Biomarkers in inherited arrhythmias: opportunities for validation and collaboration

This commentary refers to ‘A highly specific biomarker for Brugada syndrome. Also too good to be true?’, by A.A.M. Wilde and E.M. Lodder, doi: 10.1093/eurheartj/ehaa468. We thank Drs. Wilde and Lodder for their thoughtful editorial, 1 and are honoured to have such international leaders in the field of Brugada syndrome (BrS) comment on our work. While one of the tasks of an editorial includes providing alternative viewpoints and an engaging title, we hope the audience in this field will go beyond controversial titles to read these editorials,1,2 and the articles that they address,3,4 in detail. We look forward to research colleagues repeating these studies as independent validation and hope that research journals will recognize the importance of publishing such validation studies, beyond our initial discoveries. For arrhythmogenic right ventricular cardiomyopathy (ARVC), the autoantibody target, desmoglein-2 (DSG2) protein, is insoluble in its natural state. Commercial DSG2 protein is solubilized by attaching an Fc tag, and the immunoreactivity of this Fc tag must be blocked before using it to assay anti-DSG2 antibodies. As these blocking steps made clinical translation of the original assay challenging, we have switched to using only target epitope DSG2 peptides (which are soluble) for the assay. This approach to date achieves very similar results in a test that will be more easily translated to the clinical laboratory. In contrast, the biomarker assay for BrS utilizes only highly soluble proteins that are commercially available in their natural state, which should facilitate independent validation. The requested enzyme-linked immunosorbent assay (ELISA) results are provided (Figure 1), completely discriminating BrS from ARVC. Enzyme-linked immunosorbent assay (ELISA) measurements of anti-connexin-43, anti-cardiac α-actin, anti-skeletal α-actin, and anti-keratin antibodies in sera from control subjects, Brugada syndrome subjects (discovery and validation cohorts) and ARVC subjects. Enzyme-linked immunosorbent assay (ELISA) measurements of anti-connexin-43, anti-cardiac α-actin, anti-skeletal α-actin, and anti-keratin antibodies in sera from control subjects, Brugada syndrome subjects (discovery and validation cohorts) and ARVC subjects. We sought to identify a serum test for BrS, and thus used the most recent consensus conference definition (Shanghai Score),5 for which SCN5A mutation was only one component. We did not seek a test for other SCN5A loss-of-function disorders, as there is already such an assay (SCN5A sequencing). We would be pleased to work with collaborators whose patients have loss-of-function SCN5A variant without BrS, to determine whether they have equivalent autoantibodies. We have local grant funding and a national grant application under review, to assess whether BrS autoantibodies are predictive and prognostic. We have extended this collaboration to 11 international sites to date, and welcome any additional collaborators to further explore this discovery. We would like to highlight that the identification of specific protein aggregates in the sarcoplasm of BrS cardiac tissue may have additional clinical/pathological utility, specifically in the post-mortem evaluation of victims of sudden cardiac death. This is an additional aim of our multicentre studies, and additional collaborators are also welcome to this study. Finally, pending funding, we seek to explore preclinical drug discovery focusing on the apparent trafficking defects identified, as highlighted in this editorial. We look forward to fruitful collaborations and engaging discussions around BrS as we all work towards better understanding this enigmatic disorder. Sincerely, R.M.H., D.C., and A.M.S. for the authors. Conflict of interest: none declared.