Long QT syndrome

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

The long QT syndrome (LQTS) is a heart condition associated with prolongation of polarization (recovery) following depolarization (excitation) of the cardiac ventricles. It is associated with syncope (fainting) and sudden death due to ventricular arrhythmias. Arrhythmias in individuals with LQTS are often associated with exercise or excitement. LQTS is also associated with torsade de pointes, a the rare ventricular arrhythmia which can deteriorate into ventricular fibrillation and ultimately death.

Individuals with LQTS have a prolongation of the QT interval on the EKG. The Q wave on the EKG corresponds to ventricular depolarization while the T wave corresponds to ventricular repolarization. The QT interval is measured from the beginning of the Q wave 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 QT prolongation; in these individuals, the QT interval may prolong with the administration of certain medications.

There are multiple genetic mutations that account for LQTS, but LQT1, LQT2, and LQT3 account for approximately 75% of all LQTS cases and approximately 89% genotype-positive LQTS cases. ^[1][2]

LQT1 is the most common type of long QT syndrome, making up about 40-55% of all cases. This variant will sometimes come to the attention of the cardiologist following a cardiac event during exercise like swimming.^[3] The LQT1 gene is KCNQ1 located on chromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1 that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the I_Ks ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential.

Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern within the same family. In the autosomal recessive mutation of this gene, homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the I_Ks ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome.

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.

The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 35-45% of all cases. This variant will sometimes 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.^[3] This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (HERG) that is found on chromosome 7q36.1. The HERG gene (also known as KCNH2) codes for 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).

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

The LQT3 type of long QT syndrome accounts for 5-10% of cases, and cardiac events can occur during sleep. 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. 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. Furthermore mutations in SCN5A can cause Brugada syndrome, cardiac conduction disease, and dilated cardiomyopathy. Although rare, some affected individuals can have combinations of these diseases.

The pathophysiology of Long QT syndrome involves an inhereted or congenital abnormality in the cardiac ion channels leading to prolongation of the action potential and early after depolarization. There is also an imbalance in the sympathetic innervation of heart.

A number of syndromes are associated with LQTS.

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 is an autosomal dominant form of LQTS that is not associated with deafness. It occurs more frequently than Jervell and Lange-Nielsen syndrome.

There are multiple causes of QT prolongation that are distinct from Long QT syndrome such as drugs (anti-arrhythmic drugs, anti-psychotic drugs), electrolyte disturbances (hyperkalaemia, hypocalcaemia, hypoglycaemia, hypokalaemia, and hypomagnesemia), neurologic events such as subarachnoid hemorrhage, and anorexia nervosa.

The prevalence of LQTS is approximately 50/100,000 individuals (i.e. between 1:1100 and 1:3,000).^[4]

The genetic variant (LQT1-8), the gender and the QT interval are associated with the risk of a cardiac event. A history of prior events (syncope, fainting spells, seizures, sudden death) and a family history of cardiac events are associated with an increased risk of subsequent cardiac events.

• Persons with a history of repeated fainting episodes or syncope. If there are more than 2 fainting spells in under 2 years, the risk of an aborted SCD or SCD is increased 18 fold.^[5]
• Repeated blackouts or fainting spells in the context of the following are due to a malignant arrhythmia until proven otherwise:

• Exertion
• Loud startling noise
• Postpartum syncope
• Seizures

• A prior history of cardiac arrest.
• Family members of persons with repeated fainting, accidents, seizures or a history of cardiac arrest.
• Persons who are on certain medications that are known to cause a prolonged QT interval on electrocardiogram.
• Persons who are first degree relatives of people with know long QT syndrome.
• Persons who suffer from anorexia nervosa, or who have low levels of magnesium, calcium or potassium in their blood

About half the patients with long QT syndrome will have an arrhythmia that degenerates into Torsade de Pointes that may terminate spontaneously or may end in sudden cardiac death.

