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Long QT Syndrome

Long QT Syndrome. Dominique Marion, MD March 29 th , 2006. Overview. History Cardiac physiology Presentation Diagnosis Risk stratification Treatment SIDS Psychological impact. Long QT Syndrome (LQTS). Congenital or acquired Cardiac channelopathy Six genetically distinct types

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Long QT Syndrome

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  1. Long QT Syndrome Dominique Marion, MD March 29th, 2006

  2. Overview • History • Cardiac physiology • Presentation • Diagnosis • Risk stratification • Treatment • SIDS • Psychological impact

  3. Long QT Syndrome (LQTS) • Congenital or acquired • Cardiac channelopathy • Six genetically distinct types • 1 in 5,000 people • 8,000 sudden deaths in children yearly in the United States • The International Long QT Registry

  4. "She was struck by repentance and grief and fell dead to the floor“ Meissner, 1857

  5. Jervell and Lange-Neilson (1957) Autosomal recessive 4 siblings with deafness and recurrent syncope 3 died suddenly Romano and Ward (1963) Autosomal dominant 3-month-old with recurrent syncope 2 siblings died suddenly Father and uncle with seizures History

  6. Normal Cardiac Physiology • Voltage-gated ion channels • Passive movement toward equilibrium • LQTS mutations effect K+ or Na+ channel function

  7. Delayed Repolarization • Abnormal channels cause K+ to leave cell too slowly or Na+ to leak back in

  8. Early After-depolarizations • Occur during phase 2 or 3 of action potential • Risk of meeting threshold before complete repolarization • Lead to ventricular arrhythmias • Torsades de pointes

  9. Romano-Ward Syndrome • LQT1 • 40-55% • Autosomal dominant • KVLQT1 • Discovered in 1991 • 11p15.5 • Mutation in alpha subunit of slow K+ channel • Alters ion permeability

  10. LQT2 35-45% HERG Discovered in 1994 7q35-36 Mutation in fast K+ channel LQT3 5-10% SCN5A 3p21-23 Impaired inactivation of Na+ channel SIDS Brugada Syndrome Romano-Ward Syndrome

  11. Jervell and Lange-Nielson Syndrome • Autosomal recessive • Two genetically distinct types • Same genes as LQT1 and LQT5 • Affect slow K+ channels • Channel also present in inner ear • Contributes to endolymph production in cochlea • 0.3-3.7% of patients with congenital sensorineural deafness have LQTS • Higher rates of cardiac events and mortality

  12. Presentation • Asymptomatic - 40% • Affected family member (30%) • Routine EKG (10%) • Sensorineural deafness • Symptomatic - 60% • Syncope (30%) • Seizures (10%) • Resuscitated sudden death (10%) • 15% of LQT1 present with event while swimming

  13. Case • 15-year-old female “pretending to drown” • Spontaneously recovered after being pulled from pool • Initial EKG showed ventricular bigeminy

  14. Case • Continued ventricular arrhythmias on PICU monitors

  15. Treated with beta blocker after discharge Runs of slow ventricular tachycardia on Holter monitoring Follow-up EKGs showed QTc 430 – 490 ms No further symptoms or events Genetic testing pending Case

  16. Occurrence of Gene-Specific Triggers Circ 2001;103:89-95

  17. Seizures • Result from brain hypoxia • Is the timing of loss of consciousness predictive? • Davis et al • 126 consecutive patients presenting to neurology clinic with seizures • 2 patients had LQTS, but no history of LOC before seizure • 8 patients without LQTS had LOC before seizure J Ped Health 1998;34:410

  18. Cumulative Probability of Cardiac Event NEJM 1998;339:960-965

  19. Overall Mortality • Initially reported as 10 year mortality of 50% • Untreated • 1-2% per year • Inclusion of asymptomatic family members • Treated • 0.3-0.4% per year • Genotypes have different rates of events, but similar mortality by age 40

  20. Cumulative Probability of Death JAMA 1998;339:960

  21. Gender differences • Highest risk • Pre-pubertal males • Adult females • Males have earlier symptoms • 8 vs. 14 years despite same QTc

  22. Diagnosis • Circumstances of event • Trigger • Family History • Recurrent syncope • Premature death, SIDS • Unexplained drowning, MVA • Deafness • Exclude Acquired LQTS

