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Primary Arrhythmogenic Cardiomyopathies. Channelopathies  

Long QT syndrome (LQTS) is a group of disorders of cardiac repolarization characterized by an excessive and heterogeneous prolongation of the ventricular AP and of the corrected QT interval (QTc) of the surface (QTc Bazzet >440 ms in men, >460 ms in females) that predisposes affected subjects to syncope, seizures and polymorphic VT and/or VF and increases the risk of SCD (Goldenberg and Moss, 2008). It usually affects children and young adults apparently healthy, the average age of onset of symptoms (syncope or SCD) being 12 years of age or even earlier in the most serious forms of LQTS (Goldberg y Moss, 2008; Priori et al., 2003). Syncope and seizures associated with LQTS are caused by a specific polymorphic VT called torsade de pointes (“twisting of the points”) characterized by sinusoidal twisting of the QRS axis around the isoelectric line of an ECG tracing. Although the torsade de pointes are self-limited, sometimes they can degenerate into VF and SCD.

There are two forms of inherited LQTS. The LQTS is transmitted most often in families as an autosomal dominant trait (Romano-Ward syndrome) and less commonly as an autosomal recessive disease combined with congenital deafness (Jervell and Lange-Nielsen syndrome).

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1. Prevalence

The incidence of congenital LQTS has not been accurately defined, but it has been estimated that as many as 1 in 2,000-5,000 people worldwide are affected and a mortality rate of 21% for symptomatic patients not receiving therapy within one year from the first syncope event (Schwartz et al., 2012). However, given that up to 2/3 of patients are probably missed and that 10% to 35% have a normal corrected QT (QTc) interval it is likely that the actual prevalence is much higher. The Jervell-Lange Nielsen appears in 1.6-6 per million births (Schwartz et al., 2006).

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2. Electrofisiological basis

The main feature of the LQTS is the marked non-uniform prolongation of the ventricular APD and of the corrected QT interval (QTc) of the ECG resulting from an increase in the inward-depolarizing Na+ and Ca2+ currents and/or a decrease in outward-repolarizing K+ currents. The prolongation of the APD increases the dispersion in the recovery of ventricular excitability and facilitates the occurrence of early afterdepolarizations during the phase 2 and the beginning of phase 3. The early afterpotentials occurring during the proloned plateau of the AP would result from the activation of the INaL, the reactivation-reopening of the L-type Ca2+ channels or the activation of the current generated by the Na+-Ca2+ exchanger (INCX). The onset of early afterdepolarizations in the presence of an increased dispersion of refractoriness among the various ventricular regions can alter the pattern ventricular conduction, causing unidirectional block and slow conduction, conditions that may facilitate ventricular reentry.

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3. Genetic basis

1. Romano-Ward syndrome. At present, 15 different variants of the Romano-Ward syndrome have been published resulting from mutations in genes coding for cardiac proteins including ion channels, accessory subunits, and associated modulator proteins, responsible for orchestrating the cardiac AP. The first three LQTS genes identified were: KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) encoding for the proteins that conducts IKs, IKr and INa, respectively. Mutations in KCNQ1 and KCNH2 cause a decrease in the corresponding K+ current, while mutations in the SCN5A gene cause a gain-of-function phenotype leading to a prolongation of the ventricular AP repolarization and of the QTc interval (Curran et al., 1995; Goldenberg and Moss, 2008). Mutations in the 3 major LQTS-susceptibility genes (KCNQ1, KCNH2 and SCN5A) account for approximately 60–75% of congenital LQTS cases with a strong clinical phenotype, while the 15 other minor genes contribute approximately an additional 5% (Tester et al., 2006). The frequency of clinical events prior to initiation of beta-blocker therapy from birth to 40 years of age is significantly higher in LQT2 (46%) and LQT3 (42%) patients relative to those with LQT1 (30%) (Priori et al., 2003), but events in LQT3 are more likely to be lethal (Zareba et al., 1998).

