Long QT Syndrome

Practice Essentials

Long QT syndrome (LQTS) is a congenital disorder characterized by a prolongation of the QT interval on electrocardiograms (ECGs) and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. See the image below.

View Image

Marked prolongation of QT interval in a 15-year-old male adolescent with long QT syndrome (LQTS) (R-R = 1.00 s, QT interval = 0.56 s, QT interval corr....

See 7 Can't-Miss Life-Threatening ECG Findings, a Critical Images slideshow, to help recognize the conditions shown in various tracings.

Signs and symptoms

LQTS is usually diagnosed after a person has a cardiac event (eg, syncope, cardiac arrest). In some situations, this condition is diagnosed after a family member suddenly dies. In some individuals, the diagnosis is made when an ECG shows QT prolongation.

A history of cardiac events is the most typical clinical presentation in patients with LQTS.

See Presentation for more detail.

Diagnosis

Findings on physical examination usually do not indicate a diagnosis of LQTS, although some patients may present with excessive bradycardia for their age, and some patients may have hearing loss (congenital deafness), indicating the possibility of Jervell and Lange-Nielsen syndrome. Skeletal abnormalities, such as short stature and scoliosis are seen in the LQT7 type (Andersen syndrome), and congenital heart diseases, cognitive and behavioral problems, musculoskeletal diseases, and immune dysfunction may be seen in those with LQT8 type (Timothy syndrome).

Testing

Diagnostic studies in patients with suspected LQTS include the following:

• Serum potassium and magnesium levels
• Thyroid function tests
• Pharmacologic provocation with epinephrine or isoproterenol in patients with a borderline presentation
• Electrocardiography of the patient and family members
• Genetic testing of the patient and family members

An increased corrected QT (QTc) interval in response to standing up (“response to standing” test), which is associated with increased sympathetic tone, can provide more diagnostic information in patients with LQTS.^[1] This increase in QTc in response to standing may persist in these patients even after their heart rate returns to normal.^[2]

See Workup for more detail.

Management

No treatment addresses the cause of LQTS. Antiadrenergic therapeutic measures (eg, use of beta-blockers, left cervicothoracic stellectomy) and device therapy (eg, use of pacemakers, implantable cardioverter-defibrillators) aim to decrease the risk and lethality of cardiac events.

Pharmacotherapy

Beta-adrenergic blocking agents are the drugs of choice to treat LQTS and include the following medications:

• Nadolol
• Propranolol
• Metoprolol
• Atenolol

Nadolol, however, is the preferred beta-blocker to be used at a dose of 1-1.5 mg/kg/day (once a day for patients older than 12 years; divided twice a day for younger patients).^[3]

Surgical option

Surgical intervention in patients with LQTS may include the following procedures:

• Implantation of cardioverter-defibrillators
• Placement of a pacemaker
• Left cervicothoracic stellectomy

Nonpharmacotherapy

Patients with LQTS should avoid participation in competitive sports, strenuous exercise, and stress-related emotions.

These individuals should also avoid the following agents:

• Anesthetics or asthma medication (eg, epinephrine)
• Antihistamines (eg, diphenhydramine; terfenadine and astemizole [both recalled from the US market])
• Antibiotics (eg, erythromycin, trimethoprim and sulfamethoxazole, pentamidine)
• Cardiac medications (eg, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, dofetilide, ibutilide)
• Gastrointestinal medications (eg, cisapride)
• Antifungal medications (eg, ketoconazole, fluconazole, itraconazole)
• Psychotropic medications (eg, tricyclic antidepressants, phenothiazine derivatives, butyrophenones, benzisoxazole, diphenylbutylpiperidine)
• Potassium-losing medications (eg, indapamide, other diuretics; medications for vomiting/diarrhea)

See Treatment and Medication for more detail.

• References

Background

Long QT syndrome (LQTS) is a congenital disorder characterized by a prolongation of the QT interval on electrocardiograms (ECGs) and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. (See Etiology, Prognosis, Presentation, and Workup.)

The QT interval on the ECG, measured from the beginning of the QRS complex to the end of the T wave, represents the duration of activation and recovery of the ventricular myocardium. A QT interval corrected for heart rate (QTc) that is longer than 0.44 seconds is generally considered to be abnormal, although a normal QTc can be more prolonged in females (up to 0.46sec). The Bazett formula is the formula most commonly used to calculate the QTc, as follows: QTc = QT/square root of the R-R interval (in seconds). (See Workup.)

To measure the QT interval accurately, the relationship of QT to the R-R interval should be reproducible. This issue is especially important when the heart rate is lower than 50 beats per minute (bpm) or over 120 bpm, and when athletes or children have marked beat-to-beat variability of the R-R interval. In such cases, long recordings and several measurements are required. The longest QT interval is usually observed in the right precordial leads. When marked variation is present in the R-R interval (atrial fibrillation, ectopy), correction of the QT interval is difficult to define precisely. (See Workup.)

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Etiopathophysiology

The QT interval represents the duration of activation and recovery of the ventricular myocardium. Prolonged recovery from electrical excitation increases the likelihood of dispersing refractoriness, when some parts of myocardium might be refractory to subsequent depolarization.

From a physiologic standpoint, dispersion occurs with repolarization between three layers of the heart, and the repolarization phase tends to be prolonged in the mid myocardium. This is why the T wave is normally wide and the interval from T_peak to T_end (T_p-e) represents the transmural dispersion of repolarization (TDR). In long QT syndrome (LQTS), TDR increases and creates a functional substrate for transmural reentry.

Hypokalemia, hypocalcemia, and use of loop diuretics are risk factors for QTc interval prolongation.^[4]

LQTS has been recognized as mainly Romano-Ward syndrome (ie, familial occurrence with autosomal dominant inheritance, QT prolongation, and ventricular tachyarrhythmias) or as Jervell and Lang-Nielsen (JLN) syndrome (ie, familial occurrence with autosomal recessive inheritance, congenital deafness, QT prolongation, and ventricular arrhythmias). Two other syndromes are described, namely, Andersen syndrome and Timothy syndrome, although there is some debate on whether they should be included in LQTS.

