Pediatr Drugs DOI 10.1007/s40272-014-0090-4

THERAPY IN PRACTICE

Congenital Long QT Syndromes: Prevalence, Pathophysiology and Management Alon Barsheshet • Olena Dotsenko Ilan Goldenberg

•

Ó Springer International Publishing Switzerland 2014

Abstract Long QT syndrome is a genetic disorder associated with life threatening ventricular arrhythmias and sudden death. This inherited arrhythmic disorder exhibits genetic heterogeneity, incomplete penetrance, and variable expressivity. During the past two decades there have been major advancements in understanding the genotype-phenotype correlations in LQTS. This genotype-phenotype relationship can lead to improved management of LQTS. However, development of genotype-specific or mutation-specific management strategies is very challenging. This review describes the pathophysiology of LQTS, genotype-phenotype correlations, and focuses on the management of LQTS. In general, the treatment of LQTS consists of lifestyle modifications, medical therapy with beta-blockers, device and surgical therapy. We further summarize current data on the efficacy of pharmacological treatment options for the three most prevalent LQTS variants including beta-blockers in LQT1, LQT2 and LQT3, sodium channel blockers and ranolazine for LQT3, potassium supplementation and spironolactone for LQT2, and possibly sex hormone-based therapy for LQT2.

Key Points There is an association between the long QT syndrome genetic background, ECG features, triggers for cardiac events, risk for cardiac events and response to medical therapy. Beta blockers are most effective among LQT1 patients, but they also confer significant benefit among LQT2 and LQT3 patients. Potassium supplementation may protect patients with LQT2. Sodium channel blockers such as mexiletine, flecainide, and ranolazine could be treatment options in LQT3.

1 Background A. Barsheshet Cardiology Department, Rabin Medical Center, Petach Tikva, Israel A. Barsheshet
I. Goldenberg Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel A. Barsheshet
O. Dotsenko
I. Goldenberg Cardiology Division, University of Rochester Medical Center, Rochester, NY, USA I. Goldenberg (&) Leviev Heart Center, Sheba Medical Center, 52621 Tel Hashomer, Israel e-mail: [email protected]

Congenital long QT syndrome (LQTS) is a genetic disorder involving principally the myocyte ion channels. Most affected patients have delayed ventricular repolarization recognized by abnormal prolongation of the QT interval on the ECG. It is associated with increased risk of syncope and sudden cardiac death caused by ventricular tachyarrhythmias. This genetic disorder exhibits genetic heterogeneity (different type of mutations in multiple genes), incomplete penetrance (not all patients having phenotypic expression) and variable expressivity (the level of phenotypic expression differs among patients). The estimated prevalence of LQTS is approximately 1 in 2,500 [1]. The prevalence of LQTS may be even higher than reported because up to

A. Barsheshet et al.

37 % of genotype-confirmed LQTS patients may have a normal-range QTc (i.e. concealed LQTS) [2–4]. The normal and prolonged QTc values depend on age and gender. Suggested QTc values for diagnosing QTc prolongation among patients aged 1–15 years, adult males, and adult females are QTc [460 ms, QTc [450 ms, and QTc [470 ms, respectively [5]. The diagnosis of LQTS relies on ECG findings, clinical history, and/or genetic testing. A recent expert consensus statement [6] recommended that a diagnosis of LQTS can be made if one or more of the following criteria are fulfilled: (1) a prolonged QTc is identified after a syncopal event in the absence of acquired causes of QT prolongation; (2) In the presence of a very prolonged QTc (C500 ms) in repeated 12-lead ECG and in the absence of a secondary cause for QT prolongation. (3) In the presence of an LQTS risk score (based on personal and family history, symptomatology, and ECG) [7, 8] C3.5 (4) and/or in the presence of an unequivocally pathogenic mutation in one of the LQTS genes.

2 Pathophysiology of LQTS To date, over 600 mutations have been recognized in 16 LQTS genes. LQT1, LQT2 and LQT3 account for the majority of cases, comprising more than 95 % of genotypepositive LQTS patients and about 75 % of all patients with LQTS [9]. The most common pattern of inheritance is autosomal dominant (Romano–Ward syndrome). The Jervell–Lange-Nielsen syndrome a severe form of LQTS is inherited in an autosomal recessive fashion and is associated also with congenital deafness. The mutations leading to LQTS affect several various ion channels genes and produce loss or gain of function that determine the phenotypic manifestation of the disease. Most commonly, these mutations are found in genes encoding the potassium or sodium channels leading to a decrease in repolarizing potassium current during phase 3 of action potential, or to a persistent inward sodium current resulting in prolonged depolarization, respectively. Figure 1 shows a schematic diagram of the influence of the most common altered ionchannel currents on the action potential duration in LQTS. The protein structure of each channel comprises of primary alpha- and secondary beta-subunits joined together into the polymer to form a functional ion channel. The alpha-subunit of the voltage-gated potassium channels includes six membrane-spanning segments, S1 through S6, connected by alternating intra- and extra-cellular loops, and a pore region located between S5 and S6 segments with the amino and carboxyl termini, located inside the cytoplasm. The cardiac sodium channel SCN5A consists of four homologous domains, and each domain contains six

transmembrane domains, similar to four linked potassium channel modules. LQT1 is caused by a loss of function mutation in the KCNQ1 gene leading to reduction in the slowly activating delayed rectifier potassium currents (IKs). In LQT2, the mutation involves a loss of function mutation in the KCNH2 gene leading to reduction in the rapidly activating delayed rectifier potassium currents (IKr). LQT3 results from a gain of function mutation in the SCN5A gene encoding for the alpha-subunit of the voltage-gated sodium channel (Nav1.5 protein), causing incomplete channel inactivation and allowing persistent sodium current influx. These changes in ion currents lead to prolongation of the cardiac action potential creating the substrate for early after-depolarization and ventricular arrhythmia induction [10].

