Hereditary Conditions Predisposing to Sudden Death

Transcription

1 Hereditary Conditions Predisposing to Sudden Death Barry London, MD PhD University of Pittsburgh Medical Center Pittsburgh, PA SCAA/HRS/UPMC Symposium Managing the Patient at Risk for Sudden Death 10/08/10 Nothing to Disclose

2 15 Year Old with Syncope

3 Baseline Holter Tracing

4 Nightmare at 3:30 AM

5 Cardiac Arrhythmias Major cause of morbidity and mortality At least 250,000 sudden deaths per year in US Treatment is inadequate Most are associated with structural heart disease (MI, CHF) A lot is known about rare syndromes simple inheritance (long QT & Brugada syndromes)

6 Inherited Arrhythmopathies Long QT Syndrome Short QT Syndrome Brugada Syndrome Familial Atrial Fibrillation Progressive Conduction Defects (Lev, Lenegre) Catecholaminergic Polymorphic VT WPW

7 Inherited Cardiomyopathies with Arrhythmias Dilated Cardiomyopathy Hypertrophic Cardiomyopathy Arrhythmogenic Right Ventricular Dysplasia LV Noncompaction Restrictive Cardiomyopathies

8 Why Study Rare Inherited Arrhythmia Syndromes? Gene & mutation based diagnosis, prognosis, and treatment for the few Hope that the lessons learned about mechanisms that predispose to arrhythmias can be extrapolated to the many

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12 Modified from Bers

13 Long QT Syndrome Loci/Genes Locus Protein Gene Current Chromosome LQT1 KvLQT1 KCNQ1 I Ks 11p15.5 LQT2 HERG KCNH2 I Kr 7q35-36 LQT3 Na v 1.5 SCN5A I Na 3p21 LQT4 Ankyrin-B ANK2 I Na? 4q25-27 LQT5 KCNE1 KCNE1 I Ks 21q21-22 LQT6 MiRP1 KCNE2 I Kr? 21q21-22 LQT7 Kir2.1 KCNJ2 I K1 17q23 LQT8 Ca v 1.2 CACNA1C I Ca 12p13.3 LQT9 Caveolin3 CAV3 I Na? 3p25.3 LQT10 Na v β4 SCN4B I Na 11q23.3 LQT11 Yotiao AKAP9 I Ks 7q21-22 LQT12 Syntrophin SNTA1 I Na? 20q11.2

14 Long QT Syndrome: Mechanism of Ion Channel Mutations Fewer functional K + channels Mutations that alter RNA or protein expression Mutations that alter channel trafficking to membrane Abnormal channels Nonfunctional K + channels Dysfunctional K + channels: Abnormal kinetics Dysfunction Na + channels: Persistent late current Dominant negative K + channel subunits

15 Arrhythmic Mechanisms - Initiation Triggered Activity: long APD EADs Early Afterdepolarizations Action potential prolongation leading to reactivation of inward Ca 2+ currents Triggered Activity: long APD DADs Delayed Afterdepolarizations Abnormal release of Ca 2+ from the SR triggers inward current via Na-Ca exchanger EAD: mdconsult.com DAD: mdconsult.com

16 Arrhythmic Mechanisms Maintenance (Reentrant Substrate) Slow conduction Abnormal Na + currents Abnormal intercellular connections Anatomical barriers block Scar, fibrosis Functional barriers block Dispersion of repolarization and refractoriness Heterogeneities: Apex/base, endocardium/epicardium, Purkinje fibers

17 Long QT Syndrome: Types Autosomal dominant: Romano Ward Heterozygous mutations of all LQT genes Autosomal recessive: Jervell-Lange-Nielsen Homozygous KCNQ1 or KCNE1 mutations Very long QTc, severe arrhythmias, congenital deafness Acquired: Drug Induced Binding to the pore of HERG

18 Long QT Syndrome: Symptoms Syncope Sudden Death Unexplained seizures SIDS

19 Long QT Syndrome: Diagnosis QTc prolongation, Torsade, T-Wave alternans, T-Wave abnormalities, Low heart rate, Syncope, Deafness, Family history Genotype-Phenotype correlations Molecular Diagnosis: Familion, GeneDx