Torsade de pointes

In LQTS, QT prolongation can lead to polymorphic ventricular tachycardia, or torsade de pointes, which itself may lead to ventricular fibrillation and sudden cardiac death. Torsade de pointes is widely thought to be triggered by reactivation of calcium channels, reactivation of a delayed sodium current, or a decreased outward potassium current that results in early afterdepolarization (EAD), in a condition with enhanced TDR usually associated with a prolonged QT interval.^[5] TDR serves as a functional reentry substrate to maintain torsade de pointes.

TDR not only provides a substrate for reentry but also increases the likelihood of EAD, the triggering event for torsade de pointes, by prolonging the time window for calcium channels to remain open. Any additional condition that accelerates the reactivation of calcium channels (eg, increased sympathetic tone) increases the risk of EAD.

Genetics

LQTS is known to be caused by mutations of the genes for cardiac potassium, sodium, or calcium ion channels; at least 10 genes have been identified. Based on this genetic background, 6 types of Romano-Ward syndrome, 1 type of Andersen syndrome and 1 type of Timothy syndrome, and 2 types of JLN syndrome are characterized (see Table 1, below).

LQTS results from mutations of genes encoding for cardiac ion channel proteins, which cause abnormal ion channel kinetics. Shortened opening of the potassium channel in LQT1, LQT2, LQT5, LQT6, JLN1, and JLN2 and delayed closing of a sodium channel in LQT3 overcharges a myocardial cell with positive ions. At least 10 genes have been identified in LQTS.

Table 1. Genetic Background of Inherited Forms of LQTS (Romano-Ward Syndrome: LQT1-6, Anderson Syndrome: LQT7, Timothy Syndrome: LQT8, and Jervell and Lang-Nielsen Syndrome: JLN1-2)

View Table

See Table

LQT1, LQT2, and LQT3 account for most cases of LQTS, with estimated prevalences of 45%, 45%, and 7%, respectively. In LQTS, QT prolongation is due to an overload of myocardial cells with positively charged ions during ventricular repolarization. In LQT1, LQT2, LQT5, LQT6, and LQT7, potassium ion channels are blocked, they open with a delay, or they are open for a shorter period than they are in normally functioning channels. These changes decrease the potassium outward current and prolong repolarization.

LQT1

The LQT1 gene (KVLQT1 or KCNQ1) encodes for part of the I_Ks slowly deactivating, delayed rectifier potassium channel.^[6] More than 170 mutations (most missense) of this gene have been reported. Their net effect is a decreased outward potassium current. Therefore, the channels remain open longer than usual, with a delay in ventricular repolarization and with QT prolongation.

LQT2

The LQT2 gene (HERG or KCNH2) encodes for part of I_Kr rapidly activating, rapidly deactivating, delayed rectifier potassium channel.^{[7, 8]} Mutations in this gene cause rapid closure of the potassium channels and decrease the normal rise in I_Kr. They also result in delayed ventricular repolarization and QT prolongation. About 200 mutations in this gene have been detected.

Japanese researchers have identified two novel KCNH2 missense mutations, G785D and T826I, that disrupt the intracellular transport of KV11.1 to the plasma membrane; low-temperature incubation appears to restore plasma membrane expression of Kv11.1-T826I but not G785D.^[9]

More than 30% of identified LQT2 mutations consist of nonsense or frameshift mutations that introduce premature termination codons (PTCs), which lead to the degradation of mutant mRNA by nonsense-mediated mRNA decay, an RNA surveillance mechanism that selectively eliminates the mRNA transcripts that contain PTCs.^[8]

LQT3

In LQT3, caused by mutations of the SCN5A gene for the sodium channel, a gain-of-function mutation causes persistent inward sodium current in the plateau phase, which contributes to prolonged repolarization.^[10] Some loss-of-function mutations in the same gene may lead to different presentations, including Brugada syndrome. More than 50 mutations have been identified in this gene.

Cardiac events are less frequent in congenital LQT3 than in LQT1 and LQT2, but they are more likely to be lethal (20% mortality with cardiac events in families with LQT3 mutations; 4% in those with an LQT1 or LQT2 mutation).^[10]

In some patients, caveolae proteins have been recognized as responsible for the increased sodium current in LQTS3.^[11] Caveolae are small (50-100 nm) microdomains that exist on the membrane of a variety of cells, including cardiac myocytes and fibroblasts. Some ion channels, and in particular the SCN5A-encoded voltage-gated sodium channels, are mainly co-localized with caveolae on the membrane. Thus, absence or abnormal formation of caveolae may have some effects on the availability of sodium channels. For example, Vatta and colleagues demonstrated that mutations in caveolin-3 protein exist in LQTS3 and that they can cause an increase in late sodium current.^[11]

Nevertheless, caveolae are present in the membrane of many other cell types and are also involved in many cellular activities, thus, their impairment is expected to be associated with multisystemic diseases. For example, Rajab and colleagues reported genetic mutations resulting in defective caveolae in families with congenital generalized lipodystrophy who have several systemic manifestations, such as hypertrophic pyloric stenosis, impaired bone formations, ventricular arrhythmia, and sudden cardiac death.^[12] The fact that mutations in proteins associated with ion channels may result in a change in the availability of channels on the membrane, and therefore a significant change in total current, has added another window for investigating the genetic abnormalities resulting in LQTS.

LQT4 gene

The LQT4 gene (ANK2 or ANKB) encodes for ankyrin-B. Ankyrins are adapter proteins that bind to several ion channel proteins, such as the anion exchanger (chloride-bicarbonate exchanger), sodium-potassium adenosine triphosphatase (ATPase), the voltage-sensitive sodium channel (I_Na), the sodium-calcium exchanger (NCX, or I_Na-Ca), and calcium-release channels (including those mediated by the receptors for inositol triphosphate [IP₃] or ryanodine).

Mutations in this gene interfere with several of these ion channels. The end result is increased intracellular concentration of calcium and, sometimes, fatal arrhythmia. Five mutations of this gene are reported. LQT4 is interesting, because it provides an example of how mutations in proteins other than ion channels can be involved in the pathogenesis of LQTS.

