Abstract Body: Autoantibodies (AAbs) that activate beta1-adrenoreceptor (β1AR) are linked to heart failure (HF) progression. Circulating β1AR-AAbs, especially those targeting the second extracellular loop (ECL2), are typically associated with poor outcomes. However, we recently observed that certain HF patients with reduced ejection fraction (HFrEF) possessing IgG3(+) β1AR-AAbs exhibit improved clinical outcomes. These patients showed enhanced cardiac function with medical therapy compared to those without IgG3(+) β1AR-AAbs or those lacking β1AR-AAbs. In vitro, IgG3(+) β1AR-AAbs targeting ECL2 boosted the therapeutic effects of metoprolol by increasing cAMP production and adenylyl cyclase activity, suggesting that specific AAbs may confer cardioprotective effects.
To explore the potential cardioprotective effect of β1AR-AAbs in HF, we conducted computational analyses, in vivo animal studies, and in vitro cell assays. We also performed phage display immunoprecipitation-sequencing (PhIP-Seq) on serum from HF patients, suspected autoimmune cardiomyopathy cases, and healthy controls. Computational analysis revealed that IgG3(+) β1AR-AAbs interact with other ECL domains beyond ECL2, which may serve as key epitopes mediating cardioprotective signaling. In vitro, HEK293 cells expressing human β1AR were treated with IgG3(+) β1AR-AAbs, followed by competitive binding assays with different ECL peptides and cAMP measurements after metoprolol treatment. One of the tested ECL segments was associated with increased cAMP generation, suggesting that targeting this specific region may have functional effects. In an isoproterenol-induced HF model, immunization with this particular ECL segment exhibited a trend toward reduced cardiac fibrosis, suggesting that AAbs against this region may play a beneficial role in modulating fibrosis in HF. Additionally, PhIP-Seq confirmed that AAbs targeting this β1AR ECL region are detectable in humans, with preserved LVEF individuals more likely to harbor them. These findings suggest that different β1AR epitopes influence signaling in distinct ways, potentially impacting HF outcomes.
Our findings highlight the complexity of β1AR AAbs interactions in HF, showing that AAbs can be either pathogenic or protective depending on the epitope targeted. IgG3(+) β1AR-AAbs engaging certain ECL regions may enhance cardiac function and improve beta-blocker response. Further research is needed to clarify the mechanisms underlying this cardioprotective effect.