β1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis

Background - Antibodies to the beta(1)-adrenergic receptor (beta(1)AR) 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 beta(1)AR-specific autoantibodies mediate noninflammatory cardiomyocyte cell death during murine DCM. Methods and Results - We used the beta(1)AR protein as an immunogen in SWXJ mice and generated a polyclonal battery of autoantibodies that showed selective binding to the beta(1)AR. After transfer into naive male hosts, beta(1)AR antibodies elicited fulminant DCM at high frequency. DCM was attenuated after immunoadsorption of beta(1)AR IgG before transfer and by selective pharmacological antagonism of host beta(1)AR but not beta(2)AR. We found that beta(1)AR autoantibodies shifted the beta(1)AR 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 beta(1)AR 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 beta(1)AR-specific autoantibodies elicit DCM by agonistically inducing cardiomyocyte apoptosis.