Ischemic Modified Albumin (IMA) as a Novel Marker for Ischemic Heart Disease and Surrogate Marker for Other High Oxidative -Ischemic Conditions

Nepal, Jaisawal, Guragain, Kafle, Mukkera, Ghimire, Simmonds, Harris, and Berger: Ischemic Modified Albumin (IMA) as a Novel Marker for Ischemic Heart Disease and Surrogate Marker for Other High Oxidative -Ischemic Conditions

Authors

INTRODUCTION

Acute myocardial infarction and ischemic cardiac conditions are one of the most difficult situations emergency physician has to deal in view of exercising clinical decisions regarding admission or discharge from the emergency department. Studies over past couple of years have shown that ischemia-modified albumin (IMA) is a biomarker of ischemia in several clinical scenarios and it is highly sensitive for the diagnosis of myocardial ischemia in patients presenting with symptoms of acute chest pain.1 It has been shown to increase in presence of myocardial ischemia associated with percutaneous coronary intervention (PCI) and is also high in conditions of high oxidative stress.2 However, little is known about its ability to diagnose ischemic cardiac conditions accurately and differentiate it from other ischemic conditions or predict future adverse outcomes in patients with positive markers presenting to the hospital. Emergency physicians utilize ischemia-modified albumin (IMA) for the diagnosis of myocardial ischemia as it improves the usefulness of standard cardiac biomarkers for the diagnosis of myocardial ischemia in the emergency department setting.3

Cardiac ischemia is the most common mechanisms underlying acute coronary syndrome (ACS).4,5 Ischemia modified albumin (IMA) is produced as a result of tissue ischemia and is present in blood in easily detectable concentrations.6,7 We thus decided to find out the utility of ischemia modified albumin (IMA) in patients suspected of acute coronary syndrome, its role to predict adverse outcome with high IMA and thus short and long-term prognostic significance of high ischemia modified albumin (IMA) during hospitalizations and for six months after discharge as this has not been studied previously. Since the relationship between ischemia modified albumin (IMA) and other conditions like stroke, inflammations etc. which could be grouped as non-cardiac ischemic events has not been clearly understood,7 we also analyzed relationship of the rise in IMA in other conditions as described below (stroke, sepsis, seizure, etc.).

MATERIALS AND METHODS

Total of 400 patients who presented with chest pain and subsequently were evaluated for ischemic heart disease were taken into the study. Retrospective chart reviews of these patients were done during 2006 and 2007. Few patients did not follow up and had inadequate data, thus 351 patients fulfilled criteria for final analysis and others were excluded. Local institutional review board (IRB) at Mercy Fitzgerald Hospital approved the study in January 2008 as per the protocol of the institution for any study.

Inclusion criteria included - All patients who were evaluated in the emergency department for coronary artery disease were included in the study. An exclusion criterion was frank ST elevation at the time of presentation. Data collections were done at Mercy Fitzgerald Hospital and final diagnosis was analyzed with reference to the utility of ischemic modified albumin (IMA) and troponin (TnT) as a cardiac biomarker and their prognostic significance. ST-segment elevation myocardial infarction (STEMI) was diagnosed if there was ST segment elevation >0.1mv in 2 or more contiguous leads with cardiac troponin (cTnT) >0.05ng/ml; non-ST-segment elevation myocardial infarction (NSTEMI) was diagnosed if EKG did not show ST-segment elevation and troponin (cTnT) was >0.05ng/ml. Patients were classified as atypical chest pain when i) a non-cardiac mechanism was confirmed as the cause of chest pain ii) troponin (cTnT) results were negative on serial sampling ( three samples six hours apart) iii) neither Electrocardiogram (EKG) changes nor evidence of coronary artery disease were present. Other conditions contributing rise in ischemic modified albumin (IMA) were also analyzed on the basis of final discharge diagnosis. Primary outcome measures were cardiac events and secondary outcomes included- need of cardiac interventions, days of hospitalizations, course in the hospital including arrhythmias and deaths, disposition from hospital, readmission in next six months.

