Skip to main content
Top
Published in: BMC Cardiovascular Disorders 1/2016

Open Access 01-12-2016 | Research article

Serum insulin-like growth factor-1 and its binding protein-7: potential novel biomarkers for heart failure with preserved ejection fraction

Authors: Michael Coll Barroso, Frank Kramer, Stephen J. Greene, Daniel Scheyer, Till Köhler, Martin Karoff, Melchior Seyfarth, Mihai Gheorghiade, Wilfried Dinh

Published in: BMC Cardiovascular Disorders | Issue 1/2016

Login to get access

Abstract

Background

Insulin-like growth factor binding protein-7 (IGFBP-7) modulates the biological activities of insulin-like growth factor-1 (IGF-1). Previous studies demonstrated the prognostic value of IGFBP-7 and IGF-1 among patients with systolic heart failure (HF). This study aimed to evaluate the IGF1/IGFBP-7 axis in HF patients with preserved ejection fraction (HFpEF).

Methods

Serum IGF-1 and IGFBP-7 levels were measured in 300 eligible consecutive patients who underwent comprehensive cardiac assessment. Patients were categorized into 3 groups including controls with normal diastolic function (n = 55), asymptomatic left ventricular diastolic dysfunction (LVDD, n = 168) and HFpEF (n = 77).

Results

IGFBP-7 serum levels showed a significant graded increase from controls to LVDD to HFpEF (median 50.30 [43.1-55.3] vs. 54.40 [48.15-63.40] vs. 61.9 [51.6-69.7], respectively, P < 0.001), whereas IGF-1 levels showed a graded decline from controls to LVDD to HFpEF (120.0 [100.8-144.0] vs. 112.3 [88.8-137.1] vs. 99.5 [72.2-124.4], p < 0.001). The IGFBP-7/IGF-1 ratio increased from controls to LVDD to HFpEF (0.43 [0.33-0.56] vs. 0.48 [0.38-0.66] vs. 0.68 [0.55-0.88], p < 0.001). Patents with IGFB-7/IGF1 ratios above the median demonstrated significantly higher left atrial volume index, E/E’ ratio, and NT-proBNP levels (all P ≤ 0.02).

