Long QT Syndromes and Torsade de Pointes

I. Long QT syndrome: What every physician needs to know.

Long QT syndrome (LQTS) is an inherited disorder of delayed ventricular repolarization characterized by a prolonged QT interval on electrocardiography (ECG) and a propensity to torsades de pointes (TdP). TdP by definition is: (1) a polymorphic ventricular tachycardia that occurs specifically under conditions of QT prolongation; and (2) it is almost always initiated by R-on-T ectopic beats. Clinical manifestations of TdP include syncope (fainting), seizure (epilepsy), or sudden cardiac death. As shown in Figure 1, an episode of sustained TdP was recorded in a patient aged 13 years with LQTS type 2. The episode during which the boy had “seizures” was triggered by the alarm clock in the early morning.

Figure 1:

Although QT prolongation and TdP can be acquired due to use of certain drugs and a variety of pathophysiological conditions such as electrolyte disturbances, ventricular hypertrophy, and Takotsubo cardiomyopathy, the term “LQTS” is normally used to refer to the congenital forms of QT prolongation. To date, more than 1,000 mutations in 13 LQTS-susceptible genes encoding potassium, sodium, and calcium channels have been identified, among which mutations leading to loss of function in outward potassium currents are most common. Mutations in the KCNQ1 gene that encodes slowly activating delayed rectifier potassium channel (I_Ks) cause subtype 1 LQTS (LQT1), accounting for approximately 30 to 35% of patients with clinical evidence of LQTS. LQT2 is due to mutations in the KCNH2-encoded rapidly activating delayed rectifier potassium channel (I_Kr). LQT2 is the second most common type of LQTS, accounting for 25 to 30% of cases. LQT3 results from mutations in SCN5A leading to gain of function in the inward sodium current (I_Na). It is less common (5–10% of cases). Other LQTS subtypes (LQT4 to LQT13) are extremely rare. These three most common LQTS subtypes (LQT1, LQT2, and LQT3) are inherited in an autosomal dominant pattern. LQTS has diverse clinical features influenced by mutation types, mutation locations, and the biophysical properties of the ionic channels. Other uncommon LQTS subtypes include LQT4 to LQT13 (Table 1).

Table 1.n

“Acquired QT prolongation” and TdP are most commonly induced by drugs that inhibit rapidly activating delayed rectifier current I_Kr. The management of acquired QT prolongation is markedly different from that for congenital LQTS.

II. Diagnostic Confirmation: Are you sure your patient has long QT syndrome?

To diagnose LQTS, we should first know how long a QT interval is too long. Since the QT interval varies with heart rate, we must use the rate-corrected QT (QTc) interval calculated using the Bazett formula (QTc = QT/square root of the R-R interval in seconds). The latest American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement for interpretation of ECG in 2009 defines prolonged QT as follows:

• women, QTc lasts for 460 ms or longer

• men, QTc lasts longer than 450 ms

However, QT prolongation per se is far from sufficient for making a diagnosis of LQTS. For example, a woman would have a chance of LQTS of probably less than 1% if she demonstrated a borderline QT prolongation (QTc of approximately 460ms) and less than 5% if she demonstrated mild-to-moderate prolongation (QTc of approximately 480ms) if she is asymptomatic and has no family history of LQTS. On the other hand, if a teenaged girl or boy has a “seizure” during exercise or after a sudden onset and loud noise from alarm clocks or a telephone ringing, and her/his immediate ECG after the event reveals a prolonged QT interval of longer than 500ms, diagnosis of LQTS would be almost certain. Schwartz et al in 1993 proposed a score table to integrate multiple clinical factors and ECG parameters for the diagnosis of LQTS (Table 2).

Table 2.n

A. History Part I: Pattern Recognition:

Nearly 50% of LQTS patients never have a symptom. On the other hand, nearly 50% of symptomatic LQTS proband (the family member who is first identified with LQTS within a family and triggers for investigation of the genetic inheritance) experience their first cardiac event by the age of 12 years. The most common symptoms in LQTS patients are TdP-mediated syncope, “seizure” activities, and sudden cardiac death. In 5 to 10% of cases, sudden cardiac arrest is the first presenting symptom. TdP-mediated cardiac events occur commonly in the first four decades of life. Since TdP occurs in an “all-or-none” pattern, LQTS patients are normally asymptomatic between cardiac events.

