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European Journal of Heart Failure 2002 4(6):673-680; doi:10.1016/S1388-9842(02)00162-9
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© 2002 European Society of Cardiology

Heart failure as an inflammatory condition: potential role for androgens as immune modulators

Peter J. Pugha,b, Richard D. Jonesb, T.Hugh Jonesb and Kevin S. Channera,*

a Department of Cardiology, Royal Hallamshire Hospital Glossop Road, Sheffield S10 2JF, UK
b Academic Unit of Endocrinology, Division of Genomic Medicine, University of Sheffield Medical School Sheffield, UK

* Corresponding author. Tel.: +44-114-271-3473; fax: +44-114-271-2042. E-mail address: kevin.channer{at}sth.nhs.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Current understanding and...
 3. Immune function in...
 4. Influence of androgens...
 5. Clinical implications of...
 6. Conclusion
 References
 
Heart failure has traditionally been considered a disease of the myocardium, with symptoms arising from altered haemodynamics. However, it is now recognised that, in addition to marked neuroendocrine disturbance, there is perturbation of cytokine expression in patients with heart failure, resulting in an inflammatory imbalance. This not only influences symptoms, but also plays a central role in the underlying pathophysiological processes of heart failure, leading to disease progression and poorer prognosis. Recognition of the influence of cytokines, in particular tumour necrosis factor, has opened a new avenue for potential therapies for heart failure. Current approaches involve immunomodulation, aimed at suppressing tumour necrosis factor. We suggest that androgens may potentially offer a superior therapeutic strategy by their well-recognised non-specific immunosuppressive and anti-inflammatory effects. Studies of cell lines, human mononuclear cells and animals in vivo have demonstrated the ‘anti-cytokine’ actions of androgens, and we have found a similar action in whole blood from patients with heart failure. These effects, along with the anabolic action of these agents, make androgens an attractive potential option for treatment of patients with heart failure.

Key Words: Androgens • Cytokines • Heart failure • Immunosuppression

Received December 17, 2001; Revised February 22, 2002; Accepted March 26, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Current understanding and...
 3. Immune function in...
 4. Influence of androgens...
 5. Clinical implications of...
 6. Conclusion
 References
 
Chronic heart failure is a major public health burden in the Western world and remains a therapeutic challenge for clinicians. Although recent advances in drug therapy have reduced morbidity and delayed mortality associated with this condition, the outlook remains bleak [1]. Cardiac transplantation, a scant resource, is the only option offering long-term survival. There is therefore a clear requirement for new strategies that may alter disease progression, relieve symptoms and prolong life. In this article, we discuss the pathophysiological processes involved in disease progression, focusing on alterations in immune function. We describe how future therapies may target some of these immune mechanisms and we present the novel hypothesis that modulation of immune function by androgens may influence disease progression, based on a review of the literature and experimental data from our laboratory.


   2. Current understanding and treatment of heart failure
Top
 Abstract
 1. Introduction
 2. Current understanding and...
3. Immune function in...
 4. Influence of androgens...
 5. Clinical implications of...
 6. Conclusion
 References
 
It would seem logical to target new treatment strategies at the underlying disease mechanisms, thereby to modify or block pathological processes. These processes have traditionally been explained by the cardiovascular model of heart failure, in which the clinical features of the disease result from alterations of cardiac function and of systemic and pulmonary haemodynamics. However, cardiovascular parameters such as left ventricular ejection fraction often do not correlate with clinical disease severity [2] and therapies directed at augmenting left ventricular function do not improve survival [3–6]. In addition, established heart failure is a multi-organ disease involving the musculo-skeletal, respiratory and endocrine systems. The classical cardiovascular model is therefore no longer sufficient to describe the underlying pathology and has been supplemented by other models.

The musculo-skeletal model describes how alterations of skeletal muscle mass, function and energy-handling contribute to the clinical features of fatigue and breathlessness [7]. Clinical trials of physical exercise and breathing therapies have been promising but small, and have not yet led to widespread changes in clinical practice [8].

