Autoantibodies activating human β1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure

Background-Autoantibodies against synthetic peptides of beta-adrenergic recehtors have been observed in human cardiomyopathy. However, it has never been shown that such antibodies really interact with native human beta-adrenergic receptors, nor has the clinical impact of such an interaction been investigated in larger groups of patients. Methods and Results-We screened 104 patients with dilated or ischemic cardiomyopathy (NYHA functional classes II to IV) and 108 healthy subjects for IgG antibodies reacting with beta-receptor peptides. Such IgGs were further analyzed for binding and functional interactions with native recombinant human beta-adrenergic receptors. Antibodies reacting with synthetic receptor peptides were present in 51% of the patients. However, only a subgroup directed against the second extracellular receptor domain also recognized native human beta-adrenergic receptors situated in a cell membrane. All antibodies of this subgroup impaired receptor ligand binding and enhanced receptor-mediated signaling, which could be blocked by 5 mu mol/L bisoprolol in vitro. Their prevalence was 1% in healthy subjects and 10% in ischemic cardiomyopathy, whereas it amounted to 26% in dilated cardiomyopathy and was associated with a significantly poorer left ventricular function. Conclusions-Our data show that activating autoantibodies against human beta-adrenergic receptors exist in approximate to 25% of patients with dilated cardiomyopathy. Counteraction of such autoantibodies might contribute to the beneficial effects of beta-adrenergic receptor blockade in chronic heart failure.