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(Circulation. 2007;116:399-410.)
© 2007 American Heart Association, Inc.

Heart Failure

ß₁-Adrenergic Receptor Autoantibodies Mediate Dilated Cardiomyopathy by Agonistically Inducing Cardiomyocyte Apoptosis

Daniel Jane-wit, MD, PhD; Cengiz Z. Altuntas, PhD; Justin M. Johnson, BS; Sandro Yong, PhD; Peter J. Wickley, BS; Pamela Clark, BS; Qing Wang, PhD; Zoran B. Popovi, MD, PhD; Marc S. Penn, MD, PhD; Derek S. Damron, PhD; Dianne M. Perez, PhD; Vincent K. Tuohy, PhD

From the Departments of Immunology (D.J.-w., C.Z.A., J.M.J., V.K.T.), Molecular Cardiology (S.Y., Q.W., D.M.P.), Anesthesiology Research (P.J.W., D.S.D.), Central Cell Services (P.C.), and Cardiovascular Medicine and Cell Biology (Z.B.P., M.S.P.), Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Correspondence to Vincent K. Tuohy, Department of Immunology, NB30, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail tuohyv{at}ccf.org

Received December 8, 2006; accepted May 11, 2007.

Background— Antibodies to the ß₁-adrenergic receptor (ß₁AR) are detected in a substantial number of patients with idiopathic dilated cardiomyopathy (DCM). The mechanism whereby these autoantibodies exert their pathogenic effect is unknown. Here, we define a causal mechanism whereby ß₁AR-specific autoantibodies mediate noninflammatory cardiomyocyte cell death during murine DCM.

Methods and Results— We used the ß₁AR protein as an immunogen in SWXJ mice and generated a polyclonal battery of autoantibodies that showed selective binding to the ß₁AR. After transfer into naive male hosts, ß₁AR antibodies elicited fulminant DCM at high frequency. DCM was attenuated after immunoadsorption of ß₁AR IgG before transfer and by selective pharmacological antagonism of host ß₁AR but not ß₂AR. We found that ß₁AR autoantibodies shifted the ß₁AR into the agonist-coupled high-affinity state and activated the canonical cAMP-dependent protein kinase A signaling pathway in cardiomyocytes. These events led to functional alterations in intracellular calcium handling and contractile function. Sustained agonism by ß₁AR autoantibodies elicited caspase-3 activation, cardiomyocyte apoptosis, and DCM in vivo, and these processes were prevented by in vivo treatment with the pan-caspase inhibitor Z-VAD-FMK.

Conclusions— Our data show how ß₁AR-specific autoantibodies elicit DCM by agonistically inducing cardiomyocyte apoptosis.

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