20 Long QT Syndrome: Treatment Avoid acquired long QT drugs Beta Blockers Implanted Cardioverter-Defibrillator

21 Inherited Arrhythmopathies: ICD Guidelines in Long QT Syndrome High risk features for sudden death Aborted SCD Recurrent symptoms (syncope, VT) on β-blockade Jervell & Lange-Nielsen, Very long QTc?Gender,?age,?FHx SCD (Goldenberg and Moss, JACC 2008;51:2291)

22 LQTS: Genotype-Phenotype Arrhythmia by genotype: LQT1: Exercise LQT2: Noise LQT3: Rest (Schwartz et al., J Intern Med 2006; 259: 39) More malignant mutations Dominant negative and pore K + channel mutations Gene-specific therapies LQT1, LQT2: β-blockade; LQT2: K + + Aldactone; LQT3: Mexilitine Relevance for ICD placement?

23 Long QT Syndrome: A Disorder of Repolarization A limited number of dysfunctional K + channel cause disease Na + channels with impaired inactivation have a similar clinical phenotype Genotype-phenotype correlations exist, and may lead to gene-based treatments Catalyzed a huge amount of work on cardiac ion channels

24 Short QT Syndrome Also associated with syncope, sudden death Decreased APD and QT interval (<300 msec) K + channel mutations that increase current

25 Short QT Syndrome Loci/Genes Locus Protein Gene Current Chromosome SQT1 HERG KCNH2 I Kr 7q35-36 SQT2 KvLQT1 KCNQ1 I Ks 11p15.5 SQT3 Kir2.1 KCNJ2 I K1 17q23

26 Brugada Syndrome: 45 year old with syncope

27 T353I Mutation in Conserved Region of SCN5A

28 Mutant Channels Have Decreased Peak I Na and Increased Late I Na (Pfahnl et al., Heart Rhythm 2007; 4: 46-53)

29 T353I Trafficking Defect Rescued by Mexiletine T353I + Mexiletine (Pfahnl et al., Heart Rhythm 2007; 4: 46-53)

30 T353I Brugada Syndrome Mutation Causes decreased peak Na + current due to trafficking defect Causes late Na + current but no QT prolongation due to trafficking defect

31 Brugada Syndrome Loci/Genes Locus Protein Gene Current Chromosome BRUG1 Na v 1.5 SCN5A I Na 3p21 BRUG2 GPD1-L GPD1L I Na 3p24 BRUG3 Ca v 1.2 CACNA1C I Ca 12p13.3 BRUG4 Ca v β2 CACNB2B I Ca 10p12 BRUG5 MiRP2 KCNE3 I to 11q13.4 BRUG6 Na v β1 SCN1B I Na 19q13

32 EKG of Proband with Syncope

33 Polymorphic VT from Stored Electrogram of ICD

34 FN Pedigree

35 Clinical Characteristics: Affected AGE* GENDER SYMPTOMS EKGS ECHO MRI PROC (Affected) (Infiltrate) 75 M No 6/6 (100%) 2+ MR None Positive 73 M Syncope 9/9 (100%) 1+ MR ND Positive 72 M Near Syncope 2/5 (40%) 2+ MR None Positive 65 F No 2/2 (100%) ND ND ND 62 M Near Syncope 2/4 (50%) ND None ND 60 M No 2/5 (40%) 3+ MR None Negative 58 M No 2/5 (40%) Trace MR None Positive 56 M Syncope 7/7 (100%) Normal Fatty Variable 43 M No 1/2 (50%) ND ND ND 29 M No 1/1 (100%) ND ND ND 31 M Syncope 5/5 (100%) ND None ND 29 M No 3/3 (100%) Normal None ND 22 M Syncope 1/6 (17%) Trace MR None Negative

36 Two-Point LOD Scores at 3p22-24 Loc θ = D3S D3S D3S D3S D3S D3S D3S D3S D3S D3S SCN5A D3S

37 GPD1-L (KIAA0089) 3954 bp, 351 amino acid, 8 exons No known function Homologous (84%) to glycerol-3-phosphate dehydrogenase (GPD) GPD may play a role in energy production, osmoregulation, tumor growth, apoptosis Predicted NAD binding and membrane binding domains N terminus

