Gene-Specific Therapy for Congenital Long QT Syndrome

Are We There Yet?

• arrhythmia
• mutation
• sodium-channel blocker
• sudden cardiac death

During the past 2 decades, there has been substantial progress in the study of molecular and cellular arrhythmogenesis in inherited cardiac channelopathies. The majority of these life-threatening primary arrhythmia syndromes have been associated with mutations in specific genes, leading not only to a better diagnosis but also, to some degree, to improved risk stratification and management of patients.

Congenital long QT syndrome (LQTS) is probably the clearest example of how molecular genetics can influence the traditional clinical approach. This disease is caused by mutations encoding cardiac ion channels, which results in an impairment of cardiac repolarization and an increased risk of sudden death due to ventricular arrhythmias. More than 500 mutations have been identified in 16 different genes (1); however, the most common forms of LQTS are caused by mutations in KCNQ1 (LQTS type 1), KCNH2 (LQTS type 2), and SCN5A (LQTS type 3), accounting for approximately 75% of genotype-positive LQTS cases (1). Genotype-phenotype correlations have provided new insights into mechanisms, electrocardiographic features, and the natural history of this disease. Apart from distinctive T-wave repolarization patterns on the electrocardiogram, gene-specific differences have been described in terms of triggers for ventricular arrhythmias and risk of cardiac events (2–5). Because of the impairment of the delayed rectifier potassium current (IK_s) (responsible for QT shortening during increase in heart rate), for LQTS type 1 (LQT1) patients, most life-threatening events occur during sympathetic activation, mainly exercise or emotional stress. LQT2 and LQT3 patients have a normal IK_s current; therefore, they are at a low risk of life-threatening arrhythmias during exercise. β-blockers are the first line of therapy for LQTS with demonstrated efficacy (6). Yet, large series of genotyped LQTS patients have shown that the response to β-blockade may be influenced by the genetic substrate, showing a better response in LQT1 than in LQT2 and LQT3 (3,5).

The incomplete efficacy of β-blockers, together with the identification of precise triggers and, especially, the functional characterization of mutant proteins, has promoted the search of gene-specific or mutation-specific therapies that may allow better prevention of arrhythmic events. Unfortunately, the search for the “Holy Grail” in the treatment of inherited arrhythmia syndromes has remained elusive so far and, as outlined in recent guidelines (7,8), the main recommendations of management still rest on medical therapy with β-blockers, supported with an implantable cardioverter defibrillator and/or cervical sympathectomy in severe cases.

The first attempts for a gene-specific therapy with mexiletine in patients with LQT3 were made in 1995 and 1996 by Drs. Peter Schwartz, Silvia Priori, and colleagues (9,10). Since LQT3-causing SCN5A mutations produce an increase of inward sodium current leading to prolongation of the action potential duration, the use of sodium-channel blockers seemed a reasonable genotype-specific therapy for patients with LQT3. These preliminary experiences showed that, at an experimental and clinical level, mexiletine effectively shortened the action potential and the duration of the QTc. However, shortening of the QTc does not automatically imply a reduction in the risk of life-threatening arrhythmias and sudden cardiac death.

With this in mind, in this issue of the Journal, Mazzanti et al. (11) present the continuation of this prior work regarding the use of mexiletine in LQT3 patients. The authors present a retrospective analysis of a single cohort of 34 patients (13 previously symptomatic) diagnosed with LQT3 and analyzed before and after mexiletine treatment. After a median follow-up of 35 months (interquartile range: 19 to 64), there was a reduction of arrhythmic events as compared to a similar-duration period before starting therapy with the sodium-channel blocker. The QTc was shortened to “normal” values (≤460 ms) in 20 of 34 (59%) individuals. None of the asymptomatic LQT3 patients became symptomatic during follow-up. However, 3 children were unresponsive to mexiletine and experienced sudden death. All of them had a QTc much higher than 500 ms after initiation of mexiletine.

In addition to the authors’ conclusion that mexiletine reduces the occurrence of life-threatening events, there are other considerations. Not all patients carrying a SCN5A mutation respond to a sodium-channel blocker. Although response to therapy was not described by type of mutation in this study, prior work from the same group has suggested that mexiletine’s effectiveness may be mutation specific (12) and may even cause further QT prolongation (13). In fact, this study states that 1 of the children who died during follow-up had initially shown response to mexiletine but later experienced severe QTc prolongation and sudden death. The genotype-phenotype relationship of the more than 200 SCN5A mutations is widely variable. This may be due to the different mutations themselves or to the influence of the so-called modifier genes (polymorphisms) on the biophysical and electrophysiological properties of the cardiac ion channel. Additionally, some mutations can result in different syndromes as Brugada syndrome, sick sinus syndrome, atrial standstill, atrial fibrillation, and cardiac conduction defects (overlap syndromes) that may be unmasked by the use of a sodium-channel blocker (14). Thus, its use should be weighted and monitored carefully. Ruan et al. (12) suggested that in vitro testing may help to predict the response to mexiletine in LQT3. In the clinical setting, it may be more suitable to test the efficacy of the drug in shortening the QTc during an acute oral test (1).

The study by Mazzanti et al. (11) has to be commended for being the first evaluating the clinical impact of a sodium-channel blocker in the midterm prognosis of LQT3. Unfortunately, the retrospective design of the study advises caution before applying these results in general practice. It is well understood that with LQT3 being such a rare condition, it is difficult to assess the benefit of mexiletine—or any other drug—through a prospective randomized trial. Still, it would be interesting to validate these findings through a larger study, in which potential biases can be better controlled.

Gene-specific therapy development for rare diseases, such as cardiac channelopathies, still represents a challenge 20 years after the first mutations were identified. However, we should not only pursue this goal, but also move towards “mutation-specific” management. First, by extensive characterization of the biophysical and biochemical properties of mutations; after that by a joint international effort that allows us to obtain solid prospective data on a larger series of patients with channelopathies. Genetic manipulation using delivery vectors is currently being investigated and may emerge as an alternative in the management of inherited arrhythmia syndromes in the future.

• American College of Cardiology Foundation