LONG QT SYNDROME Author: Ali A Sovari, MD; Chief Editor: Jeffrey N Rottman, MD Long QT syndrome (LQTS) is a congenital disorder

characterized by a prolongation of the QT interval on ECG and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. 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. QT intervals corrected for heart rate (QTc) longer than 0.44 seconds are generally considered abnormal, though a normal QTc can be more prolonged in females (up to 0.46 sec). 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). To measure 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 < 50 bpm or >120 bpm and when athletes or children have marked beatto-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. Pathophysiology 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 3 layers of the heart, and the repolarization phase tends to be prolonged in the myocardium. This is why the T wave is normally wide and the interval from Tpeak to Tend (Tp-e) represents the transmural dispersion of repolarization (TDR). In long QT syndrome (LQTS), TDR increases and creates a functional substrate for transmural reentry. 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. 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. 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, though some debate centers on whether they should be included in LQTS. 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). 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) (Open Table in a new window) Type of LQTS LQT1 LQT2 LQT3 LQT4 LQT5 LQT6 LQT7 (Anderson syndrome) LQT8 (Timothy syndrome) LQT9 LQT10 Chromosomal Locus 11p15.5 7q35-36 3p21-24 4q25-27 21q22.1-22.2 21q22.1-22.2 17q23.1-q24.2 12q13.3 3p25.3 11q23.3 Mutated Gene KVLQT1 or KCNQ1 (heterozygotes) HERG, KCNH2 SCN5A ANK2, ANKB KCNE1 (heterozygotes) MiRP1, KNCE2 KCNJ2 CACNA1C CAV3 SCN4B Ion Current Affected Potassium (IKs) Potassium (IKr) Sodium (INa) Sodium, potassium and calcium Potassium (IKs) Potassium (IKr) Potassium (IK1) Calcium (ICa-Lalpha) Sodium (INa) Sodium (INa)

LQT11 LQT12 JLN1 JLN2

7q21-q22 11p15.5 21q22.1-22.2

AKAP9 SNTAI KVLQT1 or KCNQ1 (homozygotes) KCNE1 (homozygotes)

Potassium (IKs) Sodium (INa) Potassium (IKs) Potassium (IKs)

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 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. The LQT1 gene (KVLQT1 or KCNQ1) encodes for part of the IKs slowly deactivating, delayed rectifier potassium channel. 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. The LQT2 gene (HERG or KCNH2) encodes for part of IKr rapidly activating, rapidly deactivating, delayed rectifier potassium channel. Mutations in this gene cause rapid closure of the potassium channels and decrease the normal rise in IKr. They also result in delayed ventricular repolarization and QT prolongation. About 200 mutations in this gene have been detected. 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. Some loss-offunction mutations in the same gene may lead to different presentations, including Brugada syndrome. More than 50 mutations have been identified in this gene. In some patients, caveolae proteins have been recognized as responsible for the increased Na+ current in LQTS3. [1] Caveolae are small (50100 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 Na+ channels, are mainly colocalized with caveolae on the membrane. Thus, absence or abnormal formation of caveolae may have some effects on the availability of Na+ channels. For instance, Vatta and colleagues demonstrated that mutations in caveolin-3 protein exist in LQTS3 and that they can cause an increase in late Na+ current. [1] Nevertheless, caveolae are present in the membrane of many other cell types and are 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. [2] The fact that mutations in proteins associated with ion channels may result in change in the availability of channels on the membrane and therefore a significant change in total current has added a new window for investigating the genetic abnormalities resulting in LQTS. The LQT4 gene (ANK2 or ANKB) encodes for the 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 (INa), and the sodium-calcium exchanger (NCX, or INa-Ca), and calcium-release channels (including those mediated by the receptors for inositol triphosphate [IP 3] 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. The LQT5 gene encodes for the IKs potassium channel. Similar to LQT1, LQT5 results 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 beta subunits of IKr potassium channels. The LQT7 gene (KCNJ2) encodes for potassium channel 2 protein that plays an important role in inward repolarizing current (IKi), 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 both 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 (NaV b3) is associated with this protein. Functional studies have demonstrated that CAV3 mutations are associated with persistent late sodium current and have been reported in cases of sudden infant death syndrome (SIDS).[3] LQT9 and LQT4 serve as examples of LQTS with nonchannel mutations.

A novel mutation in the LQTS10 gene encoding the protein Na V b4, a subunit of the voltage-gated sodium channel of the heart NaV 1.5 (gene: SCN5), results in a positive shift in the inactivation of the sodium current. To date, only a single mutation in 1 patient has been described.[4] 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. [5] In patients with LQTS, a variety of adrenergic stimuli, including exercise, emotion, loud noise, and swimming may precipitate an arrhythmic response. However, it also may occur without such preceding conditions. 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 are female sex, electrolyte disturbances (hypokalemia and hypomagnesemia), hypothermia, abnormal thyroid function, structural heart disease, and bradycardia. Some have also suggested that affected individuals have mutations that affect cardiac ion channels, altering repolarization reserve. Epidemiology United States Long QT syndrome (LQTS) remains an underdiagnosed disorder, especially because at least 10-15% of LQTS gene carriers have a normal QTc duration. The prevalence of LQTS is difficult to estimate. However, given the currently increasing frequency of diagnosis, LQTS may be expected to occur in 1 in 10,000 individuals. International The occurrence of long QT syndrome internationally is similar to that in the United States. Mortality/Morbidity Mortality, morbidity, and responses to pharmacologic treatment differ in the various types of long QT syndrome (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 4000 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 happens with the first episode of syncope in about 30% of the patients. This occurrence emphasizes the importance of diagnosing LQTS in the presymptomatic period. Depending on the type of mutation present, sudden cardiac death may happen 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.

Race No clear evidence suggests race-related differences in the occurrence of long QT syndrome. Sex New cases of long QT syndrome are diagnosed more in female patients (60-70% of cases) than male patients. The female predominance may be related to the relatively prolonged QTc (as determined by using the Bazett formula) in women compared with 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. Age 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, and the risk is similar in male and female patients thereafter.

