|Year : 2015 | Volume
| Issue : 2 | Page : 65-70
Ischemia modified albumin in myocardial infarction and its correlation with selected acute phase reactants
Neepa Chowdhury1, Angshuman De2, Rabindra Bhattacharya3, Indranil Chakraborty4
1 Department of Biochemistry, Central Laboratory, Suraksha Diagnostic Private Limited, Saltlake, Kolkata, India
2 Department of Biochemistry, Murshidabad Medical College, Berhampore, Murshidabad, India
3 Department of General Medicine, College of Medicine and JNM Hospital, Kalyani, India
4 Department of Biochemistry, Malda Medical College and Hospital, Malda, West Bengal, India
|Date of Web Publication||30-Jul-2015|
Building Name Anamika, Flat No. 6, P-68, Subodh Park, P.S.+P.O. Bansdroni, Kolkata - 700 070, West Bengal
Source of Support: Department of Biochemistry, Medical College and Hospital, Kolkata, Department of Cardiology, Medical College and Hospital, Kolkata, Conflict of Interest: None
Background: There is evidence that ischemia modified albumin increases (IMA) in acute coronary syndrome, but enough work has not been done in assessing the correlation between IMA and inflammatory markers in myocardial infarction (MI).
Objective: The objective of the present study was to observe whether IMA would significantly be altered in MI patients and also whether the same would be correlated with selected acute phase reactants.
Methods: The present hospital based, noninterventional, cross-sectional study was undertaken in Medical College and Hospital, Kolkata. Fifty cases of acute MI (AMI) and 50 suitable controls were enrolled for the study. Serum IMA, serum albumin, serum total cholesterol, serum high-sensitivity C-reactive protein (hsCRP), serum ceruloplasmin and serum transferrin were measured in blood from the study population.
Results: Serum IMA and hsCRP (P < 0.0005) were significantly higher in cases whereas serum transferrin (P < 0.0005) and albumin (P < 0.005) were significantly lower in cases as compared to controls. In cases, IMA was found to be positively correlated (r = 0.470, P = 0.001) with hsCRP, one of the common markers of inflammation in AMI. Serum IMA, hsCRP and transferrin play a significant role (P < 0.05) in assessing the severity of inflammation.
Conclusion: Serum IMA was altered in AMI patients and positive correlation was obtained between IMA and positive acute phase reactant hsCRP. This study encourages future studies probing the role of inflammation in the causation of MI.
Keywords: Albumin, high-sensitivity C-reactive protein, ischemia modified albumin, myocardial infarction, transferrin
|How to cite this article:|
Chowdhury N, De A, Bhattacharya R, Chakraborty I. Ischemia modified albumin in myocardial infarction and its correlation with selected acute phase reactants. Nig J Cardiol 2015;12:65-70
|How to cite this URL:|
Chowdhury N, De A, Bhattacharya R, Chakraborty I. Ischemia modified albumin in myocardial infarction and its correlation with selected acute phase reactants. Nig J Cardiol [serial online] 2015 [cited 2020 Sep 27];12:65-70. Available from: http://www.nigjcardiol.org/text.asp?2015/12/2/65/152028
| Introduction|| |
Acute coronary syndromes (ACSs) represent a continuum of disease ranging from unstable angina (UA), associated with reversible myocardial cell injury, to frank ST-segment elevation myocardial infarction (STEMI) with large areas of necrosis. In the majority of patients presenting with ACSs,  the thrombus is partially obstructive or only transiently occlusive, resulting in coronary ischemia without persistent ST-segment elevation (UA or non-ST-elevation MI).  In the remaining 30% of patients with ACS, the intracoronary thrombus completely occludes the culprit vessel, resulting in STEMI. The contribution of inflammation to the pathogenesis of ACS  has attained increasing recognition as evident from changes in the level of acute-phase reactants, the nonspecific markers of inflammation.  Furthermore, increased concentrations of the acute-phase reactant high-sensitivity C-reactive protein (hsCRP) appear to be predictive of higher risk for long-term cardiovascular morbidity/mortality in patients with ACS.  This potential predictive capacity of hsCRP warrants further evaluation alone and in conjunction with other positive acute phase reactant ceruloplasmin as well as the negative acute phase reactants (transferrin, albumin, and total cholesterol). ,
Several biomarkers of myocardial ischemia are under investigation. Serum ischemia modified albumin (IMA) is among the most thoroughly studied of these markers and has been approved by the US Food and Drug Administration for clinical use. , Previous studies have shown that , IMA which is considered for use in conjunction with electrocardiogram (ECG) and cardiac troponins for exclusion of ACS,  increases in stable as well as UA but enough work has not been done in assessing the correlation between IMA and inflammatory markers in MI. Though we have gained substantial information regarding these individual parameters, enough work has not been done in assessing the correlation between these parameters. The present study was designed to assess whether correlation existed between the cobalt binding property of albumin and positive (serum hsCRP and serum ceruloplasmin) and negative (serum albumin, serum transferrin and serum total cholesterol) acute phase reactants in MI. The authors hypothesized that inflammation may not modify the cobalt binding property of albumin in patients with MI.
