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Pages 739-752 (July 2007)
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Vol. 60. Issue 7.
Pages 739-752 (July 2007)
DOI: 10.1016/S1885-5857(08)60010-9
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Clinical and Genetic Characteristics of Long QT Syndrome
Clínica y genética en el síndrome de QT largo
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Argelia Medeiros-Domingoa, Pedro Iturralde-Torresb, Michael J Ackermanc
a Unidad de Biología Molecular y Medicina Genómica, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de Mexico, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico.
b Instituto Nacional de Cardiología Ignacio Chávez, Mexico
c Department of Medicine/Department of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN, USA
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TABLE 1. Genes Envolved in the Long QT Syndrome
Figure 2. Genotype-phenotype correlation in the most frequent long QT syndromes. *Refers to cases that have the mutation and manifest the phenotype.
TABLE 2. Schwartz Score for the Diagnosis of Long QT Syndrome (1993)
Figure 3. Model showing distribution of the heart rate-corrected QT interval (QTc) in patients with mutations in KVLQT1, HERG, or SCN5A, and their unaffected family members. The curve to the left describes distribution of unaffected members and the curve to the right, affected members.
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Long QT syndrome (LQTS) is an arrhythmogenic ion channel disorder characterized by severely abnormal ventricular repolarization, which results in prolongation of the electrocardiographic QT interval. The condition is associated with sudden cardiac death due to malignant ventricular arrhythmias similar in form to the hallmark torsade de pointes. Eleven years after the identification of the principle cardiac channels involved in the condition, hundreds of mutations in, to date, 10 genes have been associated with the syndrome. Genetic investigations carried out up until the present have shown that, although the severe form of the disease is sporadic, there are a number of common polymorphisms in genes associated with the condition that may confer susceptibility to the development of torsade de pointes in some individuals, particularly when specific drugs are being administered. Moreover, some polymorphisms have been shown to have regulatory properties that either enhance or counteract a particular mutation's impact. Understanding of the molecular processes underlying the syndrome has enabled treatment to be optimized and has led to better survival among sufferers, thereby demonstrating a key correspondence between genotype, phenotype and therapy. Despite these developments, a quarter of patients do not have mutations in the genes identified to date. Consequently, LQTS continues to be an area of active research. This article contains a summary of the main clinical and genetic developments concerning the syndrome that have taken place during the last decade.
Keywords:
Long QT syndrome
Arrhythmias
Sudden death
Cardiac arrest
Syncope
Gene mutation
Torsade de pointes
El síndrome de QT largo (SQTL) es una canalopatía arritmogénica caracterizada por una grave alteración en la repolarización ventricular, traducida electrocardiográficamente por una prolongación del intervalo QT. Predispone a muerte súbita por arritmias ventriculares malignas del tipo de torsade de pointes. A 11 años de la identificación de los principales canales afectados en esta enfermedad, se han descrito cientos de mutaciones distribuidas en hasta ahora 10 genes relacionados con el síndrome. El escrutinio genético realizado desde entonces ha mostrado que, si bien la forma grave de la enfermedad es esporádica, hay polimorfismos comunes en los genes relacionados con la enfermedad que pueden generar susceptibilidad individual al desarrollo de torsade de pointes, en particular con el uso de determinados fármacos; más aún, se han identificado polimorfismos con cualidades reguladoras que pueden exacerbar o silenciar la gravedad de una mutación. El entendimiento de los procesos moleculares de la enfermedad ha permitido optimizar el tratamiento y mejorar la supervivencia de los afectados, generando así una importante correlación genotipo-fenotipo-tratamiento. A pesar de los avances, una cuarta parte de los casos no tiene mutaciones en los genes descritos hasta el momento, por lo que el SQTL continúa siendo motivo de investigación. El presente artículo representa el análisis de los principales conceptos clínicos y genéticos desarrollados en los últimos años sobre esta singular enfermedad.
Palabras clave:
Síndrome de QT largo
Arritmias
Muerte súbita
Parada cardiaca
Síncope
Mutación genética
Torsade de pointes
Full Text

INTRODUCTION

Long QT syndrome (LQTS) is characterized by severely altered ventricular repolarization, resulting in prolongation of the QT interval on electrocardiogram (ECG). The condition predisposes patients to malignant ventricular arrhythmia (torsade de pointes) and sudden death. The clinical and electrocardiographic description of long QT syndrome was reported in 1957 by Anton Jervell and Fred Lange Nielsen,1 who published their studies on a family of nonconsanguineous parents with 6 children. Four of the children had congenital deafness and syncopal episodes, and 3 presented sudden death. ECG study of these patients showed an unusually long QT interval. Both parents were asymptomatic, had a normal ECG, and presented no hearing problems. In 1964, Romano and Ward independently reported a cardiac syndrome characterized by recurrent syncope, a family history of sudden death, and prolongation of the QT interval without neuronal deafness.2 Later genetic studies showed that the syndrome described by Jervell and Lange Nielsen, which is accompanied by congenital neuronal deafness, corresponds to homozygous mutations, with a severe phenotype and high risk of sudden death. The condition known as Romano-Ward syndrome generally corresponds to heterozygous mutations, patients do not display hearing alterations, and the severity of the disease varies considerably. Almost half a century later, in 1995,3,4 the principal genes associated with LQTS were described and the disease was recognized as a cardiac ion channel disorder. It was the first cardiac channelopathy to be described and is perhaps the most extensively investigated arrhythmogenic ion channel disorder to date. The clinical picture varies greatly: the patient can be asymptomatic, or show recurrent syncope, seizures, or sudden death as the first manifestation of the disease. Initially, LQTS was considered a rare syndrome and, in effect, the severe presentation of the disease is sporadic. Nonetheless, the incidence of related mutations is estimated at 1/3000-5000 cases,5 32% of asymptomatic carriers can have a heart rate-corrected QT interval (QTc) within normal limits, the disease is transmitted to 50% of their descendants, they are more susceptible to develop arrhythmia when compared to the general population, and up to 20% can become symptomatic.6

Long QT syndrome displays great genetic heterogeneity. More than 500 mutations distributed in 10 genes have been described in this condition: KCNQ1, HERG, SCN5A, KCNE1, KCNE2, ANKB, KCNJ2, CACNA1, CAV3, and SCN4B. Despite the advances in this area, a genetic diagnosis cannot be established in 25%-30% of patients.7,8 The presentation of the disease is mainly monogenic6; polygenic or composite varieties usually have a more severe phenotype. Penetrance, ie, patients who have the mutation and manifest the phenotype, ranges from 25% to 90%.9 Less frequently, there may be variations in the expressivity of the disease, with several phenotypes resulting from the same mutation. Molecular genetic studies developed over the last 11 years have yielded important genotype-phenotype correlations, which have helped to guide the treatment approach. In addition, interesting observations have been made on individual susceptibility to developing arrhythmia in studies investigating the frequent nonsynonymous polymorphisms in this population, an aspect that has aroused considerable interest, particularly in the area of pharmacogenomics.

CLASSIFICATION OF LONG QT SYNDROME

General Concepts

The LQTS classification used in the past was based on the homozygous or heterozygous presentation of the disease, which gives rise to Jervell-Lange-Nielsen syndrome (with deafness) and Romano-Ward syndrome (without deafness), respectively. The present classification emphasizes the genetic findings, as is illustrated in Table 1. The 3 main genes associated with the disease were described in 1995-1996. These genes, which code for pore-forming units of the potassium channels IKs and IKr, and the sodium channel Nav1.5, account for nearly 65% of the cases. Although in subsequent years seven additional genes have been included in the list, they account for only 5% of the cases.

