Eur J Heart Fail 2001 Adamopoulos 517 26

8/3/2019 Eur J Heart Fail 2001 Adamopoulos 517 26

http://slidepdf.com/reader/full/eur-j-heart-fail-2001-adamopoulos-517-26 1/10

Ž .European Journal of Heart Failure 3 2001 517526

Review

A glossary of circulating cytokines in chronic heart failure

Stamatis AdamopoulosU, John T. Parissis, Dimitrios Th. Kremastinos

Second Department of Cardio¨ ascular Medicine, Onassis Cardiac Surgery Center, Athens, Greece

Received 14 December 2000; received in revised form 11 April 2001; accepted 26 April 2001

Abstract

Recent studies have emphasized the importance of biologically active molecules, termed cytokines, in the development andprogression of the syndrome of chronic heart failure. This article summarizes a glossary of major cytokines and othercytokine-related inflammatory factors implicated in the pathophysiology of chronic heart failure, describing the source of theirsynthesis and factors regulating their secretion and analyzing their biologic effects on the cardiovascular system. 2001European Society of Cardiology. All rights reserved.

Keywords: Chronic heart failure; Cytokines; Inflammatory factors; Immune activation

1. Introduction

Cytokines are hormone-like peptides that play aw x very important role in the cellular interactions 1 .

They participate in a wide range of biologic processesand their effects on the cardiovascular system includepromotion of inflammation, intravascular coagulation,free-radical generation, endothelial injury and car-

w xdiomyocyte or endothelial cell apoptosis 2,3 . Theyare produced by the immunological as well as cardio-

w x vascular system structural cells 1,4 . Cytokines arepathogenic factors in many disorders, where inflam-mation etiology is suspected. Accumulating evidence

indicates that these inflammatory mediators play animportant role, not only in the pathogenesis of

w xatherosclerosis 5 and in the cardiac dysfunction thatw x w xaccompanies systemic sepsis 6 , viral myocarditis 7

w xand cardiac allograft rejection 8 but also in theŽ . w xsyndrome of chronic heart failure CHF 3,9,10 .

Thus, it has been suggested that an abnormal

U

Corresponding author. Zinonos 9, Halandri, 15234, Athens,Greece. Tel.: q30-16848463; fax: q30-19493373.

Ž . E-mail address: [email protected] S. Adamopoulos .

inflammatory response, including overexpressionof proinflammatory cytokines, soluble adhesionmolecules and chemoattractant factors, may be re-sponsible for the progression and clinical deteriora-

w xtion of CHF 10,11 . Fig. 1 describes the inflammatorycascade implicated in the pathophysiology of CHF.

In the failing heart, elevated left ventricular end-di-astolic wall stress causes myocardial expression of cytokines, which directly or indirectly influence left ventricular contractile performance and remodeling.When proinflammatory cytokines are overproduced within the myocardium, they can spill over into the

peripheral circulation, where they are capable of sec-w xondarily activating the immune system 4,9 . Alterna-tively, raised plasma levels of cytokines in CHF maybe the result of extramyocardial production becauseof altered tissue perfusion and tissue hypoxia, possiblyenhanced by bacterial endotoxin release from the gut

w xin the congestive condition of the syndrome 4,10 . Inthis article, we present a glossary of major proin-flammatory cytokines and other cytokine-related in-flammatory factors associated with the pathophysi-ology of CHF as evidenced by recent experimentaland clinical data, and describe briefly their biologic

1388-9842r01r$20.00 2001 European Society of Cardiology. All rights reserved.Ž .PII: S 1 3 8 8 - 9 8 4 2 0 1 0 0 1 5 6 - 8



( )S. Adamopoulos et al. r European Journal of Heart Failure 3 2001 517 526518

Fig. 1. Schematic representation of inflammatory cascade impli-cated in the pathophysiology of CHF.

effects on the cardiovascular system in the setting of CHF.

2. Cytokine glossary

( ) 2.1. Tumor necrosis factor- TNF-

This cytokine was originally identified for its potenttoxicity against tumor cells, hence its name. The TNF-

Ž . molecule a 157-amino acid polypeptide exists as amembrane bound and a secreted molecule, both

w xbioactive 12 . The activated macrophage is the mainsource of TNF- containing both cell associated and

w xmembrane bound TNF- 13 . Other cells releasingTNF- include lymphocytes, fibroblasts, neutrophils,

w xsmooth muscle and mast cells 13 . Furthermore, adult

mammalian myocardial cells are able to produceTNF- after extracellular stimuli such as endotoxin,

w xhypoxia or increased mechanical stress 14 .TNF- acts at the cellular level via both type I

Ž . Ž . Žp55 and type II p75 receptors TNFRI and TN-.FRII and recently, it has been suggested that TNFRI

and TNFRII are present in the human myocardiumw x15 . TNF- activates multiple transduction pathways,inducing or suppressing a wide variety of genes, in-cluding those encoding the production of other cy-tokines, adhesion molecules and inducible nitric oxide

Ž . w xsynthase iNOS 16 . Additionally, it orchestrates theinflammatory response through activation of proin-

Žflammatory cytokine such as interleukin-1 and inter-. w xleukin-6 genes, as well as its own production 16 .