3 Genotype-Phenotype Correlations in LQTS The genotype and molecular mechanisms play a key role in the clinical course of LQTS. It has been recognized that there is an association between the genetic background and clinical characteristics of the LQTS, including electrocardiographic features, triggers for cardiac events, risk stratification and long-term course of the disease. The ST-T wave repolarization pattern on the ECG may differ among the LQTS genotypes. In LQT1, patients typically have a broad-based T-wave pattern; in LQT2, patients typically have a low amplitude bifid T-wave, whereas in LQT3, T-wave is usually late onset and peaked. Multiple studies have shown that there are genotype-specific triggers for arrhythmic events among LQTS patients [11–15]. Patients with the LQT1 genotype are at a higher risk for arrhythmic events triggered by sympathetic activation induced by exercise. Among the different types of exercise, swimming was shown to be a specific trigger for LQT1 patients [11, 12, 15]. Patients with the LQT2 genotype experience cardiac events during emotional stress (including fear, anger, startle, or sudden noise during sleep), whereas patients with the LQT3 genotype experience events during sleep or at rest without emotional arousal. Risk stratification in LQTS relies on a combined assessment of clinical information, ECG and mutationspecific factors. The very high-risk group includes patients with a history of aborted cardiac arrest (ACA) and/or spontaneous VT. The high-risk group includes subjects with history of prior syncope or QTc [500 ms; the low risk group includes subjects with QTc duration B500 ms, without prior syncopal event. Furthermore, it has been shown that there are genotype-specific factors affecting the risk of cardiac events in patients with LQTS; those risk

Congenital Long QT Syndromes Fig. 1 Schematic diagram of the effect of altered ion-channel currents on the action potential duration in LQTS. Inward currents are indicated below the line and outward currents are indicated above the line. The hatched rectangles denote the timing location of the effect of mutations in LQT1, -2, and -3 genes on sodium and potassium ion-channel currents. The action potential (AP) is prolonged (horizontal arrow) when there is inappropriate gain of function (GOF) in late sodium current INa or loss of function (LOF) in slowly (IKs) or rapidly (IKr) activating delayed rectifier potassium currents. Taken with permission from [49]

factors include age, gender [15–17] the post partum time period [18], resting heart rate [15, 19], prior syncope [20], mutation location, type of mutation (missense/non-missense) [21, 22], the biophysical function of the mutation [23] and response to beta-blockers [21, 24]. In a recent study [16], we assessed the sex-specific risk factors for life threatening events including aborted cardiac arrest (ACA) or sudden cardiac death (SCD) in a cohort of 1,051 subjects with LQT1. This study has shown that during childhood (age group 0–13 years) males had [2fold (p \ 0.003) increased adjusted risk for ACA/SCD compared with women, whereas after the onset of adolescence the adjusted risk for ACA/SCD was similar between men and women (HR 0.89, p = 0.64). Figure 2 shows the Kaplan–Meier event rates of ACA/SCD among patients with LQT1 by gender. Life-threatening cardiac events among men occurred predominantly during childhood, the gap between the male and female curves remained the same after this time period. In patients with LQT2, the adjusted risk for life-threatening cardiac events during childhood (ages 0–13 years), was similar between women and men (HR 1.53, p = 0.33), whereas after the onset of adolescence (age [13 years), women showed a significantly higher adjusted risk for ACA or SCD as compared with men (HR 2.23, p \ .001) [17]. Figure 3 shows the Kaplan–Meier event rates of ACA/SCD among patients with LQT2 by gender. In contrast, there was no trend toward age- and gender-dependency of the risk for cardiac events in the patients with LQT3. The lethality of cardiac events was similarly high in both males and females

Fig. 2 Kaplan–Meier estimates of the cumulative probability of aborted cardiac arrest (ACA) or sudden cardiac death (SCD) in patients with LQT1 by sex. Taken with permission from [16]

with LQT3 [25]. LQT1 patients appeared to be the youngest at the time of first clinical manifestation of the disease (86 % of them become symptomatic before the age of 20, with majority of the events triggered by exercise), whereas 50 % of LQT2 and LQT3 patients remained asymptomatic at the age of 16 years [15].

