The activated immune system in congestive heart failure – from dropsy to the cytokine paradigm
1998; Wiley; Volume: 243; Issue: 2 Linguagem: Inglês
10.1046/j.1365-2796.1998.00265.x
ISSN1365-2796
Autores Tópico(s)Cardiovascular Function and Risk Factors
ResumoJournal of Internal MedicineVolume 243, Issue 2 p. 87-92 Free Access The activated immune system in congestive heart failure – from dropsy to the cytokine paradigm First published: 09 October 2008 https://doi.org/10.1046/j.1365-2796.1998.00265.xCitations: 34AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat The changing concepts of heart failure In 1785, William Withering published his 'An account of the foxglove and some of its medical uses: with practical remarks on dropsy and other diseases'. In the 200 years following Withering's description of the beneficial effect of digitalis in the treatment of dropsy, the concept of heart failure underwent several fundamental changes [ 1]. In the 1940s through to the 1960s, physicians regarded heart failure principally as an oedematous disorder and proposed a cardiorenal hypothesis in an attempt to explain the sodium retention of these patients. In the 1970s and 1980s, the cardiocirculatory model was propagated to explain patients' symptoms and disability. The subsequent neurohumoral concept of the 1990s made allowance for the fact that heart failure is not only characterized by salt and water retention but also by disease progression, with progressive myocyte loss and myocardial fibrosis. Neurohumoral adaptation and maladaptation [ 2] more easily explain the complex haemodynamic, functional and metabolic alterations seen in heart failure [ 3] than the former concepts. Finally, the gap between neuroendocrinium and inflammation was bridged by the recent cytokine hypothesis [ 4], postulating that overexpression of vasoconstrictory and proinflammatory members of the cytokine family worsens heart failure, both in the heart itself by prompting cardiodepression and apoptosis, and systemically by triggering inflammation, cachexia and profound metabolic alterations. Immune activation in heart failure – focus on proinflammatory cytokines Inflammation does not occur only in infectious heart diseases: an elevated serum level of C-reactive protein is seen in 70% of patients with heart failure, especially in acute exacerbations. In congestive heart failure, activation but also impairment of the immune system have been documented in a high percentage of patients: the rise in serum neopterin (in 56% of heart failure patients [ 5]) comes from monocyte/macrophage activation, and the increased serum levels of interleukin-2 (IL-2), soluble IL-2 receptors (56% [ 5]), soluble CD8 (24% [ 5]) and interferon-γ (40% [ 5]) indicate stimulation of T-lymphocytes (Samsonov et al., this volume; refs. 30 & 31 in [ 4]); however, an impairment of lymphocyte function in heart failure has been documented [ 6] as well. Much interest is focused on overexpression of proinflammatory cytokines, such as tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6, and their soluble receptors (sTNF-RI, sTNF-RII, sIL-6R) and receptor antagonists (IL-1Ra). After having overcome pitfalls of cytokine analysis, it has now been convincingly documented that, in patients with congestive heart failure of ischaemic as well as of non-ischaemic origin, proinflammatory cytokines are activated and subject to regulation: this is evident from increased plasma levels of TNF-α, IL-1 and IL-6, from local expression of TNF-α and downregulated TNF-receptors I and II in the heart, and from the rise of soluble TNF- and IL-6 receptors and of IL-1Ra in plasma (refs. 25,30-32 in [ 4]; [ 78]). Soluble cytokine receptors and receptor antagonists are not only indicators of an activated cytokine system: soluble receptors and receptor antagonists can either inactivate the corresponding circulating cytokine by high affinity binding, but may in turn also prolong the half-life of the cytokine then present in stable complexes in the circulation [ 9]. For a comprehensive picture of cytokine activation in heart failure, biologically active as well as antigenic (total and free) plasma cytokine activity must be determined, best in combination with the plasma concentration of the corresponding soluble receptor(s) and/or receptor antagonists [ 910]. Thus proof was given that a considerable percentage of patients with heart failure show elevated levels of cytokines and soluble receptors/receptor antagonist, increasing with the functional classes I, II, III and IV (ref. 31 in [ 4]): TNF-α: 12, 5, 25 and 42%; sTNF-RII: 12, 25, 55 and 92%; IL-β: 0, 5, 25 and 33%; IL-1Ra 19, 25, 45 and 62%; IL-6: 12, 10, 15 and 58%; sIL-6R: 0, 15, 25 and 33%. However, the modest rises in plasma levels found in patients with congestive heart failure for TNF-α (from 1 pg mL−1 to 2–6 pg mL−1), IL-6 (from 1 pg mL−1 to 3–15 pg mL−1), sTNF-RI (from 1 ng mL−1 up to 8 ng mL−1) and sTNFR-II (from 2 ng mL−1 up to 12 ng mL−1) (ref. 39 in [ 4]; [ 7, 810,]) should be interpreted with caution. First, this is not a phenomenon specific for heart failure: cytokine plasma levels are increased in many heart diseases [ Müller-Werdan U, Reithmann C, Werdan K. ], such as severe myocardial infarction (TNF-α values up to 1500 pg mL−1) and the escalating inflammatory response post cardiac surgery (TNF-α 50 pg mL−1; sTNF-RI,II 15-20 ng mL−1 [ 12]). Moreover, raised cytokine plasma levels have been reported for many disease states of non-cardiac origin, often not associated with any clinically relevant or measurable impairment of cardiac function. Secondly, the question comes up, whether the modest rise in plasma TNF-α and IL-6 of the order of 10 pg ml−1 in heart failure of functional classes III and IV really does any harm to the patient, and especially his heart, at all? In sepsis, much higher TNF-α and IL-6 levels of 19–180 and 39–1434 pg mL−1, respectively, are characteristic for surviving patients, and nevertheless myocardial depression of these survivors is fully reversible [ Müller-Werdan U, Reithmann C, Werdan K. ]. Still higher increases in TNF-α plasma levels-up to 83000 pg mL−1 for several hours-were observed in cancer patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-α, without suffering irreversible damage to the heart. Thirdly, plasma levels may not necessarily reflect cytokine contents of the heart, but rather some spillover. Thus, cardiomyocytes do produce IL-1 upon stimulation, but retain most of it intracellularly (Müller-Werdan U et al., submitted). In view of these data, one might question the relevance of the only modest rise in cytokine plasma levels in patients with congestive heart failure. However, TNF-α mRNA and TNF-α protein are expressed in the hearts of patients with severe heart failure and dilated cardiomyopathy to a much higher extent than in control subjects (ref. 26 in [ 4]). Additionally, corresponding to a downregulation by 60% of the TNF receptors I and II in the hearts of patients with end-stage dilated and ischaemic heart disease, soluble TNF receptors I and II in plasma are upregulated 1.5–3-findings document some correlation between plasma cytokine levels and local cytokine expression in the heart. Cardiodepression and apoptosis: understanding of the pleiotropic actions of cytokines in heart failure is just in its beginning Back in 1989, Medline quotations were really lacking citations such as ‘cytokines and heart failure’. However, in the following years, the interest in this topic grew exponentially. What is the clinical relevance of elevated plasma cytokine levels? Most patients with congestive heart disease die either from pump failure or from malignant arrhythmias, but not from inflammation or infection. Is, therefore, immune activation in heart failure a pure epiphenomenon? Maybe not, if immune activation and especially proinflammatory cytokines turn out to deteriorate further the clinical course of the patient with heart failure and especially depress further heart function. Referring to other medical fields such as sepsis research and oncology, we come across many experimental and clinical findings supporting the assumption that inflammation and proinflammatory cytokines can and do impair heart function [ Müller-Werdan U, Reithmann C, Werdan K. ]. To elucidate the mechanisms underlying this specific form of cardiodepression, it is pertinent that we should understand the pleiotropic actions of cytokines: binding of a cytokine molecule like TNF-α to its cardiomyocyte TNF receptors (ref. 27 in [ 4]) initiates–not within seconds to minutes but within hours to days–a complex sequence of events on the transcriptional and translational level. This finally results in a specific alteration of cellular phenotype, including proto-oncogene activation [ 9], induction of apoptosis (ref. 28 in [ 4]; [ 13]) and – probably most important – impairment of several of the inotropic signal transduction pathways [ Müller-Werdan U, Reithmann C, Werdan K. ]. Not only is the β-adrenoceptor/G proteins/adenylyl cyclase pathway – on which cardiologists focus most attention – impaired, but also other inotropic pathways of the cardiomyocyte such as the nitric oxide/cGMP system, the α-adrenoceptor/phosphoinositide axis and the Ca2+ -transient [ Müller-Werdan U, Reithmann C, Werdan K. ]. The consequence of the latter is a well documented cardiodepression and an attenuation of the effects of positive inotropic agents [ Müller-Werdan U, Reithmann C, Werdan K. ]. What triggers immune activation in heart failure? The players most intensively discussed are the neuroendocrine adaptation and maladaptation processes, especially the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS); however, the failing heart itself as well as bacterial translocation also are attractive candidates. Conflicting data have been reported with respect to the role of RAAS in this process: the results of three clinical trials yielding positive correlations (including the one of Samsonov et al. in this volume; ref. 29 in [ 4]; [ 10]) are in contrast to the results of two trials with negative findings (refs. 35 & 39 in [ 4]). And all the positive correlations are rather modest: in the publication by Samsonov et al. in this volume, the correlations for neopterin with angiotensin-converting enzyme activity and aldosterone (rs= 0.35 and rs= 0.36) and for sTNF-RI with renin activity (rs= 0.38) in serum/plasma are all significant, but only weak. In the study by Ferrari et al. [ 10] a positive correlation was found for renin activity with TNF-α (P < 0.01 and sTNF-RII (P < 0.05), but not with sTNF-RI; and neither TNF-α, sTNF-RI nor sTNF-RII correlated with plasma aldosterone. Concerning the role of the SNS, the findings are a bit more promising: again, in three studies no correlation was found for plasma noradrenaline (NA) with TNF-α and IL-6 (refs. 30,35 & 39 in [ 4]). No data are available from the publication by Samsonov et al. in this volume. However, three other trials gave encouraging results: Ferrari et al. [ 10] published a highly significant correlation between plasma NA and TNF-α (P < 0.05), sTNF-RI (P < 0.01) and sTNF-RII (P < 0.01). Similarly, highly significant correlations were reported by MacGowan et al. [ 7] for plasma NA with IL-6 (r= 0.73, P < 0.05) and TNF-α (r= 0.65, P < 0.05). A further argument in favour of some relationship between the activated SNS and the immune axis in heart failure is the finding that chronic SNS activation in patients with congestive heart disease desensitizes lymphocyte β2-adrenoceptors and thereby alters immune function [ 6]. Chronic treatment with β1-selective betablockers apparently prevents these changes [ 6]. What about immune activation by other components of the dysbalanced neurohumoral axis [ 2]? Weak correlations were reported for atrial natriuretic peptide (ANP) with TNF-α (r= 0.35, P= 0.005; ref. 39 in [ 4]) and sTNF-RII (P < 0.05; [ 10]), but not for arginine vasopressin (AVP; ref. 39 in [ 4]). No data are yet available for adrenomedullin and endothelin, the latter being a potent stimulus for monocyte activation in vitro, in some way as effective as endotoxin. One might also speculate that in the failing heart itself, induction of cytokine expression in resident leukocytes or in cardiocytes (ref. 26 in [ 4]) could contribute to the inflammatory response, as was recently shown to occur in the ischaemic and reperfused heart. However, the presently available data comparing cytokine levels in arterial and coronary sinus blood is not in line with this notion (ref. 30 in [ 4]). Another interesting hypothesis of the cause of immune activation in congestive heart failure might be gut mesenteric venous congestion with subsequent translocation of bacteria and endotoxin release. Increased plasma levels of the soluble endotoxin receptor sCD14 in heart failure patients are in favour of this hypothesis [ 15]. The markedly increased levels of TNF-α, sTNF-RI, sTNF-RII, and intercellular adhesion molecule-1 in those patients with high sCD14 levels support the concept of a chronic endotoxin challenge as a trigger of immune activation in congestive heart failure [ 14]. The endotoxin challenge hypothesis seems especially attractive, as endotoxin mimics a sepsis-like myocardial depression when given to healthy subjects (ref. 40 in [ 4]) and induces the expression of TNF-α mRNA and TNF protein in the heart (ref. 24 in [ 4]; [ Müller-Werdan U, Reithmann C, Werdan K. 13]); furthermore, in haemorrhagic shock in rats, an anti-endotoxin antibody dramatically reduces mortality. Immune activation in heart failure: a prognostic marker? What help does the clinician seek from a prognostic marker? First, he wants to describe the severity of heart disease and its progression; secondly, he looks for information about the probability of survival of his patient over a certain time; and thirdly, he is interested in assessing the effectiveness of his treatment. A prognostic laboratory marker is only helpful if it is measurable with high accuracy, specificity and sensitivity. When evaluating cytokine data from the literature, be sure that the assays applied are sensitive enough to give precise values of the cytokine plasma levels of healthy persons, which–for TNF-α and IL-6–are in the range of 1 pg mL−1. Only some years ago, assays with detection limits for TNF-α and IL-6 of >20 and >32 pg mL−1, respectively, were in use, severalfold above the increased levels now regularly measured in most patients with severe heart failure (ref. 39 in [ 4]; [ 8]). Cytokine measurements are already in the clinical arena of intensive care and cardiovascular medicine: a rapid strip-test identifies sepsis patients with plasma IL-6 levels >1000 pg mL−1 for enrolment in an ongoing sepsis trial. In postcardiac surgery patients plasma levels of TNF-α, sTNF-RI and sTNF-RII higher than 31 pg mL−1, 11 and 10 ng mL−1, respectively, on the first postoperative day identify the patient with an escalating systemic inflammatory response with very unfavourable prognosis [ 12]. In heart failure patients, precisely measured cytokine (TNF-α, IL-6) and soluble cytokine receptor (sTNF-RI, sTNF-RII) plasma levels promise to be at least as good prognostic markers as the compounds of neurohumoral dysfunction (RAAS, NA, ANP): serum/plasma levels of both systems increase with the functional class (refs. 31 and 39 in [ 4]; [ 10]), as was also nicely shown by Samsonov et al. in this volume. High TNF-α levels may indicate cardiac cachexia (ref. 29 and 33 in [ 4]; see also Samsonov et al. in this volume), though this has been questioned (ref. 35 in [ 4]; [ 710]). Cytokines may be of some prognostic value as markers of chronic disease progression (ref. 39 in [ 4]; [ 7, 8, 10,]), while acute recompensation is not accompanied by a fall in plasma TNF-α (ref. 32 in [ 4]). In particular, sTNF-RII was proposed as a more powerful independent indicator of mortality in heart failure patients than TNF-α, sTNF-RI, NYHA class, NA, and ANP [ 10]. Cytokine and soluble receptor markers will be helpful in heart failure trials to identify certain risk groups or document response to therapy, as shown recently in the amlodipine trial [ 8]; for the practising physician, however, both cytokine and neurohumoral markers will at present be of little help when he wants to determine prognosis precisely, to choose a specific treatment regimen or to follow the response to therapy in his individual patient. Modulating the immune system in heart failure: an approach to therapy? Suppressing inflammation might start as a prophylactic measure: apparently healthy men in the quartile with the highest plasma C-reactive protein have a threefold risk of developing myocardial infarction. During a follow-up period exceeding eight years, the use of aspirin reduced the risk of myocardial infarction best – namely by 55.7% (P= 0.02) – in those men with the highest quartile of plasma C-reactive protein. Consequently, antiinflammatory agents may have clinical benefits in preventing cardiovascular disease [ 15]. If one assumes that proinflammatory cytokines in heart failure are detrimental, then their neutralization by antibodies, soluble receptors or receptor antagonists should be beneficial. This concept was supported by studies showing that TNF-α induced contractile dysfunction can be antagonized by soluble TNF-α receptors and anti-TNF-α antibodies, both in cardiomyocytes (ref. 49 in [ 4]; [ Müller-Werdan U, Reithmann C, Werdan K. ]), and in patients with septic cardiomyopathy [ Müller-Werdan U, Reithmann C, Werdan K. ]. In congestive heart failure, to the best of my knowledge, no trials have been published yet with this kind of therapeutic approach [ 19]. Drugs which interfere with signal transduction, production and cellular release of cytokines may act in an anti-inflammatory fashion, as was shown for phosphodiesterase inhibitors [ 16] and also for immunoglobulins. The latter may be effective not only in the treatment of coronary involvement in Kawasaki disease, but also – as documented recently in a series of ten patients – in adults with idiopathic dilated cardiomyopathy of <6 months' duration; within 12 months, the functional class of these patients improved as well as left ventricular ejection fraction, from 0.24 ± 0.02 to 0.41 ± 0.04% (P= 0.003; [ 17]). The well known inhibition of cytokine release from monocytes and lymphocytes by immunoglobulins [ 18] forms an attractive hypothesis to explain this astonishing therapeutic effect. Our group is at present putting this therapeutic strategy to test in the placebo-controlled ESSICS study in postcardiac surgery high risk patients with escalating inflammatory response. Activated immune system in heart failure: epiphenomenon, prognostic marker or therapeutic target? Looking into the inconsistent cytokine findings in heart failure research several years ago, one was tempted to classify immune activation and especially proinflammatory cytokine production in heart failure as epiphenomena: only a small fraction of the patients with heart failure had elevated cytokine plasma levels, with large variations and a lack of clear-cut correlations with clinical and laboratory data of the patients. With the optimized analytical tests available nowadays, however, we can be relatively sure that immune activation and inflammation occur in a relatively large proportion of patients with symptomatic heart failure, and that at least some parameters correlate with the severity of the disease, with disease progression, with prognosis and–as first findings show – even with the response to therapy [ 8]. Does the cytokine network contribute to the progression of heart failure? It might! Once activated by still unknown trigger mechanisms – with the sympathetic nervous system being my favourite! – proinflammatory cytokines could initiate structural derangements in the heart by proto-oncogene activation and apoptosis, and cardiodepression by impairment of inotropic cascades. However, whether these experimentally proven cytokine effects are clinically relevant in heart failure remains to be proven. Will counteracting immune activation become a target for heart failure treatment? Not at the present, but possibly in the future! There is no doubt: we really do have effective anti-inflammatory agents, not only aspirin and immunoglobulins, but also antibodies, soluble receptors, binding proteins and receptor antagonists for neutralizing all proinflammatory cytokines which are likely candidates for treatment. The crucial question, however, is: how relevant is this immune activation in heart failure? 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