Background--Antibodies to the ₁-adrenergic receptor (₁AR) 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 ₁AR-specific autoantibodies mediate noninflammatory cardiomyocyte cell death during murine DCM.

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