Stefan D Anker, Stephan von Haehling

464 See end of artile for authors affiliations Correspondene to: Dr Stefan D Anker, National Heart and Lung Institute, Department of Clinial Cardiology, Dovehouse Street, London SW3 6LY, UK; s.anker@imperial.a.uk Heart failure INFLAMMATORY MEDIATORS IN CHRONIC HEART FAILURE: AN OVERVIEW ROLE C Stefan D Anker, Stephan von Haehling Heart 2004; 90:464 470. doi: 10.1136/hrt.2002.007005 hroni heart failure (CHF) represents a major publi health burden, and its prognosis is omparable to that of different malignant diseases. Our understanding of CHF has developed from the rather simplisti model of mere pump failure to that of a multisystem disorder whih affets not only the ardiovasular system but also the musuloskeletal, renal, neuroendorine, and immune systems. Thus, the pathophysiology of CHF is exeedingly omplex. Therapies to blok exessive neuroendorine ativation have beome a ornerstone of treatment. CHF progresses beause of ativation of neurohormones and pro-inflammatory ytokines following an initial ardia injury or a mutation of the geneti programme. 1 Virtually any heart disease an ultimately lead to heart failure, although the initial event leading to the development of this syndrome is in many ases unknown. However, CHF is always the result of some underlying proess and the diagnosis annot stand alone. The ativation of the aforementioned systems maintains and worsens CHF. In partiular, the ativation of the immune system has reeived onsiderable interest in the last deade. There are several different omponents to this system whih interat with eah other in a omplex manner. It is beoming inreasingly apparent that inflammatory mediators play a ruial role in the development of CHF, and several strategies to ounterbalane different aspets of the inflammatory response are onsidered. Possible targets involve pro- and anti-inflammatory ytokines and their reeptors, endotoxin, adhesion moleules, nitri oxide and nitri oxide synthase, reative oxygen speies, and different types of leuoytes. The purpose of this review is to give a brief overview of the urrent understanding of the role of inflammation in CHF. Furthermore, we will disuss reent advanes in the development of new therapeuti strategies in this field. OF PRO-INFLAMMATORY CYTOKINES Cytokines form a vast array of relatively low moleular weight, pharmaologially ative proteins. These substanes are sereted by different ell types for the purpose of altering either their own funtion (autorine) or that of adjaent ells (pararine). The most important ytokines impliated in the progression of CHF are tumour nerosis fator a (TNFa), interleukin (IL) 1, and IL-6. These ytokines share some of their major harateristis (redundany), and all at in a proinflammatory sense. Among those, TNFa is the ytokine whih has been studied in greatest detail. Several hypotheses have been suggested to desribe the origin of immune ativation in CHF (fig 1). The prodution of pro-inflammatory ytokines has mostly been attributed to seretion by mononulear ells, although the myoardium seems to be another important soure. Some evidene suggests that ateholamines augment this myoardial ytokine prodution. The onepts trying to explain inreased prodution of pro-inflammatory mediators omprise response to myoardial injury 2 and underperfusion of peripheral tissues 3 (fig 1). We have proposed that inreased bowel wall oedema auses transloation of baterial endotoxin from the gut whih eventually yields pro-inflammatory ytokine prodution from monoytes in the bloodstream and possibly other tissues. 4 Indeed, endotoxin, also known as lipopolysaharide (LPS), is one of the strongest induers of TNFa and other pro-inflammatory mediators (fig 2A). Very small amounts of this substane are apable of induing TNFa seretion. 5 Attempts to prove any of the aforementioned hypotheses, however, yielded only indiret evidene. Thus, the elevation of the plasma onentrations of several pro-inflammatory mediators in aute myoarditis and aute myoardial infartion may hint towards the tissue injury hypothesis. 2 Also, peripheral IL-6 spillover was found to be inreased in patients with CHF when omparing arterial and venous plasma onentrations, thus indiating a peripheral ytokine prodution. 3 This, however, has not been demonstrated for TNFa. Moreover, soluble CD14, a marker of endotoxin ell interation and shedding from the ell membrane (fig 2A), was found to be inreased in some patients with CHF (ontrols: 2714 (121) ng/ml; CHF patients: 3401 (134) ng/ml, p = 0.0048), espeially in those with ahexia. 4 It was subsequently shown that LPS onentrations are raised in CHF patients