History Long QT syndrome (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 ECG shows QT prolongation. A history of cardiac events is the most typical clinical presentation in patients with LQTS. 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 a patient and his or her 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 (ArizonaCERT) provides lists of Drugs that Prolong the QT Interval and/or Induce Torsades 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. Physical 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. Findings on physical examination usually do not indicate a diagnosis of long QT syndrome (LQTS), though some patients may present with excessive bradycardia for their age, and some patients may have hearing loss (congenital deafness), indicating the possibility of 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). Hinterseer et al found that increased short-term variability of 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. This study is the first in humans to observe this association.[6]
Causes

Details of the genetic background of long QT syndrome (LQTS) are presented in Pathophysiology. LQTS is caused by mutations of genes encoding for cardiac ion channel proteins that 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. Secondary (drug-induced) QT prolongation also may have a genetic background, consisting of 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. ArizonaCERT provides lists of Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia. Work-up Laboratory Studies 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. Genetic testing for known mutations in DNA samples from patients is becoming accessible in specialized centers. Identification of an long QT syndrome (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 a low sensitivity.

Imaging Studies Imaging studies (eg, echocardiography, 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 small subset of patients with long QT syndrome, such as those with LQT8. Other Tests A presentation with syncope or sudden cardiac death and a long QT on ECG typically suggests long QT syndrome (LQTS) and leads to genetic testing to diagnose the disease. However, in many patients, the presentation may not be typical. Therefore, other tests may be indicated. In 1993, Schwartz et al suggested diagnostic criteria that still serve as the best criteria for clinicians. [7] In their model, the criteria are divided to 3 main categories, as shown in Table 2. The maximum score is 9, and a score of >3 indicates a high probability of LQTS. Table 2. Diagnostic Criteria for LQTS (Open Table in a new window) Criterion ECG findings * QTc, ms Points >480 460-469 450-459 in male patient 3 2 1 2 1 1 0.5

Torsade de pointes T-wave alternans Notched T wave in 3 leads Low heart rate for age Clinical history Syncope With stress 2 Without stress 1 Congenital deafness 0.5 Family history A. Family members with definite LQTS# 1 B. Unexplained sudden cardiac death < 30 y in an immediate family member 0.5 *In the absence of medications or disorders known to affect these electrocardiographic features. QTc calculated by Bazett's formula Mutually exclusive Resting heart rate below the second percentile for the age. ||Mutually exclusive The same family member cannot be counted in A and B. #Definite LQTS is defined by an LQTS score of more than 3 ( 4).

As criteria above suggest, the most helpful ECG findings are prolongation of the QT interval, torsade de pointes, Twave alternans, and certain morphology of the T waves (wide-based T wave, and notched T wave in 3 leads). Correlation between the type of mutation and T-wave morphology has been suggested. Wide-based T waves are most frequently seen in LQT1, and notched T waves are most commonly seen in LQT2. In LQT3, T waves may appear normal with a long, isoelectric ST segment. Prolongation of the QTc interval is defined on the basis of age- and sex-specific criteria (see Table 3). 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 >0.46 seconds indicates an increased likelihood of LQTS (see following 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 corrected for heart rate [QTc] = 0.56 s). 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 LQTS.

However, approximately 10-15% of gene-positive patients with LQTS present with a QTc duration in the reference range (see following 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, QT interval corrected for heart rate [QTc] = 0.44 s) in a 12-year-old girl. Note the abnormal morphology of the T wave (notches) in leads V2-V4. Table 3. Definition of QTc Based on Age- and Sex-Specific Criteria (Open Table in a new window)

Group Children and adolescents (< 15 y) Men Women

Prolonged QTc, s >0.46 >0.45 >0.46

Borderline QTc, s 0.44-0.46 0.43-0.45 0.45-0.46

Reference Range, s < 0.44 < 0.43 < 0.45

Both bradycardia and tachycardia need special attention. Bradycardia is among diagnostic criteria and adds 0.5 point to the score. Tachycardia needs special attention, too, because the QTc may be overcorrected in tachycardic situation (eg, in infants). In patients with suspected LQTS with borderline QTc values (or even values in the reference range) on standard ECGs or patients with a score of 2-3 based on the 1993 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 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. Visible T wave alternans in patients with LQTS indicate 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 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. The patients with a clinical or ECG presentation of LQTS need genetic testing to identify the mutation. These genetic tests are now commercially available but can entail considerable expense, and insurance coverage for genetic testing often requires specific physician intervention. In a patient with a high probability of LQTS, an absence of any mutation on genetic testing based on diagnostic criteria does not rule out the possibility of LQTS. The patient might have an as-yet unidentified mutation. 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 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. A 2010 study Viskin and colleagues demonstrated that the expected shortening of QT interval in response to sinus tachycardia induced by standing from a supine position is impaired in patients with LQTS. In fact, the QTc interval in patients with LQTS increased with standing position and more 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. In addition, this study may reveal an important point that standing up in patients with LQTS may be associated with more focal activities (perhaps due to early afterdepolarization that contributes to APD and therefore QT prolongation) 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.[8] Medical Care All patients with long QT syndrome (LQTS) should avoid drugs that prolong the QT interval or reduce their serum potassium or magnesium levels. Potassium and magnesium deficiency should be corrected. 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. The protective effect of beta-blockers is related to their adrenergic blockade that diminishes the risk of cardiac arrhythmias. They may also reduce the QT interval in some patients. Although for years the recommended dosage of beta-blockers was relatively large (eg, propranolol 3 mg/kg/d, or 210 mg/d in a 70-kg individual), recent data suggest that dosages lower than this have a protective effect similar to that of large dosages. Beta-blockers are effective in preventing cardiac events in approximately 70% of patients, whereas cardiac events continue to occur despite beta-blocker therapy in the remaining 30%. Propranolol and nadolol are the beta-blockers most frequently used, though atenolol and metoprolol are also prescribed in patients with LQTS. Different beta-blockers demonstrate similar effectiveness in preventing cardiac events in patients with LQTS.

