Therapeutic approaches for Long QT syndrome type 3: an update

This editorial refers to ‘Long-term flecainide therapy in type 3 long QT syndrome’ by Chorin et al., on pages 370–376. Five to ten percent of genotyped patients with long QT are diagnosed as long QT syndrome type 3 (LQT3) which is caused by gain-of-function mutations in the SCN5A-encoded Nav1.5 sodium channel. The gain of sodium channel function is predominantly caused by the enhanced inward sodium current during the plateau phase of the action potential and is due to either a sustained (‘late’) current (INa,late or INaL) secondary to incomplete or slowed inactivation of the channel, or to an increased voltage range of incomplete current inactivation (i.e. an increase in the window current), or by a combination of the two.1 The LQT3 phenotype differs from the more common LQT1 and LQT2 forms in various aspects. First of all, the trigger for cardiac events is less likely to be adrenergic,2 and events, which are more often lethal and seem to occur later in childhood, during or after puberty,3,4 mostly occur at rest or with inactivity.2 Furthermore, patients with LQT3 have more marked resting bradycardia,3 and the arrhythmias appear to be predominantly bradycardia related.2 In addition, LQT3 patients also frequently have characteristics of other SCN5A phenotypes [e.g. Brugada syndrome (BrS), progressive cardiac conduction disease, atrial arrhythmias, and sinus node disease], even when the causal mutation predominantly associates with a typical gain of sodium channel function (at least, as established in heterologous expression systems).1,5 Related to the above described complexity of the phenotype, optimal therapeutic strategies for LQT3 have been debated for many years. One approach is to reduce arrhythmia triggers by minimizing adrenergic stimulation. The efficacy of beta-blockers in LQT3 has, early on, been questioned and it seems that implantable cardioverter-defibrillators (ICDs) have been implanted more liberally,6 with a significant burden of adverse events,6 as is rather common in primary prevention implants in patients with inherited arrhythmia syndromes.7 Beta-blocker efficacy was addressed in a recent large cohort study (391 patients, 51 different sodium channel mutations) and it could, however, be demonstrated that without doubt beta-blockers are not proarrhythmic. Instead, in females there is a strong protective effect, but in males, due to the low-event rate, this effect could not be determined conclusively.6 The pathophysiological argumentative approach to inhibit INaL has also been explored. Indeed, attempts with various sodium channel blockers have been performed among which lidocaine, mexiletine, flecainide (Class I antiarrhythmic drugs with varying selectivity for INaL over peak INa), and the more specific INaL inhibitors ranolazine and eleclazine. Theoretical adverse effects of this approach are related to simultaneous blockade of the peak sodium current leading to loss-of-function phenotypes (i.e. BrS). In addition, some cardiac INa blockers (specifically, mexiletine) may rescue trafficking of the aberrant channel and thereby worsen the (gain-of-function) phenotype and increase QTc.8 Furthermore, due to non-specific effects, blockade of one of the repolarizing potassium currents (mostly IKr inhibition by ranolazine and flecainide) may further prolong action potential duration. Nevertheless, pharmacological INaL inhibition appears of potential clinical benefit in LQT3 patients. An early study demonstrated a ‘LQT3-specific’ QTc shortening effect of the Class Ib sodium channel blocker mexiletine,9 and more recently long-term positive effects in LQT3 patients were reported for this drug, both in terms of marked QTc shortening as well as a significant reduction of arrhythmic events.10 In acute studies, ranolazine i.v. and oral and i.v. flecainide were shown to shorten the QTc interval in a small number of carriers of the ΔKPQ mutation.11,12 Also, in carriers of the D1790G mutation, ranolazine significantly shortened the QTc, also on the long-term.13 In a female SCN5A-N1325S mutation carrier, with a very high arrhythmia burden, chronic ranolazine treatment prevented further arrhythmic events.14 Eleclazine, the most specific INaL inhibitor available significantly shortened QTc in LQT3 patients,15 but further development of this line was recently discontinued by Gilead Sciences (as mentioned on the unofficial HCMBeat weblog https://hcmbeat.com/2016/12/27/end-of-the-road-for-eleclazine-and-liberty-hcm-study/#more-2890). In this issue of the Journal, the group of Dr Benhorin describes the long-term effect of flecainide in 30 patients with the D1790G mutation (and not in LQT3, as the title suggests).16 In an earlier report, flecainide was already studied in 8 carriers of this mutation, demonstrating significant QTc-reduction during a follow-up of 9–17 months.17 In the present study,16 extended long-term treatment (mean 145 months) with flecainide consistently reduced QTc interval in D1790G carriers with the exception of one patient who developed a new LBBB (with QTc prolongation secondary to the