Long QT syndrome can result in fatal heart arrhythmias and death. Certain medications can increase the risk of fatal arrhythmias and death in persons with long QT syndrome.

People who are treated with lifestyle modifications and medications live longer than those who are not. For people who are not treated, half of them, mostly those with the inherited form of long QT syndrome, will die within 10 years.

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.

You should inquire about the following as part of the thistory:

• Persons with a history of repeated fainting episodes or syncope. If there are more than 2 fainting spells in under 2 years, the risk of an aborted SCD or SCD is increased 18 fold.^[6]
• Repeated blackouts or fainting spells in the context of the following are due to a malignant arrhythmia until proven otherwise:

• Exertion
• Loud startling noise
• Postpartum syncope
• Seizures

• A prior history of cardiac arrest.
• Family members of persons with repeated fainting, accidents, seizures or a history of cardiac arrest.
• Persons who are on certain medications that are known to cause a prolonged QT interval on electrocardiogram.
• Persons who are first degree relatives of people with know long QT syndrome.

• Fainting – fainting or syncope is the most common symptom in persons with long QT syndrome. The fainting can occur spontaneously without warning, or in response to certain stressors such as emotional stress, exercise, excitement or loud noises. Often when people are about to faint, they may experience lightheadedness, heart palpitations, blurred vision or weakness.
• Seizures – if the heart continues to beat abnormally, the brain can become deprived of oxygen, which can then cause seizures.
• Sudden death – in some circumstances a fatal arrhytmia that is not quickly intervened on, may cause sudden death.

The diagnosis of LQTS is difficult in so far as 2.5% of the healthy population have a prolonged QT interval, and 10% of LQTS patients have a normal QT interval (known as concealed LQTs). The presence of LQTs in the absence of QT prolongation (concealed LQTs) underscores the importance of genetic testing in the diagnosis of LQTs. It should be noted that the QT interval is often overestimated in the presence of a u wave.

The QT interval is often measured incorrectly. It is measured incorrectly by 33% of EP physicians and 75% of general cardiologists. It is measured incorrectly by <5% of Long QT syndrome experts who deal with this on a frequent basis. ^[7] The presence of a U wave can often lead to a false diagnosis of QT prolongation. In order to avoid this, the “teach the tangent” or “avoid the tail” rule is applied. In this method, a line is drawn on top of the downslope of the T wave as shown below with the dotted green line. The QT interval is measured where this green dotted line intersects with the isoelectric line as shown by the large green arrow. The red arrow is an incorrect assessment of the QT interval at the end of the U wave. Using the red arrow would lead to a misdiagnosis of QT prolongation.

A commonly used criterion to diagnose LQTS is the LQTS “diagnostic score”. 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. Two or 3 points indicates intermediate probability.

• QTc (Defined as QT interval / square root of RR interval)
  • >= 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 points
• Syncope (one cannot receive points both for syncope and Torsades de pointes)
• With stress – 2 points
• Without stress – 1 point

• Congenital deafness – 0.5 points
• Family history (the same family member cannot be counted for LQTS and sudden death)
• Other family members with definite LQTS – 1 point
• Sudden death in immediate family (members before the age 30) – 0.5 points

Shown below are examples of ECGs demonstrating QT prolongation in Long QT syndrome.

• LQT 1 shows ‘early onset’ broad based, slowly generated T waves
• LQT 2 shows small late T waves. Sometimes these T waves will be notched or double humped in lead V4.
• LQT 3 shows a flat and prolonged ST segment with a ‘late onset’ T wave that is normal in configuration.

Either compressive testing for all variants of LQTs or for the LQTs 1-3 variants is recommended in any patient in whom there is a strong clinical suspicion based on the family history, symptoms, resting EKG, provoked findings on an exercise treadmill test or during catecholamine infusion. Genetic studies remain to be the gold standard in the diagnosis of long QT syndrome.

