Physiology in medicine
Molecular biology and the prolonged QT syndromes

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Abstract

The prolonged QT syndromes are characterized by prolongation of the QT interval corrected for heart rate (QTc) on the surface electrocardiogram associated with T-wave abnormalities, relative bradycardia, and ventricular tachyarrhythmias, including polymorphic ventricular tachycardia and torsades de pointes. These patients tend to present with episodes of syncope, seizures, or sudden death typically triggered by exercise, emotion, noise, or, in some cases, sleep. These disorders of cardiac repolarization are commonly inherited, with the autosomal dominant form, Romano-Ward syndrome, most common. A rare autosomal recessive form associated with sensorineural deafness, Jervell and Lange-Nielsen syndrome, in which the cardiac disorder is autosomal dominant and deafness is a recessive trait, also occurs. The underlying genetic causes of these forms of prolonged QT interval syndromes are heterogeneous, with at least seven genes responsible for the clinical syndromes. All of the five genes identified to date encode ion channel proteins, suggesting this to be an ion channelopathy. In this review, the genetic basis of the prolonged QT interval syndromes will be discussed, genotype-phenotype correlations identified, and the approaches to genetic testing and treatments will be outlined.

Section snippets

Clinical features

The typical clinical presentation of LQTS is the occurrence of syncope or cardiac arrest precipitated by emotional or physical stress in a young, usually healthy individual. Females are affected more commonly than males, with a ratio of approximately 2:1 5, 6, but this is age dependent. An equal number of males and females are diagnosed between infancy and age 15 years, after which time there is a sharp increase in the female-to-male ratio 6, 7. Importantly, the age at initial syncopal event is

Electrocardiographic features

The classical electrocardiographic (ECG) features of LQTS include prolongation of the rate-corrected QT interval (QTc; Figure 1) as measured by Bazett’s formula (QTc = QT/RR) (13). The ECG changes in LQTS include considerably more than just the simple prolongation of the QT interval. Indeed, most of the characteristic ECG findings are consistent with the concept that repolarization in LQTS displays substantial spatial and temporal heterogeneity. Some of these important ECG features include T-

Disease classification

LQTS occurs either as an inherited disorder, sporadic disorder, or it may be acquired. The clinical presentation is similar in all forms of LQTS, but minor variations should be noted. Two inherited forms of LQTS have been described thus far and include the Romano-Ward syndrome (3) and the Jervell and Lange-Nielsen syndrome (JLNS) (1).

Epidemiology

LQTS was considered to be a very rare disorder until recently. Early in the course of studying LQTS there was speculation that LQTS was “undoubtedly more unrecognized than rare” (22), and this has recently been shown to be true as many new cases became identified. This new ability to identify patients was the result of improved physician education and awareness, the new molecular genetic information recently obtained, and the computer-based advertising by the LQTS support groups.

The incidence

Diagnostic criteria

In those patients with LQTS in which classical, clear-cut evidence of disease is apparent, the diagnosis can be made rapidly by simply taking a history and evaluating the electrocardiogram. As with many other clinical disorders, however, many cases are borderline or are confusing based on the lack of clinical correlation between history and the classical diagnostic methods. Another problem that existed until recently was that this disorder was believed to be rare and many physicians were

Provocative tests

The diagnosis of LQTS can be quite difficult in some patients using the surface electrocardiogram alone. While some ECG abnormalities, such as obvious QTc prolongation and T-wave abnormalities such as T-wave alternans, are diagnostic of LQTS, many patients have borderline QT interval prolongation or normal QT intervals with either symptoms (ie, syncope), torsades de pointes, or a family history of LQTS. In these patients, provocative tests may be useful. The tests may include determining the

Genetics of long QT syndrome

As previously noted, three forms of inherited LQTS have been described, including autosomal dominant (Romano-Ward syndrome), autosomal recessive (JLNS), and sporadic cases. Over the past decade, the genetic aspects of all three forms of LQTS have been unraveled. In 1991, Keating et al (36) identified genetic linkage to the short arm of chromosome 11 (11p15.5) in several families with Romano-Ward syndrome. Shortly thereafter, we demonstrated genetic heterogeneity, and this was confirmed by