The aim of the present study was to observe whether IMA would significantly be altered in MI patients and also whether it would be correlated with the positive (serum hsCRP and serum ceruloplasmin) and the negative (serum albumin, serum transferrin and serum total cholesterol) acute phase reactants.
| Materials and methods|| |
The present study was a hospital-based, noninterventional, cross-sectional case control study. This work was undertaken in the Department of Biochemistry of Medical College and Hospital, Kolkata in collaboration with the Department of Cardiology, Medical College and Hospitals, Kolkata, West Bengal from May 2009 to May 2010.
Totally, 50 cases (the mean standard deviation [SD] for age is 59.64 [8.15] years) including 21 women attending the cardiology and emergency department diagnosed to have MI were selected on the basis of clinical features and ECG changes. Clinical features included chest pain lasting for >30 min, diaphoresis.
ST-segment elevation acute MI (AMI) was defined as persistent ST-segment elevation of ≥1 mm in 2 contiguous ECG leads or the presence of a new left bundle branch block in the setting of positive cardiac enzyme results. 
Non-STEMI was defined as the occurrence of AMI in the setting of positive cardiac enzyme results with or without accompanying ECG changes other than ST-segment elevation. 
Similarly, 50 age and sex matched apparently healthy individuals (the mean [SD] for age is 58.73 [7.89] years) including 23 women were selected from the relatives of patients attending the cardiology department.
The cases and controls were selected by a simple random method. All the cases and controls were informed about the purpose of the study and written consent for inclusion in the study and for the publication of the study report was obtained. The study was approved by a properly Constituted Institutional Ethical Committee of Medical College, Kolkata.
Five milliliter venous blood was collected from the median antecubital vein of the subjects within 3 h of their admission and from controls using standard aseptic technique and the collected clotted blood was centrifuged at 1500 rpm speed for 3-5 min. All the tests were done with serum harvested from clotted blood. The assays were performed on fresh samples.
Serum IMA was measured by adding a known amount of cobalt (II) to serum sample and the unbound cobalt (II) was measured by intensity of the colored complex formed by adding mercaptoethanol by colorimeter at 470 nm. One unit of IMA was defined as "mg of free Co (II) in the reaction mixture per mL of serum sample." The IMA was measured by the method described by Christenson et al.  and modified in Biochemistry Department of Medical College and Hospital (intra-assay coefficient of variation [CV%] was 4.81% [0.0151/0.32]). CV% was calculated by measuring cobalt binding activity of albumin of 20 samples, dividing the SD by mean value and expressed in percentage. Serum albumin was measured by bromo cresol green dye binding method  by XL-600 Auto analyzer (Transasia) (Intra-assay CV was 1.55% [0.067/4.33]). Serum total cholesterol was estimated by cholesterol oxidase and peroxidase method  (Intra-assay CV was 2.21% [3.1/139.90]).
Serum hsCRP, (Intra-assay CV was 4.77% [0.13/2.72]) was estimated by standard kits utilizing the immunoturbidimetric method. 
Serum ceruloplasmin (Intra-assay CV was 2.5% [0.011/0.44]) and serum transferrin (Intra-assay CV was 2.6% [0.0702/2.70]) were measured by standard kits utilizing the nephelometric method  in BN prospec nephelometer.