Figure 1 Competing theories. Several theories to explain the ause(s) of inflammatory immune ativation in CHF have been suggested. These theories may in fat omplement eah other. The myoardium itself is able to release proinflammatory ytokines, whih is augmented by adrenergi stimulation. Myoardial tissue injury for example, myoardial infartion, baterial transloation, and peripheral tissue hypoxia may lead to mononulear ell ativation, whih eventually leads to pro-inflammatory ytokine ativation. See text for details. LPS, lipopolysaharide; LV, left ventrile; RV, right ventrile. Figure 2 (A) TNFa signalling via a reeptor omplex omprising CD14 and toll-like reeptor 4 (TLR4). Upon LPS binding to this omplex, signal transdution via TLR4 leads to the ativation of the transription fator NF-kB. Therefore, IkB is leared off the moleule. After transription and translation, trimeri TNFa is inserted into the ell membrane. The TNFa onverting enzyme (TACE) leaves TNFa off the membrane to yield its soluble form (stnfa). (B) IL-6 signalling via IL-6R and gp130. Only the latter has to be expressed to render the respetive ell suseptible to IL-6, beause soluble IL-6R an interat with membrane bound gp130. The ativation of the reeptor omplex leads to the ativation of different transription fators, suh as STAT1 and STAT3. (C) TNFa mediated effets. Several untoward effets have been impliated into the over-expression of TNFa. See text for details. gp, glyoprotein; IkB, inhibitory kb; IL, interleukin; inos, induible isoform of nitri oxide synthase; LPS, lipopolysaharide; LV, left ventriular; NF-kB, nulear fator-kb; R, reeptor; s, soluble; STAT, signal transduers and ativator of transription; TACE, TNFa onverting enzyme; TNFa, tumour nerosis fator a. 465

466 with peripheral oedema and that diureti treatment results in redution of LPS values. 6 It might eventually be found that all of the above mehanisms take part in what is now known as immune ativation in CHF. Tumour nerosis fator a TNFa was first desribed in 1975 and termed ahetin. In 1990 Levine and assoiates observed that mean (SEM) serum onentrations of TNFa were higher in CHF patients than in healthy subjets (115 (25) v 9 (3) U/ml, p, 0.001). 7 They also demonstrated that those patients with high onentrations of TNFa were more often suffering from ardia ahexia. 7 TNFa exerts its effets via TNFa reeptors (TNFR), whih are expressed by almost all nuleated ells. Two TNFRs have so far been identified. 8 9 TNFR-1 is more abundantly expressed and appears to be the main signalling reeptor. The majority of deleterious effets aused by TNFa seem to be mediated via this reeptor, whereas TNFR-2 appears to have a more protetive role in the heart. Previous studies have identified both types of reeptors in non-failing and failing human myoardium. After translation, both reeptors, like TNFa itself, are inserted into the ell membrane of the respetive ell. 8 9 Proteolyti leavage by TNFa onverting enzyme (TACE) yields the soluble forms (fig 2A). The preise role of the soluble TNFRs remains unlear, although some evidene suggests that they stabilise the TNFa moleule, thus potentiating its detrimental long term ations. However, higher onentrations of TNFRs appear to inhibit TNFa ativity. It is thought that high plasma onentrations of soluble TNFRs primarily indiate a history of raised TNFa values. The reproduibility of plasma onentrations of soluble TNFRs is higher than that of TNFa itself. This may be the reason why soluble TNFRs predit short term 10 and long term 11 prognosis better than TNFa in CHF patients. Several untoward effets seem to be assoiated with raised TNFa prodution in CHF (fig 2C). TNFa has been impliated in the development of left ventriular dysfuntion, left ventriular remodelling, inreased ardia myoyte apoptosis, the development of anorexia and ahexia, redued skeletal musle blood flow and endothelial dysfuntion, severity of insulin resistane, ativation of the induible form of nitri oxide synthase (inos), b reeptor unoupling from adenylate ylase, and other effets. 1 8 9 Interleukin 6 TNFa is not the only ytokine whih worsens CHF. Aording to the ytokine hypothesis, CHF progresses beause ytokines exaerbate haemodynami abnormalities or exert diret toxi effets on the heart. 