A highly specific biomarker for Brugada syndrome. Also too good to be true?

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This editorial refers to ‘An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins’^†, by D. Chaterjee et al., on page 2878.

‘Too good to be true?’ was the subtitle of an Editorial associated with a paper presenting a specific anti-desmoglein-2 antibody for arrhythmogenic right ventricular cardiomyopathy (ARVC).^{1  ,  2} Dr Calkins argued that such a finding would have ‘enormous diagnostic potential’ but that, based on the presented data, it was ‘far too early’ to conclude that a new way to diagnose and risk-stratify ARVC patients had opened up.¹ A literature survey to date does not reveal a confirmatory study. The same group now presents a specific set of antibodies for Brugada syndrome (BrS),³ and whether this is also too good to be true will be discussed.

BrS was originally described as an electrical disease, like long QT syndrome, characterized by specific ECG markers and associated lethal ventricular arrhythmias.^{4  ,  5} In more recent years, it became clear that the disease entity should probably be placed in a spectrum of right ventricular cardiomyopathies,⁶ with—localized—structural abnormalities in the right ventricular outflow tract region, the predominant site of origin of the arrhythmias. The diagnosis of BrS requires the ECG signature sign, i.e. right precordial ST-segment elevation (≥2 mm) with successive negative T waves. This ECG type (‘type 1’) is present intermittently and that fact imposes a potential problem for reaching the diagnosis of BrS. Indeed, in a small series of 43 consecutive BrS patients, only one patient consistently had a type 1 ECG, whereas it disappeared transiently during follow-up in one-third of patients and was only inducible by drugs in almost half of patients.⁷ Another important problem in diagnosing BrS is the presence of ‘Brugada phenocopies’, i.e. an acquired Brugada-like ECG pattern,⁸ with ECGs that are visually identical and indistinguishable from true Brugada syndrome.⁹ Both potential pitfalls, i.e. temporary absence of the diagnostic ECG pattern and the presence of potential Brugada phenocopies, mandate an active search for more specific criteria for the diagnosis BrS.

In this issue of the European Heart Journal, Chatterjee et al. describe a set of auto-antibodies in sera of BrS recognizing cardiac proteins (discovery cohort n = 3, and replication cohort n = 18, all fulfilling the Shanghai criteria;⁵ 13 with a spontaneous type 1 and eight with a drug- or fever-induced type 1 ECG).³ The identified BrS-specific profiles were compared with sera from controls (n = 8 + 24), dilated cardiomyopathy (DCM; n = 3), hypertrophic cardiomyopathy (HCM; n = 2), and, most importantly, given the potential clinical overlap, ARVC patients (n = 20). The results presented suggest 100% specificity and sensitivity for BrS.³ Mass spectrometry was used to identify the specific autoantibody protein targets as α-cardiac actin, α-skeletal actin, keratin, and connexin-43 (Cx43). In myocardium from nine BrS patients, each protein demonstrated abnormal expression profiles, i.e. aggregates in the sarcoplasm of myocardial cells. A similar finding was obtained with the sodium channel protein type 5 alpha subunit (Na_V1.5).

The potential importance of these findings is that a highly specific serum profile could serve as the gold standard for the diagnosis of BrS. In this study, BrS patients clearly differentiate from control patients. In addition, and this is an important asset of this study, in none of the 20 ARVC patients was a comparable antibody profile found, although confirmation of this absence with the developed enzyme-linked immunosorbent assay (ELISA) is missing. This would potentially allow differentiation from ARVC which on a clinical basis is not always possible with sufficient sensitivity and specificity. Differentiation from DCM and HCM also seems to be possible, although the numbers of samples tested are very small. On the other hand, this does not impose a clinical problem. However, the elephant in the room, as we believe, is whether this BrS-specific profile can differentiate true BrS from other loss-of-function sodium channelopathies. Patients with a loss-of-function SCN5A variant without BrS are not included in this study. Furthermore, whether this profile can distinguish patients at risk for malignant arrhythmias from low-risk patients remains to be seen.

BrS has a complex genetic basis,¹⁰ but there is no doubt that single loss-of-function SCN5A variants can cause BrS.¹¹ In an estimated 20–30% of BrS patients, a pathogenic loss-of-function SCN5A variant is identified, but the penetrance of these variants is far from 100%. Other SCN5A loss-of-function phenotypes are sick sinus syndrome, conduction disease, dilated cardiomyopathy, and combinations thereof.¹⁰ The pathophysiology of the right precordial ST-segment elevation, as indicated by the electrocardiographic signature of BrS, in patients with or without pathogenic SCN5A variants is disputed.⁴ Age, gender, body temperature, and drugs are important modifiers of the penetrance. Indeed, BrS is more prevalent in middle-aged men, compared with younger age and women at any age.⁴ The present study, including BrS patients with a different underlying genetic cause (61% carry a potential loss-of-function SCN5A variant), may provide some insight.

The cellular localization data demonstrate that components of the cytoskeletal network, i.e. α-actin and keratin, as well as the ion channels Cx43 and Na_V1.5 (encoded by SCN5A) which are dependent on the cytoskeletal network for trafficking to the sarcolemma, aggregate in the sarcoplasm in BrS cardiac tissue.³ This suggests that reduced cellular trafficking of these proteins is involved in the pathogenesis of the right precordial ST-segment elevation. For Na_V1.5, that does not come as a surprise because reduced Na_V1.5 expression is undisputedly involved in the disease pathophysiology. For Cx43, it has been shown that Cx43 is reduced in post-mortem samples of sudden cardiac death victims with a first-degree relative with BrS.¹² It is postulated that these aggregates may leak into the extracellular space and give rise to an autoimmune response and the resultant antibody generation. However, what the cellular expression profile and biomarker profile would look like in patients with similar loss-of-function SCN5A variants without right precordial ST-segment elevation is not studied (Figure 1). Such data are mandatory before the conclusion that BrS patients have a specific antibody profile involving the aforementioned four proteins can be drawn.

The authors are to be complimented on opening up an additional exciting avenue in BrS research with the potential to further understand the pathogenesis of the fascinating signature ECG feature. It seems that they have already succeeded in discriminating BrS from ARVC, albeit in a small set of patients, which we do consider a major step forward. However, is seems too early to proclaim victory about the identification of a specific BrS biomarker set, let alone a biomarker set that can play a role in risk stratification, the Holy Grail in the Brugada syndrome world.

Figure 1

Schematic representation of the identified antibodies in the different cohorts that have been studied (Brugada syndrome, n = 21; ARVC, n = 20; control population, n = 32; DCM, n = 2; and HCM, n = 3). The ECGs (lead V2) at the left side are all typical examples of loss-of-function sodium channelopathies [respectively G1743E (BrS), W156X and R225W (conduction disease), D1275N (atrial standstill), and E161K (sick sinus syndrome]. Whether or not the lower three disease entities express similar antibody patterns is not studied.

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The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Footnotes

Acknowledgements

We acknowledge the support of 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 (Predict2).

References