Latest Diagnostic and Treatment Strategies for the Congenital Long QT Syndromes

Home , Long QT syndrome, Syncope (medicine)

Michael J. Ackerman, MD, PhD Windland Smith Rice Cardiovascular Genomics Research Professor Professor of Medicine, Pediatrics, and Pharmacology Director, Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory President, Sudden Arrhythmia Death Syndromes (SADS) Foundation

Learning Objectives to Disclose: • To RECOGNIZE the “faces” (phenotypes) of the congenital long QT syndromes (LQTS) • To CRITIQUE the various diagnostic modalities used in the evaluation of LQTS and UNDERSTAND their limitations • To ASSESS the currently available treatment options for the various LQT syndromes and EVALUATE their efficacy

WINDLAND Smith Rice Sudden Death Genomics Laboratory Conflicts of Interest to Disclose: • Consultant – Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical, and Transgenomic/FAMILION • Royalties – Transgenomic/FAMILION Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT 1. Syncope 2. Seizures 3. Sudden death

Torsades de pointes Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT 1. Syncope 2. Seizures 3. Sudden death

Torsades de pointes Congenital Long QT Syndrome

Normal QT interval ♥ 1957QT – firstQT clinical description – JLNS ♥ 1960s – RomanoProlonged-Ward QT syndrome ♥ 1983 – “Schwartz/Moss score”1. Syncope ♥ 1991 – first LQTS chromosome locus 2. Seizures ♥ March 10, 1995 – birth of cardiac channelopathies 3. Sudden death ♥ 1995 - 2004 - research LQTS testing ♥ August 2004 Torsades- clinical de pointes LQTS genetic test ♥ April 2008 - +ve BCBS TEC summary ♥ August 2011 - HRS/EHRA Guidelines Congenital Long QT Syndrome

Normal QT interval QT QTAugust 2011 HRS/EHRA ConsensusProlonged QT Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies

Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011

May 2013 HRS/EHRA/APHRS♥ 1995 - 2004 - research Expert ConsensusLQTS testing Statement ♥ onAugust the Diagnosis 2004 Torsades- andclinical Management de pointes LQTS genetic of Patients test with Inherited Primary Arrhythmia Syndromes ♥ April 2008 - +ve BCBS TEC summary ♥ AugustPriori, Wilde, 2011 et al.- HRS/EHRAHeart Rhythm 10:1932 Guidelines-1963, 2013 Long QT Syndrome

Expert Consensus Recommendations on Diagnosis 1. LQTS is diagnosed: a) In the presence of an LQTS risk score > 3.5 in the absence of a secondary cause for QT prolongation, and/or b) In the presence of an unequivocally pathogenic mutation in one of the LQTS genes, or c) In the presence of a QTc > 500 ms in repeated 12- lead ECG and in the absence of a secondary cause for QT prolongation. 2. LQTS can be diagnosed in the presence of a QTc between 480-499 ms in repeated 12-lead ECGs in a patient with unexplained syncope in the absence of a secondary cause for QT prolongation and in the absence of a pathogenic mutation. LQTS Diagnostic Criteria (1993-2011) - aka “The Schwartz Score” - Electrocardiographic Findings A QTc Points > 480 ms 3 460-479 ms 2 450-459 ms (in males) 1 B QTc 4th minute of recovery from stress test > 480 ms 1 C Torsade de pointes 2 D T wave alternans 1 E Notched T wave in 3 leads 1 F Low heart rate for age (< 2nd percentile) 1/2 Clinical History A Syncope With stress 2 Without stress 1 B Congenital deafness 1/2 Family History A Family members with definite LQTS 1 B Unexplained sudden cardiac death < 30 years in near relative 1/2 LQTS Diagnostic Criteria (1993-2011) - aka “The Schwartz Score” -

Points

The Story is King! Clinical History A Syncope < 1: LowWith stress Probability of LQTS 2 Without stress 1 1.5B Congenital to 3: Intermediate deafness Probability of LQTS 1/2 Family History A Family members with definite LQTS 1 >B 3.5: Unexplained High suddenProbability cardiac death of LQTS< 30 years in near relative 1/2 Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT 1. Syncope 2. Seizures 3. Sudden death Starting Point of LQTS Evaluation -Torsades The Storyde pointes - “Don’t Blow Off a Blackout”

