Name of Presenter: Marwan Refaat, MD

Transcription

1 NAAMA s 24 th International Medical Convention Medicine in the Next Decade: Challenges and Opportunities Beirut, Lebanon June 26 July 2, 2010 I have no actual or potential conflict of interest in relation to this program or presentation. I will inform the audience of any off-label uses discussed. Name of Presenter: Marwan Refaat, MD

2 Arrhythmogenic Hereditary Syndromes Genetic-based syndromes associated with a primary electrical disease (channelopathy) or structural heart disease that increases the risk for malignant ventricular arrhythmias - Variable penetrance - Interplay of biophysical function, environment, drug therapy

3 Inherited Arrhythmopathies Long QT Syndrome, Short QT Syndrome Brugada Syndrome Catecholaminergic polymorphic VT Arrhythmogenic Right Ventricular Dysplasia Hypertrophic Cardiomyopathy

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6 Locus Long QT Syndrome Loci/Genes Protein Current Chromosome LQT1 KvLQT1 I Ks 11p15.5 LQT2 HERG I Kr 7q35-36 LQT3 SCN5A I Na 3p21 LQT4 ANK2 I Na 4q25-26 LQT5 mink I Ks 21q21-22 LQT6 MiRP1 I Kr 21q21-22 LQT7 Andersen-Tawil Kir2.1 I K1 17q23.1-q24.2 LQT8 Timothy Ca v 1.2 I Ca 12p13.3 LQT9 Caveolin3 I Na 3p25.3 LQT10 SCN4B I Na 11q23.3 LQT11 AKAP-9 I Ks 7q21-22 LQT12 SNTA1 I Na 20q11.2

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9 Long QT Syndrome: Arrhythmia Mechanisms Early afterdepolarizations Calcium overload & delayed afterdepolarizations Increased dispersion of repolarization and enhanced reentry

10 Risk Stratification in the LQTS Priori et al, NEJM 2003

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13 Gaita et al, Circulation 2003

14 Short QT Syndrome Associated with syncope, sudden death Locus Gene Protein Current Chromosome SQTS1 KCNH2 HERG I Kr 7q35-36 SQTS2 KCNQ1 KvLQT1 I Ks 11p15.5 SQTS3 KCNJ2 Kir2.1 I K1 17q23 SQTS4 CACNA1C Ca v 1.2 I Ca-L 12p13.3 CACNB2b Ca v 1.2 I Ca-L 10p12

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

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

18 Brugada Syndrome Loci/Genes Locus Protein Pathophys Chromosome BRUG1 SCN5A I Na 3p21 BRUG2 GPD1-L I Na 3p24 BRUG3 CACNA1c I Ca 12p13.3 BRUG4 CACNB2b I Ca 10p12 BRUG5 SCN1B I Na 19q13 BRUG6 KCNE3 I Ks /I to 11q13-q14 BRUG7 SCN3B I Na 11q23.3

19 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, Gene Dx, PARTNERS

20 Long-Term Prognosis of Patients With Brugada Syndrome Results From the FINGER Brugada Syndrome Registry -11 tertiary centers in 4 European countries. - Inclusion criteria: type 1 ECG present - baseline or after drug challenge consecutive individuals (745 men; 72%) - Median age of 45 (35 to 55) years. -Dx : (1) aborted SCD (6%);(2) Unexplained syncope (30%) (3) asymptomatic patients (64%). -Median follow-up of 31.9 (14 to 54.4) months -Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events -Gender, Fhx of SCD, inducibility of VT during EPS, drug provocation and presence of an SCN5A mutation were not predictive of arrhythmic events. Probst V, Circulation 2010

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23 CPVT1 CPVT2

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29 USA 286 ATHLETES ITALY 49 ATHLETES 36% (HCM) 13%(Anomalous Coronary Artery) 7%(Myocarditis) 22% (ARVD) 18%(Atherogenic Coronary Artery Disease) 12%(Anomalous Coronary Artery) 2% (HCM) Maron BJ et al. JACC 2003;41:974

30 Asymptomatic Athlete

31 Hypertrophic Cardiomyopathy - AD trait, variable penetrance, 1:500 adults - Overall risk SCD 1-4%/yr - VT common - Arrhythmogenic myocardial substrate: myocyte disarray/hypertrophy & interstitial fibrosis

32 Hypertrophic Cardiomyopathy Risk factors for SCD: Secondary prevention - Aborted SCD/sustained VT Primary Prevention: - Family history of SCD - LV hypertrophy (> 30mm) - Unexplained syncope -NSVT on Holter Monitoring Maron BJ, et al. JAMA 2007

33 Maron,B et al JAMA 2007

34 Maron, B et al. JAMA 2007

35 Maron, B et al. JAMA 2007

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

37 Arrhythmogenic Right Ventricular Dysplasia (ARVD) Fibrofatty replacement of the myocardium Sx: presyncope, syncope, SCD Recurrent VT-LBBB morphology Familial disorder in 30% of cases AD, Chromosome 1, 3, & 14 variable genetic penetrance Incidence of SCD ~ 2%/yr Corrado D et al, J. Am Coll Cardiol 1997; 30:

38 Moric-Janiszewska et al, Europace 2007

39 Arrhythmias Arise from 1 of 3 sites of Fatty Degeneration called the Triangle of Dysplasia APEX ARVD Anterior Surface pulmonary infundibulum Inflow (Subtricuspid)

40 ARVC/D Thin/Fatty RV infiltration on Cardiac MRI

41 ICD-Therapy in ARVC/D Single-Center Experience Münster Wichter et al, Circulation 2004

42 Defibrillators In Arrhythmogenic RV Cardiomyopathy/Dysplasia In North Italy & Boston DARVIN study Corrado,Circ 2003

43 Risk Factors for Appropriate ICD Therapy and/or Life Threatening Arrhythmic Events - Hx cardiac arrest - Severe RV dysfunction (RVEF<45%) - LV dysfunction (LVEF< 55%) - Inducible VF at EPS - VT with hemodynamic compromise - Unexplained syncope - Younger age Wichter et al, Circulation 2004 Corrado et al, Circulation Newfoundland cohort: non-desmosomal gene mutation Transmembrane (TMEM43) Gene S358L mutation 50% affected men (ARVD 5) die before age 50 Haywood et al, Am Soc Hum Genetics 2009

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