Statistical analysis

Statistical software SPSS version 16.0 for windows (SPSS, Chicago, IL, USA) and analyse-it for Microsoft Excel version 2.09 (www.analyseit.com) were used for analysis. Receivers operating characteristic (ROC) curves were plotted for ischemia-modified albumin (IMA). Positive troponin value was considered >0.05ng/ml and IMA >95 IU/L. Sensitivity, Specificity, Positive and Negative predictive values calculated. Chi Square and two tailed students t-test were used where required. Significant levels were taken as p≤0.05.

RESULTS

Final analysis was done in 351 subjects who fulfilled requirements for analysis. Males and females were 173 (49.3%) and 178 (50.7%) respectively. African Americans 189 (53.8%) was the majority followed by Caucasians 143(40.7%), Hispanic 15(4.3%), and Asian 4(1.1%) populations. The area under the ROC curve for ischemia-modified albumin (IMA) was 0.753±SE0.98 (95% CI 0.56- 0.945). At optimum level of 95.5 IU/L, sensitivity and specificity was 80% and 50% respectively. Similarly positive and negative predictive values calculated for ischemia modified albumin (IMA) alone were 18% and 88% respectively. Age, sex, race and previous interventions including cardiac catherizations with or without stents and coronary artery bypass surgery did not have influence in ischemia modified albumin (IMA) values. Highest values of ischemia-modified albumin (IMA) were found in non-cardiac conditions (Table 1) like sepsis (mean±SD) 148±17.68, Cholecystitis 118±23.92,venous thromboembolism 112±13.87,Seizure 111±0.01, etc. Five people with borderline ST elevation at presentation were finally considered to have definite ST-elevation myocardial infarction showed even less ischemia modified albumin (IMA) values possibly because the ischemia might have already occurred and infarction might have ensued. Rise in ischemia-modified albumin (IMA) alone did not influence cardiovascular outcomes including need of interventions like stress tests, cardiac catherizations, stenting and coronary artery bypass surgery. People with higher troponins showed more arrhythmias than higher IMAs (p=0.000) (table2). Death was higher in people with high ischemia modified albumin (IMA) and Troponin T (TnT) level (p=0.000). People with higher ischemia modified albumin (IMA) showed more hospitalization days (p=0.025) and had more readmissions in next six months (p=0.02). They also require nursing homes or skilled nursing facility on discharge from the hospital due to higher disability and dispositions needs like rehabilitation and safety.

DISCUSSION

Our study for the first time has highlighted the novel biomarker has many potential utilities including diagnosing many conditions , differentiating ischemic heart disease from non-ischemic and even prognostic value. High levels of ischemia modified albumin (IMA) clearly predicted adverse outcomes in patients namely increasing hospitalization days, requiring nursing home and skilled nursing facility for safe discharges, more morbidity and mortality and even poorer prognosis even after six months as they had high readmission rates. These findings complement7-9 and expand the findings in the earlier study by Consumer-Sanchez et al10 for predicting short-term prognosis and 1-year mortality for the first time and the study by Sinha et al6 that people with high ischemia modified albumin (IMA) should be followed up carefully during hospitalization and post-discharge.

There have been very little studies assessing the prognostic value of ischemia-modified albumin (IMA). Recently Consuegra-Sanchez et al10 prospectively studied 207 patients presenting to emergency department with chest pain within 3 hours of onset of pain. Ischemia modified albumin (IMA) was obtained on admission. 30-day combined end points including cardiac death, myocardial infarction, recurrent angina and 1-year all-cause mortality was evaluated. People with higher IMA above 93.3U/ml showed higher short-term end points (20.4%Vs 9.6%) and higher 1-year mortality rate (11.7% vs 3.8%) that High ischemia modified albumin (IMA) was independent predictor of both of these outcomes. Meta-analysis done by Peacock et al11 had also shown that triple negative prediction test of ischemia modified albumin (IMA), electrocardiogram and troponin measured within 3 hours of chest pain had not only have high negative predictive value for excluding acute coronary syndrome but also was cost-effective and did have better 30-day and 6-month outcomes.

