Long QT Syndrome(LQTS)

What is Long QT Syndrome (LQTS)

Long QT syndrome is a heart condition in which the heart takes longer than normal to recharge after each heartbeat.

This is caused by an abnormal electrical system in the heart. LQTS can upset the timing of your heartbeats.

It can cause dangerous changes in your heart rate and rhythm (arrhythmia).

Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolongation of the QT interval on the ECG associated with an increased risk of developing life-threatening ventricular arrhythmias, most commonly torsades de pointes (a specific type of polymorphic ventricular tachycardia), which may lead to ventricular fibrillation and sudden cardiac death (SCD).

This syndrome may be either genetic or acquired.

There are several types of LQTS. The three most common types are:

• Type 1. This can be triggered by stress or exercise, especially swimming.
• Type 2. This can be triggered by strong emotions or surprise.
• Type 3. This can be triggered when your heart slows during sleep.

You can be born with LQTS, or you can develop it later in life.

Synonyms

• LQTS
• Congenital forms:
  • Jervell and Lange-Nielsen syndrome (associated with deafness)
  • Romano-Ward syndrome (associated with normal hearing)

How common is Long QT syndrome?

Prevalence of Long QT syndrome

The prevalence of congenital causes, also known as Long QT syndrome (LQTS), is difficult to estimate but may be expected in 1 in 2,500 to 1 in 10,000 individuals.

It is more common in females and usually presents with cardiac events in childhood, adolescence, or early adulthood. There are, however, case reports of it manifesting in the fifth decade of life.

Family history is positive for Long QT syndrome in 40%, and for sudden cardiac death in 30% of patients.

Acquired causes are relatively more common than congenital causes.

Some studies report the prevalence of QT prolongation to be as many as 30% of patients in the intensive care unit

What are the causes?

The cause of this condition depends on the type of LQTS that you have.

• Inherited LQTS. You are born with this condition. It is caused by an abnormal gene that is passed down through your family.
• Acquired LQTS. You get this condition later in life. It may be caused by: 
  • Certain medicines that affect your heartbeat. Some examples are methadone and antihistamines.
  • Long periods of vomiting or diarrhea.
  • An eating disorder.
  • A thyroid disorder.

What increases the risk?

This condition is more likely to develop in:

• People who are born deaf.
• Women.
• People who have an eating disorder, such as anorexia nervosa or bulimia.
• People who have a family member with LQTS.
• People who have a family history of unexplained fainting, drowning, or sudden death.

What are the symptoms?

Symptoms of this condition include:

• Fainting.
• A fluttering feeling in your chest.
• Loud gasping during sleep.
• Seizures.

Symptoms of inherited LQTS almost always start before age 40.

Some people with this condition have no symptoms.

How is this diagnosed?

This condition may be diagnosed based on:

• Your symptoms.
• Your medical history and family history.
• A physical exam.
• Some tests, including:
  • An electrocardiogram (ECG) to measure electrical activity in your heart.
  • Holter monitoring to record your heartbeat for 1–2 days.
  • Stress test to record your heartbeat while you exercise.
  • A blood test to look for genes that cause LQTS.

How is this treated?

There is no cure for this condition. Treatment depends on the cause, your symptoms, and whether you have a family history of sudden death. Treatment may include:

• Making lifestyle changes, such as avoiding competitive sports or stressful situations.
• Taking supplements to correct abnormal salt (sodium), potassium, calcium, and magnesium levels.
• Stopping the use of a medicine. Do not stop the use of medicines without first talking to your health care provider.
• Taking heart medicines, such as beta blockers.
• Implanting a device that corrects a dangerous heartbeat, such as:
  • A pacemaker. This helps your heart beat in a normal rhythm.
  • A cardioverter-defibrillator. This senses a fast heartbeat and shocks the heart to restore normal heart rate.
• Having heart surgery to prevent arrhythmias.

Follow these instructions at home:

Medicine

• Take over-the-counter and prescription medicines only as told by your health care provider.
• If you want to take any new medicine, get approval from your health care provider first. Avoid any medicines that can cause this condition.

