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European Journal of Heart Failure 1999 1(2):127-131; doi:10.1016/S1388-9842(99)00006-9
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© 1999 European Society of Cardiology

Heart failure as a metabolic problem

Stefan D. Ankera,b,* and Mathias Rauchhausa,c

a Department of Cardiac Medicine National Heart and Lung Institute, Dovehouse Street, London SW3 6LY UK
b Franz-Volhard-Klinik at Max-Delbrück-Centrum, Charité Campus Berlin-Buch, Berlin, Germany
c Klinik Innere Medizin III/Kardiologie Martin-Luther-Universität Halle-Wittenberg, Halle, Germany

* Corresponding author. Tel.: +44 171 3518203; fax: +44 171 3518733, e-mail: s.anker{at}ic.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Metabolic abnormalities
 3. Conclusion
 References
 
Chronic heart failure (CHF) remains an important and increasing public health care problem. Not until recently it has been recognised that CHF is a chronic progressive disorder affecting different physiological and metabolic pathways. Nowadays CHF is reviewed as the consequence of an interplay of haemodynamic, neurohormonal, immunological, and endocrine mechanisms, initially thought to have beneficial adaptive effects for the organism to compensate the heart's inability to pump properly. However, these secondary changes eventually contribute to further deterioration of CHF. This review focuses on metabolic features observed in patients with CHF and discusses immunological and neuroendocrine aspects and their potential contribution to the pathogenesis of CHF. The overall evidence suggests that advanced CHF is a multifactorial metabolic syndrome that can lead to cardiac cachexia and then carries a very poor prognosis. Joint efforts of cardiologists, endocrinologists, and immunologists are required to develop therapeutic strategies able to improve the metabolic status of CHF patients.

Key Words: Chronic heart failure • Metabolism • Hormones • Neuroendocrine activation • Cytokines

Accepted December 18, 1998


   1. Introduction
Top
 Abstract
 1. Introduction
2. Metabolic abnormalities
 3. Conclusion
 References
 
Chronic heart failure (CHF) is a leading cause of morbidity and mortality worldwide with a poor prognosis, comparable to many highly malignant cancers [1]. During most of the past 50 years, physicians have seen CHF primarily as an oedematous disorder, in which fluid retention occurs because the heart can not pump adequate quantities of blood to the kidneys. Only recently has it been recognised that CHF is a chronic progressive disorder resulting from the interplay of haemodynamic [2], neurohormonal [3], immunological [4], and metabolic disturbances [5]. A variety of regulatory systems, reflecting hormonal and immunological metabolic abnormalities, have been described in patients with CHF.


   2. Metabolic abnormalities
Top
 Abstract
 1. Introduction
 2. Metabolic abnormalities
3. Conclusion
 References
 
2.1. Neurohormonal activation
Several neurohormonal alterations including raised catecholamine levels [6], over-activity of the renin-angiotensin-aldosterone system [7], and elevation of natriuretic peptides [8]occur as heart failure progresses. Initially, these systems are thought to be compensatory but eventually they contribute to increased vascular resistance and ventricular remodelling [6]. The neurohormonal hypotheses [3]postulates that heart failure progresses because the activated endogenous neurohormonal system exerts a deleterious effect on the heart and circulation. Several studies have found neurohormonal activation to be strongly related to mortality [8–10]. However, a drug's ability to reduce plasma catecholamine levels is not directly related to a mortality benefit of such a drug [11]. Both norepinephrine and epinephrine can cause an increased metabolic rate [12], and we found markedly increased norepinephrine and epinephrine levels only in CHF patients with cardiac cachexia (Fig. 1), whereas the vast majority of non-cachectic CHF patients had normal catecholamine levels [13]. Additionally, cortisol (Fig. 2) and aldosterone plasma levels as well as plasma renin activity were particularly increased in patients with cardiac cachexia [13], suggesting a specific association between the development of body wasting and the presence of neurohormonal activation in CHF. Furthermore, plasma levels of the anabolic steroid dehydroepiandrosterone (DHEA) were lowest in cachectic patients when compared to those of non-cachectic CHF patients and healthy control subjects (Fig. 2). This led to the introduction of the conceptial model of catabolic/anabolic imbalance as the potential cause of the metabolic dearrangements in advanced heart failure [13].


Figure 1
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  		Fig. 1 Plasma levels of norepinephrine and epinephrine in CHF patients (with and without cachexia) and healthy control subjects. (mean±SEM, data taken from Anker et al. [13]).

