Abstract

Methods: Fifty elective isolated ONCABG patients (41 males, 9 females; mean age 66 years; range 56 to 75 years) were included in the study. Patients were divided into perioperative myocardial infarction (PMI; n=8) and non-infarction (NPMI; n=42) groups according to perioperative cardiac troponin I (cTnI) values and ECG findings. Serum IMA levels were measured preoperatively, 20 minutes after aortic cross clamping, 30 minutes, at 3, 6, 12 and 24 hours after declamping.

Results: Compared to the NPMI group, the declamping 30 minutes, 3, 6 and 12 hours IMA levels were higher in the PMI group (p=0.002, p=0.048, p=0.023, p=0.007, respectively). In both NPMI and PMI groups, the 20 minutes after aortic cross clamping IMA levels were higher compared to the preoperative IMA levels (p=0.0001, p=0.038, respectively).

Conclusion: Our study results show that IMA may be an early marker of myocardial infarction in the ONCABG patients.

The classic criteria and diagnostic methods used for myocardial infarction (MI) have serious limitations in the perioperative period,[3,5] and blood-based biomarkers are now considered to be attractive alternatives because they are easily applicable, cheap, and more rapidly reachable.[5-8] In particular, cardiac troponin I (cTnI) is known to cause myocardial damage, but it is currently accepted as the most sensitive and specific marker for diagnosing myocardial damage after CABG.[3,5,6]

Because cTnI is a necrosis marker rather than an ischemia marker,[9] new markers are needed that can define ischemia in the earlier pre-necrosis period. In addition, such markers may be useful for the early diagnosis of myocardial ischemia when it has not progressed to irreversible necrosis.

Exposure to ischemic tissue alters the N-terminus of albumin. This decreases its binding capacity for metals, resulting in the formation of ischemiamodified albumin (IMA).[10,11] The IMA levels, which increase within minutes after the start of ischemia, remain high for 6-12 hours and then return to normal levels within 24 hours. In this way, IMA is valuable for determining ischemia in the early period before myocardial necrosis.[12] There are currently many biomarkers for cardiac ischemia [fatty acid-binding protein (FABP), choline, and IMA], but only IMA is licensed for routine use when cardiac ischemia is present. Furthermore, IMA has been approved by the Food and Drug Administration (FDA) and has been approved for use by the European Union and thus has received OE marking.[8,10] The aim of this study was to evaluate the potential of IMA for predicting MI in on-pump CABG (ONCABG) patients.

Methods

The sociodemographic characteristics, the values before surgery and 48 hours after declamping, the cTnI and IMA values, the preoperative results, and the first, second, and fifth-day postoperative electrocardiogram (ECG) results of all of the patients were recorded. Fortytwo patients were placed in the non-PMI group and eight in the PMI group according to their perioperative cTnI values and ECG findings. Perioperative MI was defined as a cTnI value of more than 10 times the 99th percentile of the upper reference limit (URL) during the first 48 hours following CABG based on a normal baseline cTnI value of ≤ the 99th percentile of the URL. In addition, either new pathological Q waves or a new left bundle branch block (LBBB) must also be present to have PMI.[13]

Initially, radial and pulmonary arterial catheters were introduced in the patients under local anesthesia. After standard general anesthesia, a median sternotomy was performed followed by routine aortic and right atrial cannulation. Cardiopulmonary bypass (CPB) was then carried out using membrane oxygenators and moderate systemic hypothermia. Myocardial protection was achieved via antegrade mild hypothermic (32 °C) blood cardioplegia, and this was repeated every 20 minutes or whenever needed. Heparin 3.0 mg.kg-1 w as a lso a dministered, and the activated clotting time (ACT) was maintained at >400 seconds during the procedure. The heparin was neutralized with protamine at a ratio of 1:1.3 within 10 minutes after being weaned from CPB, and all of the patients were followed up in the intensive care unit (ICU) after surgery.

Blood samples for IMA determination were drawn preoperatively, at 20 minutes after aortic crossclamping (ACC), at 30 minutes after declamping, and at 3, 6, 12, and 24 hours after declamping when the cross clamp was released. For standardization purposes, all of the blood samples from each subject were collected by the same venipuncture staff in vacutainer tubes without an anticoagulant. They were then centrifuged at 2000 g for 10 minutes and stored at -80 °C until the biochemical assays were performed.

The ultrasensitive cTnI levels were estimated using a chemiluminescence-based immunoassay method on the Siemens Advia Centaur® CP Immunoassay System (Siemens Healthcare Diagnostics Inc, Tarrytown, NY, USA) via the Siemens Troponin-I-Ultra assay test (Siemens Healthcare Diagnostics Inc, Tarrytown, NY, USA) (URL= 0.04 ng/mL).