Lifestyle

• Make any lifestyle changes that are recommended by your health care provider. You may need to avoid:
  • Competitive sports.
  • Strenuous exercises and activities, such as swimming.
  • Stress.
  • Situations where sudden loud noises are likely.
• If you drink alcohol, limit how much you have:
  • 0–2 drinks a day for men.
  • 0–1 drink a day for women.
    • Be aware of how much alcohol is in your drink. In the U.S., one drink equals one typical bottle of beer (12 oz), one-half glass of wine (5 oz), or one shot of hard liquor (1½ oz).
• Do not use any products that contain nicotine or tobacco, such as cigarettes and e-cigarettes. If you need help quitting, ask your health care provider.

General instructions

• Develop a plan with your health care provider for how to deal with a sudden arrhythmia.
• Tell people who live with you about the signs of a sudden arrhythmia.
• Wear a medical ID necklace or bracelet that states your diagnosis and contact information.
• Have an automated external defibrillator (AED) available at home or work.
• Get treatment and support if you feel stress, fear, anxiety, or depression.
• Keep all follow-up visits as told by your health care provider. This is important.

Contact a health care provider if:

• You are suffering from stress, fear, anxiety, or depression.
• You vomit.
• You have diarrhea.

Get help right away if:

• You have chest pain or difficulty breathing.
• You have a fluttering feeling in your chest.
• You faint.
• You have a seizure.

These symptoms may represent a serious problem that is an emergency. Do not wait to see if the symptoms will go away. Get medical help right away. Call your local emergency services (911 in the U.S.). Do not drive yourself to the hospital.

Summary

• Long QT syndrome (LQTS) is a heart condition in which your heart takes longer than normal to recharge after each heartbeat. This is caused by an abnormal electrical system in your heart.
• LQTS can upset the timing of your heartbeats and cause dangerous changes in your heart rate and rhythm (arrhythmia).
• Some people are born with LQTS (inherited). Others develop it later in life (acquired).
• Some people with this condition have no symptoms. Those who do have symptoms may experience fainting, a fluttering feeling in the chest, loud gasping during sleep, or seizures.
• There is no cure for this condition. Treatment depends on the cause, your symptoms, and whether you have a family history of sudden death.

Detailed Info on Long QT Syndrome

Epidemiology & Demographics

• •Congenital LQTS is thought to account for >3000 deaths in childhood per yr in the United States.
• •The prevalence of congenital LQTS is at least 1 in 2000 live births and may even be higher because that estimate is based on genetic testing of infants in whom the QTc was in excess of 470 and 460 ms, respectively.
• •Incidence of LQTS is thought to be between 1:2500 and 1:10,000 in the general population, although it has been difficult to estimate because of incomplete penetrance. Congenital form associated with deafness is autosomal recessive (Jervell and Lange-Nielsen syndrome) and is less common than the autosomal dominant form as well as more severe.
• •Congenital form associated with normal hearing (Romano-Ward syndrome) is autosomal dominant. Although inheritance of LQTS is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. LQTS is more likely to express itself before puberty in males and after puberty in females.
• •At least 17 different LQTS genes have been identified to date. However, as clinical genetic testing evolves, some previously associated LQTS-susceptibility genes have been reconsidered as unlikely to be causative for congenital LQTS.
• •Mortality rate is estimated to be about 1% per yr.
• •Multiple mutations causing congenital LQTS have been described. The most common types of LQTS are described in

Common Types of Long QT (LQT) Syndrome

From Issa Z et al: Clinical arrhythmology and electrophysiology, ed 2, Philadelphia, 2012, Saunders.

	LQT1	LQT2	LQT3
Pathophysiology
Gene	KCNQ1 (KvLQT1)	KCNH2 (formerly “HERG”)	SCN5A
Protein	Kv7.1	Kv11.1	Nav1.5
Ionic current	Decreased IKs	Decreased IKr	Increased late INa
Clinical Presentation
Incidence of cardiac events	63%	46%	18%
Incidence of SCD	4%	4%	4%
Arrhythmia triggers	Emotional/physical stress (swimming, diving)	Emotional stress, arousal (alarm clock, telephone), rest, postpartum period	Sleep/rest
ECG	Broad-based T wave	Low-amplitude, bifid T wave	Long isoelectric ST segment
QT response to exercise	Attenuated QTc shortening and an exaggerated QTc prolongation during early and peak exercise	Normal QT during exercise but with exaggerated QT hysteresis	Supernormal QT shortening
Management
Exercise restriction	+++	++	?
Response to beta-blockers	+++	+++	?
Potassium supplement	+	++	+
Left cervicothoracic sympathectomy	++	++	++
Response to mexiletine	+	+	++

