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

Abstract

Background Fragments 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 Results We 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.