The Role of Defibrillator Therapy in Genetic Arrhythmia Syndromes

Transcription

1

2 The Role of Defibrillator Therapy in Genetic Arrhythmia Syndromes RHEA C. PIMENTEL, MD, FACC, FHRS UNIVERSITY OF KANSAS HOSPITAL MID AMERICA CARDIOLOGY AUGUST 19, 2012

3 Monogenic Arrhythmia Syndromes Mendelian genetics pattern Single gene mutation causes disease phenotype Cause alterations in cardiac morphology (Hypertrophic Cardiomyopathy, Arrhythmogenic RV Dysplasia) Or: Structurally normal hearts Variabilities in Genotype and Phenotype Genotype: Specific DNA alteration causing problem Phenotype: Clinical presentation No randomized trials of therapy available Registries often biased to sicker/symptomatic patients

4 Doyle MacKinnon. Science 280:69-77, 1998 FAF SIDS SUDS SSS TS DI-TdP DCM CPVT SQTS Cardiac Channelopathies LQTS - RWS - JLNS FAVCB ATS IVF BrS

5 Primary Ion Channels in the Heart Mutations in ion channel genes result in disturbances to normal heart rhythm.

6 The Challenges of Diagnosing an Inherited Cardiac Arrhythmia Syndrome Variable Clinical Expression Penetrance The extent to which individuals with the same genotype display the same phenotype Age of onset Triggers Variable Expressivity Phenotype variations with same /similar mutations Brugada syndrome vs. conduction disease in same/similar SCN5A mutations

7 Reduced Penetrance Reduced Penetrance 90% of those with mutation will have HCM 83% of those with mutation will have CPVT ~50% of those with mutation will have LQTS 37% LQTS1, 54% LQTS2, 82%LQTS3 30% of those with mutation will have clinical Brugada Syndrome

8 Current Risk Stratification Schemes Clinical Symptoms: syncope, palpitations Family history: first degree relatives EKG abnormalities Diagnostic testing: EP study, SAECG Specific genetic mutation: genetic testing

9 ICD Therapy in Genetic Arrhythmia Syndromes Increased use of defibrillators Population specific considerations Age of patient Psychosocial aspects for patient Implications for family members True risk of ICD discharge --Risk of Inappropriate shocks

10 Efficacy of ICD Therapy in Hypertrophic Cardiomyopathy Retrospective multicenter study 128 patients received ICD to prevent sudden death Mean follow up 3.1 years VT/VF is the principle mechanism of death Rate of appropriate discharge was 7% a year 25% had episodes of inappropriate discharges ICD s highly effective at preventing sudden death in HOCM patients Maron BJ et al. NEnglJ med 10Feb 2000;342(6):

11 Risk factors for SD in HOCM Bos et al. Am J Cardiol 2010;106:

12 VA Associated With Cardiomyopathies Hypertrophic Cardiomyopathy (HCM) I IIa IIb III I IIa IIb III ICD therapy should be used for treatment in patients with HCM who have sustained VT and/or VF and who are receiving chronic optimal medical therapy and who have reasonable expectation of survival with a good functional status for more than 1 year. ICD implantation can be effective for primary prophylaxis against SCD in patients with HCM who have 1 or more major risk factor for SCD and who are receiving chronic optimal medical therapy and in patients who have reasonable expectation of survival with a good functional status for more than 1 year.

13 an exhilarating moment in human history Francis Collins June 22, 2000

14 Benefits of Genetic Testing Confirm and/or Exclude Diagnosis Predict Future Disease (Asymptomatic, Predisposition) Provide Risk Estimates: Comprehensive Treatment Plan Reproductive decisions Medical decisions Risk information for family members Prophylactic Intervention

15 Impediments to Interpretation of Genetic Testing Locus Heterogeneity Many genes Increases cost and complexity Genetic Cause Not Identified in All Cases DCM (25-33%) HCM (30-40%, greater in familial cases) LQTS (65-75%) Negative Test Limits Clinical Utility Unless a familial mutation known