There are genotype-related triggers for TdP-mediated cardiac events. For LQT1, the triggers are physical and emotional stress such as swimming, running, fright, and anger. I_Ks, which is the target current by the mutation responsible for LQT1, is modulated by catecholamines. LQT2 patients tend to have cardiac events triggered by auditory stimulation such as an alarm clock or telephone ringing. On the other hand, LQT3 patients often have cardiac events during rest or sleep. Since QTc is relatively longer in LQT3, functional 2:1 atrioventricular (AV) block due to an excessively prolonged refractory period in the ventricles (i.e., that the AV block is not at the level of AV node) may be present.

In females, pregnancy and delivery per se are not associated with an increased incidence of cardiac events. However, cardiac events increase during the postpartum period, particularly in the subset of patients with LQT2. This increase is probably related to changes in hormones, higher levels of stress, and disturbances of sleep.

B. History Part 2: Prevalence:

The estimated prevalence of congenital LQTS is approximately 1 case per 2,500 population to 1 case per 5,000 population. However, LQTS still remains underdiagnosed. With increased awareness of LQTS and the availability of a commercial genetic test for LQTS, more LQTS cases will be diagnosed and the real prevalence of LQTS is probably higher. Male and female children have an equal chance to inherit the LQTS gene from their affected parent. However, in clinical practice, slightly more females are diagnosed with LQTS because females have relatively longer QTc interval and labile T-wave morphologies. There is no clear evidence that suggests significant differences in the prevalence of the common forms of LQTS among races.

Up to 90% of inherited LQTS is transmitted as an autosomal dominant trait. Approximately 5 to 10% of LQTS gene mutations are de novo, i.e. sporadic. Autosomal recessive transmission of LQTS (Jervell and Lange-Nielsen syndrome) is extremely rare at a prevalence of approximately 1.6 cases per 1 million population. However, Jervell and Lange-Nielsen syndrome is relatively common in Denmark where its estimated prevalence is approximately 1 case per 200,000 population.

LQTS is thought to be responsible for approximately 4,000 deaths per year in the United States. LQTS is one of the causes for sudden infant death syndrome, accounting for approximately 10% of total cases.

C. History Part 3: Competing diagnoses that can mimic long QT syndrome.

Diagnosis of LQTS is mostly based upon patient history and stories. Integrating the patient’s clinical history, family history, and ECG features is the key to lead to the correct diagnosis of LQTS (Table 2). Other channelopathies such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and J-wave syndromes (Brugada syndrome as type 4 in J wave syndromes) may sometimes mimic LQTS. An exercise-induced cardiac event in LQT1 patients should be distinguished from that of CPVT in which the resting QTc is normal. In LQT3 patients, cardiac events such as “seizure” activities and sudden cardiac death often occur during sleep. Similarly, cardiac events in J-wave syndromes are also common after midnight when patients are in sound sleep. The typical patient with a J-wave syndrome is a young male aged 20 to 30 years with ECG characteristics including J wave, which is also called Brugada type 1 and 2 waves when seen in precordial lead V1 to V3, and associated ST segment elevation in absence of QT prolongation. On the other hand, symptomatic LQT3 patients tend to have their first cardiac event in their childhood.

An atypical phenotype of LQT4 includes severe sinus node dysfunction and paroxysmal atrial fibrillation.

D. Physical Examination Findings.

The physical examination of the majority LQTS patients (LQT1 to LQT3) is essentially normal. The resting heart rate of some LQTS patients is below the second percentile for their age. In uncommon LQTS, specific physical abnormalities may be associated with the disease. In LQT7 (Andersen–Tawil syndrome), clinical features include potassium-sensitive periodic paralysis and skeletal developmental abnormalities typically limited in the head, face, and limbs such as low-set ears, an small lower jaw (micrognathia), and an abnormal curvature of the fingers (clinodactyly). Jervell and Lange-Nielsen syndrome is associated with deafness. In LQT8 (Timothy syndrome), the mutation may involve multiple systems, leading to congenital heart disease, cognitive and behavioral problems, syndactyly, and immune system dysfunction.

