Free IGF-1, Intact IGFBP-4, and PicoPAPP-A are Altered in Acute Myocardial Infarction Compared to Stable Coronary Artery Disease and Healthy Controls

Abstract

Insulin-like growth factor-1 (IGF-1) and its binding proteins have been implicated in the pathophysiology of coronary artery disease (CAD) and myocardial infarction (MI). We investigated components of the IGF-1 system in circulation at the time of acute MI and following reperfusion in relation to levels of stable CAD patients and controls. Patients with MI (MI Group, n=31) treated with percutaneous coronary intervention (PCI) were compared to patients with stable CAD subjected to scheduled PCI (CAD Group, n=40) and controls with symptoms mimicking CAD without stenosis in angiography (Control Group, n=43). The number and extent of stenosis were recorded. Total and free IGF-1, total and intact IGF binding protein (IGFBP)-3 and -4, pico-Pregnancy Associated Plasma Protein-A (PAPP-A), and the known markers ALT, AST, CK and CK-MB were measured at baseline and 6 or 24 h after the intervention. Patients with MI had higher free IGF-1 (p=0.003) and PAPP-A (p=0.011), but lower intact IGFBP-4 (p=0.006) compared with patients with stable CAD or healthy controls. None of the investigated molecules changed following reperfusion or correlated with the extent of stenosis. AST (p<0.001), CK (p<0.001) and CK-MB (p<0.001), were also higher. Free IGF-1, intact IGFBP-4 and PAPP-A could predict MI, but with lower accuracy than CK-MB. In conclusion, free IGF-1 levels are higher in MI compared to CAD patients and controls and this could result from increased cleavage of its binding protein IGFBP-4 by the higher PAPP-A levels. Free IGF-1, intact IGFBP-4, and/or PAPP-A are inferior to CK-MB as predictors or markers of myocardial damage.

Key words

IGF - IGFBP - myocardial infarction - PAPP-A - percutaneous coronary intervention

• References

• 1 Neri M, Riezzo I, Pascale N, Pomara C, Turillazzi E. Ischemia/reperfusion injury following acute myocardial infarction: A critical issue for clinicians and forensic pathologists. Mediators Inflamm 2017; 7018393
• 2 Boldt HB, Conover CA. Pregnancy-associated plasma protein-A (PAPP-A): A local regulator of IGF bioavailability through cleavage of IGFBPs. Growth Horm IGF Res 2007; 17: 10-18
• 3 Oxvig C. The role of PAPP-A in the IGF system: Location, location, location. J Cell Commun Signal 2015; 9: 177-187
• 4 Hjortebjerg R. IGFBP-4 and PAPP-A in normal physiology and disease. Growth Horm IGF Res 2018; 41: 7-22
• 5 Hoeflich A, David R, Hjortebjerg R. Current igfbp-related biomarker research in cardiovascular disease-we need more structural and functional information in clinical studies. Front Endocrinol 2018; 9: 388
• 6 Grant MB, Wargovich TJ, Ellis EA, Tarnuzzer R, Caballero S, Estes K, Rossing M, Spoerri PE, Pepine C. Expression of IGF-I, IGF-I receptor and IGF binding proteins-1, -2, -3, -4 and -5 in human atherectomy specimens. Regul Pept 1996; 67: 137-144
• 7 Bornfeldt KE, Raines EW, Nakao T, Grave LM, Krebs EG, Ross R. Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. J Clin Invest 1994; 93: 1266-1274
• 8 Henson M, Damm D, Lam A, Garrard LJ, White T, Abraham JA, Schreiner GF, Stanton LW, Joly AH. Insulin-like growth factor-binding protein-3 induces fetalization in neonatal rat cardiomyocytes. DNA Cell Biol 2000; 19: 757-763
