteristic ECG alterations have been useful tools in the diagnosis of AMI.6 However, symptoms may be non-specific in up to one-third of chest pain patients, and the ECG misses up to 50% of the patients who have had an AMI.7–9 Hence, the diagnosis of ACS has become increasingly dependent on serum markers of myocardial injury.10 The first markers of AMI such as creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) have a low specificity and their detection in the blood stream cannot guarantee myocardial involvement. The discovery of assays that could measure the CK-MB isoenzyme improved specificity and sensitivity, but values may be normal at presentation in up to one half of patients with AMI.11 Since an early and accurate diagnosis can improve outcome, researchers reported on biochemical markers that are rapidly released after myocardial injury. Myoglobin, a muscle protein, appeared promising as an early marker of myocardial injury, as it increases 3–4 h after the appearance of symptoms, but it is less cardiospecific than CK-MB and disappears rapidly from the blood stream.10 Troponins are nowadays the “gold standard” test for the detection of myocardial necrosis. They have greater sensitivity and specificity than any other biomarker for the diagnosis of myocardial infarction. Very low concentrations of troponins can be detected and this means that even very small myocardial injuries can be recognised. Although troponins have great sensitivity, they are unsuitable for early diagnosis, as nearly 50% of patients may present at EDs with non-diagnostic concentrations. This happens either because patients present early after the onset of AMI and troponin is not yet detectable or because patients present with acute myocardial ischaemia without necrosis.12 Patients with myocardial ischaemia pose a greater challenge than patients with AMI because the patient may have acute chest pain, a non-diagnostic ECG and normal levels of all the aforementioned biomarkers. Thus, despite the fact that patients with myocardial ischaemia are at high risk for subsequent coronary events, they often get discharged because there is not enough evidence to justify hospital admission. Furthermore, the sensitivity of necrosis markers is time dependent and they often give false negative results at presentation to the ED. Hence, the usefulness of the standard biomarkers of myocardial necrosis for the early and confident exclusion of the diagnosis of myocardial ischaemia is limited. New markers capable of identifying early myocardial ischaemia before it progresses to the irreparable myocardial cell damage might play an important role in the clinical setting because they will give the emergency physician the opportunity to intervene and prevent progression to infarction.10,13,14
Therefore, the ideal biochemical marker of myocardial ischaemia should be released solely from the myocardium and should achieve high concentrations and rapid release into the blood stream at the time of ischaemia. Furthermore, its concentrations should be related to the extent of injury and should be detectable in the blood for long enough to be measured even in late-presenting patients. Another feature of the ideal biochemical marker is a steep decrease after a period of 24 h, so that recurrent ischaemia can easily be detected. The test should also be rapid, easy and cheap.12 Ischaemia modified albumin A modification of human serum albumin (HSA) caused by ischaemia has been recently proposed as a serum biomarker of myocardial ischaemia. Under physiological conditions, the amino terminal end (N-terminal) of HSA binds transitional metals such as cobalt, copper and nickel. During ischaemia several changes occur in the amino terminal end (N-terminus) of HSA, possibly caused by oxidative free radicals, which reduces its capacity to bind transition metals, notably cobalt. This new, chemically changed albumin is called ischaemia modified albumin (IMA).14,15 A recent study that correlated IMA with levels of melatonin in ST segment elevation infarction (STEMI) patients supports the suspicion that reactive oxygen species may be responsible for the creation of IMA.16 Approximately 1–2% of the total albumin concentration in the normal population is IMA compared to 6–8% in patients experiencing ischaemia. IMA is detected by the albumin cobalt binding (ACB) test. The test provides results in about 30 min.17 Investigations are ongoing for the discovery of an immunoassay.18,19 Various studies have shown that IMA increases within minutes after the onset of ischaemia, remains elevated for 6–12 h, and returns to normal within 24 h.10,15 Thus, it may be a valuable aid for the clinician because it enables early detection of ischaemia before the development of myocardial necrosis. The optimum IMA cut-off value for ruling out ACS differs from study to study. Table 