Should all individuals with a non-diagnostic electrocardiogram undergo ajmaline challenge to unmask the concealed arrhythmic overlap syndromes?

We read the two articles with a great interest by Hohmann et al.1 published in Europace entitled ‘Systematic ajmaline challenge in patients with long QT 3 syndrome (LQT3) caused by the most common mutation: a multicentre study’ and also by Georgopoulos et al.2 entitled ‘A meta-analysis on the prognostic significance of inferolateral early repolarization (ER) pattern in Brugada syndrome (BrS)’. We want to address some points that merit more attention. Phenotypic overlap of LQT3, BrS, arrhythmogenic dilated cardiomyopathy (ARVC), cardiac conduction disease, and sinus node dysfunction is observed with SCN5A mutations in the α-subunit of cardiac sodium channel gene.3 Although these various arrhythmia syndromes were originally considered separate entities, recent evidence indicates more overlap in clinical presentation and biophysical defects of associated mutant channels than previously appreciated. It has been reported that there could be the overlap syndromes between the ARVC and BrS,4 between the spontaneous atrioventricular nodal re-entrant tachycardia and concealed BrS, between the ER syndrome and BrS, and between the LQT3 and BrS. An interesting electrocardiogram in a BrS patient with ER and LQT3 which presented as sudden cardiac arrest is seen Figure 1. Identification of patients with an overlap phenotype is crucial before initiation of Class I antiarrhythmic drugs for LQT3, since class IC drugs should be avoided in patients with BrS. Indeed, the class IA and IC antiarrhythmic drugs and beta blockers increase ST-segment elevation in BrS, whereas these agents shorten the repolarization and QT interval, and thus may be beneficial in LQT3 syndrome. Since the life-threatening ventricular arrhythmias often occur in the concealed phase of the disease before the onset of structural changes, the ajmaline challenge should be performed in patients suspicious of concealed BrS and/or overlap syndromes. The intravenous flecainide or ajmaline challenge1 represents an important step to rule out potential BrS overlap in individuals with concealed forms of the disease before starting oral flecainide, which has been proposed as a treatment option for LQT3 patients because it may shorten their QT interval.1 It has been also reported that the values of HV interval > 70 ms in basal conditions and ≥ 100 ms after ajmaline challenge seem appropriate to unmask infrahisian disease in patients with recurrent and unexplained syncope, regardless of the existence of conduction disturbances on surface ECG. Intravenous ajmaline challenge could also demonstrate a definite link between ARVD/C and BrS, and between the ER syndrome and BrS2 and may identify patients at higher risk of arrhythmic events. Therefore, ajmaline challenge could be used for all these overlapping arrhythmic syndromes in an appropriate environment in which advanced life support facilities are present.5 Moreover, the test positivity may change with age in individuals with an initial negative drug test, suggesting that the test should be repeated in the late teenage years or early adulthood. Only deepened understanding of the genotype-phenotype correlation will allow the definition of the individual patient’s risk and the development of guidelines for clinical management. The electrocardiogram showing an overlap syndrome of Brugada and LQT3. Conflict of interest: none declared.