Patients with chronic heart failure (CHF) have metabolic abnormalities, leading to a catabolic syndrome, with progressive loss of skeletal muscle in advanced stages of the disease. Leptin, the product of an obesity gene, has been associated with energy expenditure and weight regulation. The aim of this study was to assess serum levels of leptin and its soluble receptor in relation to exercise intolerance and neurohumoral activation in patients with CHF. We investigated 53 patients with CHF left ventricular ejection fraction (LVEF) 25+/-1%, age 56.6+/-1.3 years, Maximal oxygen uptake (VO(2) max) 16.3+/-0.6 ml/min.kg) sub-classified according to peak oxygen consumption of > or <or=14 ml/min.kg and 11 age-matched controls (LVEF 70+/-1, age 60.5+/-4.0 years, (VO(2)max) 26.9+/-1.6 ml/min.kg). Body mass index-adjusted serum levels of leptin and soluble leptin receptor were increased in patients with CHF compared to the controls (0.28+/-0.03 vs. 0.22+/-0.04 ng.m(2)/ml.kg and 32.6+/-1.9 ng/ml vs. 22.9+/-2.3, P<0.05). This increase was even more pronounced in patients with CHF and severe exercise intolerance (0.43+/-0.08 vs. 0.21+/-0.02 and 0.22+/-0.04 ng.m(2)/ml.kg; P<0.01 vs. VO(2)max>14 ml/min.kg and controls). Elevated levels of leptin correlated with an increased serum concentration of TNFalpha (r=0.749, P<0.01) in this subgroup of patients with CHF. We conclude that patients with advanced CHF show elevated serum levels of leptin and its soluble receptor. This finding indicates that leptin may participate in the catabolic state leading to the development of cardiac cachexia in the course of CHF.