January 14-15, 2011 SCA Conference 2

Electrical Abnormalities: Long QT and Beyond Yaniv Bar-Cohen, M.D. Assistant Professor of Pediatrics Division of Cardiology / Electrophysiology Childrens Hospital Los Angeles Keck School of Medicine Genetic Electrical Myopathies Channelopathies Long QT Syndrome Short QT Syndrome Brugada Syndrome Catecholaminergic Polymorphic Ventricular Tachyardia (CPVT) January 14-15, 2011 SCA Conference 1

Long QT Syndrome Prolongation of the QT interval associated with syncope, polymorphic VT (torsades de pointes) or sudden cardiac death (SCD). Heterogeneous disorder Usually genetic disorder of either potassium or sodium ion channels Can be acquired (medications, electrolytes, etc.) Incidence: ~1 in 3000 Long QT Syndrome Cardiac events - syncope, cardiac arrest, or SCD - occur in approximately 1/3 of patients with known LQTS. In patients with symptomatic, untreated LQTS, the mortality rate is as high as 20% for the first year and 50% at 10 years. Prioro SG, Schwartz PJ, Napolitano C, et al.: Risk stratification in the long-qt syndrome. N Engl J Med 2003, 348:1866 1874. Goel AK, Berger S, Pelech A, Dhala A: Implantable cardioverter defibrillator therapy in children with long QT syndrome. Pediatr Cardiol 2004, 25:370 378. January 14-15, 2011 SCA Conference 2

Long QT Syndrome Ackerman, MJ. The Long QT Syndrome: Ion Channel Diseases of the Heart. Mayo Clin Proc. 1998, 73:250-269269 Long QT Subtypes Genetic Testing: positive in 75% Subtype % Gene Mutation Manifestation Long QT 1 42% KCNQ1 K+ Channel mutation (IK S ) Events with exercise / swimming (IK S ) Long QT 2 45% HERG K+ Channel mutation (IK R ) Events with loud noises K+ Channel mutation (IK R ) Long QT 3 8% SCN5A Na+ Channel mutation Events during sleep Gain of function SCN5A mutations Gain of function causes long QT syndrome (LQT 3) Loss of function causes Brugada Syndrome Others (9 other LQT variants) account for remaining 5% of positive gene tests Splawski I, Shen J, Timothy KW, et al.: Spectrum of mutations in long-qt syndrome genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE. Circulation 2000,102:1178 1185. January 14-15, 2011 SCA Conference 3

LQT Subtypes ECG Manifestations Normal ECG Long QT 1: Wide-based T-wave Long QT 2: Notched T-wave Long QT 3: Late peaking T-wave after long isoelectric ST segment Diagnosis? January 14-15, 2011 SCA Conference 4

What is a normal QTc? Long QT Long QT Syndrome ECG findings Points QTc duration 480 ms 3 460-470470 ms 2 450 ms (if male) 1 Torsade de pointes 2 T-Wave alternans 1 Notched T wave in three leads 1 Low heart rate for age (<2 percentile) 0.5 Clinical history: Syncope With stress 2 Without stress 1 Congenital deafness (Jervell and Lange-Neilsen Syndrome?) 0.5 Family history: Family members with definite LQTS 1 Unexplained sudden cardiac death below age 30 0.5 among immediate family members Patients with 4 or more points are categorized as a high probability, 2-3 points as intermediate and one or less as low probability of having long QT syndrome. Schwartz PJ, et al. Circulation 1993;88:782-784. January 14-15, 2011 SCA Conference 5

Prognosis and Risk Mean age at first manifestation is 12 years. Longer QTc (>500 ms) more worrisome Family history of SCD not clearly related to risk of SCD LQT Subtype is important LQT Risk Pyramid Priori et al., N Engl J Med 2003, 348;19 January 14-15, 2011 SCA Conference 6

