0. Overview and Management Cardiac electrophysiologist
The Long QT Syndrome
Overview and Management
Edited by A.Kharazi M.D
Cardiac electrophysiologist

1. LQTS Outline Background Identification Therapies Available
Current Management
Ongoing Research
Case Studies
Conclusions

2. Background and the Risk of Sudden Cardiac Death
Long QT Syndrome
Background and the Risk of Sudden Cardiac Death

3. Sudden Cardiac Death (SCD)
Affects 350, ,000 each year in the US alone
Only 5% of victims survive
Causes of SCD may include structural heart disease or a genetic channelopathy
Recognition of risk factors can help identify those at risk of SCD

4. Risk Factors for SCD in Young People
Structural congenital heart disease - before and after corrective surgery
Congenital anomalies of coronaries
Myocarditis
Hypertrophic and other cardiomyopathies
Wolff-Parkinson-White Syndrome
Long QT Syndrome
Sudden Cardiac Death in young people is rare. Known risk factors for Sudden Cardiac Death in young people include:
Presence of congenital heart disease both before and after corrective surgery
Congenital anomalies of coronaries such as: anomalous origin of a LCA from the pulmonary artery (relatively common and has a high rate of death if not surgically treated), anomalous origin of the RCA from the left sinus of Valsalva, hypoplastic or aplastic coronary arteries, and other coronary AV fistulas
Myocarditis: serious ventricular arrhythmias can occur – with or without clinical evidence of left ventricular dysfunction
HCM: There appear to be electrophysiological abnormalities related to the hypertrophied muscle, even in the absence of symptoms
WPW: SCD in these patients is rare. RFA ablation is highly successful in curing many of these patients and eliminating the risk for SCD
LQTS: Some patients may have prolonged Q-T intervals throughout life without experiencing an arrhythmia; the risk for SCD increases with the length of the QTc interval
LQTS is the focus of this presentation.

5. LQTS: Historical Aspects
1957: 1st LQTS family reported
: Romano-Ward Syndrome
: 25 LQTS cases reported
1971: 1st LQTS Rx (left stellate ganglionectomy)
1979: LQTS Registry Started
: 6 LQTS genes identified
Jervell and Lange-Nielsen provided the first documented description of this syndrome in They described a family with 4 deaf children with QT prolongation and syncope. 3 of the children died suddenly. The parents, and 2 other children had normal ECGs and normal hearing. This report was critical to the development of current knowledge regarding LQTS.
Romano in 1963, and Ward in 1964 separately reported patients who were not deaf, but had an almost identical cardiac disorder. Later called the “Romano-Ward syndrome,” this disorder was realized to be much more common than the “Jervell-Lange-Nielsen syndrome.” The genetic transmission was thought to be autosomal dominant.
Between 1958 and 1970, there are only 25 cases of LQTS reported.
In 1971, Moss and McDonald performed the first successful therapy for LQTS in a patient who had not responded to any other antiarrhythmic therapy: left cardiac sympathetic denervation to shorten the QT interval.
In 1979,Drs. Moss, Schwartz, and Crampton started the International Registry for LQTS, with headquarters in Rochester, NY.
Between 1991 and 2001, a total of 6 LQTS genes were identified, 3 of which were reported between March 1995 and January 1996.

6. Long QT Syndrome Genetic disorder (1:5,000-10,000)
ECG evidence: QTc interval prolonged
>440 ms in males
>450 ms in females
Hallmark arrhythmia: Torsade de pointes VT
Primary presenting symptom: Syncope
SCD in children or young adults
The congenital long QT syndrome occurs in 1:5,000-10,000 people, and is caused by mutations on several genes. LQTS is 2.5 times more common than childhood leukemia, and occurs half as often as cystic fibrosis.
Most subjects affected with LQTS have prolonged QTc intervals, but 10-15% can have QTc intervals within the normal range.
Many LQTS patients are highly susceptible to ventricular arrhythmias, especially the torsade de pointes form of ventricular tachycardia.
Recurrent syncope, especially during exercise, is a significant risk factor for SCD.
It is estimated that SCD occurs at a rate of 1-2% per year in patients who have been definitively diagnosed with LQTS. Females are at higher risk, and the incidence of SCD appears to peak in adolescence and young adulthood.