TNF- effects on cardiac function are dependentfrom the amount and duration of cytokine expression.Short term expression within the heart may be anadaptive response to different forms of ‘stress’,

whereas long term expression may be maladaptive byw xproducing cardiac decompensation 17 . Excessive

TNF- levels can produce left ventricular dysfunctionand cardiomyopathy and may be related with theclinical manifestations and the progression of CHFw x18,19 . This proinflammatory cytokine participates inthe pathophysiology of heart failure progress, at leastpartially, by stimulating myocyte hypertrophy throughthe generation of reactive oxygen intermediates incardiac myocytes, by inducing ventricular remodelingthrough stimulating extracellular matrix protein pro-duction and increased turnover of matrix, by causing

cardiomyocyte loss through necrosis and apoptosis,and by depressing myocardial function through thenitric oxide-dependent and sphingomyelinase path-

w x ways 20,21 . In addition, TNF- overexpression causesskeletal myopathy and endothelial dysfunction in CHFpatients through free radical and nitric oxide overpro-duction, leading to skeletal myocyte and endothelialcell apoptosis. These peripheral deleterious effectscontribute significantly to further clinical deteriora-

w xtion of the syndrome 20,21 . Recently Mann’s grouphas scheduled and administered a novel anti-TNF-

Ž .molecule, the Etanercept 75 p75 Fc fusion protein , with beneficial effects on cardiac function and left ventricular remodeling in a small patient population

w x with severe CHF 22,23 . However, to assess the longterm effects of Etanercept, randomized, double-blind

Žand placebo-controlled clinical trials RENAIS-.SANCE, RECOVER are presently enrolling patients

with NYHA class IIIV heart failure symptoms in thew xUSA and other countries 20,22 .

( 2.2. Soluble TNF receptors I and II sTNFRI and ) sTNFRII

The extracellular domain fragments of both TNF



( )S. Adamopoulos et al. r European Journal of Heart Failure 3 2001 517 526 519

receptors shed from cell surfaces can be detected asŽ .soluble forms sTNFRI and sTNFRII in the urine

w xand blood 24 . These soluble proteins are supposedto regulate the TNF- bioactivity either by inhibitingthe binding of TNF- trimers to the membrane recep-tors or by preventing TNF- trimers from dissociation

w xto inactive monomers 24 . It has been shown that atphysiological concentrations, sTNFRs may act as‘slow-release reservoir’ of bioactive TNF-, thus in-

w xcreasing its half life 25 . The stabilization of TNF-by its soluble receptors is reminiscent of the stabiliza-tion of enzymes by their substrates. When present athigher concentrations, as in patients with severe CHF,sTNFRs could inhibit the pathological increase of

w xTNF- activity 4,26 . Under these conditions, sTN-FRs could act as anti-TNF molecules by formingcomplexes with high affinity to the cytokine. Theshedding of these receptors and the resultant de-crease in their concentration on the cell surface could

w xalso prevent cell damage 27 . Alternatively, sinceTNF- induces the shedding of its soluble receptors,it is possible that increased sTNFRs simply reflect

w xactivation of the cytokine at a local level 28 .Recently, it has been suggested that measurement

of sTNFRs is essential for the evaluation of TNF-w xactivation in CHF 29 . Both sTNFRs are increased in

severe CHF patients and might inhibit the in vitrow xcytotoxicity of TNF- 30 . Finally, the increased lev-

els of sTNFRII were significantly correlated with poorw xshort-term prognosis of CHF patients 30 .

( ) 2.3. Interleukin-6 IL-6

Ž .Interleukin-6 IL-6 is another multifunctional cy-tokine, which mediates both immune and inflamma-tory responses. IL-6 is produced by a variety of dif-ferent cell types including mononuclear phagocytes,some activated T-cells, vascular endothelial cells and

w x w xfibroblasts 31 . Several studies 3237 have consis-tently found elevated levels of IL-6 in the setting of CHF. Although, IL-6 may be locally produced in themyocardium, data suggest that IL-6 is peripherally

w xreleased in CHF patients 34 . Although the mecha-nism for increased elaboration of IL-6 in CHF is notknown, TNF- is sufficient to induce IL-6 gene andprotein expression in a variety of cell types, suggestingthat there may be a ‘cytokine cascade’ in the setting

w x w xof CHF 10,20 . Some investigators 35 have identi-fied a significant correlation between elevated levelsof TNF- and elevated levels of IL-6 in severe CHF.

w xIn the report by Mac Gowan et al. 36 , there was astatistically significant correlation between elevatedlevels of IL-6 and elevated right heart pressures of

w xCHF patients. Finally, in a recent study 37 , serumIL-6 was identified during follow-up of severe CHFpatients as the most powerful independent predictor

of new heart failure episodes, death or need for hearttransplantation, a better predictor than TNF-,plasma neurohormones or left ventricular function.

( ) 2.4. Soluble interleukin-6 receptor sIL-6R

Human IL-6 receptor is a glycoprotein with amolecular mass of 80 kDa. In contrast to the TNFreceptors, the cytoplasmic domain of IL-6 is not nec-essary for intracellular signaling to occur. Moreover,IL-6 when bound to its receptor is known to associate with a second membrane glycoprotein with a molecu-

Ž . w xlar mass of 130 kDa gp 130 38 . The extracellulardomain of human IL-6 receptor can be detected as

Ž .soluble form sIL-6R into circulation of CHF patientsw x39,40 . The exact clinical significance of these find-ings in CHF remain uncertain. However, it has beenpostulated that mechanisms similar to those of TNFsystem overactivation may be responsible for sIL-6R

w xrelease into circulation of CHF patients 39,40 .


