Pediatric Long QT Syndrome


Background

Many causes of sudden death in the pediatric population are due to genetic heart disorders, which can lead to structural abnormalities (eg, hypertrophic cardiomyopathy) and arrhythmogenic abnormalities (eg, familial long QT syndrome). Indeed, sudden cardiac death in the pediatric population can be the first presentation of an underlying heart problem. (See Etiology and Pathophysiology and Presentation.)

Long QT syndrome is a genetically transmitted cardiac arrhythmia caused by ion channel protein abnormalities. It is characterized by electrocardiographic abnormalities and a high incidence of syncope and sudden cardiac death. (See Etiology and Pathophysiology, Prognosis, and Workup.)

Long QT syndrome can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. [1The diagnosis is suggested when ventricular repolarization abnormalities result in prolongation of the corrected QT interval. (See DDx and Workup.)

Diagnostic criteria

Schwartz et al suggested incorporating clinical and electrocardiogram (ECG) findings in a probability-based diagnostic criteria for long QT syndrome. [2The maximum score is 9, and a score of more 3 indicates a high probability of long QT syndrome. The criteria are as follows (see Presentation and Workup):

ECG findings (without medications or disorders known to affect ECG features) include the following:

  • QT corrected for heart rate (QTc), calculated using Bazett's formula, of more than 480 milliseconds (ms) - 3 points

  • QTc of 460-470 ms - 2 points

  • QTc of 450 ms in male patients - 1 point

  • Torsade de pointes (mutually exclusive) - 2 points

  • T-wave alternans - 1 point

  • Notched T wave in 3 leads - 1 point

  • Low heart rate for age (ie, resting heart rate below the second percentile for age) - 0.5 point

Clinical history includes the following:

  • Syncope with stress (mutually exclusive) - 2 points

  • Syncope without stress - 1 point

  • Congenital deafness - 0.5 point

Family history includes the following (the same family member cannot be counted in both categories):

  • Family member with definite long QT syndrome - 1 point

  • Unexplained sudden cardiac death (age < 30 y) in an immediate family member - 0.5 point

Epidemiology

The frequency of long QT syndrome is unknown (possibly about 1 per 5000 population). The condition is present in all races and ethnic groups, although frequency may differ among these populations. However, population-based prevalence studies are not available on this disease at the current time.

Long QT syndrome is responsible for approximately 1000 deaths each year in the United States, most of which occur in children and young adults.

Etiology and Pathophysiology

This syndrome, once diagnosed by clinical profile, has been more clearly defined by specific genetic defects that cause ion channel abnormalities, resulting in a syndrome that predisposes to lethal cardiac arrhythmias.

Initial studies using monophasic action potentials have shown evidence of early after depolarizations (EADs) in congenital and acquired long QT syndrome. Excessive prolongation of action potential results in reactivation of certain L-type calcium channels, leading to after depolarizations.

Sympathetic activity is thought to enhance the EADs, which, in turn, can initiate a lethal form of ventricular arrhythmia termed torsade de pointes. Abnormal cardiac repolarization renders the heart susceptible to these lethal ventricular tachyarrhythmias, increasing the risk of sudden cardiac death in patients of all ages.

Molecular basis of long QT syndrome

Six genetic loci for long QT syndrome have been identified. Sporadic cases occur as a result of spontaneous mutations. Jervell and Lang-Nielsen (JLN) syndrome is an autosomal recessive form of congenital long QT syndrome. Romano-Ward syndrome (RWS) is the dominant form.

The establishment of a long QT syndrome registry and the discovery of genetic mutations that cause long QT syndrome have greatly contributed to the understanding of this condition. Since the first report in 1991 of a deoxyribonucleic acid (DNA) marker in the short arm of chromosome 11, numerous studies have reported genetic mutations and molecular descriptions of ion channel abnormalities in long QT syndrome.

However, the genetic heterogeneity of this condition has made using genetic mutations to screen for it difficult. Nevertheless, the genetic markers have been effectively translated for the clinical management of this disease. They include KCNQ1KCNH2SCN5AKCNE1KCNE2KCNJ2, and CAV3.

The clinical heterogeneity is usually attributed to variable penetrance. One of the reasons for this variability in expression could be the coexistence of common single nucleotide polymorphisms (SNPs) on long QT syndrome ̶ causing genes, on unknown genes, or on both. Some synonymous and nonsynonymous exonic SNPs identified in long QT syndrome–causing genes may have an effect on the cardiac repolarization process and may modulate the clinical expression of a latent long QT syndrome pathogenic mutation.