1 shows the sensitivity, specificity, positive and negative predictive value (NPV) as well as the area under the receiver operating characteristic curves at various cut-off points. IMA and transient myocardial ischaemia Many reports have demonstrated that percutaneous transluminal coronary angioplasty (PTCA) can be a useful in vivo model of mild transient myocardial ischaemia in humans.20–22 Therefore, Bar-or et al. measured IMA, CK-MB, myoglobin, and cardiac troponin I (cTnI) before, immediately after and 6 and 24 h after elective PTCA in 41 patients. The control group consisted of 13 patients that underwent diagnostic coronary angiography without PTCA. Albumin cobalt binding test results demonstrated a significant mean percent difference of 10.1% compared with baseline immediately after PTCA. At the same time, ACB assay values were also significantly higher than in the control group (10.1% versus −0.9%, p < 0.001). Mean CK-MB, myoglobin, and cTnI were not significantly increased immediately after PTCA, when compared with baseline levels, but were significantly elevated at 6 and 24 h later. This study demonstrated that IMA is an early marker of myocardial ischaemia
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in contrast with CK-MB, myoglobin and cTnI, which increase later after the onset of ischaemia.23 Ischaemia modified albumin concentrations were higher in patients with more balloon inflations, higher pressure inflations, and longer inflation duration, so IMA may also indicate the severity of ischaemia.24 Ischaemia modified albumin concentrations were also significantly lower in patients with collateral circulation compared with those without collateral circulation. The IMA concentration is extremely sensitive and reflects even the protective effect of the collateral circulation against PCI-induced ischaemia.25 In patients that underwent intracoronary ergonovine spasm provocation tests for the diagnosis of variant angina, IMA levels were elevated.26 IMA, ECG, current biomarkers and the final diagnosis Several studies have compared IMA values with ECG changes and current biomarkers in patients with myocardial ischaemia. Sinha et al. recorded a 12 lead ECG and collected blood for IMA and cardiac troponin T within 2 h of arrival in 208 patients that presented to the ED within 3 h of acute chest pain. A cardiologist determined that all patients had high initial clinical risk. The final diagnosis of non-ischaemic chest pain, unstable angina, STEMI and NSTEMI, was based on the history, clinical examination, serial cTnT results and data from medical records. These included results of ECG, exercise stress testing, perfusion scans, and coronary angiography, as available. The sensitivity of IMA at presentation (with a cut-off point of 85 U/ml) for the diagnosis of myocardial ischaemia was 82%, compared with 45% for the ECG and only 20% for cTnT. The combination of IMA and cTnT increased sensitivity to 90%, while combination of IMA and ECG raised sensitivity to 92%. When all three tests were combined, 95% of the patients with myocardial ischaemia were recognised.27 The role of IMA has been compared with standard biomarkers (myoglobin, CK-MB, TnI) in the assessment of 200 patients with ACS symptoms within 3 h of ED presentation.14 The clinical history, physical examination, ECG, cardiac biomarker values (other than IMA), and hospital course (including results of diagnostic studies such as cardiac catheterisation) were presented to a clinical cardiologist who was blinded to the values of IMA. A clinical diagnosis of ischaemia was assigned and correlated with biomarker test results. The albumin cobalt binding test proved to have 80% sensitivity for the diagnosis of myocardial ischaemia (with a cut-off point of 90 U/ml), while the combination of myoglobin, CK-MB and TnI had a sensitivity of 57%. When IMA was added to the diagnostic algorithm, sensitivity increased to 97%, with a NPV of 92%. A comparison of IMA levels with ECG changes in the same patient group showed that IMA was positive in four of five patients with ECG evidence of ischaemia (ST segment depression or elevation or a new LBBB) and 16 of 20 patients with coronary ischaemia, but negative ECG.14 These findings were confirmed by other investigators who correlated clinical diagnoses of myocardial ischaemia or non-myocardial ischaemia with results of IMA.28 Clinical assessment of myocardial ischaemia included several objective clinical indices, imaging studies, ECG studies, and serum cardiac biochemical markers (CK-MB, cTnI). The sensitivity and specificity of the ACB test for the detection of ischaemia were 88% and 94%, respectively, while positive and negative predictive values were 92% and 91%.28 Roy et al. studied 131 patients presenting to the ED with symptoms suggestive of ACS but with normal or non-diagnostic ECGs. All patients arrived to the ED within 3 h of the last episode of chest pain and had negative cTn results on admission to the ED. Cardiologists, unaware of IMA results, reviewed all the patients’ notes and hospital test results (ECG exercise stress testing, dobutamine stress echo and coronary angiography) to establish a final diagnosis of ACS or non-ischaemic chest pain. Ischaemia modified albumin
