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Published in: Clinical Research in Cardiology 8/2012

01-08-2012 | Original Paper

Complement anaphylatoxin C3a as a novel independent prognostic marker in heart failure

Authors: Tímea Gombos, Zsolt Förhécz, Zoltán Pozsonyi, Gábor Széplaki, Jan Kunde, George Füst, Lívia Jánoskuti, István Karádi, Zoltán Prohászka

Published in: Clinical Research in Cardiology | Issue 8/2012

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Abstract

Objectives

The purpose of this study was to evaluate complement activation in a heart failure cohort. Based on their powerful biological activity, we hypothesized that the levels of anaphylatoxin C3a are related to pathological signs and outcomes in heart failure.

Design, setting and patients

Complement activation products C3a and SC5b9 were determined in 182 consecutive CHF patients (single centre, prospective cohort study), with a left ventricular ejection fraction <45%. Mortality and re-hospitalisation due to the progression of CHF were assessed after a median follow-up of 14 months.

Interventions

None.

Results

In the univariate analysis, high level of anaphylatoxin C3a was significantly associated with clinical events (p < 0.0001), whereas SC5b9 showed a tendency of association (p = 0.094). In multivariable Cox analysis, adjusted for age, NT-proBNP, diastolic blood pressure, body mass index (BMI), haemoglobin and creatinine levels, C3a was a significant predictor of HF-related re-hospitalization or death (HR 1.189 per 1-SD increase, 95% CI 1.023–1.383), and of cardiovascular events or death (HR 1.302, CI 1.083–1.566). C3a was strongly associated with the presence of peripheral oedema, inflammatory markers (CRP, prealbumin, IL-6, sTNFRI, sTNFRII), heat-shock protein 70 levels and endothelial activation markers (von-Willebrand factor and endothelin-1).

