Autoantibodies Activating Human β 1 -Adrenergic Receptors Are Associated With Reduced Cardiac Function in Chronic Heart Failure

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Abstract
Background—Autoantibodies against synthetic peptides of β-adrenergic receptors have been observed in human cardiomyopathy. However, it has never been shown that such antibodies really interact with native human β-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 β-receptor peptides. Such IgGs were further analyzed for binding and functional interactions with native recombinant human β-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 β-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 μmol/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 β-adrenergic receptors exist in ≈25% of patients with dilated cardiomyopathy. Counteraction of such autoantibodies might contribute to the beneficial effects of β-adrenergic receptor blockade in chronic heart failure.