Studies have shown that all mammalian speciesexpress two IL-1 related genes, IL-1 and IL-1, which mediate systemic immune responses as well asthe production of inflammatory responses via produc-

w xtion of prostaglandins 2,41 . Although monocytes arethe major source of IL-1, almost every cell type in thebody can produce IL-1 under the appropriate condi-

w xtions 2,3 . While there are few reports on the effects

of IL-1 on myocardial function, some of them suggestthat this cytokine is also capable of independentlyw xmodulating myocardial function 3,10,16 . Further-

more, there is little clinical evidence that supports anelevation of IL-1 in CHF and an important role forthis cytokine in the pathophysiology of the syndromew x10,39 . It has been reported that IL-1 can lead touncoupling of the -adrenoreceptor from adenylatecyclase, which has been postulated as one of themechanisms responsible for the progression of CHFw x10 . Thus, IL-1 may be a basal part of overactivated

w xcytokine cascade in the setting of CHF 3,10,16 .

( ) 2.6. Interleukin-1 receptor antagonist IL-1ra

There is a discrete inhibitor for the IL-1 receptor,the so-called IL-1ra, which antagonizes IL-1 for bind-ing to its receptor and can, thus, attenuate, the effects

w xof IL-1 42 . IL-1ra is a member of the IL-1 genefamily and its production from activated humanmonocytes increases under the same inflammatory

w xconditions that stimulate IL-1 and IL-1 43 . IL-1rais often considered as more sensitive marker of IL-1system activation than IL-1 levels and may be corre-lated better with the severity of various diseases with




Žimmune system activation septic shock, coronary.artery disease, CHF , in which IL-1 levels into the

w xcirculation are usually low 39 . On the other hand,given that IL-1ra is a specific antagonist of IL-1,elevated levels of IL-1ra could represent a suitableresponse to counteract the inflammatory process

w xcaused by IL-1 44 . Finally, recombinant IL-1ra hasbeen used for the blockage of IL-1 activity in various

w xanimal models of disease, including septic shock 45 .


Antigenic stimulants or proinflammatory cytokinesŽ .e.g. IL-1 induce the synthesis of IL-2 by T lympho-cytes which in turn is an endogenous T-cell mitogen.IL-2 increases expression of its own receptor on T

w xcells and markedly enhances T-cell proliferation 46 . As a result, this cytokine amplifies the immune re-sponse and dramatically expands the population of

antigen-specific T lymphocytes. Furthermore, it stimu-lates, through the IFN- production, the release of other inflammatory factors, such as TNF- and GM-

w xCSF, from activated macrophages 46 . Recent experi-mental and clinical data have shown that circulatingIL-2 is actively implicated in the pathophysiology of myocarditis and idiopathic dilated cardiomyopathy,reflecting an abnormal T-lymphocyte activation in

w xthese disorders 7,46,47 . It has been reported thatIL-2 serum concentrations were abnormally increasedin idiopathic dilated cardiomyopathy patients and rel-atives with asymptomatic left ventricular enlargement

as compared with those with ischemic cardiomyopathyw x47 . On the other hand, the expression of IL-2 recep-tor after the stimulation with either concavalin A oranti-T monoclonal antibody was found to be reduced3

in patients with idiopathic dilated cardiomyopathy when the results were compared with those of normal

w xcontrols 48 . A significant correlation was noticedbetween the expression of IL-2 receptor and the left ventricular end-diastolic pressure, suggesting that IL-2system and subsequent T-lymphocyte activationabnormalities may be associated with pathogenesisand hemodynamic deterioration of idiopathic dilated

w xcardiomyopathy 48 .

( ) 2.8. Soluble IL-2 receptor sIL-2R

Extracellular domain of T-lymphocyte IL-2 recep-w xtor is the circulating sIL-2R 46 . It has been reported

that high levels of circulating sIL-2R do not neutral-ize the actions of IL-2 but are a sensitive marker forthe interaction of the cytokine with its target cells andreflect the cellular autoimmune activation and espe-cially T-lymphocyte-dependent tissue injury in variousinflammatory diseases including myocarditis and idio-

w xpathic dilated cardiomyopathy 49 . High serum sIL-

2R levels were also correlated with the clinical deteri-oration of patients with CHF due to idiopathic dilatedcardiomyopathy, as well as were identified as signifi-cant independent predictors of death or need for

w xheart transplantation in the same population 50 .

( ) 2.9. Soluble Fas sFas

Fasr APO-1 is a 45-kDa type I membrane proteinthat belongs to the tumor necrosis factor receptorsuperfamily and mediates apoptosis when cross-linked

Ž . with a specific agonistic antibody or Fas ligand Fas Lw x51 . Cardiomyocytes might cleave and release theextracellular domain of this apoptosis-signalingmolecule into circulation as a consequence of apopto-

w x Ž .sis 52 . This soluble form of Fas sFas may block thew xaction of inducer of apoptotic cell death, Fas L 52 .

Elevated levels of apoptosis mediator sFas were foundin the serum of patients with autoimmune diseases

w x w x w x53 , myocarditis 54 and severe CHF 52 , suggestingthat FasrFaL system may play an important role inthe regulation of peripheral immune responses in

w xthese disorders. Recent studies 52,55 have also shownthat the peripheral overactivation of the FasrFasLsystem, as expressed by elevation of Fas soluble forms,may be related with the degree of left ventricularremodeling and have prognostic value in CHF.

( ) 2.10. Soluble Fas ligand sFas L

Fas L, a TNF- related cytokine, is synthesized as a

membrane-bound protein that can be converted byŽproteolytic cleavage into a soluble form 26 kDa gly-. w xcoprotein that is then released into circulation 52 .

In many cell types including human cardiomyocytesand endothelial cells, cross-linking of Fas with sFasLis followed by intercellular Ca2q homeostasis alter-ations, caspase activation, apoptotic gene transcrip-

w xtion and, finally, apoptotic cell death 56 . This sFasL-induced apoptotic process is closely related with theprogression of CHF. A recent study has also demon-strated that elevated plasma levels of sFasL weresignificantly correlated with the severity of symptoms

w xand functional status of CHF patients 57 .