LQT5, 6, 7, 8, 9, 10

The LQT5 gene encodes for the I_Ks potassium channel. Similar to LQT1, LQT5 is involved in a decreased outward current of potassium and in QT prolongation.

LQT6 involves mutations in the gene MiRP1, or KCNE2, which encodes for the potassium channel beta subunit MinK-related protein 1 (MiRP1). KCNE2 encodes for the beta subunits of I_Kr potassium channels.

The LQT7 gene (KCNJ2) encodes for potassium channel 2 protein, which plays an important role in inward repolarizing current (I_Ki), especially in phase 3 of the action potential. In this subtype, QT prolongation is less prominent than in other types, and the QT interval is sometimes in the normal range. Because potassium channel 2 protein is expressed in cardiac and skeletal muscle, Andersen syndrome is associated with skeletal abnormalities, such as short stature and scoliosis.

Mutations in the LQT8 gene (CACNA1C) cause loss of L-type calcium current. So far, a limited number of cases of Timothy syndrome have been reported. They have been associated with abnormalities such as congenital heart disease, cognitive and behavioral problems, musculoskeletal diseases, and immune dysfunction.

The LQT9 gene encodes for caveolin 3, a caveolae plasma membrane component protein involved in scaffolding proteins. The voltage-gated sodium channel (Na_V b3) is associated with this protein. Functional studies have demonstrated that CAV3 mutations are associated with persistent late sodium current, and they have been reported in cases of sudden infant death syndrome (SIDS).^[13] LQT9 and LQT4 serve as examples of LQTS with nonchannel mutations.

A novel mutation in the LQT10 gene encoding the protein Na_V b4, a subunit of the voltage-gated sodium channel of the heart, Na_V 1.5 (gene SCN5), results in a positive shift in the inactivation of the sodium current. To date, only a single mutation in one patient has been described.^[14]

Alpha-1-syntrophic gene mutation

The newest genetic missense mutation associated with LQTS has been described in the alpha-1-syntrophin gene and results in gain of function of the sodium channel similar to that observed in LQT3.^[15]

Stimuli

In patients with LQTS, a variety of adrenergic stimuli, including exercise, emotion, loud noise, and swimming, may precipitate an arrhythmic response. However, arrhythmia may occur without such preceding conditions.

Drug-induced QT prolongation

Secondary (drug-induced) QT prolongation may also increase the risk of ventricular tachyarrhythmias (eg, torsade de pointes) and sudden cardiac death. The ionic mechanism is similar to that observed in congenital LQTS (ie, mainly intrinsic blockade of cardiac potassium efflux).

In addition to the medications that potentially can prolong the QT interval, several other factors play a role in this phenomenon. Important risk factors for drug-induced QT prolongation include the following:

• Female sex^[4]
• Electrolyte disturbances (hypokalemia and hypomagnesemia)
• Hypothermia
• Abnormal thyroid function
• Structural heart disease
• Bradycardia

Drug-induced QT prolongation may also have a genetic background, consisting of the predisposition of an ion channel to abnormal kinetics caused by gene mutation or polymorphism. However, data are insufficient to claim that all patients with drug-induced QT prolongation have a genetic LQTS-related mechanism. The Arizona Center for Education and Research on Therapeutics (AZCERT) provides lists of drugs that prolong the QT interval and/or induce torsade de pointes ventricular arrhythmia.

• References

Epidemiology

United States data

Long QT syndrome (LQTS) remains an underdiagnosed disorder, especially because some individuals may LQTS gene mutation carriers who have a normal QTc duration.^[16]

The prevalence of LQTS is difficult to estimate. However, LQTS may be expected to occur in the range of 1 in 2,000 to 1 in 5,000 individuals.^{[16, 17]}

International data

The occurrence of long QT syndrome internationally is similar to that in the United States.

Sex-related demographics

Newly diagnosed cases of LQTS are more prevalent in female patients (60-70% of cases) than in male patients. The female predominance may be related to the relatively prolonged QTc (as determined by using the Bazett formula) in women compared to men and to a relatively higher mortality rate in young men.

In women, pregnancy is not associated with an increased incidence of cardiac events, whereas the postpartum period is associated with a substantially increased risk of cardiac events, especially in the subset of patients with LQT2. Cardiac events have been highly correlated with menses.

In addition, a significantly higher risk of cardiac events (a 3- to 8-fold increase, mainly in the form of recurrent episodes of syncope) has been reported in women with LQT2 syndrome during and after the onset of menopause, compared with the reproductive years.^[18]

Age-related demographics

Patients with LQTS usually present with cardiac events (eg, syncope, aborted cardiac arrest, sudden death) in childhood, adolescence, or early adulthood. However, LQTS has been identified in adults as late as in the fifth decade of life. The risk of death from LQTS is higher in boys than in girls younger than 10 years; the risk is similar in male and female patients thereafter.

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Prognosis

The prognosis is good overall for patients with long QT syndrome (LQTS) treated with beta-blockers (and other therapeutic measures, if needed). Fortunately, episodes of torsade de pointes are usually self-terminating in patients with LQTS; 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 (ICDs); their prognosis after implantation of an ICD is good.

Morbidity and mortality

Mortality, morbidity, and responses to pharmacologic treatment differ in the various types of LQTS. This issue is under investigation.

LQTS may result in syncope and lead to sudden cardiac death, which usually occurs in otherwise healthy young individuals. LQTS is thought to cause about 4,000 deaths in the United States each year. The cumulative mortality rate reaches approximately 6% by the age of 40 years.

Although sudden death usually occurs in symptomatic patients, it can also materialize with the first episode of syncope in about 30% of the patients. This finding emphasizes the importance of diagnosing LQTS in the presymptomatic period. Depending on the type of mutation present, sudden cardiac death may take place during exercise, emotional stress, at rest, or at sleep. LQT4 is associated with paroxysmal atrial fibrillation.

