Receptor autoantibodies: Associations with cardiac markers, histology, and function in human non‐ischaemic heart failure
Authors: Zweck Elric , Karschnia Maximilian , Scheiber Daniel , Heidecke Harald , Dechend Ralf , Barthuber Carmen , Kaufmann Sina , Kelm Malte , Roden Michael , Westenfeld Ralf , Szendrödi Julia , Boege Fritz 
Published: January 2023

Aims

A causal link between non‐ischaemic heart failure (HF) and humoral autoimmunity against G‐protein‐coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio‐pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF.

Methods

Ninety‐five non‐ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for β1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high‐resolution respirometry.

Results

Autoantibodies against β1 adrenergic (β1AR), M5‐muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P < 0.001). Autoantibodies against α1‐adrenergic (α1AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. β1AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = −0.362, P < 0.05) and global longitudinal strain (r = −0.323, P < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high‐resolution respirometry in myocardial biopsies (r = −0.352, P < 0.05). In insulin‐resistant HF patients, AT2R autoantibodies were decreased (r = −.240, P < 0.05), and AT1R autoantibodies were increased (r = 0.212, P < 0.05).

Conclusions

GPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio‐pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non‐ischaemic HF.