Further mystification of SCN5A phenotypes: sodium channel blockade in individuals with loss-of-function sodium channel mutations dangerous or helpful?

This editorial refers to ‘Clinical profile and prognosis of brugada syndrome SCN5A variant carriers with negative sodium channel blocker challenge’ by E. Surget et al., https://doi.org/10.1093/europace/euag014.

Cardiac channelopathies are part of human life (and probably for most vertebrates and many invertebrates too), but only in the past decades we started to unravel the mechanisms and consequences of these channelopathies for individual humans and their families.¹ There appears to be an amazing variability in the clinical phenotype that these channelopathies can produce, even when we know they exhibit loss- or gain-of-function properties. Unmistakably, the complex architecture of the human race, including its response to internal and external variation, creates so many different outcome possibilities that the effects of variability due to single or multiple inherited variants in the genome can still surprise us.² The cardiac sodium channel SCN5A or Nav1.5 is one of those intriguing proteins that can produce a wide array of phenotypes, ranging from severe forms of long-QT syndrome, multifocal ectopic Purkinje-related premature contractions, cardiomyopathy, conduction disease, sinus node disease, atrial standstill, atrial fibrillation, Brugada syndrome, ventricular tachycardia, and ventricular fibrillation, alone or in combinations, to actually no discernible phenotype at all.^3–6 Loss-of-function cardiac sodium channel mutations are the most commonly observed, and this has several consequences for recognition and treatment.

One of those consequences is that we generally advise to abstain from sodium channel blocking drugs in these patients,⁷ to not push them into a potentially life-threatening phenotype when sodium channel function is excessively compromised.⁸ In contrast, in the diagnostic workup of patients, we deliberately use sodium channel blockers to provoke a pathogenic phenotype in those patients in whom we suspect Brugada syndrome or need to uncover its substrate.^9–12 Noteworthy, extra diligence and precautions are advised when we suspect or know of SCN5A mutations, again to not induce malignant arrhythmia.¹¹ However, from previous work, we know that not all individuals with (loss-of-function) SCN5A mutations show a Brugada phenotype when challenged with sodium channel blockers.¹³ Such findings exemplify the complex background and lack of direct causality of SCN5A mutations in Brugada syndrome. And that complexity is exactly what Surget and colleagues from multiple centres in France further investigated in their paper: ‘Clinical Profile and Prognosis of Brugada syndrome SCN5A Variant Carriers with Negative Sodium Channel Blocker Challenge’, as published in this edition of Europace.¹⁴

In their paper, data on 162 SCN5A mutation-positive individuals from 43 families evaluated in 5 French university hospitals were merged to investigate the presence or absence of the characteristic type-1 Brugada syndrome ECG changes upon sodium channel blocker challenge. Although they specifically selected families in whom negative sodium channel blocker provocation in individuals positive for the pathogenic or likely-pathogenic familial SCN5A mutation was present (presumably representing only a fraction (e.g. < 5%) of their complete cohorts), they found a staggering 69 individuals (43%) with a negative provocation test. During a mean follow-up of >6 years in most of these individuals, they did find some progressive conduction slowing with +11 ms on the PR interval and +8 ms on the QRS interval, albeit less than in the patients with a positive provocation test. In addition, one older patient received a pacemaker, another received an ICD due to progressive conduction slowing in combination with a family history of sudden cardiac death (again, less than in the patients with a positive provocation test), three developed dilated cardiomyopathy, and six had supraventricular arrhythmias. Still, none of these SCN5A-positive individuals with a negative provocation test presented with ventricular arrhythmias.

All together it appears that individuals with an SCN5A mutation quite often have an adequate depolarisation reserve that even withstands provocation with the strongest sodium channel blockers. In addition, these individuals do not seem to be vulnerable to ventricular arrhythmias during many years of follow-up. Although they may still have other phenotypes that can (in part) be attributed to their SCN5A mutation, the variability in their phenotype as compared to their family members (who do exhibit characteristic Brugada syndrome and even more conduction slowing) is remarkable. Notably, the presence and relevance of modifiers to the phenotype of sodium channel mutations, including genetic modifiers, allele penetrance and/or developmental factors, was already posed 25 years ago.¹⁵

Importantly, there are several ultimate conclusions to be made for these individuals without a clear phenotype despite their SCN5A mutation. For one, they may not be patients, but just individuals with an SCN5A mutation without any symptoms, phenotype or added risk. This is very important and helpful, as these patients do not necessarily need to adhere to our general advice to avoid sodium channel-blocking drugs.⁷ Although long-term follow-up is still advisable, to evaluate the occurrence of progressive conduction slowing, for example, this likely can be performed at lenient intervals (e.g. every 2–3 years). Hence, we should really reconsider our current practices in these SCN5A-positive but phenotype-negative individuals. Maybe all these patients should be offered sodium channel blocker provocation to differentiate their phenotype into concealed forms of SCN5A disease/Brugada syndrome and those who are really phenotype negative. Albeit that there still might be a change in their phenotype—which might even suggest considering repeated testing every 10–15 years, for example—these individuals can be reassured for many years (despite the phenotypes in their family members). In addition, further scientific scrutiny of why their phenotype is not affected by their SCN5A mutation may uncover more insights into the mechanisms involved and may even prove to be of clinical use in the future. A word of caution is appropriate here, though. Ajmaline testing requires diligence and experience, especially in patients with SCN5A mutations. Even in experienced hands, patients may convert into ventricular fibrillation, which may continue for quite some time before the provocative agent is washed out. So indeed, sodium channel blockade in patients with loss-of-function SCN5A mutations can be dangerous but may also be very helpful.

Funding

Dutch Heart Foundation (Nederlandse Hartstichting) grant 03–003-2021-T061.

Data availability

Not applicable.