4 Management In general, the treatment of LQTS consists of lifestyle modifications, medical therapy with beta-blockers, device and surgical therapy. Consistent with the ACC/AHA/ESC guidelines [26] and a recent expert consensus statement [6],

A. Barsheshet et al.

lifestyle modifications are recommended for all patients with a diagnosis of LQTS. Beta-blockers are recommended as a Class I indication for all patients with a clinical diagnosis of LQTS and as Class IIa indication for patients with a genetic diagnosis of LQTS who have a normal QTc duration. Although there are limited data on the most effective dosage, full dosing for age and weight, if tolerated, is recommended. Abrupt discontinuation of betablockers should be avoided as this may cause exacerbation [6]. It should be also noted that there are multiple issues related to dosages and methods of LQTS-related drug administration in neonates and infants that should be further studied. Device therapy with an implantable cardioverter-defibrillator (ICD) is recommended for LQTS patients with a previous cardiac arrest or experiencing syncope and/or VT despite beta-blockers administration (class I and IIa indications, respectively). The recent expert consensus statement recommends performing left cardiac sympathetic denervation (LCSD) in high-risk patients with a diagnosis of LQTS in whom: implantable cardioverterdefibrillator (ICD) therapy is contraindicated or refused and/or beta-blockers are either not effective in preventing syncope/arrhythmias, not tolerated, not accepted or contraindicated (class I indication). LCSD can be useful in patients with a diagnosis of LQTS who experience breakthrough events while on therapy with beta-blockers/ICD (class IIa) [6]. LCSD may be also indicated for infants and small children (for whom an ICD implant represents a major problem). LCSD requires the removal of the first 4 thoracic ganglia (T1–T4 part of the sympathetic trunk). This procedure is performed by an extrapleural approach, thoracoscopy, or by opening the second left intercostal space. LCSD is associated with a major reduction in norepinephrine release at ventricular level with the absence of post-denervation supersensitivity, and no reduction in heart rate [27]. In addition, the consensus statement has added that sodium channel blockers can be useful, as add-on therapy, for LQT3 patients with a QTc [500 ms who

Fig. 3 Kaplan–Meier estimates of the cumulative probability of aborted cardiac arrest (ACA) or sudden cardiac death (SCD) in LQT2 patients by gender. Taken with permission from [17]

shorten their QTc by [40 ms following an acute oral sodium channel blocker test (class IIa indication) [6]. The fact that patients with certain genotypes are more likely to experience their events under well-defined circumstances may provide insights into preventive measures [28]. Patients with LQT1 have most of their events during exercise. Therefore, they should avoid strenuous exercise activity, particularly swimming, without supervision and those at intermediate or high risk should not engage into competitive sports [6, 11, 29]. Patients with LQT2 should be advised to stay away from unexpected auditory stimuli, as their cardiac events are predominantly associated with sudden arousal [14, 15]. Removal of loud noise stimuli at home and work such as elimination of alarm clocks, door bells and telephone ringing is usually recommended. LQT3 patients mainly experience events during sleep and at rest; they should be considered for a special intercom system in the bedroom [30]. Young patients with LQT3 should not sleep alone. All patients with LQTS should avoid drugs known to prolong QT interval, or decrease potassium and magnesium level. It is important to identify and correct electrolyte abnormalities that may occur during diarrhea, vomiting, metabolic conditions, or imbalanced diets for weight loss [6].

5 Beta-Blockers Beta-blocker therapy is the mainstay treatment of patients with LQTS. The efficacy of this therapy in LQTS has been demonstrated in multiple studies. Moss et al. [31] have reported the efficacy of beta-blockers in 869 LQTS patients. Beta-blocker therapy was associated with a significant reduction in the rate of cardiac events in probands (0.97 ± 1.42 to 0.31 ± 0.86 events per year, p \ 0.001) and in affected family members (0.26 ± 0.84 to 0.15 ± 0.69 events per year, p \ 0.001) during 5-year matched periods (after versus before starting beta-blocker therapy). It should be noted, however, that patients who had symptoms before starting beta-blockers had 5.8-fold increased risk for recurrent cardiac events during betablocker therapy compared with asymptomatic patients. Furthermore, 14 % of patients with history of ACA prior to beta-blockers therapy had another aborted or fatal cardiac arrest within 5 years on beta-blockers, demonstrating that cardiac events may continue to occur while patients are on prescribed beta-blockers, particularly in those who are symptomatic before starting beta-blockers. In another study among 549 LQT1 and 422 LQT2 patients from the International LQTS Registry, we have found that beta-blocker therapy was associated with a prominent risk-reduction in high-risk patients, including a 67 % reduction (p = 0.02) in LQT1 males and a 71 % reduction (p \ 0.001) in LQT2

