DUKE EP SYMPOSIUM. Long QT Syndrome: Genotype- Phenotype Correlations

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1 DUKE EP SYMPOSIUM Long QT Syndrome: Genotype- Phenotype Correlations Arthur J. Moss, MD Professor of Medicine/Cardiology University of Rochester Med Center Rochester, NY Cary, NC January 21, 2011

2 CONFLICT OF INTEREST and DISCLOSURE INFORMATION LQTS Research Grants: NIH (24 + years) R01 grant Gilead (ranolzine) part of a U-01 NIH grant BioReference Labs LQTS grant GeneDx LQTS mutation analysis Hold no stock or stock options in any LQTS or device company. Not a member of any corporate advisory group or speakers bureau.

3 INHERITED CHANNELOPATHIES Cardiac 1. Long QT Syndrome (LQTS) Na + & K + channelopathy 2. Brugada Syndrome Na + channelopathy 3. Short QT Syndrome K+ channelopathy ( in function) Non-Cardiac 1. Cystic Fibrosis CFTR gene; Cl - ; F508; >1200 mutat. 2. Hyperkalemic Periodic Paralysis SCN4a Na+ channel 3. Myotonia Congenita CLCN1 Cl - channel gene 4. Autosomal Dominant Epilepsy - mutations in neuronal α- and -subunits of the SCN1A gene; LQT1-3 mutations 5. Familial hemiplegic migraine mutations in CACNA1A and SCN1A genes

4 LQTS: HISTORICAL ASPECTS 1957: 1 st LQTS family reported : 25 LQTS cases reported 1971: 1 st LQTS Rx (Moss & McDonald) : International LQTS Registry (n=8,231; average FU 18.8 yrs/pt) : 11 LQTS genes identified : gene-specific therapy

5 CLINICAL SPECTRUM OF LQTS with focus on LQT 1, 2, & 3

6 LQTS: Clinical Features Symptoms Deafness Palpitations Syncope Sudden death ECG Signs Prolonged QTc Abn T-wave shape T-wave alternans Torsade de pointes

7 Electrical Features of LQTS

8 What are we trying to prevent?

9 #1

10 #2

11 Percent Triggers for Arrhythmic Events in LQTS Exercise Emotional Stress Rest LQT1 LQT2 LQT3 Schwartz PJ, Moss AJ, et al. Circ 2001;103:89-95

12 LQTS: CLINICAL RISK FACTORS FOR SYNCOPE, ACA, SCD (30 years of studies from our LQTS Registry) Gender risk for males age 1-12 risk for females age18-40 Similar risk in males & females Length of the QTc interval (>0.50s) Hx of recent syncope (past 2 years) LQT1 & 2 - LQT3

13 LQTS GENETIC RISK FACTORS

14 DENDROGRAM: Phylogenetic Evolutionary Tree of Ion Channels KCNH2 (LQT2) Kv11.1 SCN5A (LQT3) Na v 1.5 KCNQ1 (LQT1) Kv7.1 KCNJ2 (LQT7) Kir 2.1 Pharm Rev 2005

15 CHANNEL ARCHITECTURE A. Linear topology B. Tetrameric assemby C. X-ray crystallographic structure D. Resolution X-ray crystallographic structure

16 FORMATION OF ION CHANNELS Gene Functional ion channel Transcription & translation of gene by mrna into channel protein subunits Assembly of the 4 subunits protein Transport to the cell surface (trafficking) Anchoring of tetromeric channel in myocyte memb. Controlled degradation of channel protein

17 Exon Intron x DNA Mutation DNA LQT Gene Transcription into mrna x mrna (all exons) Translation into channel protein x Channel protein (amino acids) Cell Membrane Pore NH 2 COOH

18 LQTS: Genes & Encoded Proteins LQT1 (KCNQ1): encodes -subunit of I Ks potassium channel LQT2 (HERG): encodes -subunit of I Kr potassium channel LQT3 (SCN5A): encodes I Na sodium channel LQT5 (mink): encodes -subunit of I Ks LQT6 (MiRP1): encodes -subunit of I Kr

19 LQTS Protein Ion Genes Channels Currents LQT1 & LQT5 KCNQ1-minK IKs LQT2 & LQT6 HERG-MiRP1 IKr LQT3 SCN5A INa

20 Inherited LQTS-Related Disorders Genes Protein Ion Channel Comment LQT4 Ankyrin-B Mem. Adapter Ca i Late Na LQT7 KCNJ2 Kir2.1 Andersen Synd. LQT8 CACNA1C Ca v 1.2 Timothy Synd. LQT9 CAV3 Caveolin-3 Late Na LQT10 SCN4B NavB4 Late Na LQT11 α-1 Syntro- Na1.5 Late Na phin