• 9 Cohick WS, Gockerman A, Clemmons DR. Vascular smooth muscle cells synthesize two forms of insulin-like growth factor binding proteins which are regulated differently by the insulin-like growth factors. J Cell Physiol 1993; 157: 52-60
• 10 Voudris KV, Chanin J, Feldman DN, Charitakis K. Novel inflammatory biomarkers in coronary artery disease: potential therapeutic approaches. Curr Med Chem 2015; 22: 2680-2689
• 11 Li Y, Zhou C, Zhou X, Song L, Hui R. PAPP-A in cardiac and non-cardiac conditions. Clin Chim Acta 2013; 417: 67-72
• 12 Reeves I, Abribat T, Laramee P, Jasmin G, Brazeau P. Age-related serum levels of insulin-like growth factor-I, -II and IGF-binding protein-3 following myocardial infarction. Growth Horm IGF Res 2000; 10: 78-84
• 13 Hu WS, Hwang JM. Association of serum cytokines, human growth hormone, insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein (IGFBP)-3 with coronary artery disease. Chin J Physiol 2012; 55: 267-273
• 14 Page JH, Ma J, Pollak M, Manson JE, Hankinson SE. Plasma insulin like growth factor 1 and binding-protein 3 and risk of myocardial infarction in women: A prospective study. Clin Chem 2008; 54: 1682-1688
• 15 Ruotolo G, Båvenholm P, Brismar K, Eféndic S, Ericsson CG, de Faire U, Nilsson J, Hamsten A. Serum insulin-like growth factor-I level is independently associated with coronary artery disease progression in young male survivors of myocardial infarction: beneficial effects of bezafibrate treatment. J Am Coll Cardiol 2000; 35: 647-654
• 16 Kaplan RC, McGinn AP, Pollak MN, Kuller LH, Strickler HD, Rohan TE, Cappola AR, Xue X, Psaty BM. Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. J Clin Endocrinol Metab 2007; 92: 1319-1325
• 17 Fischer F, Schulte H, Mohan S, Tataru MC, Köhler E, Assmann G, von Eckardstein A. Associations of insulin-like growth factors, insulin-like growth factor binding proteins and acid-labile subunit with coronary heart disease. Clin Endocrinol (Oxf) 2004; 61: 595-602
• 18 Clemmons DR. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinol Metab Clin North Am 2012; 41: 425-443 vii–viii
• 19 Blat C, Villaudy J, Binoux M. In vivo proteolysis of serum insulin-like growth factor (IGF) binding protein-3 results in increased availability of IGF to target cells. J Clin Invest 1994; 93: 2286-2290
• 20 Anastasilakis AD, Koulaxis D, Kefala N, Polyzos SA, Upadhyay J, Pagkalidou E, Economou F, Anastasilakis CD, Mantzoros CS. Circulating irisin levels are lower in patients with either stable coronary artery disease (CAD) or myocardial infarction (MI) versus healthy controls, whereas follistatin and activin A levels are higher and can discriminate MI from CAD with similar to CK-MB accuracy. Metabolism 2017; 73: 1-8
• 21 Møller AV, Jørgensen SP, Chen JW, Larnkjaer A, Ledet T, Flyvbjerg A, Frystyk J. Glycosaminoglycans increase levels of free and bioactive IGF-I in vitro. Eur J Endocrinol 2006; 155: 297-305
• 22 Terkelsen CJ, Oxvig C, Nørgaard BL, Glerup S, Poulsen TS, Lassen JF, Møller HJ, Thuesen L, Falk E, Nielsen TT, Andersen HR. Temporal course of pregnancy-associated plasma protein-A in angioplasty-treated ST-elevation myocardial infarction patients and potential significance of concomitant heparin administration. Am J Cardiol 2009; 103: 29-35
• 23 Conti E, Andreotti F, Sciahbas iA, Riccardi P, Marra G, Menini E, Ghirlanda G, Maseri A. Markedly reduced insulin-like growth factor-1 in the acute phase of myocardial infarction. J Am Coll Cardiol 2001; 38: 26-32
