TY - JOUR
T1 - An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins
AU - Chatterjee, Diptendu
AU - Pieroni, Maurizio
AU - Fatah, Meena
AU - Charpentier, Flavien
AU - Cunningham, Kristopher S.
AU - Spears, Danna A.
AU - Chatterjee, Dipashree
AU - Suna, Gonca
AU - Martjin Bos, J.
AU - Ackerman, Michael J.
AU - Schulze-Bahr, Eric
AU - Dittmann, Sven
AU - Notarstefano, Pasquale G.
AU - Bolognese, Leonardo
AU - Duru, Firat
AU - Saguner, Ardan M.
AU - Hamilton, Robert M.
N1 - Funding Information:
This study was funded by a Waugh Family Innovation grant from the Labatt Family Heart Centre (2019-2021), a Freeman Innovation Award from the Heart and Stroke Richard Lewar Centre of Excellence (2019), the Caitlyn Elizabeth Morris Memorial Foundation, the Alex Corrance Memorial Foundation, and Meredith Cartwright to R.M.H. M.F. is supported by a Carter Heart Rhythm Fellowship. A patent application covering this work has been submitted. The Zurich ARVC Program is supported by grants from the Georg und Bertha Schwyzer-Winiker Foundation, the Baugarten Foundation, the Swiss National Science Foundation, and the Swiss Heart Foundation. M.P was funded by a 3-year Telethon grant (GGP10186). J.M.B. and M.J.A. were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.
Publisher Copyright:
© The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - Actin
KW - Autoantibody
KW - Biomarker
KW - Brugada syndrome
KW - Connexin-43
KW - Keratin
KW - Perinexus
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U2 - 10.1093/eurheartj/ehaa383
DO - 10.1093/eurheartj/ehaa383
M3 - Article
C2 - 32533187
AN - SCOPUS:85089436438
SN - 0195-668X
VL - 41
SP - 2878-2890A
JO - European Heart Journal
JF - European Heart Journal
IS - 28
ER -