Ion channels are transmembrane proteins that transport ions through the cell membrane. The channels implicated in LQTS are selective or specialized in transporting a single ion and are voltage-dependent, ie, their activation occurs at a specific intracellular voltage, which varies according to the channel subtype. The electrical and contractile phenomena that occur in the cardiomyocyte are controlled by these structures. Ion channels form macromolecular complexes consisting of a main unit that forms the channel pore and auxiliary proteins that regulate it (Figure 1). The channel dysfunction seen in LQTS can occur at these two sites: the main protein or the regulating proteins (Table 1). Involvement of the pore-forming unit, known as alpha, generates the three most common subtypes of LQTS: LQTS1 (affecting the IKs potassium channel), LQTS2 (affecting the IKr potassium channel), and LQTS3 (affecting the sodium channel). Because these are the most frequent subtypes, they are the best characterized clinically and genetically. The phenotype-genotype correlations in these three main forms are described in Figure 2. Currently, Jervell-Lange-Nielsen syndrome corresponds to the LQTS 1 and 5 varieties. Characteristically, these patients have congenital deafness and compound homozygous or heterozygous mutations that affect the IKs current. Romano-Ward syndrome includes varieties from LQTS 1 to 10 and does not involve deafness.

Figure 1. Schematic representation of the macromolecular complex. The ion channels are transmembrane proteins (α) regulated by various proteins; one of them is the so-called β subunit.

Long QT Syndrome Type 1 (LQTS1)

Patients with LQTS1 usually present episodes of ventricular arrhythmia when exercising or when undergoing sympathetic stimulus (68%).10 Swimming has been described as a sport triggering arrhythmia in LQTS1.11 Penetrance is nearly 62% in this subtype. The T-wave in these patients often has a broad base and very prolonged duration12,13 (Figure 2). It is the most frequent subtype and explains 30%-35% of cases. The affected gene, KvLQT1 (or KCNQ1), is located on chromosome 11 (11p15.5) and codes for the IKs potassium channel α-subunit. The action potential is prolonged by a reduction in the outgoing K+ current during phase 3 of the action potential.

Figure 2. Genotype-phenotype correlation in the most frequent long QT syndromes. *Refers to cases that have the mutation and manifest the phenotype.

Long QT Syndrome Type 2 (LQTS2)

Patients with LQTS2 tend to present ventricular arrhythmia in response to emotional stress (49%) or sudden auditory stimuli (eg, an alarm-clock), and less frequently during sleep (22%) or exercise (29%).10 Women in the postpartum period are particularly susceptible.14 Estimated penetrance is 79%; hence, up to 20% of cases can have a nondiagnostic ECG. The T-wave in LQTS2 is usually low-amplitude and bifid, with notching12,13 (Figure 2). The affected gene is KCNH2 or HERG, located on chromosome 7 (7q35-36), which codes for the IKr potassium channel α-subunit and accounts for 25%-30% of cases. Dysfunction of this channel decreases the outgoing K+ current during phase 3 of the action potential, prolonging its duration.

Long QT Syndrome Type 3 (LQTS3)

Patients with LQTS3 have a greater risk of presenting malignant arrhythmias during rest (sleep) or bradycardia.15 Penetrance of the SCN5A gene mutation is nearly 90%. The ECG in LQTS3 usually shows a delayed, pointed T wave and allows clear observation of the ST segment prolongation12,13 (Figure 2). These patients usually have fewer symptoms than those with LQTS1 or LQTS2, but the events are characteristically more lethal.

The affected gene in LQTS3 is SCN5A, which codes for the Nav1.5 sodium channel α-subunit (Figure 1), located on chromosome 3 (3p21-24); it is the cause of disease in 5%-10% of the cases. Defective inactivation of the channel allows sustained input of Na+ during phase 2 of the action potential, prolonging its duration.

Long QT Syndrome Type 4 (LQTS4)

Type 4 is a rare variety of LQTS, accounting for nearly 1% of cases. It is an atypical form that produces a wide spectrum of arrhythmias, including catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation, intraventricular conduction alterations, sinus node dysfunction, and bradycardia6-18; in addition, the QTc can be within normal limits in many patients. The affected gene is ANKB, located on chromosome 4 (4q25-27), which codes for synthesis of ankyrin-β, a structural protein that links cardiomyocyte membrane proteins to cytoskeletal proteins. These proteins are the Na/K ATPase pump, Na/Ca exchanger, and inositol triphosphate receptor (InsP3R). Mutations causing a loss of ankyrin-β function lead to increases in intracellular calcium concentration and alterations in the expression of N/K ATPase and Na/Ca exchanger. The elevated calcium concentration gives rise to early and delayed after-depolarizations. Thus, the ventricular arrhythmias observed in ankyrin-β gene mutations are due to spontaneous depolarizations, usually in response to catecholaminergic stimulation.

Long QT Syndrome Type 5 (LQTS5)

Type 5 originates with changes in the sequence of the KCNE1 gene located on chromosome 21 (21q22.1p22.)19 KCNE1 codes for synthesis of the IKs channel β-subunit, also known as the minK subunit, which regulates the IKs channel. This type accounts for less than 1% of cases.

Long QT Syndrome Type 6 (LQTS6)

The affected gene in type 6 is KCNE2, located on chromosome 21 (21q22.1).20 This gene codes for the potassium channel β-subunit, also known as the MiRP1 subunit, and it regulates the IKr channel. Less than 1% of cases are type 6.

Long QT Syndrome Type 7 or Andersen-Tawil Syndrome (LQTS7)

The dysmorphic findings and electrocardiographic alterations seen in this syndrome were first described in 1971 by Dr Andersen21 and revisited in 1994 by Dr Tawil,22 but the genetic/molecular description was not reported until 2001.23 Now known as Andersen-Tawil syndrome (ATS) this condition is an autosomal dominant alteration characterized by periodic paralysis, abnormal skeletal development, ventricular arrhythmia of the type involving frequent ventricular extrasystoles, and a particular susceptibility to develop ventricular fibrillation, particularly in women. The alterations described in ATS include ventricular extrasystoles (41%), nonsustained polymorphic ventricular tachycardia (23%), bidirectional ventricular tachycardia (68%), and torsade de pointes (3%).24 Some of the observed dysmorphic characteristics include short stature, scoliosis, clinodactyly, hypertelorism, low implantation of the ears, micrognathia, and a wide forehead. Disease expression varies, a fact that complicates early diagnosis.23,25 Mutations in the KCNJ2 gene located in chromosome 17 (17q23), which codes for synthesis of the rectifying potassium channel Kir 2.1, accounts for 70% of cases. This channel participates in phase 4 of the action potential. Several authors question the inclusion of this gene within the LQTS causal group, because the QTc interval is only slightly prolonged in this syndrome or even normal, but the U wave is usually prominent, which has led to overestimation of the QT interval. The reader will find that some authors suggest that KCNJ2 mutations generate ATS1 and not LQTS7.24

Long QT Syndrome Type 8 (LQTS8)

Type 8 arises from mutations in the CACNA1 gene located on chromosome 12 (12p13.3), which codes for L-type calcium channel Cav1.2. It causes Timothy syndrome,26 a condition characterized by cardiac malformations, intermittent immunological deficiency, hypoglycemia, cognitive alterations including autism, interdigital fusion, and prolonged QT, which leads to cardiac arrhythmia and sudden death.27 Less than 0.5% of cases are type 8.