( ) 2.11. Macrophage chemoattractant protein-1 MCP-1

MCP-1 is a low-molecular-weight protein character-ized by its ability to induce directional migration of leukocytes and thought to play an important role incontrolling inflammation and immune responses. It isa member of the largest chemotactic cytokine sub-family, called CC chemokines; this class of chemokines does not have an amino acid separating

w xthe first two N-terminal cysteine residues 58 . Theinvolvement of chemokines in the pathogenesis of




atherosclerosis has been widely investigated, and itscentral role in this process has been clearly clarifiedw x w x5961 . Recently, Aukrust et al. 62 have reportedthat circulating levels of MCP-1 were increased inpatients with CHF and have suggested that it wasinvolved not only in the pathogenesis of atherosclero-

sis and ischemia-induced myocardial injury, but alsow xin the development of CHF. In this study 62 , theelevated levels of MCP-1 in CHF were correlated with the degree of left ventricular dysfunction, as wellas with enhanced circulating monocyte activity andincreased oxidative stress. On the other hand, experi-

w xmentally, it has been suggested 63 that mechanicaloverload induces the myocardial expression of MCP-1, which attracts and activates monocytes andmacrophages, and that these recruited cells produceproinflammatory cytokines which contribute to the

w xpathogenesis of CHF 64 .

( ) 2.12. Macrophage inflammatory protein-1 MIP-1

MIP-1 is also a CC chemokine produced byw x various types of inflammatory cells 58,60 . MIP-1

has chemotactic activity for both monocytes and lym-phocytes and may be a major signal for the accumula-tion of mononuclear leukocytes in inflammatory dis-

w x w xeases 60 . Aukrust et al. 62 have found that plasmaactivity of MIP-1 was significantly elevated inpatients with CHF, with particularly high levels inpatients with the most severe CHF evaluated both

Ž . Žclinically NYHA class IV and hemodynamically low

.ejection fraction . According to these observations, itis tempting to hypothesize that enhanced CCchemokine levels, possibly in combination with otherproinflammatory cytokines, may be an important fac-tor in mediating the infiltration and activation of mononuclear leukocytes into the myocardium of CHFpatients, thereby playing an important pathogenic rolein the development of CHF.

2.13. Regulated on acti ation normally T-cell expressed( ) and secreted RANTES

RANTES is a CC chemokine produced by in-flammatory cells and platelets, and regulates T-lymphocyte activation in various inflammatory dis-

w xeases including atherosclerosis 65 . In addition to itsgrowth promoting and chemotactic effects on T-lymphocytes, this cytokine may also modulate otherfunctions of this cell population such as free radical

w xgeneration and production of other cytokines 66 . Ithas been postulated that RANTES, through the abovemechanisms and vicious circles derived fromplateletinflammatory cell interactions, is elevated in

ŽCHF patients with the most severe symptoms NYHA.class IV and may actively participate in the patho-

w xphysiologic events of advanced CHF 62 . However,these findings warrant further studies investigatingthe possible pathogenic role of RANTES in the devel-opment and progression of CHF.


IL-8 is a member of the other major chemotacticŽcytokine subfamily called CXC chemokines a class

of chemotactic cytokines with one amino acid separat-. w xing the first two N-terminal cysteine residues 58 .

Recent studies suggest that IL-8 may be involved inthe pathogenesis of various heart diseases. Reperfu-sion of ischemic myocardium promotes influx of neu-trophils involving IL-8 as an important contributing

w xmediator 67 . Furthermore, a potential role inatherogenesis of IL-8, through stimulation of IL-8receptor CXCR-2, is receiving increasing attentionw x68 , while there are some reports on raised IL-8

w xlevels in patients with cardiogenic shock 69 . Damasw xet al. 70 also showed that circulating levels of IL-8

and other CXC chemokines, gradually increased inpatients with CHF in parallel with an increase inNYHA functional class. Although IL-8 and otherCXC chemokines may be produced by a variety of

Žcells e.g. T-cells, neutrophils, fibroblasts, endothelial.and vascular smooth muscle cells , the findings of this

study suggest that activated monocytes and plateletsmay contribute to the raised levels of CXCchemokines in CHF. Damas et al. believe that theinteraction between platelets and monocytes may be

an important mediator of the systemic inflammatoryresponse in CHF patients, and they suggest that IL-8may be important participant in this process. Additio-nally, the ability of IL-8 to enhance free radicalgeneration in both neutrophils and monocytes leadsin turn to further production of CXC chemokinesand increases the procoagulant activity in the syn-

w xdrome of CHF 70 .

2.15. Granulocyte-macrophage colony-stimulating factor ( )GM-CSF

This glycoprotein is a member of the large family of hemopoietic cell colony-stimulating factors and regu-lates the proliferation and differentiation of myeloid

w xprogenitor cells 71 . This inflammatory factor in addi-tion to its growth-promoting effects stimulates a rangeof functional activities of mature neutrophils, mono-cytes and eosinophils, including regulation of leuko-cyte adhesion, augmentation of surface antigenexpression, superoxide anion generation and en-

w xhancement or induction of cytokine production 72 .GM-CSF, through the above mechanisms, may con-tribute to the pathophysiologic events involved in

w xatherosclerosis and inflammation 73,74 . The biologic




Fig. 2. Biologic effects of GM-CSF on immune system.

effects of GM-CSF on the immune system are sum-marized in Fig. 2. We have also demonstrated elevated GM-CSF levels in CHF, which are associated with the hemodynamic deterioration and neurohor-

w xmonal activation characterizing this syndrome 75 .GM-CSF, a product of human monocyteendothelialcell adhesive interaction, by virtue of its characteris-tics to modulate monocytermacrophage function in vivo and subsequently to generate free radicals and

enhance cytokine production may represent the com-mon denominator of the pathophysiologic sequelaeleading to abnormal nitric oxide-synthase expressionin human myocardium and vascular endothelium of

w xpatients with CHF 75 .

