Biomarkers in inherited arrhythmias: necessity for validation and collaboration

This commentary refers to ‘Biomarkers in inherited arrhythmias: opportunities for validation and collaboration’, by R.M. Hamilton et al., on pages 4521–4522.

We are grateful for the complement regarding our expertise and thoughtful discussion by Drs Hamilton cs¹ as a response to our editorial.² We note that the authors share our vision that there is a need for independent replication of these results in order to be able to make the shift to translation. The developed autoantibody assays for arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada Syndrome (BrS)³ are promising, yet challenging to validate and bring to the clinic. First of all, as rightfully indicated, there are the various technical challenges, such as the antigen insolubility, that hamper their implementation in the ARVC domain. These technical issues are on the way to be solved, if the peptide approach proofs to be as successful as the preliminary tests mentioned. Furthermore, the results of the ELISA presented in the response¹ are very promising indeed, as the outcome is an almost binary present/absent autoantibodies response, notwithstanding the variability in the level of autoantibodies present. While this undoubtedly will become less clear with the inclusion of more samples with diverse phenotypes, the present results as to f.e. discriminating BrS from ARVC, warrant cautious optimism.

The main problem that remains is whether this assay will also be capable of distinguishing BrS from other SCN5A loss-of-function phenotypes (see figure 1 in our editorial),² which include cardiac conduction disease, sick sinus syndrome, atrial standstill, and dilated cardiomyopathy.⁴ There are ample examples throughout the literature that this is even the case within families harbouring the same pathogenic variant. While SCN5A sequencing is, of course, capable of identifying a pathogenic variant, it is not capable of distinguishing, a priori, the resultant phenotypes (for missense mutations it cannot even be predicted whether it leads to gain- or loss-of-sodium channel function phenotype). In fact, it is ill understood what actually explains the phenotypic variability and that includes the mechanism of the right precordial ST-elevation, the hallmark of BrS. A proper understanding of this seems fundamental to the question whether a specific autoantibody assay will be able to distinguish patients with the different phenotypes (but the same pathogenic variant). Families with such phenotypic variability seem most appropriate to investigate first to clear this issue. A BrS-specific autoantibody assay should be able to accurately distinguish individuals with a clinical prominent BrS from there genotype positive family members with only some minor conduction delay. Because such individuals have a marked different sudden death risk profile, one can only dream to use the antibody profile in risk stratification algorithms when this test is successfully passed. We are not too optimistic about one of these ultimate goals because the initial series of 21 BrS patients already included seven patients with a drug-induced BrS,³ also with a clearly different risk profile but apparently without a clearly distinguishable antibody profile.

We are pleased to see that the collaborations needed to advance this field are actively being formed and would recommend those who have suitable cohorts to respond positively to their eventual invitation to ‘further explore this discovery’.

Acknowledgements

We acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences.

Conflict of interest: none declared.

References