ARVC when TO IMPLANT THE ASYMPTOMATIC PERSON

EUROPACE 2011 INHERITED ELECTRICAL CARDIAC DISORDERS ARVC when TO IMPLANT THE ASYMPTOMATIC PERSON June 26 th 2011 Robert Lemery MD

CONFLICTS of INTEREST None

ASYMPTOMATIC ARVC 1. ECG 2. ASYMPTOMATIC PVC S / VT 3. ABNORMAL IMAGING STUDY 4. INVASIVE EPS FINDINGS / BX 5. GENETICS / FAMILY HISTORY 6. PRIMARY PREVENTION

ASYMPTOMATIC ARVC 1. ECG QUESTION ECG ABNORMALITIES MAY OCCUR IN ASYMPTOMATIC PATIENTS WITH ARVC 1- YES 2- NO

ARVC Corrado D et al. Eur Heart J 2011;32:934-944 Watkins H et al. N Engl J Med 2011;364:1643-1656

INCIDENTAL FINDINGS of VENTRICULAR ANEURYSMS in ARVC Ly et al. Heart Rhythm 2008;5:1455-1457

2. ASYMPTOMATIC PVC s/vt QUESTION 1. PVC s/vt usually have a RBBB 2. PVC s/vt can originate from the region of the RVOT 3. PVC s/vt only occur from the triangle of dysplasia 4. PVC s/vt do not occur in Asx ARVC

Archetypal clinical features of ARVC Delmar, M., McKenna W., Circ Res 2010; 107:700-714

ASYMPTOMATIC ARVC QUESTION SUDDEN CARDIAC DEATH CAN BE THE INITIAL PRESENTATION OF ASYMPTOMATIC PATIENTS WITH ARVC 1- YES 2- NO

SPORTS RELATED SCD Holst AG et al. Heart Rhythm 2010;7:1365-1371.

ADDING ECG to HISTORY & P/E for SCREENING of ATHLETES Malhotra R et al. Heart Rhythm 2011;8:721-727

ADDING ECG to HISTORY & P/E for SCREENING of ATHLETES Hx & P/E: $68,745 per finding ECG: $68,893 per finding Malhotra R et al. Heart Rhythm 2011;8:721-727

Annual incidence rates of sudden cardiovascular death per 100,000 person screened competitive athletes and unscreened non-athletes 12 35 years of age Veneto Region of Italy, from 1979 to 2004. Corrado D et al. Eur Heart J 2011;32:934-944

Sudden Arrhythmic Death Dx in Family Members Behr E R et al. Eur Heart J 2008;29:1670-1680

Causes of sudden cardiac death in 314 autopsied cases Marcus F I, Chugh S S Eur Heart J 2011;32:931-933, modified from Winkel et al, Eur Heart J 2011;32:983-990

PROLONGED RV ENDOCARDIAL DURATION Tandri H et al. Heart Rhythm 2009;6:769-775

ENDOMYOCARDIAL BIOPSY guided by Voltage Mapping in ARVC Avella A et al. J Cardiovasc Electrophysiol 2008;19:1127-1134

Immunostaining Desmosomal Protein Plakoglobin in ARVC N-cadherin NO ARVC ARVC Plakoglobin Asimaki A et al. N Engl J Med 2009; 360:1075-1084

ASYMPTOMATIC ARVC 5. GENETICS / FAMILY HISTORY QUESTION THE REVISED TASK FORCE CRITERIA USE GENETICS AS A MAJOR CRITERIA FOR DX. 1- YES 2- NO

TASK FORCE CRITERIA in ARVC PROPOSED MODIFICATION Marcus FI et al. Circulation 2010;121:1533-1541

TASK FORCE CRITERIA in ARVC PROPOSED MODIFICATION ORIGINAL REVISED Marcus FI et al. Circulation 2010;121:1533-1541

TASK FORCE CRITERIA in ARVC PROPOSED MODIFICATION Marcus FI et al. Circulation 2010;121:1533-1541

TASK FORCE CRITERIA in ARVC PROPOSED MODIFICATION ORIGINAL REVISED Marcus FI et al. Circulation 2010;121:1533-1541

TASK FORCE CRITERIA in ARVC PROPOSED MODIFICATION ORIGINAL 2 MAJOR 1 MAJOR + 2 MINOR 4 MINOR DIFF. GROUPS REVISED DEFINITE: 2 MAJOR 1 MAJOR + 2 MINOR 4 MINOR DIFF. GROUPS BORDERLINE: 1 MAJOR + 1 MINOR 3 MINOR DIFF. GROUPS POSSIBLE: 1 MAJOR 2 MINOR DIFF. GROUPS Marcus FI et al. Circulation 2010;121:1533-1541

Clinical Categories of Inherited Cardiomyopathies and Their Genetic Basis. Watkins H et al. N Engl J Med 2011;364:1643-1656

Proteins with inherited arrhythmogenic disorders Desmosomal structure Priori, S. G. Circ Res 2010; 107:451-456 Delmar, M., McKenna W., Circ Res 2010; 107:700-714