values were significantly higher in 64 patients with myocardial ischaemia compared with 67 patients with non-ischaemic cardiac pain (98.3 ± 11 versus 85.5 ± 15, p < 0.0001). At the optimum cut-off point of 93.5 U/ml, IMA had a sensitivity of 75% for the diagnosis of myocardial ischaemia. The combination of IMA (measured at presentation to the ED) and serial cTnT (6–12 h) increased sensitivity to 82.8%.2 Lee et al. studied 413 patients who had visited the ED for symptoms suspicious of ACS.29 The diagnosis of ACS or non-ACS was made by emergency medicine specialists and cardiologists and was based on the combination of clinical manifestation, ECG, cardiac markers, coronary angiography and echocardiography. The IMA results were unknown at the time of diagnosis. The IMA concentrations in the ACS group were significantly higher than those of the non-ACS group. Sensitivity and specificity of IMA for identifying ACS were 93% and 35.6%, respectively, and the negative and positive predictive values were 91.8% and 39.6%, respectively. The combination of myoglobin, CK-MB, and troponin T had a sensitivity of 80.2% and specificity 57% for the diagnosis of ACS. When IMA was included in the cardiac marker panel, sensitivity increased to 94.5% while specificity fell to 45.1%.29 Finally, Christenson et al., in an attempt to discover if IMA could be an early predictor of troponin I results, compared the results of IMA in the presentation sample of 224 patients with the results of a troponin test 6–24 h later. All patients arrived at the ED within 3 h of clinical signs and symptoms of ACS and had negative cTn at presentation. Patients were considered troponin positive if one or more cTnI values were above the upper reference limit within 6–24 h. With a cut-off point of 75 U/ml, ACB test had a sensitivity of 83%, specificity 69%, NPV 96% and PPV 33%. There were only six false negatives and 131 true negatives results. Christenson et al. suggested that IMA has a high NPV and sensitivity in the presentation sample for predicting troponin results 6–24 h later.30 A meta-analysis of more than 1800 patients concluded that in a large ED cohort with suspected myocardial ischaemia, the combination of ECG, troponin and IMA has 94.4% sensitivity and 97.1% negative predictive value for the final diagnosis.3 Ischaemia modified albumin in non-coronary syndromes Recognition that IMA is an early and sensitive marker of myocardial ischaemia gave clinicians the opportunity of new cardiology research. Measurements of cTnT have been used in the past to indicate that direct-current cardioversion (DCCV) does not cause cardiac damage.31 Roy et al. measured IMA concentrations in 24 patients before and at 1 and 6 h after DCCV for atrial fibrillation, to determine whether transient myocardial ischaemia occurs. Fourteen patients developed ECG changes (ST depression and/or T wave inversion). IMA results were elevated in all patients after DCCV from baseline and were significantly higher in patients who developed ST-T ECG changes. There was no significant increase in CK and cTnT after cardioversion. Roy et al. claimed that ECG changes and an increase in IMA levels suggest that DCCV may cause transient myocardial ischaemia.32 The extent of any myocardial injury that occurs during transvenous lead implantation for permanent pacemakers or implantable cardioverter defibrillators has been investigated.33–35 In 64 patients, compared with baseline, IMA values increased at 6 and 48 h after pacemaker insertion or defibrillator implantation. It was concluded that the myocardial injury was caused by ischaemia and not acute coronary events. 35 Discussion The ACB test can bring a new dimension to the care of patients with ACS. It may reduce the 6–24 h delay for a reliable
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Table 2 Test characteristics of IMA in combination with traditional diagnostic markers of ACS. Study 24
Sinha et al. Anwaruddin et al.11 Roy et al.2 Peacock et al.3 (meta-analysis) Lee et al.46
n
Combination of tests
Sensitivity (%)
Specificity (%)
NPV (%)
PPV (%)
208 200 131 1800 413
IMA, cTnT, ECG, IMA, cTnI, Myo, CK-MB IMA, cTnT IMA, cTn, ECG IMA, cTnT, Myo, CK-MB
95 97 82.8 94.4 94.5
42 – 74.6 – 45.1
84 92 82 97.1 94.6
74 – – – 44.6
PPV, positive predicted value; NPV, negative predictive value; ECG, electrocardiogram; cTnT, cardiac troponin T; cTnI, cardiac troponin I; IMA, ischaemia modified albumin; myo, myoglobin.
