1. Risk of Life-Threatening Cardiac Events in Patients with Genotype-Confirmed Long-QT Syndrome and a Normal-Range QTc Ilan Goldenberg, MD,* Samuel Horr, MA,* Arthur J. Moss, MD,* Coeli M. Lopes, PhD,† Alon Barsheshet, MD, * Scott McNitt, MS, * Wojciech Zareba, MD,* PhD, Mark L. Andrews, BBA,* Jennifer L. Robinson, MS,* Emanuela H. Locati, MD,‡ Michael J. Ackerman, MD, PhD,§ Jesaia Benhorin, MD,¶ Elizabeth S. Kaufman, MD,║Carlo Napolitano, MD,# Pyotr G. Platonov, MD,** PhD, Silvia G. Priori, MD, PhD, # Ming Qi, MD,†† Peter J. Schwartz, MD,‡‡ Wataru Shimizu, MD, PhD,§§ Jeffrey A. Towbin, MD,¶¶ G. Michael Vincent, MD, ## Arthur A.M. Wilde MD, PhD,*** Li Zhang, MD.## From the *Cardiology Division of the Department of Medicine and the †Cardiovascular Research Institute and ††Pathology, University of Rochester Medical Center, Rochester, NY; ‡Cardiovascular Department De Gasperis, Niguarda Hospital, Milan, Italy; ¶Bikur Cholim Hospital, University of Jerusalem, Jerusalem, Israel; §Departments of Medicine, Pediatrics, and Molecular Pharmacology &Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic College of Medicine, Rochester, Minn;║The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; #Molecular Cardiology, Fondazione S. Maugeri-University of Pavia, Pavia, Italy and Leon Charney Division of Cardiology, New York University School of Medicine; the ‡‡Department of Cardiology, Fondazione Policlinico S. Matteo IRCCS and University of Pavia, Italy; the **Department of Cardiology, Lund University, Lund, Sweden; the §§Division of Cardiology, Department of Internal Medicine National Cardiovascular Center, Suita, Japan; the ¶¶Department of Pediatric Cardiology, Baylor College of Medicine, Houston, Tex; the ***Department of Cardiology Academic Medical Center, Amsterdam, the Netherlands; and the ##Department of Medicine University of Utah School of Medicine, Salt Lake City. Academic Medical Center, Amsterdam Ilan Goldenberg, MD,* Samuel Horr, MA,* Arthur J. Moss, MD,* Coeli M. Lopes, PhD,† Alon Barsheshet, MD, * Scott McNitt, MS, * Wojciech Zareba, MD,* PhD, Mark L. Andrews, BBA,* Jennifer L. Robinson, MS,* Emanuela H. Locati, MD,‡ Michael J. Ackerman, MD, PhD,§ Jesaia Benhorin, MD,¶ Elizabeth S. Kaufman, MD,║Carlo Napolitano, MD,# Pyotr G. Platonov, MD,** PhD, Silvia G. Priori, MD, PhD, # Ming Qi, MD,†† Peter J. Schwartz, MD,‡‡ Wataru Shimizu, MD, PhD,§§ Jeffrey A. Towbin, MD,¶¶ G. Michael Vincent, MD, ## Arthur A.M. Wilde MD, PhD,*** Li Zhang, MD.## From the *Cardiology Division of the Department of Medicine and the †Cardiovascular Research Institute and ††Pathology, University of Rochester Medical Center, Rochester, NY; ‡Cardiovascular Department De Gasperis, Niguarda Hospital, Milan, Italy; ¶Bikur Cholim Hospital, University of Jerusalem, Jerusalem, Israel; §Departments of Medicine, Pediatrics, and Molecular Pharmacology &Experimental Therapeutics/Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic College of Medicine, Rochester, Minn;║The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio; #Molecular Cardiology, Fondazione S. Maugeri- University of Pavia, Pavia, Italy and Leon Charney Division of Cardiology, New York University School of Medicine; the ‡‡Department of Cardiology, Fondazione Policlinico S. Matteo IRCCS and University of Pavia, Italy; the **Department of Cardiology, Lund University, Lund, Sweden; the §§Division of Cardiology, Department of Internal Medicine National Cardiovascular Center, Suita, Japan; the ¶¶Department of Pediatric Cardiology, Baylor College of Medicine, Houston, Tex; the ***Department of Cardiology Academic Medical Center, Amsterdam, the Netherlands; and the ##Department of Medicine University of Utah School of Medicine, Salt Lake City. Academic Medical Center, Amsterdam