7. LQTS: Identification

8. LQTS: Identification of Risk
Most common presenting symptom: unexplained syncope.
Syncope on exertion in pediatric patients should be considered malignant until proven otherwise.
History & ECG:
Onset and offset of syncopal episode
Siblings, or family members with unexplained syncope or sudden death
Family history of “seizures” or congenital deafness
Prolonged QTc on ECG
The Long QT Syndrome and other serious arrhythmic diseases are often first identified by an episode of unexplained syncope.
A careful history and physical examination are critical for the evaluation of syncope. If other common causes of syncope have been ruled out (medications, neurological disorder, anemia, hypotension, etc.) additional questions should be asked to determine if a cardiac or arrhythmic cause exists.
A question that is often missed is regarding the onset and offset of the syncopal episode.
Family history is critical in the identification of the long QT syndrome.

9. Aortic Stenosis, HCM, Myxoma
Syncope
Slow Onset
Abrupt Onset
Abrupt Onset
Slow Offset
Abrupt Offset
Slow Offset
Hyperventilation
Seizure disorder
Hypoglycemia
Obstructive
Arrhythmic
Vascular
If all other diagnoses have been ruled out, it may be helpful to evaluate the presentation of the syncopal episode, if this information is available.
1. Slow onset and slow offset
When syncope comes on slowly, and fades away slowly, causes are usually related to an episode of hypoglycemia or hyperventilation.
2. Abrupt onset and abrupt offset
The sudden onset and sudden termination of a syncopal episode usually indicates a cardiac cause. There are 3 major categories of cardiac causes:
Obstructive origin: Could be related to aortic stenosis, hypertrophic cardiomyopathy, or myxoma
Arrhythmic origin: Could be either a brady or tachyarrhythmia
Vascular origin: Most common causes are orthostatic hyoptension or vasovagal attack
3. Abrupt onset and slow offset
Episodes of syncope that start suddenly and then slowly dissipate are most often related to a seizure disorder.
ECGs are recommended in almost all patients because the results can lead to decisions about immediate management of underlying disease, or can help identify further testing.
Vasovagal,
Orthostatic
Hypertension
Aortic Stenosis, HCM, Myxoma
Brady
Tachy

10. Causes of Arrhythmic Syncope
Very rapid VT or TdP, with hypotension
Atrial fibrillation or atrial flutter with very rapid ventricular response as in WPW
AV block
Sinus arrest
All of these can be causes of arrhythmic syncope. An accurate ECG reading can further define the arrhythmia.

11. Holter ECG Recording in LQTS Patient with Syncope (representative strips of ECG recording, part 1 of 2)

12. Holter ECG Recording in LQTS Patient with Syncope (representative strips of ECG recording, part 2 of 2)

13. LQTS: Clinical Features
Symptoms
Syncope
Seizures
Sudden death
Palpitations or “chest pain”
ECG Signs
Prolonged QTc
Torsade de pointes
Symptoms include:
The presence of palpitations or children may describe as “chest pain”
Recurrent syncope
Seizures
SCD can occur if the symptoms are ignored
ECG signs include:
QTc abnormal or borderline
Evidence of Torsade de pointes is also common
Patients at higher risk are those with deafness, female, syncope, and documented torsades or VF.

14. LQTS ECG Patterns
Although the long QT syndrome often presents as unexplained syncope, the ECG is the definitive factor in differential diagnosis of the syndrome.
This slide displays examples of delayed repolarization patterns observed in lead II of the ECG in patients with long QT syndrome. (Reproduced with permission from Moss AJ: Clinical features of idiopathic long QT syndrome. Circulation 1992;85[Suppl I]:I140-I144.)
Circ 1992;85[Suppl I]:I140-I144

15. Additional LQTS ECG Patterns
Additional examples of delayed repolarization patterns observed in lead II of the ECG in patients with long QT syndrome. (Reproduced with permission from Moss AJ: Clinical features of idiopathic long QT syndrome. Circulation 1992;85[Suppl I]:I140-I144.)
Circ 1992;85[Suppl I]:I140-I144

16. What Should You do with the ECG?
Don’t rely on computer evaluation of ECG
Obtain an independent review of the ECG
Have an experienced cardiologist measure the QTc interval
If the ECG is suspicious for LQTS, refer the patient for cardiac evaluation
Many LQTS patients have ECGs that are read as “normal” by the computer.