QRS widening). The QTc-decreasing effect was largest in those patients with the longest baseline QTc. Arrhythmic events were not observed during flecainide therapy, whereas in 6 out of 20 patients within the first months after discontinuing flecainide severe arrhythmias occurred. A Brugada-like ECG pattern (indicating significant loss of function effects) was induced in 6 (20%, type 1 in 4), but, as stated, no arrhythmic events were reported. Interestingly, flecainide restored sinus node dysfunction in three out of six patients where it was clearly present. Although flecainide has been advocated as drug of first choice for D1790G, potentially detrimental effects have also been reported in carriers of this mutation, including non-sustained ventricular tachycardias at high dose and a Brugada ECG pattern.18,19 In other SCN5A mutations, flecainide therapy has also demonstrated both QTc-decreasing efficacy as well as uncovering of a concealed BrS.12,20,21 While the overall results with various sodium channel blockers are promising, treatment efficacy is variable and mutation-specific (and likely also individual-specific). The question emerges whether efficacy and adverse responses of sodium channel blockers can be predicted. On a theoretical basis one may predict that sodium channel blockers will be particularly effective in those mutations were INaL is the predominant mechanism (including D1790G),22 although they may also decrease window current.23 Mutant channels often display increased sensitivity to sodium channel blockers, facilitating predominant block of dysfunctional channels.24 However, differential sensitivity to flecainide (an open-channel blocker) vs. mexiletine (which preferentially blocks inactivated channels) is observed among mutations, which is difficult to predict. For instance, mexiletine has been suggested to be most effective in mutations which cause a negative shift in voltage dependence of inactivation,25 but beneficial effects have also been observed in mutations not displaying this specific biophysical defect.26 It is important to realize that biophysical consequences are typically established using heterologous expression systems, and may not reflect the actual situation in the cardiomyocyte environment. On the proarrhythmic side, mutations with additional loss-of-function characteristics may be particular sensitive to drugs that also block the peak sodium current (i.e. flecainide in particular). In the current study in D1790G carriers,16 13% conversion to a Brugada type 1 pattern under flecainide is not trivial and may even be an underestimation given the fact that it is not reported whether this involves higher placed intercostal leads and ECGs during fever (known to be maybe even more specific than flecainide).27 Moreover, mutations displaying decreased membrane current density may be susceptible to mexiletine-induced rescue of trafficking of defective channels with consequent QTc-prolongation and pro-arrhythmia.8 Clinically, these adverse, potentially life threatening, responses all appear to be related to immediate visible alterations in the ECG (i.e. further QT prolongation or right precordial ST segment elevation). Careful electrocardiographic monitoring should therefore always be performed when initiating flecainide or mexiletine therapy. Additional care should be taken in the setting of myocardial ischemia (i.e. older patients), left ventricular hypertrophy and/or dilated cardiomyopathy, conditions which are known to enhance sensitivity to flecainide block of peak INa, potentially setting the stage for conduction slowing and re-entrant arrhythmias. Taken together, pharmacological treatment should be considered in every LQT3 patient with a clear phenotype. Overall, the absolute risk in LQT3 patients of dying suddenly by the age of 40 is <15%, and the length of the QTc interval and the presence of symptoms are strong predictors of this risk.6 Beta-blocker treatment should be the standard.6 ICD treatment is recommended in LQT3 patients at highest risk and pacemaker treatment may needed in those with a symptomatic bradycardia or with a very clear pattern of (nocturnal) bradycardia related excessive QT prolongation not sufficient responsive to drug treatment. Syncopal patients and patients with long QTc (≥500 ms) potentially need additional pharmacological treatment among which sodium channel blockers aimed at decreasing QTc-intervals. Since it is as yet impossible to predict treatment efficacy based on biophysical properties obtained in vitro in heterologous expression systems, choice of sodium channel blocker of preference should be validated for each mutation and patient by acute administration of a test dose during ECG monitoring, followed by regular clinical assessment of efficacy and potential side-effects. Continued development of novel, more selective INaL blockers would greatly improve treatment LQT3 patients. Conflict of interest: none declared. This work was funded by a ZonMW Priority Medicines Rare Diseases and Orphan Drugs (PM-Rare) grant (113303006) and by the Netherlands CardioVascular Research Initiative (PREDICT, CVON2012-10).