2. Presenter Disclosure Information DISCLOSURE INFORMATION The following relationships exist related to this presentation: The LQTS Registry is supported by research grants HL-33843 and HL-51618 from the National Institutes of Health, Bethesda, Md. Ilan Goldenberg, MD Risk of Life-Threatening Cardiac Events in Patients with Genotype- Confirmed Long-QT Syndrome and a Normal-Range QTc J Am Coll Cardiol 2010;57:51-59

3. Background

4. CURRENT STATUS 12 identified LQTS genotypes (>500 mutations) Most frequent clinical types (LQT1-3): LQT1 (43%) LQT2 (45%) LQT3 (7%) LQT4-12 make up less than 5% of cases J Am Coll Cardiol 2010;57:51-59

5. LQTS Phenotype  Expressed by:  QTc:  QTc ≥450 msec  Events:  syncope, aborted cardiac arrest, SCD J Am Coll Cardiol 2010;57:51-59

6. Clinical Course and Risk Stratification Studies comprised mainly LQTS pts with QTc ≥450 msec Clinical factors (QTc duration, age-gender interactions) in this population No specific data regarding clinical course and risk factors in LQTS pts with normal QTc (referred to as: phenotype-negative LQTS or concealed LQTS) J Am Coll Cardiol 2010;57:51-59

7. Mutation-Specific Risk Factors in LQTS Moss et al. Circulation 2007 KCNQ1 SCN5A

8. Study Hypothesis  We hypothesized that genetic factors and mutation characteristics may help identify high- risk LQTS patients who do not exhibit the phenotypic QTc prolongation of the disease J Am Coll Cardiol 2010;57:51-59

9. Study Purpose Assess the risk of life-threatening events among LQT1-3 pts with normal-range QTc Identify specific clinical and genetic risk factors for life-threatening cardiac events in this population J Am Coll Cardiol 2010;57:51-59

10. Methods

11. Study Population: Inclusion Criteria  3,386 genotyped subjects from proband identified LQT1-3 families  International LQTS Registry:  US (n=2630)  Denmark (n=90)  Italy (n=28)  Israel (n=25)  Sweden (n=17)  Netherlands’ LQTS Registry (n=391)  Japanese LQTS Registry (n=205) J Am Coll Cardiol 2010;57:51-59

12. Study Population: Exclusion Criteria  >1 LQTS identified mutation  JLN with deafness or one known KCNQ1 mutation and congenital deafness  No identified mutation on genetic testing with a prolonged QTc (>440 msec) [ J Am Coll Cardiol 2010;57:51-59

13. Phenotype Characterization  Unaffected family members (n=1525):  Negative for a known LQTS mutation with QTc ≤440 msec  LQTS and normal-range QTc (n=469):  Positive for a known LQT1-3 mutation with QTc ≤440 msec  LQTS and prolonged-QTc ( n=1392):  Positive for a known LQT1-3 mutation with QTc >440 msec. J Am Coll Cardiol 2010;57:51-59

14. Outcome Measures  Primary end point:  Aborted cardiac arrest (ACA) or sudden cardiac death (SCD).  Prespecified candidate clinical and genetic risk factors:  Gender  Qtc duration  Genotype  Mutation location/type (transmembrane-missense [TM-MS] vs. others)  Family history of SCD J Am Coll Cardiol 2010;57:51-59

15. Results

16. J Am Coll Cardiol 2010;57:51-59

17. Unaffected Family Members (n=1525) LQTS and Normal- Range QTc (n=469) LQTS and Prolonged QTc (n=1392) Female52%48%61%* QTc Median 420 msec 490 msec Mean 412 msec 419 msec501 msec Genotype LQT1 NA 40%39% LQT2 NA 45%47% LQT3 NA 16%14% Mutation TM-MS NA 35%43% P < 0.05 Baseline Characteristics J Am Coll Cardiol 2010;57:51-59