The diagnosis of long QT syndrome can be difficult when abnormalities on electrocardiogram are borderline or intermittent. In cases where the history and symptoms are suggestive of long QT syndrome, but few or no abnormalities are seen on electrocardiogram, further testing can be done to unmask long QT syndrome with the use of exercise treadmill testing, and catecholamine provocation testing.

During this type of test, an EKG is performed while the patient is given an infusion of epinephrine. The epinephrine challenge is a useful test to establish electrocardiographic diagnosis in silent LQT1 mutation carriers, thus allowing implementation of prophylactic measures aimed at reducing sudden cardiac death. This test can unmask what is known as concealed long QT syndrome, which shows a normal QT interval on EKG at rest. This test can show a prolonged QT interval in persons who have a history of fainting spells in response to intense exercise or emotional upset, and therefore point to the diagnosis of long QT syndrome.

Similar to catecholamine provocation testing, an exercise treadmill test with EKG, can unmmask concealed long QT syndrome. This is also used as a provocation test for persons who have a pertinent history suggestive of long QT syndrome, or a family history of long QT syndrome, but do not have any abnormalities on resting EKG. Studies have shown not only the usefulness of exercise stress testing in the diagnosis of long QT syndrome, but also it’s utility in determining the subtype of long QT syndrome that the patient has. Krahn et al. showed that the hysteresis of the QT segment observed during exercise may be helpful in the diagnosis of long QT syndrome. They also showed that differences in the QT interval that were greater than 21ms between 1 min into recovery and early exercise may be indicative of long QT syndrome ^[8] . A study done by Takenaka et al. demonstrated that the QTc in LQT1 patients was significantly prolonged during exercise, whereas in LQT2 patients, exercise did not cause any significant changes in the QTc, however did show a prominent notch on the descending limb of the T wave. They also showed that there is a steeper QT/R-R slope in LQT2 patients than in LQT1 patients during exercise ^[9].

Beta-blockers are first line treatment in LQTs along with electrolyte repletion, and avoidance of triggers (drugs, supplements, loud noises). LQTs is one of the few diseases where genetic testing actually can provide important guidance such as who to put a AICD (defibrillator) in for primary prevention. ^[10] Left stellectomy is not a cure, but is second line therapy to reduce the risk of sudden cardiac death and is indicated if the patient does not tolerate beta blockers or breaks through beta blockers, as well as in young patients under the age of 12 where beta blockers are not deemed protective enough and where the morbidity of an AICD seems excessive. Patients with Long QT syndrome should undergo secondary prevention with AICD implantation for secondary prevention if they sustain an aborted cardiac arrest or sudden cardiac death.

Class I

“1. Lifestyle modification is recommended for patients with an LQTS diagnosis (clinical and/or molecular). (Level of Evidence: B)”

“2. Beta blockers are recommended for patients with an LQTS clinical diagnosis (i.e., in the presence of prolonged QT interval). (Level of Evidence: B)”

“3. Implantation of an ICD along with use of beta blockers is recommended for LQTS patients with previous cardiac arrest and who have reasonable expectation of survival with a good functional status for more than 1 y. (Level of Evidence: A)”

Class IIa

“1. Beta blockers can be effective to reduce SCD in patients with a molecular LQTS analysis and normal QT interval. (Level of Evidence: B)”

“2. Implantation of an ICD with continued use of beta blockers can be effective to reduce SCD in LQTS patients experiencing syncope and/or VT while receiving beta blockers and who have reasonable expectation of survival with a good functional status for more than 1 y. (Level of Evidence: B)”

Class IIb

“1. Left cardiac sympathetic neural denervation may be considered for LQTS patients with syncope, torsades de pointes, or cardiac arrest while receiving beta blockers. (Level of Evidence: B)”

“2. Implantation of an ICD with the use of beta blockers may be considered for prophylaxis of SCD for patients in categories possibly associated with higher risk of cardiac arrest such as LQT2 and LQT3 and who have reasonable expectation of survival with a good functional status for more than 1 y. (Level of Evidence: B)”