Glamour March 2000 > 2 FAINTS in < 2 years -- HR 18.1 --

Hobbs et al. (LQTS Registry). Risk of aborted cardiac arrest of sudden cardiac death during adolescence in the long QT syndrome. JAMA 296:1249-1254, 2006 “Don’t Blow Off a Blackout” EXERTIONAL/AUDITORY/ POSTPARTUM SYNCOPE/SEIZURES ARE MALIGNANT UNTIL PROVEN OTHERWISE!! Be a Detective

WHO? WHAT? WHEN? WHERE? WHY? ~ 40% of the patients that came to Mayo Clinic with the diagnosis of “Don’t Blow Off a Blackout” LQTSWHAT? left without it! Taggart … Ackerman. Circulation 115:2613-2620, 2007

Vanilla Faint + Borderline QT = Possible LQTS

QT Inflation Secondary to U Wave Inclusion Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT 1. Syncope 2. Seizures 3. Sudden Starting Point of LQTS Testingdeath - The 12-Lead ECG - Torsades de pointes LQTS Diagnostic Criteria (1993-2011) - aka “The Schwartz Score” - Electrocardiographic Findings A QTc Points > 480 ms 3 460-479 ms 2 450-459 ms (in males) 1 B QTc 4th minute of recovery from stress test > 480 ms 1 C Torsade de pointes 2 D T wave alternans 1 E Notched T wave in 3 leads 1 F Low heart rate for age (< 2nd percentile) 1/2 The ECG and LQTS

QTc = 760 ms QTc = 362 ms

QTc = 760 ms The ECG and LQTS

QTc = 760362 ms QTc calculated INCORRECTLY by - < 5% of LQTS experts QTc = 760 ms - > ONE-THIRD of heart rhythm specialists

- > THREE-FOURTHS of cardiologistsHeart Rhythm 2005;2:569 -574 The ECG and LQTS

QTc = 760 ms

“Teach-the-Tangent” or “Avoid-the-Tail” The ECG and LQTS

LQT Genotype by ECG? 1. LQT1 V4 2. LQT2 3. LQT3

4.QTc =LQT9 760 ms 5. Don’t have a clue

QTc = 475 Measuring the QT Interval – 5 Pearls 1. Use lead II and/or V5! Stay away from V2 and V3! 2. If your QT interval matches the computer’s QT interval, you have verified the computer’s QTc! 3. If the QT interval is less than ½ the RR interval, Heart Rhythm 2005;2:569-574 the QTc will be < 460 ms!

4. If sinusQTc calculated arrhythmia INCORRECTLY or AF present, do by NOT take the maximum- < 5% QT of intervalLQTS experts and the minimum RR interval! That will grossly inflate the QTc. Take the average! - > ONE-THIRD of heart rhythm specialist 5. Remember- > THREE that-FOURTHS the patient’s of cardiologists QTc reality will be UNDERESTIMATED at low heart rates (< 50 bpm) and OVERESTIMATED at high heart rates (> 100 bpm)! Measuring the QT Interval

2. If yourBONUS QT PEARLinterval – matches Wide QRS the QTc computer’s Adjustment QT Ininterval, wide QRS you scenarios, have verified easiest the computer’s to just make QTc a “wide! QRS adjustment”. QTc(adjusted) = QTc – [QRS – 100].

A. Confirm the computer’s QTc - 560 ms for example B. Note the QRS because of the paced rhythm, BBB, etc. – 220 ms for example, then C. QTc(adjusted) = 560 – [220 – 100] = 560 – 120 = 440! I Think a QTc > ___ is Too Long

1. 420 ms 2. 440 ms 3. 460 ms

QTc = 760 ms 4. 480 ms 5. 500 ms 365 ms

340 Persons (no.) 360 380 “BORDERLINE” Normals 400 2000 420

440 QTc (ms) 482 460 + 480 1 LQTS

57 ms

500

520 540 560 580 600 800 ms 620 2000 Increased Risk - HR > 2.5 (boys 1-12 yrs) - HR > 2 (10 – 20 yrs) - HR > 4 (18 – 40 yrs)

(no.) Persons

1 Normals

LQTS

340 360 380 400 420 440 460 480 500 520 540 560 580 600 620 From the LQTS Registry. JAMA 2006, JACC 2007, Circulation 2008, Circulation 2008 340 Persons (no.) 360 380 Normals 400 2000 420