• 24 Lee WL, Chen JW, Ting CT, Lin SJ, Wang PH. Changes of the insulin-like growth factor I system during acute myocardial infarction: implications on left ventricular remodeling. J Clin Endocrinol Metab 1999; 84: 1575-1581
• 25 Janssen JA, Stolk RP, Pols HA, Grobbee DE, Lamberts SW. Serum total IGF-I, free IGF-I, and IGFB-1 levels in an elderly population: relation to cardiovascular risk factors and disease. Arterioscler Thromb Vasc Biol 1998; 18: 277-282
• 26 Juul A, Scheike T, Davidsen M, Gyllenborg J, Jørgensen T. Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: A population-based case-control study. Circulation 2002; 106: 939-944
• 27 Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Zuppi C, Andreotti F. Insulin-like growth factor-1 as a vascular protective factor. Circulation 2004; 110: 2260-2265
• 28 Ricketts SL, Rensing KL, Holly JM, Chen L, Young EH, Luben R, Ashford S, Song K, Yuan X, Dehghan A, Wright BJ, Waterworth DM, Mooser V. GEMS Investigators. Waeber G, Vollenweider P, Epstein SE, Burnett MS, Devaney JM, Hakonarson HH, Rader DJ, Reilly MP, Danesh J, Thompson SG, Dunning AM, van Duijn CM, Samani NJ, McPherson R, Wareham NJ, Khaw KT, Boekholdt SM, Sandhu MS. Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease. Int J Mol Epidemiol Genet 2011; 2: 261-285
• 29 Chang RL, Lin JW, Hsieh DJ, Yeh YL, Shen CY, Day CH, Ho TJ, Viswanadha VP, Kuo WW, Huang CY. Long-term hypoxia exposure enhanced IGFBP-3 protein synthesis and secretion resulting in cell apoptosis in H9c2 myocardial cells. Growth Factors 2015; 33: 275-281
• 30 Wo D, Peng J, Ren DN, Qiu L, Chen J, Zhu Y, Yan Y, Yan H, Wu J, Ma E, Zhong TP, Chen Y, Liu Z, Liu S, Ao L, Liu Z, Jiang C, Peng J, Zou Y, Qian Q, Zhu W. Opposing roles of wnt inhibitors IGFBP-4 and Dkk1 in cardiac ischemia by differential targeting of LRP5/6 and b-catenin. Circulation 2016; 134: 1991-2007
• 31 Prentice RL, Paczesny S, Aragaki A, Amon LM, Chen L, Pitteri SJ, McIntosh M, Wang P, Buson Busald T, Hsia J, Jackson RD, Rossouw JE, Manson JE, Johnson K, Eaton C, Hanash SM. Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling. Genome Med 2010; 2: 48
• 32 Hjortebjerg R, Lindberg S, Hoffmann S, Jensen JS, Oxvig C, Bjerre M, Frystyk J. PAPP-A and IGFBP-4 fragment levels in patients with ST-elevation myocardial infarction treated with heparin and PCI. Clin Biochem 2015; 48: 322-328
• 33 Konev AA, Smolyanova TI, Kharitonov AV, Serebryanaya DV, Kozlovsky SV, Kara AN, Feygina EE, Katrukha AG, Postnikov AB. Characterization of endogenously circulating IGFBP-4 fragments-Novel biomarkers for cardiac risk assessment. Clin Biochem 2015; 48: 774-780
• 34 Postnikov AB, Smolyanova TI, Kharitonov AV, Serebryanaya DV, Kozlovsky SV, Tryshina YA, Malanicev RV, Arutyunov AG, Murakami MM, Apple FS, Katrukha AG. N-terminal and C-terminal fragments of IGFBP-4 as novel biomarkers for short-term risk assessment of major adverse cardiac events in patients presenting with ischemia. Clin Biochem 2012; 45: 519-524
• 35 Schulz O, Postnikov AB, Smolyanova TI, Katrukha AG, Schimke I, Jaffe AS. Clinical differences between total PAPP-A and measurements specific for the products of free PAPP-A activity in patients with stable cardiovascular disease. Clin Biochem 2014; 47: 177-183
• 36 Conover CA, Harrington SC, Bale LK. Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells. Growth Horm IGF Res 2008; 18: 213-220
• 37 Bonaca MP, Scirica BM, Sabatine MS, Jarolim P, Murphy SA, Chamberlin JS, Rhodes DW, Southwick PC, Braunwald E, Morrow DA. Prospective evaluation of pregnancy-associated plasma protein-a and outcomes in patients with acute coronary syndromes. J Am Coll Cardiol 2012; 60: 332-338