38 GPD1-L (KIAA0089) C/T base pair change - Exon 6 A280V, Hyp188I restriction site (TCNGA) Links to phenotype, LOD score > 4 Not present in 200 controls of mixed race Conserved amino acid in gene family *

39 GPD1-L Mutant Decreases Na + Currents Na Current in HEK Cells Current-Voltage Curves The GPD1-L mutant leads to a 60% decrease in Na current

40 Membrane Localization of SCN5A A WT GPD1-L A280V GPD1-L % SCN5A membrane expression n = 16 each p =.01 GPD1L-w t GPD1L-m ut

41 Brugada Syndrome: Characteristics Characterized by a right bundle branch block pattern (RBBBp) and ST elevation in the right precordial leads (STE) of the EKG which can vary from day to day (Brugada & Brugada, 1992) Autosomal dominant, male predominance No structural heart disease Rare, but more common in Southeast Asia (Bangungut, Pokkuri, Lai Tai, SUDS).

42 Brugada Syndrome: Symptoms Syncope Sudden Death Unexplained seizures SIDS

43 Brugada Syndrome: Arrhythmia Mechanisms Truncated Epicardial APs Phase 2 Reentry

44 Brugada Syndrome Diagnosis Syncope, aborted SCD, Family history Typical ECG pattern (coved vs. saddleback) Na + channel blockers (e.g. ajmaline, flecainide, procainamide) exacerbate the ECG findings and are used diagnostically (Brugada et al., 2000) EP study: HV prolongation, inducible VF Molecular diagnosis: Familion, GeneDx

45 Brugada Syndrome Treatment ICD?Quinidine

46 Brugada Syndrome: A Disorder of Depolarization Reduced depolarizing current in the epicardial cells of the RV (Antzelevitch, 1998) The repolarizing current I to leads to: loss of the action potential plateau premature repolarization of the epicardium transmural current flow with STE reentrant arrhythmias

47 Catecholaminergic Polymorphic VT Gene Pathophys Chromosome Reference RyR2 Abnormal SR 1q42 Priori et al., 2001 Ca 2+ Release Laitinen et al., 2001 CASQ2 Abnormal SR 1p de Barletta et al., 2006 Ca 2+ Release Knollman et al., 2006

48 CPVT: Characteristics Exercise or adrenergic-induced arrhythmias Bidirectional VT

49 CPVT: Symptoms Syncope Sudden Death Unexplained seizures SIDS

50 Exercise Test CPVT: Diagnosis Isoproterenol infusion

51 CPVT: Treatment Beta blockers Calcium channel blockers ICD Flecainide (Watanabe et al., Nat Med 2009; 15:380-3)

52 Progressive Cardiac Conduction Defect Loci (Lenegre-Lev) Gene Pathophys Chromosome Reference?? 19q13.3 Brink et al., 1995 de Meeus et al., 1995 SCN5A I Na 3p21 Schott et al., 1999

53 Familial Atrial Fibrillation Locus Gene Pathophys Chromosome Reference?? 10q22-24 Brugada et al., 1997?? 6q14-16 Ellinor et al., 2003?? 4q25 Gudbjartsson et al, 2007 KvLQT1 Atrial I Ks 11p15.5 Xu et al., 2003 HERG Atrial I Kr 7q35-36 Hong et al., 2005 Cx40 Atrial Coupling 1q21 Gollob et al., 2006

54 Familial Wolff-Parkinson-White Gene Pathophys Chromosome Reference PRKAG2 Storage Disease 10q22-24 Gollob et al., 2001

55 ARVD Loci Locus Gene Pathophys Chromosome ARVD1 TGF β3? 14q24 ARVD2 RyR SR Ca 2+ Release 1q42 ARVD3?? 14q12-22 ARVD4?? 2q32 ARVD5?? 3p23 ARVD6?? 10p12-14 ARVD7?? 10q22.3 ARVD8?? 6p24 Naxos Dis Plakoglobin Desmosome 17q21 (Autosomal Recessive, Woolly Hair, Palmoplantar Keratoderma)

56 Arrhythmogenic Right Ventricular Dysplasia Replacement of right ventricular myocardium by fibrous and fatty tissue (pathology, MRI) with RV dilitation and failure (Thiene et al., 1988) Long QRS, ε waves in right precordial EKG leads Disease of the desmosome: Desmoplakin (Rampozzo et al., 2002) Plakophilin-2 (Gerull et al., 2004) Desmoglein-2 (Pilichou et al., 2006) Desmocollin-2 (Syrris et al., 2006)