Table 1. Genetic Basis of Long QT Syndrome, Including Jervell and Lang-Nielsen (JLN) Syndrome (Open Table in a new window)

Type of Long QT Syndrome

Chromosomal Locus

Mutated Gene

Ion Current Affected

LQT1

11p15.5

KVLQT1or KCNQ1 (heterozygotes)

Potassium (IKs)

LQT2

7q35-36

HERG, KCNH2

Potassium (IKr)

LQT3

3p21-24

SCN5A

Sodium (INa)

LQT4

4q25-27

ANK2, ANKB

Sodium, potassium and calcium

LQT5

21q22.1-22.2

KCNE1 (heterozygotes)

Potassium (IKs)

LQT6

21q22.1-22.2

MiRP1, KNCE2

Potassium (IKr)

LQT7 (Andersen syndrome)

17q23

KCNJ2

Potassium (IK1)

LQT8 (Timothy syndrome)

12q13.3

CACNA1C

Calcium (ICa-Lalpha)

JLN1

11p15.5

KVLQT1or KCNQ1 (homozygotes)

Potassium (IKs)

JLN2

21q22.1-22.2

KCNE1 (homozygotes)

Potassium (IKs)

Acquired long QT syndrome

The acquired causes of long QT syndrome include drugs, electrolyte imbalance, marked bradycardia, cocaine, organophosphorus compounds, subarachnoid hemorrhage, myocardial ischemia, protein-sparing fasting, autonomic neuropathy, and human immunodeficiency virus (HIV) disease.

Drug-induced long QT syndrome is characterized by a prolonged QTc and an increased risk of torsade de pointes. Virtually all drugs that prolong QTc block the rapid component of the delayed rectifier current (Ikr). Some drugs prolong QTc in a dose-dependent manner, whereas others do so at any dose.

Most patients who develop drug-induced torsade de pointes have underlying risk factors. Incidence is more common in females. Implicated drugs include the following [3:

  • Class IA and III antiarrhythmics

  • Macrolide antibiotics

  • Pentamidine

  • Antimalarials

  • Antipsychotics

  • Arsenic trioxide

  • Methadone

Prognosis

The prognosis for patients with long QT syndrome who have been treated with beta-blockers (and other therapeutic measures, if needed) is satisfactory. Fortunately, episodes of torsade de pointes are usually self terminating in patients with long QT syndrome; only about 4-5% of cardiac events are fatal.

Patients at high risk (ie, those with aborted cardiac arrest or recurrent cardiac events despite beta-blocker therapy) have a markedly increased risk of sudden death. Treat these patients with an implantable cardioverter-defibrillator (ICD), which will lead to a good prognosis.

In a study of adolescent patients with clinically suspected long QT syndrome, Hobbs et al found that the timing and frequency of syncope, QTc prolongation, and sex were predictive of risk for aborted cardiac arrest and sudden cardiac death during adolescence. [4]

Neurologic deficits after aborted cardiac arrest may complicate the clinical course even after successful resuscitation.

JLN syndrome

A study by Goldberg et al found that patients with JLN syndrome experienced a high rate of cardiac and fatal events from early childhood despite medical therapy. The investigators studied the clinical course and risk stratification of 44 patients with JLN syndrome from the US portion of the International Long QT Syndrome Registry. [5They compared these patients with 2174 patients who had the phenotypically determined dominant form of long QT syndrome, RWS.

Patient Education

The importance of educating the patient and his or her caregivers cannot be overstated. At least 2 family members (one of which should be the primary care giver) should enroll and master the basics of cardiopulmonary resuscitation (CPR).

Information regarding the drugs that should not be given in patients with long QT syndrome and the drugs that can prolong QT interval are available at the Arizona Center for Education and Research on Therapeutics Web site under Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia.

The Sudden Arrhythmia Death Syndromes Foundation (SADS) and Cardiac Arrhythmias Research and Education Foundation (CARE) have support groups for families with long QT syndrome.

CLINICAL PRESENTATION


History

The clinical diagnosis of long QT syndrome is prompted by a high degree of clinical suspicion, which arises from the presenting complaints. [6A detailed family history for similar symptoms is warranted. The presenting complaints may include the following:

  • Unexplained bradycardia - Especially in the newborn

  • Syncope - Especially when associated with a triggering event (eg, drowning, near drowning) [6]

  • Epilepsy - Especially not controlled by conventional medications

  • Palpitations

  • Aborted or sudden cardiac death in the patient or family history of sudden cardiac death

  • Sudden infant death syndrome (SIDS)

  • Depressive symptoms [7]

Physical Examination

Certain physical findings in long QT syndrome, such as skeletal abnormalities (eg, short stature, scoliosis), may suggest Andersen syndrome, whereas congenital heart diseases, along with cognitive and behavioral problems, musculoskeletal diseases, and immune dysfunction, may suggest Timothy syndrome. Congenital deafness is seen in JLN syndrome, although the incidence of long QT syndrome in patients with congenital deafness is very low.