Table. Genetic loci and genes associated with the long QT Syndrome

Syndrome

Locus

Gene

Gene product

Current

Function

Romano-Ward (autosomal dominant)

LQT1 (30-35%)

11p15.5

KCNQ1

Kv 7.1 α subunit

IKs

(-)

LQT2 (25-30%)

7q35-q36

KCNH2

HERG/Kv11.1 α subunit

IKr

(-)

LQT3 (5-10%)

3p21

SCN5A

Nav1.5 α subunit

INaL

(+)

LQT4 (<1%)

4q25-q27

ANK2

Anquirina 2

INCX, INa,K

(-)

LQT5 (<1%)

21q22.1-q24.2

KCNE1

β subunit (MinK)

IKs

(-)

LQT6 (<1%)

21q22.1-q22.2

KCNE2

β subunit (MiRP1)

IKr

(-)

LQT7 (AT) (<1%)

17q23.1-q24.2

KCNJ2

Kir 2.1 α subunit

IK1

(-)

LQT8 (TS)

12p13.3

CACNA1C

Cav1.2 α subunit

ICa, L

(+)

LQT9

3p24

Cav3

Caveolin-3

INaL

(+)

LQT10

11q23.3

SCN4B

Nav 1.5 ⓸ subunit

INaL

(+)

LQT11

7q21-q22

AKAP9 (Yotiao)

A-kinase anchoring protein

IKs

(-)

LQT12

20q11.2

SNTA1

α1-syntrophin

INaL

(+)

LQT13

11q23.3-24.3

KCNJ5

Kir4.3 α/GIRK4

IKACh

(-)

LQT14 (<1%)

14q32 CALM1 Calmodulin Altered Ca2+ signaling  
LQT15 (<1%) 2p21 CALM2 Calmodulin IKs  

Jervell-Lange-Nielsen (autosomal recessive)

JLN1 (80%)

11p15.5

KCNQ1

Kv 7.1 α subunit

IKs

(-)

JLN2 (20%)

21q22.1-q22.2

KCNE2

β subunit (MinK β)

IKr

(-)

(+): Gain-of-function. (-): loss-of-function.
AT: Andersen-Tawil syndrome. INCX: Na+-Ca2+ exchanger current. TS: Timothy syndrome.

Na+ channel-linked mutations result in a gain-of-function from at least four distinct mechanisms.

1) Most of these mutations are missense mutations that disrupt the fast inactivation n, leading to bursting activity, which underlies the late Na+ current (INaL) over the plateau voltage range (Bennet et al., 1995). This increase in Na+ entry prolongs the plateau phase and produces a delayed repolarization that facilitates the induction of early afterdepolarizations that trigger the torsade de pointes (Yan et al., 2001). These mutations are localized in the a subunit regions implicated in the fast inactivation (i.e., S4 in DIV, DIII - DIV linker and cytoplasmic loops between S4 and S5 in DIII and DIV) or that stabilize the fast inactivation (C- terminal) (Tester et al., 2005, Zimmer and Surber, 2008). A general slowing of inactivation can be present in mutations associated with severe LQTS.

2) Less commonly the mutations facilitate the reopening of the channel (the so called"window current") over voltage ranges for which steady-state inactivation and activation overlap. The INa increases when the inactivation of mutant channels occurs at more depolarized levels, while activation is unchanged, increasing the voltage range at which the channel can be reactivated and generate the INa (Wang et al., 1996).

These two mechanisms exert their effects during phases 2 and 3 of the AP, where normally no (<1%) Na+ current is present. The delay in the repolarization process triggers early afterdepolarizations, especially in Purkinje and M cells, which present longer APD and induce torsades de pointes (Yan et al., 2001).

3) Mutations can induce a faster recovery from inactivation, leading to larger peak INa by increasing the fraction of channels available for activation during subsequent depolarizations (Amin et al., 2010).

