The growth hormone/insulin‐like growth factor‐I system in chronic heart failure and its interaction with adiponectin

An area of research which has attracted attention during recent years and which has been subject to some controversy is the possible role of growth hormone (GH) and its mediator insulin-like growth factor I (IGF-I) in the development of cardiovascular disease (CVD) in general and in chronic heart failure (CHF) in particular. Possible pathophysiological mechanisms seem to involve direct CV actions of GH and IGF-I as well as indirect effects through changes in CV risk factors. Based on available evidence, the predominant hypothesis is that reduced IGF-I signalling might be harmful in patients with CHF. Importantly, in clinical studies investigating circulating levels of the different components of the GH/IGF-I system, it has not been possible to determine in a consistent way whether low IGF-I action is harmful in CHF. In the general population, low as well as high IGF-I levels have been identified as independent risk factors for the development of CHF. In cross-sectional studies of patients with prevalent CHF, low, unchanged, or high levels of IGF-I have been reported. Adding to the confusion, two prospective studies have reported that low levels of IGF-I were associated with increased mortality, a third study found an association between mortality and the IGF-I/GH ratio, and a fourth study found that IGF-I levels did not provide prognostic information about survival in CHF patients. The reason for these conflicting results is at present unclear. The complexity of the GH/IGF-I system, consisting of GH, IGF-I, different binding proteins, and regulatory hormones means that a large variety of different biochemical analyses can be used to estimate GH/IGF-I activity. It is unclear which measurements are superior for estimating the biological activity of GH/IGF-I in different tissues. Measurement of total levels of GH and IGF-I is still considered to be the principal biochemical marker. However, the clinical utility of a single measurement of GH is limited by its short half-life (about 18 min) and pulsatile secretion. In contrast, circulating IGF-I has a longer half-life (about 7–20 h) and exhibits only minor diurnal variations, implying that single measurements of IGF-I can be used for scientific purposes. Circulating IGF-I is primarily of hepatic origin, but importantly IGF-I is also produced locally in almost all other organs and tissues where IGF-I exerts autocrine/paracrine effects via the IGF-I receptor. Another issue that should be considered is the fact that less than 1% of IGF-I molecules circulate in a free non-protein bound form, the remaining molecules form complexes with a family of six different IGF-I binding proteins (IGFBP1–6) and acid labile subunit. To obtain an estimate of the biologically active fraction of total IGF-I, different assays for the measurement of free IGF-I have been developed, but their importance is not yet well established. Another analytical approach is to use the molar ratio between IGF-I /IGFBP3 as a rough estimate of the free biological active fraction of total IGF-I. In the current issue of the European Journal of Heart Failure, Watanabe et al. report new and interesting data on the prognostic information provided by the molar IGF-I/IGFBP3 ratio (the IGF-I axis) in a thoroughly examined cohort of Japanese patients with CHF. The authors observed higher total levels of IGF-I and IGFBP3 in patients compared with a matched control group. However, the increases were disproportionate in such a way that bioactive IGF-I as judged by the IGF-I/IGFBP3 ratio was actually reduced in the patients. Furthermore, the severity of CHF was inversely related to the IGF-I/ IGFBP3 ratio predicting mortality and hospitalizations. Thus, these data suggest, to some extent, that reduced IGF-I signalling might be a risk factor in patients with prevalent CHF. It is a new observation that increased protein binding of IGF-I is an important factor in this scenario. In contrast, another report has suggested that reduced IGFBP3 and IGFBP2 might represent independent risk factors in CHF. Thus, the importance of the different components of the IGF-I system in CHF remains unclear. There are several ways by which GH/IGF-I activity may be involved in the development of CVD. Importantly, the direct CV