Antibodies against the β1-adrenergic receptor induce progressive development of cardiomyopathy

Different immune disturbances have been found among patients with dilated cardiomyopathy (DCM), including antibodies directed against different cardiac antigens, such as the second extracellular loop of the β1-adrenergic receptor. The aim of our study was to investigate antibodies directed against the second extracellular loop of the β1-adrenergic receptor effect on cardiac functions at an early and late stage during DCM development. This was made in a mouse model, in which DCM was induced by immunization with the second extracellular loop of the β1-adrenergic receptor. Mice were immunized for 14 or 25 weeks respectively with the second extracellular loop of the β1-adrenergic receptor. At 14 weeks, there was no decreased heart function reviled by echocardiography at rest, but when dobutamine stress echocardiography was used, a lower cardiac reserve was shown in the mice with antibodies against the second extracellular loop of the β1-adrenergic receptor. By 25 weeks, decreased heart function, dilatation of the left ventricle and thinner left ventricular posterior wall were observed. Further biochemical analyses at 25 weeks showed increased mRNA expressions for β1-adrenergic receptor kinase, monocyte chemoattractant protein-1 and the brain natriuretic peptide as well as increased concentrations of complement factor 3 in sera in the immunized animals. Our data suggest a cardiotoxic effect of antibodies directed against the second extracellular loop of the β1-adrenergic receptor and a capacity to induce DCM with progressive remodeling, decreased cardiac function, altered β1AR signaling and upregulation of proinflammatory components.