Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy

Abstract

Anti-beta-1-adrenergic receptor antibodies (anti-β1AR Abs) have long been implicated in the pathogenesis of dilated cardiomyopathy (DCM). It is believed that these autoantibodies bind to and constitutively stimulate the β1AR to promote pathological cardiac remodelling and β1AR desensitization and downregulation. The prevalence of anti-β1AR Abs in patients with DCM ranges from 26% to 60%, and the presence of these autoantibodies correlates with a poor prognosis. Several small studies have shown improvements in functional status, haemodynamics, and biomarkers of heart failure upon removal or neutralization of these antibodies from the sera of affected patients. Traditionally, removal of anti-β1AR Abs required immunoadsorption therapy with apheresis columns directed against human immunoglobulins (Igs) and subsequent i.v. Ig infusion, thereby essentially performing a plasma exchange transfusion. However, recent advances have allowed the development of small peptides and nucleotide sequences that specifically target and neutralize anti-β1AR Abs, providing a hopeful avenue for future drug development to treat DCM. Herein, we briefly review the clinical literature of therapy directed against anti-β1AR Abs and highlight the opportunity for further research and development in this area.

Keywords: Antibodies; Beta-1-adrenergic receptors; Cardiomyopathy; Immunoadsorption; Immunoglobulins.

Figure 1

Prevalence of anti-beta-1-adrenergic receptor antibodies (anti-β₁AR Abs). Patients with dilated cardiomyopathies have a higher burden of anti-β₁AR Abs than those with ischaemic cardiomyopathy or normal subjects, though observed rates vary widely and are based on observations from very small studies.^,– The epidemiology of anti-β₁AR Abs in other cardiac disease states has not been studied. VAD, ventricular assist device.

Figure 2

Mechanism of toxicity of anti-beta-1-adrenergic receptor antibodies (anti-β₁AR Abs). Anti-β₁AR Abs have been shown to bind the first and, more commonly, the second extracellular loop of the β₁AR to promote persistent downstream signalling that leads to apoptosis, pathological remodelling, and β₁AR desensitization and downregulation.^,, Inhibitors of the β₁AR, protein kinase A (PKA), L-type calcium channels, caspases, and inert cAMP analogues mitigate the detrimental effects of anti-β₁AR Abs, suggesting that traditional G-alpha protein subunit (Gs)-mediated signalling pathways are responsible for the deleterious effects of anti-β₁AR Abs.