© 2007 European Society of Cardiology
Metabolic disturbances in chronic heart failure: A case for the "macho" approach with testosterone?!
Applied Cachexia Research Unit, Department of Cardiology, Campus Virchow Clinic, Charité-Universitätsmedizin Berlin, Germany General Hospital Murska Sobota, Department of Internal Medicine Murska Sobota, Slovenia
Applied Cachexia Research Unit, Department of Cardiology, Campus Virchow Clinic, Charité-Universitätsmedizin Berlin, Germany
Applied Cachexia Research Unit, Department of Cardiology, Campus Virchow Clinic, Charité-Universitätsmedizin Berlin, Germany Department of Cardiac Medicine, National Heart and Lung Institute London, UK
* Corresponding author. Applied Cachexia Research Unit, Department of Cardiology, Campus Virchow Clinic, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany E-mail address: s.anker{at}cachexia.de
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Chronic heart failure (CHF) primarily affects the cardiovascular system. In addition, there is strong evidence that CHF is a complex metabolic disorder. Metabolic abnormalities include insulin resistance and lack of anabolic hormone activity. To date there have been few interventional trials targeting insulin sensitivity. A recent study suggests a link between testosterone therapy and improvements in insulin sensitivity, measured using the homeostatic model assessment (HOMA-IR). We discuss this study in detail. Further studies are needed to substantiate this link and to generally explore the value of testosterone therapy in CHF patients.
Key Words: Cachexia • Testosterone • Insulin resistance
Received May 25, 2006;
Chronic heart failure (CHF) is a syndrome, primarily affecting the heart and circulation. However; over time, several other organ systems become increasingly involved in the deterioration process of CHF. This results in significant co-morbidity, predominantly of the lungs, kidney, endocrine glands, blood, and central nervous system. Whilst anaemia, renal impairment, and recently also pulmonary disease have been widely investigated, endocrine dysfunction has not been investigated in detail. Endocrine impairments are mostly subtle and are often difficult to diagnose in everyday clinical practice, but they may contribute significantly to clinical symptomatic status as well as to disease progression and mortality. The EuroHeart Failure survey showed that diabetes mellitus occurred as a co-morbidity in 27% of hospitalised CHF patients (range in participating countries 12% to 46%) [1]. Given that insulin resistance precedes diabetes mellitus by years if not decades, the true prevalence of impaired glucose metabolism may have been substantially underestimated in this study.
The heart has been at the centre of CHF investigation for many years, but there is now a very strong evidence that CHF is a complex metabolic disorder. The ultimate clinical consequence is anabolic/catabolic imbalance and cardiac cachexia [2]. However, the hormonal and metabolic changes can be observed long before they become clinically apparent and chronic exposure may eventually lead to irreversible effects. Evidence of disturbances in growth hormone, sex hormones, and insulin metabolic pathways has been reported [3]. Despite the many metabolic changes that are present in CHF, the applicability of the updated definition of "metabolic syndrome" for patients with CHF can be argued [4]. All patients should comply with the hypertension criteria, some might have falsely enlarged waist circumference, but there is no conclusive data on HDL and LDL cholesterol.
Whilst the definition of metabolic syndrome may need to be adapted for patients with CHF, there is enough observational data to start interventional trials to counterbalance the known metabolic changes. In this issue of the European Journal of Heart Failure, Malkin et al [5] address the interesting topic of modifying insulin resistance with intramuscular depot injections of testosterone. In their randomised, single-blind, placebo controlled cross-over trial, they report data for 13 male patients with mild to severe CHF (mean age 74 years, mean LVEF 30%). Treatment with testosterone over a period of four weeks was found to significantly increase insulin sensitivity as assessed by HOMA-IR (mean effect of testosterone v placebo –1.9, 95% CI –0.16 to –3.6, p=0.03). Additionally, the authors report a concomitant increase in total body mass (+1.5 kg, 95% CI+0.4 kg to+2.5 kg, p=0.008) and decrease in %body fat (–0.8%, 95% CI –0.3% to –0.9%, p=0.02).
The reported results are intriguing and set the stage for future testosterone research on modifying insulin resistance, body composition, metabolic disease, and probably also prognosis in non-cachectic and cachectic patients with CHF. Insulin resistance has been shown to occur in CHF independently of ischaemic aetiology and relates not only to clinical severity of CHF but also to impaired prognosis [6]. This suggests that insulin resistance might be important in CHF pathophysiology.
Malkin et al [5] present pilot data that need confirmation in further studies. Notably, insulin sensitivity was assessed by HOMA-IR which might only provide limited information. HOMA-IR gives a single time point-estimate in fasting conditions only. Given the small sample size, assessment of the dynamic of insulin sensitivity over the physiologic range of glucose metabolism seems preferable. Besides clamp techniques, minimal modelling techniques have been optimized to suit assessment of insulin sensitivity specifically in the setting of CHF [7].
The authors [5] also suggest that the effects seen with testosterone are predominantly due to a decrease in body fat and, though not measured, are suggestive of an increase in lean body mass. They did not however, exclude the potential confounding effect of increased water retention due to testosterone therapy. Detailed body composition analyses by Dual Energy X-ray Absorptiometry may help to identify changes in body compartments. It is well known that body wasting and cachexia are deleterious in CHF [2]. Furthermore, preliminary reports suggest that body fat mass is more closely related to survival in CHF than lean tissue mass, as also seen in chronic renal failure [8]. An increase in body fat has also been reported in patients treated with beta blockers [9]. Treatment with beta blockers does not necessarily alter insulin sensitivity in CHF [10]. Hence, the proposal by Malkin et al. that testosterone improves insulin sensitivity in CHF via its effects on fat tissue is open for debate. We think that a direct muscle-effect of testosterone seems more likely.
Investigators and patients also need to be aware of the potential side effects of testosterone treatment. In addition to skin reactions as reported in a previous study using dermal patches, more serious complications involving the prostate, kidney, liver, and the heart may also occur. Thus, an alternative approach using a specific androgen receptor agonist without mineralocorticoid effects has been suggested for cachectic patients [11].
Although the intramuscular route for drug administration seems attractive, as it eliminates non-compliance and has a long duration of action, dermal patches could be a useful alternative in some patients. A new threshold for diabetes screening has been accepted and should be adopted in future studies. It would also be interesting to see if there is a difference between cachectic and non-cachectic patients, and also between patients with a normal oral glucose tolerance test versus those with impaired glucose tolerance or impaired basal glycaemia. For future studies, it would also be important to include CHF patients with preserved systolic function. The pioneering work by Malkin et al [5] gives some indications. However, whether there is a future for this specific hormonal treatment in CHF remains to be established.
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