troponin-negative classification and it has an important role, alone or in combination with markers of necrosis, in reducing the inappropriate admission of low-risk patients.30 Table 2 shows test characteristics of IMA in combination with traditional diagnostic markers of ACS. Combining IMA with ECG and cTn has the highest NPV. A very high NPV is important because IMA would be able to help the emergency physician to identify the non-cardiac chest pain cases, which can then be shifted to low-risk areas.36 Concentrations of IMA are related significantly to left ventricular ejection function and represent an early marker of left ventricular dysfunction in patients with STEMI undergoing PCI.37 The IMA concentration can also be used for identifying the patient who has a high risk of subsequent cardiac events. In a study by Aparci et al., 50 ACS patients were followed for 1 year after the ischaemic event.38 In patients with IMA values above 477 U/ml, mortality was significantly higher than in those with values below 477 U/ml. The sensitivity and specificity for 1-year mortality at the cut-off point of 477 U/ml were 70% and 82%, respectively.38 The IMA concentration may also be useful as a discriminative marker to exclude pulmonary embolism and acute mesenteric ischaemia.39,40 It may also have a place in the early identification of acute stroke.41 There are limitations to the use of IMA values. It is not specific for cardiac ischaemia and there is anecdotal evidence which suggests that IMA increases in most patients with cirrhosis, bacterial and viral infections, advanced cancers, stroke, and end-stage renal disease.18 Furthermore, a decrease in IMA values has been documented after muscle ischaemia.42,43 It has been demonstrated (in vivo and in vitro) that an increase in lactate concentration, which occurs after a forearm ischaemia test (skeletal muscle ischaemia), decreases true IMA values and therefore the diagnostic sensitivity. Clinicians must be careful when interpreting IMA negative values in patients with uncontrolled diabetes, sepsis and renal failure, all of which are associated with increased lactate concentrations.42,43 Apple et al. found that in a group of 19 marathon runners, IMA values did not increase immediately after the race but increased significantly 24–48 h later. The ACB test results 24–48 h after the race were significantly higher than the values at baseline and immediately after the race. This was attributed to gastrointestinal ischaemia or a delayed response to skeletal muscle ischaemia.44 In patients with peripheral vascular disease, compared with baseline, IMA concentrations are significantly lower immediately after exercise-induced leg ischaemia.42 This decrease in IMA values or latent increase (that occurred in marathon runners) may potentially complicate use of the test in clinical practice. The relationship between IMA levels and exercise stress testing was investigated in 40 patients with established coronary artery disease. The IMA concentrations decreased significantly at peak exercise compared with baseline and returned to initial values after 60 min. This occurred similarly in both positive and negative exercise tests and it was concluded that IMA does not increase the diagnostic value of exercise stress testing.45 The ACB test is an indirect method of measurement. It is expected that the amount of cobalt able to bind to albumin
would be low at low serum albumin concentration (<20 g/l) and high at high albumin concentration (>55 g/l). An albumin adjusted marker, which includes the serum albumin concentration in the interpretation of IMA measurement, has been described.29,46 The albumin adjusted IMA marker = serum albumin concentration (g/dl) × 23 + IMA (U/ml) − 100. It has been suggested that an albumin-adjustment index should be established in each laboratory. Conclusion Failure to recognise ACS often has unfavourable consequences for patients and physicians. During ischaemia, the capability of HSA to bind transitional metals is modified and this can be used for the early detection of ischaemia in patients with chest pain. The IMA value may predict the onset of irreversible cardiac damage before irreversible injury.10 Many questions about IMA remain unanswered. The test is likely to be most valuable for ruling out ACS in low to moderate pre-test probability conditions with negative necrosis markers and a negative ECG. However, it is unclear if IMA testing will actually reduce the number of inappropriate admissions of low-risk patients. Its higher sensitivity comes at the expense of a lower specificity. Thus, although more patients with possible ischaemia may be identified, many will be admitted that do not have ischaemia. Thus, it might increase the number of patients admitted, in the same way that d-dimer testing increased the number of CT scans performed for pulmonary embolism.47–49 Further studies are required to investigate the role of IMA in cardiac and non-cardiac ischaemic diseases in the ED setting. An example is the international multicentre IMAGINE trial, which will evaluate IMA values in 1200 patients across five sites.3 Conflict of interest statement The authors of this manuscript have no conflict of interest to declare. References 1. Duseja R, Feldman JA. Missed acute cardiac ischemia in the ED: limitations of diagnostic testing. Am J Emerg Med 2004;22:219–25. 2. Roy D, Quiles J, Aldama G, et al. Ischemia modified albumin for the assessment of patients presenting to the emergency department with acute chest pain but normal or non-diagnostic 12-lead electrocardiograms and negative cardiac troponin T. Int J Cardiol 2004;97:297–301. 3. Peacock F, Morris DL, Anwaruddin S, et al. Meta-analysis of ischemia-modified albumin to rule out acute coronary syndromes in the emergency department. Am Heart J 2006;152:253–62. 4. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342:1163–70. 5. Montagnana M, Lippi G, Guidi GC. New perspectives in the diagnostic approach to acute coronary syndrome. Recenti Prog Med 2005;96:171–7. 6. Rajappa M, Sharma A. Biomarkers of cardiac injury: an update. Angiology 2005;56:677–91. 7. Green GB. Green SF markers of myocardial injury in the evaluation of the emergency department patient with chest pain. In: Wu AHB, editor. Cardiac markers. Totawa, NJ: Humana Press; 1998. p. 75–89. 8. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
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