4) Mutations can increase in the expresion of the a subunits in the cell membrane and, therefore, peak INa. This can result from an increased expression of mutant a subunits through enhanced mRNA translation or protein trafficking to the sarcolemma, decreased protein degradation, or altered modulation by β -subunits and regulatory proteins (Amin et al., 2010).

Mutations occurring in the K+ channels can cause a loss of function and a decrease in outward K+ currents secondary because:
1)
mutant and wild-type protein subunits may coassemble and exert a dominant negative effect on the current
2) some mutant subunits may not coassemble with the wild-type peptides, resulting in a loss of function that reduces by = 50% (haploinsufficiency)
3) mutations interfere with intracellular subunits trafficking, preventing the mutated peptides from reaching the cell membrane
4) changes in the opening-closing (gating) of the channel, and 5) changes in channel response to sympathetic stimulation and/or in ion channel nitrosylation (Sanguinetti, 2010).

Zhou et al (1998) described that some HERG mutations (Y611H and V822M) caused defects in biosynthetic processing of HERG channels with the protein retained in the endoplasmic reticulum (ER). ER-retained subunits are then rapidly degraded by the ubiquitin–proteasome pathway. Other mutations (I593R and G628S) were processed similarly to wild type HERG protein, but these mutations did not produce functional channels, while the T474I mutation expressed HERG current but with altered gating properties. At the present time, it is known that defective protein folding, retention in the ER, or disrupted trafficking to the Golgi and surface membrane is the primary mechanism of loss of function caused by missense mutations in HERG (Anderson et al., 2006). Mutations that enhance inactivation (e.g., G584S) (Zhao et al., 2009) or accelerate the rate of deactivation (e.g., M124R or other mutations in the PAS domain) (Sushi et al., 2005) reduce the IKr during repolarization of the action potential. LQT2 nonsense mutations cause a decrease in mutant mRNA levels by nonsense-mediated mRNA decay rather than production of truncated proteins (Gong et al., 2007).

LQT4 is linked to loss-of-function mutations on the ANK2 gene encoding for ankyrin-B (Mohler et al., 2003,2004), a protein required for the proper localization of Na+/Ca2+ exchanger (NCX1), Na+/K+-ATPase (NKA), IP3 receptor (IP3R), and Cav1.3. The mutations cause an increase in intracellular Na+ facilitating afterdepolarizations and triggered arrhythmias under adrenergic stimulation (Ackerman and Mohler 2010). Mutations in the KCNE1 and KCNE2 genes encoding the auxiliary subunits MinK and MiRP1 are linked to LQT5 and LQT6, respectively (Abbott et al., 1999; Splawski, et al., 1997). Caveolin-3 is the main isoform expressed in the heart and coimmunoprecipitates with Nav1.5 subunits (Yarbrough et al., 2002). The LQTS9 is associated to mutations in the CAV3 gene encoding for caveolin 3 (Vatta et al., 2006), which results in a 2- to 3-fold increase in late sodium current with no changes in peak INa density and gating (Vatta et al., 2006).

The LQT10 is linked to mutations in the SCN4B gene that encodes the β4-subunit of the Na+ channel (Medeiros-Domingo et al., 2007) and LQT11 to mutations on the AKAP9 gene (Chen et al., 2007) that encodes the Yotiao protein, a scaffolding protein that control the protein kinase A pathway. Yotiao modulates the response of IKs to α-adrenergic stimulation (Marx et al., 2002). The LQT12 variant is associated with mutations in the gene SNTA1 encoding for cardiac α1-syntrophin (Ueda et al., 2008; Chen et al., 2009), a protein linking the extracellular matrix to the intracellular cytoskeleton. Mutant SNTA1 releases inhibition of associated neuronal nitric oxide synthase by the plasma membrane Ca2+-ATPase (PMCA4b), leading to an increase in peak and late INa via S-nitrosylation of the cardiac Na+ channel. The LQT13 has been identified in a Chinese family carrier of a mutation in the KNCJ5 gene, encoding for the Kir3.4 subunit of the IKACh (Yang et al., 2010). The mutant protein interferes with the formation of functional KACh channels.