Data analysis was performed using SPSS statistical analysis software (SPSS version 17.0, Chicago, IL, USA). Statistically, significant difference was determined by the Student's t-test. All P values are two-sided, with values <0.05 considered significant. Correlation coefficients were calculated according to the Brave-Pearson function. The six parameters measured were examined whether they exhibit any bivariate and partial correlation.
| Results|| |
[Table 1] displays all the results of the two groups. Results are displayed in the form of mean (SD). It displays the results of unpaired t-test for equality of means of the control population and diagnosed cases of MI. From [Table 1], it was observed that serum IMA (P < 0.0005), serum ceruloplasmin (P = 0.014) and serum hsCRP (P < 0.0005) were significantly higher in individuals with MI relative to controls. Furthermore, serum albumin (P = 0.002) and serum transferrin (P < 0.0005) were significantly less in MI cases as compared to controls. No significant difference in serum cholesterol levels was observed between the two groups (P = 0.975).
|Table 1: Group statistics and test of significance (independent samples test) of different parameters between MI patients (cases) and age and sex matched healthy individuals (controls)|
Click here to view
[Table 2] shows the results of bivariate correlation analysis among different parameters of cases and controls. In cases with MI, there was a significant positive correlation between serum IMA and serum hsCRP. Other parameters, in MI, did not show any significant positive or negative correlation with IMA. These are summarized in [Table 2]. Controls also showed the same result as cases.
|Table 2: Bivariate correlation analysis among different parameters in MI (cases) and healthy individuals (controls)|
Click here to view
[Table 3] shows partial correlation analyses between each parameter and IMA albumin keeping the other variables constant that is eliminating the effects of other variables. A significant partial correlation (r = 0.44, P = 0.002) had also been observed between serum IMA and serum hsCRP in case of MI.
|Table 3: Partial correlations of IMA with others one eliminating the effect of remaining parameters in cases and controls|
Click here to view
[Table 4] displays the parameter estimates which have been obtained through multinomial logistic regression through multivariate approach using the SPSS software. This table describes that in case of MI, serum IMA, serum hsCRP, and serum transferrin play significant roles in assessing irreversible injury to myocardium having β-values of 0.324, 27.837 and −9.910 respectively.
| Discussion|| |
Acute coronary syndromes encompass a spectrum of unstable coronary artery disease from UA to transmural MI in which inflammation and oxidative stress are the major contributors. ,, Thus, in this present work, it was our objective to find out whether suspected inflammatory process in patients with MI modifies the cobalt binding property of albumin and whether this change correlates with the other markers of inflammation which had been included in this study. That inflammation participates in atherosclerosis from its inception and development to its ultimate endpoint, that is, thrombotic complications, is evident from the data in [Table 1]. The study demonstrates that markers of inflammation viz. Serum hsCRP (P < 0.0005) and serum ceruloplasmin (P = 0.014) were significantly elevated in cases with MI in comparison to controls. Various other studies have shown a rise in acute phase reactants in MI/ACS. ,,, The present study concurred with the study of Fichtlscherer et al.  who in 2000 found that elevated CRP levels were independent predictors of endothelial dysfunction in patients with coronary artery disease. This finding was also in agreement with the works of Tomai et al.  and Yip et al.  that had shown that serum levels of hsCRP were significantly higher in patients with an onset of AMI and UA. These findings were further corroborated by the work of Schiele et al., in 2010 who emphasized that elevated CRP level is a modest but independent risk factor in ACS patients,  again supported by present study [vide [Table 4]].
In the present study, serum ceruloplasmin (P = 0.014) had been found to be significantly higher in individuals with MI relative to controls. This rise in case of serum ceruloplasmin was also consistent with the work of Sirajwala et al.  The present study also concurs with the works of Reunanen et al.  and Zakirova  who concluded that high serum ceruloplasmin level is a risk factor for MI. Therefore that hsCRP and ceruloplasmin have emerged as important novel inflammatory markers in MI suggests the role of inflammation in the causation of ACS.
In cases with MI, serum IMA is significantly elevated in comparison to controls (P < 0.0005), thus suggesting altered cobalt binding activity of albumin. Similar findings have been described by different workers that IMA is increased in ACS. ,,,
Bivariate correlation analysis between parameters of MI with IMA revealed no significant correlation except serum hsCRP that showed a significant positive correlation in cases with MI (r = 0.47, P = 0.001) [Table 2]. A significant partial correlation (r = 0.44, P = 0.002) had also been observed between serum IMA and serum hsCRP in case of MI. A significant negative correlation (r = −0.282, P = 0.048) had been observed between serum total cholesterol and serum IMA. Studies by Borderie et al.  in 2004 showed that IMA reflected oxidative stress in patients with systemic sclerosis, and high IMA levels correlated well with other markers of oxidative stress. Kumar et al.  have described that IMA in normolipidemic patients may provide an index of oxidative stress and ischemia in AMI. This is in agreement with the finding of the present study as evident from multinomial logistic regression analysis [Table 4]. In the case of multi-variate analysis, serum IMA had come out as a significant marker of inflammation in MI (P = 0.035) along with serum hsCRP and serum transferrin.
