LQT2

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

Overview

LQT2 is the second most common subtype of mutations within long QT syndrome, occurring in 35-45% of LQTS patients. This subtype has been known to come to the attention of the cardiologist as a result of a cardiac event during the post-partum period, or after being triggered by an alarm clock or other auditory stimuli. The LQT2 mutation involves the HERG gene on chromosome 7, which regulates the channel responsible for the potassium rectifying current, which terminates the cardiac action potential. Most drugs that cause acquired long QT syndrome, do so by blocking the potassium rectifying current via the HERG gene. These drugs include antiarrhythmic drugs, certain non-sedating antihistamines, macrolide antibiotics, certain psychotropic medications, and certain gastric motility agents.

LQT2 Subtype

Type	OMIM	Mutation	Notes
LQT2	152427	alpha subunit of the rapid delayed rectifier potassium channel (HERG + MiRP1)	Current through this channel is known as IKr. This phenotype is also probably caused by a reduction in repolarizing current.

Genetics and Pathophysiology

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 (I_Kr). (The I_Kr 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).

There is a possibility, that like in LQT1 mutations, the location of the mutation may have a differing impact on the individual who is affected. A study of 201 patients showed that persons with mutations in the pore region had a greater risk of cardiac events and sudden cardiac death, and that these manifestations occurred earlier than in persons with mutations in the non-pore regions .

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 arrhytmia that is not quickly intervened on, may cause sudden death.
• In LQT2, syncope, prodrome, or other events may particularly occur in the post-partum period, or in response to auditory stimuli.

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 mexelitine 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.

Acquired LQTS with Medications

In some patients, drug associated LQTS appears to be due to a congenital form of LQTS which is clinically latent until until the patient is exposed to a drug, or another factor which may bring forth the manifestations of long QT syndrome. Most drugs that cause long QT syndrome do so by blocking the I_Kr current via the HERG gene. This causes rapid closure of the potassium channels and an abnormal rise in I_Kr. Similar to LQT1 this also causes results in a delayed ventricular repolarization and a lengthened QT interval.These include erythromycin, terfenadine, and ketoconazole. The HERG channel is very sensitive to unintended drug binding due to two aromatic amino acids, the tyrosine at position 652 and the phenylalanine at position 656. These amino acid residues are poised so drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are therefore not as prone to blockage. Treatment of drug induced LQTS includes acute therapy for the arrhythmia, discontinuation of the drug that precipitated the long QT syndrome, and the correction of any co-existing metabolic abnormalities such as hypomagnesemia and hypokalemia.

Drug Class	Examples
Antiarrhythmics	amiodarone, procainamide, quinidine, sotalol, disopyramide, ibutilide, dofetilide
Antibiotics	gatifloxacin, levofloxacin, ofloxacin, sparfloxacin, moxifloxacin, ciprofloxacin, azithromycin, erythromycin, telithromycin, clarithromycin, ketoconazole, fluconazole, itraconazole, terfenadine, trimethoprim-sulfamethoxazole
Antipsychotics	haloperidol, quetiapine, chlorpromazine, clozapine, risperidone, thioridazine
Antidepressants	amitriptyline, imipramine, nortriptyline, desipramine, doxepin, citalopram, paroxetine, sertraline, fluoxetine, venlafaxine
Antimotility Agents	ondansetron, prochlorperazine