Long QT Syndrome Type 9 (LQTS9)

This variety of LQTS develops from mutations in the CAV3 gene, located on chromosome 3 (3p25), which codes for caveolin 3 synthesis. The caveola is an invagination of the plasma membrane implicated in endocytosis, lipid homeostasis, and signal transduction. An important component of this structure is caveolin, which has 3 known subtypes; subtype 3 is specific for skeletal and cardiac muscle. Some ion channels are co-located in the caveola, including a cardiac isoform of sodium channel Nav1.5. Several mutations in this protein have been recently described. These alter the biophysical properties of sodium channel Nav1.5 in vitro, generating a phenotype similar to that observed in LQTS3.28 Less than 1% of cases are attributed to this cause.

Long QT Syndrome Type 10 (LQTS10)

Type 10 was described in a very severe case, with QTc >600 ms, fetal bradycardia, and 2:1 atrioventricular (AV) block. It results from mutations in the SCN4B gene, located on chromosome 11 (11q23), which codes for the sodium channel β4-subunit. Four different subtypes of β subunits have been described, which interact and regulate the various sodium channel isoforms; nonetheless, only subtype 4 has been associated with arrhythmogenesis up to now.29 The incidence of mutations of this gene has not been examined, but is estimated at <1%.

Mutations of the Jervell-Lange-Nielsen Variety

This severe form of LQTS is caused by homozygous30 or compound heterozygous mutations of the KCNQ1, and/or KCNE1 genes, which code for the IKs current; ie, a very severe variety of the LQTS1 or LQTS5 forms. This condition is characteristically associated with congenital deafness. Patients usually have a QTc>500 ms and recurrent syncope, and are at a high risk for sudden death. The parents of patients with this variety are usually heterozygous and have less severe disease, or show no symptoms.31

DIAGNOSIS OF LONG QT SYNDROME

Schwartz Score

In 1985, Schwartz et al32 published the criteria for diagnosing LQTS, which were modified in 1993 and contain important guidelines for the initial evaluation of potential cases. This system uses a score of 1 to 9 based on the family history, and the clinical and electrocardiographic findings. The probability of disease is low at a score of ≥1, intermediate at 2-3, and high at ≥4 (Table 2).

Prenatal Diagnosis of Long QT Syndrome

Fetal bradycardia can be one of the first clinical manifestations of LQTS. Retrospective series have shown that up to 70% of patients diagnosed with LQTS during childhood have a history of bradycardia, usually accompanied of fetal hydrops.33 Assessment of fetal cardiac repolarization between weeks 14 and 39 is useful for early diagnosis of LQTS.34

Gonadal mosaicism for LQTS has been associated with recurrent fetal losses during the third trimester of pregnancy.35 If the disease is highly suspected, amniocentesis after 16 weeks of gestation can be useful for establishing the diagnosis, which is easily reached when one of the parents is known to be the carrier of a specific mutation.36

STUDY OF A PATIENT WITH LONG QT SYNDROME

Clinical History

A family and/or personal history of sudden death is of crucial importance for both the diagnosis and risk stratification of LQTS. In addition, precipitating factors and the context of syncope can indicate the LQTS subtype. In the initial evaluation of a suspected case, the use of drugs that can prolong the QT interval should be ruled out.

QT Interval: What Is Normal?

The QT interval should be measured preferentially in leads II or V5,37 where it has been proven to have greater predictive value.38 This interval indicates the duration of ventricular repolarization and is measured from the beginning of the Q wave to the end of the T wave. Conventionally, the formula proposed by Bazett39 is employed to correct the duration of the interval according to the heart rate (QTc=QT/√RR, expressed in seconds). Although measurement of the QT interval seems simple, in a multicenter study carried out by Viskin et al,40 less than 40% of physicians other than cardiologists, less than 50% of cardiologists, and more than 80% of specialists in arrhythmia knew how to measure it properly. It is advisable for physicians to carry out manual measurement and not trust automated measurements, which may be useful for other intervals, but are imprecise when calculating the QT interval. The QT is a dynamic interval and the normal limits depend on several factors. Although a QTc interval of é440 ms in males and é460 ms in females is considered abnormal, one can find carriers of mutations as well as healthy individuals within this range (Figure 3). In families with LQTS1, Vincent et al41 demonstrated that none of the cases with a positive genotype had a QTc<410 ms and none with a negative genotype had a QTc>470 ms. Monnig et al38 recently showed that QTc>440 ms suffices to detect patients with LQTS-associated mutations, QTc>470 ms is useful to identify patients at risk of developing symptoms, and QTc>500 ms is found in symptomatic patients undergoing treatment.

Figure 3. Model showing distribution of the heart rate-corrected QT interval (QTc) in patients with mutations in KVLQT1, HERG, or SCN5A, and their unaffected family members. The curve to the left describes distribution of unaffected members and the curve to the right, affected members.

Other Electrocardiographic Alterations Associated With Long QT Syndrome

Patients with LQTS can present multiple T wave alterations: polarity alternans, amplitude variations, notching, and a biphasic appearance, among others.42 T wave alternans (Figure 4A) is defined as a beat-by-beat variation in amplitude, morphology and polarity of a sinus rhythm T wave, without variations in the QRS complex. It is an indicator of electrical instability,43 reflecting regional dispersion of ventricular repolarization, and occasionally precedes ventricular fibrillation.44

Figure 4. Electrocardiographic alterations in long QT syndrome. A: T wave electrical alternans. B: atrioventricular block 2:1. C: self-limited torsade de pointes.

Patients with LQTS can progress with signs of sinus node dysfunction, bradycardia, and/or pauses.45 The LQTS1 and LQTS3 subtypes, particularly the latter, often present sinus bradycardia,46 whereas LQTS4 has been associated with sinus node dysfunction.18

Since the decade of 1970-1980, the coexistence of AV conduction defects with LQTS47 has been observed (Figure 4B). Two-to-one AV block is an infrequent manifestation with a poor prognosis that can be present since the fetal stage in the form of persistent bradycardia. The incidence of this abnormality has been reported at 4%-5%48 and it is associated with high mortality despite treatment with beta-blockers and/or pacemakers.49,50 This phenomenon can be explained by a lengthy duration of the action potential. When the ventricular refractory period is extended, the following impulse of sinus activity is blocked because it reaches the ventricles when they are still in the refractory period. This alteration seems to occur exclusively in LQTS, because the ventricular refractory period is greater than that of the AV conduction system.51 The slope of the QRS complex is usually steep and the block has been localized in the infraHis area,46,51,52 but the site of the block may depend on the genotype. Up to now, 4 genes have been related to 2:1 block in LQTS: HERG (LQTS2),53,54 SCN5A (LQTS3),52 CACNA1 (LQTS8),26 and SCN4B (LQTS10).55

The characteristic ventricular arrhythmia of LQTS is known as torsade de pointes (Figure 4C). It presents when the QT interval is prolonged, regardless of the etiology. It is a polymorphic ventricular tachycardia due to reentry, characterized electrocardiographically by continuous twisting of the QRS axis around an imaginary line. It is commonly preceded by a pause followed by an extrasystole (short-long-short RR interval), as is shown in the figure.56-58 It can culminate in ventricular fibrillation and sudden death. If this does not occur, the patient may only experience syncope, and if the episode is brief, it may go undetected.

Holter

Holter study provides a complete, dynamic assessment of the QT interval. Occasionally spontaneous episodes of asymptomatic ventricular arrhythmia are recorded, as well as episodes of sinus node dysfunction or AV block.