Studies have shown an improved response to pharmacologic treatment with a lowered rate of sudden cardiac death in LQT1 and LQT2, compared with LQT3.

Neurologic deficits after aborted cardiac arrest may complicate the clinical course of patients with LQTS after successful resuscitation.

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Patient Education

Educate patients regarding the nature of long QT syndrome (LQTS) and factors that trigger cardiac events. Patients should avoid sudden noises (eg, from an alarm clock), strenuous exercise, water activities, and other arousal factors.

Educate patients and family members about the critical importance of systematic treatment with beta-blockers. Advise family members and the patient's teachers at school to undergo training in cardiopulmonary resuscitation (CPR).

Educate patients and family members about medications that may induce QT prolongation and that should be avoided in patients with LQTS. The Arizona Center for Education and Research on Therapeutics (AZCERT) provides lists of drugs that prolong the QT interval and/or induce torsade de pointes ventricular arrhythmia.

The Sudden Arrhythmia Death Syndromes Foundation (SADS) has support groups for families with LQTS.

• References

History

A history of cardiac events is the most typical clinical presentation in patients with long QT syndrome (LQTS). LQTS is usually diagnosed after a person has a cardiac event (eg, syncope, cardiac arrest). In some situations, LQTS is diagnosed after a family member suddenly dies. In some individuals, LQTS is diagnosed because an electrocardiogram (ECG) shows QT prolongation.

Exercise, swimming, or emotion may trigger events, but they may also occur during night sleep.

Triggering events are somewhat different by genotype. Patients with LQT1 usually have cardiac events preceded by exercise or swimming. Sudden exposure of the patient's face to cold water is thought to elicit a vagotonic reflex. Patients with LQT2 may have arrhythmic events after an emotional event, exercise, or exposure to auditory stimuli (eg, door bells, telephone ring). Patients with LQT3 usually have events during night sleep.

Obtain information about hearing loss (deficit) in patients and their family members to determine a possibility of Jervell and Lang-Nielsen (JLN) syndrome.

Information about what medication the patient has taken is critical for the differential diagnosis of congenital LQTS and of drug-induced QT prolongation (which also may have genetic background). The Arizona Center for Education and Research on Therapeutics (AZCERT) provides lists of drugs that prolong the QT interval and/or induce torsade de pointes ventricular arrhythmia.

A family history of cardiac arrest and sudden death, especially at a young age, may suggest a congenital (familial) form of LQTS.

Analysis of repolarization duration (QTc) and morphology on the patient's ECG and on ECGs of the patient's relatives frequently leads to the proper diagnosis.

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Physical Examination

Findings on physical examination usually do not indicate a diagnosis of long QT syndrome (LQTS), although some patients may present with excessive bradycardia for their age, and some patients may have hearing loss (congenital deafness), indicating the possibility of Jervell and Lang-Nielsen (JLN) syndrome.

Skeletal abnormalities, such as short stature and scoliosis are seen in LQT7 (Andersen syndrome), and congenital heart diseases, cognitive and behavioral problems, musculoskeletal diseases, and immune dysfunction may be seen in those with LQT8 (Timothy syndrome).

Also perform the physical examination to exclude other potential reasons for arrhythmic and syncopal events in otherwise healthy people (eg, heart murmurs caused by hypertrophic cardiomyopathy, valvular defects)

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Approach Considerations

Routinely check serum levels of potassium (and sometimes magnesium) and thyroid function in patients who present with QT prolongation after arrhythmic events, to eliminate secondary reasons for repolarization abnormalities.

Analysis of repolarization duration (QTc) and morphology on a patient's electrocardiogram (ECG) and on the ECGs of the patient's relatives frequently leads to an accurate diagnosis.

Hinterseer et al found that increased short-term variability of the QT interval—ie, STV(QT)—in symptomatic patients with congenital long QT syndrome (LQTS) could be a useful noninvasive additive marker for diagnostic screening to bridge the gap while waiting for results of genetic testing.^[19]  This study is the first in humans to observe this association.

Imaging studies

Imaging studies (eg, echocardiography, magnetic resonance imaging [MRI]) may help only in excluding other potential reasons for arrhythmic events (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy) or associated congenital heart diseases in a small subset of patients with LQTS, such as persons with LQT8.

Diagnostic criteria

A presentation with syncope or sudden cardiac death, in combination with a long QT interval on an ECG, typically suggests long QT syndrome (LQTS) and leads to genetic testing to diagnose the disease. In many patients, however, the presentation may not be typical. Therefore, other tests may be indicated.

Schwartz et al suggested diagnostic criteria for LQTS in 1993 that still serve as the best criteria for clinicians.^[20] In their model, the criteria are divided to three main categories, as shown in Table 2, below. The maximum score is 9—A score above 3 indicates a high probability of LQTS.

Table 2. Diagnostic Criteria for LQTS

View Table

See Table

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Electrocardiography

As the criteria for long QT syndrome (LQTS) by Schwartz et al suggest, the most helpful electrocardiographic (ECG) findings are prolongation of the QT interval, the presence of torsade de pointes, the presence of T-wave alternans, and the presence of certain morphology of the T waves (wide-based T wave, and notched T wave in three leads).

Correlation between the type of mutation and T-wave morphology has been suggested. Wide-based T waves are most frequently seen in LQT1, whereas notched T waves are most commonly seen in LQT2. In LQT3, T waves may appear normal, with a long, isoelectric ST segment.