Conclusion

In conclusion, this hypothesis-generating pilot study suggests the IGFBP-7/IGF-1 axis correlates with diastolic function and may serve as a novel biomarker in patients with HFpEF. A rise in IGFBP-7 or the IGFBP-7/IGF-1 ratio may reflect worsening diastolic function, adverse cardiac remodeling, and metabolic derangement.
Literature
1.
go back to reference Shah RV, Desai AS, Givertz MM. The effect of renin-angiotensin system inhibitors on mortality and heart failure hospitalization in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis. J Card Fail. 2010;16(3):260–7.CrossRefPubMed Shah RV, Desai AS, Givertz MM. The effect of renin-angiotensin system inhibitors on mortality and heart failure hospitalization in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis. J Card Fail. 2010;16(3):260–7.CrossRefPubMed
2.
go back to reference Shah SJ. Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter. J Am Coll Cardiol. 2013;62(15):1339–42.CrossRefPubMed Shah SJ. Matchmaking for the optimization of clinical trials of heart failure with preserved ejection fraction: no laughing matter. J Am Coll Cardiol. 2013;62(15):1339–42.CrossRefPubMed
3.
go back to reference Chen D, Yoo BK, Santhekadur PK, Gredler R, Bhutia SK, Das SK, Fuller C, Su ZZ, Fisher PB, Sarkar D. Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma. Clin Cancer Res. 2011;17(21):6693–701.CrossRefPubMedPubMedCentral Chen D, Yoo BK, Santhekadur PK, Gredler R, Bhutia SK, Das SK, Fuller C, Su ZZ, Fisher PB, Sarkar D. Insulin-like growth factor-binding protein-7 functions as a potential tumor suppressor in hepatocellular carcinoma. Clin Cancer Res. 2011;17(21):6693–701.CrossRefPubMedPubMedCentral
4.
go back to reference Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG. Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II. J Biol Chem. 1996;271(48):30322–5.CrossRefPubMed Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG. Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II. J Biol Chem. 1996;271(48):30322–5.CrossRefPubMed
5.
6.
go back to reference Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006;114(17):1829–37.CrossRefPubMed Jankowska EA, Biel B, Majda J, Szklarska A, Lopuszanska M, Medras M, Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski P. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006;114(17):1829–37.CrossRefPubMed
7.
go back to reference Gandhi PU, Gaggin HK, Sheftel AD, Belcher AM, Weiner RB, Baggish AL, Motiwala SR, Liu PP, Januzzi Jr JL. Prognostic usefulness of insulin-like growth factor-binding protein 7 in heart failure with reduced ejection fraction: a novel biomarker of myocardial diastolic function? Am J Cardiol. 2014;114(10):1543–9.CrossRefPubMed Gandhi PU, Gaggin HK, Sheftel AD, Belcher AM, Weiner RB, Baggish AL, Motiwala SR, Liu PP, Januzzi Jr JL. Prognostic usefulness of insulin-like growth factor-binding protein 7 in heart failure with reduced ejection fraction: a novel biomarker of myocardial diastolic function? Am J Cardiol. 2014;114(10):1543–9.CrossRefPubMed
8.
go back to reference Motiwala SR, Szymonifka J, Belcher A, Weiner RB, Baggish AL, Gaggin HK, Bhardwaj A, Januzzi Jr JL. Measurement of novel biomarkers to predict chronic heart failure outcomes and left ventricular remodeling. J Cardiovasc Transl Res. 2014;7(2):250–61.CrossRefPubMed Motiwala SR, Szymonifka J, Belcher A, Weiner RB, Baggish AL, Gaggin HK, Bhardwaj A, Januzzi Jr JL. Measurement of novel biomarkers to predict chronic heart failure outcomes and left ventricular remodeling. J Cardiovasc Transl Res. 2014;7(2):250–61.CrossRefPubMed
9.
go back to reference Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–63.CrossRefPubMed Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–63.CrossRefPubMed
10.
go back to reference Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10(2):165–93.CrossRefPubMed Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10(2):165–93.CrossRefPubMed
11.
go back to reference Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975.CrossRefPubMed Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975.CrossRefPubMed
12.
go back to reference Prontera C, Zucchelli GC, Vittorini S, Storti S, Emdin M, Clerico A. Comparison between analytical performances of polyclonal and monoclonal electrochemiluminescence immunoassays for NT-proBNP. Clin Chim Acta. 2009;400(1–2):70–3.CrossRefPubMed Prontera C, Zucchelli GC, Vittorini S, Storti S, Emdin M, Clerico A. Comparison between analytical performances of polyclonal and monoclonal electrochemiluminescence immunoassays for NT-proBNP. Clin Chim Acta. 2009;400(1–2):70–3.CrossRefPubMed
