Skip to main content
SpringerLink
Log in

HMGB1 is an independent predictor of death and heart transplantation in heart failure

  • Original Paper
  • Published:
Clinical Research in Cardiology Aims and scope Submit manuscript

Abstract

Background

High-Mobility-Group Box 1 (HMGB1) has been established as an important mediator of myocardial inflammation and associated with progression of heart failure (HF). The aim of this study was to analyze the prognostic value of systemic HMGB1 levels in HF patients with ischemic and non-ischemic cardiomyopathy.

Methods and results

We conducted an analysis (median follow-up time 2.5 years) of HMGB1 plasma concentration in 154 patients with systolic HF and correlated the results with disease severity and prognosis. HMGB1 in HF patients with severe symptoms (NYHA III/IV; 5.35 ng/ml; interquartile range (IQR) = 3.48–8.42 ng/ml) was significantly elevated compared with that in patients with mild symptoms (NYHA I/II; 3.37 ng/ml, IQR = 2.31–5.22 ng/ml, p < 0.0001) and with controls (3.25 ng/ml, IQR = 3.04–3.67 ng/ml, p < 0.0001). HMGB1 levels correlated with other markers of heart failure indicating an association of HMGB1 with disease severity in HF. In a univariate cox regression model for the combined endpoint of death and heart transplantation, HMGB1 proved to be a predictor at cut-off values based on HMGB1 terciles of either 3.4 or 6.1 ng/ml (p = 0.001 and p < 0.0001, respectively). In a multivariate cox regression model, which included NT-proBNP, creatinine, age, NYHA class, white blood cell count, anemia, and age, HMGB1 remained an independent predictor of the combined endpoint (hazard ratio (HR) = 2.48, 95% confidence interval (CI) = 1.06–5.83, p = 0.037 and HR = 2.48, 95% CI = 1.31–4.71, p = 0.005, respectively).

Conclusion

Our findings demonstrate that HMGB1 plasma concentration is elevated in HF and correlates with disease severity and that is an independent predictor of the combined endpoint death and heart transplantation in HF patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Thomas JO (2001) HMG1 and 2: architectural DNA-binding proteins. Biochem Soc Trans 29(Pt 4):395–401

    Article  PubMed  CAS  Google Scholar 

  2. Manfredi AA, Capobianco A, Esposito A, De Cobelli F, Canu T, Monno A, Raucci A, Sanvito F, Doglioni C, Nawroth PP, Bierhaus A, Bianchi ME, Rovere-Querini P, Del Maschio A (2008) Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes. J Immunol 180(4):2270–2275. doi:180/4/2270

    PubMed  CAS  Google Scholar 

  3. Dumitriu IE, Baruah P, Manfredi AA, Bianchi ME, Rovere-Querini P (2005) HMGB1: guiding immunity from within. Trends Immunol 26(7):381–387. doi:10.1016/j.it.2005.04.009

    Article  PubMed  CAS  Google Scholar 

  4. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279(9):7370–7377. doi:10.1074/jbc.M306793200

    Article  PubMed  CAS  Google Scholar 

  5. Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, Dumitriu IE, Muller S, Iannacone M, Traversari C, Bianchi ME, Manfredi AA (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 5(8):825–830. doi:10.1038/sj.embor.7400205

    Article  PubMed  CAS  Google Scholar 

  6. Bierhaus A, Nawroth PP (2009) Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications. Diabetologia 52(11):2251–2263. doi:10.1007/s00125-009-1458-9

    Article  PubMed  CAS  Google Scholar 

  7. Inoue K, Kawahara K, Biswas KK, Ando K, Mitsudo K, Nobuyoshi M, Maruyama I (2007) HMGB1 expression by activated vascular smooth muscle cells in advanced human atherosclerosis plaques. Cardiovasc Pathol 16(3):136–143. doi:10.1016/j.carpath.2006.11.006

    Article  PubMed  CAS  Google Scholar 

  8. Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ (2009) HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 28:367–388. doi:10.1146/annurev.immunol.021908.132603

    Article  Google Scholar 

  9. Porto A, Palumbo R, Pieroni M, Aprigliano G, Chiesa R, Sanvito F, Maseri A, Bianchi ME (2006) Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein. FASEB J 20(14):2565–2566. doi:10.1096/fj.06-5867fje

    Article  PubMed  CAS  Google Scholar 

  10. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, Suffredini AF (2003) Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101(7):2652–2660. doi:10.1182/blood-2002-05-1300

    Article  PubMed  CAS  Google Scholar 

  11. Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plachky J, Grone HJ, Kurschus FC, Schmidt AM, Yan SD, Martin E, Schleicher E, Stern DM, Hammerling GG, Nawroth PP, Arnold B (2004) Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest 113(11):1641–1650. doi:10.1172/JCI18704

    PubMed  CAS  Google Scholar 

  12. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, Czura CJ, Roth J, Warren HS, Fink MP, Fenton MJ, Andersson U, Tracey KJ (2004) Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 101(1):296–301. doi:10.1073/pnas.2434651100