T-wave analysis also appears to have the potential to differentiate acquired QT prolongation from congenital LQTS,^[21]  as well as help identify on-therapy breakthrough arrhythmic risk in LQT1 and LQT2.^[22]  Using an automated T-wave analysis program to retrospectively evaluate 12-lead ECGs of 38 patients with congenital LQTS and 114 patients with drug-induced and/or electrolyte-mediated QT prolongation, Sugrue et al noted the following differences in lead V₅ of those with acquired QT prolongation could distinguish these individuals from patients with congenital LQTS in 77% of cases (90% sensitivity, 58% specificity)^[21] :

• Shallower T-wave right slope
• Larger T-peak to T-end interval
• Smaller T-wave center of gravity on the x axis

The same investigators used a T-wave analysis program to evaluate ECGs from 407 genetically confirmed patients with LQT1 (n = 246) and LQT2 (n = 161) over a mean follow-up of 6.4 ± 3.9 years and found two independent predictors of future LQTS-associated cardiac events were left slope of T waves in lead V₆ and a T-wave center of gravity on the x axis in lead I, particularly in patients with LQTS2.^[22]

Prolongation of the QTc interval is defined on the basis of age- and sex-specific criteria (see Table 3, below). QTc is calculated by dividing the measured QT by the square root of the R-R interval, both of which are measured in seconds. QTc prolongation longer than 0.46 seconds indicates an increased likelihood of LQTS. (See the image below.)

View Image

Marked prolongation of QT interval in a 15-year-old male adolescent with long QT syndrome (LQTS) (R-R = 1.00 s, QT interval = 0.56 s, QT interval corr....

However, approximately 10-15% of gene-positive patients with LQTS present with a QTc duration in the reference range. (See the image below.)

View Image

Genetically confirmed long QT syndrome (LQTS) with borderline values of QT corrected for heart rate (QTc) duration (R-R = 0.68 s, QT interval = 0.36 s....

Table 3. Definition of QTc Based on Age- and Sex-Specific Criteria

View Table

See Table

In patients with suspected LQTS with borderline QTc values (or even values in the reference range) on standard ECGs or in patients with a score of 2-3 based on the 1993 Schwartz et al diagnostic criteria, an analysis of the dynamic behavior of QTc duration during exercise ECG or long-term Holter monitoring may reveal maladaptation of the QT interval to a changing heart rate. QTc prolongation may be evident at a fast heart rate. Ventricular arrhythmias are rarely observed during exercise testing or Holter recording in patients with LQTS.

No evidence indicates that invasive electrophysiology with attempts to induce ventricular tachycardia facilitates diagnosis.

Bradycardia and tachycardia

Bradycardia and tachycardia each need special attention. Bradycardia is included in the diagnostic criteria and adds 0.5 points to the score. Tachycardia requires special attention, too, because the QTc may be overcorrected in a tachycardic situation (eg, in infants).

T-wave alternans

Visible T-wave alternans in patients with LQTS indicates an increased risk of cardiac arrhythmias (ie, torsade de pointes and ventricular fibrillation).

Detection of microvolt T-wave alternans has low sensitivity and high specificity in diagnosing LQTS. The prognostic value of microvolt T-wave alternans has not been studied systematically.

Pharmacologic provocation

Pharmacologic provocation with epinephrine or isoproterenol helps in diagnosing LQTS in patients with a borderline presentation. It may also provide information regarding the type of mutation present.

Testing family members

It is important to review the ECGs of family members of a patient with LQTS, to obtain detailed histories, and to perform physical examinations. However, an absence of ECG findings of LQTS in family members does not exclude LQTS. In the ideal setting, all family members should be tested for LQTS mutations to help limit the small, but definite, risk of arrhythmia and sudden cardiac death. Testing is especially relevant if the patient was exposed to a drug that prolongs the QT interval.

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Genetic Testing

Patients with a clinical or electrocardiographic (ECG) presentation of long QT syndrome (LQTS) need genetic testing to identify the mutation. Genetic testing for known mutations in deoxyribonucleic acid (DNA) samples from patients is becoming accessible in specialized centers, although such tests can entail considerable expense, and insurance coverage for genetic testing often requires specific physician intervention.

Identification of an LQTS genetic mutation confirms the diagnosis. However, a negative result on genetic testing is of limited diagnostic value, because only approximately 50% of patients with LQTS have known mutations. The remaining half of patients with LQTS may have mutations of yet unknown genes. Therefore, genetic testing has high specificity but low sensitivity.

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Response to Standing

Viskin and colleagues demonstrated that the expected shortening of the QT interval in response to sinus tachycardia induced by standing from a supine position is impaired in patients with long QT syndrome (LQTS).^[1] In fact, the QTc interval in patients with LQTS increased with standing position, and more premature ventricular contractions (PVCs) were detected during standing in these patients. Thus, the increased QTc interval in response to standing up, which is associated with increased sympathetic tone, can provide more diagnostic information in patients with LQTS.^[1] The increase in QTc in response to standing may persist in patients with LQTS even after heart rate returns to normal.^[2]

In addition, this study may reveal that standing up in patients with LQTS may be associated with more focal activities and ventricular arrhythmias. Therefore, syncope while standing up in a patient with LQTS may not be simply a vasovagal syncope but may represent a more dangerous condition.

In a more recent study, investigators evaluating the standing test in 36 congenital LQTS patients (LQT1, LQT2, LQT7, and unidentified genotypes) and 41 control subjects found that the corrected QT interval (QTc) obtained immediately after standing and the QTc change from baseline were significantly higher in the LQTS group than in the control group, and that these QTc evaluations had a high diagnostic value when compared to the baseline QTc.^[23] In addition, the use of beta-blocker therapy ameliorated the standing response in the LQTS patients.

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Approach Considerations

All patients with long QT syndrome (LQTS) should avoid drugs that prolong the QT interval or that reduce their serum potassium or magnesium levels. In a study of 133,359 electrocardiograms from 40,037 patients, the use of a single QT-prolonging agent increased the corrected QT (QTc) interval by 11.08 ms; when two such drugs were used, there was another 3.04 ms increase in the QTc interval relative to when a single drug was used.^[4]

Potassium and magnesium deficiency should be corrected. 