Physical Findings & Clinical Presentation

• •Palpitations, presyncope.
• •Syncope suggestive of cardiac/arrhythmic origin (not vasovagal syncope).
• •Resuscitated sudden cardiac arrest.
• •Seizure (often, patients with LQTS are misdiagnosed with epilepsy).
• •Family history of LQTS, but a family history of SCD has not been proved to be a risk factor for SCD in patients with LQTS.
• •Abnormal ECG (prolonged QT) in asymptomatic relatives of known case.
• •Prolonged QTc interval on average among patients with genetically confirmed LQTS is approximately 470 ms. In general the 99th percentile QTc values are 460 ms (prepuberty), 470 ms in postpubertal males, and 480 ms in postpubertal females.
• •In case of congenital LQTS the presentation of syncope or SCD is typically triggered by exercise and swimming in LQT1 patients (45% cases); in LQT2 (25%-40% cases) patients by emotion, pregnancy, or noise; and patients with LQT3 (5%-10% cases) are at highest risk of events when at rest or asleep.

Etiology

• •Cardiac repolarization abnormality
• •Congenital cause (hundreds of mutations on more than 10 genes have been identified)
• •Most of the gene mutations affect function of ion channels leading to prolonged repolarization (i.e., sodium and potassium channels resulting in either increased Na⁺ influx or decreased K⁺ efflux). These mutations prolong depolarization and predispose the patient to torsades de pointes
• •Acquired causes:
  • 1.Drugs: Dofetilide, ibutilide, bepridil, quinidine, procainamide, sotalol, amiodarone, ranolazine, disopyramide, phenothiazines and antiemetic agents (droperidol, domperidone), tricyclic antidepressants, antipsychotics (quetiapine, ziprasidone, iloperidone), citalopram, antihistamines, quinolones, azithromycin, astemizole or cisapride given with ketoconazole or erythromycin, clarithromycin, and antimalarials, particularly among patients with asthma or those using potassium-lowering medications; also common in patients receiving methadone
  • 2.Hypokalemia, hypomagnesemia, hypocalcemia (especially in patients with malabsorption syndrome)
  • 3.Liquid protein diet
  • 4.Central nervous system lesions
  • 5.Structural heart disease (heart failure, diastolic dysfunction, myocardial ischemia, and LVH)
  • 6.Hypothyroidism
  • 7.Bradyarrhythmias

Differential Diagnosis

• Brugada syndrome, arrhythmogenic right ventricular dysplasia, and LQTS are major causes of genetic sudden death syndromes

Diagnostic criteria for the congenital LQTS as per 2013 HRS Guidelines:

LQTS is diagnosed:

• •In the presence of an LQTS risk score ≥3.5 in the absence of a secondary cause for QT prolongation and/or

ong QT Syndrome Risk Score

From Schwartz PJ, Crotti L: QTc behavior during exercise and genetic testing for the long-QT syndrome, Circulation 124(20):2181-2184, 2011.

ECG Criteria
QTc >480 ms	3 points
QTc 460-480 ms	2 points
QTc 450-460 ms (males)	1 point
QTc 4th minute of recovery from exercise stress test >480 ms	1 point
Torsades de pointes	2 points
T-wave alternans	1 point
Notched T-wave in three leads	1 point
Bradycardia	0.5 point
History
Syncope with stress	2 points
Syncope without stress	1 point
Congenital deafness	0.5 point
Definite family history of long QT	1 point
Unexplained cardiac death in first-degree relative <30 yr	0.5 point

• In the presence of an unequivocally pathogenic mutation in one of the LQTS genes or
• •In the presence of a QT interval corrected for heart rate using Bazett formula (QTc) ≥500 ms in repeated 12-lead electrocardiogram (ECG) and in the absence of a secondary cause for QT prolongation
• •LQTS can be diagnosed in the presence of a QTc between 480 and 499 ms in repeated 12-lead ECGs in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation and in the absence of a pathogenic mutation

Workup

Cardiology referral is recommended for all cases.

