Compensatory Upregulation of Anti-Beta-Adrenergic Receptor Antibody Levels Might Prevent Heart Failure Presentation in Pediatric Myocarditis

Franziska Seidel; Carmen Scheibenbogen; Harald Heidecke; Bernd Opgen-Rhein; Thomas Pickardt; Karin Klingel; Felix Berger; Daniel Messroghli; Stephan Schubert

doi:10.3389/fped.2022.881208

Compensatory Upregulation of Anti-Beta-Adrenergic Receptor Antibody Levels Might Prevent Heart Failure Presentation in Pediatric Myocarditis

Front Pediatr. 2022 Apr 28:10:881208. doi: 10.3389/fped.2022.881208. eCollection 2022.

Authors

Franziska Seidel^{1

2

3

4

5}, Carmen Scheibenbogen⁶, Harald Heidecke⁷, Bernd Opgen-Rhein², Thomas Pickardt⁸, Karin Klingel⁹, Felix Berger^{1

2

5}, Daniel Messroghli^{5

10

11}, Stephan Schubert^{1

5

12}

Affiliations

¹ German Heart Center Berlin, Department of Congenital Heart Disease and Pediatric Cardiology, Berlin, Germany.
² Charité - Universitätsmedizin Berlin, Department of Pediatric Cardiology, Berlin, Germany.
³ Experimental and Clinical Research Center, a Cooperation between the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and the Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁴ Charité - Universitätsmedizin Berlin, Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Berlin, Germany.
⁵ DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
⁶ Charité - Universitätsmedizin Berlin, Outpatient Clinic for Immunodeficiencies, Institute for Medical Immunology, Berlin, Germany.
⁷ CellTrend GmbH, Luckenwalde, Germany.
⁸ Competence Network for Congenital Heart Diseases, Berlin, Germany.
⁹ Department of Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.
¹⁰ German Heart Center Berlin, Department of Internal Medicine - Cardiology, Berlin, Germany.
¹¹ Charité - Universitätsmedizin Berlin, Department of Internal Medicine and Cardiology, Berlin, Germany.
¹² Center for Congenital Heart Disease/Pediatric Cardiology, Heart and Diabetes Center NRW, University Clinic of Ruhr-University Bochum, Bad Oeynhausen, Germany.

Abstract

Background: Myocarditis can be associated with severe heart failure and is caused by different inflammatory and autoimmune responses. The aim of this study was to describe the immunological response in children with myocarditis by analyzing anti-beta-adrenergic receptor antibodies (anti-β-AR Abs).

Methods: Sera of children who were hospitalized with biopsy-proven myocarditis were prospectively collected between April 2017 and March 2019. Anti-β1-AR Ab, anti-β2-AR Ab, and anti-β3-AR Ab were quantified by a CE-certified ELISA kit. According to normal values for immunoglobulin G (IgG), three age groups, <1, 1-5, and >5-17 years, were defined. Children without inflammatory cardiac pathology and no heart failure signs were served as a control group.

Results: We compared 22 patients with biopsy-proven myocarditis and 28 controls. The median age (interquartile range) of the myocarditis group (MYC) was 12.1 (2.7-16.4) years, 13 men, left ventricular ejection fraction (LVEF) 51% and for control group, the median age was 5.0 (3.0-6.8) years, nine men, LVEF 64%. Myocarditis patients in the age group >5-17 years showed significantly higher anti-β3-AR Ab levels as compared to controls (p = 0.014). Lower anti-β2-AR Ab and anti-β3-AR Ab levels were significantly correlated with higher left ventricular diameters in myocarditis patients. The event-free survival using a combined endpoint (mechanical circulatory support [MCS], transplantation, and/or death) was significantly lower in myocarditis patients with antibody levels below the median as compared to myocarditis patients with antibody levels ≥ the median.

Conclusion: Anti-β-AR Ab levels are increased in children with myocarditis and >5 years of age. These antibodies might be upregulated compensatory to prevent further cardiac deterioration. A worse event-free survival in patients with lower anti-β-AR Ab levels might be a therapeutic target for immunoglobulin substitution.

Keywords: anti-beta-adrenergic receptor antibodies; autoimmune; endomyocardial biopsy; myocarditis; pediatric.