Long QT syndrome

From Academic Kids

The long QT syndrome (LQTS) is a heart disease in which there is an abnormally long delay between the electrical excitation (or depolarization) and relaxation (repolarization) of the ventricles of the heart. It is associated with syncope (loss of consciousness) and with sudden death due to ventricular arrhythmias. Arrhythmias in individuals with LQTS are often associated with exercise or excitement. The cause of sudden cardiac death in individuals with LQTS is ventricular fibrillation.

Individuals with LQTS have a prolongation of the QT interval on the ECG. The Q point on the ECG corresponds to the beginning of ventricular depolarization while the T point corresponds to the beginning of ventricular repolarization. The QT interval is measured from the Q point to the end of the T wave. While many individuals with LQTS have persistent prolongation of the QT interval, some individuals do not always show the QT prolongation; in these individuals, the QT interval may prolong with the administration of certain medications.

Contents

Genetics

The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype, with some variants having associated syndactyly or congenital neural deafness. A number of specific genes loci have been identified that are associated with LQTS. Following is a list of the most common mutations:

  • LQT1 - mutations to the alpha subunit of the slow delayed rectifier potassium channel (KCNQ1 or KvLQT1). The current through the heteromeric channel (KCNQ1+KCNE1) is known as IKs. This mutation is thought to cause LQT by reducing the amount of repolarizing action potential current that prolongs action potential duration (APD). These mutations tend to be the most common yet least severe.
  • LQT2 - mutations to the alpha subunit of the fast delayed rectifier potassium channel (HERG). Current through this channel is known as IKr. This phenotype is also probably caused by a reduction in repolarizing current.
  • LQT3 - mutations to the alpha subunit of the sodium channel (SCN5A). Current through is channel is commonly referred to as INa. Depolarizing current through the channel late in the action potential is thought to prolong APD. The late current is due to failure of the channel to remain inactivated and hence enter a bursting mode in which significant current can enter when it should not. These mutations are more lethal but less common.
  • LQT4 - mutations in an anchor protein Ankyrin B which anchors the ion channels in the cell. Very rare.
  • LQT5 - mutations in the beta subunit MinK which coassembles with KvLQT1.
  • LQT6 - mutations in the beta subunit MiRP1 which coassembles with HERG.
  • LQT7 - mutations in the potassium channel KCNJ2 which leads to Andersen-Tawil syndrome.
  • LQT8 - mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c leading to Timothy's syndrome

Other mutations affect the beta subunits ion channels or even ryanodine receptors. For example LQT6 affects minK (aka KCNE1) which is the beta subunit that coassembles with KCNQ1 to form IKs channels.

Drug induced LQT is usually a result of treatment by anti-arrhythmic drugs such as amiodarone or a number of other drugs that have been reported to cause this problem (e.g. cisapride). Genetic mutations may make one more prone to drug induced LQT.

LQT1

LQT1 is the most common type of long QT syndrome, making up about 40 to 55 percent of all cases. The LQT1 gene is named KVLQT1 (also known as KCNQ1), and has been isolated to chromosome 11p15.5. Studies of the gene product suggest that KVLQT1 encodes for a voltage-gated potassium channel that is highly expressed in the heart. It is believed that the product of the KVLQT1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the IKs ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential.

The KVLQT1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene, homozygous mutations of KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness.

Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine. This can also unmark latent carriers of the LQT1 gene.

Many missense mutations of the LQT1 gene have been identified. These are often associated with a high risk percentage of symptomatic carriers and sudden death.

LQT2

The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 35 to 45 percent of all cases. This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (HERG) on chromosome 7. The HERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning HERG gene allows protection against early after depolarizations (EADs).

Most drugs that cause long QT syndrome do so by blocking the IKr current via the HERG gene. These include erythromycin, terfenadine, and ketoconazole.

LQT3

The LQT3 type of long QT syndrome involves mutation of the gene that encodes the alpha subunit of the Na+ ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and NaV1.5). The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization. Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.