The implantable cardioverter-defibrillator (ICD) was shown to be highly effective to prevent sudden cardiac death (SCD) in high-risk patients. In a study of 125 patients with LQTS with ICDs, there was 1.3% death in high-risk ICD patients, compared with 16% in non-ICD patients during mean 8-year follow-up (p=0.07).[9] 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 is beta-blockade in combination with a pacemaker and/or stellectomy in some patients. Use of an ICD may be considered as primary therapy if the patient has a strong family history of SCD. However, since some studies showed that family history of SCD is not an independent risk factor [10] , some experts do not recommend ICD therapy based on only a family history of SCD[11] . Early ICD therapy should be considered in high-risk patients with Jervell and Lange-Nielsen syndrome, because the efficacy of beta-blockers was found to be more limited in these patients.[12] 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, diminishing the risk of torsade de pointes ventricular tachycardia. Pacemakers are particularly helpful in patients with documented pause-bradycardiainduced torsade de pointes and in patients with LQT3.

However, recent 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.

Left cervicothoracic stellectomy is another antiadrenergic therapeutic measure used in high-risk patients with 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, and it is more effective in patients with LQT1 than those with other types of LQTS. Although this technique decreases the risk of cardiac events, it does not eliminate the risk. Therefore, ICD is superior therapy to cervicothoracic stellectomy. 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.

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, and 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 the patients. Some experts suggest the use of a beta-blocker combined with mexiletine in patients with LQT3.

Gene-specific therapy is an area under investigation. For example, since LQT3 is associated with gain of function mutations in Na+ channels, antiarrhythmic agents with Na+ 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 instance, Ruan and colleagues found that mexiletine, an Na+ channel blocker, can facilitate F1473 mutant protein trafficking resulting in a net effect of further increase in Na current and worsening of QT prolongation in a subset of patients with LQTS3 with this specific mutation. [13] Trigger-specific risk stratification and therapy has been suggested by some studies. For example, Kim and colleagues showed that certain types of mutations in LQT2 are associated with certain trigger events (exercise triggers vs arousal triggers vs nonarousal/nonexercise triggers) and that patients with exercise trigger events respond to the treatment with beta-blockers.[14] A summary of guidelines suggested by the American College of Cardiology, the American Heart Association, and the European Society of Cardiology, in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society for management of patients with LQTS include:[15, 16] No participation in competitive sports for patients with the diagnosis established by means of genetic testing only. Beta-blockers should be given to patients who have QTc-interval prolongation (>460 ms in women and >440 ms in men) and is recommended (class IIa) for patients with a normal QTc interval. ICD should be implanted for survivors of cardiac arrest and is recommended (class IIa) for patients with syncope while receiving beta-blockers. ICD therapy can be considered (class IIb) for primary prevention in patients with characteristics that suggest high risk; these include LQT2, LQT3, and QTc interval greater than 500 ms.

Consultations A cardiologist and a cardiac electrophysiologist are typically consulted when patients with long QT syndrome (LQTS) are evaluated. In families of patients with genotypically confirmed LQTS, genetic counseling of patients and family members should be considered. 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. This recommendation is most important for patients with LQT1 or LQT2. See also the Medical Care section. 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, ICDs) aim to decrease the risk and lethality of cardiac events.

Beta-Adrenergic Blocking Agents Class Summary Antiadrenergic therapy effectively protects most patients with 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 and not stopped. Interruption in beta-blocker therapy may increase the risk of cardiac events. Propranolol (Inderal) Decreases effect of sympathetic stimulation on heart. Decreases conduction through atrioventricular (AV) node and has negative chronotropic and inotropic effects. Consult 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 ICDs as first-line therapy. Nadolol (Corgard) Frequently prescribed because of long-term effect. Decreases effect of sympathetic stimulation on heart. Decreases conduction through AV node and has negative chronotropic and inotropic effects. Consult cardiologist because dosing varies and is individualized in patients with LQTS. Patients with asthma should use cardioselective betablockers. Patients with LQTS who cannot take beta-blockers may require ICDs as first-line therapy. Metoprolol (Lopressor) Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor BP, heart rate, and ECG. Consult cardiologist because dosing varies and is individualized in patients with LQTS. Patients with LQTS who cannot take beta-blockers may require ICDs as first-line therapy. Atenolol (Tenormin) Selectively blocks beta1-receptors with little or no effect on beta2 types. Consult cardiologist because dosing varies and is individualized in patients with LQTS. Patients with LQTS who cannot take Further Inpatient Care Patients with long QT syndrome (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. Asymptomatic individuals with LQTS usually do not require hospitalization. However, carefully evaluate them and provide follow-up care in an ambulatory setting. Further Outpatient Care A cardiologist or a cardiac electrophysiologist should examine patients with long QT syndrome on a regular basis. Deterrence/Prevention Antiadrenergic therapy (eg, beta-blockers, stellectomy) aims to prevent future cardiac events. Use implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death in patients with long QT syndrome (LQTS) who develop ventricular tachyarrhythmias. Educate family members of patients with LQTS regarding the disorder and the basics of cardiopulmonary resuscitation (CPR). The Sudden Arrhythmia Death Syndromes Foundation (SADS) and Cardiac Arrhythmias Research and Education Foundation (CARE) have support groups for families with LQTS. Educate patients and family members about medications that may induce QT prolongation and that should be avoided in patients with LQTS. ArizonaCERT provides lists of Drugs that Prolong the Qt Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia. Anesthetics or asthma medication - Epinephrine (Adrenaline) for local anesthesia or as an asthma medication Antihistamines o Terfenadine (Seldane [recalled from US market]) for allergies o Astemizole (Hismanal [recalled from US market]) for allergies o Diphenhydramine (Benadryl) for allergies Antibiotics o Erythromycin (E-Mycin, EES, EryPed, PCE) for lung, ear, and throat infections o Trimethoprim and sulfamethoxazole (Bactrim, Septra) for urinary, ear, and lung infections o Pentamidine (Pentam, intravenous) for lung infections Heart medications