Exercise Stress Test

Patients with LQTS cannot reach the maximum expected heart rate calculated according to age. In addition, under exertion the QT interval can display paradoxical behavior, by increasing rather than decreasing.59,60 The electrocardiographic pattern during exercise stress testing will be different depending on the type of LQTS. Patients with LQTS1, in addition to not reaching the maximum calculated heart rate for their age, frequently show an increased QT interval, while those with LQTS2 can reach their expected heart rate and show only a mild QT interval increase or none at all.61,62 In general, patients with LQTS3 have a physiologic response to exercise, ie, normal shortening of the QT interval.63 Stress testing can also be useful for assessing treatment response and for stratifying risk in asymptomatic cases, or when there are doubts as to the events leading to arrhythmia.

Genetic Screening

In the last years, genetic studies in LQTS have been limited to research laboratories. Nevertheless, the information derived from these efforts has been extremely useful for treating patients, particularly high-risk cases. Perhaps the main application of screening is in genetic counseling, but it also has important implications in treatment, which can be oriented according to the affected channel. The precise location of a given mutation can provide additional information regarding the evolution of risk. Patients with mutations in the transmembrane region of KCNQ1 (IKS) have a greater probability of presenting arrhythmic events than those with mutations in the C-terminal region64; the same is true for patients with mutations in the pore region of KCNH2 or HERG65 as compared to those with mutations in the N- or C-terminal regions.66

Initial screening may perhaps be limited to the KCNQ1, HERG, and SCN5A genes, which provide the possibility of encountering mutations in 65% of cases. When the results obtained are negative, screening can be extended to the KCNE1, KCNE2, ANKB, KCNJ2, CACNA1, CAV3, and SCN4B genes, which will increase the possibility of positive results by 5% to 10%.

Postmortem Genetic Screening

It is interesting that gene mutations leading to LQTS have been found in children who experienced sudden death and in inexplicable cases of sudden death in young adults.

Postmortem genetic studies of patients with sudden death and negative autopsy have shown mutations leading to LQTS in varying percentages67-69: close to 10% in children and 35% in young adults.70-72 Based on these results, routine ECG study has been proposed in all newborns.73,74

Postmortem genetic study, also known in the literature as "molecular autopsy," in addition to legal repercussions, has important implications in families who might be affected without their knowing it.

Regulatory Polymorphisms

Several frequently occurring polymorphisms have been described in the LQTS population, distributed in nearly all the genes associated with this condition. Although these changes are apparently not pathogenic, some can have the following effects75-78:

1. Generate individual susceptibility to develop arrhythmia.

2. Favor the pathogenic impact of another nonsynonymous change.

3. Decrease the pathogenic effect of another nonsynonymous change.

This is the case of the K897T polymorphism in KCNH2 (HERG), which is present in up to 15% of the population and is not only linked with susceptibility to certain drugs,79 but also favors the pathogenic effect of mutations in the same gene.78 Another example is the S1103Y polymorphism in the SCN5A gene, found mainly in blacks, which has an incidence of nearly 13% and is associated with an increased risk of sudden death in childhood.80

Interestingly, two alternative processing sites generating two types of sodium channels have been described in the product of the SCN5A gene, (which codes for the Nav1.5 sodium channel isoform in humans): one with 2016 aminoacids containing glutamine in the 1077 (Q1077) position, and another with 2015 aminoacids lacking glutamine (Q1077del). Transcripts of these alternative processings are present in a 2:1 proportion in the same human heart and several frequent polymorphisms will have different effects on channel functioning, depending on whether the context is Q1077 or Q1077del. This was initially shown with the H558R polymorphism of SCN5A, present in up to 30% of the population. When H558R was expressed in the context of Q1077, a profound reduction in the ion current was observed.81 A similar effect was documented with the S524Y82 polymorphism. These findings have provided factors to explain the varying severity of the disease, as well as the different phenotypes of the same mutation observed in some families.77

Pharmacological Testing With Adrenaline

Pharmacological testing with low-dose adrenalin is a safe, useful option to unmask suspected cases of LQTS with a borderline QTc. It is particularly effective for detecting asymptomatic forms of LQTS1, with a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96%. It can also be useful in the diagnosis of LQTS2, with lower sensitivity and specificity. It is not useful for LQTS3 or other forms of LQTS. Under normal conditions, sympathetic stimulation induces phosphorylation of the IKs potassium channel, optimizing its function and giving rise to shortening of the action potential. In patients with LQTS, in particular type 1, a paradoxical response to administration of low-dose adrenalin (0.025-0.2 µg/kg/min) that prolongs the QT interval to more than 30 ms83-86 is observed.

QT INTERVAL PROLONGATION AND DRUG-INDUCED TORSADE DE POINTES

A great variety of drugs used in different medical specialties can cause a iatrogenic increase in the QT interval. Some drugs have been removed from the market because of this undesirable effect (eg, astemizole and cisapride, among others; for more information, visit www.qtdrugs.org).87,88

Ventricular arrhythmia secondary to non-antiarrhythmic drugs occurs in less than one of every 10 000 to 100 000 exposed subjects. Considering that clinical studies include between 2000 and 3000 subjects, this undesirable and fatal adverse event would easily escape detection during the clinical phase of drug development.89 This point has generated enormous interest in aspects referring to safety in the study and development of new drugs.

The factors related to individual susceptibility include female gender, hypocalcemia, hypomagnesemia, bradycardia, heart failure, postcardioversion, atrial fibrillation, left ventricular hypertrophy, undetected LQTS, predisposing polymorphisms, and high serum concentrations of predisposing drugs.90

The channel that typically interacts with drugs is IKr, coded by the KCNH2(HERG) gene, because of its molecular structure. Other potassium channels have 2 proline residues angled toward the channel pore, reducing its lumen. In contrast, IKr lacks these residues, a larger pore vestibule is generated, and exposure to large molecules is facilitated. In addition, it has 2 aromatic residues (tyrosine and phenylalanine) that favor binding with aromatic molecules present in several drugs able to block the channel.91

As was mentioned above, LQTS penetrance is incomplete and some asymptomatic carriers of mutations might manifest malignant arrhythmia upon receiving one of these drugs. In addition, polymorphisms considered frequent in the population confer individual susceptibility to the development of torsade de pointes when some drugs are used. This is the case of the R1047L polymorphism, the second most frequent in KCNH2, which has been associated with the development of torsade de pointes with use of the drug dofetilide.92 At least 20 KCNH2 gene polymorphisms have been described in healthy persons and their effect in individual susceptibility to develop drug-related arrhythmia remains to be determined.93 Polymorphisms that confer susceptibility to the development of ventricular arrhythmia have also been documented in sodium channel Na1.5. This is the case of the H558R polymorphism, which is present in up to 30% of the population, or S1103Y, which is frequent in blacks80,81,90,94,95; their implication in drug-induced susceptibility has not been investigated.

LONG QT SYNDROME AND PREGNANCY

Genetic counseling is important in LQTS, but in general terms there is no contraindication for pregnancy in women who are carriers, although each case is different and should be assessed individually in the appropriate context.