21 Genotype-Phenotype Studies in LQT1, LQT2, & LQT3 Three LQTS Registries: Rochester, Netherlands, and Japan Many subjects with many different mutations Evaluated clinical course by location and functional effect of the mutation

22 LQT1

23 # Subjects N-terminus: 2 Transmembrane: 452 C-terminus: 127 Intron: 19 (not shown) LQT1: Distribution KCNQ1 of Potassium 75 Exon Mutations Channel in Mutations the (600 KCNQ1 subjects Channel with 77 different mutations in 101-proband identified families) Extracellular S1 S2 S3 S4 S5 S6 Membrane Intracytoplasmic Loops Intracellular N Intracellular <15 subjects subjects >30 subjects C Moss, et al. Circulation 2007

24 LQT1: Risk of Cardiac Event by Mutation Location (risk independent of QTc) Hazard Ratios TM:C-term HR = 2.06, P< blocker HR = 0.26, P<0.001 Transmembrane including intracytoplasmic loops Moss A, et al. Circulation 2007

25 Intracytoplasmic Loops (IC-loops) in LQT1 1. Exercise is the main trigger for events in LQT1 2. During exercise, I Ks is activated by - adrenergic stimulation via direct protein kinase A (PKA) phosphorylation 3. Hypothesis: pts with IC-loop mutations may be at increased risk for adrenergic-mediated cardiac events d/t I Ks activation Lopes C, Barsheshet A, et al 2010

26 KCNQ1: Risk Associated with Missense Mutations in the Intracytoplamic Loops Hazard Ratios IC-loops:C/N term HR = 3.27, P< blocker HR = 0.12, P<0.01 Lopes C, Barsheshet A, et al 2010

27 LQT2

28 LQT2: KCNH2 Potassium Channel Mutations (860 patients with 162 different mutations) Pre-pore S5-loop-S6 Extracellular S1 S2 S3 S4 S5 S6 Membrane #657 #398 Intracellular N # Mutations N-terminus: 46 S1-S4: 14 S5-loop-S6: 52 C-terminus: 50 C Shimizu, et al. JACC 2009

29 LQT2: Risk of Cardiac Event by Mutation Location S5-loop-S6 Hazard Ratios S5-loop-S6:C-term HR = 1.56, P= blocker HR = 0.37, P<0.001 Shimizu W, et al JACC 2009

30 LQT3

31 LQT3: Probability of Cardiac Event by Gender

32 LQT3: SCN5a Sodium Channel Mutations (407 patients with 53 different mutations) Single Functional Defect: late Na+ current or window Na+ current Double Functional Defect: late Na+ current and window Na+ current Preliminary findings: Wilde A, et al. International LQT3 Research Group.

33 LQT3: Risk of Cardiac Event by Transmembrane vs. C-term Mutation Location in SCN5a

34 LQT3: Risk of ACA/SCD by Single vs. Double Functional Defect in SCN5a Hazard Ratio Double : Single HR = 2.48, P=0.001 HR -blocker = 0.27, P=0.01 Preliminary findings: Wilde A, et al. International LQT3 Research Group.

35 Efficacy of Beta-blocker Therapy for Preventing Cardiac Events in LQTS Genotype -B Hazard Ratio P-value LQT1 (n=600) ~0.2 <0.001 LQT2 (n=860) ~0.4 <0.001 LQT3 (n=407) ~

36 LQTS ICD THERAPY

37 LQTS: CASE REPORT 12 y/om with known LQTS Hx recurrent syncope Rx effectively with beta-blockers for several years Aborted cardiac arrest June 1998 ICD implanted after ACA Episode on first day of school Sept. 1998

38 Moss & Daubert. NEJM 2000

39 LQTS P = 0.07 No ICD (n=161) ICD (n=73) Zareba, et al. JCE 2003

40 ACC/AHA/ESC GUIDELINES: LQTS THERAPEUTIC RECOMMENDATIONS Class I (good evidence and agreement) 1. Life style modifications 2. Beta-blockers in those with clinical Dx 3. BB + ICD in those with aborted cardiac arrest Class IIa (weight of evidence favors Rx) 1. BB in those with genetic Dx and normal QT 2. ICD in those with recurrent syncope on BB Class IIb (weight of evidence less well established) 1. LCTSG in those with recurrent syncope on BB 2. ICD in asymptomatic high-risk patients (QTc>0.53s) JACC 2006