Conclusions

Results of the present study showed that complement activation is strongly linked to unfavourable outcomes in heart failure. High levels of anaphylatoxin C3a predicted re-hospitalization, cardiovascular events and mortality in adjusted survival model. Increased C3a levels were associated with biomarkers of acute-phase reaction, inflammation, cellular stress response, endothelial-cell activation and oedematous complications independently from disease severity.
Literature
1.
go back to reference Celis R, Torre-Martinez G, Torre-Amione G (2008) Evidence for activation of immune system in heart failure: is there a role for anti-inflammatory therapy? Curr Opin Cardiol 23:254–260PubMedCrossRef Celis R, Torre-Martinez G, Torre-Amione G (2008) Evidence for activation of immune system in heart failure: is there a role for anti-inflammatory therapy? Curr Opin Cardiol 23:254–260PubMedCrossRef
2.
go back to reference Anker SD, Egerer KR, Volk HD, Kox WJ, Poole-Wilson PA, Coats AJ (1997) Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am J Cardiol 79:1426–1430PubMedCrossRef Anker SD, Egerer KR, Volk HD, Kox WJ, Poole-Wilson PA, Coats AJ (1997) Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am J Cardiol 79:1426–1430PubMedCrossRef
3.
4.
go back to reference Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M, Poole-Wilson PA, Coats AJ, Anker SD (1999) Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 353:1838–1842PubMedCrossRef Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M, Poole-Wilson PA, Coats AJ, Anker SD (1999) Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 353:1838–1842PubMedCrossRef
5.
go back to reference Markiewski MM, Lambris JD (2007) The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol 171:715–727PubMedCrossRef Markiewski MM, Lambris JD (2007) The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol 171:715–727PubMedCrossRef
6.
go back to reference Harboe M, Mollnes TE (2008) The alternative complement pathway revisited. J Cell Mol Med 12:1074–1084PubMedCrossRef Harboe M, Mollnes TE (2008) The alternative complement pathway revisited. J Cell Mol Med 12:1074–1084PubMedCrossRef
7.
go back to reference Muller-Eberhard HJ (1988) Molecular organization and function of the complement system. Annu Rev Biochem 57:321–347PubMedCrossRef Muller-Eberhard HJ (1988) Molecular organization and function of the complement system. Annu Rev Biochem 57:321–347PubMedCrossRef
8.
go back to reference Matsushita M (1996) The lectin pathway of the complement system. Microbiol Immunol 40:887–893PubMed Matsushita M (1996) The lectin pathway of the complement system. Microbiol Immunol 40:887–893PubMed
9.
go back to reference Guo RF, Ward PA (2006) C5a, a therapeutic target in sepsis. Recent Pat Antiinfect Drug Discov 1:57–65PubMedCrossRef Guo RF, Ward PA (2006) C5a, a therapeutic target in sepsis. Recent Pat Antiinfect Drug Discov 1:57–65PubMedCrossRef
10.
go back to reference Torre-Amione G (2005) Immune activation in chronic heart failure. Am J Cardiol 95:3C–8C discussion 38C–40CPubMedCrossRef Torre-Amione G (2005) Immune activation in chronic heart failure. Am J Cardiol 95:3C–8C discussion 38C–40CPubMedCrossRef
11.
go back to reference Aukrust P, Gullestad L, Lappegård KT, Ueland T, Aass H, Wikeby L, Simonsen S, Frøland SS, Mollnes TE (2001) Complement activation in patients with congestive heart failure: effect of high-dose intravenous immunoglobulin treatment. Circulation 104:1494–1500PubMedCrossRef Aukrust P, Gullestad L, Lappegård KT, Ueland T, Aass H, Wikeby L, Simonsen S, Frøland SS, Mollnes TE (2001) Complement activation in patients with congestive heart failure: effect of high-dose intravenous immunoglobulin treatment. Circulation 104:1494–1500PubMedCrossRef
12.
go back to reference Clark DJ, Cleman MW, Pfau SE, Rollins SA, Ramahi TM, Mayer C, Caulin-Glaser T, Daher E, Kosiborod M, Bell L, Setaro JF (2001) Serum complement activation in congestive heart failure. Am Heart J 141:684–690PubMedCrossRef Clark DJ, Cleman MW, Pfau SE, Rollins SA, Ramahi TM, Mayer C, Caulin-Glaser T, Daher E, Kosiborod M, Bell L, Setaro JF (2001) Serum complement activation in congestive heart failure. Am Heart J 141:684–690PubMedCrossRef
13.
go back to reference Zwaka TP, Manolov D, Ozdemir C, Marx N, Kaya Z, Kochs M, Höher M, Hombach V, Torzewski J (2002) Complement and dilated cardiomyopathy: a role of sublytic terminal complement complex-induced tumor necrosis factor-alpha synthesis in cardiac myocytes. Am J Pathol 161:449–457PubMedCrossRef Zwaka TP, Manolov D, Ozdemir C, Marx N, Kaya Z, Kochs M, Höher M, Hombach V, Torzewski J (2002) Complement and dilated cardiomyopathy: a role of sublytic terminal complement complex-induced tumor necrosis factor-alpha synthesis in cardiac myocytes. Am J Pathol 161:449–457PubMedCrossRef
14.
