Skip to main content
Erschienen in: Clinical Research in Cardiology 8/2012

01.08.2012 | Original Paper

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

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

Erschienen in: Clinical Research in Cardiology | Ausgabe 8/2012

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat Rauchhaus M, Coats AJ, Anker SD (2000) The endotoxin-lipoprotein hypothesis. Lancet 356:930–933PubMedCrossRef Rauchhaus M, Coats AJ, Anker SD (2000) The endotoxin-lipoprotein hypothesis. Lancet 356:930–933PubMedCrossRef
4.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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
Metadaten
Titel
Complement anaphylatoxin C3a as a novel independent prognostic marker in heart failure
verfasst von
Tímea Gombos
Zsolt Förhécz
Zoltán Pozsonyi
Gábor Széplaki
Jan Kunde
George Füst
Lívia Jánoskuti
István Karádi
Zoltán Prohászka
Publikationsdatum
01.08.2012
Verlag
Springer-Verlag
Erschienen in
Clinical Research in Cardiology / Ausgabe 8/2012
Print ISSN: 1861-0684
Elektronische ISSN: 1861-0692
DOI
https://doi.org/10.1007/s00392-012-0432-6

Weitere Artikel der Ausgabe 8/2012

Clinical Research in Cardiology 8/2012 Zur Ausgabe

Schadet Ärger den Gefäßen?

14.05.2024 Arteriosklerose Nachrichten

In einer Studie aus New York wirkte sich Ärger kurzfristig deutlich negativ auf die Endothelfunktion gesunder Probanden aus. Möglicherweise hat dies Einfluss auf die kardiovaskuläre Gesundheit.

Intervallfasten zur Regeneration des Herzmuskels?

14.05.2024 Herzinfarkt Nachrichten

Die Nahrungsaufnahme auf wenige Stunden am Tag zu beschränken, hat möglicherweise einen günstigen Einfluss auf die Prognose nach akutem ST-Hebungsinfarkt. Darauf deutet eine Studie an der Uniklinik in Halle an der Saale hin.

Shunt-Therapie bei Herzinsuffizienz: Kein Anzug, der allen passt

13.05.2024 Chronische Herzinsuffizienz Nachrichten

Die Anlage eines interatrialen Shunts zur Reduktion des linksatrialen Drucks ist ein neuer Therapieansatz bei Herzinsuffizienz. Viele Patienten sprechen darauf an, andere jedoch nicht. 

Vorsicht, erhöhte Blutungsgefahr nach PCI!

10.05.2024 Koronare Herzerkrankung Nachrichten

Nach PCI besteht ein erhöhtes Blutungsrisiko, wenn die Behandelten eine verminderte linksventrikuläre Ejektionsfraktion aufweisen. Das Risiko ist umso höher, je stärker die Pumpfunktion eingeschränkt ist.

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.