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Elevated levels of tumour necrosis factor alpha (TNF-alpha) are associated with the development of heart failure. TNF-alpha antagonists, etanercept (ETA) and infliximab (INF) have been used for treating different clinical conditions. Anti-TNF-alpha therapy did not show favourable results in patients with chronic heart failure (CHF). This review analyses the reasons for anti-TNF-alpha therapy failure in CHF patients; potential approaches for improved clinical outcome are also addressed.
Design and methods
Data analysis from clinical trials of CHF patients treated with ETA and INF.
Results
In heart failure patients, ETA and INF therapy did not lead to improved clinical outcomes and high doses of INF were associated with worsening of cardiac events. This contrasts with the observation that these agents are associated with reduced cardiac events when used in patients with inflammatory diseases such as rheumatoid arthritis (RA).
Conclusions
Treatment of CHF patients with TNF-alpha antagonists did not show encouraging results. There is a need for the development of better treatment strategies for CHF. Perhaps, tailored anti-TNF-alpha therapy in relation to the TNF-alpha genotype of CHF patients and targeting of the cytokine gene expression via signalling pathway inhibitors may have useful clinical implications.
]. The cytokine levels are elevated in CHF and are related to cardiac complications. TNF-alpha expression increases in the blood mononuclear cells of patients with congestive heart failure [
]. The role of TNF-alpha in the pathogenesis of cardiovascular disease is widely accepted, and has been reviewed extensively. This article focuses on the use of TNF-alpha antagonists in the treatment of CHF.
Anti-TNF-alpha therapy is gaining importance in the treatment of inflammatory diseases in patients. The cytokine antagonists, etanercept (ETA) and infliximab (INF) are licensed for clinical use. With ETA, recombinant soluble TNF receptors bind to TNF-alpha and inactivate the cytokine, whereas INF monoclonal antibody binds to both soluble and transmembrane TNF-alpha. Both ETA and INF are effective in the treatment of RA and reduce clinical inflammation [
]. Heart failure is relatively common in RA especially in patients with pre-existing cardiac risk factors, though the incidence appears lower in anti-TNF-alpha treated patients [
]. These observations suggest that treatment with anti-TNF-alpha may directly influence the incidence of heart failure in RA patients.
Clinical implications of anti-TNF-alpha therapy in CHF patients
In a small preliminary clinical trial conducted in advanced heart failure patients, a single intravenous injection of ETA reduced biologically active levels of the cytokine leading to improvements in quality of life and left ventricular ejection fraction [
]. Small sample size of 18 patients and a short follow up duration of 14 days were limiting factors of the study. Another randomised, double-blind, placebo-controlled, multidose trial of ETA was conducted by Bozkurt and colleagues [
]. In this study 47 patients were treated with biweekly subcutaneous injections of 5 and 10 mg/m2 ETA with a follow up duration of three months. Treatment with ETA was safe and well tolerated and it led to a significant dose-dependent improvement in left ventricular function and remodelling. There was no worsening of clinical status at the end of three months’ therapy. The findings from this study were regarded as provisional because of relatively small number of patients and the short follow-up duration.
Two multicentre clinical trials called the RENAISSANCE (randomized Etanercept North American Strategy to study antagonism of cytokines) and RECOVER (research into Etanercept cytokine antagonism in vascular dysfunction) were conducted with ETA [
]. These trials had parallel study design, but differed in the dose regimen of ETA. In RENAISSANCE, 25 mg twice a week versus 25 mg thrice a week were used, whereas RECOVER used doses of 25 mg once versus twice a week. In these trials, a clinical composite score (CCS) classified patients as ‘improved, unchanged or worsened’ after clinical intervention. The CCS was similar for placebo group and ETA treated patients. The combined data from these two trials were analysed in RENEWAL (randomized Etanercept worldwide distribution) [
]. The primary end point of RENEWAL was all-cause mortality, which was similar in the placebo group and patients randomised to receive ETA.
The pilot trial ATTACH was a randomised, double blinded, placebo-controlled study that aimed to evaluate the effects of INF monoclonal antibody to TNF-alpha in 150 patients with moderate to severe heart failure [
Anti-TNF therapy against congestive heart failure investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial.