o Quinidine (Quinidine, Quinidex, Duraquin, Quinaglute) for heart rhythm abnormalities o Procainamide (Pronestyl) for heart rhythm abnormalities o Disopyramide (Norpace) for heart rhythm abnormalities o Sotalol (Betapace) for heart rhythm abnormalities o Probucol (Lorelco) for high triglycerides, cholesterol o Bepridil (Vascor) for chest pain (angina) o Dofetilide (Tikosyn) for atrial fibrillation o Ibutilide (Corvert) for atrial fibrillation Gastrointestinal medications - Cisapride (Propulsid) for esophageal reflux, acid indigestion Antifungal drugs o Ketoconazole (Nizoral) for fungal infections o Fluconazole (Diflucan) for fungal infections o Itraconazole (Sporanox) for fungal infections Psychotropic drugs o Tricyclic antidepressants (Elavil, Norpramin, Vivactil) for depression o Phenothiazine derivatives (Compazine, Stelazine, Thorazine, Mellaril, Trilafon) for mental disorders o Butyrophenones (Haloperidol) for mental disorders o Benzisoxazol (Risperdal) for mental disorders o Diphenylbutylperidine (Orap) for mental disorders Medications for potassium loss o Indapamide (Lozol) for water loss, edema o Other diuretics o Medications for vomiting and diarrhea

Complications Sudden cardiac death is the most devastating complication of the long QT syndrome, especially because it frequently occurs in young individuals. Neurologic deficits after aborted cardiac arrest may complicate the clinical course after successful resuscitation. Prognosis The prognosis for patients with long QT syndrome (LQTS) treated with beta-blockers (and other therapeutic measures if needed) is good overall. 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 ICDs. Their prognosis after implantation of cardioverter-defibrillators is good. Patient Education Educate patients regarding the nature of the long QT syndrome 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 CPR. beta-blockers may require ICDs as first-line therapy.

Long QT Syndrome: Diagnosis and Management

Abstract Background: Long QT syndrome (LQT) is characterized by prolongation of the QT interval, causing torsade de pointes and sudden cardiac death. The LQT is a disorder of cardiac repolarization caused by alterations in the transmembrane potassium and sodium currents. Congenital LQT is a disease of transmembrane ion-channel proteins. Six genetic loci of the disease have been identified. Sporadic cases of the disease occur as a result of spontaneous mutations. The acquired causes of LQT include drugs, electrolyte imbalance, marked bradycardia, cocaine, organophosphorus compounds, subarachnoid hemorrhage, myocardial ischemia, protein sparing fasting, autonomic neuropathy, and human immunodeficiency virus disease. Methods: Data on the diagnosis and management of LQT were thoroughly reviewed. Results and Conclusions: The diagnosis of LQT primarily rests on clinical and electrocardiographic features and family history. The clinical presentations range from dizziness to syncope and sudden death. Genetic screening is available primarily as a research tool. Short-term treatment of LQT is aimed at preventing the recurrences of torsades and includes intravenous magnesium and potassium administration, temporary cardiac pacing, withdrawal of the offending agent, correction of electrolyte imbalance, and, rarely, intravenous isoproterenol administration.