16 Current HRS Recommendations

17 Effect of Cascade Screening on Prophylactic Treatment Mutations carrying relatives of proband with an inherited arrhythmia syndrome 130 probands, 509 mutation positive relatives LQTS, CPVT, and BrS Carriers treated more aggressively LQTS (65%) and CPVT (71%) started on beta blockers 59% of LQT patients had QTc <460 msec 6% BrS treated with ICD Hofman N et al. J Am Coll Cardiol 2010 Jun 8;55(23):

18 Doyle MacKinnon. Science 280:69-77, 1998 FAF SIDS SUDS SSS TS DI-TdP DCM CPVT SQTS Cardiac Channelopathies LQTS - RWS - JLNS FAVCB ATS IVF BrS

19 Congenital Long QT Syndrome QT QT Normal QT interval Prolonged QT 1. Syncope 2. Seizures 3. Sudden death Torsades de pointes

20 Schwartz Score Schwartz et al. Circulation 1993 Aug 88(2);782-4

21

22 Torsades de Pointes Spontaneous conversion to NSR (continuous lead II monitor strip)

23 Persons (no.) 3,000 33% of gene positive carriers for LQT have normal QT intervals Normals 1 LQTS QTc (ms)

24 Molecular Basis for Long QT Syndrome JCE 1999;10:

25 Congenital Long QT Syndrome QT QT Normal QT interval Prolonged QT 1. Syncope 2. Seizures 3. Sudden death Torsades de pointes Tester Ackerman. Heart Rhythm 2: , 2005

26 CAV3-LQT (LQT9) Ch 3p25 Caveolin-3 < 1% TS1 (LQT8) Ch 1q42 CACNA1C <<1% ATS1 (LQT7) Ch 17q23 KCNJ2 <1% SCN4B-LQT (LQT10) Ch 11q23.3 NaV1.5 b4 subunit < 1% LQTS Susceptibility LQT6 Ch 21q22 KCNE2 <1% Genes LQT5 Ch 21q22 KCNE1 1% LQT1 Ch 11p15.5 KCNQ % LQT2 Ch 7q35-36 KCNH % LQT3 Ch 3p21-24 SCN5A 5-10% LQT4 Ch 4q25-27 ANK2 < 1%

27 Khositseth and Ackerman. Cardiac Repolarization Chapter 20, 2003 KCNQ1 (LQT1) Genotype-Specific Triggers? 30-35% SCN5A (LQT3) KCNH2 (LQT2) 5-10%

28 Percent (%) LQT1 LQT2 LQT3 Genotype Negative Exertion N = 124 Swimming N = 71 Postpartum N = 24 Auditory N = 24

29 KCNQ1 (LQT1) Effect of Beta Blocker Therapy % SCN5A (LQT3) KCNH2 (LQT2) +/- ++ Khositseth and Ackerman. Cardiac Repolarization Chapter 20, 2003

30 LQTS Susceptibility LQT6 Ch 21q22 KCNE2 <1% Genes LQT5 Ch 21q22 KCNE1 1% LQT1 Ch 11p15.5 KCNQ % LQT2 Ch 7q35-36 KCNH % LQT3 Ch 3p21-24 SCN5A 5-10%

31 Khositseth and Ackerman. Cardiac Repolarization Chapter 20, 2003 KCNE1 (LQT5) KCNE2 (LQT6) KCNQ1 (LQT1) < 1% < 1% SCN5A (LQT3) 30-35% KCNH2 (LQT2) 5-10% 25-30%

32 Probability of Cardiac Event Circ 2000;101:

33 High Risk (> 50%) QTc > 500 LQT1, LQT2 LQT3 Intermediate (30-49%) Low Risk (<30%) QTc < 500 QTc > 500 LQT2, LQT3 LQT3 LQT3 QTc < 500 ms LQT2 LQT1 Priori SG, Schwartz PJ, et al. NEJM 348: , 2003