Congenital Long QT Syndromes

females [32]. The high efficacy rate of beta-blockers in reducing the risk for cardiac events is maintained as long as patients are compliant with their medications and avoid QT-prolonging medications [33, 34]. The response to beta-blocker therapy may depend on the trigger of cardiac event, the genotype, and mutation location [35]. LQT1 patients experience most of their cardiac events during exercise at the time of sympathetic hyperactivity, as they are not able to effectively shorten the QT interval during tachycardia [15]. Experimental data have confirmed that malfunction of IKs channels alone does not induce torsades de pointes (TdP) but that the presence of high catecholamine state predisposes the myocardium to augmentation of transmural dispersion of repolarization setting up the stage for TdP [36]. Therefore, antiadrenergic therapy is expected to be an effective modality in this group of patients. Beta-blocker therapy was associated with a 78 % (p \ 0.001) or a 71 % (p = 0.01) reduction in the risk for exercise-triggered cardiac events in LQT1 and LQT2 patients, respectively, but did not have a significant effect on events associated with arousal or sleep/rest in both LQT1 and LQT2 patients [13, 14]. Priori et al. [24] have analyzed the efficacy of betablockers in the 3 most common LQTS genotypes (LQT13). In this study, comprising 335 LQTS patients treated with beta-blockers for an average of 5 years, LQT1 patients experienced the lowest rate of cardiac events, including unexplained syncope, VT, ACA, and SCD (10 vs. 23 vs. 32 % for LQT1, LQT2 and LQT3 patients, respectively; p = 0.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk 2.81; p = 0.001) and LQT3 (adjusted relative risk, 4.00; p \ 0.001) patients than among LQT1 patients, suggesting inadequate protection from beta-blocker therapy in LQT2 and LQT3. Nevertheless, preliminary data from the International LQT3 group has shown that beta-blockers are also effective in preventing cardiac events among LQT3 patients. It should be noted, though, that the slower heart rates may be arrhythmogenic in LQT2 and LQT3 patients, and their arrhythmias are usually pause dependent [37]. Therefore, cardiac pacing in addition to beta-blockers may be advised for better protection in selected patients with LQT2/LQT3 [38]. The protective effects of beta-blockers among LQTS patients may also depend on mutation location. We have shown among 860 patients with genetically confirmed LQT1 that beta-blocker therapy was associated with a significant 88 % reduction in the risk of life-threatening cardiac events among LQT1 carriers of the cytoplasmic loops (C-loop) missense mutations (p = 0.02), whereas among LQT1 carriers of non-C-loop missense mutations there was no significant reduction in the risk for life threatening cardiac events (HR 0.82, p = 0.68) [21]. It is

known that the C-loops play an important role in the sympathetic regulation of the KCNQ1 channel [39]. Cellular expression studies have suggested that there is a combination of decrease in basal function and altered adrenergic regulation of the IKs channel in patients with C-loops missense mutations that may provide a potential explanation why beta-blockers are particularly effective in patients with this type of mutation [21]. The benefit associated with the various beta-blocker subtypes in the management of LQTS may not be equal. We have analyzed the efficacy of different beta-blockers among 971 LQT1 and LQT2 patients from the International LQTS Registry [32] and found out that among LQT1 patients atenolol treatment was associated with a pronounced reduction in cardiac events (HR = 0.23, p = 0.008), whereas nadolol, propranolol and metoprolol were not associated with a statistically significant reduction in the risk of cardiac events. It should be noted that the effects of atenolol in LQTS patients are controversial; Chatrath et al. [40] have previously suggested that among several factors, treatment with atenolol and noncompliance may be important factors underlying beta-blocker therapy failures. In LQT2 patients, nadolol was associated with a pronounced reduction in cardiac events (HR = 0.13, p = 0.01), whereas atenolol, propranolol and metoprolol were not associated with a statistically significant reduction in cardiac events [32]. (Table 1) In a recent multicenter retrospective analysis of 382 subjects with LQT1 and LQT2, Chockalingham et al. [41] have compared the effects of three most commonly used beta blockers—propranolol, nadolol and metoprolol. The primary endpoint included syncope, near drowning, seizures, or aborted cardiac arrest. The authors found that QTc shortening was more pronounced among patients treated with propranolol compared with nadolol or metoprolol. Importantly, they found that metoprolol was the least effective medication Table 1 Risk-reduction by beta-blocker type in LQT1 and LQT2 patients High-risk group

LQT1 patients

LQT2 patients

HR

95 % CI

p value

HR

95 % CI

p value

0.45

0.26–0.80

0.006

0.42

0.23–0.76

0.004

Atenolol

0.23

0.08–0.67

0.008

0.69

0.32–1.49

0.34

Nadolol

0.40

0.14–1.16

0.09

0.13

0.03–0.62

0.01

Propranolol

0.60

0.27–1.34

0.21

0.49

0.21–1.16

0.10

Metoprolol

0.65

0.32–1.44

0.27

0.64

0.08–5.17

0.67

Any type of b-blocker By beta-blocker subtype

Models were carried out separately for 549 LQT1 and 422 LQT2 patients, events were assessed from birth through age 40 years; all models were adjusted for genotype, gender, baseline QTc (dichotomized at C500 ms) and ICD implantation The results of this study should be interpreted with caution, as there was no significant interaction between the benefits among the beta-blocker subtypes. There is insufficient data to conclude that there is a need to switch from one beta-blocker subtype to another. Taken with permission from [32]

A. Barsheshet et al.

among the 3 groups of beta-blockers. The risk of cardiac events was 3.9-fold greater when patients were treated with metoprolol compared with propranolol or nadolol (p = 0.025). Thus, both studies [32, 41] may suggest that metoprolol is the least effective beta-blocker among LQT1 and LQT2 patients. The results of these studies should be interpreted with caution, as there was no significant interaction between the benefits among the beta-blocker subtypes. In addition, these analyses are limited by possible differences in the dose-related effects of beta-blockers in patients. There is insufficient data to conclude that there is a need to switch from one beta-blocker subtype to another.

6 Medical Treatment of Patients with Both LQTS and Asthma Management of patients with LQTS and asthma is challenging because beta2-agonist therapy may potentially trigger ventricular tachyarrhythmias in LQTS and betablockers may potentially exacerbate asthma. Thottathil et al. [42] analyzed the risk associated with beta2-agonist inhaled therapy for asthma and the influence of betablockers on outcome in patients with LQTS. Among 3,287 affected patients with LQTS from the International LQTS registry, 101 patients (3.1 %) utilized beta2-agonist therapy. Beta2-agonist therapy for asthma was associated with a two fold increased risk for cardiac events (p = 0.003) after adjustment for clinical and ECG covariates. This risk was most pronounced within the first year after the initiation of beta2-agonist therapy (HR = 3.53, p = 0.006). The combined use of beta2-agonist therapy and steroids was associated with a 3.7-fold risk for cardiac events (p \ 0.01). In contrast, beta-blocker therapy was associated with a reduction in cardiac events in those using beta2 agonists (HR = 0.14, p = 0.05) and was usually well tolerated in majority of patients with history of asthma. An alternative option is to perform LCSD to patients who cannot tolerate beta-blockers [43].