It has been noted that the risk of presenting malignant ventricular arrhythmia decreases with pregnancy. In contrast, greater vulnerability to present malignant arrhythmia has been reported within the first 9 months after delivery, particularly in patients with LQTS2. This risk decreases considerably with beta-blocker therapy.96

RISK STRATIFICATION

The evolution of LQTS varies and is influenced by the duration of the QTc interval, environmental factors, age, genotype, and response to treatment.97,98 Ventricular arrhythmia is more frequent in LQTS1 and LQTS2, but is more severe in LQTS3.99 As was mentioned above, women are especially susceptible to malignant arrhythmia during the postpartum period.14

Long QT syndrome should be considered high-risk when it is associated with the following:

1. Congenital deafness (Jervell-Lange-Nielsen syndrome).

2. Recurrent syncope due to malignant ventricular tachyarrhythmia.

3. Family history of sudden death.

4. QTc>500 ms.

5. 2:1 atrioventricular block.

6. T wave electric alternans.

7. LQTS3 genotype.

The study by Priori et al97 performed in 647 patients showed that the probability of presenting a major event (syncope, cardiac arrest, sudden death) before 40 years of age is high (>50%) when QTc is >500 ms in LQTS1, LQTS2, and in males with LQTS3. Recently, an analysis of the international LQTS registry was reported. The risk of sudden death was analyzed in 2772 adolescents with the disease, and 3 factors associated with higher risk in this population were identified: QTc>530 ms, history of syncope in the past 10 years, and gender; 10 to 12-year-old boys had a higher risk than girls, but in the 13 to 20 age range, the risk was comparable.100

TREATMENT

Symptomatic patients who do not receive treatment have a yearly mortality rate of 20% and 10-year mortality of 50% after a first event of ventricular arrhythmia. Although it is clear that treatment should be established when there are symptoms, the approach to use in asymptomatic patients is still under debate. It has been documented that cardiac arrest may be the first manifestation of the disease in 9% of patients,48 and that 12% of asymptomatic patients will develop symptoms and may experience sudden death. Initial treatment with beta-blockers should be started in all patients with LQTS. Exercise restriction is recommendable, but the clinical and electrocardiographic risk markers are a useful basis for decision-making. It is important to inform patients about the risk of using several drugs that can prolong the QT interval and favor the development of ventricular arrhythmia, as is mentioned above. Genetic diagnosis, apart from allowing appropriate family counseling related to the disease, is a help for assessing the prognosis and orienting specific treatment.

Beta-Blockers

Beta-blockers are the first-line treatment for LQTS and all patients should receive them as the initial therapy.101 They provide a reduction in the risk of cardiovascular events of up to 64%100 and are particularly effective in patients with IKs channel mutations (LQTS1),102 which are regulated to a great extent by the sympathetic system. Beta-blockers do not modify the QT interval, but instead, its dispersion.103 Although these drugs decrease the incidence of events,104,105 it has been shown that 10% of patients with LQTS1, 23% with LQTS2, and 32% with LQTS3 will have cardiovascular symptoms despite treatment.106 Patients with LQTS3, in particular, do not seem to obtain important benefits; in fact, this drug group should be used with caution in these patients, because episodes of ventricular arrhythmia in LQTS3 are more common when the heart rate is low. In general terms, 32% of symptomatic patients will have recurrent symptoms in the first 5 years before beginning beta- blocker treatment, and 14% of patients rescued from a sudden death episode will present another similar event within 5 years if they receive only this therapy.107 Several beta-blockers have been used in the treatment of LQTS, mainly nadolol (0.5-1 mg/kg/day), propranolol (2-4 mg/kg/day), metoprolol (0.5-1 mg/kg/day), and atenolol (0.5-1 mg/kg/day). Atenolol may not be beneficial in LQTS, however; it has been notified that at least 75% of patients who did not respond to beta-blocker therapy were receiving atenolol, although this finding may be related to the use of suboptimal doses.104 Exercise testing is useful to establish the appropriate dose. Maximum heart rate should not exceed 130 beats/min during treatment.

Sodium Channel Blockers

Sodium channel mutations that cause LQTS3 produce defective inactivation of the channel; sodium channel block has proven to be useful in these patients. Studies done with flecainide have documented improvements in the heart rate, T wave alterations, and QT interval.108 Mexiletine has also been reported to improve the electrocardiographic risk markers.63,109,110 In vitro studies with ranolazine have shown decreases in the deleterious effects of mutations reported in humans.111 Although the results are encouraging, it should be kept in mind that there are no long-term studies assessing this therapy, and no reported findings from large series. Sodium channels blockers should not be administered if there is no confirmed genetic diagnosis.

Potassium Supplementation and Drugs That Increase Its Availability

Potassium supplements and/or potassium-sparing drugs, such as spironolactone, shorten the QTc interval in 24% of cases.112,113 Drugs that favor opening of the potassium channels, such as aprikalim, levcromakalim, nicorandil, and pinacidil, have shown to be useful in the treatment of LQTS. The subtypes in which they are of particular benefit are LQTS1 and LQTS2.114

Pacemakers and Defibrillators

Pacemaker stimulation has been used in patients with pause-dependent arrhythmia.115,116 Patients with LQTS3 usually benefit more from this treatment because the prevalence of bradycardia is greater in this group. DDD pacing is indicated in patients with pause-dependent arrhythmia or high-grade 2:1 AV block. Frequencies programmed below 70 beats/min117 are not useful for preventing ventricular arrhythmia. It is recommended to program the sensor to fast response, because these patients usually have inappropriate heart rate acceleration in response to exercise. All functions that imply the presence of pauses should be shut off, such as the hysteresis and nocturnal function. The PARP (postventricular atrial refractory period) should be as short as possible. The frequency regulation function should be on to prevent postextrasystolic pause. It should be remembered that T wave oversensing and capture failures can also give rise to pauses. Combined use of an implantable cardioverter defibrillator (ICD) and beta-blockers substantially decreases the incidence of sudden death.118-120 The indication for these measures is clear in high-risk cases.121 Programming of the device will vary according to the needs of the individual patient, but, generally, administration of treatment in asymptomatic, self-limited events should be avoided; to this end, a detection time of 15 s is indicated. Arrhythmic storm is a complication of AID therapy. Nearly 15% of patients can experience this complication, which is due, in good part, to increased sympathetic tone following the ICD shock.118 This problem can be managed by increasing the beta-blocker dose. If this measure is not useful, resection of the sympathetic chain ganglia should be considered.

Left Sympathectomy

In 1971 sympathetic gangliectomy was introduced as a useful therapeutic option in these patients.122 In 1991, Schwartz et al123 published the first series of 85 patients with a poor response to beta-blocker treatment, in whom a left stellectomy was performed with encouraging results: a 5-year survival rate of 94%. Currently, this therapeutic option is offered to high-risk patients who persist with syncope despite beta-blocker treatment and/or pacemaker implantation, and those who experience frequent shocks from their implanted defibrillator. The procedure consists of resection of the inferior portion of the stellate ganglion and the T2 to T4 left thoracic ganglia of the sympathetic chain, since simple left stellectomy has not proven sufficiently effective. Microinvasive thoracoscopy124,125 has been used with good results. The largest series of patients treated with this method was recently reported and showed a significant reduction in the number of syncope episodes or sudden deaths, as well as a 5-year survival rate of 95%. In patients with previous syncope, 5-year survival was 97%, with an 11% possibility of recurrence, which, in the majority, consisted of a single syncopal event. There was also a significant reduction in the QT segment following left sympathectomy. Despite these favorable results, prevention of sudden death is not complete, but has been reduced to 3%. In patients with an ICD who underwent surgery because of multiple defibrillator shocks, the mean number of events decreased from 25 to 0, a 95% reduction. A beneficial effect was confirmed in LQTS1. Benefits are likely to be smaller in patients with LQTS2, and in LQTS3, its effectiveness has not been proven.126

Ablation

It has been reported that ablation of the extrasystole, which in some cases initiates the ventricular arrhythmia, can be carried out with a reduction in the incidence of episodes.127 However, there are no long-term studies with an appropriate number of patients to justify routine use of this technique.