34 Family History Risk in LQTS Kaufman et al. Heart Rhythm 2008;5:

35 Degree of QT prolongation Kaufman ES et al. June Heart Rhythm;5(6):

36 Probability of a Cardiac Event No. of Subjects LQT1 group LQT2 group LQT3 group Zareba W et al. NEJM 1998;339:

37 LQT1-Associated Mutations Tester Ackerman. Heart Rhythm 2: , 2005

38 Probability of a Cardiac Event LQT1-Associated Mutations Unadjusted P< TRANSMEMBRANE C-TERMINUS AGE (years) Moss, Shimizu, Wilde... Circulation 115: , 2007

39 Probability of a Cardiac Event Probability of a Cardiac Event LQT1-Associated Mutations Unadjusted Unadjusted P<0.001 P<0.001 DOMINANT NEGATIVE TRANSMEMBRANE HAPLOINSUFFICIENCY C-TERMINUS AGE AGE (years) (years) Moss, Shimizu, Wilde... Circulation 115: , 2007

40 LQT1-Associated Mutations Location and Function Matters -- HR > 2 -- * Independent of Traditional Risk Factors * Tester Ackerman. Heart Rhythm 2: , 2005

41 LQT2-Associated Mutations KCNH2/HERG N = 89 C 1159 Tester Ackerman. Heart Rhythm 2: , 2005

42 LQT2: Pore Mutations Behave Porely KCNH2/HERG N = 89 C 1159 Moss et al. Circulation 105: , 2002

43 LQT3 Gain-of-Function SCN5A Loss-of-Function BrS1

44 Long QT Syndrome I IIa IIb III I IIa IIb III Beta blockers can be effective to reduce SCD in patients with a molecular LQTS analysis and normal QT interval. Implantation of an ICD with continued use of beta blockers can be effective to reduce SCD in LQTS patients with syncope and/or VT while receiving beta blockers and who have reasonable expectation of survival with a good functional status for >1 year. I I IIa IIb III IIa IIb III Left cardiac sympathetic neural denervation may be considered for LQTS patients with syncope, torsades de pointes, or cardiac arrest while receiving beta blockers. Implantation of an ICD with the use of beta blockers may be considered for prophylaxis of SCD for patients in categories possibly associated with higher risk of cardiac arrest such as LQT2 and LQT3 and who have reasonable expectation of survival with a good functional status for >1 year.

45 (Circulation. 2005; 111: )

46 Brugada Syndrome Incidence 5/10,00 More common in Southeast Asia Mean age 41 ± 15 years, male predominance 4% of all sudden death At least 20% of sudden death in structurally normal hearts Characteristic EKG pattern Coving ST segment elevation in precordial leads V1 to V3 (>2 mm) +/- RBBB pattern Spontaneous or drug induced

47 Atrial Arrhythmias and Brugada 20% develop SVT Atrial Fibrillation in 10-20% of cases Have been described in association AVNRT WPW Prolonged SNRT Prolonged SART Slowed atrial conduction Atrial standstill

48 Brugada Syndrome (Typical ST-T abnormality V1-V2)

49 V1 V2 V3 Cardiac Channelopathies BrS

50 Genetic Factors Autosomal Dominant SCN5A More than 80 mutations linked to the syndrome since dozen associated with loss of function on Na channel SCN5A mutations account for 18-30% of Brugada Syndrome cases Negative SCN5A does not rule out causal gene mutations

51 Sodium Channel Macromolecular Complex Glycerol-3-Phosphate Dehydrogenase 1-Like Gene Loss-of-Function = BrS2 Genetic Heterogeneity Na v 1.5 in BrS Ankyrin Syntrophin BrS2 Na + Ch 3p24 GPD1L % Yield?? London et al. Circulation 2007(in press)

52 LQT3 Gain-of-Function SCN5A Loss-of-Function BrS1

53 Incidence of Sudden Death Brugada et al. Aborted sudden death Recurrence 69% at 54 ± 54 months Syncope and spontaneous Type 1 pattern 19% at 26 ± 36 months 8% risk of occurrence in initially asymptomatic patients