Although psychoactive medications are known to have effects on the cardiovascular system, such as QT prolongation, sometimes their use may be necessary to treat psychiatric conditions.^[24] To minimize the cardiovascular effects of these drugs, clinicians should carefully select appropriate patient-related drugs, closely monitor drug-specific cardiac adverse effect risks, and follow up assiduously. This process will help with early detection of adverse reactions and dose adjustments. Initiate therapy with low doses and then carefully titrate and adjust the dosing and/or drug regimen based on the patient's clinical responses.^[24]

There may be an LQTS genotype-specific effect of antidepressants on the risk of arrhythmic events. In a study that evaluated the LQTS genotype-specific risk of recurrent cardiac arrhythmic events (CAEs) associated with these agents, investigators noted an increased risk of CAEs associated with antidepressant drug therapy in patients with LQT1, particularly individuals receiving selective serotonin reuptake inhibitors or antidepressants with a known risk of torsade de pointes,^[25]  but there was no such associated risk in those with LQT2. Furthermore, antidepressants considered as having a "conditional risk of torsade de pointes" were not linked to a risk of recurrent CAEs in any patients from the LQT1 and LQT2 groups.

Although treating asymptomatic patients is somewhat controversial, a safe approach is to treat all patients with congenital LQTS because sudden cardiac death can be the first manifestation of LQTS.

Beta-blockers are drugs of choice for patients with LQTS.^[7] The protective effect of beta-blockers is related to their adrenergic blockade, which diminishes the risk of cardiac arrhythmias. They may also reduce the QT interval in some patients.

Consultations

A cardiologist and a cardiac electrophysiologist are typically consulted when patients with LQTS are evaluated.

In families of patients with genotypically confirmed LQTS, genetic counseling of patients and family members should be considered.

Inpatient care

Patients with LQTS are frequently hospitalized in a monitored unit after they have a cardiac event (eg, syncope, cardiac arrest) to enable immediate rescue if cardiac arrhythmias recur.

Follow-up

Asymptomatic individuals with LQTS usually do not require hospitalization. However, carefully evaluate them and provide follow-up care in an ambulatory setting. A cardiologist or a cardiac electrophysiologist should examine patients with LQTS on a regular basis.

• References

Beta-Blockers

Beta-blockers are effective in preventing cardiac events in approximately 70% of patients with long QT syndrome (LQTS), whereas cardiac events continue to occur despite beta-blocker therapy in the remaining 30%.

Propranolol and nadolol are the most frequently used beta-blockers, although atenolol and metoprolol are also prescribed in patients with LQTS. Different beta-blockers demonstrate similar effectiveness in preventing cardiac events in patients with LQTS. Nadolol is effective for reducing cardiac events in patients with LQT1 and in those with LQT2, whereas atenolol and propranolol appear to decrease this risk only for LQT1, and metoprolol does not appear to have any significant risk reduction for LQT1 or LQT2.^[26] Beta-blocker therapy may not be as effective for LQT3 as for LQT1 or LQT2, but there are not enough data to make a more conclusive assessment.^[26]

Response to beta-blocker therapy may also vary depending on the triggering event. A study by Goldenberg et al found that in patients with LQT1, beta-blocker therapy is effective when exercise triggers the event, but it is ineffective if the event happens during sleep or arousal.^[27]

Koponen et al collected follow-up data, covering a mean of 12 years, for 316 genotyped LQT1 and LQT2 patients aged 0 to 18 years. In this pediatric group of genotyped and appropriately treated LQTS patients, they found that severe cardiac events were uncommon.^[28]  In addition, treatment with beta-blocker medications reduced the risk of cardiac events and was generally well tolerated.

Previously, the recommended dosage of beta-blockers was relatively large (eg, propranolol 3 mg/kg/day, or 210 mg/day in a 70-kg individual); more recent data suggest that lower dosages have a protective effect similar to that of large dosages.

• References

Pacemakers and ICDs

The implantable cardioverter-defibrillator (ICD) has been shown to be highly effective in preventing sudden cardiac death in high-risk patients. During a mean 8-year follow-up study of 125 patients with long QT syndrome (LQTS) who received an ICD, there was a 1.3% death rate in high-risk ICD patients, compared to 16% in non-ICD patients.^[29] High-risk patients are defined as those with aborted cardiac arrest or recurrent cardiac events (eg, syncope or torsade de pointes) despite conventional therapy (ie, beta-blocker alone) and those with very prolonged QT interval (>500 ms).

An alternative treatment is beta blockade in combination with pacemaker implantation and/or stellectomy in some patients.

The use of an ICD may be considered as primary therapy if the patient has a strong family history of sudden cardiac death. However, because some studies showed that a family history of sudden cardiac death is not an independent risk factor,^[30] some experts do not recommend ICD therapy based only on a family history of sudden cardiac death.^[31]

Early ICD therapy should be considered in high-risk patients with Jervell and Lang-Nielsen (JLN) syndrome, because the efficacy of beta-blockers has been found to be more limited in these patients.^[32]

The usefulness of implanted cardiac pacemakers is based on the premise that pacing eliminates arrhythmogenic bradycardia, decreases heart-rate irregularities (eliminating short-long-short sequences), and decreases repolarization heterogeneity, thereby diminishing the risk of torsade de pointes ventricular tachycardia. Pacemakers are particularly helpful in patients with documented pause-bradycardia–induced torsade de pointes and in patients with LQT3.

However, data indicate that cardiac events continue to occur in high-risk patients with cardiac pacing. Because newer models of ICDs include a cardiac pacing function, cardiac pacing (without defibrillators) is unlikely to be used in patients with LQTS. Pacing alone may be used in low-risk patients with LQT3.

• References

Stellectomy

Left cervicothoracic stellectomy is another antiadrenergic therapeutic measure used in high-risk patients with long QT syndrome (LQTS), especially in those with recurrent cardiac events despite beta-blocker therapy.

Stellectomy decreases the risk of cardiac events in high-risk patients with LQTS, although it is more effective in patients with LQT1 than in those with other types of LQTS.

Although this technique decreases the risk of cardiac events, it does not eliminate the risk. Therefore, the use of an implantable cardioverter-defibrillator (ICD) is superior to cervicothoracic stellectomy. However, cervicothoracic stellectomy may be indicated in some high-risk patients and in patients who have several ICD discharges while being treated with beta blockade and an ICD.

• References

Considerations in Physical Activity

Physical activity, swimming, and stress-related emotions frequently trigger cardiac events in patients with long QT syndrome (LQTS). Therefore, discourage patients from participating in competitive sports.

