Markers of Plaque Instability in the Early Diagnosis and Risk

Study Questions:

Are markers of plaque instability useful in the early diagnosis and risk stratification of patients with acute myocardial infarction (AMI)?

Methods:

In this multicenter study, the authors examined four markers of plaque instability, myeloperoxidase (MPO), myeloid-related protein 8/14 (MRP-8/14), pregnancy-associated plasma protein-A (PAPP-A), and C-reactive protein (CRP). MPO is a leukocyte-derived enzyme that catalyzes the formation of reactive oxidants and is thought to be a potential participant in plaque formation and plaque rupture. MRP-8/14 is secreted by activated monocytes and neutrophils, has proinflammatory properties, and is expressed in atherosclerotic lesions. PAPP-A is a protease produced by fibroblasts, osteoblasts, and vascular smooth muscle cells. Some studies reported PAPP-A to be highly expressed in unstable plaques. CRP is a well known biomarker of inflammation, and independently predicts cardiac events in primary and secondary prevention studies, as well as patients with acute coronary syndromes. These four markers were measured in 398 consecutive patients presenting to the emergency department with acute chest pain, and compared to normal and high-sensitivity cardiac troponin T (cTnT and hs-cTnT). Endpoints included AMI and death during a median follow-up of 27 months.

Results:

AMI was diagnosed in AMI in 76 patients (19%). At emergency department presentation, concentrations of all four biomarkers of plaque instability were significantly higher in patients with AMI than in patients with other diagnoses. However, their diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (AUC) was low (MPO 0.63, MRP-8/14 0.65, PAPP-A 0.62, and CRP 0.59) and inferior to both normal and hs-cTnT (cTnT 0.88, hs-cTnT 0.96; p < 0.001 for all comparisons). Diagnostic performance was poor for the four markers of plaque instability when the combined endpoint of AMI and unstable angina were combined, and was worse than for AMI alone. Thirty-nine patients (10%) died during follow-up. Concentrations of MPO, MRP-8/14, and CRP were higher in nonsurvivors than in survivors, and predicted all-cause mortality with moderate accuracy.

Conclusions:

The authors concluded that markers of plaque instability were not useful for the early diagnosis of AMI, but may provide some incremental value in the risk stratification of patients with acute chest pain.

Perspective:

This is an interesting analysis of several markers—MPO, MRP-8/14, PAPP-A, and CRP—thought to be indicative of ‘vulnerable plaque.’ They were examined for their early diagnostic and long-term prognostic importance in a modest-sized cohort diagnosed with both the standard cTnT assay and the hs-cTnT assay. None of the markers added to early diagnosis, likely because the gold standard used relied so heavily on cTn and because it is likely, assuming one believes in vulnerable plaque markers, that all of the AMIs were not due to plaque rupture. AMIs were due to endothelial dysfunction, to fixed coronary artery disease with supply-demand imbalance, or to other causes not associated with plaque rupture. There was some long-term prognostic value, although modest. It would be of interest (although not reported) to know if the patients identified by these markers were indeed those with type 1 AMIs (i.e., those due to plaque rupture). It is known that they have a worse prognosis. If so, perhaps these markers would help identify those in need of early invasive evaluation and treatment.

Clinical Topics: Acute Coronary Syndromes, Prevention, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers

Keywords: Risk, Coronary Artery Disease, Follow-Up Studies, Monocytes, Biological Markers, Cardiovascular Diseases, ROC Curve, Pregnancy-Associated Plasma Protein-A, Inflammation, Myocardial Infarction, Acute Coronary Syndrome, Plaque, Atherosclerotic, Area Under Curve, Fibroblasts, Early Diagnosis, Osteoblasts, Troponin T, Prognosis, C-Reactive Protein, Secondary Prevention, Chest Pain, Peroxidase, Neutrophils, Oxidants


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