  23. Drugs Antibiotics Antifungal agents Antihistamines Antidepressants Antipsychotics Antiarrhythmic agents Electrolyte Disturbances Hypokalemia Hypocalcemia Hypomagnesemia Medical Conditions Bradycardia Myocardial dysfunction Endocrinopathy Neurologic Nutritional Acquired Causes of QT Prolongation

  24. Measurement of QT Interval Using Lead II, measured in ms over 3-5 beats and averaged

  25. Abnormal T wave Morphology

  26. T wave Morphology Varies with Genotype Circ 1995;92:2929-2934

  27. Other EKG Features • T wave alternans • Beat to beat variation in amplitude • Sign of enhanced electrical instability • Increased QT dispersion • Measure of QT variability • Low heart rate for age

  28. Arrhythmias • Bradyarrhythmias • More common in LQT3 • Children under 3 with LQT1 • Villain et al • 15 neonates with long QT and partial AV block • Most with 2:1 block • 8 had LQT2 positive genotyping • 2 died in first month Eur Heart J 2004;25;1405-1411

  29. Diagnosis • EKG of Family • Exercise testing • Borderline cases • QT fails to shorten or lengthens • QT stays prolonged after exercise • Pediatric Electrophysiology Society • 30% - ventricular arrhythmias • 9% - unsustained torsades • 1-3% - ventricular tachycardia Circ 1993;87;1866

  30. Holter monitoring Young children Cannot use QT interval Vent arrhythmias in 41% vs. 16% on routine EKG Facial immersion test Epinephrine challenge Electrophysiology studies unhelpful Diagnostic Adjuncts

  31. Schwartz Scoring for Diagnosis

  32. Genetic Testing • Over 300 mutations • Mutation found in 72% of LQTS patients • Compound mutations worse because effects are additive • 2-3% of patients • Variable penetrance • Patients prone to drug-induced acquired LQTS may have congenital form of disease

  33. Who should get tested? European Working Group on Arrhythmias Treatment modifications Borderline cases Asymptomatic family members Commercially available since May 2004 $5700 new patient $500 identified mutation Genetic Testing

  34. Case • 14-year-old female • Reported peak-exercise dizziness to pediatrician during sports physical • Two separate EKGs show borderline QTc of 450 ms and 457 ms • Cousin with “heart problem” and pacemaker

  35. Case • Testing negative for cousin’s mutation • Unrestricted sports participation

  36. Case • 20-month-old boy adopted from Russia • Sensorineural deafness • ENT obtained EKG showing QTc = 464 ms • No reported symptoms or family history • Genetic testing showed no mutations • Beta blocker stopped and activities unrestricted

  37. Autosomal recessive form Recurrent syncope Documented ventricular arrhythmias Family history of sudden death Medical non-compliance after an event Events after medical therapy Risk Factors for Sudden Death

  38. QTc Interval and Risk Risk for Cardiac Event QTc AJC 1993;72:21B

  39. NEJM 2003 348;1866-1874

  40. Other Risk Factors • Pregnancy • 422 patients from International LQT Registry • 40 weeks pre-pregnancy vs. 40 weeks postpartum • 3.8% vs. 23.4% cardiac events • Treatment decreases incidence to 1 in 2500 pregnancies • Mutation specific • Transmembrane region of ion channel

  41. Case • 6-year-old boy from South Africa • Event at age 2 while swimming • Second event after missing beta blocker for 48 hours • Multiple affected family members • Genetic testing positive for LQT1 • Collapsed while running and “started shaking” • ICD placed

  42. Mutation-Specific Phenotype • 166 individuals • Founding couple married in 1730 • High incidence of cardiac events and sudden death Circ 2005;112:2602-2610

  43. Treatment Goals • Minimize symptoms • Prevent sudden death • Preserve quality of life

  44. Beta Blockers • Blocks adrenergic enhancement of calcium channels • Goal • max heart rate 120-150 bpm • Non-selective • Propranolol • Nadalol • Cardioselective • Atenolol • Metoprolol • Lower incidence of bronchospasm, fatigue and mood changes

  45. Efficacy of Beta Blockers Circ 2000;101;616-623

  46. Efficacy of Beta Blockers by Genotype Circ 2001;103;89

  47. Treatment • High Left Thoracic Sympathectomy • Pacemaker • 17% will still have arrest • Other Medications • Mexiletine • Potassium

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