The triggering effect of exercise and tachycardia, and therefore the protective effect of beta-blockers, varies depending on the type of LQTS.

Exercise and tachycardia trigger LQT1 events. Therefore, patients with LQT1 should avoid strenuous exercise; beta-blockers are expected to provide excellent help by preventing cardiac events. Syncope and sudden cardiac death during swimming or diving are strongly related to LQT1. Therefore, patients with LQT1 should avoid swimming with no supervision. LQT2 is also exercise induced but to a lesser degree than LQT1.

Tachycardia and exercise do not trigger LQT3; events typically happen during sleep. Because tachycardia is not a trigger, the role of beta-blockers in preventing the cardiac events of LQT3 is debated. Mexiletine, a sodium channel blocker, may improve protection in this subgroup of patients. Some experts suggest the use of a beta-blocker combined with mexiletine in patients with LQT3.^[33]

• References

Gene Therapy

Gene-specific therapy is an area under investigation in the treatment of long QT syndrome (LQTS). For example, because LQT3 is associated with gain-of-function mutations in sodium channels, antiarrhythmic agents with sodium channel blocking properties have been suggested as gene-specific therapy for patients with LQTS3. Nevertheless, this area is complex and requires further investigations and studies.

For example, Ruan and colleagues found that mexiletine, a sodium channel blocker, can facilitate F1473 mutant protein trafficking, resulting in a net effect of a further increase in the sodium current and a worsening of QT prolongation in a subset of patients with LQTS3 who have this specific mutation.^[34]

In a retrospective cohort study of 34 LQT3 patients, Mazzanti et al found evidence that mexiletine is an effective therapy. The median duration of oral mexiletine therapy was 36 months. Mexiletine significantly shortened QTc, reduced the percentage of patients with arrhythmic events, reduced the mean number of arrhythmic events per patient, and reduced the annual rate of arrhythmic events.^[33]

Trigger-specific risk stratification and therapy have been suggested by some studies. For example, Kim and colleagues showed that certain types of mutations in LQT2 are associated with certain triggering events (exercise triggers vs arousal triggers vs nonarousal/nonexercise triggers) and that patients with exercise-related triggering events respond to the treatment with beta-blockers.^[35]

• References

Drugs To Be Avoided in LQTS

Anesthetics or asthma medication

Epinephrine (adrenaline) for local anesthesia or as an asthma medication should be avoided in patients with long QT syndrome (LQTS).

Antihistamines

Antihistamines to be avoided include the following:

• Terfenadine (Seldane [recalled from US market]): For allergies
• Astemizole (Hismanal [recalled from US market]): For allergies
• Diphenhydramine (Benadryl): For allergies

Antibiotics

Antibiotics to be avoided include the following:

• Erythromycin (E-Mycin, EES, EryPed, PCE): For lung, ear, and throat infections
• Trimethoprim and sulfamethoxazole (Bactrim, Septra):  For urinary, ear, and lung infections
• Pentamidine (Pentam, intravenous): For lung infections

Heart medications

Heart medications to avoid in patients with LQTS include the following:

• Quinidine (Quinidine, Quinidex, Duraquin, Quinaglute): For heart rhythm abnormalities
• Procainamide (Pronestyl): For heart rhythm abnormalities
• Disopyramide (Norpace): For heart rhythm abnormalities
• Sotalol (Betapace): For heart rhythm abnormalities
• Probucol (Lorelco): For high triglycerides, cholesterol
• Bepridil (Vascor): For chest pain (angina)
• Dofetilide (Tikosyn): For atrial fibrillation
• Ibutilide (Corvert): For atrial fibrillation

Gastrointestinal medications

Cisapride (Propulsid), for esophageal reflux and acid indigestion, should be avoided.

Antifungal drugs

Antifungal agents to be avoided include the following:

• Ketoconazole (Nizoral): For fungal infections
• Fluconazole (Diflucan): For fungal infections
• Itraconazole (Sporanox): For fungal infections

Psychotropic drugs

The following psychotropic drugs should be avoided in patients with LQTS:

• Tricyclic antidepressants (Elavil, Norpramin, Vivactil): For depression
• Phenothiazine derivatives (Compazine, Stelazine, Thorazine, Mellaril, Trilafon): For mental disorders
• Butyrophenones (Haloperidol): For mental disorders
• Benzisoxazole (Risperdal): For mental disorders
• Diphenylbutylpiperidine (Orap): For mental disorders

Medications for potassium loss

Potassium-loss medications to be avoided include the following:

• Indapamide (Lozol): For water loss, edema
• Other diuretics
• Medications for vomiting and diarrhea

• References

Guidelines Summary

Diagnosis

2013 HRS/EHRA/APHRS recommendations

In its 2013 expert consensus statement on inherited primary arrhythmia syndromes, the Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society (HRS/EHRA/APHRS) recommended a diagnosis of long QT syndrome (LQTS) when any of the following criteria is met^[36] :

• LQTS risk score of at least 3.5 in the absence of a secondary cause for QT prolongation 
• Presence of confirmed LQTS gene mutation
• QTc of at least 500 ms in repeated 12-lead electrocardiograms (ECGs) and in the absence of a secondary cause for QT prolongation.

LQTS can also 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.