POPULATION-PREVALENT DESMOSAL MUTATIONS PREDISPOSING to ARVC (1/200 FINNS) 929 Finish ARVC probands 31/6,334 (0.5%) individuals Founder Mutation in 0.3% Finns Lahtinen et al. Heart Rhythm 2011, in press

Natural History and Risk Stratification in ARVC 154 Patients: VT (81%), SCD (10%), Syncope (6%), Asx (3%) Follow-up of up to 29 years, (10+/- 7 years) Annual Mortality rate 1.5% Paul et al. Heart Rhythm 2011;Poster 1-70

Type of Mutation and Phenotypic Expresssion in Relation to Clinical Outcome in Genotyped Patients with ARVC 91 Patients, mean f-up of 12 +/- 7 years Mutations in PKP-2: 35/91 (39%) 12/35: Frameshift 9/35: Missesnse 14/35: Stop Extensive disease in 6, Sustained VT in 11 Risk Stratification & Silent Mutation carriers without overt heart disease Paul et al. Heart Rhythm 2011;Poster 6-97

GENOTYPE-PHENOTYPE RELATIONS in ARVC FAMILIAL RISK: FAMILIAL CASES in 45% of families screened ASYMPTOMATIC RELATIVES: 20% ARVC, mostly ECG abnormalities-tad prolongation (84% mutation carriers) Mutation-carrying relatives: 6x ARVC vs Relatives of index patients without mutations: ++ risks Vent. Arrh. & earlier onset of disease In young relatives <20 years of age, SD and signs of ARVC exclusively in PKP2 mutation carriers PKP2 mutations were identified in 90% familial ARVC Cox, M. G. P. J. et al. Circulation 2011;123:2690-2700

Age at sudden cardiac death of the 45 patients with pathologically proven ARVC Quarta, G. et al. Circulation 2011;123:2701-2709

FAMILY EVALUATION in ARVC FAMILIAL RISK: MARKED INTRAFAMILIAL PHENOTYPE DIVERSITY DIFFERENCE IN DISEASE SEVERITY BETWEEN PROBANDS AND RELATIVES. IN PROBANDS, 50% DIED SUDDENLY RELATIVES HAVE A BETTER PROGNOSIS MALES=PROBANDS, FEMALES=RELATIVES 2/8 DECEASED PROBANDS: MULTIPLE MUTATIONS MECHANISMS UNDERLYING VARIABLE PENETRANCE and EXPRESSIVITY in ARVC REMAINS COMPLEX Quarta, G. et al. Circulation 2011;123:2701-2709

PRIMARY PROPHYLAXIS in ARVC Klein G. et al. J Cardiovasc Electrophysiol 2005;16:S28-S34

R Lemery, P Brugada, J Janssen, E Cheriex, T Dugernier, and HJ Wellens Nonischemic sustained ventricular tachycardia: clinical outcome in 12 patients with arrhythmogenic right ventricular dysplasia ALL PATIENTS HAD SMVT Mean F-UP of 7.9 YEARS 1 pt died 1 week following RV disconnection, ALL OTHERS ALIVE in spite of VT recurrence J. Am. Coll. Cardiol., Jul 1989; 14: 96-105

Number of affected patients among clinically evaluated subjects for each family in 37 affected families FOLLOW-UP 2-18 YEARS (MEAN 8+/-5): ONLY 1 PATIENT DIED SUDDENLY MORTALITY RATE OF 0.08 PATIENT/YEAR BLACK=AFFECTED Nava, A. et al. J Am Coll Cardiol 2000;36:2226-2233

PROPHYLACTIC ICD in ARVC Corrado D et al. Circulation 2010;122:1144-1152

PROPHYLACTIC ICD in ARVC SYNCOPE, <0.01 ASYMPTOMATIC, ns Corrado D et al. Circulation 2010;122:1144-1152

PROPHYLACTIC ICD in ARVC ASYMPTOMATIC PATIENTS 106 patients from 6 centers in Europe and USA 27 Asx patients received an ICD because of a family history of sudden death: NONE had appropriate shocks INFECTIONS & INAPPROPRIATE SHOCKS 18 pts. (17%) had device-related complications 20 pts. (19%) received inappropriate shocks Corrado D et al. Circulation 2010;122:1144-1152

Corrado D et al. Heart 2011;97:530-539

ARVC when TO IMPLANT THE ASYMPTOMATIC PERSON 1. RELATIVE OF PROBAND WITH SCD? 2. GENE NEGATIVE INDIVIDUAL? 3. YOUNGER MALE PHENOTYPE / GENOTYPE POSITIVE? 4. ASX. PATIENT WITH 2 MUTATIONS? 5. RARE FAMILIAL SYNDROMES WITH RV DYSFUNCTION AND SCD?

ARVC when TO IMPLANT THE ASYMPTOMATIC PERSON 1. RELATIVE OF PROBAND WITH SCD: NO 2. GENE NEGATIVE INDIVIDUAL: NO 3. YOUNGER MALE PHENOTYPE / GENOTYPE POSITIVE: YES 4. ASX. PATIENT WITH 2 MUTATIONS: YES 5. RARE FAMILIAL SYNDROMES WITH RV DYSFUNCTION AND SCD: YES