7 Potassium Supplementation Potassium supplementation and spironolactone were proposed for patients with LQT2 who exhibit mutation of the hERG (or KCNH2) gene encoding for the cardiac rapidly activating delayed rectifier potassium current channel. hERG function is highly dependent on the extracellular potassium. It has been suggested that potassium administration will increase serum potassium level and improve repolarization abnormalities. Although the exact mechanism of potassium effect on hERG channel is unknown, it was suggested that the increase in extracellular potassium

level may enhance the inward rectifier potassium current and/or reduce the rate of inactivation of the voltage dependent hERG channel, resulting in increase in channel availability [44–47]. Two small studies have shown that potassium supplements and spironolactone are associated with a significant shortening of the QTc [47, 48]. Etheridge et al. [47] have shown among eight subjects with six distinct hERG mutations that a mean increase of 1.2 meq/L in serum potassium level results in QTc interval shortening from a mean ± SD of 526 ± 94 to 423 ± 36 ms (p = 0.003), as well as significant improvement in both QT dispersion and T-wave morphology abnormalities. Unfortunately, there are no data that potassium supplements or spironolactone can decrease the risk of cardiac events. One unpublished randomized trial investigating the combined effect of potassium supplementation and spironolactone on the risk of cardiac events was stopped prematurely due to safety concerns including higher rates of hyperkalemia.

8 Sex-Hormonal Therapy Sex hormones are known to play a significant role in the risk of cardiac events in patients with LQTS. LQT1 males have a higher risk for cardiac events than females during childhood (age group 0–13 years), whereas LQT2 females have a higher risk compared with males from birth through the age of 40 years [49]. Progesterone was shown to shorten the action potential duration and provide protection against rhythm disturbances through modulation of the slowly activating delayed rectifier potassium currents and L-type calcium currents [50, 51]. In contrast, estrogen can lead to prolongation of the action potential due to a decrease in the rapidly activating delayed rectifier potassium currents and an increase in L-type calcium currents [52, 53]. It has been also observed, that postmenopausal women treated with hormone therapy developed a significant QTc prolongation with unopposed estrogen therapy compared with no effect on QTc duration with combined estrogen-progesterone therapy [54]. Testosterone has been shown to shorten the cardiac action potential duration and ventricular repolarization via modulation of the rapidly acting potassium channel. These hormonal relationships provide a possible explanation for the increased risk of cardiac events among LQT2 women mainly after the onset of adolescence, particularly in the postpartum period and after the onset of menopause [18, 25, 55]. Recently, Odening et al. [51] have investigated whether sex hormones influence the arrhythmogenic risk in a transgenic LQT2 rabbit model. It has been revealed that estradiol promotes sudden cardiac death, whereas progesterone is protective in LQT2 rabbit model. These data may suggest a

Congenital Long QT Syndromes

possible role for sex hormones (particularly progesterone) in the management of LQT2 patients.

9 Sodium Channel Blockers Over the last decade, sodium channel blockers such as mexilitine and flecainide have been investigated as a potential treatment option for patients with LQT3 [56– 61]. Mexilitine blocks the rapid inward sodium current responsible for phase 0 of cardiac action potential. Under normal conditions, the open state is very brief, which precludes significant interaction of the channel with the drug. However, in the mutant sodium channel the gating is affected which permits abnormal repetitive reopening leading to a sustained ‘‘late’’ inward current and prolonged cardiac action potential. Dumaine et al. [56] and Wang et al. [57] have demonstrated that mexilitine selectively suppresses the defective late current as compared with the peak sodium current. Clinically, mexilitine appeared to significantly shorten QT interval among LQT3 patients (QTc from 535 ± 32 to 445 ± 31 ms, p \ 0.005) but not among LQT2 patients (QTc from 530 ± 79 to 503 ± 60 ms, p = NS) [58]. Ruan et al. [59] have shown that the response to mexilitine among LQT3 patients is mutation specific, suggesting that there is a need to examine whether mexiletine can be effective for a specific patient and chronic therapy should be started [6]. Similar to mexilitine, flecainide was also shown to shorten the QT interval in LQT3 patients [60, 62–65] In LQT3, flecainide binds to activated mutant sodium channel [65] preferentially blocking the ‘‘late’’ component of sodium current flowing after the peak current that influences the action potential duration of the mutant channel where this late component is increased [60]. Consistent with in vitro studies, Moss et al. [63] have demonstrated that chronic low dose flecainide significantly shortened QTc interval in LQT3 patients with DKPQ mutation (average reduction in QTc of -27.1 ms; p \ 0.001). No major adverse drug effects were observed during this trial. Benhorin et al. [61] have found among LQT-3—affected patients who are carriers of the D1790G mutation similar effects of flecainide, which has significantly shortened QTc in LQT3 patients (n = 8) but not in control subjects (n = 5) and normalized the dispersion of repolarization in most mutation carriers. These effects among carriers were maintained during long-term (9–17 months) flecainide therapy with no adverse effects. Priori et al. [66] have shown that intravenous Flecainide significantly shortens QTc in LQT3 patients, but among 6 out of 13 patients, flecainide induced ST segment elevation in leads V1 through V3 with a Brugada like ECG pattern,

raising concerns about the safety of flecainide therapy in LQT3 patients. In addition, it should be noted that Flecianide (unlike mexiletine) also blocks the IKr current [67] and that for this reason it is not used routinely in LQT3 patients.