17. LQTS: Diagnostic Criteria
ECG findings:  QTc, TdP, notched T waves, slow heart rate for age
Clinical history: syncope, seizures, aborted cardiac arrest
Family history: family member with LQTS, unexplained SCD in a first-degree relative who was <55yrs of age
The 3 major components of information needed are:
A detailed ECG
A thorough clinical history, including onset, frequency and predisposing factors of the syncopal episodes
A thorough family history
Circ 1993;88:

18. QTc Interval and Risk Risk for Cardiac Event QTc
The risk increases significantly with increased QTc above 440ms.
QTc
AJC 1993;72:21B

19. LQTS: Who is at Risk for SCD?
Aborted cardiac arrest
Family history of unexplained sudden death
Syncope
Torsade de pointes
T-wave alternans
Prolonged QTc
Highest risk patients are those who have already experienced a SCD event, those with recurrent syncope, those with ECG evidence of torsade de pointes, alternation of the T-wave, and those with significantly prolonged QT.
Family history may include unexplained car accident, drowning, or other sudden death.

20. Probability of Cardiac Event in LQTS
Probands
Affected
Undetermined
Unaffected
Circ 1991;84:

21. Triggering Events for Syncope or SCD
3 main factors contributing to syncope or SCD
Exercise (LQT1), especially swimming
Emotions or emotional stress (LQT2)
Events occurring during sleep or at rest, with or without arousal (LQT2 or LQT3)
Exercise is a source of physical stress, that induces an increase in heart rate and a release of catecholamines.
Research has shown that swimming is a gene-specific trigger for cardiac events in LQTS.
Emotional stress can include fear, anger, stressful events or arousals during normal daily activities, or arousal due to a noise or startling during sleep.
Events during sleep are difficult to document. Events here would not include those triggered by arousal (startling or noise). These are most likely related to a decrease in heart rate.
Circ 2001;103:89-95 Mayo Clin Proc. 1999;74:
Exercise is the most common triggering event in LQT1. Emotions or emotional stress are the most common trigger in LQT2, and events occurring during sleep are more common in LQT2 or LQT3.

22. Occurrence of Gene-Specific Triggers
Percent
This study identified patients of a known genotype, who had experienced significant cardiac events. Triggers for cardiac events according to 3 genotypes: percentage of patients in each genotype, and the pattern of triggers within each genotype.
(Schwartz, et al. Circulation. 2001;103:89-95).
In the LQT1 variant, exercise is a trigger for >60%, while barely 3% are triggered while at rest.
In the LQT2 variant, a significant number of events occur due to emotional stress or while at rest, while exercise is a trigger in only 13%.
In LQT3, the majority of events appear to occur during sleep or at rest.
LQT1 is the only variant that has a high percentage of events occurring during exercise, and thus is very different from LQT2 or LQT3. LQT1 patients would be advised not to participate in competitive athletic activities.
Circ 2001;103:89-95

23. Basis for the Long QT Syndrome
Major currents underlying the ventricular action potential. As shown on the lower left, interventions that decrease outward currently (primarily through K+ channels), or increase inward current (through Na+ or Ca2+ channels) during the plateau, delay repolarization at the level of the ECG and individual action potentials, and prolong QT interval (upper left). The generic action potential on the right shows the major currents flowing during the cardiac cycle. The five LQTS genes and the currents they underlie are shown in bold.
(Reprinted with permission from the authors and the Journal of Cardiac Electrophysiology. 1999;10: ).
JCE 1999;10:

24. LQTS: Phenotype-Genotype Considerations
6 genotypes; ~200 different mutations
Clinical differences among LQT1, LQT2, & LQT3 genotypes
Clinical variability within a genotype
Clinical variability among members of a family with the same gene mutation suggests presence of modifier genes
Researchers have already identified 6 genes that are affected, with more than 200 mutations identified to date. (By analogy, contrast this to cystic fibrosis, in which only 1 gene is thought to be responsible, with more than 800 different mutations).
Many more mutations could still be unidentified.
Even individuals in the same family, with the same gene and the same mutation, can have significant variations in severity. This provides support to the theory that there are modifying factors, which as of yet are undefined.

