European Heart Journal Advance Access originally published online on June 25, 2007
European Heart Journal 2007 28(14):1676-1677; doi:10.1093/eurheartj/ehm233
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Does adiponectin resistance exist in chronic heart failure?
Center for Cardiovascular Research (CCR), Institute of Pharmacology, Charité – Universitätsmedizin Berlin, Hessische Str. 3–4, 10115 Berlin, Germany
Corresponding author: Tel: +49 304 50525276; fax: +49 304 50525901. E-mail address: ulrich.kintscher{at}charite.de
This editorial refers to ‘Total and high molecular weight adiponectin, haemodynamics, and mortality in patients with chronic heart failure’ by T. Tsutamoto et al., on page 1723
Adiponectin is an adipocytokine, which is mainly expressed in adipose tissue and has been identified as a potent insulin-sensitzing hormone.1 Adiponectin administration lowers glucose levels and ameliorates insulin resistance in mice.1 In humans, plasma levels of adiponectin correlate inversely with visceral fat accumulation and insulin resistance.2 Prospective and longitudinal studies have demonstrated that lower adiponectin levels are closely associated with a higher incidence of type 2 diabetes mellitus.3 In addition, adiponectin exerts pronounced anti-atherogenic and anti-inflammatory actions; therefore, it is not surprising that hypoadiponectinemia has been shown to be an independent risk factor for myocardial infarction.4
Adiponectin exists in a wide range of multimer complexes in plasma and circulates as three major oligomeric forms: a low-molecular-weight trimer, a hexamer (trimer–dimer) of medium molecular weight, and a high-molecular-weight (HMW) 12–18-mer adiponectin.5 Recently, several studies reported that HMW adiponectin is the more active form of the protein and has a more important role in insulin sensitivity and the pathogenesis of type 2 diabetes mellitus. For example, after treatment with insulin-sensitizing thiazolidinediones, changes in HMW adiponectin, but not total adiponectin, were correlated with improvement in hepatic insulin sensitiviy.6 Furthermore, the ratio of HMW adiponectin to total plasma adiponectin was more significantly associated with glucose and insulin levels than did the total adiponectin level alone.7 Finally, HMW adiponectin and the HMW-to-total ratio are significantly lower in diabetic patients with coronary artery disease (CAD) than those without CAD.8 In summary, adiponectin, in particular HMW adiponectin, is inversely correlated with an increased cardiovascular risk, and hypoadiponectinemia has been established as an independent cardiovascular risk factor.
Whereas the relationship between low adiponectin levels and an increased risk of CAD or myocardial infarction seems to be robust, the role of plasma adiponectin in chronic heart failure (CHF) appears to be more complex. In the present issue, Tsutamoto et al.9 investigated the relevance of total- and HMW-adiponectin plasma levels as prognostic predictors in patients with CHF. Interestingly, they found that total adiponectin is better for mortality risk assessment in CHF patients than HMW adiponectin, implicating that under specific pathophysiological conditions HMW adiponectin loses its functional predominance and its predictive value. To understand this leakage of relevance, one has to contemplate the distinct interactions between adiponectin and mortality risk during CHF. Previous studies that investigated the relationship between total adiponectin level and mortality in CHF have demonstrated that the well-established inverse association between adiponectin levels and cardiovascular risk does not apply for mortality risk assessment in patients with CHF.10 Surprisingly, high adiponectin levels in CHF patients are associated with an increased mortality risk and not with lower risk.10 However, in a cohort of 946 men (Uppsala Longitudinal Study of Adult Men), who were free of CHF at baseline, neither low nor high circulating adiponectin levels could predict the development of CHF.11 These results illuminate important processes that become more and more relevant during the progression of cardiovascular disease related to insulin resistance and obesity. It appears that ‘classical’ risk predictors such as increased body weight, high serum cholesterol, and low adiponectin levels lose their predictive risk value during disease progression. A possible explanation for this ‘paradox’ may be provided by the causes–consequences relationship for adiponectin and cardiovascular disease. Adiponectin has been established as an important pathophysiological mediator of several conditions that promote the development of cardiovascular disease. By acting on two different receptors (AdipoR1 and R2), adiponectin exhibits insulin-sensitizing, antiproliferative, anti-hypertrophic, and anti-inflammatory properties.1 At the same time, plasma concentrations are strictly regulated by adipose tissue mass whereby increased body weight is associated with low circulating adiponectin levels.1 How are these processes regulated during CHF? The progression to end-stage CHF is closely associated with a reduction in total body weight as part of a wasting process and a chronic stress situation.12 More importantly, this decrease in body weight will result in an increase in adiponectin plasma concentrations; however, this adiponectin does no longer exert its cardiovascular protective actions. In other words, it appears that the relevance of increased adiponectin plasma levels in CHF as an indicator of disease severity is becoming more relevant than its function as a pathophysiological mediator. This would also provide an explanation for the reduced importance of HMW–adiponectin, which is known as the ‘functionally more active’ multimer. In situations where adiponectin function is reduced such as in CHF, the relevance of multimeric complexes with increased functional activity will also be diminished.
This line of arguments would imply the existence of a ‘functional adiponectin resistance’, which occurs in CHF. The hypothesis is supported by a recently published study showing a decrease mRNA and protein expression of the adiponectin receptor AdipoR1 in the left ventricle of infarcted mouse hearts compared with normal hearts.12 These results suggest an ‘adiponectin resistance’ at the receptor level induced by target end-organ damage. Future studies are required to confirm the importance of attenuated adiponectin responses at the receptor- and post-receptor level along the continuum of CHF progression, and whether their restoration will lead to functional improvements.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
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