12 Inreased onentrations of IL-6 have been shown in the irulation of CHF patients. IL-6 an produe myoyte hypertrophy, myoardial dysfuntion, and musle wasting. On the other hand, IL-6 seems to blok ardia myoyte apoptosis. Sine IL-6 is thought to be released in diret response to TNFa, it was not surprising that a linear orrelation between the two was observed. Therefore, the existene of a ytokine asade has been suggested. 12 While inreased onentrations of IL-6 were found to be assoiated with a poorer prognosis in CHF patients, those of the soluble IL-6 reeptor (IL-6R) were not. Interestingly, it is a small transmembrane glyoprotein termed gp130, but not IL-6R itself, whih renders ells suseptible to IL-6 (fig 2B). Indeed, IL-6 an at on ells laking the expression of IL-6R after omplex formation with soluble IL-6R. Both gp130 and IL-6R are always required for signalling. The soluble form of gp130 inativates the soluble IL-6/IL-6R omplex. However, both the onentrations of gp130 and the overall level of bioativity of IL-6 are inreased in CHF. Interleukin 1 Another important ytokine in the setting of CHF is IL-1. IL-1 along with TNFa are generally thought of as prototypial pro-inflammatory ytokines. IL-1 has been demonstrated in the myoardium of patients with idiopathi dilated ardiomyopathy, and it depresses myoardial ontratility in a dose dependent fashion. This effet is synergisti with that of TNFa, and the stimulation of inos seems to be involved. Additional findings have shown IL-1 being involved in myoardial apoptosis, hypertrophy, and arrhythmogenesis. When summarising the role of IL-6 and IL-1 in the setting of CHF one must admit that the preise mehanisms involved are far from being entirely lear. In fat, both substanes also exert some benefiial (ardioprotetive) effets, although the role of these remains to be eluidated in more detail. Downstream signalling pathways Nulear fator kb (NF-kB) is ruially involved in the regulation of a battery of inflammatory genes, inluding pro-inflammatory ytokines, hemokines, and adhesion moleules. The NF-kB family onsists of a number of proteins, whih make up homo- and heterodimers to form the ative transription fator. In unstimulated ells, ytoplasmi NF-kB is bound to its inhibitory protein IkB with its nulear loalisation signal being masked (fig 2B). Different stimuli, among them a good many of those that are regulated by NF-kB itself, lead to IkB degradation. This leads to NF-kB transloation into the nuleus, where it binds to promotor or enhaner regions of speifi genes. Only very few data about NF-kB in CHF are available. Sine pro-inflammatory ytokines are raised in CHF, it is tempting to speulate that NF-kB ativity is elevated in the respetive ells as well. Indeed, myoardial tissue from patients with CHF exhibits ativation of NF-kB. A study in 16 patients with end stage heart failure showed that left ventriular assist devies, used to bridge the time until transplantation, redued the number of NF-kB positive ardiomyoyte nulei signifiantly. 13 Healthy hearts do not normally express NF-kB to a detetable extent. In the light of these findings it has been speulated that NF-kB is involved in what is alled reverse remodelling of the heart during treatment with suh devies. Interleukin 10 IL-10 is one of the most important anti-inflammatory ytokines. It is known to down regulate the prodution of TNFa, IL-1, and IL-6, respetively. This has been onfirmed in LPS stimulated peripheral blood mononulear ells from CHF patients. 14 Furthermore, IL-10 limits the prodution of marophage derived nitri oxide (NO) and oxygen-free radials. IL-10 also enhanes the release of soluble TNFR, whih ontributes to the redution of TNFa ativity. Similar to pro-inflammatory ytokines, IL-10 mrna has also been deteted in the failing myoardium. Cirulating IL-10 onentrations have been reported to be either inreased or dereased in CHF patients ompared to healthy, age mathed