]. Of the 150 patients with similar baseline characteristics, 49 were randomised to placebo, 50 to 5 mg/kg INF, and 51 to 10 mg/kg INF. Patients treated with different dose regime did not show any improvement in clinical assessments. Instead, high dose of INF was associated with worse clinical status and a high frequency of worsening heart failure was reported as a critical adverse event. Kwon et al. described a case series of 47 patients (29 received ETA and 18 received INF) who developed heart failure after anti-TNF-alpha therapy [
]. After therapy, 38 patients developed new-onset heart failure and nine patients experienced heart failure exacerbation. Discontinuation of the TNF antagonists therapy, and administration of heart failure drugs to 10 patients (age < 50 years) resulted in complete resolution of heart failure in three, and improvement in six patients while one individual died. This report pointed towards a potential causal connection between TNF-alpha antagonist and new-onset heart failure or worsening of existing heart failure. In contrast, TNF-alpha antibody therapy was shown to improve and preserve cardiac function and limit cardiac dilatation in an animal model [
] demonstrating neutralising effect of TNF-alpha antibody on the cytokine bioactivity, the failure of response to TNF-alpha antibody treatment in CHF patients is surprising, and suggests the influence of TNF-alpha in CHF patients is much more complex than previously thought.
Effect of TNF-alpha antagonists on heart failure in RA patients
RA patients are at increased risk of heart failure. Listing et al. reported that RA patients on treatment for their inflammatory condition with ETA, INF and adalimumab showed anti-TNF-alpha therapy, although effective in reducing inflammatory activity of RA, is also likely to be beneficial rather than harmful for the risk of heart failure, especially if there is no concomitant therapy with glucocorticoids or cyclogenase-2-inhibitors [
]. These data were from a registry and therefore limited as patients were not randomised to active treatment. Nevertheless, this report concluded that anti-TNF-alpha therapy may have better outcome in RA patients with regards to heart failure. This concept is further strengthened by another report which suggests that the risk of developing coronary heart disease (CHD) is lower in the RA patients treated with TNF-alpha antagonists [
Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis.
]. The study demonstrated that in the anti-TNF-treated patients, the incident rate of first CHD event was 14.0/1000 persons-years compared with 35.4/1000 person-years in the untreated group. Evidence shows that long-term INF treatment in RA patients increased adiponectin levels which may improve cardiovascular and cerebrovascular symptoms in patients with RA [
Induction of hyperadiponectinemia following long-term treatment of patients with rheumatoid arthritis with infliximab (IFX), an anti-TNF-alpha antibody.
Despite encouraging results from initial studies of anti-TNF-alpha therapy in CHF patients, and reduced risk of disease events in RA patients treated with TNF antagonists, large-scale multicentre trials showed adverse effects of INF treatment in patients with moderate-to-severe heart failure in a dose-dependent manner [
Anti-TNF therapy against congestive heart failure investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial.
]. At this stage it is not clear as to why TNF-alpha antagonist adversely affected the clinical outcome in these heart failure patients. Infliximab can bind to both transmembrane TNF-alpha as well as soluble cytokine. Evidence shows that anti-TNF-alpha antibody after complexing with transmembrane TNF-alpha may activate immune effector functions which can cause cell lyses in the presence of complement [
]; such an effect in the cardiomyocytes of CHF patients may have led to the adverse clinical outcomes observed.
Differential response to anti-TNF-alpha treatment is a major concern in which the antagonists show better outcome in one disease and not in other clinical condition [
]. Recent reports suggest that genotype of individuals can also affect the outcome of anti-TNF-alpha therapy. The RA patients with the −308G/G TNF-alpha genotype showed better response to INF treatment compared to the A/A or A/G genotypes [
]. TNF-alpha also contributes to vasculitis, and coronary artery aneurysm (CA) in patients. A recent report shows that intravenous infusion of INF (5.0 mg/kg) to a child suffering from Kawasaki disease improved the CA symptoms without complications 20 months after the onset [
]. The polymorphic alleles produced high levels of TNF-alpha in these patients. Anti-TNF treatment may limit the inflammatory response. Furthermore, polymorphisms in TNF-alpha receptors may also determine the efficacy of anti-TNF therapy [
]. Thus, it appears that the genetic makeup of patients may be a useful tool for predicting response to the treatment. Whether anti-TNF therapy tailored to the cytokine genotype of heart failure patients will have useful clinical applications is not known.
Other potential targets for preventing TNF-alpha production
Multiple mechanisms lead to TNF-alpha production in vivo (Fig. 1). Intracellular pathways of signalling cascade contribute to the production of proinflammatory mediators. The p38 mitogen-activated protein kinase (p38 MAPK) is considered to be a pivotal MAPK in the signalling cascade involved in TNF-alpha gene induction [
]. The p38 MAPK inhibitors’ effect on TNF-alpha down-regulation has not been studied in CHF patients so far. TNF-alpha contributes to cardiac dysfunction and the cardiomyocytes’ death; interference with TNF-alpha transcription may be effective in inhibiting the cytokine production and therefore, p38 MAPK inhibitors could be potentially useful for the treatment of patients with CHF. A preliminary phase I study has been conducted in healthy human volunteers using RWJ-67657, a synthetic inhibitor of p38 MAPK, to monitor inflammatory response after endotoxin infusion [
Supression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers.