440 QTc (ms) QTc QTc”“Prolonged JACC Recommendations AHA/ACCF/HRS QTc 460 LQTS < 1% PPV for

480 1 LQTS > > 53:982- 500 450 460

520 – – 991, 2009. 991, 540 males females

560

580

600 620 340 Persons (no.) 360 380 Normals 400 2500 420

440 QTc (ms) 460 480 1 LQTS 500 - - -

> 500 ms Direct EPDirect referral PPV: 50% > Frequency: 1 in 4000 Frequency: 520 540 560 580 600

620 340 Persons (no.) 360 380 Normals 400 2500 420

440 QTc (ms) 460 480 1 LQTS > 480 ms in women 500

520 540 560 580 600 620 340 Persons (no.) 360 380 Normals 400 2500 420

440 QTc (ms) 460 480 1 LQTS > 470 ms in men 500

520 540 560 580 600 620 340 Persons (no.) 360 380 Normals 400 2500 420

440 QTc (ms) 460 > 460 ms pre-puberty 480 LQTS - QTc(qrs)= QTc –[QRS - - - - (1 in 100to1 in 500) Frequency: 0.2 If QRS QRS If HR < 50,repeat test HR PPV: 4 500 >

50; QRS 520 > –

120 ms, then 25% 540

560 <

1% – 1% 120 ms 580

600 100] 620

The ECG and LQTS

ECG Diagnosis 1. Normal 2. Abnormal

QTc = 760 ms

QTc = 415 The ECG and LQTS

Mutation-specific genetic testing is recommended for family members andECG other Diagnosis appropriate relatives subsequently following1. Normal the identification of the LQTS- causative mutation2. in Abnormal an index case.

QTc = 760 ms Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011

QTc = 415 Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT 1. Syncope 2. Seizures 3. Sudden Latest Diagnostic Strategiesdeath - Genetic Testing - Torsades de pointes Latest Diagnostic and Treatment Strategies for the Long QT Syndromes – Genetic Testing

Disease Diagnostic Prognostic Therapeutic LQTS +++ +++ ++ CPVT +++ + - BrS + + - CCD + + + SQTS +/- - - AF - - - HCM +++ ++ + ARVC + +/- - DCM +/- - - LVNC + - - RCM + + + Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 Long QT Syndrome Genetic Testing

1. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A) targeted+++ LQTS genetic+++ testing is recommended++ +++ + - for any patient in whom+ a cardiologist+ has established- a strong clinical indexAugust+ of suspicion 2011 +for LQTS based+ on HRS/EHRA +/Consensus- Statement- - on the examinationState of ofthe Genetic-patient’s clinical Testing- history, for family the- history, andChannelopathies expressed electrocardiographic and Cardiomyopathies (resting 12-lead +++ ++ + Ackerman, Priori,+ et al. Heart Rhythm+/- 8:1308-1339,- 2011 ECGs and/or provocative+/- stress testing- with exercise- or catecholamine infusion)+ phenotype.- - + + + Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 Long QT Syndrome Genetic Testing

2. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic testing is recommended for any asymptomatic patient with QT prolongation in the absence of other clinical conditions which might prolong the QT interval (such as electrolyte abnormalities, hypertrophy, bundle branch block, etc., i.e. otherwise idiopathic) on serial 12-lead ECGs defined as QTc > 480 ms (prepuberty) or > 500 ms (adults).

Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 Long QT Syndrome Genetic Testing

3. Comprehensive or LQT1-3 (KCNQ1, KCNH2, and SCN5A) targeted LQTS genetic testing may be considered for any asymptomatic patient with otherwise idiopathic QTc values > 460 ms (prepuberty) or > 480 ms (adults) on serial 12-lead ECGs.

4. Mutation-specific genetic testing is recommended for family members and other appropriate relatives subsequently following the identification of the LQTS- causative mutation in an index case.

Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 SNTA1-LQT LQT1 AKAP9-LQT (LQT12) KCNJ5-LQT Ch 11p15.5 SCN4B-LQT ( ) LQT11 NaV1.5 ChIP (LQT13) KCNQ1

(LQT10) IKs ChIP < 1% Kir3.4 30-35% Ch 11q23.3 < 1% < 1% NaV1.5 β4 LQT2 < 1% CALM1-LQT CALM2-LQT Ch 7q35-36 (LQT14) (LQT15) KCNH2

CAV3-LQT CaV1.2 ChIP CaV1.2 ChIP < 1% < 1% 25-30% (LQT9) Ch 3p25 CALM3-LQT LQT3 TRDN-LQT Caveolin-3 (LQT16) Ch 3p21-24 (LQT17) < 1% CaV1.2 ChIP SCN5A < 1% < 1% 5-10% TS1 (LQT8) ATS1 LQT4 LQT5 Ch 1q42 (LQT7) LQT6 Ch 4q25-27 Ch 21q22 Ch 21q22 CACNA1C Ch 17q23 ANK2 <<1% KCNE2 KCNE1 KCNJ2 < 1% 1% <1%a <1% LQTS GeneticSNTA1 Testing-LQT LQT1 AKAP9-LQT (LQT12) KCNJ5-LQT Ch 11p15.5 SCN4B-LQT ( ) LQT11 NaV1.5 ChIP (LQT13) KCNQ1

(LQT10) IKs ChIP < 1% Kir3.4 30LQT1-35% Ch 11q23.3 < 1% < 1% Ch 11p15.5 NaV1.5 β4 LQT2KCNQ1 < 1% CALM1-LQT CALM2-LQT Ch30 7q35-35%-36 (LQT14) (LQT15) KCNH2

CAV3-LQT CaV1.2 ChIP CaV1.2 ChIP < 1% < 1% 25LQT2-30% (LQT9) Ch 7q35-36 Ch 3p25 CALM3-LQT LQT3 TRDN-LQT KCNH2 Caveolin-3 (LQT16) Ch 3p21-24 (LQT17) 25-30% < 1% CaV1.2 ChIP SCN5A < 1% < 1% 5-10% TS1 LQT3 (LQT8) ATS1 LQT4Ch 3p21 -24 LQT5 Ch 1q42 (LQT7) LQT6 ChSCN5A 4q25-27 Ch 21q22 Ch 21q22 CACNA1C Ch 17q23 ANK25-10% <<1%~75% of LQTS patients haveKCNE2 a mutation KCNE1 in one KCNJ2 < 1% 1% <1%aof these three<1% genes KCNE2 (LQT6) KCNE1 (LQT5) < 1% KCNQ1 (LQT1)

< 1% 30-35%

SCN5A (LQT3) KCNH2 (LQT2)

5-10% 25-30%

Khositseth and Ackerman. Cardiac Repolarization – Chapter 20, 2003 KCNQ1 (LQT1) Gene-Suggestive ECG Patterns 30-35%

SCN5A (LQT3) KCNH2 (LQT2) ++ Khositseth and Ackerman. Cardiac Repolarization – Chapter 20, 2003 KCNQ1 (LQT1) Gene-Specific Triggers 30-35%

SCN5A (LQT3) KCNH2 (LQT2)

5-10%

Khositseth and Ackerman. Cardiac Repolarization – Chapter 20, 2003 KCNQ1 (LQT1) Gene Specific Responses to 30-35% Beta Blocker Therapy +++

SCN5A (LQT3) KCNH2 (LQT2) + ++ Khositseth and Ackerman. Cardiac Repolarization – Chapter 20, 2003 Genetic Testing’s Achilles’ Heel

Is the “X” that marks the spot truly THE disease-causing mutation? Genetic Testing’s Achilles’ Heel

- “Maybe” Test Result ? “Possible Deleterious” “Variant of Uncertain Significance (VUS)” “Genetic Purgatory is a Real Place and its Scary!” Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT 1. Syncope 2. Seizures 3. Sudden death Latest Treatment Strategies Torsades de pointes Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT

www.qtdrugs.org www.crediblemeds.org Torsades de pointes Congenital Long QT Syndrome