The ‘neuro-hormonal’ hypothesis of heart failure describes how over-expression of catabolic and pressor hormones, such as catecholamines, angiotensin II and aldosterone, may contribute both to the clinical presentation and to disease progression [9]. Anabolic impairment—insulin- and growth hormone-resistance [10,11] and reduced androgen levels [12]—results in failure to compensate for these changes in endocrine function. Drug treatments aimed at modulating neuro-endocrine activation by inhibition of angiotensin-converting enzyme [13], β-blockade [14] and aldosterone-antagonism [15] have proved successful in reducing symptoms and mortality in heart failure. Anabolic treatment with growth hormone may also have the potential for providing clinical benefit in heart failure patients. In a small study, it has been shown to improve exercise duration in patients with heart failure secondary to coronary artery disease [16], although this finding was not confirmed in a larger, randomised, double-blind, placebo-controlled trial in patients with heart failure due to dilated cardiomyopathy [17]. The role of anabolic therapy for patients with heart failure remains unclear. However, an anabolic agent with additional properties, such as immune modulation, might in theory provide greater benefit for these patients.

The ‘cytokine hypothesis’ of heart failure is perhaps a natural progression of the neuro-hormonal model [18]. It holds that heart failure progresses because cytokine cascades that are activated following myocardial injury—in a fashion similar to neuro-hormonal activation—exert deleterious effects on the heart and circulation. Cytokines are protein molecules elaborated by many cell types in response to a variety of stimuli and are intimately involved in mediating immune function.


   3. Immune function in heart failure
Top
 Abstract
 1. Introduction
 2. Current understanding and...
 3. Immune function in...
4. Influence of androgens...
 5. Clinical implications of...
 6. Conclusion
 References
 
The role of immune mechanisms in heart failure has been the focus of a surge of interest in recent years. The influence of cytokines has received particular attention. Levine et al. in 1990 first described elevated circulating levels of tumour necrosis factor (TNF) in patients with severe heart failure, especially those with cachexia, drawing analogies with other chronic wasting conditions [19]. It was not initially clear whether the high TNF levels found represented cause or effect, or were simply an epiphenomenon. Subsequent research, however, has provided convincing evidence that TNF, along with other pro-inflammatory cytokines, is an important mediator of the pathological processes involved in disease progression and organ dysfunction, as well as of the clinical features of chronic heart failure.

3.1. Association of cytokines with heart failure
Circulating levels of TNF and interleukin-6 (Il-6) are elevated in proportion to clinical severity of heart failure, as measured by New York Heart Association class and the distance walked in the 6-min walk test [20–22]. Higher Il-6 levels have been associated with lower left-ventricular ejection fraction and with higher pulmonary-capillary wedge pressure [23]. Elevated levels of Il-1, Il-2, Il-8 and soluble cytokine receptors have also been found in association with heart failure [24–28]. Improvement of the clinical condition by treatment with angiotensin-converting enzyme inhibitors [29] and β-blockers [30] or by implantation of a left ventricular assist device [31] may lead to improvements in the abnormal immune responses.

Importantly, plasma levels of cytokines have prognostic significance. Il-6 level was found to be an independent predictor of mortality in 100 patients with severe congestive heart failure, ahead of established factors [32]. However, there may be wide variability in plasma levels of cytokines over time [33]. Soluble cytokine receptors, in particular soluble TNF receptors, exhibit greater stability than their cytokine counterparts, and may therefore be more representative of a patient's inflammatory activation. A recent study involving 152 patients with severe chronic heart failure evaluated the prognostic significance of plasma levels of TNF, its soluble receptors (sTNF-R1 and sTNF-R2) and Il-6 [34]. Interestingly, sTNF-R1 emerged as the strongest and most accurate prognosticator of all cytokine parameters measured, independently of traditional markers. Over 24 months of follow-up, subjects in the upper quartile of sTNF-R1 had a highly significant 12-fold greater risk of death than those in the lowest quartile. Soluble TNF receptors are the extracellular domain fragments of membrane TNF receptors, which are shed following interaction with TNF. In the short term, this may lead to down-regulation of membrane TNF receptor density and reduced sensitivity to TNF. However, it has been demonstrated that, at physiological levels, sTNFRs may stabilise the TNF molecule and prolong its half-life, thereby enhancing its biological activity [27]. At much higher levels, sTNFRs block the action of TNF, raising the possibility of therapeutic intervention.