]. Data from this investigation suggested that the drug suppressed the clinical and cytokine response to endotoxin infusion in the study subjects. Miwatashi et al. have reported a novel series of 4-phenyl-5-pyridyl-1,3-thiazole analogues with in vitro inhibitory activity against p38 MAPK and the release of TNF-alpha from human monocytes [
Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent.
]. The thiazole analogues showed significant anti-TNF-alpha activity and good oral absorption in an animal model. The potent analogue inhibited p38 MAPK pathway and the drug administration in mice (10 mg/kg) resulted in a significant decline (67%) in the TNF-alpha production. Further investigations are warranted to study the effects of p38 MAPK inhibitors particularly in heart failure patients.
Fig. 1Targets for the inhibition of TNF-alpha synthesis. Mitogenic stimuli leads to rapid intracellular tyrosine phosphorylation of Ras by phosphotyrosine kinase (PTK); the protein kinase cascade leads to TNF-alpha production. Ras activates Raf-1/mitogen-activated protein kinase, which in turn activates members of the mitogen-activated protein kinase (MAPK) family of protein kinases, extracellular signal-related kinase (ERKs), stress-activated protein kinase (SAPK), and Jun nuclear kinase (JNK). The P38 MAPK appears to have an important role in the cascade in the MAPK leading to TNF-alpha gene expression. NFkB is activated by phosphorylation (which disassociates inhibitory kappa B; IkB) and translocates to the nucleus to activate TNF-alpha promoter sites. The pro-TNF-alpha is synthesised in the cytosol, myristoylation permits membrane insertion, where pro-TNF-alpha remains until it is cleaved to its mature form by TNF-alpha-converting enzyme (TACE). Mature TNF-alpha molecules are released into the extracellular environment. The cytokine signals activate the CD 14 receptor, whereas ischaemia, oxidant stress, and hydrogen peroxide may directly activate P38 MAPK and NFkB to induce TNF alpha production. The P38 MAPK may be a suitable target for the prevention of TNF-alpha production.
Current evidence suggests that high TNF-alpha concentration is associated with heart failure. However, multicentre placebo-controlled studies conducted in heart failure patients did not show better outcome with anti-TNF alpha therapy. The following may provide plausible reasons for the adverse effects of TNF-alpha antagonist in CHF patients: (1) intrinsic toxicity either due to ETA or INF, or due to interaction between the cytokine antagonists and other heart failure medications being used by the patients at the time of the treatment; (2) most of the clinical trials were conducted in the New York Heart Association (NYHA) class III and IV patients – it is probable that such subjects with relatively advanced stage disease may not be suitable candidates for ETA or INF treatment; (3) high doses of TNF-alpha antagonists were associated with adverse clinical outcome, and, therefore, the effect of lower doses of the drugs in CHF patients especially in patients at early stages of the disease should be investigated thoroughly; and (4) treatment with TNF-alpha antagonists was not tailored in relation to the TNF-alpha genotype of patients with CHF. This aspect may have important clinical implications as evidence shows that the TNF-alpha gene polymorphism affects the outcome of INF treatment in patients with rheumatoid arthritis [
CHF patients treated with ETA or INF have failed to show improvement in clinical outcome. Moreover, high dose INF was associated with worsening of heart failure symptoms. In contrast, observational studies in RA patients treated with TNF-alpha antagonists showed beneficial effects of the therapy with lower incidence of heart failure in this group of patients. The effects of ETA and INF treatment based on the TNF-alpha genotype of the heart failure subjects have yet to be studied. In addition, future studies may also evaluate the effects of TNF-alpha antagonists in heart failure patients at earlier stages of the disease (e.g. in NYHA class I or II), keeping in mind to monitor these patients closely for any adverse outcome. Furthermore, studies to investigate the effects of cell signalling inhibitors such as p38 MAPK in CHF patients should be considered.
References
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A polymorphism in the promoter of the tumor necrosis factor-alpha gene (−308) is associated with coronary heart disease in type 2 diabetic patients.
Anti-TNF therapy against congestive heart failure investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial.
Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis.
Induction of hyperadiponectinemia following long-term treatment of patients with rheumatoid arthritis with infliximab (IFX), an anti-TNF-alpha antibody.
Supression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers.
Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl] benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent.
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