Summary
The congenital long QT syndrome (CLQTS) is a genetic channelopathy that affects sodium and calcium kinetics, resulting in prolonged ventricular repolarization. This channelopathy is associated with increased propensity to syncope, malignant ventricular arrhythmias and sudden arrhythmic death in children with normal cardiac structure. Recently, the published data from the International LQTS Registry have established risk factors for sudden cardiac death and aborted cardiac arrest in children. P-blockers are the first-line drug therapy for congenital long-QT syndrome in children. Several P-blockers (propranolol, atenolol, nadolol, metoprolol,..) were used in CLQTS with a significant reduction of cardiac events in patients with LQT1 and LQT2 mutations, but no evident reduction in those with LQT3 mutations. Infrequently, additional Drugs (mexiletine and flecainide) were used in children with CLQTS. The implantable cardioverter defibrillator and left cervicothoracic sympathetic denervation are other therapeutic options in children who remain symptomatic despite P-blocker therapy. Genetic factors may be used to improve risk stratification in genotyped patients and to predict the response to P-blockers.
Introduction
Congenital long QT syndrome (CLQTS) is a genetic disorder caused by mutations that encode cardiac ion channel proteins, which regulate the flux of sodium, potassium, and calcium ions across myocellular membranes [1]. This channelopathy is characterized by the prolongation of the QT interval in the ECG and life-threatening cardiac arrhythmias, occurring especially during conditions of increased sympathetic activity [2]. The genetic disorder is an important cause of sudden cardiac death (SCD) in children without structural heart disease [3].
Recently, the published data from the International LQTS Registry have established risk factors for sudden cardiac death and aborted cardiac arrest in children [4]. Three important implications emerge from the analysis of the registry: 1) Risk factors for aborted cardiac arrest (ACA) or SCD can be assessed from male gender, a history of syncope at any time during childhood, and a QTc duration > 500 ms; 2) Significant interactions exist among the 3 clinical risk factors that can identify risk subsets in children; 3) P-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events in CLQTS in children.
Because of technical issues with Intracardiac cardioverter defibrillators implantation, a high incidence of leads dislocation and rupture resulting in inappropriate shocks [5] and their psychological impact in children, Pharmacological therapy remains the first line treatment of CLQTS in this young population.
The application of molecular genetics to cardiovascular disease has allowed the identification of mutations in ion channel genes as the cause of LQTS. Following the identification, in 1995 and 1996, of the first three LQTS genes associated with the most frequently encountered LQTS variants called respectively LQT1, LQT2, and LQT3, there has been a flourishing of identifications of genes proven or just thought to be associated with LQTS [5-7]. This includes the genes for LQT4 through LQT10 (Table 1) [8].
The specific genotype influences the characteristics of the clinical phenotype, including the arrhythmia trigger, frequency of life threatening events, and T-wave morphology [9-11]. The discovery of a distinct molecular basis for LQTS has fostered a hope for specific therapy against the gene defect.
p-Blockers
Pharmacological therapy with P-blockers is considered the first choice prophylactic therapy, unless specific contraindications are present. It’s recommended to administer P-blockers in all LQTS patients, even those at very low risk [4]. In patients with LQT1 and LQT2 syndrome, life-threatening arrhythmias including torsades de pointes tachyarrhythmia and sudden cardiac death tend to occur with physical or emotional stress [11]. Thus, the attenuation of adrenergic-mediated triggers in LQTS seems to be the mechanism of action of P-blockers, especially in individuals with the LQT1 and LQT2 genotypes [11]. Recent study from the International LQTS Registry has demonstrated that P-blocker therapy is associated with a significant and pronounced reduction in the risk of life-threatening cardiac events in high-risk LQTS in children [4]. However, despite these beneficial effects, some patients receiving P-blocker therapy had a high rate of residual cardiac events [4,12-15]. In a cohort of 335 genotyped LQTS patients receiving P-blocker therapy [15], cardiac events occurred in 10%, 23%, and 32% of LQT1, LQT2, and LQT3 patients, respectively. Since the HERG channel function is defective in LQT2 patients and HERG channel dependency is increased in LQT1 patients, it is reasonable to consider that P-blockers without HERG channel blocking activity are more preferable for the treatment of these patients. These disparities between LQTS genotype and response to P-blockers seem to be attributed to different practices with respect to type of P-blocker used for the treatment of LQTS. Few data exists about the uniform efficacy between the various P-blockers. Indeed physicians use frequently propranolol, nadolol, atenolol, or metoprolol and make ”lateral” substitutions if/when side effects become an issue (Table 2).