    Article  PubMed  CAS  Google Scholar 

  13. Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, Buss S, Autschbach F, Pleger ST, Lukic IK, Bea F, Hardt SE, Humpert PM, Bianchi ME, Mairbaurl H, Nawroth PP, Remppis A, Katus HA, Bierhaus A (2008) High-mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation 117(25):3216–3226. doi:10.1161/CIRCULATIONAHA.108.769331

    Article  PubMed  CAS  Google Scholar 

  14. Hu X, Zhou X, He B, Xu C, Wu L, Cui B, Wen H, Lu Z, Jiang H (2010) Minocycline protects against myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. Eur J Pharmacol 638(1–3):84–89. doi:10.1016/j.ejphar.2010.03.059

    Article  PubMed  CAS  Google Scholar 

  15. Yan XX, Lu L, Peng WH, Wang LJ, Zhang Q, Zhang RY, Chen QJ, Shen WF (2009) Increased serum HMGB1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients. Atherosclerosis 205(2):544–548. doi:10.1016/j.atherosclerosis.2008.12.016

    Article  PubMed  CAS  Google Scholar 

  16. Giallauria F, Cirillo P, Lucci R, Pacileo M, D’Agostino M, Maietta P, Vitelli A, Chiariello M, Vigorito C (2009) Autonomic dysfunction is associated with high mobility group box-1 levels in patients after acute myocardial infarction. Atherosclerosis 208(1):280–284. doi:10.1016/j.atherosclerosis.2009.07.025

    Article  PubMed  Google Scholar 

  17. Kohno T, Anzai T, Naito K, Miyasho T, Okamoto M, Yokota H, Yamada S, Maekawa Y, Takahashi T, Yoshikawa T, Ishizaka A, Ogawa S (2009) Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling. Cardiovasc Res 81(3):565–573. doi:10.1093/cvr/cvn291

    Article  PubMed  CAS  Google Scholar 

  18. Giallauria F, Cirillo P, Lucci R, Pacileo M, D’Agostino M, Maietta P, Vitelli A, Chiariello M, Vigorito C (2009) Effects of exercise-based cardiac rehabilitation on high mobility group box-1 levels after acute myocardial infarction: rationale and design. J Cardiovasc Med (Hagerstown) 10(8):659–663. doi:10.2459/JCM.0b013e32832d4979

    Article  Google Scholar 

  19. Volz HC, Seidel C, Laohachewin D, Kaya Z, Muller OJ, Pleger ST, Lasitschka F, Bianchi ME, Remppis A, Bierhaus A, Katus HA, Andrassy M (2010) HMGB1: the missing link between diabetes mellitus and heart failure. Basic Res Cardiol 105(6):805–820. doi:10.1007/s00395-010-0114-3

    Article  PubMed  CAS  Google Scholar 

  20. Wang LJ, Lu L, Zhang FR, Chen QJ, De Caterina R, Shen WF (2010) Increased serum high-mobility group box-1 and cleaved receptor for advanced glycation endproducts levels and decreased endogenous secretory receptor for advanced glycation endproducts levels in diabetic and non-diabetic patients with heart failure. Eur J Heart Fail. doi:10.1093/eurjhf/hfq231

    Google Scholar 

  21. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, Tavazzi L, Smiseth OA, Gavazzi A, Haverich A, Hoes A, Jaarsma T, Korewicki J, Levy S, Linde C, Lopez-Sendon JL, Nieminen MS, Pierard L, Remme WJ (2005) Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): the task force for the diagnosis and treatment of chronic heart failure of the european society of cardiology. Eur Heart J 26(11):1115–1140. doi:10.1093/eurheartj/ehi204

    Article  PubMed  Google Scholar 

  22. Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD (2000) Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102(25):3060–3067

    PubMed  CAS  Google Scholar 

  23. Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL (2001) Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103(16):2055–2059

    PubMed  CAS  Google Scholar 

  24. Jensen J, Ma LP, Fu ML, Svaninger D, Lundberg PA, Hammarsten O Inflammation increases NT-proBNP and the NT-proBNP/BNP ratio. Clin Res Cardiol 99 (7):445-452. doi:10.1007/s00392-010-0140-z

  25. Sun M, Dawood F, Wen WH, Chen M, Dixon I, Kirshenbaum LA, Liu PP (2004) Excessive tumor necrosis factor activation after infarction contributes to susceptibility of myocardial rupture and left ventricular dysfunction. Circulation 110(20):3221–3228. doi:10.1161/01.CIR.0000147233.10318.23

    Article  PubMed  CAS  Google Scholar 

  26. Nian M, Lee P, Khaper N, Liu P (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94(12):1543–1553. doi:10.1161/01.RES.0000130526.20854.fa94/12/1543

    Article  PubMed  CAS  Google Scholar 

  27. Maekawa Y, Anzai T, Yoshikawa T, Asakura Y, Takahashi T, Ishikawa S, Mitamura H, Ogawa S (2002) Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction:a possible role for left ventricular remodeling. J Am Coll Cardiol 39(2):241–246. doi:S0735109701017211