Treatment Beta Blockers Beta-blockers are the mainstay of therapy in LQTS Decreases eases risk for cardiac ac events Can shorten QT interval by decreasing activation from the left stellate ganglion Moss et al.: 869 LQTS patients treated with B-blockers Beta blockers reduced cardiac events from 0.97 to 0.31 per year Moss et al. Circulation 2000; 101:616-623. 623. Treatment Beta Blockers Jons et al. J Am Coll Cardiol 2010, 55: 783-288. January 14-15, 2011 SCA Conference 7

Beta-Blockers Blockers work in LQT 1 216 long QT1 patients on beta blockers 157 (73%) with cardiac events prior to beta- blockers (syncope, CA, SCD) 75% asymptomatic after beta blockers If you take them 12 cardiac arrests / SCD 8 non-compliant 2 QT-prolonging drugs 1 both Vincent et al. Circulation 2009; 119:215-221. 221. Beta-blockers by LQT Subtype Priori et al. JAMA 2004;292:1341-1344. 1344. January 14-15, 2011 SCA Conference 8

Treatment -ICD Implantable Cardioverter Defibrillators (ICD) For high risk patients Sudden cardiac arrest (secondary prevention) LQT1 with syncope on beta-blockers blockers LQT2 with syncope All LQT 3 patients??? ICD outcomes in LQT International Long QTS Registry 125 with ICD s 54 survivors of CA, 19 syncope on beta-blockersblockers 161 controls without ICD s 89 survivors of CA, 72 syncope on beta-blockersblockers Zareba et al. J Cardiovasc Electrophysiol 2003. 14:337-341. 341. January 14-15, 2011 SCA Conference 9

Treatment Sympathectomy Left cardiac sympathetic denervation Interrupts major source of norepinephrine to the heart via preganglionic denervation Decreases cardiac adrenergic tone without decreasing heart rate Resection of lower half of left stellate ganglion as well as second and third thoracic ganglia. Ocular fibers in upper half (lower risk of Horner s syndrome) Consider when:» Small size difficult to place ICD» Asthma and cannot tolerate beta-blockers blockers» ICD s and frequent shocks» LQT3 Collura et al. Heart Rhythm 2009;6:752-759. 759. Treatment Sympathectomy Large study of 147 LQTS patients with sympathectomy y Event rate improved from 1.32 to 0.19 events per year» SCD or aborted CA from 0.13 to 0.06 events per year In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-lcsd count of shocks decreased by 95% (P = 0.02) from a median number of 25 to 0 per patient. More useful in LQT1 and LQT3 than LQT 2 Schwartz et al. Circulation 2004;109;1826-1833. 1833. January 14-15, 2011 SCA Conference 10

Long QT Syndrome Pearls Comprehensive family history is imperative (syncope, seizures, SCD) Exercise test can be very useful for diagnosis Genetic testing should be considered Avoid QT prolonging drugs Exercise restriction generally advised Beta blockers mainstay of treatment unless LQT 3 Don t forget sympathectomy Genetic Electrical Myopathies Long QT Syndrome Short QT Syndrome Brugada Syndrome Catecholaminergic Polymorphic Ventricular Tachyardia (CPVT) January 14-15, 2011 SCA Conference 11

Short QT Syndrome Abnormally short QTc interval (<340 ms) and a propensity for atrial fibrillation and sudden cardiac death (SCD) Short QT Syndrome Linked to mutations in several genes all LQT genes encoding a different potassium ion channel involved in repolarization: KNCQ1, HERG, KCNJ2 Shortening of the effective refractory period combined with increased dispersion of repolarization is the substrate for reentry and life threatening arrhythmias Diagnosis in children may be difficult because the short QT interval may only become apparent at heart rates less than 80 per minute Therapies have not been clearly defined, although quinidine may lengthen ventricular refractoriness and reduce vulnerability to VF. Gaita F, et al. J Am Coll Cardiol 2004;43:1494-1499. January 14-15, 2011 SCA Conference 12