18. Unaffected Family Members (n=1525) LQTS and Normal- Range QTc (n=469) LQTS and Prolonged QTc (n=1392) Therapies Beta-blockers 6 % 38 %54 % Pacemaker 0.3 % 0.6 %5 % LCSD 0.1 % 0.2 %1.4 % ICD 0.6 % 614 % Events Syncope 10% 21%40% ACA 0.2 % 1.3 %8.4 % SCD 0.1 % 1.5 %4.4 % ACA/SCD 0.3% 2.8%11.3% P < 0.05 Therapies and Events during FU J Am Coll Cardiol 2010;57:51-59

19. Gen+/QTc >440msec Probability of ACA/SCD by Genotype/QTc Category e.+/QTc>440 Ge.+/QTc≤440 J Am Coll Cardiol 2010;57:51-59

20. End Point: ACA/SCD Risk-Group HRP-value LQTS and Prolonged QTc vs. Unaffected family members 36.53<0.001 LQTS and Prolonged QTc vs. Unaffected family members 10.25<0.001 LQTS and Prolonged QTc vs. LQTS/Normal-range QTc 3.57<0.001 *Adjusted for gender and time-dependent beta-blocker therapy Multivariate Analysis: Total Population* J Am Coll Cardiol 2010;57:51-59

21. LQTS/Normal-Range QTcLQTS/Prolonged QTc Risk Group HRP-value HRP-value P-value for interaction Gender Female >13 yrs 1.320.64 1.900.0020.53 Gender LQT1 vs. LQT2 9.88 0.030.530.0020.006 LQT3 vs. LQT2 8.04 0.071.070.770.08 Mutation TM-MS6.320.0061.240.220.02 QTc Per 10 msec inc 1.20 0.351.08<0.0010.58 >median vs. ≤median 1.03 0.952.96<0.001NA *All findings were further adjusted for time-dependent beta-blocker therapy and family history of sudden cardiac death Multivariate Analysis: Risk Factors for ACA/SCD* J Am Coll Cardiol 2010;57:51-59

22. Probability of ACA/SCD in LQTS Pts with a Normal-Range QTc by Mutation Location/Type J Am Coll Cardiol 2010;57:51-59

23. Probability of ACA/SCD in LQTS Pts with Prolonged QTc by Mutation Location/Type J Am Coll Cardiol 2010;57:51-59

24. A: Baseline ECG (QTc = 410 msec) B: Development of Polymorphic VTC: After initiation of beta-blocker and ICD therapy Development of Polymorphic VT in an LQT1 Patients with Normal-Range QTc

25. Probability of ACA/SCD in LQTS Pts with Prolonged QTc by Mutation Location/Type J Am Coll Cardiol 2010;57:51-59

26. Probability of ACA/SCD in LQTS Pts with Prolonged QTc by Mutation Location/Type J Am Coll Cardiol 2010;57:51-59

27. Conclusions Carriers of the LQT1-3 genotypes exhibit a wide QTc distribution 25% have normal-range QTc Rate of ACA or SCD in Gen+/QTc≤440 msec Relatively low (4% from birth through age 40 yrs) >10-fold risk increase compared with unaffected family members J Am Coll Cardiol 2010;57:51-59

28. Clinical Implications Risk assessment among phenotype-negative family members of LQTS probands should include genetic testing, Genetic data may be used to identify phenotype-negative patients with increased risk for fatal ventricular tachyarrhythmias LQTS patients with a normal-range QTc and a high-risk profile (i.e. LQT1 and LQT3 with TM-MS mutations) should receive similar management as phenotype-positive LQTS patients LQTS patients with a normal-range QTc and a low risk profile (i.e. concealed LQT2 and non-transmembrane-missense LQT1 and LQT3) may need of only preventative health recommendations such as QT drug avoidance. J Am Coll Cardiol 2010;57:51-59

29. Clinical Implications Distinct predictors of life-threatening event among LQTS pts with normal and prolonged QTc: LQTS with normal-range QTc: Genotype: LQT1, LQT3 Mutation characteristics (location/type) LQTS with prolonged QTc: Gender QTc duration LQT2 J Am Coll Cardiol 2010;57:51-59