Direct evidence for a beta 1-adrenergic receptor-directed autoimmune
attack as a cause of idiopathic dilated cardiomyopathy
J Clin Invest, 113 (10):
1419-29 (May 2004)Jahns, Roland Boivin, Valerie Hein, Lutz Triebel, Sven Angermann,
Christiane E Ertl, Georg Lohse, Martin J Research Support, Non-U.S.
Gov't United States The Journal of clinical investigation J Clin
Invest. 2004 May;113(10):1419-29..Abstract
Today, dilated cardiomyopathy (DCM) represents the main cause of severe
heart failure and disability in younger adults and thus is a challenge
for public health. About 30% of DCM cases are genetic in origin;
however, the large majority of cases are sporadic, and a viral or
immune pathogenesis is suspected. Following the established postulates
for pathogenesis of autoimmune diseases, here we provide direct evidence
that an autoimmune attack directed against the cardiac beta(1)-adrenergic
receptor may play a causal role in DCM. First, we immunized inbred
rats against the second extracellular beta(1)-receptor loop (beta(1)-EC(II);
100% sequence identity between human and rat) every month. All these
rats developed first, receptor-stimulating anti-beta(1)-EC(II) Ab's
and then, after 9 months, progressive severe left ventricular dilatation
and dysfunction. Second, we transferred sera from anti-beta(1)-EC(II)-positive
and Ab-negative animals every month to healthy rats of the same strain.
Strikingly, all anti-beta(1)-EC(II)-transferred rats also developed
a similar cardiomyopathic phenotype within a similar time frame,
underlining the pathogenic potential of these receptor Ab's. As a
consequence, beta(1)-adrenergic receptor-targeted autoimmune DCM
should now be categorized with other known receptor Ab-mediated autoimmune
diseases, such as Graves disease or myasthenia gravis. Although carried
out in an experimental animal model, our findings should further
encourage the development of therapeutic strategies that combat harmful
anti-beta(1)-EC(II) in receptor Ab-positive DCM patients.