E. What diagnostic tests should be performed?

12-lead electrocardiography

12-lead ECG remains the cornerstone for the diagnosis of LQTS. A QT interval is considered prolonged when it is longer than 450ms in males and 460ms in females after the correction for heart rate using the Bazett formula (QTc = QT/square root of the R-R interval in seconds).

The QT interval is measured from the beginning of the QRS complex to the end of the T wave on any lead of a 12-lead ECG in which the T wave should be large enough to identify the end of T wave correctly. In the clinical setting, however, there are pitfalls and misuses that could lead to inaccurate measurement of the QT interval. Limb lead II or precordial lead V5 are recommended for measurement of the QT interval unless T waves are not discernible in these two leads. In ECGs with flattened or complex T waves, physicians should compare the QT intervals on several leads, using a caliper for accuracy.

Another confounding factor that influences accurate measurement of the QT interval is the appearance of a physiological U wave. A physiologic U wave in the presence of a normal serum potassium concentration is defined as a small deflection following the T wave. Its height is generally less than one third of the T-wave height. If the physiological U waves are included in the measurement of the QT interval, the QT interval would be falsely prolonged and the QTc would be significantly overestimated. A physiological U wave should be distinguished from a notched or bifid T wave. The second component of a notched T wave is similar to or larger in size than the first component, and the junction between the two components is often above the isoelectric line. The QT interval should cover the second component of a notched T wave. The notched T wave in precordial leads V3 to V4 or in inferior leads is an ECG feature of LQT2.

There are a number of common errors in determining QTc interval that should be avoided. In heart rates close to 60 beats per minute, the Bazett formula gives the most accurate correction of the QT interval. One should avoid QTc determination when the patient’s heart rate is too fast (>100 beats per minute) or too bradycardia (<50 beats per minute). Bazett formula tends to overestimate QTc at faster heart rates. Also, when RR intervals on the ECG vary, such as during sinus arrhythmias, one should not use the shortest RR interval or the longest QT interval for calculation of QTc.

If there is suspicion of LQTS or an ECG from a patient with syncope or “seizure”, the QTc interpreted by computer must be manually verified and better confirmed by an electrophysiologist or a LQTS expert. In a clinical survey, less than 25% of nonelectrophysiologists are able to diagnose a prolonged QT in an LQTS patients. As shown in
Figure 2, the QTc given by the computer was 434 ms, apparently “normal” in a boy aged 13 years who presented with ringing-triggered “seizure” resulting from TdP (Figure 1) and was later diagnosed with LQT2. The QTc calculated from manually measured QT and RR interval was 490 ms. Misdiagnosis of LQTS from computer-derived QT intervals has led to not only a catastrophic consequence for the patients but also legal liability for the physicians.

Figure 2.

There are genotype-specific T wave patterns on 12-lead ECG in the common forms of LQTS (Figure 3). For LQT1, QTc prolongation is accompanied by broad-based T waves. Notched or bifid T waves in precordial leads V3 to V4 and inferior leads are features of LQT2. Patients with LQT3 tend to have a long isoelectric ST segment that is followed by a normal T wave.

Figure 3.

Genetic testing

American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) 2006 practice guidelines recommend genetic analysis for identifying all mutation carriers within an LQTS family. The genetic testing for LQTS has been commercially available since 2004. In the majority of LQTS cases, the mutation involves only a single gene that is often family-specific. To date, more than 1,000 mutations in 13 LQTS-susceptible genes encoding potassium, sodium, and calcium channels have been identified.

In patients with LQTS, the genetic testing provides useful information for risk stratification and making therapeutic decisions. The absence of a gene mutation in the genetic test does not necessarily rule out LQTS because the current genetic testing can identify a mutation in approximately 75% of patients with clinically diagnosed LQTS. On the other hand, a mutation in LQTS-related genes may have multiple phenotypic (or clinical) expressions. Up to 50% carriers of a gene mutation are silent or subclinical mutation carriers who have a normal QTc interval.

It is clinically impractical to screen all known LQTS-specific genes in all LQTS patients because the test is time consuming and costly. The genetic testing is recommended for the following clinical scenarios: (1) the test should be performed first on the proband or a family member with clinical manifestations of LQTS, then all first-degree relatives; (2) clinically unexplained QTc prolongation of greater than 500 ms; (3) clinically suspected LQTS regardless of baseline QTc.

