Pathophysiological importance of Beta1-Adrenergic receptor autoantibodies in the development of cardiomyopathy and heart failure. Clinically and experimentally

Abstract

Idiopathic Dilated Cardiomyopathy (DCM) is a heart muscle disease of unknown originthat is characterized by ventricular dilation and the impaired contraction of the left orboth ventricles, resulting in progressive heart failure and sudden cardiac death. Antibodiesagainst different cardiac proteins have been found in DCM; they include antibodiesagainst the â1-adrenergic receptor (â1AR). The second extracellular loop of the â1AR(â1AR ECII) has been shown to be the most immunogenic target of this receptor inDCM patients. Recently, new immunomodulatory treatments which improve heartfunction, such as intravenous immunoglobulin treatment (IVIG) and immunoadsorption(IA), have been tested in DCM patients.The aim of our study was to elucidate the underlying mechanism regarding: 1) therole of â1AR antibodies in the beneficial effect following IVIG or IA treatment and 2) theimportance of â1AR antibodies and their interplay with inflammation in the developmentof cardiomyopathy at both early and late stages of the disease.IVIG treatment was not shown to involve the neutralization of â1AR antibodies,since the â1AR ECII antibody titer was not lowered following IVIG treatment. On theother hand, the removal of antibodies in IA treatment plays an important role in cardiacimprovement among DCM patients by removing antibodies which have cardiotoxiceffects in terms of chronotropic action, complement-dependent cytotoxicity andapoptosis. Our in vivo models (rat and mouse), which were immunized with a peptidecorresponding to the â1AR ECII, showed signs of adverse cardiac remodeling and cardiacdysfunction. The transcription of G-coupled receptor kinase 2 (GRK2) was upregulatedin both animal models. The mice displayed a reduction in cardiac reserve at an early stage,followed by more pronounced cardiomyopathic changes at a later stage, with increasedheart weight, left ventricular dilation and thinner left ventricular posterior walls. The laterstage in the mice was also correlated to an increase in inflammatory molecules, such ascomplement component 3 in plasma, and increased transcription of monocytechemotactant protein 1 in the heart.These results reinforce the pathological importance of â1AR ECII antibodies in thedevelopment of cardiomyopathy and heart failure and promote specific immunologicaltreatment in the management of DCM.