See editorial on pages 675-82

ABBREVIATIONS
AV: atrioventricular
AID: automatic implantable defibrillator
ECG: electrocardiogram
QTc: heart rate-corrected QT
ATS: Andersen-Tawil syndrome
LQTS: long QT syndrome

Dr. Medeiros receives economic support from CONACyT and FUNSALUD.


Correspondence:
Dra. A. Medeiros-Domingo.
Unidad de Biología Molecular. Instituto Nacional de Ciencias Médicas
y Nutrición Salvador Zubirán.
Vasco de Quiroga, 15.
Tlalpan 14000. Mexico DF. Mexico.
E-mail: argeliamed@yahoo.com

Bibliography
[1]
Jervell A, Lange-Nielsen F..
Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death..
Am Heart J, 54 (1957), pp. 59-68
[2]
Romano C, Gemme G, Pongiglione R..
Rare cardiac arrhythmias of the pediatric age. I. Repetitive paroxysmal tachycardia..
Minerva Pediatr, 15 (1963), pp. 1155-64
[3]
Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT..
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome..
Cell, 80 (1995), pp. 795-803
[4]
Wang Q, Shen J, Li Z, Timothy K, Vincent GM, Priori SG, et al..
Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia..
Hum Mol Genet, 4 (1995), pp. 1603-7
[5]
Ackerman MJ..
The long QT syndrome: ion channel diseases of the heart..
Mayo Clin Proc, 73 (1998), pp. 250-69
[6]
Priori SG..
Inherited arrhythmogenic diseases: the complexity beyond monogenic disorders..
[7]
Tester DJ, Will ML, Haglund CM, Ackerman MJ..
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing..
[8]
Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, et al..
Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice..
JAMA, 294 (2005), pp. 2975-80
[9]
Priori SG, Napolitano C, Schwartz PJ..
Low penetrance in the long-QT syndrome: clinical impact..
Circulation, 99 (1999), pp. 529-33
[10]
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, 103 (2001), pp. 89-95
[11]
Ackerman MJ, Tester DJ, Porter CJ..
Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome..
Mayo Clin Proc, 74 (1999), pp. 1088-94
[12]
Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, et al..
Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes..
Circulation, 102 (2000), pp. 2849-55
[13]
Zareba W..
Genotype-specific ECG patterns in long QT syndrome..
J Electrocardiol, 39 (2006), pp. S101-6
[14]
Khositseth A, Tester DJ, Will ML, Bell CM, Ackerman MJ..
Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome..
Heart Rhythm, 1 (2004), pp. 60-4
[15]
Beaufort-Krol GC, van den Berg MP, Wilde AA, van Tintelen JP, Viersma JW, Bezzina CR, et al..
Developmental aspects of long QT syndrome type 3 and Brugada syndrome on the basis of a single SCN5A mutation in childhood..
J Am Coll Cardiol, 46 (2005), pp. 331-7
[16]
Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, du-Bell WH, et al..
Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death..
Nature, 421 (2003), pp. 634-9
[17]
Mohler PJ, Bennett V..
Ankyrin-based cardiac arrhythmias: a new class of channelopathies due to loss of cellular targeting..
Curr Opin Cardiol, 20 (2005), pp. 189-93
[18]
Mohler PJ, Splawski I, Napolitano C, Bottelli G, Sharpe L, Timothy K, et al..
A cardiac arrhythmia syndrome caused by loss of ankyrin-B function..
Proc Natl Acad Sci USA, 101 (2004), pp. 9137-42
[19]
Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT..
Mutations in the hminK gene cause long QT syndrome and suppress IKs function..
Nat Genet, 17 (1997), pp. 338-40
[20]
Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, et al..
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia..
Cell, 97 (1999), pp. 175-87
[21]
Andersen ED, Krasilnikoff PA, Overvad H..
Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies..
A new syndrome? Acta Paediatr Scand, 60 (1971), pp. 559-64
[22]
Tawil R, Ptacek LJ, Pavlakis SG, deVivo DC, Penn AS, Ozdemir C, et al..
Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features..
Ann Neurol, 35 (1994), pp. 326-30
[23]
Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, et al..
Mutations in Kir21 cause the developmental and episodic electrical phenotypes of Andersen's syndrome..
Cell, 105 (2001), pp. 511-9
[24]
Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz PJ, et al..
Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype..
Circulation, 111 (2005), pp. 2720-6
[25]
Yoon G, Oberoi S, Tristani-Firouzi M, Etheridge SP, Quitania L, Kramer JH, et al..
Andersen-Tawil syndrome: Prospective cohort analysis and expansion of the phenotype..
Am J Med Genet A, 140 (2006), pp. 312-21
[26]
Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al..
Ca(V)12 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism..
[27]
Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, et al..
Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations..
Proc Natl Acad Sci USA, 102 (2005), pp. 8089-96
[28]
Mutant Caveolin-3 induces persistent late sodium current and is associated with long QT syndrome. Circulation. 2006 [in press].
[29]
Medeiros A, Kaku T, Tester DJ, Iturralde P, Itty A, Ye B, et al..
subunit mutation causes congenital long QT syndrome. Heart Rhyth, 3 (2006), pp. S34
[30]
Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, et al..
A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome..
Nat Genet, 15 (1997), pp. 186-9
[31]
The Jervell and Lange-Nielsen Syndrome. natural history, molecular basis, and clinical outcome. Circulation. 2006.
[32]
Schwartz PJ, Moss AJ, Vincent GM, Crampton RS..
Diagnostic criteria for the long QT syndrome. An update..
Circulation, 88 (1993), pp. 782-4
[33]
Chang IK, Shyu MK, Lee CN, Kau ML, Ko YH, Chow SN, et al..
Prenatal diagnosis and treatment of fetal long QT syndrome: a case report..
Prenat Diagn, 22 (2002), pp. 1209-12
[34]
Zhao H, Strasburger JF, Cuneo BF, Wakai RT..
Fetal cardiac repolarization abnormalities..
Am J Cardiol, 98 (2006), pp. 491-6
[35]
Miller TE, Estrella E, Myerburg RJ, Garcia de Viera J, Moreno N, Rusconi P, et al..
Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome..
Circulation, 109 (2004), pp. 3029-34
[36]
Tester DJ, McCormack J, Ackerman MJ..
Prenatal molecular genetic diagnosis of congenital long QT syndrome by strategic genotyping..
Am J Cardiol, 93 (2004), pp. 788-91
[37]
Cowan JC, Yusoff K, Moore M, Amos PA, Gold AE, Bourke JP, et al..
Importance of lead selection in QT interval measurement..
Am J Cardiol, 61 (1988), pp. 83-7
[38]
Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J. 2006.
[39]
Bazett H..
An analysis of the time-relations of electrocardiograms..
Heart, 7 (1920), pp. 353-70
[40]
Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, et al..
Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one..
Heart Rhythm, 2 (2005), pp. 569-74
[41]
Vincent GM, Timothy KW, Leppert M, Keating M..
The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome..
N Engl J Med, 327 (1992), pp. 846-52
[42]
Perkiomaki JS, Zareba W, Nomura A, Andrews M, Kaufman ES, Moss AJ..
Repolarization dynamics in patients with long QT syndrome..