Genetic Electrical Myopathies Long QT Syndrome Short QT Syndrome Brugada Syndrome Catecholaminergic Polymorphic Ventricular Tachyardia (CPVT) Brugada Syndrome First described in 1992 88 patients with right bundle branch block, ST elevation in the right precordial leads and sudden cardiac death. Mean age of sudden death 41 years Incidence not clear, but may be 1 in 2,000. Rare, but can be cause of SCD in children 20% - 25% have mutations in SCN5A (Alpha-subunit of Cardiac Na+ channel) loss of function Other rare gene mutations as well Loss of function can be exacerbated by sodium channel blocking agents (Class I antiarrhythmic medications) medications (procainamide, ajmaline) may be used to unmask the diagnostic ECG findings Brugada, Pedro; Brugada, Josep. J Am Coll Cardiol 1992;20:1391-1396. Beaufort-Krol GC et al. Developmetnal aspects of long QT syndrome type 3 and Brugada syndrome on the basis of an single SCN5A mutation in childhood. J Am Coll Cardiol 2005; 46:331-337 January 14-15, 2011 SCA Conference 13

Brugada Syndrome Brugada Syndrome in Pediatrics Has been diagnosed in children, generally beyond 5 years of age Diagnosis in children is difficult Dynamic ECG findings ECG features which are similar to those characteristic of the Brugada syndrome may occur in healthy young children Brugada Syndrome has also been associated with other arrhythmias including sinus node dysfunction, supraventricular and ventricular arrhythmias, and AV node conduction delay January 14-15, 2011 SCA Conference 14

Brugada Syndrome Risk factors for arrhythmic event Spontaneous ST-segment elevation in leads V1 through V3 (as opposed to diagnostic ECG findings only after sodium channel blocker challenge) History of syncope Induction of VT or VF by programmed electrical stimulation has not been a consistent risk factor for SCD. Fever associated with events Quinidine can normalize ST and decrease risk for arrhythmias Probst et al. Circulation. 2007;115:2042-20482048 Brugada Pearls Remember the classic Brugada ECG: ECG findings may only show up at a later age (>5 years), so continue to follow if clinical concern Genetic testing is of limited utility (sensitivity 25-40%) Fever associated with events in children January 14-15, 2011 SCA Conference 15

Genetic Electrical Myopathies Long QT Syndrome Short QT Syndrome Brugada Syndrome Catecholaminergic Polymorphic Ventricular Tachyardia (CPVT) Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Catecholaminergic VT is a malignant disorder that presents in childhood or adolescence as syncope, polymorphic VT or SCD preceded ddb by exertion or stress Hypersensitivity to inward calcium currents and abnormal release of calcium ions from the sarcoplasmic reticulum. Calcium overload results in delayed cardiac afterdepolarizations, which trigger ventricular arrhythmias. Adrenergic stimulation due to emotional stress or physical activity can lead to calcium overload and precipitate tachyarrhythmias Sumitomo N, et al. Heart 2003;89:66-70. www.med.uc.edu January 14-15, 2011 SCA Conference 16

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Catecholaminergic VT is a malignant disorder that presents in childhood or adolescence as syncope, polymorphic VT or SCD preceded ddb by exertion or stress Genetically heterogeneous, involving mutations in the cardiac ryanidine and calsequestrin receptors. Ryanidine Receptor (RyR2) - mediates the release of calcium from the sarcoplasmic reticulum that is required for myocardial contraction Autosomal dominant Calsequestrin (Casq 2) - Major calcium reservoir within the sarcoplasmic reticulum of cardiac myocytes. Autosomal recessive George et al. Circ Res 2003;93:531 Yano et al. Mol Cell Biochem1994;135:61 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Frequent ventricular ectopy and ventricular tachycardia with exercise Incidence ~1 in 10,000 30% have family history of sudden death before age 40 Genetic testing positive in ~70% (RYR2, Casq2) Hoffman et al.: 25 Sudden deaths (age 1-18 years) without initially clear etiology 14 with disease identified (after testing of patients and families)» 7 LQT» 3 CPVT»2 HCM» 1 ARVD» 1 myocarditis Napolitano et al Heart Rhythm 2007; 4:675-678. 678. Hoffman et al. Pediatrics 2007;120; e967-e973e973 January 14-15, 2011 SCA Conference 17