Genetic analysis is an essential step for risk stratification of patients with congenital prolonged QT and is important for identification of potential mutation carriers within the proband family.

There is evidence for gene-specific triggers of events and therapeutic efficacy. Molecular screening should become part of the routine clinical management of LQTS.

In relatives of known patients with LQTS or in young patients with syncope:

• •Stress test may prolong the QT interval or cause T-wave alternans.
• •Valsalva maneuver: May prolong the QT interval or cause T-wave alternans.
• •Prolonged ECG monitoring with various stimulations aimed at increasing catecholamines and assess for QT prolongation (perform in a setting that can provide resuscitation with α- and β-antagonists readily available).
• •Epinephrine-induced prolongation of the QT interval (epinephrine infusion QT stress test).
• •Genetic analysis:
  • 1.LQT1 locus of KCNQ1 potassium channel gene.
  • 2.LQT2 locus of KCNH2 (formerly “HERG”) potassium channel gene.
  • 3.LQT3 locus of SCN5A sodium channel gene.
  • 4.These three variants account for >90% of all genotyped LQTS patients, whereas the remaining genes are responsible for a minority of cases.
• •Risk stratification for each genetic variant on the basis of gender and QTc: Groups are defined on the basis of the probability of the first cardiac event (syncope, cardiac arrest, or sudden death) before age 40 yr or before therapy. Specific mutations, depending on type, location, and degree, may confer a high risk even if the ECG abnormalities are mild. Clinically, QT interval duration was the strongest predictor of risk for cardiac events; a QTc exceeding 500 ms identifies patients with the highest risk.
  • 1.High risk (>50% of cardiac event): QTc ≥500 ms and LQT1 or LQT2, or male with LQT3.
  • 2.Moderate risk (30%-50%): QTc <500 ms in male with LQT3 or in female with LQT2 or LQT3, and female with LQT3 with QTc ≥500 ms.
  • 3.Low risk (<30%): QTc <500 ms and LQT1 or male LQT2 with QTc <500 ms.
  • 4.Prophylactic treatment should be considered in all patients with moderate or high risk for cardiac events based on the above risk stratification scheme 

Cardiac Event Risk Stratification Scheme Based on Genes, Gender, and QTc

	QTc <500 ms	QTc ≥550 ms
Genetic Subtype	Male	Female	Male	Female
LQT1	Low	Low	High	High
LQT2	Low	Intermediate	High	High
LQT3	Intermediate	Intermediate	High	Intermediate

Probability of the first cardiac event (syncope, cardiac arrest, or sudden death) before the age of 40 yr or before therapy. High = >50%, Intermediate = 30%-50%, Low = <30%.

Treatment

Nonpharmacologic Therapy

• •Physical activity and LQTS
  • 1.LQT1 patients experience 90% of lethal events under physical and emotional stress. Swimming and diving should be avoided or performed under supervision. In patients with LQT2 and LQT3, children and adolescents can resume participation in physical education classes, and adults should be encouraged to stay physically active.
  • 2.Regarding competitive athletics for individuals with congenital LQTS, there is a difference of opinion between the 2015 AHA/ACC Scientific Statement on Eligibility and the Disqualification Recommendations for Competitive Athletes, which allows participation in competitive events and training sessions dependent on availability of automated external defibrillator (AED). In contrast, previous European guidelines advise precautionary restriction from competitive sports in these situations.
• •Implantation of an implantable cardioverter-defibrillator (ICD) in the vast majority of LQTS patients is not necessary, and most patients with LQTS (90% or more in LQTS expert centers) do not need and should not receive an ICD. Consider ICD placement in following situations:
  • 1.Survivors of sudden cardiac arrest without a reversible cause.
  • 2.In patients with LQTS-associated sudden cardiac arrest while compliant with beta-blocker therapy.
  • 3.In patients with recurrent cardiac syncope in spite of beta-blockers and left cardiac sympathetic denervation.
  • 4.In an asymptomatic patient with either LQT2 or LQT3 whose resting QTc is >550 ms, consider prophylactic ICD.

Management of Patients with Long QT Syndrome

Adapted from Crawford MH et al [eds]: Cardiology, ed 2, St Louis, 2004, Mosby.

Type of Syndrome	Management	Indication
Congenital	Beta-blockers	Asymptomatic patients, symptomatic patients (who do not have bronchospasm)
	Cervicothoracic sympathectomy	Refractory symptoms, especially in pediatric patients
	Cardiac pacing	Refractory symptoms associated with bradycardia, pauses
	Implantable cardioverter-defibrillator	Cardiac arrest, refractory syncope, prophylaxis for moderate- to high-risk patients for cardiac events
Acquired	Elimination of causative drug or condition	All patients
	Magnesium sulfate	Nonsustained ventricular tachycardia, torsades de pointes (even with a normal serum magnesium concentration)
	Administration of potassium (to keep serum K+ >4.5 mEq/L)	Serum K+ <4.5 mEq/L
	Maneuvers to increase heart rate (cardiac pacing, isoproterenol)	Bradycardia, arrhythmias refractory to magnesium sulfate

K ⁺ , Potassium.

• ICD is never indicated based solely on the family history, as it is not a personal risk factor for the patient with LQTS.

Pharmacologic Therapy

• •All patients with LQTS and a history of syncope, seizures, or resuscitated SCA should be treated with a beta-blocker.
• •Beta-blockers, chiefly propranolol and nadolol, are an initial therapy of choice—there are differential responses to β-blocker therapy among different genetic variants; especially effective among LQT1 or LQT2 patients. Studies showed the efficacy of β-blockers with an overall mortality <2% over a mean follow-up exceeding 5 yr.
• •In patients with LQT3, mexiletine shortens the QTc and, increasingly, combination therapy with propranolol and mexiletine is utilized in these patients.
• •In the 20% to 30% of patients who continue to have symptoms on a β-blocker, the main options are either left cardiac sympathetic denervation (LCSD) or the prophylactic implantation of an ICD.
• •In patients with frequent ICD shocks or in those with high risk for SCD where ICD placement cannot be performed, cardiac pacing and/or LCSD may be indicated.
• •In patients with recurrent syncope and/or aborted cardiac arrest despite combined ICD and β-blocker, LCSD as adjunctive therapy can be performed.
• •For patients with LQTS who continue to receive appropriate ICD shocks or who have a high-risk phenotype but prefer to avoid an ICD, potassium retention strategies are implemented, regardless of the underlying LQTS genotype.
• •Correctable factors including electrolyte disorders—hypokalemia and hypomagnesemia—and avoidance of precipitating drugs that may further prolong the QT interval is mandatory. A complete list of drugs that can potentially prolong QT may be found at www.crediblemeds.org.
• •For patients with acquired form and torsades de pointes, IV magnesium and atrial or ventricular pacing are initial choices.

Prognosis

• •In carefully treated patients, mortality is around 0.5% to 1% over 20 yr.
• •The timing and frequency of syncope, QTc prolongation, and gender are predictive of risk for aborted cardiac arrest and SCD during adolescence. Higher risk is present in those with one or two or more episodes of syncope in the last 10 yr compared with those with no syncopal episodes, those with QTc >530 ms, and males ages 10 to 12 yr.

Pearls & Considerations

• •Family history should be assessed for a history of sudden death and other deaths that may have occurred as manifestations of LQTS (e.g., sudden infant death, drowning, and loss of consciousness while driving).
• •ICDs are an important component of therapy, but most LQTS patients do not need and should not receive an ICD based only on LQTS diagnosis.
• •Propranolol and nadolol are considered superior to metoprolol for prevention of arrhythmias in LQTS.

Seek Additional Information

• Al-Khatib S.M.: AHA/ACC/HRS Guideline for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a REPORT of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. 2017. Heart Rhythm,
• Maron B.J.: American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology: Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: preamble, principles, and general considerations: a scientific statement from the American Heart Association and American College of Cardiology. Circulation 2015; 132 (22):
• Fugate T.:U.S.: Portion of International Long QT Syndrome Registry Investigators. Long QT syndrome in African-Americans. Ann Noninvasive Electrocardiol 2010; 15 (1): pp. 73-76.
• Nakano Y., et al.: Genetics of long-QT syndrome. J Hum Genet 2015; 10 (1038):
• Priori S.G., et al.: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS and by ACCF, AHA, PACES, and AEPC. Heart Rhythm 2013; 10: pp. 1932-1963.
• Schwartz P.J., Crotti L.: QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124 (20): pp. 2181-2184.