ontrols. However, the intravenous administration of immunoglobulin to 40 CHF patients during a small double blind, plaebo ontrolled trial inreased plasma onentrations of IL-10, whih eventually yielded improvements in left ventriular ejetion fration (LVEF) (from 26 (2)% at baseline to 31 (3)% after treatment, p, 0.01). 15 IL-10 and other substanes augmenting its prodution may offer therapeuti possibilities in CHF. C REACTIVE PROTEIN C reative protein (CRP) was first disovered in 1930. It was so named beause it reats with the somati C polysaharide of Streptoous pneumoniae. CRP speifially binds to speifi mirobial polysaharides (phosphoholine moieties), whih gives this substane a host defensive role. Upon binding to these strutures, CRP ativates the lassial omplement pathway and opsonises ligands for phagoytosis. CRP is exlusively produed in the liver. It is sereted in inreased amounts within six hours of an inflammatory stimulus and is therefore regarded as a marker of aute inflammation. The first observation of raised onentrations of CRP in CHF was published in 1990. Reently, another group measured CRP values in 188 patients with idiopathi dilated ardiomyopathy. 16 All patients had an impaired LVEF of less than 40%. Those patients who died during a follow up period of five years had signifiantly higher CRP onentrations than those who survived (1.05 (1.37) mg/dl v 0.49 (1.04) mg/dl, p, 0.05). Moreover, CRP is able to augment IL-1b indued prodution of inos, although NF-kB prodution is not altered. However, it is not lear if CRP is merely a marker of inflammation with no partiular role in the development of ardia disease or if it diretly modulates disease proess. ADHESION MOLECULES Adhesion moleules are ell surfae reeptors involved in the binding of leuoytes to eah other, to endothelial ells, or to the extraellular matrix (fig 3). These moleules have been impliated in a vast number of ardiovasular diseases. Three different families of proteins have been desribed so far: (1) The immunoglobulin superfamily onsists of a number of adhesion moleules inluding intraellular adhesion moleule-1 (ICAM-1), ICAM-2, ICAM-3, vasular ell adhesion moleule-1 (VCAM-1), and others. (2) Integrins form the ounterreeptor to the latter type of reeptor, mediating leuoyte adherene to the vasular endothelium and other ell ell interations. Integrins are heterodimers of a and b subunits. Among them, lymphoyte funtion assoiated antigen-1 (LFA-1) and glyoprotein IIb/IIIa an be found (fig 3). (3) The seletins are involved in the adhesion of leuoytes to ativated endothelium. These weak interations ause a typial rolling of leuoytes on the endothelial surfae, whih is mainly mediated by leuoyte (L)-seletin and platelet (P)-seletin (fig 3). Other seletins, suh as endothelial (E)-seletin, seem to produe a stronger interation, whih eventually leads to ell extravasation. Sine immune ativation is an important finding in CHF, it is tempting to speulate that the interation between endothelial ells, leuoytes, and possibly platelets is of partiular importane in this ondition. An upregulation of plasma soluble ICAM-1 has been shown in a group of 102 CHF patients. 17 Thevaluesinthisstudy inreased from the normal onentration (149 (10) ng/ml) to 207 (9.4) ng/ml in mild CHF, and 293.18 ng/ml in severe CHF (all p, 0.05). Moreover, a signifiant negative orrelation between LVEF and soluble ICAM-1 was observed (r = 20.36; p, 0.001), and these values independently predited survival. Elevated serum onentrations have also been demonstrated for other soluble markers, suh as VCAM-1, P-seletin, and E-seletin. 4 18 Interestingly, only VCAM-1 onentrations dereased after heart transplantation. The failing myoardium itself displays an inreased expression of ICAM-1 and LFA-1. 19 TNFa indues adhesion moleules. Thus, this ytokine may aount for mononulear ell infiltration into the myoardium, whih has been reported in CHF. NITRIC OXIDE Nitri oxide (NO) was originally disovered in 1980 by Furhgott and Zawadski. It is a lipophili, freely diffusible, soluble gas, whih has a short half life of less than four seonds in biologial solutions. Its nearly ubiquitous involvement has resulted in an explosion in the NO field in the last years. NO is produed from the amino aid L-arginine by nitri oxide synthase (NOS) (fig 3), and it reats with O 2 in aqueous solutions yielding the relatively inert nitrate (NO 2 3 ) and nitrite (NO 2 2 ). However, NO also reats with oxygen derived free radials, namely superoxide anion, to form the toxi peroxynitrite (ONOO 2 ). NO is produed by a group of well haraterised isoforms of nitri oxide synthase (NOS). Three isoforms have been identified. (1) The endothelial (onstitutive) isoform (NOS, also known as NOS3) produes a ontinuous amount of NO, whih ats as a vasodilator. In endothelial ells, NOS is mainly found in the membrane of aveolae, small invaginations, whih