Recognition of the role of plaque rupture in the pathogenesis of cardiac ischemia has led to investigation of serum markers for plaque instability. These markers include whole blood choline levels, pregnancy-associated plasma pro-tein-A (PAPP-A), and malondialdehyde-modified LDL.
Choline is thought to be released from leukocytes and platelets in response to activation of phospholipase D during plaque rupture. In patients presenting with symptoms of ACS and negative troponin levels on admission, an elevated choline level predicts higher risk for cardiac death, nonfatal cardiac arrest, life-threatening arrhythmias, heart failure, and future angioplasty within 30 days . Furthermore, in the absence of MI, choline detects patients who have high-risk unstable angina (prolonged chest pain, ischemia-related pulmonary edema, rest pain with dynamic ECG changes, or hypotension) with a sensitivity and specificity of 86%. Unlike troponin, choline is not a marker of myocardial cell necrosis. Its use as an early biomarker of MI is limited, with a sensitivity of 41%, specificity of 79%, PPV of 51%, and NPV of 71%. The weak association of choline with ST-elevation MI has been attributed to the possibility a different mechanism of plaque rupture, whereby rapid red thrombus formation leaves limited time for the injured endothelium and collagen tissue to activate phospholipase D . Intermittent formation of nonoccluding white thrombi in the setting of unstable angina leads to phospholipase D activation in platelets and choline release. Therefore, choline may provide early detection of patients who have high-risk unstable angina, indicating subendocardial rather than transmural injury.
Another emerging marker of plaque instability is PAPP-A, a zinc-binding matrix metalloprotei-nase that activates insulin-like growth factor I (IGF-I), a mediator of atherosclerosis. IGF-I induces migration of vascular smooth muscle cells, monocyte chemotaxis, and release of cyto-kines. Histologically, PAPP-A is abundantly expressed in ruptured or eroded plaques but not in stable plaques, suggesting a potential enzymatic role in extracellular matrix degradation and fibrous cap weakening that contributes to plaque rupture . Circulating levels of PAPP-A were significantly higher in patients who had unstable angina or MI compared with patients who did not have an ACS; the areas under the receiver operating curve were 0.94 and 0.88, respectively, at the threshold level of 10 mIU/L. The sensitivity and specificity were 89.2% and 81.3%, respectively. PAPP-A levels did not correlate with markers of cardiac necrosis such as troponin and CK-MB, suggesting its role as a marker of early ischemia but not infarction . In troponin-neg-ative patients presenting with ACS, those who had elevated PAPP-A levels had a 4.6-fold higher risk for cardiovascular morbidity at 6 months compared with those who had low PAPP-A levels .
During ischemic injury of the endothelium, a cascade of platelet adhesion and activation involving the prostaglandin pathway results in the release of aldehydes that bind to the apo-B100 moiety of LDL, forming malondialdehyde (MDA)-modified LDL . Plasma levels of
MDA-modified LDL become elevated in patients who have ACS within the first 6 hours of symptom onset. In patients presenting with ACS, the sensitivity of admission MDA-modified LDL was 95% compared with 38% for troponin I in the diagnosis of unstable angina , and the specificity was 95%. The use of troponin I and MDA-modified LDL in combination achieved a sensitivity of 98%. MDA-modified LDL levels were threefold higher in patients who had unstable angina compared with those who had stable CAD. In acute MI, MDA-modified LDL is 95% sensitive when used alone, troponin I is 90% when used alone, and the combination had a sensitivity approaching 100% . This evidence suggests that MDA-modified LDL, reflecting endothelial injury and plaque rupture, is useful in discriminating unstable from stable angina, in contradistinction to troponin, which helps to discriminate between unstable angina and myocar-dial infarction.
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