10 Ranolazine Ranolazine is an anti-anginal and anti-ischemic agent, possibly increasing myocardial glucose oxidation, decreasing fatty acid oxidation, reducing lactate production thus leading to a greater amount of ATP formed per O2 consumed [68, 69]. Ranolazine, may also have beneficial effects in LQT3 patients. It possesses complex electrophysiologic properties including inhibition of the late inward sodium current, inhibition of the rapidly activating delayed rectifying potassium channel (IKr) and inhibition of the L-type calcium channels [70]. The net physiological effect of such inhibition includes a modest prolongation of the cardiac action potential and QTc interval. Interestingly, the ranolazine-induced increase in the action potential duration was associated with decrease in early afterdepolarizations, triggered activity and spatial dispersion of repolarization, manifested clinically as suppression of the incidence of torsades de pointes [71– 73]. The electrophysiologic characteristics of ranolazine suggest that the drug may be valuable in patients with LQT3. It has been found that ranolazine displays high affinity for use-dependent block in sustained sodium current over peak sodium current in mutant LQT3 sodium channels leading to a reduction in cardiac action potential duration [74, 75]. Moss et al. [76] have assessed the effect of ranolazine on ventricular repolarization and myocardial relaxation in five patients with LQT3 (DKPQ mutation) and found that at therapeutic concentrations ranolazine shortened the QTc interval by 26 ± 3 ms (p \ 0.001). Table 2 summarizes current data on pharmacological treatment options for the three most prevalent variants of LQTS.

11 Nicorandil Nicorandil is a vasodilator drug used to treat angina pectoris. It is a potassium channel opener, which activates protein kinase G indirectly, opening K?ATP channels, leading to potassium efflux from the myocytes. It has been shown [77] that intravenous administration of nicorandil reduces epinephrine-induced prolongation of QT interval as well as suppresses early afterdepolarizations in LQT1. Experimental data using right ventricular wedge preparations has revealed that high concentrations

A. Barsheshet et al. Table 2 Summary of current data on pharmacological treatment options for the three most prevalent variants of LQTS Pharmacological treatment

LQT1

LQT2

LQT3

Beta-blockers

Reduce the risk for cardiac events [21, 24, 32]

Reduce the risk for cardiac events [32]

Less effective clinically than in LQT1 [24]

Metoprolol \ other beta-blockers [32, 41]

Preliminary data from the International LQT3 group has shown that beta-blockers reduce the risk for cardiac events in LQT3

Metoprolol \ other beta-blockers [32, 41] Sodium channel blockers (mexiletine, flecainide)

–

–

Associated with a significant shortening of the QTc interval in specific mutations [56–65]

Potassium supplementation and spironolactone

–

Associated with a significant shortening of the QTc interval in small studies [47, 48]

–

Safety issues—hyperkalemia

of nicorandil might reduce transmural dispersion of repolarization preventing torsades de pointes in LQT1 and LQT2 models but not in LQT3 [77]. Similarly, nicorandil administration was associated with a reduction of ventricular effective refractoriness in vivo as well as a reduction of action potential duration ex vivo in transgenic LQT1 rabbits [78].

12 Summary For the past two decades there have been significant advancements in understanding the relationship between the genetic background, molecular mechanisms and clinical course of LQTS. It has been recognized that there is an association between the LQTS genotype, LQTS mutation location and function, electrocardiographic features, triggers for cardiac events, risk for cardiac events and response to medical therapy. Thus, understanding of the genotypephenotype relationship can lead to improved management of LQTS. However, to date, there has not been a breakthrough in the development of genotype-specific or mutation-specific pharmacological treatments. This task is very challenging because of the presence of a significant genetic heterogeneity in LQTS having several types of mutations in multiple genes; there are complex genotype-phenotype correlations, and the need for advanced translational research studies and randomized controlled clinical trials to investigate the efficacy and safety of the pharmacological treatment options. Conflicts of interests A. Barsheshet, O. Dotsenko and I. Goldenberg report no conflict of interest relevant to this article. No sources of funding were used to support the writing of the manuscript.