A malignant form of LQTS associated to recurrent cardiac arrest due to VF in infants is associated to mutations in CALM1 and CALM2 genes encoding calmodulin (Crotti et al., 2013). Mutation carriers had recurrent cardiac arrest secondary to ventricular tachyarrhythmias, severely prolonged QTc interval (>600 ms), evidence of electrically unstable myocardium (T-wave alternans) and intermittent 2:1 AV block. Ventricular fibrillation was typically triggered by adrenergic activation, and either occurred spontaneously or was preceded by a short period of polymorphic VT that was not pause-dependent. Most carriers exhibited neurological deficits (epilepsy, neurodevelopmental delays) of variable severity that could be attributed to brain injury secondary to cardiac arrest or possibly to enhanced susceptibility to neuronal injury in the setting of circulatory insufficiency. Calmodulin serves as the Ca2+ sensor for Ca2+-dependent inactivation of L-type voltage-gated Ca2+ channels in cardiac myocytes (Peterson et al., 1999).  Defects in calmodulin function may prolong repolarization because of impaired Ca2+-dependent inactivation of L-type calcium channels or dysregulation of voltage-gated Na+ channels leading to an increased depolarizing current during the plateau phase of the cardiac action potential.. Furthermore, the voltage-gated potassium channel KCNQ1 or KV7.1 responsible for the slow component of the delayed rectifier current (IKs) requires calmodulin for activity (Shamgar et al., 2006). Thus, inhibition of calmodulin inhibits IKs and delays repolarization setting the conditions for the appearance of early afterdepolarizations and triggered arrhythmias. Inactivation of cardiac Na+ channels also involves calmodulin and disrupting this interaction might evoke sodium channel dysfunction and conduction disturbances (Potet et al., 2009).

Common variants can influence the QT interval. The NOS1AP gene that encodes nitric oxide synthase 1 adaptor protein (NOS1AP) is involved in cardiac repolarization. Variants of NOS1AP modulate the risk in LQTS and two intronic variants were associated with SCD even after controlling for QT interval (Deo et al., 2012). This association was validated to carry a 30 % increase in SCD risk in white participants, but not in African-Americans (Deo et al., 2012; George, 2009). The S1103Y variant in the SCN5A gene is common in African Americans (13 % being heterozygous) and increases the arrhythmia risk by more than 8-fold in carrier subjects (George, 2009). This variant produces an abnormal Na+ channel inactivation leading to increased susceptibility to early afterdepolarizations. In SCN5A-S1103Y homozygotes there is a 24-fold greater risk for ventricular arrhythmias and sudden death (George, 2009).

2. Jervell and Lange Nielsen syndrome. It is caused by homozygous or compound heterozygous mutations on either KCNQ1 or KCNE1 genes encoding the channel conducting IKs (Schwartz et al., 2006). Most mutations (80%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course. β-Blockers have only partial efficacy, so that 51% of the patients had events despite therapy and 27% had for cardiac arrest and SCD. Subgroups at relatively lower risk include females, patients with a QTc =550 ms, those without events in the first year of life, and those with mutations on KCNE1 (Schwartz et al., 2006).