( 2.16. Soluble intercellular adhesion molecule-1 sICAM- )1

sICAM-1 is the soluble form of cellular adhesionmolecule ICAM-1 which is a member of the immuno-globin gene superfamily found on the surface of macrophages and endothelial cells, and mediates theadhesion of inflammatory cells to endothelial wall of

w xhuman vessels 76 . The soluble forms of ICAM-1 areparts which may be shed from the endothelial surfaceand have lower molecular weight than molecules ex-pressed on endothelial cells, apparently due to absenceof the cytoplasmic domain that remains in the cell of

w xorigin 77 . The induction or upregulation of ICAM-1,as well as the release of its soluble forms into circula-tion is a process common to inflammation in manytissues, including chronic inflammatory diseases,

w xatherosclerosis and CHF 7880 . Especially, sICAM-1

is an important cell adhesion signal that mediatesleukocyte adhesion to the endothelium in blood un-der altered flow conditions such as CHF, and mayreflect the abnormal inflammatory response and en-dothelial dysfunction characterizing this syndromew x80 .

2.17. Soluble ¨ ascular cell adhesion molecule-1( ) sVCAM-1

sVCAM-1 is another well defined soluble adhesionmolecule which participates actively to the inflamma-toryendothelial adhesive interaction process in

w xatherosclerotic disease and CHF 79,80 . sVCAM-1and sICAM-1 have been used as non-invasive markersfor the evaluation of endothelial dysfunction and itsmodification with various pharmacologic and non-pharmacologic interventions in patients with CHFw x81,82 .

( ) 2.18. Nuclear factor- B NF- B

The NF-B system is a key player in control of transcription of genes for mediators of a variety of inflammatory responses in disorders such as atheroge-

w xnesis and CHF 83,84 . Experimental studies haveshown in CHF that the NF-B family of proteins arepresent in endothelial cells and activated monocytesand regulate, through different protein complexes,the initiation or enhancement of transcription of vari-ous genes, including those influencing endothelial ad-hesion of leukocytes, the production of thrombogenic

Žfactors and the release of a variety of cytokines e.g.




Fig. 3. Biologic stimuli and effects of NF-B activation on cardiovascular system in CHF.

. Ž . w xTNF-, IL-6 and chemokines e.g. MCP-1 85,86 .NF-B is activated by a battery of stimuli leading toimmune responses, including oxidative stress, TNF-

w xand angiotensin II 87,88 . Although the exact clinicalsignificance of this nuclear factor in CHF is yet un-clear, its role seems to be central to the goal of mapping the cellular and molecular pathways of vas-cular and myocardial injury as well as the subsequent

w xcardiovascular remodeling in this syndrome 8488 .Fig. 3 describes the biologic pathways of NF-B activation, which are responsible for the cardiovascularinjury in the syndrome of CHF.

3. Conclusions

Enhanced immune activation, reflected in in-creased circulating levels of various proinflammatorycytokines and other cytokine-related factors, has beenrecently recognized to play a significant role in the

w xpathophysiology of CHF 4,9,11 . This review summa-rizes recent clinical and experimental evidence, whichsuggests that proinflammatory cytokines and othercytokine-related inflammatory factors are responsiblefor some aspects of the CHF phenotype contributing

Žto the central myocardial contractility and remodel-. Žing and peripheral skeletal muscular and endothelial

.function abnormalities characterizing this syndrome.On the basis of the observed evidence for immune

mechanisms of cardiovascular injury as an importantpathogenic factor of CHF progression, the modula-tion of cytokine cascade may represent a new thera-

w xpeutic paradigm for treating patients with CHF 89,90 .

References

w x1 Abbas AK, Lichtman AH, Pober JS. Cytokines. In: Abbas AK, Lichtman AH, Pober JS, editors. Cellular and molecularimmunology. Philadelphia: WB Saunders, 1991:22543.

w x2 Dinarello CA. Proinflammatory cytokines. Chest 2000;118:5038.

w x3 Mann DL, Young JB. Basic mechanisms in congestive heartfailure: recognizing the role of proinflammatory cytokines.Chest 1994;105:897904.

w x4 Kapadia S, Dibbs Z, Kurrelmeyer K et al. The role of cytokines in the failing human heart. Cardiol Clin

Ž .1998;16 4 :64556.w x5 Libby P, Ross R. Cytokines and growth regulatory molecules.