3.2. Influence of cytokines on myocardial function
The association studies of cytokines with heart failure are supported by reports of the effects of pro-inflammatory cytokines on cardiomyocyte function in vitro and on myocardial function in vivo. Intracellular calcium flux is an important mechanism in cardiac myocyte contractility. It may be altered by TNF and Il-1β via down-regulation of mRNA translocation and protein expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA) and phospholamban [35,36]. At the cellular level, TNF induces expression of inducible nitric oxide synthase (iNOS) in cardiac myocytes. This in turn results in production of peroxynitrite, which leads to reduced mitochondrial energy production and to depression of contractility and cardiocyte death [37,38]. In isolated hamster papillary muscles, TNF was found to produce a concentration-dependent, reversible reduction of contractility, which appeared to be mediated by increased nitric oxide production [39]. However, up-regulation of iNOS expression may take several hours, whereas TNF may induce very rapid (<5 min) depression of myocardial contractility [39]. A more immediate mechanism of TNF-induced negative inotropism appears to involve up-regulation of intracellular sphingosine production [40], which inhibits calcium release by the sarcoplasmic reticular ryanodine receptor [41,42]. In vivo administration of TNF to rats [43], dogs [44] and humans [45,46] leads to reversible depression of myocardial function. Finally, transgenic mice, which exhibit amplification of myocardial TNF expression, develop fatal cardiomyopathy and heart failure [47]. Pro-inflammatory cytokines, therefore, reduce myocardial contractility at a cellular level via several mechanisms, resulting in biventricular impairment and remodelling. These findings contribute to the scientific plausibility of the theory that cytokines are active mediators of the features of heart failure.

3.3. Effect of anti-cytokine therapies in heart failure
As a result of the above findings, several small studies have been undertaken, evaluating the effect of reducing TNF bioactivity, either by inhibiting interaction of TNF with its membrane receptors or by down-regulating TNF production. Similar strategies have been utilised in other inflammatory conditions, notably rheumatoid arthritis and Crohn's disease, with encouraging results. It should be noted that most clinical trials in heart failure enrol patients at the younger end of the spectrum, whereas the elderly make up a large proportion of heart failure patients. It has been observed that inflammatory cytokine production is blunted in the elderly population compared with younger subjects [48]. Preliminary data from trials of a sTNFR-2 fusion protein given by intravenous infusion to patients with heart failure suggest that this may effectively reduce TNF bioactivity and improve cardiac function [49], although the effects of longer-term treatment have been less encouraging. Studies to evaluate this therapy further are currently ongoing. Similarly, a randomised, placebo-controlled clinical trial of pentoxifylline, which reduces TNF production, showed significant improvements in cardiac function and symptoms, associated with a reduction in circulating TNF, in 28 patients with heart failure [50].

While these studies lend support to the theory that anti-inflammatory therapies may be useful in heart failure, they have concentrated on TNF as the most-studied protagonist. It should, however, be remembered that many inflammatory factors are involved in the pathology of heart failure, and it has been suggested that less specific approaches should also be considered, which may produce a more global and safer immunomodulatory strategy [51]. Treatment of 40 heart failure patients with intravenous infusions of immunoglobulin over 6 months induced an anti-inflammatory cytokine balance and significantly improved cardiac function [52]. We propose that an alternative approach may involve the use of androgens.


   4. Influence of androgens on immune function
Top
 Abstract
 1. Introduction
 2. Current understanding and...
 3. Immune function in...
 4. Influence of androgens...
5. Clinical implications of...
 6. Conclusion
 References
 
The immune-modulating effects of androgens have long been recognised. The sex difference in the incidence of immune-mediated diseases has been attributed, in part, to the relative immunosuppressive influence of androgens compared with oestrogens [53]. Indeed, androgen therapy has been shown to produce clinical improvements in both men and women with rheumatoid arthritis, associated with a reduction in inflammatory markers [54,55]. There is accumulating evidence from laboratory and clinical research that the anti-inflammatory action of androgens is mediated, at least in part, by a suppressive effect on pro-inflammatory cytokine activation and corresponding up-regulation of anti-inflammatory cytokines.

In animal studies, pre-incubation with androgens leads to a reduced inflammatory response to stimulation of macrophages from mice and rats, with suppression of TNF, Il-1 and Il-6, and up-regulation of Il-10 [56–58]. A similar effect has been shown in mouse T-cells and astrocytes [59–61]. In vivo administration of the adrenal androgen dehydroepiandrosterone (DHEA) to mice leads to raised serum levels of Il-10 and a diminished rise in TNF in response to lipopolysaccharide (LPS) [62–64]. Similarly, treatment of obese rats with DHEA leads to reduced plasma TNF levels [65]. Mice with auto-immune encephalomyelitis have an elevated IFN-{gamma}/Il-10 ratio, which is reversed following treatment with dihydrotestosterone (DHT) [66]. Castrated mice exhibit heightened TNF responsiveness to injection of LPS, while testosterone replacement reduces this [67].