13.
go back to reference Rathmann W, Haastert B, Icks A, Lowel H, Meisinger C, Holle R, Giani G. High prevalence of undiagnosed diabetes mellitus in Southern Germany: target populations for efficient screening. The KORA survey 2000. Diabetologia. 2003;46(2):182–9.CrossRefPubMed Rathmann W, Haastert B, Icks A, Lowel H, Meisinger C, Holle R, Giani G. High prevalence of undiagnosed diabetes mellitus in Southern Germany: target populations for efficient screening. The KORA survey 2000. Diabetologia. 2003;46(2):182–9.CrossRefPubMed
14.
go back to reference Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholsterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama 2001, 285(19):2486–2497. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholsterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama 2001, 285(19):2486–2497.
15.
go back to reference Rossi A, Gheorghiade M, Triposkiadis F, Solomon SD, Pieske B, Butler J. Left atrium in heart failure with preserved ejection fraction: structure, function, and significance. Circ Heart Fail. 2014;7(6):1042–9.CrossRefPubMed Rossi A, Gheorghiade M, Triposkiadis F, Solomon SD, Pieske B, Butler J. Left atrium in heart failure with preserved ejection fraction: structure, function, and significance. Circ Heart Fail. 2014;7(6):1042–9.CrossRefPubMed
16.
go back to reference van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, Paulus WJ, Voors AA, Hillege HL. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol. 2013;61(14):1498–506.CrossRefPubMed van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, Paulus WJ, Voors AA, Hillege HL. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol. 2013;61(14):1498–506.CrossRefPubMed
17.
go back to reference Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, Goto Y, Nonogi H. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol. 2006;47(4):742–8.CrossRefPubMed Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, Goto Y, Nonogi H. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol. 2006;47(4):742–8.CrossRefPubMed
18.
go back to reference Osterziel KJ, Strohm O, Schuler J, Friedrich M, Hanlein D, Willenbrock R, Anker SD, Poole-Wilson PA, Ranke MB, Dietz R. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998;351(9111):1233–7.CrossRefPubMed Osterziel KJ, Strohm O, Schuler J, Friedrich M, Hanlein D, Willenbrock R, Anker SD, Poole-Wilson PA, Ranke MB, Dietz R. Randomised, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998;351(9111):1233–7.CrossRefPubMed
19.
go back to reference Guo XH, Liu LX, Zhang HY, Zhang QQ, Li Y, Tian XX, Qiu ZH. Insulin-like growth factor binding protein-related protein 1 contributes to hepatic fibrogenesis. J Dig Dis. 2014;15(4):202–10.CrossRefPubMed Guo XH, Liu LX, Zhang HY, Zhang QQ, Li Y, Tian XX, Qiu ZH. Insulin-like growth factor binding protein-related protein 1 contributes to hepatic fibrogenesis. J Dig Dis. 2014;15(4):202–10.CrossRefPubMed
20.
go back to reference Zile MR, Baicu CF. Biomarkers of diastolic dysfunction and myocardial fibrosis: application to heart failure with a preserved ejection fraction. J Cardiovasc Transl Res. 2013;6(4):501–15.CrossRefPubMed Zile MR, Baicu CF. Biomarkers of diastolic dysfunction and myocardial fibrosis: application to heart failure with a preserved ejection fraction. J Cardiovasc Transl Res. 2013;6(4):501–15.CrossRefPubMed
21.
go back to reference Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147–239.CrossRefPubMed Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147–239.CrossRefPubMed
22.
go back to reference Zile MR, Jhund PS, Baicu CF, Claggett BL, Pieske B, Voors AA, Prescott MF, Shi V, Lefkowitz M, McMurray JJ et al.: Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study. Circ Heart Fail 2016;99:e002551. doi: 10.1161/CIRCHEARTFAILURE.115.002551 Zile MR, Jhund PS, Baicu CF, Claggett BL, Pieske B, Voors AA, Prescott MF, Shi V, Lefkowitz M, McMurray JJ et al.: Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study. Circ Heart Fail 2016;99:e002551. doi: 10.​1161/​CIRCHEARTFAILURE​.​115.​002551
23.
go back to reference Liu Y, Wu M, Ling J, Cai L, Zhang D, Gu HF, Wang H, Zhu Y, Lai M. Serum IGFBP7 levels associate with insulin resistance and the risk of metabolic syndrome in a Chinese population. Sci Rep. 2015;5:10227.CrossRefPubMedPubMedCentral Liu Y, Wu M, Ling J, Cai L, Zhang D, Gu HF, Wang H, Zhu Y, Lai M. Serum IGFBP7 levels associate with insulin resistance and the risk of metabolic syndrome in a Chinese population. Sci Rep. 2015;5:10227.CrossRefPubMedPubMedCentral
24.