are haraterised by the presene of a marker protein termed aveolin. After synthesis in the endothelium, NO diffuses aross the ell membrane and enters vasular smooth musle ells to indue musle relaxation (fig 3). (2) The induible isoform of NOS (inos or NOS2) has already been mentioned. Unlike membrane bound NOS, inos is found in the ytoplasm of a large number of different ell types. After indution of inos by, for example, pro-inflammatory ytokines, interferon or LPS, the output of inos far exeeds that of NOS. Sine the intraellular NO ontent of marophages rises during baterial infetion, NO is thought to play an important role in mirobial killing in innate immune responses. (3) The third isoform of NOS is the neuronal isoform nnos (NOS1). It is expressed in the entral and peripheral nervous systems and in skeletal musles. The role of NO in CHF is omplex. On the one hand, lak of NO is leading to endothelial dysfuntion with its detrimental onsequenes inluding impaired tissue perfusion, myoardial ishaemia, and vasular remodelling. On the other hand, higher onentrations of NO, whih have been observed in the failing myoardium, may ause the loss of myoytes and inhibit myoyte ontratility. 20 While low (physiologial) onentrations of NO have benefiial effets, those of higher (pathologial) onentrations, possibly mediated by inos, appear detrimental. NO indued by ytokines also has negative hronotropi effets and is apable of triggering apoptosis. Indeed, high inos gene expression is assoiated with low LVEF, but not with linial disease severity of heart failure. 21 Another study desribed a linear relation between inos gene expression and LVEF. 22 In the light of this finding it is not surprising that L-NG-monomethyl-arginine (L-NMMA), an NOS inhibitor, bloks negative inotropi effets. The different mehanisms by whih NO results in these 467

468 Figure 3 Physiologial role of different types of adhesion moleules. Seletins are mainly involved in leuoyte rolling on the endothelial wall. Integrins for example, LFA-1 yield a muh stronger interation, whih eventually leads to transendothelial migration. Endothelium derived NO plays another important role in mediating endothelial funtion. Its prodution by NOS from L-arginine leads to smooth musle relaxation. NOS, onstitutive nitri oxide synthase; ICAM, intraellular adhesion moleule; LFA, lymphoyte funtion assoiated antigen; NO, nitri oxide; PECAM, platelet endothelial ell adhesion moleule. ontrasting effets seen in CHF may involve dereases and inreases in oxidative stress, respetively. LEUCOCYTE SUBSETS IN CHF Little has been published about leuoytes and their funtions in the ourse of CHF. This is fairly surprising as it is ommonly believed that CHF is a state of hroni immune ativation. In one interesting analysis, myoardial tissue was obtained from patients with end stage heart failure at transplantation. 19 Interestingly, CD3 + T lymphoytes and CD68 + marophages were more abundantly present in the myoardium of CHF patients than in ontrols, suggesting a role of adhesion moleules in this setting. Indeed, this may signifiantly ontribute to the strutural deterioration that is the basis of redued ardia funtion in this setting. A low lymphoyte ount, however, seems to be rather detrimental. On the other hand, the B ell response seems to be intat with normal antibody seretion apaity upon pneumooal vaination. 23 Another study reported a dereased perentage of T suppressor ells in patients with idiopathi dilated ardiomyopathy. The signifiane of this finding remains to be eluidated. THERAPEUTIC OPTIONS FOR CHF The prognosis of CHF remains fairly poor, although the introdution of angiotensin onverting enzyme (ACE) inhibitors and b blokers improved survival signifiantly. Reent insights into the pathophysiology of CHF provide promising targets for future treatments. However, preliminary results from the first large sale linial trial to ounterbalane TNFa ativity have been rather disappointing. Insights into other possible therapeuti targets are only about to begin. TNFa antagonism with etanerept and infliximab Only reently, two trial programmes to investigate the therapeuti impat of TNFa antagonism in vivo have been halted. These trials tested two different approahes to attenuate the detrimental effets of TNFa. Etanerept is a TNFR-2 fusion protein, whih binds to TNFa and funtionally inativates this ytokine. A small double blind, plaebo ontrolled pilot study in 18 patients with moderate heart failure showed promising results. 24 Thus, a large sale linial trial was designed with two arms. Both the Amerian arm RENAISSANCE (randomized

