Insulin‐Like Growth Factor Binding Protein 4 Fragments Provide Incremental Prognostic Information on Cardiovascular Events in Patients With ST‐Segment Elevation Myocardial Infarction

Abstract

BackgroundFragments of insulin‐like growth factor binding protein 4 (IGFBP‐4) are potential new biomarkers for cardiac risk assessment. The fragments are generated on specific cleavage by pregnancy‐associated plasma protein‐A, which exerts proatherogenic activity. This study investigated the prognostic value of IGFBP‐4 fragments in patients with ST‐segment elevation myocardial infarction.Methods and ResultsWe prospectively included 656 patients with ST‐segment elevation myocardial infarction treated with percutaneous coronary intervention from September 2006 to December 2008. Blood samples were drawn before percutaneous coronary intervention, and levels of intact IGFBP‐4 and N‐terminal and C‐terminal IGFBP‐4 fragments were measured by specific assays. End points were 5‐year all‐cause and cardiovascular mortality and the combined end point of major adverse cardiac events. Prognostic potential was evaluated on top of a clinical model in terms of discrimination, calibration, and reclassification analysis. During follow‐up, 166 patients experienced a major adverse cardiac event and 136 patients died, of whom 69 died from cardiovascular causes. Both IGFBP‐4 fragments were associated with all end points (P<0.001). After multivariable adjustments, both N‐terminal and C‐terminal IGFBP‐4 fragment levels remained associated with all end points, including cardiovascular mortality with hazard ratios per doubling in protein concentration of 2.54 (95% CI 1.59–4.07; P<0.001) and 2.07 (95% CI 1.41–3.04; P<0.001), respectively. Incorporation of IGFBP‐4 fragments into a clinical model with 15 risk factors improved C‐statistics and model calibration and provided incremental prognostic contribution, as assessed by net reclassification improvement and integrated discrimination improvement.Conclusions IGFBP‐4 fragments are associated with increased risk of all‐cause mortality, cardiovascular mortality, and major adverse cardiac events in patients with ST‐segment elevation myocardial infarction.

Prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in ST-segment elevation myocardial infarction

“…Nonetheless, our results support the evidence that in STEMI patients, IGFBP-4 is associated with an increased risk of adverse events during long term follow-up and favor the hypothesis that its prognostic ability is notable in patients in the acute phase of a myocardial infarction, even in the contemporary setting of routine primary PCI. The prognostic value of intact IGFBP-4 shown in our study, differs from what was previously observed by Postnikov [ 25 ] and Hjortebjerg [ 12 ], where measurements of full-length IGFBP4 were not predictive for MACE and intact IGFBP-4 did not perform better than C reactive protein or peak troponin I for any end point, respectively. These differences may in part be explained by the different immunoassays used in the studies.…”

“…Studies of IGFBP-4 as a cardiac risk marker have shown controversial results that may be justified by the differences in the study population, and the clinical setting where the IGFBP-4 was studied. In patients with stable cardiovascular disease, Schulz et al [ 26 ] found that CT- and NT-IGFBP4 levels failed to predict any long-term outcomes, whereas Postnikov et al [ 25 ] found that in patients with symptoms of myocardial ischemia but without ST-segment elevation, both NT- and CT-IGFBP-4 were strong predictors of major adverse cardiac events and more recently, Hjortebjerg et al [ 12 ] found that IGFBP-4 fragments were associated with increased risk of all-cause mortality, cardiovascular mortality and major adverse cardiac events in patients with STEMI. Nonetheless, our results support the evidence that in STEMI patients, IGFBP-4 is associated with an increased risk of adverse events during long term follow-up and favor the hypothesis that its prognostic ability is notable in patients in the acute phase of a myocardial infarction, even in the contemporary setting of routine primary PCI.…”

“…Collectively, the Stanniocalcin-2/PAPP-A/IGFBP-4 axis regulates local IGF bioavailability and signaling with potential biological implications in cardiovascular disease [ 8 ]. Despite recent studies showing that PAPP-A and IGFBP-4 are potentially important biomarkers for the prediction of adverse outcomes in patients with acute coronary syndrome [ 11 , 12 ], the evidence is scarce in contemporary-treated STEMI patients promptly reperfused, and to date, there are no reports on the prognostic value of Stanniocalcin-2 in this population.

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Current IGFBP-Related Biomarker Research in Cardiovascular Disease—We Need More Structural and Functional Information in Clinical Studies

“…IGFBP-4, also an abundant IGFBP, has been suggested in numerous studies to be directly involved in the inhibition of atherosclerosis ( 33 , 52 , 54 , 55 , 66 , 67 ). As demonstrated on the level of mRNA and protein, intact IGFBP-4 is produced by a variety of cell types and represents the major IGFBP secreted by myoblasts ( 68 – 70 ).…”

“…The varying results may relate to differences in follow-up period and number of patients and hence, events. Recently, the fragments were shown to prognosticate cardiovascular mortality in 330 type 1 diabetes patients without cardiovascular disease at baseline during 12 years of follow-up ( 54 ) and in 656 patients with STEMI followed for 5 years ( 55 ). Importantly, it was also verified that the IGFBP-4 fragments, unlike PAPP-A, were unaffected by heparin treatment of coronary patients ( 80 ).…”