The effect of beta-adrenergic receptor downregulation on peak exercise response in patients with heart failure has not been directly investigated. Seventy-two patients with idiopathic dilated cardiomyopathy who had a mean ejection fraction of 23 +/- 1% (mean +/- SEM) and New York Heart Association class II or III symptoms were investigated. Subjects underwent maximal exercise testing on a bicycle or a treadmill, hemodynamic assessment by right heart catheterization, and measurement of total beta-adrenergic receptor density by 125I-iodocyanopindolol binding performed in the right ventricular endomyocardial biopsy tissue and in peripheral lymphocytes. Endomyocardial biopsy beta-adrenergic receptor density (Bmax) was markedly decreased (45 +/- 2 fmol/mg), and significantly lower than lymphocytes Bmax (107 +/- 14 fmol/mg; p < 0.05). By univariate analysis, all exercise variables correlated significantly with biopsy tissue Bmax but not with lymphocyte Bmax. Maximal exercise oxygen consumption (VO2max) yielded the highest correlation with Bmax (r2 = 0.61, p < 0.001). By stepwise regression analysis, VO2 max, delta heart rate x systolic blood pressure, and ejection fraction were all independently related to Bmax. Myocardial beta-adrenergic receptor downregulation is likely to be partially responsible for the reduced chronotropic and inotropic responses to peak exercise in patients with mild to moderate symptomatic heart failure due to idiopathic dilated cardiomyopathy.