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4. Clinical presentation

The LQTS has a low and highly variable penetrance (55% in the LQTS1, 70% and 80% LQTS2 LQTS3), which indicates that 2 out of 5 mutation carriers have a normal QTc (Priori et al.,1999, 2003). This happens even in patients with a history of syncope, although they are more susceptible to develop high-risk ventricular arrhythmias than the rest of the population. Some patients may remain asymptomatic for a long time, so that SCD can be the first clinical manifestation in a young "healthy" individual. Other patients present dizziness, lightheadedness (presyncope), syncope and seizures and MSC. Syncope can start early in life, often in infancy (before age 10, indicating a malignant course), but the frequency and intensity of symptoms may decrease to reach adulthood. When seizures occur in children they can be misdiagnosed of epilepsy. The occurrence of syncope during the performance of physical activity or strong emotion is a sign suggesting that the patient can present a LQTS. When there is also a family history of unexplained syncope or SCD the possibility that we are facing a SQTLc increases significantly. Thus, it is recommended to perform an ECG in all children and young people who have had an episode of syncope and/or unexplained seizures. Unfortunately, many times an electroencephalogram (EEG) is performed but not the ECG.

Genotype/phenotype correlations in LQTS indicated that in LQT1 patients experience most of their symptoms during exercise (swimming, running o emotion); they should not practice in competitive sports. At rest, IKs has minimal activity, but this current becomes critical for shortening of the action potential at high heart rates and during adrenergic stimulation, which allows for shortening of the action potential duration with exercise (Schwartz et al., 2001; Terrenoire et al., 2005). An impairment of IKs can prevent appropriate shortening of the action potential duration during exercise, which may explain why exercise is a common trigger for sudden death in LQTS due to defects in the gene encoding IKs. Transmembrane mutations are related to longer QTc, more frequent cardiac events, and greater QTc prolongation with exercise (Jons et al., 2009). Cytoplasmic loop mutations that affect sites of adrenergically mediated phosphorylation are specifically associated with QT prolongation during exercise, but the QTc may be normal at rest. Mutations in the cytoplasmic loops of the KCNQ1 protein or mutations with dominant-negative ion current effects are associated with a worse prognosis, especially when compared with mutations affecting the C-terminal regions of the protein (Goldenberg et al., 2006; Jons et al., 2009).

Loss-of-function mutations in KCNH2 result in a reduced IKr, delayed cardiac repolarization and QT prolongation. Patients with LQT2 experience events in association with increased sympathetic tone or emotional stress (unxpected noise: alarm clock, telephone, doorbell), postpartum or in patients with hypokalemia. In these patients are advised to remove the phones and alarm clocks in their bedroom (Schwartz et al., 2001). Most events associated with LQT3 (SCN5A mutations) occurred while the patients were asleep or at rest (55% of events) (Schwartz et al., 2001). Analysis of sex in relation to genetic subtype has revealed that females with LQT2 and males with LQT3 are at particularly high risk for sudden death or first cardiac arrest (Priori et al., 2003).

When the mutant channel is expressed in other tissues, the LQTS is associated with extracardiac symptoms. Patients with Andersen - Tawil syndrome (SQTL7) caused by mutations in the gene KCNJ8 present QT prolongation, marked U waves, hypokalemic periodic paralysis, abnormal skeletal development, facial dysmorphic features (micrognathia, clinodactyly, hypertelorism, low set of ears) and and ventricular arrhythmias including bidirectional VT (Plaster et al., 2001; Yoon et al., 2011). Patients with Timothy syndrome (SQTL8) caused by gain-of-function mutations on CACNA1c gene encoding the a -subunit of the Cav1.2 channel, present marked QTc prolongation associated with facial malformations (round face, flat nasal bridge, receding upper jaw, syndactyly), congenital heart defects, atrioventricular block, intermittent hypoglycemia, cognitive disorders, autism and interdigital mergers and reduced immune response (Splawski et al., 2004). The missense mutation G406R, located in the cytoplasmic loop between domains I and II, produces maintained inward Ca2+ currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca2+ overload in multiple cell types.

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5. Diagnosis

There is a relationship between age, gender, QTc duration, family history, genotype and clinical course, that allows risk stratification. Schwartz et al., (1993) published the diagnostic criteria for LQTS (Table), including electrocardiographic criteria, medical history and family history those subjects with = 3.5 points, have a high probability of LQTS.