go back to reference Zimmermann O, Kochs M, Zwaka TP, Bienek-Ziolkowski M, Höher M, Hombach V, Torzewski J (2007) Prognostic role of myocardial tumor necrosis factor-alpha and terminal complement complex expression in patients with dilated cardiomyopathy. Eur J Heart Fail 9:51–54PubMedCrossRef Zimmermann O, Kochs M, Zwaka TP, Bienek-Ziolkowski M, Höher M, Hombach V, Torzewski J (2007) Prognostic role of myocardial tumor necrosis factor-alpha and terminal complement complex expression in patients with dilated cardiomyopathy. Eur J Heart Fail 9:51–54PubMedCrossRef
15.
go back to reference Czúcz J, Cervenak L, Förhécz Z, Gombos T, Pozsonyi Z, Kunde J, Karádi I, Jánoskuti L, Prohászka Z (2011) Serum soluble E-selectin and NT-proBNP levels additively predict mortality in diabetic patients with chronic heart failure. Clin Res Cardiol 100(7):587–594PubMedCrossRef Czúcz J, Cervenak L, Förhécz Z, Gombos T, Pozsonyi Z, Kunde J, Karádi I, Jánoskuti L, Prohászka Z (2011) Serum soluble E-selectin and NT-proBNP levels additively predict mortality in diabetic patients with chronic heart failure. Clin Res Cardiol 100(7):587–594PubMedCrossRef
16.
go back to reference Papassotiriou J, Morgenthaler NG, Struck J, Alonso C, Bergmann A (2006) Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin Chem 52:1144–1151PubMedCrossRef Papassotiriou J, Morgenthaler NG, Struck J, Alonso C, Bergmann A (2006) Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin Chem 52:1144–1151PubMedCrossRef
17.
go back to reference Cejka J (1984) Performance characteristics of a commercial kit for assay of factor viii-related antigen. Clin Chem 30:814–815PubMed Cejka J (1984) Performance characteristics of a commercial kit for assay of factor viii-related antigen. Clin Chem 30:814–815PubMed
18.
go back to reference Gombos T, Forhecz Z, Pozsonyi Z, Janoskuti L, Prohaszka Z (2008) Interaction of serum 70-kDa heat shock protein levels and HspA1B (+1267) gene polymorphism with disease severity in patients with chronic heart failure. Cell Stress Chaperones 13:199–206PubMedCrossRef Gombos T, Forhecz Z, Pozsonyi Z, Janoskuti L, Prohaszka Z (2008) Interaction of serum 70-kDa heat shock protein levels and HspA1B (+1267) gene polymorphism with disease severity in patients with chronic heart failure. Cell Stress Chaperones 13:199–206PubMedCrossRef
19.
go back to reference Franke J, Zugck C, Wolter JS, Frankenstein L, Hochadel M, Ehlermann P, Winkler R, Nelles M, Zahn R, Katus HA, Senges J (2012) A decade of developments in chronic heart failure treatment: a comparison of therapy and outcome in a secondary and tertiary hospital setting. Clin Res Cardiol 101(1):1–10PubMedCrossRef Franke J, Zugck C, Wolter JS, Frankenstein L, Hochadel M, Ehlermann P, Winkler R, Nelles M, Zahn R, Katus HA, Senges J (2012) A decade of developments in chronic heart failure treatment: a comparison of therapy and outcome in a secondary and tertiary hospital setting. Clin Res Cardiol 101(1):1–10PubMedCrossRef
20.
go back to reference Tanner H, Mohacsi P, Fuller-Bicer GA, Rieben R, Meier B, Hess O, Hullin R (2007) Cytokine activation and disease progression in patients with stable moderate chronic heart failure. J Heart Lung Transpl 26:622–629CrossRef Tanner H, Mohacsi P, Fuller-Bicer GA, Rieben R, Meier B, Hess O, Hullin R (2007) Cytokine activation and disease progression in patients with stable moderate chronic heart failure. J Heart Lung Transpl 26:622–629CrossRef
21.
go back to reference Clark AL, Loebe M, Potapov EV, Egerer K, Knosalla C, Hetzer R, Anker SD (2001) Ventricular assist device in severe heart failure: effects on cytokines, complement and body weight. Eur Heart J 22:2275–2283PubMedCrossRef Clark AL, Loebe M, Potapov EV, Egerer K, Knosalla C, Hetzer R, Anker SD (2001) Ventricular assist device in severe heart failure: effects on cytokines, complement and body weight. Eur Heart J 22:2275–2283PubMedCrossRef
22.
go back to reference Loebe M, Gorman K, Burger R, Gage JE, Harke C, Hetzer R (1998) Complement activation in patients undergoing mechanical circulatory support. ASAIO J 44:M340–M346PubMedCrossRef Loebe M, Gorman K, Burger R, Gage JE, Harke C, Hetzer R (1998) Complement activation in patients undergoing mechanical circulatory support. ASAIO J 44:M340–M346PubMedCrossRef
23.
go back to reference Loebe M, Koster A, Sänger S, Potapov EV, Kuppe H, Noon GP, Hetzer R (2001) Inflammatory response after implantation of a left ventricular assist device: comparison between the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device. ASAIO J 47:272–274PubMedCrossRef Loebe M, Koster A, Sänger S, Potapov EV, Kuppe H, Noon GP, Hetzer R (2001) Inflammatory response after implantation of a left ventricular assist device: comparison between the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device. ASAIO J 47:272–274PubMedCrossRef
