Ischemia-Modified Albumin
A biomarker that could detect ischemia alone would help identify patients at highest risk for infarction; immediate intervention could then prevent the progression of ACS, as evidenced by rising markers of necrosis. Ischemia-modified albumin (IMA), which is produced rapidly when circulating albumin comes into contact with ischemic myocardial tissue, has been touted as such a biomarker.42
Several changes occur in the human albumin molecule in the presence of ischemia, including its ability to bind transition metals—especially cobalt. This discovery led to the creation of an albumin-cobalt–binding assay, approved by the FDA for rapid detection of myocardial ischemia.19 When artificial ischemia is produced by balloon inflation during percutaneous coronary angioplasty, IMA levels can be detected, using the assay, within minutes of coronary artery occlusion. Levels tend to peak within six hours and can be elevated for as long as 12 hours.19
When IMA is used in conjunction with ECG findings and cTnT levels, a sensitivity of 97% for detecting ACS can be achieved. This could reduce the number of patients being discharged from the ED with occult ACS,43 giving IMA a potentially important precautionary and supplemental role. As with most cardiac biomarkers, IMA alone is not 100% specific for ACS since it is also present in other ischemic conditions, thus hindering its usefulness in clinical practice. Elevations had been reported in patients with liver cirrhosis, uncontrolled type 2 diabetes mellitus, obstetric conditions associated with placental ischemia, carbon monoxide poisoning, and cerebrovascular ischemia.44-47
Recent suggestions to use IMA to rule out rather than diagnose ACS show promise, since the absence of this acute-phase reactant should exclude the presence of myocardial ischemia.48 Further studies are needed to determine the exact physiology of IMA production in order to identify its cardiac specificity for clinical use.49
Homocysteine
As a marker of increased cardiovascular risk, homocysteine is thought to have multiple effects on the cardiovascular system. These include endothelial dysfunction, decreased arteriole vasodilation (ie, reduced release of nitric oxide), increased platelet activation, increased production of free radicals, and increased LDL oxidation with arteriole lipid accumulation.50
In patients with severe hyperhomocysteinemia (ie, homocysteine serum levels > 100 mol/L), risk for premature atherothrombosis and venous thromboembolism is increased. In the general public, mildly elevated homocysteine levels (> 15 mol/L) have been attributed to insufficient dietary intake of folic acid. Folate in its natural form has been known to decrease serum homocysteine levels by 25%, if supplemented appropriately with vitamins B6 and B12.50
In recent years, folate deficiency has declined due to enrichment of certain foods with this crucial nutrient, initially mandated to decrease the incidence of neural tube defects in developing embryos. From a cardiovascular standpoint, researchers have been unable to determine whether elevated homocysteine increases CVD risk or is simply a marker of existing disease burden.50 In clinical trials in which subjects took B-vitamins supplemented with folate, homocysteine levels were reduced; yet in one study, stroke risk was not reduced in patients with a history of stroke51; in a second, in-stent restenosis was more common in patients who took the supplement after undergoing angioplasty52; and in a third, patients following the vitamin regimen after a recent acute MI proved to be at higher cardiovascular risk.53
As a result of this conflicting evidence, no recommendations have been made for routine homocysteine screening except in patients with a history of markedly premature atherosclerosis or a family history of early-onset acute MI or stroke.50 Monitoring may be advisable in patients who take a folate antagonist (eg, methotrexate, carbamazepine), considering the risk for folate deficiency and subsequent hyperhomocysteinemia.
ACUTE INFLAMMATORY MARKERS OF PLAQUE RUPTURE OR VULNERABILITY
Myeloperoxidase
Many researchers have taken a particular interest in the acute substances formed as a result of atherothrombotic plaque inflammation or rupture. One such biomarker is myeloperoxidase (MPO), which is thought to be expressed from the degranulation of activated leukocytes found in atherosclerotic plaques. This acute-phase enzyme may convert LDL into a high-uptake form for macrophages, leading to foam cell formation and depletion of nitric oxide, contributing to additional ischemia by way of vasoconstriction.54
Recently, a high systemic MPO level was found to be a more significant marker of plaque at risk for rupture, compared with already-ruptured plaque.55 Although MPO elevations may also occur in a number of inflammatory, infectious, or infiltrative conditions, the association between MPO, inflammation, and oxidative stress supports its use as a marker for plaque that is vulnerable to rupture.56,57
Serum levels of MPO have been shown to predict increased risk for subsequent death or MI in patients who present to the ED with ACS, independent of other cardiac risk factors or cardiac biomarkers. In a 2001 study, Zhang et al54 established an association between elevated MPO levels and angiographically proven coronary atherosclerosis, with a 20-fold higher risk for coronary artery disease; earlier this year, Oemrawsingh et al58 reported an independent association between MPO and long-term adverse outcomes in patients who presented with non–ST-segment elevation ACS. Thus, MPO may be a significant indicator of vascular inflammation.57