Therefore, it can be concluded from this result that generation of oxidative stress in AMI is sufficient enough to alter the cobalt binding activity of albumin. It is being reflected in statistically increased level of IMA in infarction cases as compared to controls. It also can be used as a predictor of the inflammatory process and oxidative stress in MI.
Further, serum albumin (P = 0.002) had been found to be significantly lower in cases as compared to controls. These data were also in accordance with the findings of Kaysen et al. In 2001 and 2002 who had shown that ceruloplasmin and a1 acid glycoprotein (two long-lived acute-phase proteins) predict future albumin concentration  and correlate with fractional catabolic rate of albumin. , They had also shown that S-albumin correlated inversely with CRP level for a CRP level >1.3 mg/dL in hemodialysis (HD) patients.  In addition, Zimmermann et al.  reported that inflammation is associated with hypoalbuminemia and increased mortality in HD patients. Study by Hartopo et al. had brought into focus low serum albumin levels and in-hospital adverse outcomes in ACS.  It is possible that N-terminus modification of albumin due to on-going inflammatory process in MI may not react with BCG dye, and this is probably the cause of reduced albumin in the case.
Our results showed that serum transferrin, analysis was significantly decreased in MI cases in comparison to controls (P < 0.0005). In a study by San Miguel et al.  it had been found out that serum transferrin had significantly decreased in case of monoclonal gammopathy, a myeloproliferative disorder confirming its role as a negative acute phase reactant. This was in agreement with Imhof et al.  who in 2003 in their study of the effect of alcohol consumption on systemic markers of inflammation had considered the serum transferrin as a negative acute phase reactant. In a further study by Altamura et al.  in 2009 it had been concluded that serum ceruloplasmin and serum transferring levels were representative of clinical status severity in acute stroke patients play a pathogenic role in stroke progression.
The present study however suffers from some limitations such as its small sample size and the heterogenous nature of the patient population being studied. Coronary angiography could not be performed in all the study subjects due to ethical, socioeconomic constraints; hence the diagnosis of MI was only clinical.
| Conclusion|| |
Thus, it can be concluded from the present study that on-going inflammation modifies the cobalt binding activity of albumin in AMI, and this parameter (IMA) can be considered as a predictor of inflammation in these patients. Statistically significant positive correlation was obtained between IMA and positive acute phase reactant hsCRP in these patients. However, serum hsCRP and serum transferrin having corresponding β-values of 27.837 and −9.910 also play significant role in assessing the severity of ischemia in AMI and encourage future studies probing the role of inflammation in the causation of MI.
| Acknowledgements|| |
The investigators sincerely express their gratitude to Department of Biochemistry, Medical College and Hospital, Kolkata for technical support to carry out this project. The authors are thankful to the Department of Cardiology, Medical College and Hospital, Kolkata for their guidance and support to carry out the study.
| References|| |
Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992;326:310-8.
Braunwald E. Unstable angina: An etiologic approach to management. Circulation 1998;98:2219-22.
Morrow DA, Rifai N, Antman EM, Weiner DL, McCabe CH, Cannon CP, et al.
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: A TIMI 11A substudy. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol 1998;31:1460-5.
Burke AP, Tracy RP, Kolodgie F, Malcom GT, Zieske A, Kutys R, et al.
Elevated C-reactive protein values and atherosclerosis in sudden coronary death: Association with different pathologies. Circulation 2002;105:2019-23.
Myron Johnson A. Amino acids, peptides and proteins. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnosis. 4 th
ed. New Delhi: Elsevier Publication; 2006. p. 533-95.
Bismuth J, Kofoed SC, Jensen AS, Sethi A, Sillesen H. Serum lipids act as inverse acute phase reactants and are falsely low in patients with critical limb ischemia. J Vasc Surg 2002;36:1005-10.
Bar-Or D, Curtis G, Rao N, Bampos N, Lau E. Characterization of the Co (2+) and Ni (2+) binding amino-acid residues of the N-terminus of human albumin. An insight into the mechanism of a new assay for myocardial ischemia. Eur J Biochem 2001;268:42-7.
Christenson RH, Duh SH, Sanhai WR, Wu AH, Holtman V, Painter P, 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.
Peacock F, Morris DL, Anwaruddin S, Christenson RH, Collinson PO, Goodacre SW, 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.