DDx


Diagnostic Considerations

As previously mentioned, long-QT syndrome can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. [1Other conditions to consider in the differential diagnosis of long QT syndrome include the following:

  • Brugada syndrome

  • Short QT syndrome

  • Other causes of sudden cardiac death - Including hypertrophic cardiomyopathy and coronary artery anomalies

Workup

Approach Considerations

Laboratory studies in patients with suspected long QT syndrome should rule out dyselectrolytemias, especially those involving potassium, ionized calcium, and magnesium.

Epinephrine QT stress testing is an effective diagnostic tool used to unmask concealed long QT syndrome. Two protocols are followed: the Shimizu protocol and the Mayo protocol. These protocols are especially useful in patients with LQT1. Unique responses have also been observed in patients with LQT2 and LQT3, making this test invaluable in the diagnostic workup of long QT syndrome. [8]

Electrocardiography

The QT interval in the surface ECG is one of the most often used risk stratifiers in families with congenital long QT syndrome. (See the images below.)

Marked prolongation of QT interval in a 15-year-olMarked prolongation of QT interval in a 15-year-old male adolescent with long QT syndrome. Abnormal morphology of repolarization can be observed in almost every lead (ie, peaked T waves, bowing ST segment). Bradycardia is a common feature in patients with long QT syndrome. R-R = 1 s; QT interval = 0.56 s; QT interval corrected for heart rate (QTc) = 0.56 s.
Genetically confirmed long QT syndrome with borderGenetically confirmed long QT syndrome with borderline values of QT corrected for heart rate (QTc) duration in a 12-year-old girl. Note the abnormal morphology of the T wave (notches) in leads V2-V4. R-R = 0.68 s; QT interval = 0.36 s; QTc = 0.44 s.

QTc is the best diagnostic and prognostic ECG parameter in families with long QT syndrome (see Table 2, below). A single measurement should be obtained in lead II (if measurable) and then in left precordial leads (preferably V5) as a second choice. (A second opinion is recommended when the QTc is borderline.)

In a study by Mönnig et al, the predictive power for identifying carriers in families with long QT syndrome was found to be highest in leads II and V5. The investigators also found that these ECG leads were optimal for risk stratification. [9]

Table 2. Genetic Basis of Long QT Syndrome (Open Table in a new window)

Group

Prolonged QTc (s)

Borderline QTc (s)

Reference Range (s)

Children and adolescents (< 15 y)

>0.46

0.44-0.46

< 0.44

Men

>0.45

0.43-0.45

< 0.43

Women

>0.46

0.45-0.46

< 0.45

All ECGs in family members of a patient with long QT syndrome need to be reviewed, along with detailed histories and physical examinations. An absence of ECG findings that suggest long QT syndrome in family members must not be construed to exclude long QT syndrome in a patient. More recently, magneto-cartography-derived QT interval has been used along with the heart rate to determine long QT syndrome in fetuses. [1011]

Genetic Testing

Genetic testing for known mutations in DNA samples confirms the diagnosis with high specificity but low sensitivity, because only 50% of patients with long QT syndrome have known mutations. The remaining half of patients with long QT syndrome may have mutations of yet unknown genes.

However, this technology is valuable because it can help in predicting the course of the disease in these patients and aid in risk stratification. A study by Moss et al found that in patients with KCNQ1 mutations, the Cox proportional hazards survivorship model indicated an increased risk for cardiac events in patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06), as well as in patients with mutations resulting in dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26). The investigators found these risks to be independent of traditional clinical risk factors. [12]

Arnestad M et al suggested that 9.5% of the patients with sudden infant death syndrome had relevant LQTS mutations. [13On the basis of their functional effect, 8 mutations and 7 rare variants were found in 19 of 201 cases; these mutations were likely contributors to sudden death in those patients.

Tester et al sought to determine the spectrum and prevalence of long QT syndrome–associated mutations in a large cohort of autopsy-negative, sudden unexplained death cases. [14Long QT syndrome–associated mutations (4 novel) were found in 20% of these individuals. Sudden death was the sentinel event in two thirds of the cases. This underscores the importance of postmortem long QT syndrome genetic testing for sudden unexplained death in the pediatric population

TREATMENT AND MANAGEMENT


Approach Considerations

Treatment of long QT syndrome depends on the relative risk of sudden cardiac death, which is increased with longer QT durations, a history of prior cardiac events, and a family history of sudden cardiac death.

