The Long QT Syndrome

Overview and Management

Edited by A.Kharazi M.DCardiac electrophysiologist

LQTS Outline

• Background

• Identification

• Therapies Available

• Current Management

• Ongoing Research

• Case Studies

• Conclusions

Long QT Syndrome

Background and the Risk of Sudden Cardiac Death

Sudden Cardiac Death (SCD)

• Affects 350,000 - 400,000 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

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

LQTS: Historical Aspects

1957: 1st LQTS family reported

1963-1964: Romano-Ward Syndrome

1958-1970: 25 LQTS cases reported

1971: 1st LQTS Rx (left stellate ganglionectomy)

1979: LQTS Registry Started

1991-2001: 6 LQTS genes identified

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

LQTS: Identification

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

Syncope

Slow Onset Abrupt Onset Abrupt Onset

Slow Offset Abrupt Offset Slow Offset

Seizure disorderHyperventilation

Hypoglycemia

Obstructive Arrhythmic Vascular

Aortic Stenosis,HCM, Myxoma

BradyTachy

Vasovagal,Orthostatic

Hypertension

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

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

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

LQTS: Clinical Features

Symptoms

• Syncope

• Seizures

• Sudden death

• Palpitations or “chest pain”

ECG Signs

• Prolonged QTc

• Torsade de pointes

LQTS ECG Patterns

Circ 1992;85[Suppl I]:I140-I144

Circ 1992;85[Suppl I]:I140-I144

Additional LQTS ECG Patterns

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

Circ 1993;88:782-784

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

AJC 1993;72:21B

QTc Interval and Risk

1.0

1.6

2.2

2.8

440 520 600 680

QTc

Ris

k fo

r C

ard

iac

Eve

nt

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

Circ 1991;84:1136-1144

Probands

Affected

UndeterminedUnaffected

Probability of Cardiac Event in LQTS

Circ 2001;103:89-95Mayo Clin Proc. 1999;74:1088-1094

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)

Circ 2001;103:89-95

62

26

3

13

43

29

1319

39

0

10

20

30

40

50

60

70

LQT1 LQT2 LQT3

ExerciseEmotional StressRest

Pe

rce

nt

Occurrence of Gene-Specific Triggers

JCE 1999;10:1664-1683

Basis for the Long QT Syndrome

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

Moss AJ, et al. Circulation 1995;92:2929-2934

T-wave Morphology in LQTS by Genotype

NEJM 1998;339:960-965

Probability of a Cardiac Event

No. of SubjectsLQT1 group 112 72 36 27 19LQT2 group 72 56 29 16 11LQT3 group 62 56 36 24 16

Therapies Available and Current Management

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: www.qtdrugs.org

Current Treatments

• Left stellate ganglionectomy (occasionally utilized in infants and patients refractory to other forms of therapy)

• Beta blockers

• Pacemakers

• Implantable Cardioverter Defibrillators (ICDs)

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

Probands AFM†

(n=581) (n=288)

Risk exposure, yrs 5.2 4.5(pre- and post- B)

Pre-B Post- B Pre- B Post B

Pts with events 462194* 92 49*

Number events 1671 623* 245 138*

Events/pt 3.0 1.1* 0.9 0.5*

Events/pt/year 1.0 0.3* 0.3 0.15*

LQTS: Cardiac Events Before and After -blockers

Circ 2000;101:616-623 †Affected Family Member * P<0.01 vs. pre--blocker

Circ 2000;101:616-623

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

Circ 2000;101:616-623

Probability of Cardiac Event

Cumulative Probability of LQTS- Related Death w/ ß-blockers

Circ 2000;101:616-623

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

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

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 (0.1-9.0yr)

A.J. Moss; AHA Abstracts Online. 1999.

Circ. 1999;100:2431-2436

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

NEJM 2000;342:398

Sinus rhythm

Sinus rhythm

Torsade de pointes

NEJM 2000;342:398

Sinus rhythm

Torsade de pointes

Ventricular fibrillation and sinus rhythm

NEJM 2000;342:398

Ongoing Research

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

Case Studies

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?

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?

Case Study 3

• 15 year old male

• ECG as part of routine physical

• QTc = 450ms

• Asymptomatic

• No family history

• Question: Is this LQTS?

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.

Long QT Resources

• Cardiac Arrhythmias Research and Education (CARE) Foundation: www.longqt.org

• Cardiac Arrest Survivors Network (CASN): www.casn-network.org

• International Registry for Drug-Induced Arrhythmias, including drugs to use with caution or avoid in Long QT patients: www.qtdrugs.org