GRACE Investigators. Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: A multinational registry of patients hospitalized with acute coronary syndromes. Am Heart J 2001;141:190-9.
Silverman LM, Christenson RH. Amino acids and proteins. In: Burtis CS, Ashwood ER, editors. Tietz Textbook of Clinical Chemistry. 2 nd
ed. Philadelphia: W B Saunders; 1993. p. 696-8.
Rifai N, Warnick GR. Lipids, lipoproteins, apolipoproteins, and other cardiovascular risk factors. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnosis. 4 th
ed. New Delhi: Elsevier Publication; 2006. p. 903-81.
Roy D, Quiles J, Gaze DC, Collinson P, Kaski JC, Baxter GF. Role of reactive oxygen species on the formation of the novel diagnostic marker ischaemia modified albumin. Heart 2006;92:113-4.
Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000;102:1000-6.
Tomai F, Crea F, Gaspardone A, Versaci F, Ghini AS, Chiariello L, et al.
Unstable angina and elevated c-reactive protein levels predict enhanced vasoreactivity of the culprit lesion. Circulation 2001;104:1471-6.
Yip HK, Wu CJ, Chang HW, Yang CH, Yeh KH, Chua S, et al.
Levels and values of serum high-sensitivity C-reactive protein within 6 hours after the onset of acute myocardial infarction. Chest 2004;126:1417-22.
Schiele F, Meneveau N, Seronde MF, Chopard R, Descotes-Genon V, Dutheil J, et al.
C-reactive protein improves risk prediction in patients with acute coronary syndromes. Eur Heart J 2010;31:290-7.
Sirajwala HB, Dabhi AS, Malukar NR, Bhalgami RB, Pandya TP. Serum ceruloplasmin level as an extracellular antioxidant in acute myocardial infarction. J Indian Acad Clin Med 2007;8:135-8.
Reunanen A, Knekt P, Aaran RK. Serum ceruloplasmin level and the risk of myocardial infarction and stroke. Am J Epidemiol 1992;136:1082-90.
Zakirova AN. The clinico-hemodynamic effects of the antioxidant ceruloplasmin in IHD patients. Ter Arkh 1995;67:33-5.
Bhagavan NV, Lai EM, Rios PA, Yang J, Ortega-Lopez AM, Shinoda H, 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.
Kumar A, Sivakanesan R, Singh S. Oxidant stress, endogenous antioxidants and ischaemia modified albumin in normolipidemic acute myocardial infarction patients. J Health Sci 2008;54:482-7.
Borderie D, Allanore Y, Meune C, Devaux JY, Ekindjian OG, Kahan A. High ischemia-modified albumin concentration reflects oxidative stress but not myocardial involvement in systemic sclerosis. Clin Chem 2004;50:2190-3.
Kaysen GA, Dubin JA, Müller HG, Mitch WE, Levin NW, HEMO Group. Levels of alpha1 acid glycoprotein and ceruloplasmin predict future albumin levels in hemodialysis patients. Kidney Int 2001;60:2360-6.
Kaysen GA, Dubin JA, Müller HG, Mitch WE, Rosales LM, Levin NW. Relationships among inflammation nutrition and physiologic mechanisms establishing albumin levels in hemodialysis patients. Kidney Int 2002;61:2240-9.
Kaysen GA, Greene T, Daugirdas JT, Kimmel PL, Schulman GW, Toto RD, et al.
Longitudinal and cross-sectional effects of C-reactive protein, equilibrated normalized protein catabolic rate, and serum bicarbonate on creatinine and albumin levels in dialysis patients. Am J Kidney Dis 2003;42:1200-11.
Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999;55:648-58.
Hartopo AB, Gharini PP, Setianto BY. Low serum albumin levels and in-hospital adverse outcomes in acute coronary syndrome. Int Heart J 2010;51:221-6.
San Miguel J, Corrales A, Alberca I, Vicente V, Lopez Borrasca A. Acute phase reactant proteins in differential diagnosis of monoclonal gammopathy. Neoplasma 1983;30:57-62.
Imhof A, Froehlich M, Brenner H, Boeing H, Pepys MB, Koenig W. Effect of alcohol consumption on systemic markers of inflammation. Lancet 2001;357:763-7.
Altamura C, Squitti R, Pasqualetti P, Gaudino C, Palazzo P, Tibuzzi F, et al.
Ceruloplasmin/Transferrin system is related to clinical status in acute stroke. Stroke 2009;40:1282-8.
[Table 1], [Table 2], [Table 3], [Table 4]