54 Defibrillator Implantation is only known therapy for Brugada Syndrome

55 Risk Stratification in BrS Symptoms Family History? Sodium Channel Blocker Challenge Programmed Ventricular Stimulation EKG abnormalities

56 Symptoms Predicting ICD shock

57 Age and Onset of Symptoms in Brugada Syndrome Napolitano C et al.circulation.2012apr24;125(16):

58 Role of Family History in Risk of Sudden Death in BrS Sarkozy A et al. European Heart Journal (2011) 32,

59 Risk Stratification in BrS Type 1 ECG 320 patients (54% with spontaneous and 46% drug induced EKG) Spontaneous type 1 ECG and syncope significantly increased risk Delise P et al. Eur Heart J 2011 Jan;32(2):

60 PRELUDE Registry 308 patients: spontaneous or drug induced type 1 ECG and no history of cardiac arrest Programmed electrical stimulation performed 14 (4.5%) arrhythmic events occurred in 34 months Arrhythmia inducibility was not a predictor of events at follow up Syncope and spontaneous type 1 ECG were significant predictors of arrhythmias Priori SG et al. J Am Coll Cardiol Jan 3;59(1):37-45.

61 Programmed Ventricular Stimulation (PVS) in BrS: a meta-analysis 15 studies comprising 1217 patients (80% male) Divided in 3 groups: cardiac arrest, syncope and asymptomatic 1036 patients (85%) underwent PVS 548 patients (53%) inducible Highest inducibility in sudden death patients (66%) Lowest inducibility in asymptomatic patients (22%) Paul M et al. European Heart J :

62 Programmed Ventricular Stimulation (PVS) in BrS: a meta-analysis Paul M et al. European Heart J :

63 Fragmented QRS in BrS Morita et al. Circulation. 2008;118:

64 Brugada Syndrome I IIa IIb III An ICD is indicated for Brugada syndrome patients with previous cardiac arrest receiving chronic optimal medical therapy and who have reasonable expectation of survival with a good functional status for >1 year. I IIa IIb III I IIa IIb III An ICD is reasonable for Brugada syndrome patients with spontaneous ST-segment elevation in V 1, V 2, or V 3 who have had syncope with or without mutations demonstrated in the SCN5A gene and who have reasonable expectation of survival with a good functional status for >1 year. Clinical monitoring for the development of a spontaneous ST-segment elevation pattern is reasonable for the management of patients with ST-segment elevation induced only with provocative pharmacological challenge with or without symptoms.

65 Brugada Syndrome I IIa IIb III I IIa IIb III An ICD is reasonable for Brugada syndrome patients with documented VT that has not resulted in cardiac arrest and who have reasonable expectation of survival with a good functional status for >1 year. Isoproterenol can be useful to treat an electrical storm in the Brugada syndrome. I I IIa IIb III IIa IIb III EP testing may be considered for risk stratification in asymptomatic Brugada syndrome patients with spontaneous ST elevation with or without a mutation in the SCN5A gene. Quinidine might be reasonable for the treatment of electrical storm in patients with Brugada syndrome.

66 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Clinical Exertion Induced Syncope or Sudden Cardiac Death No Structural Heart Defect Phenotypically Mimics Long QT Syndrome Hallmark Arrhythmia Bi-Directional Ventricular Tachycardia Priori et al. J Clin Invest 115: , 2005

67 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Polymorphic ventricular tachycardia induced by adrenergic stress Exercise induced VT or syncope Classically a bidirectional VT Incidence 1:10,000 Mean age of presentation 7.8 years old 1 Baseline EKG normal No structural heart disease 1 Leenhardt a et al. Circulation 1995;91:

68 80% of Untreated CPVT Patients Become Symptomatic If left untreated, 30% of CPVT patients will develop symptoms by age 10, and ~80% by age Reference: 1. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol. 2007;18(7): Adapted from: Napolitano C, Priori SG. Diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2007;4:

69 Challenges in Diagnosing CPVT Cannot be diagnosed on the basis of resting ECG. 1,2 Exercise stress testing is an important part of workup - However, in as many as 20% of CPVT patients, formal exercise stress testing will not produce ventricular ectopy. 1 During exercise stress testing, bidirectional VT with a beat-to-beat 180 degree rotation of the QRS complex is often observed 1 References: 1. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol. 2007;18(7): Kontula K, Laitinen PJ, Lehtonen 69 A, Toivornen L, Viitasalo M, Swan H. Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights. Cardiovasc Res. 2005;67:

70 It Is Important to Differentiate Between CPVT and LQT1 1 CPVT is an LQT1 mimicker. 2 As many as 30% of CPVT patients have been misdiagnosed as having Long QT with normal QTc. 1,3 Differentiating CPVT from LQT1 is important for: - Developing a comprehensive treatment plan - Family specific testing References: 1. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106: Choi G, Kopplin LJ, Tester DJ, et al. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation. 2004;110: Napolitano C, Priori SG. Diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2007;4:

71 Cardiac Channelopathy Mimicry Genotype Negative N = 269, 49.7% Genotype Positive N = 272, 50.3% KCNJ2 (ATS1) ANKB (LQT4) RYR2 (CPVT1) Tester Ackerman. Heart Rhythm 2: , 2005 Tester Ackerman. Heart Rhythm 2: , 2005

72 Known mutations: CPVT Cardiac ryanodine receptor gene (RYR2) Cardiac calsequestrin gene (CASQ2) Treatment: Removal of triggers: vigorous physical activity Beta blockers to decrease adrenergic tone (46% have VT recurrence) Cervical sympathectomy Implantable defibrillator: do not use without BB Flecainide: inhibits RYR2 mediated calcium release

73 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cellular Cell membrane Molecular Sarcoplasmic reticulum RyR2 CASQ2 Calcium Induced Calcium Release (CICR) Exons 4967 amino acids RyR2 (CPVT1, Ch 1q42.1-q43) CASQ2 (CPVT2, Ch 1p13.1) 11 Exons 339 amino acids

74 Risk Stratification in CPVT Insufficient data regarding risk Highest risk: sustained VF or unstable VT while receiving beta blockers Younger age at CPVT diagnosis 2 EP studies not helpful 1 Genetic analysis doesn t contribute to risk RyR2 mutation penetrance over 80%: treat asymptomatic carriers with beta blockers 1 Priori SG et al. Circulation2002;106: Hayashi M et al. Circulation 2009;119:

75 Beta-blockers Do Not Provide Reliable Protection Against Cardiac Arrhythmias Related to CPVT 1 However, in light of incomplete protection afforded by beta-blockers in CPVT, its distinction from long-qt is clinically relevant. 1 - S. Priori MD, 2002 Nearly 50% of CPVT patients taking a betablocker continue experiencing cardiac arrhythmias and may require an ICD. 1 Reference: 1. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002;106:69-74.

76 Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) I IIa IIb III Beta blockers are indicated for patients who are clinically diagnosed with CPVT on the basis of the presence of spontaneous or documented stress-induced ventricular arrhythmias. I IIa IIb III Implantation of an ICD with use of beta blockers is indicated for patients with CPVT who are survivors of cardiac arrest and who have reasonable expectation of survival with a good functional status for >1 year.

77 CPVT I IIa IIb III I IIa IIb III Beta blockers can be effective in patients without clinical manifestations when the diagnosis of CPVT is established during childhood based on genetic analysis. Implantation of an ICD with the use of beta blockers can be effective for affected patients with CPVT with syncope and/or documented sustained VT while receiving beta blockers and who have reasonable expectation of survival with a good functional status for >1 year. I IIa IIb III Beta blockers may be considered for patients with CPVT who were genetically diagnosed in adulthood and never manifested clinical symptoms of tachyarrhythmias.

78 Conclusions Genetic arrhythmia syndromes are an important cause of sudden cardiac death in young patients Implantable cardiac defibrillators have been shown to improve mortality in monogenic arrhythmia syndromes The indications for ICD implantation in this population continues to expand as the risk factors for sudden death are elucidated.

79 Thank You!