Normal QT interval QT QT

Prolonged QT 1. Syncope 2. Seizures 3. Sudden death

Torsades de pointes Treatment Options for LQTS LQTS =X ICD Beta-Blocker Therapy

LCSD Treatment Options for LQTS

ICD ?? No Active Therapy Necessary If - Asymptomatic male - >Beta 40-Blocker years Therapy old - QTc < 460 ms - Haploinsufficient, LQT1-causing C-terminal missenseLCSD mutation Goldenberg (LQTS Registry). Circulation 117:2192-2201, 2008 Treatment Options for LQTS Nadolol – 1-1.5 mg/kg/day or 50 mg/m2/day – QD or BID or Propranolol – 3-4 mg/kg/day (BID, LA, TID for theBeta liquid)-Blocker Therapy Caution w/ Using Atenolol and Metoprolol! Chatrath, Bell, Ackerman. Pediatr Cardiol 25:459-465, 2004 Chockalingam …Wilde. JACC 2012 Propranolol and/or Mexiletine/Ranolazine (LQT3) Indications for ICD Therapy Secondary Prevention • Aborted cardiac arrest • Rx intolerance or breakthrough Indications for ICD Therapy

Primary Prevention • QTc > 550 ms and not LQT1 • LQT2 women, QTc > 500 ms, +/- Sx • Infants with 2:1 AV block? • JLNS (LQTS w/ deafness)? • +ve FHx of SCD (=1, >1, >2)? • LQT3?

Indications for ICD Therapy

Primary Prevention • QTc > 550 ms and not LQT1 • LQT2 women, QTc > 500 ms, +/- Sx • Infants with 2:1 AV block? • JLNS (LQTS w/ deafness)? Kaufmann• +ve (LQTSFHx Registry).of SCD Heart (=1, Rhythm >1, 5:831>2)?-836, 2008 • LQT3?

Treatment Options for LQTS

ICD

Beta-Blocker Therapy

LCSD Left Cardiac Sympathetic Denervation

• 1916 - First left stellectomy for angina (Jonnesco) • 1961 - First bilateral sympathectomy for VT (Estes and Izlar) • 1968 - First LCSD for VT (Zipes et al.) • 1970 - First LCSD for LQTS (Moss and McDonald) • 2003 - First reported videoscopic LCSD for LQTS (Li et al.) • 2009 - Largest series of videoscopic LCSD (Mayo Clinic) • Denervation of lower half of the left stellate ganglion (T1) and the sympathetic chain from T2 through T4 • LCSD has a potent anti-fibrillatory effect in LQTS Schwartz et al. Circulation 2004 0.86 0.9 Cardiac Event Risk 0.8 (CER) Cluster 0.7 High 0.6 Medium 0.5 Low 0.4 0.3 0.2 0.2 0.1 0.1 0.01 0.01 0.005 Cardiac event rate/month event Cardiac 0 PRE-LCSD POST-LCSD LCSD’s anti(mean- fibrillatoryCER 0.32 ± 0.64) effects(mean CER 0.07 caused± 0.27) by: - “Norepinephrine ablation” - Improved repolarization as evidenced by a decrease in QTc in ~30% Left Cardiac Sympathetic Denervation

Videoscopic Denervation Therapy at Mayo • N = 152 LCSDs from November 2005 to present • Average age: 19 + 17 years (4 weeks of age to 85 years) • LQTS (89, LQT1 in 37, LQT2 in 20, LQT3 in 8); CPVT (19); Cardiomyopathy (9); IVF (9) • LQTS: QTc = 497 + 67 ms IndicationsIndications forfor VideoscopicVideoscopic LeftLeft CardiacCardiac SympatheticSympathetic DenervationDenervation SurgerySurgery

• History of appropriate VF-terminating ICD shocks • Rx intolerance or breakthroughs • Young (< 12 years) where Rx not deemed “protective enough” but ICD- related morbidity seems excessive – - “Bridge to ICD” -

Collura, Johnson, Moir, Ackerman. Heart Rhythm June 2009 …the Congenital Long QT Syndromes

Take Home Points 1. Remember to “be a detective”, “avoid the tails” (exclude the U waves), and take careful stock of the patient with a QTc > 500 ms! 2. Genetic tests are PROBABILISTIC tests! “X” does NOT always mark the spot! 3. Most do not need and should not receive an ICD! 4. Remember denervation therapy and its anti-fibrillatory effect. Don’t just let the ICD keep firing! WINDLAND Smith Rice Sudden Death Genomics Laboratory Dr. Scholl Foundation, CJ Foundation for SIDS Hannah Wernke Memorial Foundation Sheikh Zayed Saif Mohammed Al Nahyan Fund National Institutes of Health WINDLAND Smith Rice Sudden Death Genomics Laboratory

“To heal the sick and advance the science” Dr. Charles W. Mayo