A large number of mutations have been characterized as leading to or predisposing LQT3. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3.

LQT5

is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1 which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms it can lead to Jervell and Lange-Nielsen syndrome

LQT6

is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2 which encodes for the potassium channel beta subunit MiRP1.

LQT7

Andersen-Tawil syndrome is an autosomal dominant form of LQTS associated with skeletal deformities. It involves mutation in the gene KCNJ2 which encodes for a potassium channel proteine Kir 2.1. The syndrome is characterized by Long QT syndrome with ventricular arrhythmias, periodic paralysis and skeletal developmental abnormalies as clinodactyly, low-set ears and micrognathia. The manifestations are highly variable.

LQT8

Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactily and immune defiency.

Associated syndromes

A number of syndromes are associated with LQTS.

Jervell and Lange-Nielsen syndrome

The Jervell and Lange-Nielsen syndrome (JLNS) is an autosomal recessive form of LQTS with associated congenital deafness. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes.

In untreated individuals with JLNS, about 50 percent die by the age of 15 years due to ventricular arrhythmias.

Romano-Ward syndrome

Romano-Ward syndrome is an autosomal dominant form of LQTS that is not associated with deafness.


Mechanism of arrhythmia generation

All forms of the long QT syndrome involve an abnormal repolarization of the heart. The abnormal repolarization causes differences in the refractoriness of the myocytes. After-depolarizations (which occur more commonly in LQTS) can be propagated to neighboring cells due to the differences in the refractory periods, leading to re-entrant ventricular arrhythmias.

It is believed that the after-depolarizations that are seen in LQTS are due to re-opening of L-type sodium channels during the plateau phase of the cardiac action potential. Since adrenergic stimulation can increase the activity of these channels, this is an explanation for why the risk of sudden death in individuals with LQTS is increased during increased adrenergic states (ie: exercise, excitement).

Diagnosis

The diagnosis of LQTS is not easy since 2.5% of the healthy population have prolonged QT interval, and 10% of LQTS patients have a normal QT interval. A commonly used criteria to diagnose LQTS is the LQTS1993 criteria defined by Professor Peter Schwartz, Pavia, Italy. Its based on several criteria giving points to each. With 4 or more points the probability is high for LQTS, and with 1 or less point the probability is low.

QTc

>= 480 msec                              3 points
460-470 msec                             2 points
450 msec and male gender                 1 point  

Torsades de Pointes ventricular tachycardia

                                         2 points

T wave alternans

                                         1 point

Notched T wave in at least 3 leads

                                         1 point

Low heart rate for age (children)

                                         0.5 point

Syncope

One can not receive points both for syncope and Torsades de pointes.

with stress                              2 points
without stress                           1 point

Congenital deafness

                                         0.5 point

Family History

Other family members with definite LQTS  1 point
Sudden death in immediate family
members befor the age 30                 1 point
  

Treatment options

There are two treatment options in individuals with LQTS: arrhythmia prevention, and arrhythmia termination.

Arrhythmia suppression involves the use of medications or surgical procedures that attack the underlying cause of the arrhythmias associated with LQTS. Since the cause of arrhythmias in LQTS is after depolarizations, and these after depolarizations are increased in states of adrenergic stimulation, steps can be taken to blunt adrenergic stimulation in these individuals. These include administration of beta receptor blocking agents and amputation of the cervical sympathetic chain.

Arrhythmia termination involves stopping a life-threatening arrhythmia once it has already occurred. The only effective form of arrhythmia termination in individuals with LQTS is placement of an implantable cardioverter-defibrillator (ICD).

With better knowledge of the genetics underlying the long QT syndrome, more precise treatments will be readily available.1

References

1. Compton SJ, Lux RL, Ramsey MR, Strelich KR, Sanguinetti MC, Green LS, Keating MT, Mason JW. Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation. 1996 Sep 1;94(5):1018-22. PMID 8790040
2. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). Journal of Clinical Investigation. 2002 Aug;110(3):381-8. PMID 12163457.

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