Exercise testing and epinephrine QT stress test

It is well known that the QT interval normally shortens during exercise when the heart rate is increased. However, the QT interval appears to “stretch” and fails to adapt to heart rates in patients with LQTS, particularly LQT1, during exercise and the recovery period. The treadmill exercise is the most common type of exercise used for this test. A simple method similar to the exercise testing for aiding in the diagnosis of LQTS has recently been introduced. A short-lived episode of sinus tachycardia during brick standing from a supine position provides a similar diagnostic value to exercise testing in the diagnosis of LQTS. Interestingly, unlike the traditional exercise testing that has the diagnostic value in LQT1, this simple method can unmask impaired QT adaption in patients with LQT2 to tachycardia. In other words, the QTc of LQT2 patients becomes “stretched” during the brick standing that initiates a brief episode of tachycardia. The QTc prolongation remains even after the heart rate returns to the baseline.

The epinephrine QT stress test, similarly to exercise testing, is particularly helpful in the diagnosis of LQT1. During intravenous infusion (a 25-minute infusion protocol at ≤0.1mg/kg/min) paradoxical QT prolongation occurs in patients with LQT1. For the paradoxical QT prolongation (i.e., absolute QT prolongation greater than or equal to 30ms) the protocol has a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1. Not surprisingly, the epinephrine QT stress test is not accurate in individuals who are receiving beta-blocker therapy.

It should be emphasized that the exercise testing and epinephrine QT stress test are used for unmasking certain conceal LQTS subtypes like LQT1 and LQT2.

Immediate management

TdP is a potentially lethal arrhythmia with reported TdP-related mortality in upwards of 15% of cases. For LQTS patients who present with TdP-mediated cardiac events such as syncope or cardiac arrest, immediate management includes: (1) direct current (DC) cardioversion of sustained TdP using unsynchronized shocks as needed; (2) removal of transient or reversible causes such as potential QT prolonging drugs and replacement of serum potassium for hypokalemia; (3) intravenous administration of magnesium (initially 2g) regardless of serum magnesium levels; (4) temporary transvenous fast and fix rate (90–100 beats per minute) ventricular pacing in the refractory cases.

Our clinical experience indicates that a class IB drug mexiletine can be chosen to acutely terminate TdP regardless of the underlying causes. Mexiletine likely blocks the late sodium current (I_Na,L) as well. Inhibition of I_Na,L shortens the QT interval, reduces transmural dispersion of repolarization, and blunts rate-adaptation of the QT interval.

Long-term management.

The ultimate goal of the long-term management of LQTS is prevention of TdP-mediated cardiac events.

Risk stratification

Since the phenotypic expressions of LQTS vary widely from totally free of any LQTS-related symptoms in life to sudden cardiac death at an early age, the risk stratification (i.e., to determine which patient will be at a higher risk of TdP-mediated cardiac events in the future) is the initial important step in the long term management of LQTS.

For any LQTS patients, a history of aborted cardiac arrest is associated a significantly higher risk of sudden cardiac death in the future. An implantable cardioverter defibrillator (ICD) is strongly recommended for secondary prevention in these patients. Other risk factors in LQTS include syncope (or “seizure activity”), a QTc interval >500ms, functional 2:1 AV block due to prolonged ventricular repolarization, notched T waves, macroscopic T-wave alternans, postpubertal females, and LQT2 or LQT3 genotype.

Although the likelihood of TdP-mediated cardiac events such as syncope and cardiac arrest is generally low in infants, occurrence of such events in the first 5 years of life indicates one of the severe LQTS genotypes and has a relatively poor prognosis. There are age- and sex-related differences in the risk for TdP-mediated cardiac events. Male LQTS patients have a higher risk of cardiac events before the pubertal age and a lower risk into adulthood. Asymptomatic male LQTS patients particularly associated with the C-terminal and haploinsufficient LQT1 mutations are at a much lower risk. On the other hand, female LQTS patients continue to carry a significant risk of cardiac events after the pubertal age.