LQTS Diagnostic Criteria

Features

Points

Electrocardiographic findings

- Corrected QT interval, seconds

³0.48

3

0.46-0.47

2

0.45 (in males)

1

- Torsades de pointes‡

2

- T-wave alternans

1

- Notched T wave in 3 leads

1

- Low heart rate for age

0.5

Clinical history

 

- Syncope

With stress

2

Without stress

1

- Congenital deafness

0.5

Family history‡  

 

- Family members with definite LQTS

1

- Unexplained SCD at < 30 years

0.5

1 point = low probability of LQTS. >1-3 points = intermediate probability. 3.5 points = high probability. > 3 - serial ECG records and 24-h Holter recordings
Mutually exclusive. *The same family member cannot be counted in A and B.

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6. Electrocardiographic findings

In patients with long QT syndrome, the ECG T-wave repolarization pattern is influenced by the genotype. Thus, in LQT1, the T wave is characteristically broad-based, while the T wave in LQT2 is typically bifid and of low amplitude. In contrast, in LQT3, prolongation of the ST segment accounts for QT prolongation and is typically followed by a a peaked, narrow T wave (Moss et al., 1995).

Other ECG characteristics include (Moss et al., 2002, 2007, Schwartz et al., 1993, 2006, Zhang et al., 2000):
1)
QT dispersion, reflecting the heterogeneity of ventricular repolarization (right vs left ventricle, epicardium vs endocardium). This QT dispersion is associated with an increased risk of ventricular arrhythmias.
2) T wave abnormalities, including alternans (beat-to-beat variation of the amplitude, morphology and polarity of the T wave in sinus rhythm, with no change in the QRS complex), biphasic appearance, variations in the amplitude or notches. The T -wave alternans is an indicator of electrical instability that reflects the regional dispersion of repolarization and sometimes precedes VF.
3)
Sinus node dysfunction (LQTS4), sinus bradycardia (LQTS1 and LQTS3) and/or sinus pauses.
4) 2:1 AV block occurs in 4-5% of patients, particularly in those with LQTS2, LQTS3 and SQTL8, and is associated with high mortality despite treatment with β - blockers an/or and ICD.
5) Many episodes of torsades de pointes are preceded by sudden decrements in cycle length (i.e. they are pause-dependent) (Viskin et al., 2000). An electric pause increases the QT interval and the heterogeneity of ventricular repolarization and a premature beat during the vulnerable portion of repolarization may precipitate VT. The marked QTU changes, that become apparent immediately after pauses, appear to represent enhanced early after depolarisations (or increased dispersion of repolarisation) following sudden increments in cycle length.

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7. Other diagnostic tests

Holter monitoring for 24-48 hours may be helpful in patients with a normal ECG. A stress test can allows us to detect an abnormal QTc that is not present at rest. Epinephrine infusion helps to predict the genotype (LQT1, LQT2 or LQT3) and improves the clinical diagnosis, particularly in patients with LQT1 (Shimizu et al., 2004). In patients with LQT1 adrenaline markedly prolongs the QTc interval at the time of the maximum RR interval shortening and this prolongation persists over time. It also prolongs the QTc when maximum heart rate shortening occurs in patients with LQT2, but later the QTc shortens to the baseline. However, QTc prolongation is much less marked in patients with LQT3. The interval between peak and end of T wave (Tpe) reflecting transmural dispersion of repolarization (TDR), increases during exercise in LQT1, but not in LQT2, which may partially account for the finding that fatal cardiac events in LQT1 are more often associated with exercise (Takenaka et al., 2003).

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8. Prognosis

Despite genetic heterogeneity, 3 genes explain >90% of LQTS cases: KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3). The risk of events among patients with LQTS is strongly dependent on age, sex, QTc duration, LQTS genotype and treatment response (Priori et al., 2003). It is considered that the risk is low (<30%) in patients with a QTc <500 ms, if they are males or in patients with a mutation in the LQT1 or LQT2 locus (Figure). The risk is intermediate (30-50%) in patients with a QT <500 ms if they are male with a LQT3 locus or females with a LQT2/LQT3 locus or they are women with a LQT3 locus and a QTc ≥ 500 ms. LQT2 females and LQT3 men with a QTc ≥ 500 ms fall into the higher risk category independent of other factors.