The reduced cobalt to albumin binding capacity (IMA level) was analyzed using the rapid and colorimetric method proposed by Bar-Or et al.[14] in which 200 μL of the patient’s serum was placed into glass tubes and 50 μL of 0.1% cobalt chloride (CoCl₂.6H₂O) in H₂O (Sigma-Aldrich, St. Louis, MO, USA) was added. After gentle shaking, the solution was left for 10 minutes to ensure sufficient binding, and 50 μL of dithiothreitol (DTT) (Sigma- Aldrich, St. Louis, MO, USA) in 1.5 mg/mL H2O was added as a colorizing agent. The reaction was quenched two minutes later by adding 1.0 mL of 0.9% sodium chloride (NaCl). Next, a colorimetric control was prepared for the pre- and postoperative serum samples, and for the colorimetric control samples, 50 μL of distilled water was substituted for the 50 μL of 1.5 mg/mL DTT. The absorbance of the specimens was analyzed at 470 nm using a Shimadzu Recording UV-1601 spectrophotometer (Shimadzu Medical Systems Oceania Pty, Ltd., Auburn, N.S.W., Australia), and we then compared the color of the DTT specimens with the color of the control samples, with the results being given as absorbance units (ABSUs).

Statistical analysis
Descriptive statistical analysis was applied to all the studied variables. Continuous variables were expressed as mean ± standard deviation (SD) or median and interquartile range, as appropriate. The group means for the continuous variables were compared using either Student’s t-test or the Mann-Whitney U test. Furthermore, we utilized either a paired samples t test or the Wilcoxon signed-rank test for dependent continuous variable analyses. Categorical variables were expressed as percentages and were compared using a chi-square test. A two-tailed value of p<0.05 was considered to be statistically significant.

Results

Table 1: Demographic data of the groups

Table 2: Perioperative variables of the groups

The IMA levels preoperatively and at 20 minutes after ACC were also similar in the PMI and non-PMI groups (p=0.071 and p=0.393, respectively). However, the IMA levels of the PMI group at 30 minutes and at three, six, and 12 hours after declamping were higher (p=0.002, p=0.048, p=0.023, and p=0.007, respectively), but at 24 hours after declamping, the IMA levels were similar in the two groups (p=0.221) (Table 3).

Table 3: Cardiac troponin I and ischemia-modified albumin levels of the groups

With regard to PMI development, the IMA had a cut-off value of 0.904 with 75% sensitivity and 72.2% specificity 30 minutes after declamping, whereas three hours after declamping, it had a cut-off value of 0.834 with 75% sensitivity and 50% specificity. Moreover, in both groups, the IMA levels 30 minutes after ACC were higher when compared to the preoperative IMA levels (p=0.038 and p=0.0001, respectively).

Discussion

Ischemia-modified albumin is one of the most reliable markers for myocardial ischemia, and several studies have shown that this condition is closely related to IMA.[8,10,12] In addition, IMA is recognized as a biomarker of temporary myocardial ischemia induced by coronary vasospasm.[15] Moreover, during primary percutaneous coronary intervention (PCI), IMA has been identified as an independent predictor of incomplete ST-segment resolution.[16] Sinha et a l.[17] also noted increased IMA levels in patients who experienced chest pain and ischemic ECG changes during PCI. In our study, the IMA levels at 20 minutes after ACC increased significantly in the two groups when the preoperative IMA levels were compared, which supports the fact that the IMA levels are significantly elevated when myocardial ischemia occurs during ONCABG.

Other studies have found that IMA, which increases almost immediately after ischemia, was superior to other necrosis markers for diagnosing ACS at admission.[8,9,18,19] Moreover, in a study composed of 538 patients, the IMA showed 100% sensitivity in the final diagnosis of acute myocardial infarction (AMI).[18] Furthermore, for patients who were admitted to the emergency room within three hours after the onset of chest pain, IMA was shown to be superior to 12-lead ECG, cardio troponin T (cTnT), and cTnI for diagnosing ACS.[9,19]

Perioperative myocardial ischemia may occur at varying degrees after cardiac surgery and can be identified early via IMA.[10] Dong et al.[11] found that the IMA levels at the third postoperative hour in OPCAB patients were higher in cases that involved PMI. In our study, there were similar IMA levels at 20 minutes after ACC and preoperatively in both the PMI and non-PMI groups. However, at 30 minutes and at three, six, and 12 hours after declamping, the IMA levels of the PMI group were significantly higher. In the end, all of our findings suggest that IMA may be used as an early marker for the diagnosis of PMI in ONCABG patients.

Irreversible damage to the myocardial tissue due to either mechanical or ischemic injury can lead to the destruction of the cell membrane and the contractile apparatus. In turn, this leads to the release of classic cardiac markers into extracellular space.[3,7] The in vivo production of IMA, on the other hand, can be interpreted as an effective endogenous response to the ischemia,[20] and during PCI, it has been shown that it can be an early marker of myocardial ischemia as well as an indicator of both the size and duration of the ischemia.[21] During PCI, the increased IMA levels parallel those of transmyocardial lactate, which is the gold standard for ischemia.[22] However, IMA is currently the most reliable biomarker for the early detection of ischemia before the onset of irreversible cardiac injury.[10]

Our results showed that elevated IMA levels can be used to detect myocardial ischemia and early myocardial necrosis in ONCABG patients. In addition, IMA can be utilized to predict myocardial necrosis in ONCABG patients, especially when it is ischemic in origin. However, the predictive value of IMA as an early marker for PMI in ONCABG patients needs to be confirmed via large-scale prospective studies.

Conclusion

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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