For female LQTS patients, pregnancy and delivery per se are not associated with an additional risk of cardiac events. However, the risk of cardiac events is increased in the postpartum period.

Treatment

Avoidance of contraindicated drugs and triggers for torsades de pointes

First of all, all LQTS patients should avoid any of the QT prolonging drugs or those such as catecholaminergic drugs that can facilitate the development of TdP. There are hundreds of cardiac and noncardiac drugs that can aggravate QT prolongation or trigger TdP. These drugs include (1) antiarrhythmic drugs such as dofetilide and sotalol; (2) antibiotics such as erythromycin and levofloxacin; (3) psychotropics like haloperidol; and (4) narcotics such as methadone. However, it is difficult to remember all of these drugs, particularly those noncardiac and weak QT prolonging agents. There are a number of websites where physicians can search online for QT prolonging and other contraindicated medications. The website from the University of Arizona is highly recommended. (Arizona Center for Education and Research on Therapeutics. QT drug lists by risk groups. Available at: www.qtdrugs.org. Accessed 9 August 2012.)

Hypokalemia facilitates the development of TdP. Diuretics that deplete serum potassium should be avoided. Gastrointestinal illnesses such as diarrhea that may potentially lead to hypokalemia should be treated promptly and adequately. Patients should be cautioned against use of any of over-the-counter medications without consulting a LQTS expert physician.

Alarm clocks, telephones, etc. with loud auditory triggers should be removed from the living and working environments of LQTS patients, particularly LQT2 patients. A loud noise from jet planes can also trigger TdP-mediated cardiac events in LQT2 patients. Therefore, LQT2 patients should stay away from environments with loud noises if possible.

All patients with LQTS-specific symptoms should be completely restricted from competitive sports. Asymptomatic LQTS patients with QTc values in the borderline values (QTc <470ms in males and <480ms in females) are allowed to participate in mild-to-moderate leisure exercise. All sports with burst activities or genotype-related triggers (such as swimming in LQT1 and auditory triggers in LQT2) should be absolutely avoided.

Pharmacotherapy

All LQTS patients, particularly young patients, should be treated with medications. The beta-blocker therapy is the first-line therapy for LQT1, LQT2, and those genotype-negative LQTSs. The beta-blockers have been shown to reduce cardiac events significantly. Nadolol and propranolol are the preferred beta-blockers in LQTS. For infants with LQTS, liquid nadolol and propranolol are available. Nadolol is used twice daily with a total dose of 1 to 2 mg/kg/day; and propranolol should be dosed three times daily with total of 3 to 4mg/kg/day. The long acting form of propranolol (Inderal) can be dosed twice daily.

The sodium channel blocker mexiletine is a pharmacotherapeutic choice for patients with LQT3. Mexiletine with an inhibitory effect on I_Na,L is effective in shortening QT and preventing TdP-mediated cardiac events in LQT3. Mexiletine may be also effective for other types of LQTS. A recent report reveals that mexiletine shortens QT and attenuates T wave alternans and 2:1 AV block in LQT8.

Implantable cardioverter-defibrillator

In the era of defensive medicine, use of ICD in LQTS is increased during the past two decades. However, the vast majority of LQTS patients can be managed conservatively. For the high risk patients, ICD is undeniably the most effective way to prevent TdP-mediated sudden cardiac death in LQTS.

There is a universal agreement that ICD should be recommended as secondary prevention for LQTS patients who have survived cardiac arrest. For patients with breakthrough events (documented TdP or syncope) on the beta-receptor therapy, ICD is recommended as well.

Although use of ICD as primary prevention in LQTS is a class IIb indication per the ACC/AHA/ESC 2006 guidelines, prophylactic ICD implantation is generally considered as appropriate in patients with one of the following high risk profiles: QTc greater than 550ms except in LQT1; LQT2 females with QTc greater than 500ms; infants with 2:1 AV block and Jervell and Lange-Nielsen syndrome.

A single chamber ICD is commonly recommended in LQTS patients. If the patients have bradycardia, particularly bradycardia- or pause-dependent TdP, a dual chamber ICD with atrial pacing as an adjunct therapy should be considered.