Genetic testing for long-QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1, KCNH2, and SCN5A in cases and >95% in controls; nonmissense mutations have an estimated predictive value >99% regardless of location (Kapa et al., 2009). Moss et al (2007) investigated the clinical course in 600 patients with different KCNQ1 mutations. Those with transmembrane versus C-terminus mutations or with mutations having dominant-negative (> 50% reduction in IKs) versus haploinsufficiency ion channel effects were at increased risk for cardiac events. QT1 patients with transmembrane mutations and dominant-negative ion current effects had a longer QTc interval and a higher frequency of cardiac events than individuals with mutations in other regions or mutations resulting in haploinsufficiency.

Shimuzu et al (2004) found that patients with KCNQ1 transmembrane mutations had longer QTc and more frequent LQTS-related cardiac events than those with C-terminal mutations, though the frequency of TdP was not different between the two study groups. In addition, most of the first cardiac events occurred before the age of 15 years in the LQT1 patients (particularly in males) with transmembrane mutations (only only 50% of the LQT1 patients with C-terminal mutations suffered their first cardiac events before the age of 15). Subjects with pore mutations had more severe symptoms and experienced a two times higher frequency of arrhythmia-related cardiac events compared with patients with non-pore mutations (Shimizu et al., 2009).

The location of specific mutations in the hERG channel protein might correlate with severity of disease (Moss et al., 2002). Subjects with pore mutations had more severe clinical symptoms and experienced a two times higher frequency of arrhythmia-related cardiac events than did subjects with nonpore mutations. Pore mutants are more likely to cause a strong dominant-negative effect, either increasing the rate of degradation of multimeric subunit assemblies in the ER/Golgi or by preventing ion conductance if the channels are successfully exported from the Golgi to the plasma membrane.

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9. Treatment

Antiadrenergic treatment (β -blockers) and implantable cardioverter-defibrillator (ICD) represent the first choice LQTS therapy.

β -Adrenergic blockers are the most effective drugs in the prevention of cardiac arrhythmias and SCD. Therefore, all patients, symptomatic or not, should be treated with β-blockers. They are most effective in patients with LQTS1 (90% of treated patients remains asymptomatic after 5.4 years) where life-threatening events occur most frequently during periods of sympathetic activation. The presence of a QTc > 500 ms and syncope before 7 years of age are markers of poor response to these drugs. However, β-blockers are less effective in LQTS2 and even less effective (or potentially proarrhythmic) in the setting of SCN5A mutations (LQTS3), possibly because of concomitant slowing of heart rate that accompanies decreased adrenergic activity (Bankston and Kass, 2009; Priori et al., 2004; Schwartz et al., 2001). Indeed, SQTL2/SQTL3 patients treated with a maximum dose of β -blockers show a relative risk 2.81 and 4.0 times higher than those with a LQTS1 (Figure). The mechanism for protection with β -blockers is not fully elucidated, but has been correlated with suppression of sympathetic tone that is one of the triggers of torsades de pointes, the blockade of L-type calcium channels and a decrease in QTc dispersion across the ventricular wall (Moss et al., 2000; Gemma et al., 2011). However, not all β -blockers are equally effective; propranolol and nadolol are more effective than atenolol and metoprolol (Schwartz et al., 2012). Propranolol and carvedilol block cardiac Na+ channels in a use- and state-dependent manner (block depends critically on the inactivated state of the channel) and block INaL preferentially over peak INa (Bankston and Kass, 2009). Additionally, at high concentrations propranolol also block IKr, which may explain its inferior protective capacity in LQTS2 (Kawakami et al., 2006).

