Circulation, Vol 89, 2760-2767, Copyright © 1994 by American Heart Association
Y Magnusson, G Wallukat, F Waagstein, A Hjalmarson and J Hoebeke
BACKGROUND: Autoantibodies against the beta 1-adrenoceptor have been
detected in the sera of patients with idiopathic dilated cardiomyopathy
(DCM). The mechanisms by which these autoantibodies can alter normal
receptor function are investigated, and the results are interpreted in the
light of the beneficial effects of beta 1-blockade in some of these
patients. METHODS AND RESULTS: Autoantibodies against the beta 1-
adrenoceptor, affinity purified from sera of patients with idiopathic DCM,
were analyzed in a functional test system of spontaneously beating neonatal
rat heart myocytes. Antibodies from rabbits immunized with peptides derived
from the amino acid sequence of this receptor were also analyzed.
Autoantibodies, against the second extracellular loop increased the beating
frequency of isolated myocytes in a concentration- dependent manner, to
approximately 80% of maximal isoproterenol stimulation. Rabbit anti-peptide
antibodies against the second extracellular loop increased the beating
frequency correspondingly. Autoantibodies and rabbit anti-peptide
antibodies against the second extracellular loop were able to
immunoprecipitate the unliganded receptor but not the antagonist-occupied
receptor. In contrast, rabbit antibodies against the extracellular
N-terminal sequence 34-57 of the beta 1-adrenoceptor were able to
immunoprecipitate both the unliganded and the antagonist-occupied receptor
although with no effect on the beating frequency of myocytes. The positive
chronotropic effect of the antibodies was completely neutralized both by
the addition of increasing concentrations of the beta 1-selective
antagonist bisoprolol and by preincubation with the peptide corresponding
to the second extracellular loop. The antibody-induced increase in beating
frequency remained unchanged for more than 6 hours. This should be compared
with the isoproterenol-stimulated beating frequency, which undergoes
desensitization within 60 minutes. Addition of isoproterenol to
autoantibody-stimulated myocytes resulted in only a small increase in
beating frequency and did not cause desensitization. Antibodies had only a
marginal effect on cyclic AMP production of stimulated cardiomyocytes
compared with the 10-fold increase obtained after stimulation with
isoproterenol. CONCLUSIONS: The second extracellular loop of the beta
1-adrenoceptor is a specific target for antibodies with stimulatory
activity detected in patients with idiopathic DCM. The antibodies have a
positive chronotropic effect on isolated rat heart myocytes. Autoantibody
stimulation does not cause the normal agonist- induced desensitization
phenomena of the effector system. These findings could contribute to our
understanding of the pathophysiological mechanisms of the autoantibodies
and of the beneficial effect of beta 1-blocking agents in the treatment of
patients with idiopathic DCM.
ARTICLES
Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effect
Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, Goteborg, Sweden.
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