The long-term treatment is aimed at reducing the QT-interval duration and preventing the torsades and sudden death and includes use of oral -adrenergic blockers, implantation of permanent pacemaker/cardioverter-defibrillator, and left thoracic sympathectomy. Sodium channel blockers are promising agents under investigation. Electrocardiograms are recorded for screening of family members. The data favor treating asymptomatic patients, if <40 years old at the time of diagnosis, with -adrenergic blockers. Introduction Long QT syndrome (LQT) is a disorder caused by lengthening of the repolarization phase of the ventricular action potential, although the QT interval on the surface electrocardiogram (ECG) represents the total duration of both the depolarization and the repolarization phases. Therefore it is the lengthening of the JT interval that determines the vulnerability for development of torsade de pointes (torsades), and the lengthening of QT interval, because of the mere lengthening of the duration of QRS complex, will not constitute LQT and will not precipitate torsades. The LQT is caused by congenital and acquired factors. Congenital LQT is a heritable ion channel disease caused by a number of mutations in the genes encoding for the transmembrane sodium or potassium ion channel proteins. [1] Six subsets of congenital LQT (LQT1 to LQT6) have been identified. Electrophysiologically, these mutations slow the inactivation of inward depolarizing sodium currents or cause retardation of outward repolarizing potassium currents, resulting in an increase in after depolarizations and dispersion of repolarization, both of which contribute to the final phenotype of the syndrome.[2,3] The acquired factors causing LQT include use of drugs, hypokalemia, hypomagnesemia, hypocalcemia, marked bradycardia, cocaine abuse, organophosphorus compound poisoning, subarachnoid hemorrhage, stroke, myocardial ischemia, protein-sparing fasting by using liquid protein diets, autonomic neuropathy, and human immunodeficiency virus disease. [4-10] Multiple risk factors may interplay in an individual patient to prolong QT interval and precipitate torsades. [11] Diagnosis of LQT Syndrome The diagnosis of LQT primarily depends on the clinical features, the family history, and the ECG findings of the patient. Unexplained syncope or sudden cardiac death in a child or young adult should raise a high suspicion of the possibility of presence of LQT. Electrophysiologic testing is not helpful in making the diagnosis of LQT. Genetic testing has not become a routine part of the diagnostic workup in patients with LQT, although it could be of assistance in the borderline cases or in cases where a new mutation is suspected. Schwartz[12] and Schwartz et al[13] have proposed a set of criteria to assist in diagnosing the LQT ( Table I ). These criteria provide a quantitative approach to the diagnosis of LQT by allocating numerical points to the clinical features, family history, and ECG findings and divide the possibility of LQT into low, intermediate, and high probability ranges. In the borderline cases, exercise testing may be performed to assist in the diagnosis. The QT interval may lengthen abnormally during the recovery phase of exercise testing in patients with LQT. [14,15] In a controlled study,[15] at heart rates of 110 or 100 beats/min during recovery, 100% of LQT1 patients and 89% of LQT2 patients had QT intervals longer than any of the control subjects. Clinical Features The clinical features of LQT are a result of the precipitation of torsades, and range from minor symptoms, such as dizziness, to seizure, syncope, and sudden death. An individual episode of the torsades is generally short lived, usually terminates spontaneously, and may go unrecognized. However, it has a tendency to recur in rapid succession and therefore may cause syncope and death. The characteristic electrocardiographic features of torsades include a markedly prolonged QT interval in the last sinus beat preceding the onset of the arrhythmia, progressive twisting of the QRS complex polarity around an imaginary baseline, a complete 180-degree twist of the QRS complexes in 10 to 12 beats, changing amplitude of the QRS complexes in each cycle in a sinusoidal fashion, a heart rate between 150 to 300 beats/min, and irregular RR intervals.[16,17] The initiation of torsades is usually dependent on a pause in the electrical activity created by a longer cycle length, which may be the result of bradycardia or an extrasystole. The longer cycle length usually precedes the last supraventricular beat before initiation of the torsades. In a typical short-long-short sequence, a sinus beat is followed by an extrasystole (short cycle), this extrasystole is followed by a sinus beat after a long postextrasystolic pause (long cycle), and this sinus beat, which has a longer QT interval than the preceding sinus beats, is then followed by a ventricular beat, which is the first beat of the torsades. In cases with congenital LQT, a sudden intense adrenergic stimulation can precipitate torsades. [18] The sudden intense adrenergic stimulation probably results in an extrasystole, which is followed by a long postextrasystolic pause that precipitates arrhythmia in the setting of underlying long QT interval. [19] The congenital LQT usually manifests before the age of 40 years, chiefly in childhood and adolescence. The age at which disease manifests the first time in an individual patient depends on the genotype of the family. According to the International Long QT Syndrome Registry data, the median age at which the first cardiac event occurred was 9, 12, and 16 years in subjects with LQT1 (n = 112 subjects), LQT2 (n = 72 subjects), and LQT3 (n = 62 subjects), respectively.[20] Men are less prone to the development of cardiac events because of shorter QT intervals compared with women, boys, and girls, especially in LQT1 and LQT2 groups.[21-23] The shorter QT interval for men is most evident for heart rates <60 beats/min. The risk of torsades and sudden death is highest at the early waking hours, which correlates with the diurnal peak of the QT interval at that time. The prolongation of QT interval is a risk factor for sudden cardiac death independent of the patient's age, history of myocardial infarction, heart rate, and history of drug use; the patients with a QTc interval of >440 milliseconds are at 2 to 3 times higher risk for sudden cardiac death than those with a QTc interval of <440 milliseconds. [24] The mortality rate in untreated patients with LQT is in the range of 1% to 2% per year. The incidence of sudden death varies from family to family as a function of the genotype. [20,25] In the data published from the International LongQT Syndrome Registry, the frequency of cardiac events was significantly higher among subjects with LQT1 (63%) or LQT2 (46%) than among subjects with LQT3 (18%). [20] The cumulative mortality through the age of 40 years