In: Fuster V, Ross R, Topol EJ, editors. Philadelphia: Lippin-cott-Raven, 1996:58594.w x6 Natanson C, Eichenholz PW, Danner RL et al. Endotoxin

and tumor necrosis factor challenges in dogs stimulate thecardiovascular profile of human septic shock. J Exp Med1991;169:82332.

w x7 Matsumori A, Yamada T, Suzuki H, Matoba Y, Sasayama S.Increased circulating cytokines in patients with myocarditisand cardiomyopathy. Br Heart J 1994;72:5616.

w x8 Wu CJ, Lovett M, Wong-Lee J et al. Cytokine gene expres-sion in rejecting cardiac allografts. Transplantation1992;54:32632.

w x9 Seta Y, Shan K, Bozkurt B, Oral H, Mann OL. Basic mecha-nisms in heart failure: the cytokine hypothesis. J CardiacFailure 1996;2:2439.




w x10 Paulus WJ. How are cytokines activated in heart failure? EurJ Heart Fail. 1999;1:30912.

w x11 Mann DL. Mechanisms and models in heart failure: a combi-natorial approach. Circulation 1999;100:9991008.

w x Ž .12 Old LJ. Tumor necrosis factor TNF . Science 1985;230:6302.w x13 Vassali P. The pathophysiology of tumor necrosis factors.

Annu Rev Immunol 1992;10:41152.w x14 Kapadia S, Oral H, Lee J et al. Hemodynamic regulation of

tumor necrosis factor- gene and protein expression in adultfeline myocardium. Circ Res 1997;81:18795.

w x15 Torre-Amione G, Kapadia S, Lee J, Bies RD, Lebovitz R,Mann DL. Expression and functional significance of tumornecrosis factor receptors in human myocardium. Circulation1995;92:148793.

w x16 Kelly RA, Smith TW. Cytokines and cardiac contractile func-tion. Circulation 1997;95:77881.

w x17 Packer M. Is tumor necrosis factor an important neurohor-monal mechanism in chronic heart failure? Ciruclation1995;92:137982.

w x18 Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevatedcirculating levels of tumor necrosis factor in severe chronicheart failure. N Engl J Med 1990;323:23641.

w x19 Bristow MR. Tumor necrosis factor-alpha and cardiomyopa-thy. Circulation 1998;97:13401.

w x20 Feldman AM, Combes A, Wagner D et al. The role of tumornecrosis factor in the pathophysiology of heart failure. J AmColl Cardiol 2000;35:53744.

w x21 Ferrari R. Tumor necrosis factor in CHF: a double facetcytokine. Cardiovasc Res 1998;37:5549.

w x22 Deswal A, Bozkurt B, Seta Y et al. Safety and efficacy of aŽsoluble p75 tumor necrosis factor receptor Enbrel, Etaner-

.cept in patients with advanced heart failure. Circulation1999;99:32246.

w x23 Bozkurt B, Torre-Amione G, Deswal A et al. Regression of left ventricular remodeling in chronic heart failure after

Žtreatment with ENBREL Etanercept, p75 TNF Receptor Fc. Ž .fusion protein . Circulation 1999;100 Suppl. I :645 Abstr..

w x24 Aderka D, Engelmann H, Maor Y, Brakebusch C, WallachD. Stabilization of the bioactivity of tumor necrosis factor byits soluble receptors. J Exp Med 1992;175:3239.

w x25 De Groote D, Gran GE, Dehart I, Franchimont P. Stabiliza-tion of functional tumor necrosis factor- by its soluble TNFreceptors. Eur Cytokine Netw 1993;4:35962.

w x26 Torre-Amione G, Kapadia S, Durand JB, Bies RD, YoungJB, Mann DL. Tumor necrosis factor- and tumor factorreceptors in the failing human heart. Circulation 1996;93:70411.

w x27 Van Zee K, Kohno T, Fischer E, Rock CS, Moldawer L,Lowry S. Tumor necrosis factor soluble receptors circulateduring experimental and clinical inflammation and can pro-tect against excessive tumor necrosis factor in vitro and in vivo. Proc Natl Acad Sci USA 1992;89:48459.

w x28 Kapadia S, Torre-Amione G, Yokoyama T, Mann DL. Solu-ble TNF binding proteins modulate the negative inotropicproperties of TNF- in vitro. Am J Physiol 1995;268:H517H525.

w x29 Diez-Ruiz A, Tilz GP, Zangerle R, Baier-Bitterlich G,Wachter H, Fuchs D. Soluble receptors for tumor necrosisfactor in clinical laboratory diagnosis. Eur J Haematol1995;54:18.

w x30 Ferrari R, Bachetti T, Confortini R et al. Tumor necrosisfactor soluble receptors in patients with various degrees of chronic heart failure. Circulation 1995;92:147986.

w x31 K ishi moto T . T he biology of i nt erleuk in-6. Blood1989;71:110.

w x32 Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB,Mann DL. Proinflammatory cytokines levels in patients with

depressed left ventricular ejection fraction: a report from theSOLVD study. J Am Coll Cardiol 1996;27:12016.

w x33 Roig E, Orus J, Pare C et al. Serum interleukin-6 in conges-´ ´tive heart failure secondary to idiopathic dilated cardiomy-opathy. Am J Cardiol 1998;82:68890.

w x34 Tsutamoto T, Hisanaga T, Wada A et al. Interleukin-6spillover in the peripheral circulation increases with theseverity of heart failure, and high plasma level of interleukin-6

is an important prognostic predictor in patients with conges-tive heart failure. J Am Coll Cardiol 1998;31:3918.

w x35 Koller-Strametz J, Packer R, Frey B, Kos T, Woloszczuk W,Stanek B. Circulating tumor necrosis factor-alpha. Levels inchronic heart failure: relation to its soluble receptor II,interleukin-6, and neurohormonal variables. J Heart LungTransplant 1998;17:35662.

w x36 MacGowan GA, Mann DL, Kormos RL et al. Circulatinginterleukin-6 in severe heart failure. Am J Cardiol1997;79:112831.

w x37 Orus J, Roig E, Perez-Villa F et al. Prognostic value of serum´cytokines in patients with congestive heart failure. J HeartLung Transplant 2000;19:41925.