References 1. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120(18):1761–7. 2. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99(4): 529–33. 3. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–74. 4. Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. 2011;57(1):51–9. 5. Goldenberg I, Moss AJ, Zareba W. QT interval: how to measure it and what is ‘‘normal’’. J Cardiovasc Electrophysiol. 2006;17(3): 333–6. 6. Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. HRS/EHRA/APHRS Expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes expert consensus statement on inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10(12):1932–63. 7. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993;88(2):782–4. 8. Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5(4):868–77. 9. Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AA. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol. 2013;62(3):169–80. 10. Shryock JC, Song Y, Rajamani S, Antzelevitch C, Belardinelli L. The arrhythmogenic consequences of increasing late INa in the cardiomyocyte. Cardiovasc Res. 2013;99(4):600–11. 11. Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc. 1999;74(11):1088–94. 12. Moss AJ, Robinson JL, Gessman L, Gillespie R, Zareba W, Schwartz PJ, et al. Comparison of clinical and genetic variables

Congenital Long QT Syndromes

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol. 1999;84(8):876–9. Goldenberg I, Thottathil P, Lopes CM, Moss AJ, McNitt S, OU J, et al. Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome. Heart Rhythm. 2012;9(1):49–56. Kim JA, Lopes CM, Moss AJ, McNitt S, Barsheshet A, Robinson JL, et al. Trigger-specific risk factors and response to therapy in long QT syndrome type 2. Heart Rhythm. 2010;7(12):1797–805. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103(1):89–95. Costa J, Lopes CM, Barsheshet A, Moss AJ, Migdalovich D, Ouellet G, et al. Combined assessment of sex- and mutationspecific information for risk stratification in type 1 long QT syndrome. Heart Rhythm. 2012;9(6):892–8. Migdalovich D, Moss AJ, Lopes CM, Costa J, Ouellet G, Barsheshet A, et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm. 2011;8(10):1537–43. Seth R, Moss AJ, McNitt S, Zareba W, Andrews ML, Qi M, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007;49(10):1092–8. Barsheshet A, Peterson DR, Moss AJ, Schwartz PJ, Kaufman ES, McNitt S, et al. Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome. Heart Rhythm. 2011;8(8):1207–13. Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, et al. Risk factors for recurrent syncope and subsequent fatal or nearfatal events in children and adolescents with long QT syndrome. J Am Coll Cardiol. 2011;57(8):941–50. Barsheshet A, Goldenberg I, OU J, Moss AJ, Jons C, Shimizu W, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutationspecific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation. 2012;125(16):1988–96. Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009;54(22):2052–62. Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115(19):2481–9. Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004;292(11):1341–4. Zareba W, Moss AJ, Locati EH, Lehmann MH, Peterson DR, Hall WJ, et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003;42(1):103–9. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/ American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48(5):e247–346. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J. 2013;34(40):3109–16.

28. Schwartz PJ, Crotti L. Long QT and short QT syndromes. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. 5th ed. Philadelphia: Elsevier; 2009. p. 731–44. 29. Maron BJ, Chaitman BR, Ackerman MJ, Bayes de Luna A, Corrado D, Crosson JE, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004;109(22):2807–16. 30. Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. J Intern Med. 2006;259(1):39–47. 31. Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000;101(6):616–23. 32. Goldenberg I, Bradley J, Moss A, McNitt S, Polonsky S, Robinson JL, et al. Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: implications for patient management. J Cardiovasc Electrophysiol. 2010;21(8):893–901. 33. Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C, et al. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment ‘‘failures’’. Circulation. 2009;119(2):215–21. 34. Viskin S, Halkin A. Treating the long-QT syndrome in the era of implantable defibrillators. Circulation. 2009;119(2):204–6. 35. Ruan Y, Liu N, Napolitano C, Priori SG. Therapeutic strategies for long-QT syndrome: does the molecular substrate matter? Circ Arrhythm Electrophysiol. 2008;1(4):290–7. 36. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of betaadrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation. 1998;98(21):2314–22. 37. Tan HL, Bardai A, Shimizu W, Moss AJ, Schulze-Bahr E, Noda T, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation. 2006;114(20):2096–103. 38. Viskin S. Cardiac pacing in the long QT syndrome: review of available data and practical recommendations. J Cardiovasc Electrophysiol. 2000;11(5):593–600. 39. Matavel A, Medei E, Lopes CM. PKA and PKC partially rescue long QT type 1 phenotype by restoring channel-PIP(2) interactions. Channels (Austin). 2010;4(1):3–11. 40. Chatrath R, Bell CM, Ackerman MJ. Beta-blocker therapy failures in symptomatic probands with genotyped long-QT syndrome. Pediatr Cardiol. 2004;25(5):459–65. 41. Chockalingam P, Crotti L, Girardengo G, Johnson JN, Harris KM, van der Heijden JF, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol. 2012;60(20):2092–9. 42. Thottathil P, Acharya J, Moss AJ, Jons C, McNitt S, Goldenberg I, et al. Risk of cardiac events in patients with asthma and longQT syndrome treated with beta(2) agonists. Am J Cardiol. 2008;102(7):871–4. 43. Schwartz PJ, Priori SG, Cerrone M, Spazzolini C, Odero A, Napolitano C, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004;109(15):1826–33. 44. Numaguchi H, Johnson JP Jr, Petersen CI, Balser JR. A sensitive mechanism for cation modulation of potassium current. Nat Neurosci. 2000;3(5):429–30. 45. Sakmann B, Trube G. Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea-pig heart. J Physiol. 1984;347:641–57. 46. Wang S, Morales MJ, Liu S, Strauss HC, Rasmusson RL. Time, voltage and ionic concentration dependence of rectification of h-erg expressed in Xenopus oocytes. FEBS Lett. 1996;389(2):167–73.