Cardiac pacing

The majority of TdP episodes occur during bradycardia or after a pause. Cardiac pacing at a relatively fast and fixed rate has been shown to be effective in preventing TdP-mediated cardiac events in certain LQTS subtypes such as LQT2. In the United States, few pacemakers have been implanted to manage LQTS. For example, no LQTS patients have received an isolated pacemaker in the Mayo Clinic’s LQTS clinic during the past 10 years. However, in the developing countries where patients have no access to ICD, cardiac pacing with a single chamber pacemaker (AAI pacing) is one of relatively “cheap” options. It should be emphasized that cardiac pacing should be used together with beta-blocker therapy.

Left cardiac sympathetic denervation

Left cardiac sympathetic denervation (LCSD) is useful for preventing life threatening arrhythmias that are associated with an elevated sympathetic activity such as LQTS and catecholamine-dependent polymorphic ventricular tachycardia. A number of recent studies have shown that LCSD significantly reduces cardiac events in LQTS.

LCSD involves removal of the left stellate ganglion and sympathetic chains at the level of T2 to T4. LCSD is often performed via video-assisted thoracic surgery. Since LCSD is an invasive procedure, it should be used as a secondary prevention modality. LCSD is indicated for: (1) patients who have recurrent ICD shocks from TdP; (2) patients who have breakthroughs despite adequate medication therapy or are intolerant to the drug therapy; (3) high risk children who have no access to ICD; and (4) high risk infants who may have a high incidence of complications with ICD implantation.

What's the evidence for specific management and treatment recommendations?

Schwartz, PJ, Moss, AJ, Vincent, GM, Crampton, RS. “Diagnostic criteria for the long QT syndrome: An update”. Circulation. vol. 88. 1993. pp. 782-4. (Proposed clinical diagnostic criteria for congenital long QT syndrome.)

Shu, J, Zhu, T, Yang, L, Cui, C, Yan, GX. “ST-segment elevation in the early repolarization syndrome, idiopathic ventricular fibrillation, and the Brugada syndrome: cellular and clinical linkage”. J Electrocardiol. vol. 38. 2005. pp. 26-32. (Discusses clinical and ECG features for young males with J wave syndromes who have a risk for sudden cardiac death during sleep. The syndromes should be differentiated from LQT3.)

Antzelevitch, C, Yan, GX. “J wave syndromes”. Heart Rhythm. vol. 7. 2010. pp. 549-58. (Update of J wave syndromes.)

Johnson, JN, Ackerman, MJ, Yan, GX, Kowey, PR. “Long QT Syndrome”. Management of Cardiac Arrhythmias. vol. 201. pp. 419-40. (A well-written book chapter for long QT syndrome, including indications for genetic testing, ICD placement, and left cardiac sympathetic denervation.)

Zipes, DP, Camm, AJ, Borggrefe, M. “ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death.)”. J Am Coll Cardiol. vol. 48. 2006. pp. e247-e346. (Guidelines for prevention of sudden cardiac death.)

Vincent, GM, Jaiswal, D, Timothy, KW. “Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome”. Am J Cardiol. vol. 68. 1991. pp. 498-503. (Discussion of specific QT patterns in LQT patients during exercise.)

Swan, H, Toivonen, L, Viitasalo, M. “Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome”. Eur Heart J. vol. 19. 1998. pp. 508-13. (Discussion of specific QT patterns in LQT patients during exercise.)

Viskin, S, Postema, PG, Bhuiyan, ZA. “The response of the QT interval to the brief tachycardia provoked by standing: a bedside test for diagnosing long QT syndrome”. J Am Coll Cardiol. vol. 55. 2010. pp. 1955-61. (Presenting a bedside method [i.e., QT changes during and after a brief episode of tachycardia provoked by standing] in replacement of exercise tests in diagnosing congenital LQTS.)

Vyas, H, Hejlik, J, Ackerman, MJ. “Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response”. Circulation. vol. 113. 2006. pp. 1385-92. (Evaluation of epinephrine stress testing in diagnosing LQTS.)

Gao, Y, Xue, X, Hu, D. “Inhibition of Late Sodium Current by Mexiletine: A Novel Pharmotherapeutical Approach in Timothy Syndrome”. Circ. Arrhythm. Electrophysiol. 2013. (Specific late sodium channel blockers are useful in other types of LQTS without mutations in the sodium channel.)

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