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


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.
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark rikke.hjortebjerg@clin.au.dk.|The Danish Diabetes Academy, Odense, Denmark.
Rikke
R
Hjortebjerg
Department of Cardiology P, Gentofte University Hospital, Copenhagen, Denmark.
Søren
S
Lindberg
Department of Cardiology P, Gentofte University Hospital, Copenhagen, Denmark.
Sune
S
Pedersen
Department of Cardiology P, Gentofte University Hospital, Copenhagen, Denmark.
Rasmus
R
Mogelvang
Department of Cardiology P, Gentofte University Hospital, Copenhagen, Denmark.|Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark.
Jan S
JS
Jensen
Department of Molecular Biology and Genetics, Faculty of Science and Technology, Aarhus University, Aarhus, Denmark.
Claus
C
Oxvig
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.|Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
Jan
J
Frystyk
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
Mette
M
Bjerre
D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000401:mortality*; D002423:Cause of Death; D005260:Female; D006333:Heart Failure / Q000453:epidemiology; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009203:Myocardial Infarction / Q000453:epidemiology; D010359:Patient Readmission; D010446:Peptide Fragments / Q000097:blood*; D062645:Percutaneous Coronary Intervention; D011379:Prognosis; D016016:Proportional Hazards Models; D000072657:ST Elevation Myocardial Infarction / Q000097:blood* / Q000601:surgery; D020521:Stroke / Q000453:epidemiology
D018974:Insulin-Like Growth Factor Binding Protein 4; D010446:Peptide Fragments
ST‐segment elevation myocardial infarction; biomarker; cardiovascular disease; insulin‐like growth factor binding protein 4; pregnancy‐associated plasma protein A