Inflammatory mediators in CHF: key points Immune ativation plays an important role in the disease progression of hroni heart failure (CHF) Pro-inflammatory ytokines, espeially that of TNFa, IL-6, and IL-1, exaerbate haemodynami abnormalities, exert direts toxi effets on the heart, and ontribute to tissue wasting and weight loss in CHF (that is, ahexia). The origin of pro-inflammatory ytokines in CHF is not entirely lear Endotoxin (LPS) may play an important role in the proess of ativating pro-inflammatory ytokines Adhesion moleules may ontribute to leuoyte extravasation in the myoardium, thus promoting strutural deterioration as a basis of redued ardia funtion Reent linial trials to inhibit TNFa ativity in CHF showed disappointing results. It seems likely that anti-ytokine therapy will work only in CHF patients with proven inflammatory status. Statins, beause of their pleiotropi (anti-inflammatory) effets, may prove benefiial in this setting etanerept North Amerian strategy to study antagonism of ytokines) and the European arm RECOVER (researh into etanerept: ytokine antagonism in ventriular dysfuntion) reruited a total of 2048 CHF patients, most of them with mild to moderate disease. The ombined analysis of the two trials was termed RENEWAL (randomized etanerept worldwide evaluation). Patients were treated subutaneously for 24 weeks with etanerept or plaebo in a double blind fashion (doses in RECOVER: 25 mg two times weekly or 25 mg one weekly; doses in RENAISSANCE: 25 mg three times weekly or 25 mg two times weekly). For reasons that are not entirely lear, the RENEWAL analysis exluded the lowest dose of RECOVER (that is, etanerept 25 mg one weekly). The number of patients lassified improved, unhanged, or worsened was similar for patients on plaebo or any dose of etanerept. Moreover, the primary end point (death or hospitalisation beause of CHF) was not different between the two groups (risk ratio (RR) 1.10, 95% onfidene interval (CI) 0.91 to 1.33; p = 0.33). 25 The seondary end point (all ause mortality) did also not differ between the two groups (RR 1.13, 95% CI 0.86 to 1.50; p = 0.39). The survival urves overlapped throughout the first year of treatment. Sine the ombined analysis of the two trial programmes exluded the low dose group from RECOVER, it appears noteworthy that the adjusted effets on total mortality for the individual dose levels were not reported. Of partiular interest is total mortality in the 375 patients on 25 mg etanerept one weekly ompared with the 373 patients on plaebo in RECOVER. The unadjusted mortality rates in RECOVER were 8.8% in the plaebo group, 5.9% for etanerept one weekly and 7.2% for etanerept twie weekly. In other words, the total mortality of patients treated with low dose etanerept was more than 30% redued ompared to the plaebo group. In light of these data, a so far negleted dose dependent effet may substantially hange the interpretation of the studies. 26 The ATTACH trial (anti-tnfa therapy against hroni heart failure) enrolled 150 patients with CHF to investigate the impat of treatment with infliximab, a himeri (mouse/ human) IgG 1 monolonal antibody that binds both soluble and membrane bound TNFa. 27 It is administered intravenously. Like RENAISSANCE and RECOVER, this study was designed in a multientre, randomised, double blind, plaebo ontrolled fashion. 27 It has also been stopped prematurely. However, when analysing the data from ATTACH it is noteworthy that the plasma values of infliximab ahieved in the patients were many times higher than expeted. This may aount for the inreased risk of death in the group reeiving the higher dose of infliximab (10 mg/kg body weight) observed in this study (RR 2.84, 95% CI 1.01 to 7.97; p, 0.05). There was no adverse risk assoiated with 5 mg/kg body weight infliximab (RR 0.80, 95% CI 0.22 to 2.99) and in fat in patients reeiving this dose LVEF improved (p, 0.05). 