Is adiponectin a bystander or a mediator in heart failure? The tangled thread of a good-natured adipokine in aging and cardiovascular disease.

Adiponectin is an adipose tissue-derived adipokine abundant in human plasma. Increasing evidence from experimental studies suggests that adiponectin plays a protective role in the cardiovascular system. However, epidemiological studies revealed that high levels of adiponectin were associated with increased mortality and severity of congestive heart failure. Furthermore, several prospective studies indicated that high levels of adiponectin were positively correlated with increased total and cardiovascular disease mortality in the elderly. These results are completely opposite to our expectation based on the beneficial effects of adiponectin. Clinical observations demonstrated that plasma adiponectin levels were positively associated with B-type natriuretic peptide levels. Clinical and experimental studies indicated that the administration of atrial natriuretic peptide enhanced adiponectin production. It is still controversial whether increased adiponectin production is a bystander or a key mediator in the development of heart failure. However, recent investigations strongly suggest that increased adiponectin production in patients with heart failure is a part of compensatory mechanisms against oxidative stress and inflammation. In addition, complicated "adiponectin resistance" will accelerate a counter-regulatory increase in adiponectin in patients with advanced heart failure, although direct evidence that patients with heart failure have "adiponectin resistance" is still lacking. Increased adiponectin production might contribute, at least in part, to the metabolic and structural remodeling of the failing heart via activation of AMP-activated protein kinase and induction of cyclooxygenase-2. Further investigation is needed to clarify the exact role of increased adiponectin production under pathophysiological conditions.