was similar among subjects of all 3 genotypes, but the likelihood of dying during a cardiac event was significantly higher among the subjects with LQT3 (20%) than among those with LQT1 (4%) or LQT2 (4%). The mean QTc interval was significantly longer in the LQT3 group (510 48 ms) than that in the LQT1 (490 43 ms) or LQT2 (495 43 ms) groups. Sudden cardiac death in patients with congenital LQT is often precipitated by a triggering event, such as physical exercise, swimming, sleep deprivation, auditory stimuli, and sudden intense sympathetic stimuli including grief, fright, pain, anger, fear, or startle. [26,27] These events tend to cluster in families as a function of the genotype.[26] Physical exercise is more prone to precipitate cardiac events in patients with LQT1, auditory stimuli in patients with LQT2, and rest and sleep in patients with LQT3. [26-28] Although the cause of death during rest and sleep in patients with LQT3 is not well established, it well reflects bradyarrhythmia-induced torsades because bradycardia and pauses have been reported with LQT3. The high-risk predictors of sudden cardiac death in patients with congenital LQT include recurrent episodes of syncope, failure on conventional medical therapy, survival from cardiac arrest, congenital deafness, female sex, QTc >600 milliseconds, relative bradycardia, kinship with a symptomatic patient, and sudden cardiac death in a family member at an early age. [29] Family History and Genetics A family history of unexplained syncope or sudden death, especially in the young family members of a patient with unexplained syncope or sudden death, should raise a strong suspicion of congenital LQT. Initially, the 2 welldescribed forms of the congenital LQT were the Jervell Lange-Nielsen syndrome and the Romano Ward syndrome. The Jervell Lange-Nielsen syndrome is a rare cardioauditory syndrome where the deafness is inherited in an autosomal recessive pattern, and the marked QTc prolongation reflects the double-dominant inheritance of 2 mutant alleles.[30] The more common Romano Ward syndrome, associated with normal hearing, is inherited in an autosomal dominant pattern.[31,32] During last decade, significant advancements have been made in determining the genetic basis of the congenital LQT, and on the basis of ion channel and the gene involved, 6 subtypes of congenital LQT have been characterized. Mutations in the KCNQ1 (KVLQT1) gene, located on chromosome 11, cause LQT1. The KCNQ1 gene encodes the a-subunit of a cardiac potassium channel IKs -- the slowly activating potassium-delayed rectifier.[33] The LQT1 is the principal gene responsible for both Jervell Lange-Nielsen and Romano Ward syndromes, and it accounts for approximately 50% of the genotyped LQT families.[34] The mutations in the HERG gene, located on chromosome 7, cause LQT2. The HERG gene encodes for another cardiac potassium channel I Kr -- the rapidly activating potassiumdelayed rectifier.[35] The LQT2 accounts for approximately 45% of the genotyped LQT families. The mutations in the SCN5A gene, located on chromosome 3, cause LQT3. The SCN5A gene encodes a cardiac sodium channel I Na -the cardiac voltage-dependent sodium channel.[36] The LQT3 accounts for approximately 5% of the genotyped LQT families. Interestingly, mutations in the same gene but at different loci result in Brugada syndrome and progressive conduction system disease (Lenegre-Lev disease). However, these mutations are loss of function type mutations contrary to the gain in function type mutations in LQT3. The LQT4 locus has been identified at chromosome 4 in one large French kindred but the responsible gene has not been identified yet.[37] The mutations in the KCNE1 (minK) gene, located on chromosome 21, cause LQT5. The KCNE1 gene encodes the -subunit of the cardiac potassium channel IKs.[38] The KCNQ1 (LQT1) and KCNE1 (LQT5) gene products assemble to form a complete I Ks channel protein. The LQT5 accounts for only a small number of the genotyped LQT families. The mutations in the KCNE2 (MiRP1) gene, located on chromosome 21 cause LQT6. [39] The KCNE2 (MiRP1) gene encodes a small membrane protein, which is considered a part of the I Kr channel.[39] The HERG (LQT2) and KCNE2 (LQT6) gene products assemble to form a complete IKr channel protein. Although currently >300 mutations have been discovered in the 5 known LQT genes, not all the genes responsible for LQT have been identified. In addition, the sporadic cases of LQT occur as a result of spontaneous mutations. Therefore a lack of family history does not entirely preclude the diagnosis of congenital LQT. ECG Findings In the majority of patients with congenital LQT, the QTc interval is >440 milliseconds, but in 6% to 12% of patients the QTc interval is within normal limits, and about one third of the patients have a QTc interval <=460 milliseconds.[20,40] The other ECG features, especially accompanying T-wave and U-wave abnormalities, may assist in diagnosis, especially in cases where the QTc interval is within normal limits or is borderline high. [40] Sinus bradycardia with sinus pauses has been reported in up to one third of the patients with congenital LQT, especially so in patients with LQT3.[41] Another ECG feature of the LQT is increased QT interval dispersion, which is due to labile repolarization in LQT.[42] The T wave could be larger, prolonged, and bizarre looking and may display a notched, bifid, biphasic, or alternans appearance.[40,43] T-wave alternans is a diagnostic feature of the LQT and reflects an enhanced electrical instability during repolarization.[43] The different genotypes of LQT may display specific ECG phenotypes. Zhang et al [40] identified 10 ST-T wave repolarization patterns in LQT (4 in LQT1 genotype, 4 in LQT2 genotype, 2 in LQT3 genotype). The repolarization patterns identified in LQT1 were of infantile ST-T wave, broad-based T wave, normal-appearing T wave, and late-onset normal-appearing T wave; those identified in LQT2 were of obvious bifid T wave, subtle bifid T wave with second component on top of T wave in limb and left precordial leads, subtle bifid T wave with second component on down slope of T wave in inferior and mid precordial leads, and low-amplitude bifid T wave with second component merged with U wave; and those identified with LQT3 were of late-onset peaked/biphasic T wave and asymmetric peaked T wave. These repolarization patterns had sensitivity of 61% to 100%, 62% to 100%, and 33% to 100%; and specificity of 71% to 100%, 87% to 100%, and 98% to 100% for identifying LQT1, LQT2, and LQT3, respectively. However, overlap existed among the repolarization patterns of 3 genotypes, and one third of LQT3 gene carriers had repolarization patterns similar to those of LQT1 gene carriers. The sensitivities and specificities were higher with family-grouped analysis. The U-wave abnormalities reported in LQT include prominent bizarre looking U waves and U-wave alternans. The T- and U-wave abnormalities in LQT have been reported to exaggerate with excessive sympathetic stimulation.[43] Management of LQT Syndrome