57 Hypertrophic Cardiomyopathy Genes (Keren A et al., 2008; Nat Clin Pract Cardiovasc Med doi: /ncpcardio1110)

58 Hypertrophic Cardiomyopathy: Symptoms Shortness of Breath Chest Pain Syncope Sudden Death Unexplained seizures SIDS

59 Hypertrophic Cardiomyopathy: Diagnosis Physical exam - murmur Echocardiogram, MRI, Cardiac Cath Pathology - biopsy Outflow tract obstruction? Molecular Diagnosis

60 Hypertrophic Cardiomyopathy: Treatment Beta Blockers, Calcium Channel Blockers HOCM: Surgery ICDs Aborted SCD High Risk: 3 Risk Factors (FHx SCD, Syncope, NSVT, Blunted BP response w exercise, Severe LVH) Risk Factors Proportion of Patients Sudden Deaths/Year 0 50% 0.8% ( ) 1 25% 1.2% ( ) 2 20% 3% ( ) 3 5% 6% (4-16) (Elliot et al., JACC 2000;36:2212)

61 HCM: Genotype-Phenotype 1.00 MyBP-C InsG791 β-mhc Troponin T MyBP-C SURVIVAL α Tropomyosin Asp175Asn β Myosin Val606Met MyBP-C Glu451Gln β Myosin Arg403Gln TroponinT Arg92Gln % Penetrance AGE (yrs) Age(years) Relevance for ICD placement (mutation vs. family?)

62 Inherited Sudden Cardiac Death: Diagnosis History (syncope, palpitations, aborted SCD): All Family History (Sudden death, pacers, CHF) EKG: Long QT, Short QT, Brugada, ARVD Echo/MRI: Hypertrophic CM, Dilated CM, ARVD Stress Test: Catecholinergic VT, Long QT Drug Test: Brugada EP Test (Programmed Stimulation):?Brugada

63 Inherited Sudden Cardiac Death: Treatment None Avoid medications that exacerbate Avoid competitive sports Pharmacological ICD VAD, Heart Transplant

64 Inherited Sudden Cardiac Death: Medicare Coverage of ICDs Documented familial or inherited conditions with a high risk of life-threatening VT, such as long QT syndrome or hypertrophic cardiomyopathy (04/01/05)

65 Inherited Sudden Cardiac Death: Clinical Screening? Relatives of patients? Pediatric ECGs for LQTS? School-age athletes for HCM, LQTS?

66 Inherited Sudden Cardiac Death: Genetic Testing? LQTS(~60%), Brugada (~30%), CPVT (?), ARVD (~50%), HCM (>60%), DCM (<20%) Pros: Avoid drugs and exercise Peace of mind if negative with known gene Genotype-phenotype correlations Cons: Negative test is not useful if gene is unknown Treatment of asymptomatic individuals unknown Damage careers, insurability Conclusions may be wrong

67 Genetic Testing NIH Supported Website: Clinical Genetic Testing Laboratories in US Familion / PGxHealth GeneDx Correlagen Diagnostics John Welsh Cardiovascular Diagnostic Lab (Baylor) e=genetic_testing Partners HealthCare Center for Personalized Genetic Medicine (PCPGM, Harvard) MM&subname=genetictests

68 Inherited Cardiomyopathies Structural Electrical HCM IDCM DCM & Conduction ARVD Lev Lenegre LQT Brugada Sarcomeric Proteins?? Desmosomal??? Ion Channels??

69 Acknowledgements Michael Michalec BS Haider Mehdi PhD Rebecca Gutmann RN BSN Laurie Kerchner BS Kathy Nilles BS Emory University Samuel C. Dudley MD PhD Shamarendra Sanyal MD PhD Arnold E. Pfahnl MD PhD Lijuan L. Shang PhD University of Pittsburgh M. Michael Barmada PhD Prakash Viswanathan PhD Ryan Aleong MD Dennis McNamara MD Stephen Lagana BS The Ohio State University Raul Weiss MD The Mayo Clinic Michael Ackerman MD PhD