Collinson et al4 reported outcomes in 446 patients at six months with low risk acute chest pain. In this study people with known coronary artery disease, significant electrocardiogram changes and unstable angina were excluded; the percentage of events was only 3.8% with 6 cardiac deaths. Relative risk of events was higher in those with high Troponin (cTnT) and ischemia modified albumin (IMA) (21%) versus negative ischemia modifies albumin (IMA) plus troponin (cTnT) (1.5%) but neither ischemia modified albumin (IMA) nor troponin (cTnT) alone were predictive of events as in Peacock’s meta-analysis.11

Dusek et al12 reported in 60 patients with stable angina pectoris who underwent elective percutaneous intervention (PCI) that a median follow up of 46 months, people with higher ischemia modified albumin (IMA) (>130 U/L) was found to be associated with higher target vessel revascularization rate in the univariate analysis though there were no death or myocardial infarctions noted. This shows ischemia modified albumin (IMA) may be a useful marker to predict further need of re-intervention after percutaneous intervention or revascularization (PCI).

However, Worster et al9 evaluated 189 patients with chest pain within 6 hours of onset of symptoms. Using cutoff ischemia modified albumin (IMA) of 80 U/ml, they documented 24 serious adverse outcomes at 72 hours including death, myocardial infarction (MI), congestive heart failure (CHF), and refractory chest pain. They had maximum sensitivity of 92.3% and specificity of 24.3% suggesting ischemia-modified albumin (IMA) to be a poor predictor of serious cardiac events in the short term. The long-term prognostic role of ischemia modified albumin (IMA) was evaluated by Sharma et al13 in a sample of 114 renal transplant candidates. They found that ischemia modified albumin (IMA) and troponin (cTnT) combined not alone were independent predictors of death. Ischemia modified albumin (IMA) above 95 U/ml predicted long-term mortality with a sensitivity of 75% and a specificity of 72%.

Ischemia modified albumin (IMA) test does predict early about the cardiac ischemia.14-16 and is a good prognostic marker in chronic ischemic heart failure 16 and Coronary artery bypass graft surgery (CABG).17 This is positive in a variety of conditions giving rise to tissue ischemia.18,19 Our study highlights the importance of evaluating patient populations for testing as more false positive elevations in ischemia modified albumin was found in different conditions while evaluating for ischemic heart disease including cholecystitis, pericarditis, pancreatitis, stroke, seizures and pulmonary thromboembolic phenomena.20,21,22,23,24,25,26 Ischemia modified albumin may thus be used as a surrogate marker in those conditions but more prospective detailed studies are required in the future. It can be utilized as a rule out test rather than rule in test due to high negative predictive value along with electrocardiogram (EKG) and troponin (cTnT) to increase sensitivity and specificity. It alone did not have clear edge over troponin (cTnT) in predicting cardiac arrhythmias, heart failure or need of interventions, probably because troponins are more specific and indicate injury and ischemia modified albumin (IMA) only early ischemia.27 Our study seems in concordance with all the other studies available in the literature and shows similar role of ischemia-modified albumin (IMA).

Table 1

Final Diagnosis in the Study Population

Diagnosis Atypical CP N=133 (39.3%)IMA (Mean±SD) 95.19±11.09TnT (Mean±SD) 0.03±0.03
COPD Asthma N=42(12%)95.67±11.230.0119±0.0U)
Coronary Artery Disease N=40 (11.4%)97.93±16.100.056±0.174
GERD Gastritis N=35 (10%)101.11±19.410.034±0.42
CI T N- 3 3 (9.4%)103.58 ± 115.840.99±5.46
Pneumonia N=16 (4.6%)97.31±17.530.0164±0.024
Cocain abuse N=7(2%)95.294-17.90.011-60.003
Anemia N=6(1.7%)93.33±16.330.03±0.04
TIA Stroke N=5(1.4%)99.2±10.130.01±0.00
DVT PE N=5(1.4%)112±13.370.03±0.044
STEM E N=5(1.4%)93.40±3.2640.324±1.65
Cholelithiasistholecystitis N=5(1.4%)113±23.920.01±0.00
Sepsis N=2(0.6%)143±17.6730.013±0.002
Takotsubo N=2(0.6%)96.5±6.360.13±0.24
DC 42N-2(0.6%)94-1.410.06±0.07
Rhabdomyolysis N=2(0.6%)90z5.650.01±0.00
SW N-2(0.6%)34±5.650.067±0.017
Pancreatitis N=1(0.3%)1000.21
Perirarditic N=1(0 3%)103001
Accelerated HTN N=1(0.3%)950.01
Seizure N=1(0.3%)111±0.010.01±0.00
Table 2