KVLQT1 or KCNQ1: the LQT1 gene

The first of the genes mapped for LQTS, termed LQT1, required 5 years from the time that mapping to chromosome 11p15.5 was first reported to gene cloning. This gene, originally named KVLQT1, but more recently called KCNQ1, is a novel potassium channel gene that consists of 16 exons, spans approximately 400 kb, and is widely expressed in human tissues, including heart, inner ear, kidney, lung, placenta, and pancreas, but not in skeletal muscle, liver, or brain. In the original report, 11

Age and gender influence on QTc: relationship of genotype

It has been appreciated for several years that women are more susceptible to the development of torsades de pointes in the setting of QT prolongation. Compared with men, women also exhibit a longer QTc interval 6, 7. It was assumed that this gender difference in the length of the QT interval and the propensity to torsades de pointes was the result of a QT-prolonging influence of female hormones or other modifying agent. However, using genotyped families, Lehmann et al (78) showed that KVLQT1

Molecular basis of the cardiac action potential and the effect on the electrocardiogram

The cardiac action potential is mediated by a delicate balance between inward (ie, INa, ICa) and outward (IKr, IKs) currents described above (33). Persistent noninactivated inward sodium current in the plateau phase of the action potential or reduced IKr and IKs outward currents could prolong cardiac repolarization and the cardiac action potential, leading to prolongation of the QTc on the electrocardiogram. Excessive prolongation of the cardiac action potential could result in re-activation of

Genetics of Jervell and Lange-Nielsen syndrome

Neyroud et al (80) reported the first molecular abnormality in patients with JLNS when they reported on two families in which three children were affected by JLNS, finding a novel homozygous deletion-insertion mutation of KVLQT. A deletion of 7 bp and an insertion of 8 bp at the same location led to premature termination at the C-terminal end of the KVLQT1 channel. At the same time, Splawski et al (81) identified a homozygous insertion of a single nucleotide that caused a frameshift in the

Genotype-phenotype correlations

Moss et al (79) showed that the ECG manifestations of LQTS were in great part determined by the channel mutated. Different T-wave patterns were clearly evident when comparing tracings from patients with mutations in LQT1, LQT2, and LQT3. More recently, Zareba et al (87) showed that the mutated gene may result in a specific clinical phenotype with different triggers and may predict outcome. For instance, these authors suggested that mutations in LQT1 and LQT2 result in early symptoms (ie,

Genetic testing

Currently, five LQTS-causing genes have been identified with more than 50 mutations described to date. This genetic heterogeneity makes genetic testing more difficult than if a single gene defect were responsible for the disease. However, under certain conditions genetic testing can be performed. In large families in which linkage analysis may be performed, identification of the gene of interest (if the linkage is to one of the known genes) can be discerned rapidly, and mutations can be

Management of LQTS

At present, there are three classical modalities for treatment of LQTS that have withstood the test of time: β blockers 22, 92, pacemakers 93, 94, 95, and left cervicothoracic sympathetic ganglionectomy (96). The mortality of untreated symptomatic patients with LQTS exceeds 20% in the year after their first syncopal episode and approaches 50% within 10 years of initial presentation (10). With institution of the classical therapy, this can be reduced to 3% to 4% in 5 years after initial

Acute management of torsades de pointes

Once torsades de pointes is recognized, all QT-prolonging drugs should be withdrawn (if acquired LQTS) and drugs potentially causative of torsades de pointes (Table 3)should be discontinued. In addition, even modest hypokalemia should be corrected and the serum level of potassium kept within the high normal range. Potassium not only shortens the QT interval but also can decrease the potency of QT-prolonging drugs. If the episode of torsades de pointes persists for a long period, cardioversion

Summary

During the past decade, breakthroughs in the clinical and molecular genetic understanding of the long QT syndromes have occurred. However, much remains to be learned. Collaborative interactions between clinicians and basic scientists have enabled many of the new findings to be discovered, and continued close working relationships should provide the incentive necessary to continue this growth in knowledge. It is hoped that the dawn of the twenty-first century will bring with it better diagnostic

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