A. Barsheshet et al. 47. Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol. 2003;42(10):1777–82. 48. Compton SJ, Lux RL, Ramsey MR, Strelich KR, Sanguinetti MC, Green LS, et al. Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation. 1996;94(5):1018–22. 49. Goldenberg I, Zareba W, Moss AJ. Long QT Syndrome. Curr Probl Cardiol. 2008;33(11):629–94. 50. Nakamura H, Kurokawa J, Bai CX, Asada K, Xu J, Oren RV, et al. Progesterone regulates cardiac repolarization through a nongenomic pathway: an in vitro patch-clamp and computational modeling study. Circulation. 2007;116(25):2913–22. 51. Odening KE, Choi BR, Liu GX, Hartmann K, Ziv O, Chaves L, et al. Estradiol promotes sudden cardiac death in transgenic long QT type 2 rabbits while progesterone is protective. Heart Rhythm. 2012;9(5):823–32. 52. Kurokawa J, Tamagawa M, Harada N, Honda S, Bai CX, Nakaya H, et al. Acute effects of oestrogen on the guinea pig and human IKr channels and drug-induced prolongation of cardiac repolarization. J Physiol. 2008;586(Pt 12):2961–73. 53. Sims C, Reisenweber S, Viswanathan PC, Choi BR, Walker WH, Salama G. Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2. Circ Res. 2008;102(9):e86–100. 54. Kadish AH, Greenland P, Limacher MC, Frishman WH, Daugherty SA, Schwartz JB. Estrogen and progestin use and the QT interval in postmenopausal women. Ann Noninvasive Electrocardiol. 2004;9(4):366–74. 55. Buber J, Mathew J, Moss AJ, Hall WJ, Barsheshet A, McNitt S, et al. Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2. Circulation. 2011;123(24):2784–91. 56. Dumaine R, Wang Q, Keating MT, Hartmann HA, Schwartz PJ, Brown AM, et al. Multiple mechanisms of Na? channel–linked long-QT syndrome. Circ Res. 1996;78(5):916–24. 57. Wang DW, Yazawa K, Makita N, George AL Jr, Bennett PB. Pharmacological targeting of long QT mutant sodium channels. J Clin Invest. 1997;99(7):1714–20. 58. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na? channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation. 1995;92(12):3381–6. 59. Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation. 2007;116(10): 1137–44. 60. Nagatomo T, January CT, Makielski JC. Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I(C) antiarrhythmic flecainide. Mol Pharmacol. 2000;57(1):101–7. 61. Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation. 2000;101(14):1698–706. 62. Windle JR, Geletka RC, Moss AJ, Zareba W, Atkins DL. Normalization of ventricular repolarization with flecainide in long QT syndrome patients with SCN5A:DeltaKPQ mutation. Ann Noninvasive Electrocardiol. 2001;6(2):153–8. 63. Moss AJ, Windle JR, Hall WJ, Zareba W, Robinson JL, McNitt S, et al. Safety and efficacy of flecainide in subjects with long QT-3 syndrome (DeltaKPQ mutation): a randomized, doubleblind, placebo-controlled clinical trial. Ann Noninvasive Electrocardiol. 2005;10(4 Suppl):59–66.

64. Stokoe KS, Balasubramaniam R, Goddard CA, Colledge WH, Grace AA, Huang CL. Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a ± murine hearts modelling the Brugada syndrome. J Physiol. 2007;581(Pt 1):255–75. 65. Anno T, Hondeghem LM. Interactions of flecainide with guinea pig cardiac sodium channels. Importance of activation unblocking to the voltage dependence of recovery. Circ Res. 1990;66(3): 789–803. 66. Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000;102(9):945–7. 67. Wang DW, Kiyosue T, Sato T, Arita M. Comparison of the effects of class I anti-arrhythmic drugs, cibenzoline, mexiletine and flecainide, on the delayed rectifier K? current of guinea-pig ventricular myocytes. J Mol Cell Cardiol. 1996;28(5):893–903. 68. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43(8):1375–82. 69. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291(3):309–16. 70. Schram G, Zhang L, Derakhchan K, Ehrlich JR, Belardinelli L, Nattel S. Ranolazine: ion-channel-blocking actions and in vivo electrophysiological effects. Br J Pharmacol. 2004;142(8): 1300–8. 71. Antzelevitch C, Belardinelli L, Zygmunt AC, Burashnikov A, Di Diego JM, Fish JM, et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation. 2004;110(8):904–10. 72. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLINTIMI 36) randomized controlled trial. Circulation. 2007;116(15): 1647–52. 73. Wu L, Shryock JC, Song Y, Li Y, Antzelevitch C, Belardinelli L. Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome. J Pharmacol Exp Ther. 2004; 310(2):599–605. 74. Fredj S, Sampson KJ, Liu H, Kass RS. Molecular basis of ranolazine block of LQT-3 mutant sodium channels: evidence for site of action. Br J Pharmacol. 2006;148(1):16–24. 75. Moreno JD, Yang PC, Bankston JR, Grandi E, Bers DM, Kass RS, et al. Ranolazine for congenital and acquired late INa-linked arrhythmias: in silico pharmacological screening. Circ Res. 2013;113(7):e50–61. 76. Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol. 2008;19(12):1289–93. 77. Shimizu W, Aiba T, Antzelevitch C. Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome. Curr Pharm Des. 2005;11(12):1561–72. 78. Biermann J, Wu K, Odening KE, Asbach S, Koren G, Peng X, et al. Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with long-QT syndrome 1 both in vitro and in vivo. Eur J Pharmacol. 2011;650(1):309–16.