Research in humans has further demonstrated the anti-cytokine effects of androgens. Il-6 production by human gingival fibroblasts and osteoblasts in vitro is suppressed by pre-treatment with testosterone and dihydrotestosterone [68–70]. Testosterone has been shown to reduce Il-1β and Il-6 production in vitro by monocytes from healthy subjects, patients with systemic lupus erythematosus and patients with rheumatoid arthritis [71–73]. A similar effect has been demonstrated with captopril, a widely used angiotensin-converting enzyme inhibitor, which suppressed TNF production by monocytes from men with heart failure [74]. Danazol, a synthetic androgen, also suppresses Il-1β and TNF production by stimulated monocytes from healthy subjects [75]. In a study of 60 men and 60 women, serum levels of DHEA correlated inversely with plasma Il-6 levels, and incubation with DHEA in vitro reduced Il-6 production by isolated peripheral blood monocytes [76]. Interestingly, the same group found that testosterone enhanced LPS-induced production of TNF and Il-6 in whole blood from females with chronic inflammatory disease, suggesting a gender-specific action of testosterone [77]. Recently, Yesilova and co-workers demonstrated that hypogonadal men—26 with Klinefelter's syndrome and 29 with idiopathic hypogonadotropic hypogonadism—exhibited enhanced cellular and humoral immunity, which was reversed by androgenic therapy [78,79].

Clearly, modulation of cytokine production plays a major role in the immunosuppressive action of androgens, although androgens do not appear to influence directly the cytotoxic activity of cytokines [80]. We recently presented the results of a pilot study, in which we examined the influence of testosterone on in vitro on LPS-stimulated TNF production in whole blood from male patients with heart failure [81]. In this study, addition of testosterone to samples resulted in a concentration-dependent reduction in TNF production (Fig. 1), suggesting that circulating androgen levels may have an important influence on immune activation in patients with heart failure.


Figure 1
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  		Fig. 1 TNF levels in supernatant of LPS-stimulated whole blood from 12 men with heart failure. In each sample, 5 ml of blood was mixed with 5 ml of phosphate-buffered solution with 10 U/ml heparin. Samples were incubated at 37 °C for 3 h with 1 µg/ml LPS after 30 min pre-incubation with 10–8, 10–6 or 10–4 M testosterone or with vehicle control (ethanol). TNF level varied significantly between groups (P=0.03, ANOVA). Post hoc t-tests revealed no effect of vehicle, but significant effects of testosterone at 10–6 and 10–4 M. Data presented to the European Society of Cardiology, Stockholm 2001.

 
If androgens are important modulators of immune function in heart failure, why do men with the disease fare so much worse than women, in terms of disease progression and all-cause mortality [82]? According to our hypothesis, testosterone in men should be protective, while lack of it in women should lead to deterioration. Clearly, a multitude of factors influences disease progression, of which the plasma testosterone level is not the most important. Furthermore, the overall evidence suggests that, from a cardiovascular viewpoint, androgens appear to be good for men but not women, and oestrogens good for women but not men. Any protective effect of testosterone may therefore be gender-specific, and between-sex comparisons of the influence of testosterone levels may not be meaningful. Within male gender, however, it is interesting to note that there is an age-related decline in plasma testosterone levels, with androgen deficiency occurring in 7% of men between the ages of 40 and 60 years, increasing to 35% in men over 80 years [83]. Furthermore, many of the major risk factors for the development of heart failure (e.g. coronary artery disease, hypertension) are associated with reduced testosterone levels, and it may be that the relative androgen deficiency in these patients contributes to the progression of heart failure [84]. Certainly, men with established heart failure may have markedly reduced testosterone levels, which correlate positively with cardiac function [12].

4.1. Androgen interactions with inflammatory cell signalling
It is currently unclear how androgens exert their immune modulating effects, but there may be some similarities with the actions of glucocorticoids, which alter cytokine expression by a combination of mechanisms. The activated glucocorticoid–receptor complex binds to and inactivates transcription factors, such as nuclear factor kappa B (NF{kappa}B), up-regulates expression of factors, such as inhibitor of NF{kappa}B (I{kappa}B), and reduces half-life time and utility of cytokine mRNAs. Glucocorticoids, however, are unsuitable for clinical use in heart failure patients because of their effect on salt and water retention.

