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Ischaemia Modified Albumin In Ischaemic Heart Disease

 

Søren Hjortshøj

Summary

Until now, the kinetics of IMA have not been described in detail and never during ongoing ACS. Previously, some small studies have found a high NPV for the diagnosis of ACS, suggesting that IMA may be a useful “rule-out”-marker.The aims of this PhD thesis were to investigate kinetics of IMA in more detail during ongoing ACS; to establish a reference interval for IMA; and to investigate the ability of IMA to identify acute MI in a population of chest pain patients In patients with STEMI, a rapid increase to 16 % above ULN was seen following PCI with a mean time to peak after 40 minutes of revascularization, after which IMA decreased to normal levels within 2.5-3 hours. The rapid normalization of IMA leads to a narrow diagnostic time window. A significant relationship between the coronary flow in the infarct artery on arrival and kinetics of IMA was seen. Patients with no flow in the coronary artery had a later increase in IMA as compared to those who had some degree of coronary flow on arrival. The reason for this observation could be a forced release due to the revascularization procedure, but other factors may play a role, e.g. diffuse reperfusion-induced events by ROS activity. Relative concentrations of IMA were low compared with other cardiac markers, and the signal/noise ratio was low. Only half of the patients had IMA levels above ULN on arrival, necessitating at least two consecutive samples to observe any increases. In this respect, it must be remembered that albumin is present in the blood and that probably only a small part of the total albumin is changed to IMA because of ischaemia in the tissue. After distribution in the total volume of blood, the resulting increase of IMA must be limited. This is in strong contrast to the necrosis markers that are present in myocardial cells at very high concentrations compared with plasma. Therefore, even small amounts of necrotic cells can be detected in plasma resulting in considerably increased plasma values.
A longitudinal study with several samples for 24 hours in healthy subjects did not reveal changes over time, although variations between IMA levels in  individuals. In a small study of patients with stable angina and NSTEMI undergoing PCI, less significant changes in IMA were seen following PCI.
In healthy blood donors, IMA was normally distributed, however with a wide range.
In a population of chest pain patients, low sensitivities and specificities were found for the diagnosis of AMI. The NPV was not at a level that permits use of IMA on admission as a single marker. However, the combination of IMA and ECG led to a NPV of 91 %. From a ROC analysis, we found an optimal cut-off level of 91 U/mL. By using this, we obtained similar results as with 88.2 U/mL. In the literature, confusion exists regarding the optimal cut-off threshold for IMA, but no matter which cut-off is chosen it is not possible to get a reasonable concomitant sensitivity and specificity.
Further, the diagnostic performance of IMA is not convincing, and if used as a “ruleout-marker” with only a moderately high NPV, there is a risk of discharging patients with AMI who are at risk for adverse events, unless the patient population has been carefully selected with very short duration of symptoms. The conclusions of this thesis are that, at present, IMA cannot be recommended as a standard marker in ACS due to the following limitations: 1). The IMA assay (ACB® test) has a very low amplitude of signals and a low signal/noise ratio. 2). The exact biological mechanisms behind IMA formation and clearance remain uncertain. 3). There is considerable overlap between healthy and diseased individuals and a reliable cut-off threshold in ACS for acute MI has yet to be determinedUntil now, the kinetics of IMA have not been described in detail and never during ongoing ACS. Previously, some small studies have found a high NPV for the diagnosis
of ACS, suggesting that IMA may be a useful “rule-out”-marker. The aims of this PhD thesis were to investigate kinetics of IMA in more detail during
ongoing ACS; to establish a reference interval for IMA; and to investigate the ability of IMA to identify acute MI in a population of chest pain patients In patients with STEMI, a rapid increase to 16 % above ULN was seen following PCI with a mean time to peak after 40 minutes of revascularization, after which IMA decreased to normal levels within 2.5-3 hours. The rapid normalization of IMA leads to a narrow diagnostic time window. A significant relationship between the coronary flow in the infarct artery on arrival and kinetics of IMA was seen. Patients with no flow in the coronary artery had a later increase in IMA as compared to those who had some degree of coronary flow on arrival. The reason for this observation could be a forced release due to the revascularization procedure, but other factors may play a role, e.g. diffuse reperfusion-induced events by ROS activity. Relative concentrations of IMA were low compared with other cardiac markers, and the signal/noise ratio was low. Only half of the patients had IMA levels above ULN on arrival, necessitating at least two consecutive samples to observe any increases. In this respect, it must be remembered that albumin is present in the blood and that probably only a small part of the total albumin is changed to IMA because of
ischaemia in the tissue. After distribution in the total volume of blood, the resulting increase of IMA must be limited. This is in strong contrast to the necrosis markers that are present in myocardial cells at very high concentrations compared with plasma. Therefore, even small amounts of necrotic cells can be detected in plasma
resulting in considerably increased plasma values. A longitudinal study with several samples for 24 hours in healthy subjects did not reveal changes over time, although variations between IMA levels in individuals. In a small study of patients with stable angina and NSTEMI undergoing PCI, less significant changes in IMA were seen following PCI. In healthy blood donors, IMA was normally distributed, however with a wide range. In a population of chest pain patients, low sensitivities and specificities were found for the diagnosis of AMI. The NPV was not at a level that permits use of IMA on admission as a single marker. However, the combination of IMA and ECG led to a NPV
of 91 %. From a ROC analysis, we found an optimal cut-off level of 91 U/mL. By using this, we obtained similar results as with 88.2 U/mL. In the literature, confusion exists regarding the optimal cut-off threshold for IMA, but no matter which cut-off is chosen it is not possible to get a reasonable concomitant sensitivity and specificity.
Further, the diagnostic performance of IMA is not convincing, and if used as a “ruleout-marker” with only a moderately high NPV, there is a risk of discharging patients with AMI who are at risk for adverse events, unless the patient population has been carefully selected with very short duration of symptoms. The conclusions of this thesis are that, at present, IMA cannot be recommended as a standard marker in ACS due to the following limitations: 1). The IMA assay (ACB® test) has a very low amplitude of signals and a low signal/noise ratio. 2). The exact biological mechanisms behind IMA formation and clearance remain uncertain. 3). There is considerable overlap between healthy and diseased individuals and a reliable cut-off threshold in ACS for acute MI has yet to be determined.