LQT3

Long QT Syndrome Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

LQT3 is the third most common subtype of long QT syndrome, occurring in 5-10% of LQTS cases. It is most commonly associated with cardiac events that occur during sleep. It is also associated with Brugada syndrome and sudden infant death syndrome. This subtype is highly likely to show shortening of the QT interval in response to administration of mexilitine. This subtype is caused by a mutation in the SCN5A gene on chromosome 3, which affects the sodium channels. The slow leakage of sodium into the cells causes cell membrane instability, and a prolonged QT interval on EKG.

LQT3 Subtype

Type	OMIM	Mutation	Notes
LQT3	603830	alpha subunit of the sodium channel (SCN5A)	Current through this 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.

Genetics and Pathophysiology

The LQT3 type of long QT syndrome accounts for 5-10% of cases, and cardiac events can occur during sleep. Patients with LQT3 are less likely than patients with LQT1 and LQT2 to have events due to exercise or stress. This is because patients with LQT3 shorten their QT interval with tachycardia, and therefore are less susceptible to catecholamine induced arrhythmias. This variant involves a 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 Na_V1.5). The mutations involved in LQT3 slow the inactivation of the Na⁺ channel, resulting in prolongation of the Na⁺ influx during depolarization. As the sodium channel is not adequately inactivated, the membrane remains slightly depolarized by the slow leaking of sodium into the cell. This leads to instability of the membrane, and early after-depolarizations. Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.

There have been sporadic mutations in SCN5A that have been reported where neither parent of the affected individual had a mutation or a prolonged QT interval. Individuals affected with this sporadic mutation had the added factors of prolonged opening and early re-opening of the sodium channel, resulting in an even greater prolongation of the sodium channel decay time. These sporadic mutations have also bee associated with sudden infant death syndrome .

There have been certain polymorphisms of SCN5A that have been noted in about 13 percent of the African American population. These polymorphisms, named Y1102 and S1103Y are associated with a faster sodium channel activation, however are only shown to create a minimal increase in the risk of arrhythmia. Most of the affected subjects never develop an arrhythmia, however they may be at greater risk of long QT syndrome than the general population if they take certain medications or develop hypokalemia .

History and Symptoms

• Seizures - due to oxygen deprivation that occurs during arrhythmia.
• Fainting - fainting or syncope is the most common symptom LQTS.
• A prodrome may occur before losing consciousness, which may consist of lightheadedness, heart palpitations, blurred vision or weakness.
• Sudden death - a fatal arrhythmia that is not quickly intervened on, may cause sudden death.
• In LQT3, events may particularly occur during sleep.

Therapy

• Medications to control non-malignant arrhythmias.
• Electrolytes should be repleted as neccesary.
• Avoidance of triggers (drugs, supplements, loud noises, exercise).
• LQTs is one of the few diseases where genetic testing can provide important guidance, such as in whom to place an AICD (defibrillator) for the primary prevention of cardiac events.
• Placement of a pacemaker may be indicated.
• Left stellectomy is not a cure, but is a second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and AICD is not appropriate.
• Patients with long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

Genotype-specific Therapy

Patients with the LQT3 subtype should especially consider the following therapeutic options:

• Consider not using a beta-blocker as therapy, as these patients have less or no benefit with beta blockers compared with the other subtypes.
• Consider treatment with mexilitine as this is sodium-channel blocker and LQT3 is associated with the failure to inactivate sodium channels.
• Consider placement of a pacemaker, as bradycardia is common among these patients, and can lead to pause-dependent arrhythmias.

Other Manifestations of SCN5A Mutations

A large number of mutations in the same gene that causes LQT3, called SCN5A have been shown to have a variety of cardiac manifestations. 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. Some of the manifestations that mutations in SCN5A can cause are:

• Brugada syndrome
• Cardiac conduction disease
• Dilated cardiomyopathy
• Sudden unexpected nocturnal death syndrome
• Isolated familial AV conduction defect
• Congenital sick sinus syndrome
• Familial dilated cardiomyopathy