J Cardiovasc Electrophysiol, 13 (2002), pp. 651-6
[43]
Zareba W, Moss AJ, le Cessie S, Hall WJ..
T wave alternans in idiopathic long QT syndrome..
J Am Coll Cardiol, 23 (1994), pp. 1541-6
[44]
Narayan SM..
T-wave alternans and the susceptibility to ventricular arrhythmias..
J Am Coll Cardiol, 47 (2006), pp. 269-81
[45]
Beinder E, Grancay T, Menendez T, Singer H, Hofbeck M..
Fetal sinus bradycardia and the long QT syndrome..
Am J Obstet Gynecol, 185 (2001), pp. 743-7
[46]
Lupoglazoff JM, Denjoy I, Villain E, Fressart V, Simon F, Bozio A, et al..
Long QT syndrome in neonates: conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations..
J Am Coll Cardiol, 43 (2004), pp. 826-30
[47]
Scott WA, Dick M 2nd..
Two:one atrioventricular block in infants with congenital long QT syndrome..
Am J Cardiol, 60 (1987), pp. 1409-10
[48]
Garson A Jr, Dick M 2n.d, Fournier A, Gillette PC, Hamilton R, Kugler JD, et al..
The long QT syndrome in children. An international study of 287 patients..
Circulation, 87 (1993), pp. 1866-72
[49]
Trippel DL, Parsons MK, Gillette PC..
Infants with long-QT syndrome and 2:1 atrioventricular block..
Am Heart J, 130 (1995), pp. 1130-4
[50]
Gorgels AP, Al Fadley F, Zaman L, Kantoch MJ, Al Halees Z..
The long QT syndrome with impaired atrioventricular conduction: a malignant variant in infants..
J Cardiovasc Electrophysiol, 9 (1998), pp. 1225-32
[51]
van Hare GF, Franz MR, Roge C, Scheinman MM..
Persistent functional atrioventricular block in two patients with prolonged QT intervals: elucidation of the mechanism of block..
Pacing Clin Electrophysiol, 13 (1990), pp. 608-18
[52]
Lupoglazoff JM, Cheav T, Baroudi G, Berthet M, Denjoy I, Cauchemez B, et al..
Homozygous SCN5A mutation in long-QT syndrome with functional two-to-one atrioventricular block..
Circ Res, 89 (2001), pp. E16-21
[53]
Hoorntje T, Alders M, van Tintelen P, van der Lip K, Sreeram N, van der Wal A, et al..
Homozygous premature truncation of the HERG protein: the human HERG knockout..
Circulation, 100 (1999), pp. 1264-7
[54]
Piippo K, Laitinen P, Swan H, Toivonen L, Viitasalo M, Pasternack M, et al..
Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns..
J Am Coll Cardiol, 35 (2000), pp. 1919-25
[55]
Medeiros D, Argelia TK, Tester DJ, Iturralde Torres P, Itty A, et al..
Sodium channel Subunit mutation causes congenital long QT syndrome. Heart Rhyth, 3 (2006), pp. S34
[56]
Noda T, Shimizu W, Satomi K, Suyama K, Kurita T, Aihara N, et al..
Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome..
Eur Heart J, 25 (2004), pp. 2149-54
[57]
Liu J, Laurita KR..
The mechanism of pause-induced torsade de pointes in long QT syndrome..
J Cardiovasc Electrophysiol, 16 (2005), pp. 981-7
[58]
Viskin S, Fish R, Zeltser D, Belhassen B, Heller K, Brosh D, et al..
Arrhythmias in the congenital long QT syndrome:how often is torsade de pointes pause dependent? Heart, 83 (2000), pp. 661-6
[59]
Walker BD, Krahn AD, Klein GJ, Skanes AC, Yee R..
Burst bicycle exercise facilitates diagnosis of latent long QT syndrome..
Am Heart J, 150 (2005), pp. 1059-63
[60]
Vincent GM, Jaiswal D, Timothy KW..
Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome..
Am J Cardiol, 68 (1991), pp. 498-503
[61]
Takenaka K, Ai T, Shimizu W, Kobori A, Ninomiya T, Otani H, et al..
Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome..
Circulation, 107 (2003), pp. 838-44
[62]
Swan H, Viitasalo M, Piippo K, Laitinen P, Kontula K, Toivonen L..
Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects..
J Am Coll Cardiol, 34 (1999), pp. 823-9
[63]
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, 92 (1995), pp. 3381-6
[64]
Shimizu W..
The long QT syndrome: therapeutic implications of a genetic diagnosis..
Cardiovasc Res, 67 (2005), pp. 347-56
[65]
Crozier IG, Loughnan A, Dow LJ, Low CJ, Ikram H..
Congenital long QT syndrome in adults..
N Z Med J, 102 (1989), pp. 340-1
[66]
Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, et al..
Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-gogo-related gene potassium channel..
Circulation, 105 (2002), pp. 794-9
[67]
di Paolo M, Luchini D, Bloise R, Priori SG..
Postmortem molecular analysis in victims of sudden unexplained death..
Am J Forensic Med Pathol, 25 (2004), pp. 182-4
[68]
Ackerman MJ, Tester DJ, Porter CJ, Edwards WD..
Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning..
N Engl J Med, 341 (1999), pp. 1121-5
[69]
Chugh SS, Senashova O, Watts A, Tran PT, Zhou Z, Gong Q, et al..
Postmortem molecular screening in unexplained sudden death..
J Am Coll Cardiol, 43 (2004), pp. 1625-9
[70]
Tester DJ, Ackerman MJ..
The role of molecular autopsy in unexplained sudden cardiac death..
Curr Opin Cardiol, 21 (2006), pp. 166-72
[71]
Tester DJ, Ackerman MJ..
Postmortem long QT syndrome genetic testing for sudden unexplained death in the young..
J Am Coll Cardiol, 49 (2007), pp. 240-6
[72]
Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, et al..
Prevalence of long-QT syndrome gene variants in sudden infant death syndrome..
[73]
Schwartz PJ..
Pro: newborn ECG screening to prevent sudden cardiac death..
Heart Rhythm, 3 (2006), pp. 1353-5
[74]
Quaglini S, Rognoni C, Spazzolini C, Priori SG, Mannarino S, Schwartz PJ..
Cost-effectiveness of neonatal ECG screening for the long QT syndrome..
Eur Heart J, 27 (2006), pp. 1824-32
[75]
Gouas L, Nicaud V, Berthet M, Forhan A, Tiret L, Balkau B, et al..
Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population..
Eur J Hum Genet, 13 (2005), pp. 1213-22
[76]
A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect. J Med Genet. 2006. En prensa.
[77]
Poelzing S, Forleo C, Samodell M, Dudash L, Sorrentino S, Anaclerio M, et al..
SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene..
Circulation, 114 (2006), pp. 368-76
[78]
Crotti L, Lundquist AL, Insolia R, Pedrazzini M, Ferrandi C, de Ferrari GM, et al..
KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome..
Circulation, 112 (2005), pp. 1251-8
[79]
Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, et al..
Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes..
Circulation, 105 (2002), pp. 1943-8
[80]
Plant LD, Bowers PN, Liu Q, Morgan T, Zhang T, State MW, et al..
A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y..
J Clin Invest, 116 (2006), pp. 430-5
[81]
Makielski JC, Ye B, Valdivia CR, Pagel MD, Pu J, Tester DJ, et al..
A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels..
[82]
Tan BH, Valdivia CR, Rok BA, Ye B, Ruwaldt KM, Tester DJ, et al..
Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants..
Heart Rhythm, 2 (2005), pp. 741-7
[83]
Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB..
Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome..
Mayo Clin Proc, 77 (2002), pp. 413-21
[84]
Khositseth A, Hejlik J, Shen WK, Ackerman MJ..
Epinephrineinduced T-wave notching in congenital long QT syndrome..
Heart Rhythm, 2 (2005), pp. 141-6
[85]
Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, et al..
Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome..
Heart Rhythm, 1 (2004), pp. 276-83
[86]
Vyas H, Hejlik J, Ackerman MJ..
Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response..
Circulation, 113 (2006), pp. 1385-92
[87]
Roden DM..
Drug-induced prolongation of the QT interval..
N Engl J Med, 350 (2004), pp. 1013-22
[88]
Viskin S, Justo D, Halkin A, Zeltser D..
Long QT syndrome caused by noncardiac drugs..
Prog Cardiovasc Dis, 45 (2003), pp. 415-27
[89]
Fitzgerald PT, Ackerman MJ..
Drug-induced torsades de pointes: the evolving role of pharmacogenetics..
Heart Rhythm, 2 (2005), pp. S30-7
[90]
Roden DM..
Long QT syndrome: reduced repolarization reserve and the genetic link..
J Intern Med, 259 (2006), pp. 59-69
[91]
Abriel H, Schlapfer J, Keller DI, Gavillet B, Buclin T, Biollaz J, et al..
Molecular and clinical determinants of drug-induced long QT syndrome: an iatrogenic channelopathy..
Swiss Med Wkly, 134 (2004), pp. 685-94
[92]
Sun Z, Milos PM, Thompson JF, Lloyd DB, Mank-Seymour A, Richmond J, et al..
Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced torsades de pointes..
J Mol Cell Cardiol, 37 (2004), pp. 1031-9
[93]
Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME..
Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome..
Mayo Clin Proc, 78 (2003), pp. 1479-87
[94]
Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, et al..
Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing..
Heart Rhythm, 1 (2004), pp. 600-7
[95]
Ye B, Valdivia CR, Ackerman MJ, Makielski JC..
A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation..
Physiol Genomics, 12 (2003), pp. 187-93
[96]
Seth R, Moss AJ, McNitt S, Zareba W, Andrews ML, Qi M, et al..
Long QT syndrome and pregnancy..
J Am Coll Cardiol, 49 (2007), pp. 1092-8
[97]
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, 348 (2003), pp. 1866-74
[98]
Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, et al..
Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry..
Circulation, 97 (1998), pp. 2237-44
[99]
Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, et al..
Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group..
N Engl J Med, 339 (1998), pp. 960-5
[100]
Risk of aborted cardiac arrest or sudden death during adolescence in the long-QT syndrome JAMA. 2006 [in press].
[101]
Schwartz PJ..
The congenital long QT syndromes from genotype to phenotype: clinical implications..
J Intern Med, 259 (2006), pp. 39-47
[102]
Itoh T, Kikuchi K, Odagawa Y, Takata S, Yano K, Okada S, et al..
Correlation of genetic etiology with response to beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome..
J Hum Genet, 46 (2001), pp. 38-40
[103]
Shimizu W, Tanabe Y, Aiba T, Inagaki M, Kurita T, Suyama K, et al..
Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT1 and LQT2 forms of congenital long QT syndrome..
J Am Coll Cardiol, 39 (2002), pp. 1984-91
[104]
Chatrath R, Bell CM, Ackerman MJ..
Beta-blocker therapy failures in symptomatic probands with genotyped long-QT syndrome..
Pediatr Cardiol, 25 (2004), pp. 459-65
[105]
Dorostkar PC, Eldar M, Belhassen B, Scheinman MM..
Long-term follow-up of patients with long-QT syndrome treated with betablockers and continuous pacing..
Circulation, 100 (1999), pp. 2431-6
[106]
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..
[107]
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, 101 (2000), pp. 616-23
[108]
Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, et al..
A mutation:mutation-specific therapy for long-QT syndrome? Circulation, 101 (2000), pp. 1698-706
[109]
Schulze-Bahr E, Fenge H, Etzrodt D, Haverkamp W, Monnig G, Wedekind H, et al..
Long QT syndrome and life threatening arrhythmia in a newborn: molecular diagnosis and treatment response..
Heart, 90 (2004), pp. 13-6
[110]
Kehl HG, Haverkamp W, Rellensmann G, Yelbuz TM, Krasemann T, Vogt J, et al..
Images in cardiovascular medicine. Life-threatening neonatal arrhythmia: successful treatment and confirmation of clinically suspected extreme long QT-syndrome-3..
[111]
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, 148 (2006), pp. 16-24
[112]
Shimizu W, Kurita T, Matsuo K, Suyama K, Aihara N, Kamakura S, et al..
Improvement of repolarization abnormalities by a K+ channel opener in the LQT1 form of congenital long-QT syndrome..
Circulation, 97 (1998), pp. 1581-8
[113]
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, 42 (2003), pp. 1777-82
[114]
Khan IA, Gowda RM..
Novel therapeutics for treatment of long-QT syndrome and torsade de pointes..
Int J Cardiol, 95 (2004), pp. 1-6
[115]
Viskin S..
Cardiac pacing in the long QT syndrome: review of available data and practical recommendations..
J Cardiovasc Electrophysiol, 11 (2000), pp. 593-600
[116]
Moss AJ, Liu JE, Gottlieb S, Locati EH, Schwartz PJ, Robinson JL..
Efficacy of permanent pacing in the management of high-risk patients with long QT syndrome..
Circulation, 84 (1991), pp. 1524-9
[117]
Pinski SL, Eguia LE, Trohman RG..
What is the minimal pacing rate that prevents torsades de pointes? Insights from patients with permanent pacemakers..
Pacing Clin Electrophysiol, 25 (2002), pp. 1612-5
[118]
Monnig G, Kobe J, Loher A, Eckardt L, Wedekind H, Scheld HH, et al..
Implantable cardioverter-defibrillator therapy in patients with congenital long-QT syndrome: a long-term follow-up..
Heart Rhythm, 2 (2005), pp. 497-504
[119]
Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M..
Implantable cardioverter defibrillator in high-risk long QTsyndrome patients..
J Cardiovasc Electrophysiol, 14 (2003), pp. 337-41
[120]
Kaufman ES..
Saving lives in congenital long QT syndrome:who benefits from implantable cardioverter defibrillator therapy? J Cardiovasc Electrophysiol, 14 (2003), pp. 342-3
[121]
Goel AK, Berger S, Pelech A, Dhala A..
Implantable cardioverter defibrillator therapy in children with long QT syndrome..
Pediatr Cardiol, 25 (2004), pp. 370-8
[122]
Moss AJ, McDonald J..
Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome..
N Engl J Med, 285 (1971), pp. 903-4
[123]
Schwartz PJ, Locati EH, Moss AJ, Crampton RS, Trazzi R, Ruberti U..
Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome. A worldwide report..
Circulation, 84 (1991), pp. 503-11
[124]
Wang LX..
Role of left cardiac sympathetic denervation in the management of congenital long QT syndrome..
J Postgrad Med, 49 (2003), pp. 179-81
[125]
Wang L, Feng G..
Left cardiac sympathetic denervation as the firstline therapy for congenital long QT syndrome..
Med Hypotheses, 63 (2004), pp. 438-41
[126]
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, 109 (2004), pp. 1826-33
[127]
Haissaguerre M, Extramiana F, Hocini M, Cauchemez B, Jais P, Cabrera JA, et al..
Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes..
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Revista Española de Cardiología (English Edition)

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