Class I

“1. In patients with drug-induced LQTS, removal of the offending agent is indicated. (Level of Evidence: A)”

Class IIa

“1. Management with intravenous magnesium sulfate is reasonable for patients who take QT-prolonging drugs and present with few episodes of torsades de pointes in which the QT remains long. (Level of Evidence: B)”

“2. Atrial or ventricular pacing or isoproterenol is reasonable for patients taking QT-prolonging drugs who present with recurrent torsades de pointes. (Level of Evidence: B)”

Class IIb

“1. Potassium ion repletion to 4.5 to 5 mmol/L may be reasonable for patients who take QT-prolonging drugs and present with few episodes of torsades de pointes in whom the QT remains long. (Level of Evidence: C)”

Certain medications should be avoided in persons with long QT syndrome, to avoid worsening the condition. These medications include certain appetite suppressants, decongestants, and antibiotics such as erythromycin. Illicit drugs such as cocaine and amphetamines can be even more dangerous in persons with long QT syndrome.

• Albuterol
• Alfuzosin
• Amantadine
• Amiodarone
• Amisulpride
• Amitriptyline
• Amphetamine
• Arsenic trioxide
• Artenimol + piperaquine
• Astemizole
• Atazanavir
• Atomoxetine
• Azithromycin
• Bepridil
• Chloral hydrate
• Chloroquine
• Chlorpromazine
• Ciprofloxacin
• Cisapride
• Citalopram
• Clarithromycin
• Clomipramine
• Clozapine
• Cocaine
• Desipramine
• Dexmethylphenidate
• Diphenhydramine
• Diphenhydramine
• Disopyramide
• Dobutamine
• Dofetilide
• Dolasetron
• Domperidone
• Dopamine
• Doxepin
• Dronedarone
• Droperidol
• Ephedrine
• Epinephrine
• Eribulin
• Erythromycin
• Escitalopram
• Famotidine
• Fenfluramine
• Fingolimod
• Flecainide
• Fluconazole
• Fluoxetine
• Foscarnet
• Fosphenytoin
• Galantamine
• Gatifloxacin
• Gemifloxacin
• Granisetron
• Halofantrine
• Haloperidol
• Ibutilide
• Iloperidone
• Imipramine
• Indapamide
• Isoproterenol
• Isradipine
• Itraconazole
• Ketoconazole
• Lapatinib
• Levalbuterol
• Levofloxacin
• Levomethadyl
• Lisdexamfetamine
• Lithium
• Mesoridazine
• Metaproterenol
• Methadone
• Methylphenidate
• Midodrine
• Mirtazapine
• Moexipril / HCTZ
• Moxifloxacin
• Nicardipine
• Nilotinib
• Norepinephrine
• Nortriptyline
• Octreotide
• Ofloxacin
• Ondansetron
• Oxytocin
• Paliperidone
• Paroxetine
• Pentamidine
• Perflutren lipid microspheres
• Phentermine
• Phenylephrine
• Phenylpropanolamine
• Pimozide
• Probucol
• Procainamide
• Protriptyline
• Pseudoephedrine
• Quetiapine
• Quinidine
• Ranolazine
• Ritodrine
• Ritonavir
• Roxithromycin
• Salmeterol
• Sertindole
• Sertraline
• Sevoflurane
• Sibutramine
• Solifenacin
• Sotalol
• Sparfloxacin
• Sunitinib
• Tacrolimus
• Tamoxifen
• Telithromycin
• Terbutaline
• Terfenadine
• Thioridazine
• Tizanidine
• Tolterodine
• Trazodone
• Trimethoprim-Sulfamethoxazole
• Trimipramine
• Vandetanib
• Vardenafil
• Venlafaxine
• Voriconazole
• Ziprasidone

Illness that cause hypokalemia due to vomiting and diarrhea can aggravate long QT syndrome. Medications that can lower the levels of potassium in the blood should also be avoided.

