Patients with genetic cardiomyopathies exhibit a profile of heart-reactive antibodies distinct from the general population

Aims/Introduction: Recently, we have shown that acute cardiac decompensation is associated with the induction of heart-reactive autoantibodies (HRA) and an unfavourable prognosis. To elucidate a potential role of HRA in the pathogenesis of genetic cardiomyopathy (gCMP), we compared HRA serum levels in gCMP patients with levels found in the general population.

Methods: We included consecutive gCMP patients who underwent an interdisciplinary cardiological, immunobiological and genetic work-up in our tertiary care outpatient clinic. As controls, we analysed age- and sex-matched participants from the STAAB cohort study, which provides a representative sample of the general population of Würzburg, a medium-sized city in Germany, free from manifest heart failure. From serum samples stored at -80°, the following HRA levels against sarcomeric proteins were measured: Troponin I3 (TP/TNNI3), Tropomyosin 1 (TPM), Myosin Heavy Chain 6 and 7 (MYH6/MYH7), Myosin Light Chain 7 (MYL7), and a peptide corresponding to the second extracellular loop of the β1 adrenergic receptor (β₁EC_II). We used Fluorescence Activated Cell Sorting (FACS) to identify tagged fluorescent dyes on bead based antibody-antigen  connections by laser-based detection in order to quantify each respective sarcomeric protein.

Results: 100 healthy STAAB participants (50.9±15.7 years, 53% women) and 100 patients (46.4±15.9 years, 53% women) with genetic “ascertained” and “likely” pathogenic variants associated with the following distinct cardiomyopathies were analysed: 21% with arrhythmogenic right ventricular cardiomyopathy (ARVC), 32% with dilated cardiomyopathy (DCM), 44% with hypertrophic cardiomyopathy (HCM), and 3% with restrictive cardiomyopathy. Patients with gCMP exhibited predominantly mild heart failure symptoms (75% NYHA class I or II). We detected HRA against MYH7, MYL7 and β₁EC_II to varying degrees in both healthy controls and gCMP patients, but there were no meaningful differences between both groups (Figure A). By contrast, we detected increased anti-TP antibody levels (p≤0.001) and decreased anti-TPM levels (p≤0.001) in cGMP patients relative to healthy controls (Figure A). For HRA against MYH6, there was a trend towards higher antibody levels in cGMP patients compared to healthy controls (p=0.085) – similar to our observation for anti-TP antibodies (Figure A).

Conclusion: We detected HRA against defined antigens both in gCMP patients as well as in healthy control subjects. A distinct pattern of elevated anti-TP, reduced anti-TPM, and a trend towards higher anti-MYH6 antibody levels in our patient cohort compared to controls suggests disease-induced variations in antibody production. Whether these differences contribute to disease onset and progression in patients with gCMP by affecting sarcomeric integrity, deserves further study.