• 38 Mei WY, Du ZM, Zhao Q, Hu CH, Li Y, Luo CF, Wu GF, Chen GW, Wang LX. Pregnancy-associated plasma protein predicts outcomes of percutaneous coronary intervention in patients with non-ST-elevation acute coronary syndrome. Heart Lung 2011; 40: e78-e83
• 39 Iversen KK, Teisner B, Winkel P, Gluud C, Kjøller E, Kolmos HJ, Hildebrandt PR, Hilden J, Kastrup J. Pregnancy associated plasma protein-A as a marker for myocardial infarction and death in patients with stable coronary artery disease: A prognostic study within the CLARICOR Trial. Atherosclerosis 2011; 214: 203-208
• 40 Li Y, Zhou C, Zhou X, Li L, Hui R. Pregnancy-associated plasma protein A predicts adverse vascular events in patients with coronary heart disease: A systematic review and meta-analysis. Arch Med Sci 2013; 9: 389-397
• 41 Cosin-Sales J, Kaski JC, Christiansen M, Kaminski P, Oxvig C, Overgaard MT, Cole D, Holt DW. Relationship among pregnancy associated plasma protein-A levels, clinical characteristics, and coronary artery disease extent in patients with chronic stable angina pectoris. Eur Heart J 2005; 26: 2093-2098
• 42 Cosin-Sales J, Christiansen M, Kaminski P, Oxvig C, Overgaard MT, Cole D, Holt DW, Kaski JC. Pregnancy-associated plasma protein A and its endogenous inhibitor, the proform of eosinophil major basic protein (proMBP), are related to complex stenosis morphology in patients with stable angina pectoris. Circulation 2004; 109: 1724-1728
• 43 Bayes-Genis A, Conover CA, Overgaard MT, Bailey KR, Christiansen M, Holmes DRJ, Virmani R, Oxvig C, Schwartz RS. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med 2001; 345: 1022-1029
• 44 Heeschen C, Dimmeler S, Hamm CW, Fichtlscherer S, Simoons ML, Zeiher AM. Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: Comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. J Am Coll Cardiol 2005; 45: 229-237
• 45 Conti E, Andreotti F, Zuppi C. Pregnancy-associated plasma protein-A as predictor of outcome in patients with suspected acute coronary syndromes. Circulation 2004; 109: e211-e212
• 46 Glerup S, Boldt HB, Overgaard MT, Sottrup-Jensen L, Giudice LC, Oxvig C. Proteinase inhibition by proform of eosinophil major basic protein (pro-MBP) is a multistep process of intra- and intermolecular disulfide rearrangements. J Biol Chem 2005; 280: 9823-9832
• 47 Zhabin SG, Gorin VS, Judin NS. Review: Immunomodulatory activity of pregnancy-associated plasma protein-A. J Clin Lab Immunol 2003; 52: 41-50
• 48 Matthews KG, Devlin GP, Conaglen JV, Stuart SP, Mervyn Aitken W, Bass JJ. Changes in IGFs in cardiac tissue following myocardial infarction. J Endocrinol 1999; 163: 433-445
• 49 Gómez-Mauricio G, Moscoso I, Martín-Cancho MF, Crisóstomo V, Prat-Vidal C, Báez-Díaz C, Sánchez-Margallo FM, Bernad A. Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model. Stem Cell Res Ther 2016; 7: 94
• 50 Clemmons DR. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinol Metab Clin North Am 2012; 41: 425-443
• 51 Karras DJ, Kane DL. Serum markers in the emergency department diagnosis of acute myocardial infarction. Emerg Med Clin North Am 2001; 19: 321-337
• 52 Panagiotou G, Anastasilakis AD, Kynigopoulos G, Skouvaklidou EC, Saridakis ZG, Upadhyay J, Apostolou A, Karagiozoglou-Lampoudi T, Mantzoros CS. Physiological parameters regulating circulating levels of the IGFBP-4/ Stanniocalcin-2/PAPP-A axis. Metabolism 2017; 75: 16-24