    Article  PubMed  Google Scholar 

  28. Volz HC, Kaya Z, Katus HA, Andrassy M (2010) The role of HMGB1/RAGE in inflammatory cardiomyopathy. Semin Thromb Hemost 36(2):185–194. doi:10.1055/s-0030-1251503

    Article  PubMed  CAS  Google Scholar 

  29. Tzeng HP, Fan J, Vallejo JG, Dong JW, Chen X, Houser SR, Mann DL (2008) Negative inotropic effects of high-mobility group box 1 protein in isolated contracting cardiac myocytes. Am J Physiol Heart Circ Physiol 294(3):H1490–H1496. doi:10.1152/ajpheart.00910.2007

    Article  PubMed  CAS  Google Scholar 

  30. Huang Y, Yin H, Han J, Huang B, Xu J, Zheng F, Tan Z, Fang M, Rui L, Chen D, Wang S, Zheng X, Wang CY, Gong F (2007) Extracellular hmgb1 functions as an innate immune-mediator implicated in murine cardiac allograft acute rejection. Am J Transplant 7(4):799–808. doi:10.1111/j.1600-6143.2007.01734.x

    Article  PubMed  CAS  Google Scholar 

  31. Cowie MR, Struthers AD, Wood DA, Coats AJ, Thompson SG, Poole-Wilson PA, Sutton GC (1997) Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 350(9088):1349–1353. doi:10.1016/S0140-6736(97)06031-5

    Article  PubMed  CAS  Google Scholar 

  32. Neizel M, Steen H, Korosoglou G, Lossnitzer D, Lehrke S, Ivandic BT, Katus HA, Giannitsis E (2009) Minor troponin T elevation in patients 6 months after acute myocardial infarction: an observational study. Clin Res Cardiol 98(5):297–304. doi:10.1007/s00392-009-0002-8

    Article  PubMed  CAS  Google Scholar 

  33. Smilde TD, Damman K, van der Harst P, Navis G, Westenbrink BD, Voors AA, Boomsma F, van Veldhuisen DJ, Hillege HL (2009) Differential associations between renal function and “modifiable” risk factors in patients with chronic heart failure. Clin Res Cardiol 98(2):121–129. doi:10.1007/s00392-008-0732-z

    Article  PubMed  CAS  Google Scholar 

  34. Zugck C, Haunstetter A, Kruger C, Kell R, Schellberg D, Kubler W, Haass M (2002) Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure. J Am Coll Cardiol 39(10):1615–1622. doi:S0735109702018405

    Article  PubMed  CAS  Google Scholar 

  35. Kamp O, Metra M, De Keulenaer GW, Pieske B, Conraads V, Zamorano J, Huysse L, Vardas PE, Bohm M, Dei Cas L (2010) Effect of the long-term administration of nebivolol on clinical symptoms, exercise capacity and left ventricular function in patients with heart failure and preserved left ventricular ejection fraction: background, aims and design of the ELANDD study. Clin Res Cardiol 99(2):75–82. doi:10.1007/s00392-009-0098-x

    Article  PubMed  CAS  Google Scholar 

  36. Lin HJ, Chao CL, Chien KL, Ho YL, Lee CM, Lin YH, Wu YW, Hsu RB, Chou NK, Wang SS, Chen CY, Chen MF (2009) Elevated blood urea nitrogen-to-creatinine ratio increased the risk of hospitalization and all-cause death in patients with chronic heart failure. Clin Res Cardiol 98(8):487–492. doi:10.1007/s00392-009-0025-1

    Article  PubMed  CAS  Google Scholar 

  37. Maisel AS, Bhalla V, Braunwald E (2006) Cardiac biomarkers: a contemporary status report. Nat Clin Pract Cardiovasc Med 3(1):24–34. doi:10.1038/ncpcardio0405

    Article  PubMed  CAS  Google Scholar 

  38. Lok DJ, Van Der Meer P, de la Porte PW, Lipsic E, Van Wijngaarden J, Hillege HL, van Veldhuisen DJ (2010) Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol 99(5):323–328. doi:10.1007/s00392-010-0125-y

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful for the excellent technical assistance of Kirsten Keilbach. This work was supported by Carl Baresel, Stiftung (MA), Deutsche Forschungsgemeinschaft (MA), Deutsche Herzstiftung (MA), Klaus Tschira Stiftung (HCV) and European Federation for the Study of Diabetes (MA).

Conflict of interest

None

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    H. C. Volz, D. Laohachewin, A. R. Wienbrandt, M. Nelles, C. Zugck, Z. Kaya, H. A. Katus & M. Andrassy

  2. Department of Internal Medicine II, University of Heidelberg, Heidelberg, Germany

    D. Schellberg

Authors
  1. H. C. Volz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Laohachewin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Schellberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. R. Wienbrandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Nelles
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Zugck
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z. Kaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. A. Katus
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Andrassy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Andrassy.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 150 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Volz, H.C., Laohachewin, D., Schellberg, D. et al. HMGB1 is an independent predictor of death and heart transplantation in heart failure. Clin Res Cardiol 101, 427–435 (2012). https://doi.org/10.1007/s00392-011-0409-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00392-011-0409-x

Keywords

Search

Navigation