The use of potassium supplementation is experimental and is not evidence based. The hypothesis is that ff the potassium content in the blood rises, the action potential shortens and it is for this reason that increasing potassium concentration may minimize the occurrence of arrhythmias. It should work best in LQT2 since the HERG channel is especially sensible to potassium concentration, but potassium supplementation is experimental and not evidence based.

Beta blockers are first line therapy in the treatment of Long QT syndrome.

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. beta receptor blocking agents decrease the risk of stress or catecholamine induced arrhythmias. Nadolol and propranolol are recommended, and caution should be used with atenolol.

Nadolol at a dose of 1.0 to 1.5 mg/kg/day or 50 mg/m2/day QD or BID is the dose

3-4 mg/kg/day BID for the long acting form and TID for the liquid. Often preferred in LQT3.

Mexiletine is a sodium channel blocker. In LQT3 the problem is that the sodium channel does not close properly. Mexiletine closes these channels and is believed to be potentially of use when other therapies fail. It should be especially effective in LQT3 but there is limited evidence to support this recommendation.

Genotype and QT interval duration are independent predictors of recurrence of life-threatening events during beta-blockers therapy. Specifically the presence of QTc >500ms and LQT2 and LQT3 genotype are associated with the highest incidence of recurrence. In these patients primary prevention with ICD (Implantable Cardioverster Defibrilator) implantaion can be considered.^[12]

An AICD should be implanted if:

• The QTc is > 550 ms and if it is not LQT1
• LQT2 in women and the QTc is > 500 ms, with or without symptoms
• In infants with 2:1 AV block (controversial)
• In JLNS (LQTS with deafness) given its malignant propensity (controversial)

Videoscopic Left Cardiac Sympathetic Denervation Surgery (left stellectomy) is not a cure, but reduces the risk of sudden cardiac death and is indicated if:

• The patient does not tolerate beta blockers or breaks through beta blockers
• The patient faints while on beta blockers
• There is a history of VF terminating AICD shocks
• In young patients under the age of 12 where beta blockers are not deemed protective enough and where the morbidity of an AICD seems excessive.

Patients with Long QT syndrome should undergo secondary prevention with AICD implantation if they sustain an aborted cardiac arrest or sudden cardiac death.

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

Long QT syndrome results from an inherited abnormality in the ion channels of the heart, most commonly potassium channels and sodium channels.^[1][2] In long QT syndrome, mutations in the potassium channels lead to a decrease in the potassium efflux during repolarization, whereas gain of function in the sodium channels cause a slow sodium influx during depolarization. The different mutations involved in long QT syndrome culminate in a similar outcome which is the prolongation of both the action potential and the QT interval. Arrhythmia in long QT syndrome involve an abnormal repolarization of the heart.

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 so-called early after-depolarizations (EADs) that are seen in LQTS are due to re-opening of L-type calcium 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) — especially since repolarization is impaired. Normally during adrenergic states, repolarizing currents will also be enhanced to shorten the action potential. In the absence of this shortening and the presence of increased L-type calcium current, EADs may arise.

The so-called delayed after-depolarizations (DADs) are thought to be due to an increased Ca²⁺ filling of the sarcoplasmic reticulum. This overload may cause spontaneous Ca²⁺ release during repolarization, causing the released Ca²⁺ to exit the cell through the 3Na⁺/Ca²⁺-exchanger which results in a net depolarizing current.

Most Long QT syndromes are inherited in an autosomal dominant pattern with variable penetrance,^[3] the exception being Jervell and Lange-Nielsen syndrome (JLNS) which is associated with deafness and is inherited in an autosomal recessive pattern.

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 (LQT8) or congenital neural deafness (LQT1). A number of specific genes loci have been identified that are associated with LQTS.

A number of syndromes are associated with LQTS.

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 is an autosomal dominant form of LQTS that is not associated with deafness.

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