Myocardial Recovery in Patients With Systolic Heart Failure and Autoantibodies Against β1-Adrenergic Receptors

Abstract

Background: Among various cardiac autoantibodies (AAbs), those recognizing the β₁-adrenergic receptor (β₁AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption.

Objectives: The goal of this study was to investigate the role of β₁AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy.

Methods: Peripheral blood samples were drawn at enrollment in patients with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; <6 months). The presence of IgG and IgG3-β₁AR-AAb was determined, and echocardiograms were assessed, at baseline and 6 months. Patients were followed up for ≤48 months.

Results: Among the 353 patients who had blood samples adequate for the analysis, 62 (18%) were positive for IgG3-β₁AR-AAbs (IgG3 group), 58 (16%) were positive for IgG but not IgG3 (non-IgG3 group), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. Left ventricular end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other groups (left ventricular end-diastolic diameter, p < 0.01; left ventricular end-systolic diameter, p = 0.03). At 6 months, LVEF was significantly higher in the IgG3 group (p = 0.007). Multiple regression analysis showed that IgG3-β₁AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In patients with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had a lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint.

Conclusions: IgG3-β₁AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy.

Keywords: IgG3; autoantibody; recent-onset cardiomyopathy; β-blocker.

FIGURE 1. 6-month LVEF Correlated with Baseline IgG

At 6 months, there was no significant correlation between left ventricular ejection fraction (LVEF) and the baseline titer of immunoglobulin G3 β1 adrenergic receptor autoantibodies (IgG-β1AR-AAb) (A) but the correlation became significant in the presence of the immunoglobulin G3 subclass β₁AR-AAb (IgG3) (B).

FIGURE 2. Composite Endpoint: NYHA Class

When divided into populations based on baseline New York Heart Association (NYHA) functional class status (I–II vs. III–IV), there were no significant differences in the 3 groups of β₁AR-AAb negative, non-IgG3-β₁AR-AAb positive (non-IgG), and IgG3for the composite endpoint of all-cause death, cardiac transplantation, or hospitalization due to exacerbation of heart failure in subjects with low NYHA class (A), but significance was seen in sicker patients (B). *p = 0.02 vs. Negative group; †p = 0.02 vs. non-IgG3. Abbreviations as in Figure 1.

FIGURE 3. HF Hospitalization and β-blocker Use

In 322 subjects who used β-blockers at baseline and continued at 6 months or were using β-blockers at 6 months, there was no significant difference in overall survival from heart failure (HF) hospitalization in patients whether IgG3 was present (A) but the presence of non-IgG3 was associated with worse overall survival (B). No differences were observed in the negative group (C). Abbreviations as in Figures 1 and 2.

CENTRAL ILLUSTRATION. Autoantibodies Specifically against β1ARs in Cardiomyopathy

In investigating the role of β1 adrenergic receptor autoantibodies (β1AR-AAb) belonging to the immunoglobulin G3 (IgG3) subclass in patients with recent-onset cardiomyopathy, we found no significant difference in left ventricular ejection fraction (LVEF) at baseline and 6 months based on presence or absence of total IgG (A). However, when the population was divided based on IgG3 positivity, a significant difference in LVEF emerged at 6 months (B). When the population was further divided into patients who were β₁AR-AAb negative, non-IgG3-β₁AR-AAb positive and IgG3-β₁AR-AAb positive, the IgG3 groups demonstrated significantly higher LVEF compared to each of the other cohorts.