Autoantibodies Specifically Against β1 Adrenergic Receptors and Adverse Clinical Outcome in Patients With Chronic Systolic Heart Failure in the β-Blocker Era: The Importance of Immunoglobulin G3 Subclass

Objective: To elucidate the prevalence and role of beta(1) adrenergic receptor autoantibodies (beta(1)AR-AAb) belonging to the immunoglobulin (Ig)G3 subclass in patients with heart failure (HF) treated with beta-adrenergic blockers. Background: Several cardiac AAbs have been reported to be present in sera from patients with dilated cardiomyopathy and other etiologies. Among AAbs, those recognizing beta(1)AR-AAbs show agonist-like effects, have detrimental effects on cardiomyocytes, and may induce persistent myocardial damage. Methods: We quantify total IgG and IgG3 subclass beta(1)AR-AAb in subjects with chronic stable HF with long-term follow-up. Results: In our study cohort of 121 subjects, non-IgG3-beta(1)AR-AAb and IgG3-beta(1)AR-AAb were found to be positive in 20 (17%) and 26 patients (21%), respectively. The positive rate of IgG3-beta(1)AR-AAb was significantly higher for those with nonischemic compared with ischemic HF etiology (27% vs 8%, P = .01), but the positive rate for non-IgG3-beta(1)AR-AAb was similar between the 2 groups (18% vs 16%, respectively, P = NS). There were no significant differences in clinical and echocardiographic measures among total beta(1)AR-AAb negative, non-IgG3-beta(1)AR-AAb positive, and IgG3-beta(1)AR-AAb positive groups at baseline. During 2.2 +/- 1.2 years of follow-up, we observed similar rates of the composite endpoint of all-cause mortality, cardiac transplantation, or hospitalization resulting from HF between total IgG-beta(1)AR-AAb negative and positive patients. However, the composite endpoint events were significantly more common in the patients without than in those with IgG3-beta(1)AR-AAb (P = .048, log-rank test). Conclusions: Presence of IgG3-beta(1)AR-AAb, not total IgG, was associated with paradoxically more favorable outcomes in our cohort of patients with chronic systolic HF largely treated by beta-blockers.