Takei et al. found that, in a human leukaemia cell line, DHT reduced baseline and phythaemagglutinin-stimulated levels of TNF mRNA by 50%, by destabilisation of the gene [85]. In this study, TNF{alpha} message half-life was 1 h in DHT-treated cells and 2.5 h in untreated cells. Androgens may therefore inhibit transcription of inflammatory proteins via nuclear effects. Keller et al. showed that DHT repressed activation of the Il-6 promoter via the nuclear androgen receptor, in part by inhibiting activity of NF{kappa}B, an important pathway in initiating transcription [86]. This effect appeared to be mediated by elevating levels of I{kappa}B. P38 MAP kinase appears to be a central enzyme in intracellular processes leading to TNF gene transcription [87,88], and has been considered as a target for anti-TNF therapy in heart failure [89]. In human aortic smooth-muscle cells, DHEA has been shown to inhibit MAP kinase activation by platelet-derived growth factor, again suggesting a pre-transcriptional site of action for disrupting TNF production [90].


   5. Clinical implications of androgen therapy in heart failure
Top
 Abstract
 1. Introduction
 2. Current understanding and...
 3. Immune function in...
 4. Influence of androgens...
 5. Clinical implications of...
6. Conclusion
 References
 
Before using androgens as a therapy in men with heart failure, the full range of their actions in addition to immune modulating and anabolic must be considered, in particular possible adverse effects.

Although the effects of testosterone treatment in heart failure have not been studied, anabolic androgenic steroid use by athletes has been associated with a variety of adverse cardiovascular effects, including left ventricular hypertrophy and dilatation, premature myocardial infarction, and stroke and sudden cardiac death [91]. However, the doses of steroid used by athletes far exceed (by up to 1000-fold) that which might be used in clinical practice [91]. Extrapolation of these adverse actions to the use of a more physiological dose of androgen therapy may not be appropriate. In the only published study of anabolic androgen therapy in men with heart failure, Tomoda found improvement in left ventricular function following treatment with a therapeutic dose of oxymethalone [92]. It should be noted, however, that this was a single-author study with no placebo control, and the results should be interpreted with some caution.

There are a number of extra-cardiac actions of androgens, which must also be considered. Currently, the only absolute contra-indication to androgen replacement therapy in hypogonadal men is cancer of prostate or breast. Clearly, the population of heart failure patients for whom androgen therapy might be proposed comprises older men, in whom the prevalence of overt or sub-clinical prostate cancer rises with increasing age. Administration of androgens to such patients could hasten the advance of the disease, with disastrous consequences. Stimulation of bone marrow by androgen administration may also lead to erythrocytosis. In patients with anaemia associated with advanced heart failure—especially those with renal impairment—this may be a beneficial effect. However, the development of polycythaemia could be detrimental. Androgens also possess weak mineralocorticoid properties, which could, in theory, promote fluid retention, clearly an unwanted side effect in heart failure patients. However, with physiological-dose androgen therapy, fluid retention is rarely observed. The potential for adverse effects of treatment means that regular follow-up of patients—including assessment of prostate-specific antigen, haematocrit and fluid balance—would be necessary. Currently, therefore, androgen therapy cannot be recommended for patients with heart failure, except in the context of a clinical trial assessing both efficacy and safety of treatment.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Current understanding and...
 3. Immune function in...
 4. Influence of androgens...
 5. Clinical implications of...
 6. Conclusion
References
 
Chronic heart failure is a common, debilitating condition, in which hormonal changes and inflammatory processes play a significant role. Modulation of the immune responses may lead to improvement in clinical and laboratory measures of disease severity. Agents that induce non-specific dampening of immune function, in particular suppression of cytokine activation, may offer the best strategy. Androgens may be an attractive option for use as immune modulators in patients with heart failure, who may also benefit from the anabolic actions of these agents. Further clinical and laboratory studies will be required to test this hypothesis and to determine the mechanism by which androgens influence the cytokine profile.

Note added in proofSince this article was accepted for publication several trials have reported disappointing results for antagonists of TNF. Coletta AP, Clark AL, Banarjee P, Cleland JGF. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and ATTACH. Eur J Heart Fail 2002;4:559–561.HHH


   References
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 Abstract
 1. Introduction
 2. Current understanding and...
 3. Immune function in...
 4. Influence of androgens...
 5. Clinical implications of...
 6. Conclusion
 References
 

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