 


Figure 2
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  		Fig. 2 Plasma levels of dehydroepiandrosterone (DHEA) and cortisol in CHF patients (with and without cachexia) and healthy control subjects. (mean±SEM, data taken from Anker et al. [13]).

 
2.2. Catabolic/anabolic imbalance
Interestingly, the abnormalities in steroid metabolism in CHF patients are strongly and directly related to immune activation [14]. We have suggested the cortisol/DHEA ratio as an estimate of the catabolic/anabolic status in CHF patients. This ratio is highest in the subset of cachectic patients and correlates strongly with the degree of immune activation represented by circulating TNF-{alpha} and soluble TNF receptors 1 and 2 [14]. Steroid hormone alterations may potentially contribute to the regulation of immune activation by influencing the balance of Th1 and Th2 cells [15]. The mechanisms by which changes in cytokines and hormones might lead to loss of muscle bulk are unclear, but cytokine-induced programmed cell death (i.e. apoptosis) may be present in the skeletal musculature, particularly in cachectic patients.

Another important hormonal-metabolic pathway is the growth hormone (GH) insulin-like growth factor-I (IGF-I) axis that is dramatically abnormal in patients with untreated severe heart failure [16]. It is characteristic for cachectic CHF patients that GH is raised and that IGF-I is normal or low, which could be the biochemical equivalent of acquired GH resistance [13]. These abnormalities of the GH/IGF-I system are closely linked to the other abnormal hormone systems in CHF [17]. Recent randomised studies have not been successful in achieving therapeutic benefits by administration of GH in CHF patients [18, 19], suggesting that GH resistance might causally contribute to the treatment failure [20].

Insulin resistance is another frequently observed aspect of the metabolic abnormalities in severe heart failure, independent of aetiology [21]. Insulin is the strongest endogenous anabolic hormone and it contributes substantially to the regulation of the metabolic status of peripheral musculature. Insulin resistance is already present in non-cachectic CHF patients [21]. In cachectic CHF patients, however, detailed information is not yet available. Fasting insulin levels are only significantly increased in non-cachectic CHF patients [13]. This might be a compensatory metabolic mechanism to overcome the state of insulin resistance in these patients. The metabolic impact of conventional heart failure treatment on insulin sensitivity has not been studied previously. The use of insulin sensitisers in CHF patients could prove to have powerful metabolic effects and clinical benefits.

2.3. Immune activation
Over the last few years it has been recognised that immune activation is present in CHF [4, 22, 23]. THF-{alpha} could be causal for the metabolic disturbances seen in CHF patients, such as elevated basal metabolic rate [12], impaired peripheral (nutritive) blood flow [24], and altered protein and fat metabolism [25]. TNF-{alpha} is known to influence thermogenesis [26], and might contribute to elevated insulin levels [27]. In experimental animal models, either cachexia or anorexia occurs when TNF-producing tumour cells are implanted either into skeletal muscle or the brain [28]. TNF-{alpha} is mainly elevated in cachectic CHF patients [4, 13, 23]and has been shown to be the strongest predictor of the degree of weight loss [13]. The wasting process in heart failure is probably in the majority of cases not causally related to anorexia. Patients with anorexia usually show reduced albumin levels and impaired liver function, but it has been demonstrated that albumin and liver enzyme plasma levels are not decreased in cachectic CHF patients [13]. Whether basal energy expenditure and/or protein and fat turnover are significantly influenced by TNF-{alpha} in CHF has not yet been elucidated. Preliminary data indicate that cardiac cachexia is associated with altered fat and protein metabolism [29], but further studies are needed to investigate these metabolic pathways. Potentially, these studies could utilise novel anti-cytokine drugs that are now under research [30].


   3. Conclusion
Top
 Abstract
 1. Introduction
 2. Metabolic abnormalities
 3. Conclusion
References
 
CHF is associated with a variety of neuroendocrine and metabolic disorders. It is unlikely that a single biochemical abnormality or clinical marker causes the observed disturbances. The general pattern of neuroendocrine abnormalities in CHF is that of catabolic/anabolic imbalance. TNF-{alpha} needs to be considered as a potential key factor regulating energy metabolism, immune status, and neuroendocrine and hormonal function. Advances in the field of metabolic cardiology need the co-operation of cardiologists, endocrinologists, and immunologists, resulting in a better understanding of the complex pathways and having the potential to develop new treatment strategies for better patient care.


   References
Top
 Abstract
 1. Introduction
 2. Metabolic abnormalities
 3. Conclusion
 References
 

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