Genetics of Sudden Cardiac Death. Geoffrey Pitt Ion Channel Research Unit Duke University. Disclosures: Grant funding from Medtronic.

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1 Genetics of Sudden Cardiac Death Geoffrey Pitt Ion Channel Research Unit Duke University Disclosures: Grant funding from Medtronic Duke U N I V E R S I T Y

2 Sudden Cardiac Death High incidence per in Europe and US to deaths annually in US More deaths in US than stroke, lung cancer, breast cancer, and HIV AIDS combined Poor survival Overall survival rate 4.6% Often presents without warning or recognized trigger Mean age is in the mid 60s Prediction and Prevention Remain a Challenge

3 SCD prevention and prediction challenges Limited information about specific triggers 30-40% events are unwitnessed; 95% of victims do not survive Unheralded by symptoms in 40-50% Prog Cardiovasc Dis. 2008; 51:213 80% with high-grade CAD at autopsy, but <5% with known prior CAD

4 SCD prevention and prediction challenges Non-CAD SCD Inherited rhythm abnormalities, acquired rhythm abnormalities, arrhythmogenic disorders, congenital heart disease, other causes All are substrates for SCD, but SCD only occurs in a minority of subjects Adapted from N Engl J Med 2001;345:1473

5 Types of non-cad sudden cardiac death Syndromic Inherited arrhythmias (e.g., congenital Long QT Syndrome or Brugada Syndromes) (Arrhythmogenic right ventricular dysplasia) Non-syndromic Population-based QTc changes and risk of SCD Acquired (Drug-induced Long QT Syndrome) and heart failure Arrhythmia = Mutation affecting an ion channel

6 Ion channels: the basis of the ECG Adapted from Gussak and Antzelevitch (Eds), Electrical Diseases of the Heart

7 Combined actions of multiple ion channels generate the cardiac action potential Gene Inward DEpolarizing Currents Outward REpolarizing Currents

8 Syndromic conditions Long QT Syndrome Brugada Syndrome Catecholaminergic Polymorphic Ventricular Tachycardia Short QT Syndrome Arrhythmogenic right ventricular dysplasia Arrhythmia = Mutation affecting an ion channel

9 Long QT Syndrome

10 Long QT Syndrome is a channelopathy LOD score = 26

11 Long QT Syndrome is a channelopathy Type Mutation % LQT1 alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 or KCNQ1) LQT2 alpha subunit of the rapid delayed rectifier potassium channel (HERG + MiRP1) LQT3 alpha subunit of the sodium channel (SCN5A) 5-10 LQT4 channel anchor protein Ankyrin B <1 LQT5 beta subunit MinK (or KCNE1) which coassembles with KvLQT1 ~1 LQT6 beta subunit MiRP1 (or KCNE2) which coassembles with HERG <1 LQT7 potassium channel KCNJ2 (or Kir2.1) <1 LQT8 alpha subunit of the calcium channel Cav1.2 encoded by the gene CACNA1c <1 LQT9 channel organizing protein caveolin 3 ~1 LQT10 beta subunit SCN4B which coassembles with Nav1.5 (SCN5A) <1 LQT11 channel anchor protein AKAP9 ~1 LQT12 sodium channel regulator SNTA1 ~1 LQT13 alpha subunit of the G protein-activated potassium channel 4 (GIRK4) <1

12 Long QT Syndrome: channel dysfunction LQT3 Inward DEpolarizing Currents LQT2 LQT1 Outward REpolarizing Currents

13 Long QT Syndrome: channel dysfunction LQT3 Inward DEpolarizing Currents LQT2 LQT1 Outward REpolarizing Currents

14 Evolution of LQTS diagnosis Spectrum of reported mutations KCNQ1 LQT1 SCN5A LQT3 36% yield overall 75% yield among high probability patients HERG LQT2 missense mutations non-missense mutations Heart Rhythm 2009;6:1297

15 Not all variants are mutations KCNQ1 LQT1 SCN5A LQT3 6% of normal patients have mutations HERG LQT2 cases rare variants in controls polymorphisms Circulation. 2009;120:1752

16 Genetic testing especially useful to identify at-risk family members 10-fold increased risk JACC 57, 51, 2011

17 Brugada Syndrome: channel dysfunction SCN5A mutations account for < 30% of BrS

18 Brugada Syndrome: channel regulator dysfunction Glycerol-3-phosphate dehydrogenase 1 like LOD score > 4 Circulation 116: 2260, 2007

19 New Brugada Syndrome loci? LOD scores are low 6% of normal patients have mutations

20 Non-syndromic conditions Family history of non-cad SCD Inheritability of QT interval Abnormal ECG = Ion channel mutation

21 Familial risk of SCD in men The Paris Prospective Study I Events in Subjects SCD [n=118] Fatal MI [n=192] Controls [n=6,762] p Parental History of SCD 22 [18.6%] 19 [9.9%] 716 [10.6%] 0.02 Relative Risk 1 affected parent 1.95 [p=.005] 0.97 [p=ns] Relative Risk 2 affected Parents 9.44 [p=.01] Circulation. 1999;99:1978

22 Many common variants affect QT interval Ion Channels KCNQ1, KCNH2, KCNE1, KCNJ2, SCN5A, SCN10A NOS1AP Ion Channel Regulators NOS1AP, ATP1B1, CASQ2, PLN Others Transcription factors, kinases, and others Nat Genetics 41,399 (2009) Nat Genetics 41,407 (2009) Nat Genetics 42,1068 (2010)