In patients who do not respond to β-blockers and present repeated episodes of syncope and severe ventricular arrhythmias, left cardiac sympathetic denervation (LCSD) exerts an antiarrhythmic effect because it interrupts the major source of norepinephrine released in the heart and increases the ventricular fibrillation threshold and ventricular refractoriness. In 147 LQTS patients followed for 8 years, left cardiac sympathetic denervation reduced cardiac events by ~90% (Schwartz et al., 2004).

Independent of the genotype, QT-prolonging drugs are contraindicated in patients with LQTS (www.crediblemeds.org). In LQT1, high-intensity exercise should be restricted, especially swimming and in LQT2 triggers such as loud telephones or alarms should be avoided.

However, regardless of genotype, the treatment of choice is an ICD. The ICD implantation is indicated in (Schwartz et al., 2012): a) all patients who survived a cardiac arrest regardless of treatment, except those with a reversible/preventable cause; b) those with recurrent syncope despite a full dose of β -blocker and LCSD; c) patients with a QTc >550 ms with signs of electrical instability (e.g, T wave alternans or long pauses followed by abnormal T waves) despite β -blockade and LCSD, and d) sustained ventricular arrhythmias, or sudden cardiac arrest (secondary prevention). In addition, the guidelines recommend consideration of ICD therapy for primary prevention of sudden cardiac arrest in patients with risk factors for sudden cardiac death, eg, patients with LQT1, LQTS2 and LQTS3 variants when associated with QTc > 500 ms and an early onset of cardiac events (< 7 years of age). (Epstein et al., 2008). However, the ICD does not prevent arrhythmic events in patients with LQTS2/3 and ICD implanatation is sometimes problematic in young patients.

Pacemakers can be implanted to avoid episodes of bradycardia and sinus pauses, particularly in patients with LQT2 and LQT3, who may be especially susceptible to pause-dependent phenomena, may particularly benefit from pacing. Data for pacemakers, however, is limited to small numbers of patients (Moss et al., 1991). The combination of pacemaker and β-blocker therapy may be beneficial in high-risk patients, but the incidence of sudden death and aborted sudden death (24%) strongly suggests the use of a"back-up"defibrillator, particularly in noncompliant adolescent patients. The consensus guidelines state that “permanent pacing is indicated for sustained pause-dependent VT, with or without QT prolongation"(Epstein et al., 2008).

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10. Other pharmacological treatments

In LQTS3 patients, it was suggested that mexiletine may reducing the QTc interval duration through its Na+ channel blocking properties (Schwartz et al., 1995). In patients with LQTS3 mexiletine can be administered in-hospital and if the drug shortens the QTc > 40 ms it can be associated to the treatment with β -blockers (Schwartz et al., 2012; Chockalingam et al., 2012). However, in vitro, the effect of mexiletine is influenced by the biophysical properties of the specific mutation. It s hortens the QTc interval in patients with certain mutations that shift the inactivation towards more negative values (R1626P, P1332L and R1626P) but not in others (S941N, M1652R) (Ruan et al., 2007, 2010). Ranolazine is a new antianginal drug that selectively blocks the I NaL and shortens the QTc interval in patients with LQTS 3 at concentrations at which it has no effect on heart rate, cardiac contractility or cardiac conduction velocity (Moss et al., 2008). Potassium-sparing diuretics, such as spironolactone, have been used in combination with K+ to shorten the QT interval in patients with LQTS2, but results are quite modest (Compton et al., 1996; Etheridge et al., 2003).

Intravenous isoproterenol may be useful as the increase in heart rate shortens the ventricular APD, decreases the dispersion of ventricular repolarization and suppresses early afterdepolarizations generating torsade de pointes. Preliminary evidence suggest that K+ channel agonists (nicorandil, pinacidil, cromakalim) are more effective in LQTS patients with mutations in K+ channels. Independent of the genotype, QT-prolonging drugs are contraindicated in patients with LQTS.

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11. References

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