go back to reference Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet. 2002;359(9319):1740–5.CrossRefPubMed Sandhu MS, Heald AH, Gibson JM, Cruickshank JK, Dunger DB, Wareham NJ. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet. 2002;359(9319):1740–5.CrossRefPubMed
25.
go back to reference Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y. Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem. 1997;272(49):30729–34.CrossRefPubMed Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y. Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem. 1997;272(49):30729–34.CrossRefPubMed
26.
go back to reference Lopez-Bermejo A, Khosravi J, Fernandez-Real JM, Hwa V, Pratt KL, Casamitjana R, Garcia-Gil MM, Rosenfeld RG, Ricart W. Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25). Diabetes. 2006;55(8):2333–9.CrossRefPubMed Lopez-Bermejo A, Khosravi J, Fernandez-Real JM, Hwa V, Pratt KL, Casamitjana R, Garcia-Gil MM, Rosenfeld RG, Ricart W. Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25). Diabetes. 2006;55(8):2333–9.CrossRefPubMed
27.
go back to reference Dinh W, Lankisch M, Nickl W, Scheyer D, Scheffold T, Kramer F, Krahn T, Klein RM, Coll Barroso M, Futh R: Insulin resistance and glycaemic abnormalities are associated with deterioration of left ventricular diastolic function: a cross-sectional study. Cardiovasc Diabetol, 2010;9:63. doi: 10.1186/1475-2840-9-63 Dinh W, Lankisch M, Nickl W, Scheyer D, Scheffold T, Kramer F, Krahn T, Klein RM, Coll Barroso M, Futh R: Insulin resistance and glycaemic abnormalities are associated with deterioration of left ventricular diastolic function: a cross-sectional study. Cardiovasc Diabetol, 2010;9:63. doi: 10.​1186/​1475-2840-9-63
28.
go back to reference Scherbakov N, Bauer M, Sandek A, Szabo T, Topper A, Jankowska EA, Springer J, von Haehling S, Anker SD, Lainscak M, et al. Insulin resistance in heart failure: differences between patients with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail. 2015;17(10):1015–21.CrossRefPubMed Scherbakov N, Bauer M, Sandek A, Szabo T, Topper A, Jankowska EA, Springer J, von Haehling S, Anker SD, Lainscak M, et al. Insulin resistance in heart failure: differences between patients with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail. 2015;17(10):1015–21.CrossRefPubMed
29.
go back to reference Greene SJ, Fonarow GC. Insulin resistance in heart failure: widening the divide between reduced and preserved ejection fraction? Eur J Heart Fail. 2015;17(10):991–3.CrossRefPubMed Greene SJ, Fonarow GC. Insulin resistance in heart failure: widening the divide between reduced and preserved ejection fraction? Eur J Heart Fail. 2015;17(10):991–3.CrossRefPubMed
30.
go back to reference Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA, Atar D, Butler J, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64(21):2281–93.CrossRefPubMedPubMedCentral Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, Kjeldsen K, Jankowska EA, Atar D, Butler J, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64(21):2281–93.CrossRefPubMedPubMedCentral
31.
go back to reference Sanders-van Wijk S, van Empel V, Davarzani N, Maeder MT, Handschin R, Pfisterer ME, Brunner-La Rocca HP, investigators T-C. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur J Heart Fail. 2015;17(10):1006–14.CrossRefPubMed Sanders-van Wijk S, van Empel V, Davarzani N, Maeder MT, Handschin R, Pfisterer ME, Brunner-La Rocca HP, investigators T-C. Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur J Heart Fail. 2015;17(10):1006–14.CrossRefPubMed
32.
go back to reference Emdin M, Passino C, Prontera C, Fontana M, Poletti R, Gabutti A, Mammini C, Giannoni A, Zyw L, Zucchelli G, et al. Comparison of brain natriuretic peptide (BNP) and amino-terminal ProBNP for early diagnosis of heart failure. Clin Chem. 2007;53(7):1289–97.CrossRefPubMed Emdin M, Passino C, Prontera C, Fontana M, Poletti R, Gabutti A, Mammini C, Giannoni A, Zyw L, Zucchelli G, et al. Comparison of brain natriuretic peptide (BNP) and amino-terminal ProBNP for early diagnosis of heart failure. Clin Chem. 2007;53(7):1289–97.CrossRefPubMed
Metadata
Title
Serum insulin-like growth factor-1 and its binding protein-7: potential novel biomarkers for heart failure with preserved ejection fraction
Authors
Michael Coll Barroso
Frank Kramer
Stephen J. Greene
Daniel Scheyer
Till Köhler
Martin Karoff
Melchior Seyfarth
Mihai Gheorghiade
Wilfried Dinh
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cardiovascular Disorders / Issue 1/2016
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-016-0376-2

Other articles of this Issue 1/2016

BMC Cardiovascular Disorders 1/2016 Go to the issue