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
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
Inherited Arrhythmopathies Long QT Syndrome, Short QT Syndrome Brugada Syndrome Catecholaminergic polymorphic VT Arrhythmogenic Right Ventricular Dysplasia Hypertrophic Cardiomyopathy
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
Long QT Syndrome: Arrhythmia Mechanisms Early afterdepolarizations Calcium overload & delayed afterdepolarizations Increased dispersion of repolarization and enhanced reentry
Risk Stratification in the LQTS Priori et al, NEJM 2003
Gaita et al, Circulation 2003
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
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
Brugada Syndrome: Arrhythmia Mechanisms Truncated Epicardial APs Phase 2 Reentry
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
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
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 -1029 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
CPVT1 CPVT2
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
Asymptomatic Athlete
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
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
Maron,B et al JAMA 2007
Maron, B et al. JAMA 2007
Maron, B et al. JAMA 2007
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)
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; 30:1512-1520
Moric-Janiszewska et al, Europace 2007
Arrhythmias Arise from 1 of 3 sites of Fatty Degeneration called the Triangle of Dysplasia APEX ARVD Anterior Surface pulmonary infundibulum Inflow (Subtricuspid)
ARVC/D Thin/Fatty RV infiltration on Cardiac MRI
ICD-Therapy in ARVC/D Single-Center Experience Münster Wichter et al, Circulation 2004
Defibrillators In Arrhythmogenic RV Cardiomyopathy/Dysplasia In North Italy & Boston DARVIN study Corrado,Circ 2003
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 2003 - 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