w x38 Yoshida K, Taga T, Saito M et al. Targeted disruption of gp130, a common signal transducer for the interleukin-6family of cytokines, leads to myocardial and haematologicaldisorders. Proc Natl Acad Sci USA 1996;93:40711.

w x39 Testa M, Yeh M, Lee P et al. Circulating levels of cytokinesand their endogenous modulators in patients with mild tosevere congestive heart failure due to coronary artery diseaseof hypertension. J Am Coll Cardiol 1996;28:96471.

w x40 Parissis J, Venetsanou K, Mentzikof D et al. Clinical rele- vance of cytokine receptor soluble forms in decompensated

Ž .advanced heart failure. Eur Heart J 1998;19 Suppl. :2661 Abstr..

w x41 Mizel SB. IL-1 signal transduction. Eur Cytokine Netw1994;5:54761.

w x42 Seckinger PL, Lowenthal JW, Williamson K et al. A urineinhibitor of interleukin 1 activity that blocks ligand binding. JImmunol 1987;139:15469.

w x43 Fischer E, van Zee KJ, Marano MA et al. Interleukin-1receptor antagonist circulates in experimental inflammationand in human disease. Blood 1992;79:2196200.

w x44 Dinarello C. Biologic basis for interleukin-1 in disease. Blood1996;87:2095147.

w x45 Ohlsson K, Bjork P, Bergenfeldt M et al. Interleukin-1 recep-tor antagonist reduces mortality from endotoxin shock. Na-ture 1990;348:5502.

w x46 Koike S. Immunological disorders in patients with dilatedcardiomyopathy with special reference to the production of interleukin-2 and the expression of interleukin-2 receptors inthe patients’ peripheral blood lymphocytes. Jpn Heart J1989;30:799807.

w x47 Marriot JB, Goldman JH, Keeling PJ, Baig MK, Dalgleish

AG, McKenna WJ. Abnormal cytokine profiles in patients with idiopathic dilated cardiomyopathy and their asympto-matic relatives. Heart 1996;75:28790.

w x48 Takamoto T, Hori Y, Takenaga M et al. Surface markerstudies on activated peripheral blood lymphocytes in idio-pathic dilated cardiomyopathy. J Clin Lab Immunol1987;22:15761.

w x49 Limas CJ, Goldenberg IF, Limas C. Soluble interleukin-2receptor in patients with dilated cardiomyopathy. Circulation1995;91:6314.

w x50 Klappacher G, Haab D, Mehrabi M et al. Diagnostic andprognostic value of soluble interleukin-2 receptor in theserum of patients with idiopathic or ischemic dilated car-

Ž .diomyopathy. J Am Coll Cardiol 1997;29 Suppl. A :502A Abstr..




w x51 Clement MV, Stamenkovic I. Fas and tumor necrosis factor-

receptor-mediated cell death: similarities and distinctions. JExp Med 1994;180:55767.

w x52 Nishigaki K, Minatoguchi S, Seishima M et al. Plasma Fas

ligand, an inducer of apoptosis, and plasma soluble Fas, an

inhibitor of apoptosis, in patients with chronic congestiveheart failure. J Am Coll Cardiol 1997;29:121420.

w x53 Dong C, Wilson JE, Winters GL, McManus BM. Humantransplant coronary artery disease: pathological evidence for

Fas-mediated apoptotic cytotoxicity in allograft arteriopathy.Lab Invest 1996;74:92131.

w x54 Sliwa K, Skudicky D, Bergemman A, Candy J, Puren A, Sareli

P. Peripartum cardiomyopathy: analysis of clinical outcome,

left ventricular function, plasma levels of cytokines andFasr APO-1. J Am Coll Cardiol 2000;35:7015.

w x55 Wollert KC, Heineke J, Westermann J et al. The cardiac FasŽ . APO-1rCD95 receptorrFas ligand system: relation to dias-

tolic wall stress in volume-overload hypertrophy in vivo and

activation of the transcription factor AP-1 in cardiac my-ocytes. Circulation 2000;101:11728.

w x56 Rensing-Ehl A, Frei K, Flury R et al. Local Fasr APO-1Ž .CD95 ligand-mediated tumor cell killing in vivo. Eur J

Immunol 1995;25:22538.w x57 Yamaguchi S, Yamaoka M, Okuyama M et al. Elevated

circulating levels and cardiac secretion of soluble Fas ligandin patients with congestive heart failure. Am J Cardiol1999;83:15003.

w x58 Baggiolini M, Dewald B, Moser B. Interleukin-8 and related

chemotactic cytokines: CXC and CC chemokines. Adv Im-munol 1994;55:97179.

w x59 Entmann ML, Ballantyne CM. Inflammation in acute coro-nary syndromes. Circulation 1993;88:8003.

w x60 Baggiolini M, Dewald B, Moser B. Human chemokines: anupdate. Annu Rev Immunol 1997;15:675705.

w x61 Cushing SD, Berliner JA, Valente AJ et al. Minimally modi-

fied low density lipoprotein induces monocyte chemotactic

protein 1 in human endothelial cells and smooth muscle cells.Proc Natl Acad Sci USA 1990;87:51348.

w x62 Aukrust P, Veland T, Muller F et al. Elevated circulating¨levels of CC chemokines in patients with congestive heartfailure. Circulation 1998;97:113643.

w x63 Shioi T, Matsumori A, Kihara Y et al. Increased expression

of interleukin-1 beta and monocyte chemotactic and activat-

ing factorrmonocyte chemoattractant protein-1 in the hyper-

trophied and failing heart with pressure overload. Circ Res1997;81:66471.

