An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins

Diptendu Chatterjee, Maurizio Pieroni, Meena Fatah, Flavien Charpentier, Kristopher S. Cunningham, Danna A. Spears, Dipashree Chatterjee, Gonca Suna, J. Martjin Bos, Michael J. Ackerman, Eric Schulze-Bahr, Sven Dittmann, Pasquale G. Notarstefano, Leonardo Bolognese, Firat Duru, Ardan M. Saguner, Robert M. Hamilton

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Aims Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. Methods For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelec- and results tric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be a-cardiac actin, a-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. Conclusion A biomarker profile of autoantibodies against four cardiac proteins, namely a-cardiac actin, a-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Original languageEnglish (US)
Pages (from-to)2878-2890A
JournalEuropean heart journal
Volume41
Issue number28
DOIs
StatePublished - Aug 1 2020

Keywords

  • Actin
  • Autoantibody
  • Biomarker
  • Brugada syndrome
  • Connexin-43
  • Keratin
  • Perinexus

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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