Table 1. Long QT syndrome (LQTS) subtypes and mutation-associated genes.
|
LQTS subtypes |
Gene |
|
LQT1 and JLN1 (AR) |
KCNQ1 |
|
LQT2 |
KCNH2 |
|
LQT3 |
SCN5A |
|
LQT4 |
ANK2 |
|
LQT5 (RWS) and JLN2 |
KCNE1 |
|
LQT6 |
KCNE2 |
|
LQT7 (Andersen-Tawil syndrome) |
KCNJ2 |
|
LQT8 (Timothy syndrome) |
CACNAlc |
|
LQT9 |
CAV3 |
|
LQT10 |
SCN4B |
Abbreviations:
LQTS = Long QT syndrome;
JLN = Jervell and Lange-Nielsen syndrome;
RWS = Romano-Ward syndrome;
AR = autosomal recessive
Propranolol
Propranolol is a non-selective P-blockers thus it has nonspecific pharmacological actions, blocking Na+ channels in addition to its P-adrenoceptor blocking effects. Therefore propranolol would be expected to antagonize any residual adrenergic tone caused by spontaneous release of catecholamines from nerve endings in addition to blocking Na+ channels [16]. The advantages of propranolol are its lipophilicity that allows it to cross the blood-brain barrier, and its well-known tolerability for chronic therapy. The disadvantages are the need of multiple daily administrations, the contraindications for patients with asthma and diabetes and the lipid solubility of propranolol causes side effects involving the central nervous system, such as depression. Propranolol is used at daily dosage of 2 to 3 mg/kg; sometime the dosage is increased to 4 mg/kg. At high dose, propranolol seems to prolong QT interval [17]. More recently, propranolol has been reported to have an inhibitory effect on HERG current by binding to the putative common binding site [18,19]. Thus, propranolol might have a less powerful effect on QT interval at a clinically relevant concentration as reported previously [20-22]. For these reasons propranolol may not be the treatment of choice of patients with LQT1 and LTQ2.
Table 2. The frequency use of pharmacological therapy in children from the International LQTS Registry.
|
P-Blockers (n= 643/3015 pts) |
Propranolol |
397 Pts |
61.7% |
|
Atenolol |
242 Pts |
37.6% |
|
|
Nadolol |
162 Pts |
25.2% |
|
|
Metoprolol |
27 Pts |
4.2% |
|
|
Other P-Blockers |
19 Pts |
2.9% |
|
|
Sodium channel blockers (n= 34/3015 pts) |
Flecainide |
5 Pts |
0.2% |
|
Mexiletine |
29 Pts |
1% |
Table 3. Dosages and frequency administration of the main drugs used in the LQTS.
|
Drug |
Dosages (mg/kg/day) |
Frequency administration |
|
Propranolol |
2.5 – 5 |
Twice a day |
|
Atenolol |
1 – 1.5 |
One to twice a day |
|
Nadolol |
0.75 – 1.5 |
Twice a day |
|
Metoprolol |
1 – 4 |
One to twice a day |
|
Flecainide |
2 – 5 |
Twice a day |
|
Mexiletine |
6 – 8 |
Four times a day |
|
Spironolactone |
2 – 5 |
Twice a day |
Nadolol
This drug is a non-selective P-adrenoceptor antagonist characterized by its longer half-life, thus it’s used twice a-day usually at 1 mg/kg/day.
Atenolol and Metoprolol
Atenolol and metoprolol did not inhibit HERG currents significantly at least in clinically relevant concentrations. Thus, these drugs are suitable for treatment of LQT1 and LQT2 patients [23]. But atenolol has been reported to be associated with clinical failures more often than propranolol or nadolol thus is used less frequently [9].
Carvedilol
Carvedilol has been reported to inhibit HERG by Cheng [24] and Karle [25] and has class III antiarrhythmic effect. In the COMET study [26] and its subanalysis [27], carvedilol reduced the mortality rate and sudden cardiac death rate more effectively than metoprolol. The mechanisms for this favourable clinical outcome for patients treated with Carvedilol are not clear. Kawakami and al compared the class III antiarrhythmic effects of multiple b-blockers by estimating HERG channel blocking activity. The class III antiarrhythmic effects were significantly potent for carvedilol compared with other P-blockers. Carvedilol might provide favourable outcome via class III antiarrhythmic effects, in the context of P-blockade, in chronic heart failure patients. These results seem to provide a hypothetical molecular explanation for the favourable outcome in carvedilol treated patients in the COMET study. Carvedilol directly inhibited HERG channels at clinically relevant concentrations. Thus, carvedilol might not be recommended in the treatment of patients with LQT1 and LQT2 [23].