w x64 Sasayama S, Okada M, Matsumori A. Chemokines and car-diovascular diseases. Cardiovasc Res 2000;45:2679.

w x65 Adams DH, Lloyd AR. Chemokines: leukocyte recruitmentand activation cytokines. Lancet 1997;349:4905.

w x66 Pattison J, Nelson PJ, Huie P et al. RANTES chemokineexpression in cell-mediated transplant rejection of the kidney.Lancet 1994;343:20911.

w x67 Kukielka GL, Smith CW, LaRosa GL et al. Interleukin-8

gene induction in the myocardium after ischemia and reper-fusion in vivo. J Clin Invest 1995;95:89103.

w x68 Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA. A

leukocyte homologue of the IL-8 receptor CXCR-2 mediates

the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998;101:35363.

w x69 Hasper D, Hummel M, Kleber FX, Reindl I, Volk HD.

Systemic inflammation in patients with heart failure. EurHeart J 1998;19:7615.

w x70 Damas JK, Gullestad L, Veland T et al. CXC-chemokines, a

new group of cytokines in congestive heart failure possiblerol e of pla telets a nd m onocytes. Ca rdiova sc R es2000;45:42836.

w x71 Burgess AW, Metcalf D. The nature and action of granulo-cyte-macrophage colony-stimulating factors. Blood 1980;56:94758.

w x72 Gamble JP, Elliot MJ, Jaipargas E, Lopez AF, Vadas MA.

Regulation of human monocyte adherence by granulocyte-

macrophage colony-stimulating factor. Proc Natl Acad SciUSA 1989;86:716973.

w x73 Takahashi M, Kitagawa S, Masuyama JI et al. Human mono-

cyteendothelial cell interaction induces synthesis of granulo-cyte-macrophage colony-stimulating factor. Circulation1996;93:118593.

w x74 Parissis JT, Venetsanou K, Kalantzi M, Mentzikof D, Karas

SM. Serum profiles of granulocyte-macrophage colony-stimu-

lating factor and CC chemokines in hypertensive patients

with or without significant hyperlipidemia. Am J Cardiol2000;85:7779.

w x75 Parissis JT, Adamopoulos S, Venetsanou KF, Mentzikof DG,

Karas SM, Kremastinos DT. Clinical and neurohormonal

correlates of circulating granulocyte-macrophage colony-

stimulating factor in severe heart failure secondary to is-chemic or idiopathic dilated cardiomyopathy. Am J Cardiol2000;86:70710.

w x76 Takahashi M, Ikeda U, Masuyama J et al. Involvement of

adhesion molecules in human monocyte adhesion and tran-

smigration through endothelial cells in vitro. Atherosclerosis1994;108:7381.

w x77 Gearing AJH, Newman W. Circulating adhesion molecules indisease. Immunol Today 1993;14:50612.

w x78 Kock A, Burrows J, Haines G, Carolos T, Harland J, Lei-

bovich S. Immunolocalization of endothelial and leukocyte

adhesion molecules in human rheumatoid and osteoarthriticsynovial tissue. Lab Invest 1991;64:3139.

w x79 Bla n A D, Mc Coll um CN. Circula ti ng endot heli al

cellrleukocyte adhesion molecules in atherosclerosis. ThrombHaemost 1994;72:1514.

w x80 Devaux B, Scholz D, Hirche A, Klovekorn WP, Schaper J.¨Upregulation of cell adhesion molecules and the presence of

low grade inflammation in human chronic heart failure. EurHeart J 1997;18:4709.

w x81 Tsutamoto T, Wada A, Maeda K et al. Angiotensin II type 1

receptor antagonist decreases plasma levels of tumor necrosis

factor- , interleukin-6 and soluble adhesion molecules inpatients with chronic heart failure. J Am Coll Cardiol2000;35:71421.

w x82 Adamopoulos S, Parissis J, Kroupis C et al. Physical training

reduces peripheral markers of inflammation in patients withchronic heart failure. Eur Heart J 2001;22:7917.

w x83 Endington T. More cellular signals for atherogenesis? Circu-

lation 1998;98:11512.w x84 Barnes PJ, Karin M. Nuclear Factor-B A pivotal tran-

scription factor in chronic inflammatory diseases. N Engl JMed 1997;336:106671.

w x85 Collins T, Read MA, Neish AS, Whitley MZ, Thanos D,

Maniatis T. Transcriptional regulation of endothelial cell

adhesion molecules: NF-B and cytokine-inducible en-hancers. FASEB J 1995;9:899909.

w x86 Veda A, Okuda K, Ohno S et al. NF-kappaB and Sp1

regulate transcription of the human monocyte chemoattrac-tant protein-1 gene. J Immunol 1994;153:205263.

w x87 Abe J, Berk BC. Reactive oxygen species as mediators of

signal transduction in cardiovascular disease. Trends Cardio-Ž . vasc Med 1998;8 2 :5964.




w x88 Kitamoto S, Egashira K, Kataoka C et al. Increased activityof nuclear factor-B participates in cardiovascular remodel-ing induced by chronic inhibition of nitric oxide synthesis inrats. Circulation 2000;102:80612.

w x89 Francis GS. TNF- and heart failure: the difference between

proof of principle and hypothesis testing. Circulation1999;99:32134.

w x90 Sasayama S, Matsumori A, Kihara Y. New insights into thepathophysiological role for cytokines in heart failure. Cardio- vasc Res 1999;42:55764.

Eur J Heart Fail 2001 Adamopoulos 517 26

Documents

Transcript of Eur J Heart Fail 2001 Adamopoulos 517 26