Insulin-like growth factor binding protein-3 (IGFBP-3): a biomarker of coronary artery disease induced myocardial ischaemia

Abstract

Aims: Among individuals presenting to the emergency department (ED) with chest pain, clinical uncertainty surrounds the appropriate identification of non-myocardial infarction (MI) individuals who would most benefit from objective functional/anatomical testing (e.g. imaging). We applied a proteomic biomarker discovery approach to identify novel candidates reflecting coronary artery disease (CAD) induced ischaemia that could translate to measurement in clinical samples. Methods and results: Mass spectroscopy (MS) of perfusate from an isolated rat heart model of cardiac ischaemia identified >100 novel protein biomarkers. A prominent candidate, insulin-like growth factor binding protein (IGFBP-3), was then interrogated for its ability to identify CAD-related ischaemia (e.g. positive cardiac stress test; unstable angina pectoris, UAP; arterial stenosis >70% on angiography) in multiple patient sample sets [cardiac stress testing, n = 12; septal alcohol ablation (SAA), n = 12; ED chest pain, n = 2977]. In cardiac stress testing, a significant delta IGFBP-3 (ΔIGFBP-3) between 0 and 150 min was seen in positive, but not negative, tests (P = 0.03). In SAA, peripheral IGFBP-3 levels did not change over 24 h (P = 0.57). In ED patients, ΔIGFBP-3 between 0 and 2 h (i) identified more 365-day low-risk major adverse cardiac event cases (27-30%), (ii) provided 7% improvement in positive predictive value over a clinical model for the identification of unstable angina (P = 0.01), and (iii) was a significant, independent predictor of >70% stenosis on angiography, improving indeterminate risk prediction by 9% (95% CI 3-15%). Conclusion: Our discovery approach has translated IGFBP-3 as a potential biomarker to identify significant CAD/ischaemia in patients who do not meet diagnostic thresholds for MI.