41 CONCLUSION In LQTS, the risk for life-threatening cardiac events is multifactorial and is influenced by: - QTc duration - patient age and gender - syncope in past 2 years - mutation location in the ion channel - severity in the functional defect of the ion-channel mutation - double hits - adrenergic activation - -blocker Rx

42 Co-investigators Heart Research FU Program Mark Andrews Alex Joy Scott McNitt Jennifer Robinson & LQTS group Cardiology Fellows Medical Students Visiting Cardiology Fellows Rochester Biostatisticians Jack Hall David Oakes Derick Peterson US, Europe, Japan U.S: Michael Ackerman, James Daubert, Ilan Goldenberg, Mark Haigney, Craig January, Betsy Kaufman, Minq Qi, David Tester, Jeff Towbin, Michael Vincent, Wojciech Zareba Europe: Jesaia Benhorin, Christian Jons, Jorgen Kanters, Emanuela Locati, Carlo Napolitano, Pyotr Platonov, Silvia Priori, Peter Schwartz, PE Bloch Thomsen, Arthur Wilde Japan: Wataru Shimizu

43 THANK YOU

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45 LQTS and QTc <0.44s QTc <0.44s make up 12% of genotype positive LQTS patients These are the so-called genotype positive, phenotype negative patients ACA or LQTS-related SCD is 5% in 40 years in this low-risk group Goldenberg I, et al.

46 Risk Categorization in Genotype Positive, Phenotype Negative (QTc <0.44s) LQT1 & 2 Patients Gating Region Pre-pore S4 Pore S5 and S6 Non-gating Region C-terminus N-terminus S1-S3

47 Probability of Life-Threatening Events by Mutation Location in Gen+/Phen- Patients Hazard ratio = 5.96* P<0.005 Gating Region Non-gating Region * After adjustment for relevant risk variables including QTc & genotype.

48 23 y/o M with Known LQT1 Mutation (S349W) QTc=0.44s Abrupt onset PVT or TdP without a preceding sudden sinus rate acceleration or an extrasystolic pause.

49 INHERITED FORMS OF NON- CARDIAC CHANNELOPATHIES 1. Cystic fibrosis mutation in the CFTR; F (Francis. Collins, Lap-Chee Tsui & Jack. Riordan) 2. Autosomal dominant epilepsy - mutations in neuronal α- and -subunits of the SCN1A gene 3. Hyperkalemic periodic paralysis mutations in SCN4A, the Na + channel in skeletal muscle 4. Late-onset hereditary deafness (autosomal recessive)? mutations involving a K + channel gene 6. Malignant hyperthermia mutations in RyR1 or CACNA1S genes

50 Risk of Cardiac Events in LQT1 Patients with Missense Mutations Parameter Hazard P-value Ratio QTc>500ms 2.25 <0.001 Males < age <0.001 Beta-blocker Rx 0.21 <0.001 Adjusted Shannon Entropy Score (ASE): 1 st tertile as reference 2 nd tertile _3 rd tertile 3.22 <0.001_

51 Frequency and Location of KCNQ1 Mutations

52 KCNQ1 Ion-channel Currents Before and After PKA Activator Forskolin in WT and LQT1 Mutants Non-loop Mutations Loop Mutations G168R and R225L: transmembrane non-loop mutations R243C and V254M: intracytoplasmic loop mutations Lopes C, 2010

53 Additional Genotype- Phenotype Studies in LQT1 Hypothesis: mutations in more-conserved amino-acid residues have greater virulence than those in less-conserved amino-acid residues. Jons C, et al. JCE 2009

54 KCNQ1 Conservation of Amino-acid Residues 1.Align the amino acids in 38 Kv voltage-dependent channels 2. Calculate the conservation score for each amino acid residue (adjusted Shannon entropy score: 0-1.0) 3. For each missense KCNQ1 mutation, determine its adjusted Shannon entropy conservation score

55 Example of Amino-acid Alignment in Kv Channels in Residues Amino-acid residue # Kv Adjusted Shannon Entropy KCNQ1 Mutations KCNQ A302V W305C 38 aligned human Kv channel amino acids Conservation Score A alanine; C cysteine; D aspartic acid; E glutamic acid; F phenylalanine; G glycine; I isoluceine; K lysine; M methionine; P proline; S serine; T threonine; V valine; W tryptophan; Y tyrosine Jons C, et al. JCE 2009

56 Jons C, et al. JCE 2009 Probability of Cardiac Event by Tertile Grade of the Adjusted Shannon Entropy (ASE) Conservation Score (>0.67) ( ) (<0.34) Hazard Ratios 3 rd : 1 st tertile HR=3.22, P< blockers HR=0.21, P<0.001

57 SCN5A Channel ( KPQ deletion)

58