Are There Really Biomarkers of Vulnerable Plaque?

The rationale for the search of biomarkers of vulnerable plaques seems sound. Plaque rupture is a key step in the initiation of an acute coronary syndrome (ACS).4 The atherosclerotic plaque contains large numbers of inflammatory cells that may release hydrolytic enzymes and cytokines, thereby destabilizing the plaque (1). Therefore, many inflammatory biomarkers and enzymes have been suggested as potential biomarkers of vulnerable plaques; however, considerable confusion exists in the literature regarding what is meant by “a biomarker of plaque vulnerability,” and other closely related (but not identical) concepts have emerged as alternatives. These concepts are described briefly below. A biomarker of plaque rupture would show an increasing concentration when a (coronary) atherosclerotic plaque ruptures. A biomarker of plaque rupture would be potentially useful for early diagnosis of acute myocardial infarction (AMI) because plaque rupture precedes myocardial necrosis. Another potential application would be for unstable angina in which plaque rupture, but not myocardial necrosis, occurs. The requirements that a biomarker of plaque rupture must meet to have clinical utility are considerable, however. The biomarker must be abundant in atherosclerotic plaques and be released immediately into the circulation in high concentration after rupture of the plaque. The biomarker concentration must remain increased for quite some time, because plaque rupture might occur up to several days before the patient gets ischemia and thus presents symptoms (2). Biomarker specificity is another demanding requirement. The biomarker should be not only highly specific for atherosclerotic plaques but also, ideally, specific for coronary plaques only. An important limitation on the use of a biomarker of plaque rupture for early diagnosis of AMI is that a large proportion of all infarctions are not caused by plaque rupture. Autopsy studies have shown that approximately 60% of fatal cases are associated with plaque rupture (1), and this proportion is probably even lower in real-life situations involving mainly nonfatal AMIs, especially if type 2 AMIs are included. Thus, even with a very good biomarker of plaque rupture, the sensitivity for AMI diagnosis would be limited. On the other hand, plaque rupture might occur without being followed by the formation of a flow-limiting thrombus and the development of AMI. Coronary plaque ruptures have been shown in 7%–27% of stable angina patients (3, 4) and in 3% of patients dying of noncardiac causes (5). In a study that evaluated 3 biomarkers suggested to indicate plaque rupture [myeloperoxidase (MPO), matrix metalloproteinase 9 (MMP-9), and pregnancy-associated plasma protein A (PAPP-A)] for the early diagnosis of AMI, the diagnostic information was almost nil. For all 3 biomarkers, the areas under the curve in ROC curve analyses were not significantly different from 0.50 (6).