Sodium Channel Blockers
Na+ channel blockers such as mexiletine and flecainide are effective in treating LQT-3 patients due to preferential inhibition of mutant Na + channel activity [28,29]
Flecainide
Flecainide is a class IC sodium channel blocker. It may be of therapeutic benefit in HERG phenotype and in acquired LQT [30]. Flecainide is reported to be effective in abbreviating QT interval in LQT3 patients with a specific mutation (D1790G) in SCN5A [31]. Other study [32] indicates that low-dose flecainide could be a promising therapeutic agent for LQT patients with the SCN5A: DeltaKPQ sodium channel mutation. No adverse side effects or proarrhythmias were observed with flecainide in this study. However, class IC sodium channel blockers might elicit a Brugada phenotype in LQT3 patients [33], therefore should not be used in general in LQT3 syndrome except for that with the specific SCN5A mutation.
Mexiletine
Mexiletine is a class Ib antiarrhythmic drug used for ventricular arrhythmias but is also found to be effective for long QT 3 syndrome. The potential utility of mexiletine for the treatment of drug-induced LQT has been studied in vivo in dogs, where it decreased the electrical vulnerability of the heart during cisapride overdose, suggesting that it may become a potential pharmacological strategy for drug-induced LQT [34]. Experimental data from wedge studies indicates that mexiletine is more effective in abbreviating the QT interval in the LQT3 model than in the LQT1 or LQT2 model [21,35], but that the drug reduces transmural dispersion of repolarization and suppresses the development of Torsade de Pointes equally in the LQT1, LQT2 and LQT3 models [21,35]. This effect of mexiletine to reduce TDR in all three models is attributable to the intrinsically larger late INa in M cells than in epicardial or endocardial cells [36]. Mexiletine blocks late INa, abbreviates the QT interval in LQT3 patients more effectively than in LQT2 patients [37]. This data suggest that mexiletine may be used as first line therapy in LQT3 patients. However, because of a lack of prospective clinical trials mainly due to small number of LQT3 patients, mexiletine should be used at the moment in the presence of P-blockers or under the backup of an implantable cardioverter-defibrillator even in LQT3 patients [38].
Potassium and Spironolactone
In HERG genotypes of inherited LQT patients (LQTS 2), the increasing serum potassium levels by potassium loading may be a benefit therapeutic [39-41]. Impaired IKr function could be improved by exogenously administered potassium, resulting in increased outward potassium current and shortening of repolarization. An increase in serum potassium corrected abnormalities of repolarization duration, T-wave morphology, QT-RR slope, and QT dispersion in patients with HERG genotype of LQT [40]. Although raising serum potassium by increased potassium intake and potassium-sparing drugs reverses the ECG abnormalities in HERG genotype of LQT, a long lasting rise of serum potassium is only partially achievable because in the presence of normal renal function, potassium homeostasis limits the amount of serum potassium increase [41]. Etheridge et al [42] demonstrated that a sustainable, mild increase in serum K+ can be safely maintained by oral potassium supplementation and spironolactone. The increase in serum K+ was associated with a significant reduction in QTc and QT dispersion in all subjects, as well as normalization of the T-wave morphology in one-half of the subjects. A dramatic decrease in QTc with elevated serum K+ was observed in three individuals. The improvement in repolarization parameters achieved in this study suggests that oral KCl and spironolactone may be effective adjunctive therapy, together with P-blockers, for the treatment of LQTS. It is unlikely that the improvement in repolarization parameters was due to a direct effect of spironolactone, given that spironolactone derivatives prolong the action potential duration in isolated cardiac preparations [43]. Further studies are warranted to determine whether this will reduce the incidence of life-threatening events in LQTS patients.
Calcium Channel Blockers
Early afterdepolarizations have been suggested to play a significant role in QT prolongation and ventricular arrhythmias in congenital long QT syndrome. Calcium channel blocking agents (e.g., verapamil) have been reported [44-47] to be effective in the suppression of early afterdepolarizations and ventricular arrhythmias in some patients with the congenital long QT syndrome. Shimizu et al [48] used monophasic action potentials to investigate the effects of verapamil and propranolol on epinephrine induced repolarization abnormalities in congenital long QT syndrome. This study indicates that both verapamil and propranolol were effective in suppressing early afterdepolarizations and epinephrine-induced ventricular arrhythmias, in shortening the 90% monophasic action potential duration and the QT interval and in decreasing the dispersion of 90% monophasic action potential duration. A prospective study with oral verapamil is needed to confirm these findings.
Conclusions
Pharmacological therapy, especially b blockers, holds a very important place in the treatment of long QT syndrome in children. However, there is a lack of studies comparing the efficacy between b blockers due to the poor prevalence of this syndrome. Choice of a B blocker will depend on the availability of the drug, its tolerance by the patient and the physician’s own practice.