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Bidirectional VT Bidirectional VT Silka MJ, Bar-Cohen Y. Sudden Cardiac Death. Moss and Adams Heart Disease in Infants, Children and Adolescents, 7 th Edition, 2008. CPVT Rx with beta-blockers blockers 101 patients, follow-up 7.9 years Cardiac events: syncope, aborted cardiac arrest, appropriate ICD discharge, SCD 8-year event rate: 32% On beta-blockers: blockers: 27% Not on beta-blockers: blockers: 58% Age at first symptom 12 ± 8 years Age at diagnoses 15 ± 10 years Independent d predictors of events Younger age at diagnoses not taking beta blockers Hayashi et al. Circulation. 2009;119:2426-2434. January 14-15, 2011 SCA Conference 18

CPVT Other Rx options Calcium channel blockers plus beta-blockersblockers 6 patients (5 with CPVT, 1 with HCM) 3 patients with NS-VT during exercise to none Ventricular ectopy during ETT from 78 ± 59 beats to 6 ± 8 beats One patient from 14 ICD shocks in 6 months to none in 7 months of follow-up Flecainide inhibits cardiac Ryanodine receptor channel (RyR2) reference 29 Suppressed VT in 12 of 12 mice (Casq2 deletion) 12-year-old (homozygous Casq2) and 36-year-old (heterozygous RyR2) suppressed all arrhythmias Rosso et al. Heart Rhythm 2007;4:1149-1154. 1154. Watanabe et al. Nat Med. 2009 Apr;15:380-3. 3. CPVT and Sympathectomy 3 patients with CPVT and sympathectomy All had persistent events despite beta blockers No events after sympathectomy Wilde et al. N Engl J Med. 2008 May 8;358(19):2024-9. 9. January 14-15, 2011 SCA Conference 19

CPVT Pearls Always consider CPVT when cardiac events with exercise and normal echo and ECG Exercise test is key to diagnosis Beta-blockers are first line therapy Remember sympathectomy Thank You January 14-15, 2011 SCA Conference 20

Reason to do: Diagnosis - Holter Assess for changes in QTc with changes in heart rate Look for ventricular arrhythmias (41% of LQT patients?) Problems: Inaccuracy Study comparing Holter to 12-lead showed Holter underestimated QT in V1 and overestimated in V5. Generally, there is a need for caution when using Holters to evaluate QT Christiansen et al. Pacing Clin Electrophysiol. 1996 Sep;19(9):1296-303. Garson et al. Circulation 1993, 87:1866 1872. 1872. Diagnosis Exercise testing Reason to do: Assess for changes in QTc at peak exercise and RECOVERY Problems: Difficult to measure QT during artifact and P-waves merge with T-waves Best at 3 minutes of recovery Subtype differences LQT1: QTc increases with higher heart rates and change to broad based T-wave LQT2: appearance of a notch at higher h heart rates LQT3: normal exercise test Dillenburg et al. Am J Cardiol 2002, 89:233-236236 Takenaka, et al. Circulation 2003 107:838-844 844 January 14-15, 2011 SCA Conference 21

Diagnosis electrophysiology study Reason to do:??? EP testing Torsades inducible in 10% of patients and inducibility of ventricular arrhythmias has not correlated with cardiac events Very limited utility Garson LQT syndrome in children 287 patients. Circulation 1993; 87:1866-1872. 1872. Bandari et al, Electrophysiology testin gin patients with the long QT syndrome. Circulation 1985; 71:63 Diagnosis Genetic Testing. (~75% positive in LQT) Commercially available Helpful when uncertainty regarding diagnosis Helpful for identifying subtype and therefore management January 14-15, 2011 SCA Conference 22

Brugada Syndrome January 14-15, 2011 SCA Conference 23