Short-term treatment of long QT syndrome is aimed at preventing recurrences of torsade de pointes and includes intravenous (IV) magnesium and potassium administration, temporary cardiac pacing, withdrawal of the offending agent, correction of electrolyte imbalance, and, rarely, IV isoproterenol administration.

Long-term treatment is aimed at reducing the QT interval duration and preventing torsade de pointes and sudden death. Beta-blockers are considered the initial treatment of choice, with ICD therapy warranted in high-risk patients. [15In patients with frequent ICD shocks or in those at a high risk for sudden cardiac death in whom ICD placement cannot be performed, cardiac pacing, left cardiac sympathetic denervation, or both may be indicated. [16]

Lifestyle modification to avoid triggers for malignant cardiac arrhythmias should be made to treat symptoms and reduce mortality in patients with long QT syndrome. [17]

Inpatient care

Inpatient care of long QT syndrome is in most cases related to emergencies or procedures such as ICD implantations. In certain situations, however, telemetry monitoring and observations may be necessary. Asymptomatic patients rarely need inpatient care.

Outpatient care

Outpatient care is provided by a pediatric cardiologist or an electrophysiologist. Regular monitoring is mandatory in these patients.

Deterrence/prevention

Trigger avoidance, antiadrenergic therapy, and ICDs can be used to prevent future cardiac events.

Consultations

A pediatric cardiologist or electrophysiologist should be immediately involved. A social counseling team should be involved to facilitate patient and family evaluations. [18]

Considerations in Physical Activity

Clearly, every possible trigger should be avoided in patients with long QT syndrome. If the provoking stimulus (eg, swimming, startling, alarm, or activity) is clearly identified, the patient should be encouraged to avoid it. In most instances, however, the stimulus cannot be identified. Therefore, all forms of sympathetic provocation should be avoided. However, in a more recent analysis, many patients who chose to continue competitive sports even after the diagnosis of long QT syndrome had very few cardiac events with appropriate therapy. [19]

The American Heart Association released guidelines for physical activity, including participation in recreational sports, in young patients with genetic cardiovascular disease.

MEDICATION


Medication Summary

Hobbs et al found that in patients who had suffered syncope in the previous 2 years, beta-blocker treatment was associated with a 64% risk reduction for aborted cardiac arrest and sudden cardiac death during adolescence. [4However, there seems to be variation in the efficacy in preventing cardiac events among the different classes of beta-blockers, and metoprolol seems to have the greatest risk of recurrent cardiac events. [21]

The data favor treating asymptomatic patients younger than 40 years at the time of diagnosis with beta-adrenergic blockers. Sodium channel blockers are promising agents under investigation.

Risk of cardiac events increases during pregnancy and the postpartum period. Because of this increased risk, pregnant women with long QT syndrome should be treated with beta-blockers. [22Physicians should be aware that high doses of beta blockade in the second and third trimesters may cause neonatal bradycardia at birth. Propranolol and nadolol are the preferred beta-blockers during pregnancy.

Beta-Adrenergic Blocking Agents

Class Summary

These agents currently represent the first-choice therapy in patients with symptomatic long QT syndrome unless specific contraindications are present. Patients with long QT syndrome who are unable to take beta-blockers may require an ICD as first-line therapy.

Propranolol (Inderal, InnoPran XL)

Propranolol reduces the effect of sympathetic stimulation on the heart. It decreases conduction through the atrioventricular (AV) node and has negative chronotropic and inotropic effects. Consult a cardiologist because dosing practice varies and is individualized in patients with long QT syndrome. Patients with asthma should use cardioselective beta-blockers. Patients with long QT syndrome who are unable to take beta-blockers may require an ICD as first-line therapy.

Nadolol (Corgard)

Nadolol is frequently prescribed because of its long-term effect. It reduces the effect of sympathetic stimulation on the heart. Nadolol decreases conduction through the AV node and has negative chronotropic and inotropic effects. Consult a cardiologist because dosing practice varies and is individualized in patients with long QT syndrome. Patients with asthma should use cardioselective beta-blockers. Patients with long QT syndrome who are unable to take beta-blockers may require an ICD as first-line therapy.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is a selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During IV administration, carefully monitor blood pressure, heart rate, and ECG. Consult a cardiologist because dosing varies and is individualized in patients with long QT syndrome. Patients with long QT syndrome who cannot take beta-blockers may require an ICD as first-line therapy.

Atenolol (Tenormin)

Atenolol selectively blocks beta1-receptors, with little or no effect on beta2 types. Consult a cardiologist because dosing varies and is individualized in patients with long QT syndrome. Patients with long QT syndrome who cannot take beta-blockers may require an ICD as first-line therapy

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