Short-Term Treatment Immediate cardioversion should be done in situations where torsades does not terminate spontaneously and results in hemodynamic compromise. The short-term treatment, which is aimed at prevention of the recurrences of torsades, includes withdrawal of the offending agents, correction of the underlying electrolyte abnormalities, and administration of magnesium, potassium, temporary transvenous cardiac pacing, and rarely intravenous isoproterenol. The magnesium, potassium, and temporary transvenous cardiac pacing are useful for both congenital and acquired forms of the LQT, but use of intravenous isoproterenol is limited to acquired LQT only. Withdrawal of the Offending Agent. Withdrawal of the offending agent is a crucial first step in the prevention of the recurrence of the torsades. Drugs are the most common offending agents. The important cardiac drugs that have been reported to prolong the QT interval are bepridil; phenylamine; class IA antiarrhythmic agents including, quinidine, procainamide, and disopyramide; and class III antiarrhythmic agents including, sotalol, ibutilide, azimilide, dofetilide, and amiodarone, although amiodarone is rarely associated with torsades. Class IC antiarrhythmic drugs have been implicated in torsades, but such reports are discredited because the QT-interval prolongation, if any, with the use of class IC antiarrhythmic drugs will be due to the prolongation of the QRScomplex duration (depolarization), not the prolongation of the JT interval (repolarization), and it is the prolongation of the repolarization that precipitate torsades, not that of the depolarization. A number of noncardiac drugs have been reported to prolong QT interval, including cisapride, probucol, ketanserin, papaverine, tacrolimus, arsenic trioxide, phenothiazines, haloperidol, tricyclic antidepressants, antimicrobial agents (erythromycin, grepafloxacin, moxifloxacin, pentamidine, amantidine, chloroquine, and trimethoprim-sulphamethoxazole), antifungal agents (ketoconazole and itraconazole), and antihistamines (terfenadine and astemizole). [44] A full list of cardiac and noncardiac drugs that have been reported to prolong the QT interval is available at www.qtdrugs.org. The QT-interval prolongation resulting from the use of drugs is a patient-specific phenomenon, which indicates that the patients who have a drug-induced long QT interval may be genetically predisposed because of the presence of an underlying mild or attenuated form of congenital LQT. [44,45] The principal ion channel affected by the QT-interval prolonging drugs is IKr (HERG), which, interestingly, is the same ion channel that causes congenital LQT2. [45] Therefore, a physiologic relationship may exist between drug-induced LQT and congenital LQT2, which further strengthens the possibility of a genetic basis for predisposition to the drug-induced LQT. Hence, drug-induced LQT may raise a possibility of the presence of an LQT locus in the family and thus may logically lend an extra caution in using the QT-prolonging drugs in the other family members, although this has not been examined prospectively. Certain acquired factors including left ventricular hypertrophy, myocardial ischemia, and myocardial fibrosis have been reported to facilitate the drug-induced prolongation of the QT interval.[44,46] Therefore the QT prolonging drugs should be used with caution in patients with these conditions. Magnesium. Magnesium is very effective for suppression of the short-term recurrences of torsades and is the agent of choice for the immediate treatment of the torsades associated with both congenital and acquired forms of LQT, irrespective of serum magnesium levels.[47] A single bolus of 2 g of magnesium sulfate is administered over a period of 2 to 3 minutes, followed by an intravenous infusion of magnesium at a rate of 2 to 4 mg/min, and a second bolus of 2 g of magnesium sulfate may be given if the torsades recurs while the patient is receiving the intravenous infusion of magnesium. The exact mode of action of magnesium in preventing the recurrences of torsades is not clear, but its effect may be mediated by blockade of sodium currents. [48] Magnesium does not shorten the QTc interval significantly and has no significant role in the long-term management of LQT. The treatment with intravenous magnesium is very safe and can be initiated as soon as the diagnosis is made. The only side effect reported with the use of intravenous magnesium therapy is a flushing sensation during the bolus injection. Potassium. Administration of potassium is considered an important adjunct to the intravenous magnesium therapy for the short-term prevention of the torsades, especially in the cases where the serum potassium level is in the lower limits. Data suggest that in patients with LQT2 high normal (4.5-5 mEq/L) levels of serum potassium are preferable to low normal (4-4.5 mEq/L) levels. In a controlled study, Compton et al[49] examined the effect of potassium administration on QT interval in 7 subjects with mutant HERG gene (LQT2). The serum potassium level was raised by >=1.5 mEq/L by giving oral potassium chloride (60 mEq every 2 hours), intravenous infusion of potassium chloride (20 mEq/h), and oral spironolactone (200 mg, followed by 100 mg every 2 hours). The increase in the serum potassium levels resulted in a significant shortening (24%) in the QTc interval in subjects with mutant HERG gene (from 617 92 ms to 469 23 ms) but not in control subjects. In addition, by increasing the serum potassium level, the QTc dispersion decreased significantly in subjects with mutant HERG gene (133 62 ms to 42 28 ms) but did not change in control subjects. However, caution should be used against the development of hyperkalemia while intending to maintain the serum potassium level in the high normal range. Temporary transvenous cardiac pacing. Temporary transvenous cardiac pacing at rates around 100 beats/min is another highly effective measure to prevent the short-term recurrence of the torsades associated with both acquired and congenital forms of LQT.[50] A temporary transvenous pacemaker should be placed if intravenous magnesium therapy fails to prevent the recurrence of the torsades. The cardiac pacing prevents pauses and shortens the QTc interval by enhancing the repolarizing potassium currents as a result of increased heart rates. [51] Although cardiac pacing is effective in preventing the recurrence of the torsades irrespective of the baseline heart rate, it is of particular value in the patients who display bradycardia or pauses. Isoproterenol. Isoproterenol used to be the drug of choice to prevent the short-term recurrence of torsades before the use of magnesium and cardiac pacing. Isoproterenol controls the short-term recurrence of torsades by increasing the heart rate, especially where recurrence is dependent on the bradycardia or pauses. [52] Isoproterenol may be used when specially trained medical personnel are not available to insert a temporary transvenous pacemaker. When used, it is administered as a continuous intravenous infusion at doses sufficient to maintain the heart rate at around 100 beats/min. Because of its adrenergic effects, isoproterenol should not be used in patients with congenital LQT. For similar reasons, it should be used cautiously in patients with structural heart disease. Another limiting factor in the