ESC recommendations

In 2015, the European Society of Cardiology (ESC) released guidelines for the management of ventricular arrhythmias and the prevention of sudden cardiac death (SCD) which included the following modified recommendation for the diagnosis of LQTS^[37] :

Class I (Level of evidence: C)

LQTS is diagnosed when any of the following criteria is met:

• QTc of at least 480 ms in repeated 12-lead ECGs
• LQTS risk score above 3
• Presence of a confirmed LQTS gene mutation, irrespective of the QT duration

Class IIa (Level of evidence: C)

LQTS should be considered in patients with an unexplained syncopal episode and a QTc of at least 460 ms in repeated 12-lead ECGs in the absence of secondary causes for QT prolongation

Genetic testing

In 2011, the HRS and EHRA issued a joint expert consensus statement on genetic testing for channelopathies and cardiomyopathies with the following recommendations for LQTS testing^[38] :

Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A)–targeted LQTS genetic testing for:

• Individuals with a strong clinical index of suspicion for LQTS based on their clinical history, family history, and expressed ECG phenotype (Class I)
• Asymptomatic individuals with idiopathic QT prolongation on serial 12-lead ECGs defined as QTc longer than 480 ms (prepuberty) or longer than 500 ms (adults) (Class I); may be considered for QTc values above 460 ms (prepuberty) or over 480 ms (adults) (Class IIb)

In addition, mutation-specific genetic testing is recommened for family members following identification of LQTS mutation in an index case. (Class I)

Management and prevention of sudden cardiac death

The following is a summary of recommendations included in the 2015 ESC guidelines for management of of LQTS and preventions of SCD.^[37]

Class I  (Level of evidence: B)

Lifestyle changes, such as the following:

• Avoidance of QT-prolonging drugs
• Correction of electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia) that may occur during diarrhea, vomiting, or metabolic conditions
• Avoidance of genotype-specific triggers for arrhythmias (strenuous swimming, especially in LQTS1, and exposure to loud noises in LQTS2 patients)

Beta-blockers for all patients 

Implantable cardioverter-defibrillator (ICD) placement with the use of beta-blockers for patients with a previous cardiac arrest

Class IIa 

Consider beta-blockers for carriers of an LQTS genetic mutation and normal QT interval. (Level of evidence: B)

Consider ICD implantation in addition to beta-blockers in patients with syncope and/or ventricular tachycardia (VT) while receiving an adequate dose of beta-blockers. (Level of evidence: B)

Left cardiac sympathetic denervation should be considered in patients with symptomatic LQTS when (Level of evidence: C):

• Beta-blockers are ineffective, not tolerated, or contraindicated
• ICD therapy is contraindicated or refused
• Patients on beta-blockers with an ICD experience multiple shocks

Class IIb (Level of evidence: C)

Consider sodium channel blockers (mexiletine, flecainide or ranolazine) as add-on therapy to shorten the QT interval in LQTS3 patients with a QTc longer than 500 ms.

Consider an ICD in addition to beta-blocker therapy in asymptomatic carriers of a pathogenic mutation in KCNH2 or SCN5A when the QTc is longer than 500 ms.

Class III (Level of evidence: C)

Invasive electrophysiological study (EPS) with programmed ventricular stimulation (PVS) is not recommended for SCD risk stratification.

The 2015 ESC recommendations summarized above are consistent with the recommendations of the 2006 joint guidelines of the American College of Cardiology, the American Heart Association, and the ESC (ACC/AHA/ESC).^[39]  However, the 2013 HRS/EHRA/APHRS recommendations have one significant variance in that beta-blockers are only recommended in patients who are asymptomatic with a QTc of at least 470 ms and/or symptomatic for syncope or documented ventricular tachycardia/ventricular fibrillation (VT/VF).^[36]

A scientific statement published in 2015 by the AHA/ACC on athletic competition by persons with known or suspected cardiac channelopathies includes the following recommendations related to LQTS^[40] :

• That a heart rhythm specialist or genetic cardiologist experienced in cardiac channelopathies conduct a thorough evaluation of an athlete in whom such a disorder has been diagnosed or is suspected
• That asymptomatic athletes who are genotype-positive/phenotype-negative for LQTS, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, early repolarization syndrome, short-QT syndrome, or idiopathic ventricular fibrillation be allowed to take part in all competitive sports if precautionary measures, such as the avoidance of QT-prolonging drugs, are undertaken
• That an athlete who is symptomatic for LQTS or in whom it can be found electrocardiographically be considered for competitive sports (with the exception of competitive swimming, if the athlete is a previously symptomatic LQT1 host) if precautionary measures have been undertaken, treatment is being administered, and the person has been asymptomatic on therapy for at least 3 months (although treatment involving an ICD is subject to additional recommendations)

• References

Medication Summary

No treatment addresses the cause of long QT syndrome (LQTS). Antiadrenergic therapeutic measures (eg, use of beta-blockers, left cervicothoracic stellectomy) and device therapy (eg, use of pacemakers, implantable cardioverter-defibrillators [ICD]s) aim to decrease the risk and lethality of cardiac events.

As previously mentioned, the protective effect of beta-blockers is related to their adrenergic blockade, which diminishes the risk of cardiac arrhythmias. They may also reduce the QT interval in some patients. Beta-blockers used in patients with LQTS include the following:

• Nadolol (preferred)
• Propranolol
• Metoprolol
• Atenolol

Nadolol is the preferred beta blocker to be used at a dose of 1-1.5 mg/kg/day (once a day for patients older than 12 years and divided twice a day for younger patients).^[3]

• References

Propranolol (Inderal LA, Inderal XL, InnoPran XL, Hemangeol)

• Dosing, Interactions, etc.

Clinical Context:  Propranolol decreases 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 varies and is individualized in patients with LQTS. Patients with asthma should use cardioselective beta-blockers. Patients with LQTS who cannot take beta-blockers may require an ICD as first-line therapy.

• References

Nadolol (Corgard)

• Dosing, Interactions, etc.

Clinical Context:  Nadolol is frequently prescribed because of its long-term effect. This agent decreases 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 varies and is individualized in patients with LQTS. Patients with asthma should use cardioselective beta-blockers. Patients with LQTS who cannot take beta-blockers may require an ICD as first-line therapy.

• References

Metoprolol (Lopressor, Toprol XL)

• Dosing, Interactions, etc.

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

• References

Atenolol (Tenormin)

• Dosing, Interactions, etc.

Clinical Context:  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 LQTS. Patients with LQTS who cannot take beta-blockers may require an ICD as first-line therapy.

• References

Class Summary

Antiadrenergic therapy effectively protects most patients with long QT syndrome (LQTS). Beta-blockers, especially propranolol, are the drugs most frequently used in patients with LQTS. Inform patients and their family members that beta-blockers should be continued indefinitely. Interruption in beta-blocker therapy may increase the risk of cardiac events.

• References