25. T-wave Morphology in LQTS by Genotype
Moss AJ, et al. Circulation 1995;92:

26. Probability of a Cardiac Event
Note that the peak incidence for cardiac events is from birth through adolescence for LQT1 and LQT2, with the peak incidence occurring later in LQT3. In all 3 genotypes, males are at risk primarily through age 25, and females have a persistent risk up to age 40.
No. of Subjects
LQT1 group
LQT2 group
LQT3 group
NEJM 1998;339:

27. Therapies Available and Current Management

28. Drugs in Long QT
Certain drugs may provoke life-threatening arrhythmias in LQTS patients
Examples:
Antiarrhythmic: procainamide, quinidine, amiodarone, sotalol, et al
Antihistamine: astemizole, terfenadine, et al
Antimicrobial/antifungal: thiomethoprim sulfa, erythromycin, ketoconazole, et al
Psychotropics: haloperidol, risperidone, thioridazine, tricyclics, et al
Other: epinephrine, diuretics, cisapride, bepridil, ketanserin, et al
Avoid nonessential OTC medications
For more information see:

29. Current Treatments
Left stellate ganglionectomy (occasionally utilized in infants and patients refractory to other forms of therapy)
Beta blockers
Pacemakers
Implantable Cardioverter Defibrillators (ICDs)
Surgical left stellate ganglionectomy may be useful in infants with the severe Jervell-Lange and Nielsen form of LQTS as complimentary therapy with beta blockers and pacemakers if there is profound bradycardia.
Beta-blockers have an antiadrenergic effect for arrhythmias which are precipitated by a sudden increase in sympathetic activity (role is to decrease syncopal events). (Common choices are atenolol, propanolol, nadolol). Beta-blockers have no clear benefit for LQT3 patients, but do reduce event rates for LQT1 and LQT2 patients. Beta-blockers may reduce, but not absolutely prevent SCD in LQTS patients.
Pacemakers are indicated for patients with symptomatic bradycardia, AV block, or pause-dependent malignant arrhythmias. Also used with beta-blockers for drug-induced bradycardia.
Unlike the other treatments, the ICD does not attempt to decrease or prevent the malignant arrhythmias, but it is the only therapy that can terminate a lethal arrhythmia once the arrhythmia has started. LQTS patients at risk for SCD should receive an ICD.

30. Management by Genotype
LQT1 and LQT2 benefit the most from ß-blocker therapy
The benefit of ß-blocker therapy is less clear in LQT3.
ICDs indicated:
if the patient presents as SCD survivor or aborted cardiac arrest
if ß-blockers are not effective in preventing cardiac events
Because the sympathetic nervous system plays a role in LQT1 and LQT2, these 2 genotypes benefit the most from ß-blocker therapy.
The role of ß-blocker therapy in LQT3 is less well-defined, as no clear benefit has been documented in these patients.
Since LQT3 involves a Na+ channel defect, exercise provides the benefit of shortening the QTc interval.

31. LQTS: Cardiac Events Before and After -blockers
Probands AFM†
(n=581) (n=288)
Risk exposure, yrs
(pre- and post- B)
Pre-B Post- B Pre- B Post B
Pts with events * *
Number events * *
Events/pt * *
Events/pt/year * *
This slide outlines 869 patients from the International LQTS Registry who were treated with beta-blockers.
The goal of this study was to evaluate the effectiveness of beta-blockers in LQTS patients. It also looked at specific risk factors for syncope and SCD for patients who were already on beta-blocker therapy.
Both the number of patients with events and the number of events decreased significantly after the initiation of ß-blocker therapy. In addition this reduction in events was seen in both probands and affected family members.
Circ 2000;101: †Affected Family Member * P<0.01 vs. pre--blocker