27 The lesson learned from these trials is that TNFa may not only exert detrimental effets. However, some questions remain to be addressed. Both studies inluded only a very limited number of patients with severe CHF who an be expeted to have signifiant inflammatory immune ativation. Interestingly, ATTACH aimed to reruit patients with severe CHF, but none of the 49 patients in the plaebo group died during the first 28 weeks of follow up. 25 Statins Statins (3-hydroxy-3-methylglutaryl-oenzyme A redutase inhibitors) blok the rate limiting step in holesterol biosynthesis in the liver and other tissues. These drugs are administered orally, are well tolerated, and generally safe. It has been reported that statins an improve the prognosis of oronary artery disease irrespetive of serum holesterol values, whih gave rise to the idea that effets beyond holesterol lowering so alled pleiotropi effets exist. Indeed, some substanes from this group have been shown to improve endothelial funtion by induing NOS gene transription. 28 Some statins might be able to redue vasular prodution of reative oxygen speies. Moreover, statins have been found to redue C reative protein values after myoardial infartion and in hyperholesterolaemia. Moreover, statins might derease the prodution of TNFa, IL-1, and IL-6 from marophages. 29 The availability of linial data of statin use in CHF is sare. The Sandinavian simvastatin survival study (4S) demonstrated fewer instanes of new onset CHF after simvastatin treatment. This effet seems to be mediated by the pleiotropi effets of the drug, beause hanges in the lipoprotein profiles and baseline harateristis were similar in patients with or without future events. The linial benefit assoiated with statin treatment was also independent of baseline holesterol values in WOSCOPS (West of Sotland oronary prevention study). A subgroup analysis revealed that holesterol independent mehanisms may provide additional benefits. Prospetive data are needed to examine the effets of statin treatment in CHF. The doses needed to ahieve the desired effets might be muh lower than those needed to treat hyperholesterolaemia. 29 CONCLUSION The last several years have seen onsiderable researh into the field of immune ativation in CHF. Pro-inflammatory ytokines have been impliated in the progression of heart failure. Several hypotheses were suggested to explain the development of this aspet of CHF. The role of leuoytes is not entirely understood; however, it appears that raised onentrations of adhesion moleules indiate a role for these moleules in the extravasation into the myoardium and other tissues. The role of LPS in triggering inflammation needs further study. The disappointing results of reent trials 469

470 most likely will lead to slow down of drug development proesses. We believe the ytokine story is still very muh alive in CHF. However, anti-inflammatory strategies need to be broad and foused on patients with inflammatory problems. New therapeuti developments will hopefully lead to improvements in the still poor prognosis of CHF patients. ACKNOWLEDGEMENTS SDA is supported by a Vandervell Fellowship and a donation from Dr Hubert Bailey. Applied Cahexia Researh (SDA) is supported by a grant of the Charité Medial Shool. SvH is supported by the German Heart Foundation.... Authors affiliations S D Anker*, S von Haehling, Department of Clinial Cardiology, Imperial College Shool of Mediine, National Heart & Lung Institute, London, UK *Also Applied Cahexia Researh, Department of Cardiology, Charité Medial Shool, Campus Virhow-Klinikum, Berlin, Germany REFERENCES 1 Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Cir Res 2002;91:988 98. 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Pilot study to investigate TNFa antagonism with etanerept showing benefiial effets. 25 Anker SD, Coats AJ. How to RECOVER from RENAISSANCE? The signifiane of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int J Cardiol 2002;86:123 30. Detailed desription of the available preliminary data on the large sale trials to antagonise TNFa in CHF. 26 Anker SD. Anti-tumour nerosis fator-a therapy in hroni heart failure what went wrong? In: MMurray JJ, Pfeffer MA, eds. Heart failure updates. London: Martin Dunitz, 2003:201 13. 27 Chung ES, Paker M, Lo KH, et al. Randomized, double-blind, plaeboontrolled, pilot trial of infliximab, a himeri monolonal antibody to tumor nerosis fator-alpha, in patients with moderate-to-severe heart failure: results of the anti-tnf therapy against ongestive heart failure (ATTACH) trial. Cirulation 2003;107:3133 40. 28 von Haehling S, Anker SD, Bassenge E. Statins and the role of nitri oxide in hroni heart failure. Heart Fail Rev 2003;8:99 106. 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