Fragments of the insulin-like growth factor binding protein 4 (IGFBP-4) are recognized as being promising new biomarkers of major adverse cardiovascular events risk in patients with acute coronary syndrome (ACS). They are formed from IGFBP-4 by cleavage with pregnancy-associated plasma protein-A (PAPP-A).
Previously, PAPP-A was suggested as being a potential marker of cardiovascular diseases. Several studies showed that the expression of PAPP-A was significantly increased, especially in unstable atherosclerotic plaques. Furthermore, it was shown that high levels of PAPP-A in circulation could indicate an increased risk of plaque rupture, which, in turn, could lead to a major adverse cardiac event (MACE). Unfortunately, PAPP-A assays have been shown to also recognize PAPP-A in complexes with proMBP, which is not related to atherosclerotic plaques. In addition, PAPP-A measurements have been shown to be influenced by heparin, which isan anti-coagulation agent that is routinely used in the treatment of patients with acute myocardial infarction. All in all, these limitations make PAPP-A an unreliable marker for the monitoring of plaque rupture.
PAPP-A is a metalloproteinase and its main substrate is IGFBP-4. PAPP-A specifically cleaves IGFBP-4 between Met135-Lys136 into two fragments:
N-terminal IGFBP-4 (NT-IGFPB-4) and C-terminal IGFBP-4 (CT-IGFBP-4) (see Figure 1). Due to the challenges presented by PAPP-A measurements, our researchers hypothesized that IGFBP-4 fragments could perhaps be used as surrogate markers of enzymatically active PAPP-A.