32. Efficacy of -blockers in LQTS
Significant reduction in frequency of syncopal events
Cardiac events continued to occur
May reduce the rate of SCD
Reductions in rate of cardiac events
0.97±1.42 to 0.31±0.86 events/year in probands
0.26±0.84 to 0.15 ±0.69 events/year in affected family members
P<0.001
There was a significant reduction in syncope and aborted cardiac arrest, but cardiac events continued to occur while on beta-blocker therapy – especially in those who were symptomatic prior to beta-blocker therapy.
32% of these symptomatic patients will have another event within 5 years while on beta-blockers.
In addition, of those patients who had survived a SCD event prior to beta-blockers, 14% will experience a recurrence within 5 years while on beta-blocker therapy.
Circ 2000;101:

33. Probability of Cardiac Event
Estimated cumulative probability of experiencing syncope, aborted cardiac arrest, or LQTS-related death on prescribed ß-blockers in LQTS patients who were asymptomatic (dotted line) or symptomatic (solid line) before starting ß-blockers.
LQTS patients who were symptomatic prior to ß-blocker therapy have a much higher probability of experiencing another cardiac event. More than 30% of patients who were symptomatic prior to ß-blocker therapy will have another cardiac event within 5 years.
Circ 2000;101:

34. Cumulative Probability of LQTS- Related Death w/ ß-blockers
Estimated cumulative probability of experiencing aborted cardiac arrest or death on ß-blocker therapy in LQTS patients who were asymptomatic (dotted line), experienced syncope only (dashed line), or had a prior aborted cardiac arrest (solid line) before ß-blockers. Vertical lines are 95% Confidence Intervals.
Risk curves are for LQTS patients started on ß-blockers at >10 years of age; the risk curves are higher for those started at a younger age. Time periods off therapy for more than 2 days are excluded.
Patients with a prior aborted SCD should receive an ICD, as they have a higher probability of experiencing another cardiac arrest or LQTS-related death.
Circ 2000;101:

35. Limitations of -blockers in LQTS
SCD can occur despite Rx with -blockers
Long-term compliance with daily therapy is problematic
Usual side effects of -blockers
Although -blockers reduce the number of cardiac events, syncopal events and SCD can still occur.
The challenge is to have the patient continue to take the drugs, even if they are feeling well. In addition, in young, active, healthy patients, the side effects can hamper their activity tolerance.
In standard doses, up to 15% of patients will not tolerate beta-blockers due to side effects. Common side effects include asthma, fatigue, sleep disturbances.

36. ICD Experience in LQTS
An ICD is indicated for all patients with documented VT, VF or aborted cardiac arrest
Prevents SCD in patients with prior cardiac events
Provides a back-up for patients on -blocker therapy who continue to be symptomatic
Published beta-blocker and pacemaker studies document continued cardiac events with single or combination therapy.
ICDs can treat breakthrough tachyarrhythmias to prevent sudden cardiac death.

37. ICD Experience in LQTS N 88 Age at ICD, y 23±10 Female 71%
QTc, sec 0.52±0.06
-B before/after ICD 82% / 89%
ACA before/after ICD 48% / 4%
Death after ICD 0 in 2.5yr ( yr)
In 88 patients in the LQTS Registry who received an ICD, there was a 100% survival rate after 2.5 years with ICD therapy.
82% of these patients were on beta-blockers prior to ICD placement and continued to have worrisome syncopal episodes.
(ACA = aborted cardiac arrest)
A.J. Moss; AHA Abstracts Online

38. Pacemaker Experience in LQTS
Reduces frequency of syncope in pts. with bradycardia-triggered events
Most useful when combined with -blocker therapy
Does not prevent SCD in long-term therapy
Appears most useful in patients with LQT3 and bradycardia
A retrospective study followed 37 patients with idiopathic LQTS who received both -blocker and pacing therapy, to determine the efficacy of combined therapy.
After an average of years, 28 of 37 patients remained without symptoms on combined therapy. Recurrent pacemaker malfunction causing symptoms was experienced in 3 patients, 3 patients died, and 3 patients had resuscitated cardiac arrest. An additional patient died of unrelated causes. The overall incidence of sudden death and aborted sudden death was 24% in all patients and 17% in compliant patients.
Conclusion: Even with combined therapy, these patients remained at significant risk for sudden death.
Circ. 1999;100:

39. Sinus rhythm
A 12 year-old boy with the familial long-QT syndrome had an ICD implanted after resuscitation from cardiac arrest. The device was programmed to wait 7.5 seconds before discharging in response to ventricular tachycardia or ventricular fibrillation. The boy took 120 mg of nadolol daily. Three months later, he suddenly collapsed while answering a question in school. Analysis of the ICD revealed the following sequence of events: normal sinus rhythm with a corrected QT interval of 0.66 second (top tracing)…
NEJM 2000;342:398

40. Sinus rhythm Torsade de pointes
… that was followed by Torsade de pointes (middle tracing)…
NEJM 2000;342:398

41. Ventricular fibrillation and sinus rhythm
Torsade de pointes
Ventricular fibrillation and sinus rhythm
…and ventricular fibrillation (bottom tracing), prompting discharge of the ICD (arrow) and a return to sinus rhythm within 600 msec after discharge. (The rhythm strips are not continuous). The boy regained full consciousness within two minutes, with no residual neurologic deficits. During the next 15 months, he had no syncope or evidence of recurrent ventricular tachyarrhythmias.
NEJM 2000;342:398

42. Ongoing Research

43. LQTS: Studies in Progress
LQTS Registry: risk-factor identification
Trigger factors
New gene identification – LQTx ?
Exercise stress testing for diagnosis and risk stratification
Modifier genes
Mutation-specific therapy
The Long QT Registry continues to evaluate specific risk factors for LQTS-related cardiac events.
There is potential to identify additional genes, gene mutations, and modifier genes due to the great variability in current presentation of the disease. The goal is to continue to try to develop gene- and mutation-specific therapy.

44. Case Studies

45. Case Study 1 13 year old male presents with syncope while swimming
QTc prolongation on ECG (>500ms)
Beta-blocker therapy initiated
No further cardiac events noted over 5 years
Can you consider withdrawing beta-blocker therapy?
Is an ICD indicated?
Discussion:
In most cases, once therapy has been started, it should be considered life-long therapy.
The length of the QT interval is significant, thus removing therapy is very risky.
Females with LQTS have a much higher incidence of SCD than males and thus removing beta-blocker therapy would be even more risky in females than in males.
This child should not be participating in competitive sports, and should not be swimming without supervision.
A risk for sudden cardiac death still exists in this child even after 5 years without cardiac events. Depending on the size of the patient, some would consider ICD therapy as permanent protection.

46. Case Study 2 Young male athlete diagnosed with LQTS
Beta-blockers prescribed
Patient stops drugs because he feels better without them
What should the physician do?
Options are to allow the patient to discontinue to beta-blockers, implant an ICD, encourage the patient to continue to take the beta-blockers, or implant an ICD and encourage the continuation of beta-blocker therapy.
Discussion:
In a patient who was symptomatic prior to the initiation of beta-blockers, or who has continued to have events while on therapy, an ICD would be indicated.
The ICD can be used without concurrent beta-blocker therapy, but this is not recommended.
Even with an ICD, beta-blockers have a role to decrease the event rate, thus the physician should encourage the patient to continue therapy, even if an ICD is placed.
Make sure that family members are screened with ECG.

47. Case Study 3 15 year old male ECG as part of routine physical
QTc = 450ms
Asymptomatic
No family history
Question: Is this LQTS?
Discussion:
2-3% of males of this age have QTc > 450ms, and 10% of subjects with LQTS have QTc intervals in the ms range
The individual may have LQTS
Obtain ECGs on parents and siblings
Obtain a cardiology consult
Genetic studies may be needed for clarification

48. Conclusions
Unexplained syncope with exertion in children and young adults should be considered serious until proven otherwise.
ECGs should be obtained on the patient and read by a cardiologist or pediatric cardiologist if patient is a child.
ECGs should be obtained on all immediate family members.
Referral to a cardiac specialist if suspicious for LQTS.

49. Long QT Resources
Cardiac Arrhythmias Research and Education (CARE) Foundation:
Cardiac Arrest Survivors Network (CASN):
International Registry for Drug-Induced Arrhythmias, including drugs to use with caution or avoid in Long QT patients: