SUMMARYChronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. This study determined whether peak oxygen uptake (VO 2 ) can be predicted by the degree of neurohormonal and cytokine activations in CHF. Plasma norepinephrine, epinephrine, renin-angiotensin system activity, ANP, BNP, and serum interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α were measured in 84 CHF patients (age, 59 ± 1 years, LVEF, 36 ± 1%) and 34 controls. Maximal cardiopulmonary exercise testing was performed. Peak VO 2 (Controls vs CHF: 27.8 ± 1.3 vs 18.2 ± 0.5 mL/min/kg, P < 0.0001) was lower in CHF. Patients with CHF had increased plasma norepinephrine (211 ± 11 vs 315 ± 24 pg/mL), renin activity (1.2 ± 0.2 vs 6.2 ± 1.1 ng/mL/hr), ANP (22 ± 3 vs 72 ± 7 pg/mL), and BNP levels (18 ± 3 vs 200 ± 25 pg/mL) (all P < 0.01). Serum IL-6 (1.1 ± 0.1 vs 2.4 ± 0.3 pg/mL) and TNF-α (2.7 ± 0.2 vs 4.0 ± 0.3 pg/mL) levels were higher in CHF (both P < 0.001). Univariate analysis revealed that age (P < 0.001), cardiothoracic ratio (P < 0.001), norepinephrine (P < 0.0001), ANP (P < 0.001), BNP (P < 0.01), and log IL-6 (P < 0.05) were significantly related with peak VO 2 . Stepwise regression analysis indicated that plasma norepinephrine and ANP emerged as significant determinants of peak VO 2 , independent of patient age (overall R = 0.61, P < 0.0001). In summary, patients with CHF exhibited activation of neurohormones and proinflammatory cytokines. Among the elevated hormonal and cytokine markers, plasma norepinephrine and ANP levels were independent predictors of exercise capacity. (Jpn Heart J 2003; 44: 725-734) Key words: Heart failure, Peak oxygen uptake, Neurohormones, Cytokines, Cardiopulmonary exercise test CHRONIC heart failure (CHF) is characterized by the activation of neurohormones and cytokines.1,2) Among the activated neurohormonal systems, the sympathetic nervous and renin-angiotensin systems play a key role in the pathophysiology and progression of this syndrome.3) The natriuretic peptide system is also activated in CHF, and the degree of the activation has been related to