23 Many common variants affect QT interval Ion Channels KCNQ1, KCNH2, KCNE1, KCNJ2, SCN5A, SCN10A NOS1AP Ion Channel Regulators NOS1AP, ATP1B1, CASQ2, PLN Others Transcription factors, kinases, and others Nat Genetics 41,399 (2009) Nat Genetics 41,407 (2009) Nat Genetics 42,1068 (2010) NOS1AP NOS1AP-1 Hz PNAS , 2008 Loss of Function

24 Abnormal ECG = Mutation affecting an ion channel

25 Early repolarization and SCD

26 Acquired conditions Drug-induced LQTS Heart failure Multi-hit hypothesis

27 % patients with c LQTS locus mutation Drug induced LQTS: an acquired condition with genetic susceptibility QT prolonging drug Circ Arrhythmia Electrophysiol. 2009;2:511

28 Elevated risk of SCD in heart failure MADIT II SCD-HEFT N Engl J Med 2002; 346:877 N Engl J Med 2005; 352:225

29 Prolonged QTc in heart failure associated with decreased survival and sudden death DIAMOND study of Dofetilide in heart failure Circulation 2003;107:1764

30 Not all patients with heart failure have a prolonged QTc: an acquired condition? European Heart Journal (1986) 7, 14

31 Heart failure, like drug-induced LQTS: A multi-hit hypothesis? Circ. Res. 2004;95;754

32

33 SCN5A S1103Y allele is associated with SCD from multiple triggers

34 Duke EPGEN case-control study Is SCN5A S1103Y associated with appropriate ICD therapy? Ischemic or non-ischemic cardiomyopathy, EF < 35% 112 Primary Prevention ICDs Shock and/or Anti-tachycardia pacing Appropriate ICD Rx None / Inappropriate ICD Rx Allele Status at 1103 Allele Status at 1103 Sun et al., Circ: Genetics, in press

35 Baseline Characteristics Stratified by ICD Therapy Entire Cohort (n=112) Appropriate ICD Therapy (n=23) No Appropriate ICD Therapy (n=89) Characteristic Age, Mean (SD), y 63 (12) 64 (9) 63 (13) Male, No. (%) 74 (66) 18 (78) 56 (63) Medical History Non-Ischemic Cardiomyopathy, No. (%) + 60 (54) 17 (74) 43 (48) Diabetes, No. (%) 57 (51) 11 (46) 46 (52) Tobacco Use, No. (%) 59 (53) 12 (52) 47 (53) Hypertension, No. (%) 101 (90) 22 (96) 79 (89) Hyperlipidemia, No. (%) 81 (72) 18 (78) 63 (71) Atrial Fibrillation, No. (%) 51 (46) 9 (39) 42 (47) NYHA Class, Mean (SD) 2.4 (0.6) 2.3 (0.7) 2.4 (0.6) Ejection Fraction, Mean (SD), % 25 (6) 24 (7) 25 (6) QTc, Mean (SD), ms 464 (41) 463 (45) 465 (40) Serum K + at Enrollment, Mean (SD), mmol/l 4.2 (0.5) 4.1 (0.4) 4.2 (0.5) QT Interval corrected using Bazett s Formula (QTc=QT/ RR) + P=0.03 Sun et al., Circ: Genetics, in press

36 S1103Y SNP predicts ICD therapy in African Americans with Reduced LVEF Adjusted Hazard Ratio= 4.33 (95% CI , p=<0.01) Sun et al., Circ: Genetics, in press

37 S1103Y SNP predicts ICD therapy in African Americans with Reduced LVEF Adjusted Hazard Ratio= 4.33 (95% CI , p=<0.01) Transient Hypokalemia? Sun et al., Circ: Genetics, in press

38 S524Y SNP does not alter channel function: NOT predictive of ICD therapy P = NS Albert Sun, Patrick Hranitzky

39 Rates of Sudden Death According to EF VALIANT N Engl J Med 2005;352:2581

40 Will S1103Y be prognostic fro ICD therapy in African Americans with LVEF >35%? High EF 35% Low EF Incidence of SCD Number of SCD Events

41 SUMMARY Syndromic conditions Many discovered mutations; not all are pathogenic: effect upon channel function should be validated Several disease gene loci (channel modulators) not yet discovered Non-syndromic/Acquired conditions Manifestations of a genetic predisposition Proof of principle: arrhythmias in heart failure may have a genetic basis Future biomarkers? What are methods for discovery of new loci/biomarkers and subsequent validation?

42 Fibroblast Growth Factor Homologous Factors (FHFs) FGF11-14 Not secreted Do not bind FGF-Rs Bind to Na + channels Modulate Na + channel function Regulate neuronal excitability FGF14: locus for spinocerebellar ataxia 27 (SCA27) FGF14 -/- mice are ataxic FHFs Function of FHFs in heart - unexplored

43 FGF13 knockdown affects Na + currents Chuan Wang, Jessica Hennessey

44 FGF13: a cardiac Na + channel modulator Increases Na + channel availability Accelerates conduction velocity Candidate for an arrhythmogenic locus Loss of function mutations: BrS Molecular, cellular, and animal models useful for analyses of new candidate loci

45 Acknowledgements Pitt Lab Jessica Hennessey Albert Sun Chaojian Wang Chuan Wang Collaborators Robert Kirkton Nenad Bursac Pat Hranitzky Medtronic-Duke Strategic Alliance