use of isoproterenol is the scarcity of the drug. The common side effects reported with the use of isoproterenol infusion are palpitations and feeling of flushing sensations. Long-Term Treatment Long-term treatment is generally not required in cases with acquired prolongation of the QT interval because the QT interval often becomes normal by treating the underlying cause. The torsades in these situations, however, often require acute emergency treatment along with the withdrawal of the offending agents and correction of the electrolyte imbalance. The long-term treatment of acquired LQT is limited to permanent pacemaker implantation in patients with sick sinus syndrome or atrioventricular block in whom a pause or the bradycardia is a precipitating event for torsades. On the other hand, long-term treatment of congenital LQT is mandatory and is aimed to prevent the recurrence of torsades by shortening the QTc interval. The standard treatment options available for long-term management of the patients with congenital LQT are the use of oral -adrenergic blockers, permanent pacemaker placement, and implantation of cardioverter-defibrillator. Therapies targeting the mutated ion channels are under investigation. Education of the patient is crucial to avoid risk-associated behaviors. -Adrenergic blockers. Long-term treatment with -adrenergic blockers has shown to result in a significant reduction in the incidence of cardiac events in patients with congenital LQT. [52,53] According to a recently published report,[53] long-term -adrenergic blocker therapy has been shown to result in a significant reduction in the rates of cardiac events in probands (0.97 1.42 events/year before vs 0.31 0.86 events/year after initiation of -blockers) and in affected family members (0.26 0.84 events/year before vs 0.15 0.69 events/year after initiation of blockers) during a 5-year matched period. Among -adrenergic blocking agents, propranolol has been widely used at a daily dose of 2 to 3 mg/kg, but all -blockers should be effective, as protection against the precipitation of torsades provided by the use of -blocker class effect. The dose of -adrenergic blocking agent should be maximized, aiming a maximal heart rate of 130 beats/min or less on treadmill exercise testing. Therapy with -adrenergic blockers should be continued for life and should be supplemented with implantation of a permanent pacemaker in cases where bradycardia is a prominent feature of the syndrome.[54] -Adrenergic blocking agents are most efficacious in LQT1, where exercise and physical exertion are the most common triggers for an arrhythmic event. [28] Left thoracic sympathectomy. High left thoracic sympathectomy has been used, chiefly in Europe, as second-line therapy in patients who were nonresponders to -adrenergic blockers. It is a highly effective method of surgical antiadrenergic therapy but now has been largely replaced with permanent pacemaker and cardioverter-defibrillator implantation.[55] Permanent pacemaker and cardioverter-defibrillator. Implantation of a permanent pacemaker is a standard adjunct to -adrenergic blocker therapy in patients who are symptomatic despite being on the full doses of adrenergic blockers and in cases where bradycardia is a prominent feature of the syndrome.[56,57] -Adrenergic blocker therapy should be continued along with implantation of the permanent pacemaker. [58] Pacing rates should be adjusted to normalize QT interval, and the pacemaker features that allow heart rate slowing beyond the lower rate limit or that may trigger pauses should be turned off because such pauses could be highly proarrhythmic in this patient population.[59] The patients with LQT3 have been reported to more likely benefit from permanent cardiac pacing because they are more prone to have sudden cardiac death at slower heart rates. [54] Implantable cardioverter-defibrillators are used when the combination of the -adrenergic blocker therapy and the pacing fails to prevent presyncopal or syncopal episodes or when the initial presenting event is a resuscitated cardiac arrest.[60] Because of the availability of the cardioverter-defibrillator with dual-chamber pacing capabilities and because of the potential lethality of the failure of -blocker therapy, many electrophysiologists today prefer to use this device as first-line therapy to prevent sudden cardiac death in all symptomatic patients with congenital LQT. The implantable cardioverter-defibrillator will not prevent the precipitation of torsades but will prevent sudden cardiac death when torsades is prolonged or degenerates to ventricular fibrillation. Therefore, to prevent the precipitation of torsades, the use of a -adrenergic blocking agent should be continued along with the implantation of the cardioverter-defibrillator. The unnecessary shocks from the cardioverter-defibrillator device and the emotional distress associated with these shocks may cause adrenergic stimulation sufficient to result in the precipitation of torsades, which gives an even stronger position for continuation of the -adrenergic blocker therapy after implantation of a cardioverter-defibrillator.[52] Mutation-specific therapies. Knowledge about the mutations causing congenital LQT has initiated research on the therapies targeted at the mutant ion channels.[61] The sodium channel blockers flecainide and mexiletine have been reported beneficial in the LQT3, which is caused by a gain in function-type mutations in SCN5A -- a gene that encodes for a cardiac sodium channel.[62-64] Benhorin et al[62] tested the effect of flecainide (75 to 150 mg twice daily orally) on QTc interval in 8 asymptomatic carriers of the SCN5A mutation (LQT3). Flecainide therapy significantly shortened the QT interval (from 523 94 ms to 435 40 ms) and QTc interval (from 517 45 ms to 468 36 ms). In an animal model, mexiletine was also reported to markedly shorten the erythromycin-induced prolongation of the action potential duration and abolish the erythromycin-induced early afterdepolarizations.[65] Other sodium channel blockers including lidocaine, phenytoin, and pentisomide have been reported to be beneficial for termination or prevention of short-term recurrences of the torsades, but the effectiveness of these agents has not been consistent. [66] Similarly, many other experimental agents tested, including potassium channel activators (nicorandil, pinacidil) and calcium channel blockers, have shown inconsistent results and await further investigation. [67,68] Currently, these agents may be considered only as adjuncts to the standard therapy. Screening of family members. Each child of a parent affected with Romano Ward syndrome has a 50% chance of inheriting the LQT gene. The ECGs of all the family members of a patient with LQT are recorded for screening. The identification of QTc interval prolongation and T-wave abnormalities in the family members of a patients with sudden cardiac death is suggestive of presence of the LQT gene in the family and will likely establish LQT as the cause of death in the deceased family member. The genetic screening is available but primarily as a research tool. Routine genetic screening is not feasible currently because only about 60% of families that have been clinically

diagnosed with LQT can be genotyped.[69] Furthermore, numerous different genetic mutations have been discovered involving each of the known LQT genes, making screening laborious. [70,71] Nonetheless, genetic testing is available on a limited basis for those who want to know whether they are genetic carriers, but with the caution that negative results would not entirely rule out the possibility of harboring the LQT gene. Family-grouped ECG analysis improves the accuracy of genotype identification and can simplify genetic screening by targeting the gene for initial study.[40] Treatment of asymptomatic patients. The treatment option offered for asymptomatic patients with LQT is the long-term use of a -adrenergic blocker agent, the dose of which should be maximized aiming at a maximal heart rate of <=130 beats/min on treadmill exercise testing. It is generally recommended to treat all asymptomatic patients <40 years old at the time of diagnosis because it is not possible to predict which asymptomatic patient will become symptomatic and 30% to 40% of sudden deaths occur at the first event. [72,73] Furthermore, although most cases of inherited LQT usually manifest clinically in early childhood, the possibility of a late manifestation of the disease cannot be ruled out, which makes the case stronger for treating asymptomatic patients.[74] However, on the other hand, some investigators have recommended treating asymptomatic patients only if they have high-risk characteristics, including the presence of congenital deafness, QTc interval >600 milliseconds, T-wave alternans, neonates and infants, or affected siblings of children who have died suddenly or if the family desires treatment. [75] Patient education. Patients with congenital LQT should be well informed about the risk-associated behaviors to prevent sudden death, about compliance to -blocker therapy, and about the resources available to provide information on the progress being made in the management of LQT. They should be aware of the drugs and substances with known risk of precipitating torsades. Educational information for patients is provided at several Web sites, including www.sads.org and www.qtsyndrome.ch.