Final results (NH-nursing home, SNF-Skilled Nursing Facility, NS-non-significant, CTA- CT angiography)

Outcome VariablesNumber (% of total )IMA (mean±SD)TnT (mean±SD)P value (significant <0.05)
Course /Arrythmia NoYes18(5.1%)95.83±11.390.26±0.890.000
328(93.4%)97.95±14.760.04±0.16NS 
Death 5 (1.4%)104.4±28.646.32±14.030.000
Hospitalization ( Days)< 5 days295 (84%)97.02±13.660.15±1.830.025
5–9 days44(12.5%)103.36±16.550.11±0.570.025
>10 days12(3.4%)100.50±28.240.06±0.080.025
DispositionHome307(87.7%)96.13±12.490.04±0.17NS
NH/SNF38(10.9%)111.95±21.530.14±0.610.000
Readmission (in next 6 months)Yes81(23.1%)101.20±SE1.890.08±SE0.050.02
No270(76.9%)96.96±SE0.850.16±SE0.120.7
InterventionsNo219(69.4%)97.97±15.840.18±2.130.5
Cath29(8.3%)94.48±8.650.07±0.12NS
Stress47(13.4%)98.98±14.940.10±0.550.5
Echo53(15.1%)98.85±13.170.02±0.020.5
CT A (angio)2(0.6%)104.5±9.190.10±0.130.5

Study limitations

Our study was retrospective and was conducted in a single teaching center, which may limit the generalizability of the results. In our study, time of onset of symptoms was also variable from few minutes to hours; this might need caution in interpretation to general population. However, this is the first report of its kind which not only shows its definite usefulness in utilizing it as a novel biomarker in cardiac ischemia and other oxidative conditions but also prognostic implications of high ischemia modified albumin (IMA) in other conditions, namely to find who needs more hospitalization days, will need better dispositions along with their poor outcomes in next six months. Nonetheless, this has yet to be confirmed with randomized large-scale randomized trials before larger applications into the general population.

CONCLUSION

There were no statistical significant differences in predicting cardiovascular endpoints by ischemia modified albumin (IMA) test as compared to troponin (cTnT) alone. As ischemia modified albumin had more negative predictive value, it could be utilized in combination with electrocardiogram and troponin in discharging patients from emergency departments. Troponin did predict significant arrhythmias than ischemia modified albumin (IMA) but people with higher ischemia modified albumin (IMA) test did show more hospitalization days, needing skilled nursing facility on discharge and more readmissions as compared to troponin that was statistically significant. It has also shown its potential role as a surrogate marker in predicting ischemic stroke and severity of sepsis. However more prospective and elaborate studies are required before it can be utilized in any other areas as a surrogate marker. Finally, high ischemia modified albumin (IMA) may help identifying patients with short and long term poor prognosis other than only diagnosis of ischemic heart disease. Thus we recommend that people with high ischemia modified albumin (IMA) on arrival to the emergency department should be evaluated and followed up carefully even if electrocardiogram (EKG) and troponin (cTnT) are negative for ischemic heart disease for possible other etiologies of high oxidative stress and potential for long term poor outcomes.

ACKNOWLEDGEMENT

We would like to acknowledge everybody who helped during the study. Special thanks go to Zachareas Berhane, statistician who helped in evaluating the data and Dr Ajay Kumar, Dr Arif Shaik, Dr Arnold Eiser helping in preparing the manuscript.

Notes

[1] Conflicts of interest CONFLICT OF INTEREST The authors are declared no conflict of interest.

ABBREVIATION USED

ACS

Acute coronary syndrome

ED

Emergency Department

EKG

Electrocardiogram

CTA

CT angiogram

IMA

Ischemia modified albumin

STEMI

ST elevated myocardial infarction

NSTEMI

Non-ST elevated myocardial infarction.

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