24.
go back to reference Jahns R, Boivin V, Siegmund C, Inselmann G, Lohse MJ, Boege F (1999) Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation 99:649–654PubMedCrossRef Jahns R, Boivin V, Siegmund C, Inselmann G, Lohse MJ, Boege F (1999) Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation 99:649–654PubMedCrossRef
25.
go back to reference Pye M, Rae AP, Cobbe SM (1990) Study of serum C-reactive protein concentration in cardiac failure. Br Heart J 63:228–230PubMedCrossRef Pye M, Rae AP, Cobbe SM (1990) Study of serum C-reactive protein concentration in cardiac failure. Br Heart J 63:228–230PubMedCrossRef
26.
go back to reference Beranek JT (1997) C-reactive protein and complement in myocardial infarction and postinfarction heart failure. Eur Heart J 18:1834–1836PubMedCrossRef Beranek JT (1997) C-reactive protein and complement in myocardial infarction and postinfarction heart failure. Eur Heart J 18:1834–1836PubMedCrossRef
27.
go back to reference Collard CD, Väkevä A, Morrissey MA, Agah A, Rollins SA, Reenstra WR, Buras JA, Meri S, Stahl GL (2000) Complement activation after oxidative stress: role of the lectin complement pathway. Am J Pathol 156:1549–1556PubMedCrossRef Collard CD, Väkevä A, Morrissey MA, Agah A, Rollins SA, Reenstra WR, Buras JA, Meri S, Stahl GL (2000) Complement activation after oxidative stress: role of the lectin complement pathway. Am J Pathol 156:1549–1556PubMedCrossRef
28.
go back to reference Knowlton AA, Eberli FR, Brecher P, Romo GM, Owen A, Apstein CS (1991) A single myocardial stretch or decreased systolic fiber shortening stimulates the expression of heat shock protein 70 in the isolated, erythrocyte-perfused rabbit heart. J Clin Invest 88:2018–2025PubMedCrossRef Knowlton AA, Eberli FR, Brecher P, Romo GM, Owen A, Apstein CS (1991) A single myocardial stretch or decreased systolic fiber shortening stimulates the expression of heat shock protein 70 in the isolated, erythrocyte-perfused rabbit heart. J Clin Invest 88:2018–2025PubMedCrossRef
29.
go back to reference Tanonaka K, Yoshida H, Toga W, Furuhama K, Takeo S (2001) Myocardial heat shock proteins during the development of heart failure. Biochem Biophys Res Commun 283:520–525PubMedCrossRef Tanonaka K, Yoshida H, Toga W, Furuhama K, Takeo S (2001) Myocardial heat shock proteins during the development of heart failure. Biochem Biophys Res Commun 283:520–525PubMedCrossRef
30.
go back to reference Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF, Espevik T, Sundan A (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105:685–690PubMedCrossRef Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF, Espevik T, Sundan A (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105:685–690PubMedCrossRef
31.
go back to reference Genth-Zotz S, Bolger AP, Kalra PR, von Haehling S, Doehner W, Coats AJ, Volk HD, Anker SD (2004) Heat shock protein 70 in patients with chronic heart failure: relation to disease severity and survival. Int J Cardiol 96:397–401PubMedCrossRef Genth-Zotz S, Bolger AP, Kalra PR, von Haehling S, Doehner W, Coats AJ, Volk HD, Anker SD (2004) Heat shock protein 70 in patients with chronic heart failure: relation to disease severity and survival. Int J Cardiol 96:397–401PubMedCrossRef
32.
go back to reference Prohászka Z, Singh M, Nagy K, Kiss E, Lakos G, Duba J, Füst G (2002) Heat shock protein 70 is a potent activator of the human complement system. Cell Stress Chaperones 7:17–22PubMedCrossRef Prohászka Z, Singh M, Nagy K, Kiss E, Lakos G, Duba J, Füst G (2002) Heat shock protein 70 is a potent activator of the human complement system. Cell Stress Chaperones 7:17–22PubMedCrossRef
33.
go back to reference Bauersachs J, Widder JD (2008) Endothelial dysfunction in heart failure. Pharmacol Rep 60:119–126PubMed Bauersachs J, Widder JD (2008) Endothelial dysfunction in heart failure. Pharmacol Rep 60:119–126PubMed
34.
go back to reference Hindmarsh EJ, Marks RM (1998) Complement activation occurs on subendothelial extracellular matrix in vitro and is initiated by retraction or removal of overlying endothelial cells. J Immunol 160:6128–6136PubMed Hindmarsh EJ, Marks RM (1998) Complement activation occurs on subendothelial extracellular matrix in vitro and is initiated by retraction or removal of overlying endothelial cells. J Immunol 160:6128–6136PubMed
Metadata
Title
Complement anaphylatoxin C3a as a novel independent prognostic marker in heart failure
Authors
Tímea Gombos
Zsolt Förhécz
Zoltán Pozsonyi
Gábor Széplaki
Jan Kunde
George Füst
Lívia Jánoskuti
István Karádi
Zoltán Prohászka
Publication date
01-08-2012
Publisher
Springer-Verlag
Published in
Clinical Research in Cardiology / Issue 8/2012
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI
https://doi.org/10.1007/s00392-012-0432-6

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