DIAGNOSIS AND MANAGEMENT OF ARRHYTHMOGENIC CARDIOMYOPATHY. David SIU MD ( 蕭頌華醫生 ) Division of Cardiology The University of Hong Kong
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1 APHRS Summit 2018 in conjunction with HKCC Heart Rhythm Refresher Course DIAGNOSIS AND MANAGEMENT OF ARRHYTHMOGENIC CARDIOMYOPATHY David SIU MD ( 蕭頌華醫生 ) Division of Cardiology The University of Hong Kong
2 Arrhythmogenic Cardiomyopathies Arrhythmogenic Cardiomyopathy Characterized by frequent ventricular arrhythmias and increased risk of SCD typically as early manifestation before the onset of significant myocardial remodeling Channelopathies Primarily Electrical disease with no or minimal structural changes LQTS, I ks, I kr, I Na BrS, I Na Cardiomyopathies Primarily contractile disease with electrical changes in relatively late stage HCM e.g. Sarcomeric proteins DCM e.g. Lamin A/C
3 Arrhythmogenic Cardiomyopathies Ventricular arrhythmias/scd in young Prevalence in the general population: % (average 1:5,000) High prevalence in certain regions of Italy (Padua, Venice) and Greece (Island of Naxos), prevalence: % 80% ARVC is diagnosed in patients > 40 years. M/F ratio: 2.7/1.0 Focal fibrofatty infiltration of RV Primarily autosomal dominant inheritance with variable penetrance and expressivity (1/3 Familial)
4 NATURAL HISTORY OF CLASSICAL RIGHT-SIDED ACM 1 st phase: minimal or no structural abnormalities. Yet, the patient is at risk of SCD. 2 nd phase: Characterized by ventricular arrhythmias of left bundle branch block morphology and structural changes, typically confined to the RV, which can be observed using echocardiography, angiography, and/or magnetic resonance imaging. During this phase, patients might experience syncope and/or palpitations. 3 rd phase: Overt RV failure with overall preserved LV function. 4 th phase: Overt LV involvement and biventricular heart failure. Left dominant ACM is characterized by primary (but not necessarily exclusive) LV involvement, and biventricular ACM is defined by early and parallel involvement of both ventricles.
5 Genetics of Arrhythmogenic Cardiomyopathies E.T. Hoorntje. Cardiovascular Research 2017
6 Genetics of Arrhythmogenic Cardiomyopathies E.T. Hoorntje. Cardiovascular Research 2017
7 Proposed Cellular And Molecular Cascades Underlying Arrhythmogenic Cardiomyopathy E.T. Hoorntje. Cardiovascular Research 2017
8 ARVC and Brugada Syndrome The intercalated discs that connect cardiomyocytes control cell-to-cell adhesion and communication. Several macromolecular structures (desmosomes, fascia adherens junctions, gap junctions, and sodium-channel complexes) coexist in, and confer their mechanical and electrical properties to, the intercalated disc. Javier Moncayo-Arlandi and Ramon Brugada. Nature Review Cardiology 2017
9 1. Global or regional dysfunction & structural alterations 2. Tissue characterization of wall 3. Repolarization abnormalities 4. Depolarization abnormalities 5. Arrhythmias 6. Family history Circulation 2010; EHJ 2010
10 Diagnostic Criteria: 1. Global or regional dysfunction & structural alterations (ECHO) Major Criteria Regional RV akinesia, dyskinesia, or aneurysm + 1 of the following (end diastole): PLAX RVOT 32 mm (corrected for body size [PLAX/BSA] >=19 mm/m2) PSAX RVOT 36 mm (corrected for body size [PSAX/BSA] >=21 mm/m2) Fractional area change <=33% Minor Criteria Regional RV akinesia or dyskinesia + 1 of the following (end diastole): PLAX RVOT 29 to,32 mm (corrected for body size [PLAX/BSA] 16 to 19 mm/m2) PSAX RVOT 32 to,36 mm (corrected for body size [PSAX/BSA] 18 to 21 mm/m2) Fractional area change 33% to 40% Circulation 2010; EHJ 2010
11 Diagnostic Criteria: 1. Global or regional dysfunction & structural alterations (ECHO) RV R TV RVOT-Prox RVOT-Distal L LV Ao RA PA LA LA PARASTERNAL LONG AXIS PARASTERNAL LONG AXIS
12 Diagnostic Criteria: 1. Global or regional dysfunction & structural alterations (ECHO) RV RV RV Fractional Area Change (%) = 100 X (RV end diastolic area - RV end systolic area) RV end diastolic area RA RA End-diastolic End-systolic APICAL 4-CHAMBER VIEW
13 Diagnostic Criteria: 1. Global or regional dysfunction & structural alterations (MRI) Major Criteria Regional RV akinesia or dyskinesia or dyssynchronous RV contraction + 1 of the following: Ratio of RVEDV/BSA 110 ml/m 2 (male) or 100 ml/m 2 (female) RVEF <40% Minor Criteria Regional RV akinesia or dyskinesia or dyssynchronous RV contraction + 1 of the following: Ratio of RVEDV/BSA ml/m 2 (male) or ml/m 2 (female) RVEF 40-45%
14 Diagnostic Criteria: 1. Global or regional dysfunction & structural alterations (RV angiography) Major Criteria Regional RV akinesia, dyskinesia, or aneurysm
15 Diagnostic Criteria II. Tissue Characterization of Wall Major Criteria Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of RV free wall myocardium in >=1 sample, with or without fatty replacement of tissue on endomyocardial biopsy Minor Criteria Residual myocytes 60% to 75% by morphometric analysis (or 50% to 65% if estimated), with fibrous replacement of RV free wall myocardium in >=1 sample, with or without fatty replacement of tissue on endomyocardial biopsy Circulation 2010; EHJ 2010
16 Diagnostic Criteria III. Repolarization abnormalities Major Criteria Inverted T waves in right precordial leads (V1, V2 and V3) or beyond in individuals > 14 years of age (in the absence of complete RBBB QRS >=120ms) Minor Criteria Inverted T waves in V1 and V2 in individuals > 14 years of age (in the absence of complete RBBB QRS >=120ms) or in V4, V5, or V6 Inverted T waves in V1, V2, V3 and V4 in individuals > 14 years of age in the presence of complete RBBB Circulation 2010; EHJ 2010
17 Diagnostic Criteria Major Criteria IV. Depolarization & Conduction abnormalities Epsilon wave (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in the right precordial leads (V1 to V3) Minor Criteria Late potentials by SAECG in 1 of 3 parameters in the absence of a QRS duration of 110 ms on the standard ECG Filtered QRS duration (fqrs) >= 114 ms Duration of terminal QRS <40 uv (low-amplitude signal duration) >=38 ms Root-mean-square voltage of terminal 40 ms <=20 mv Terminal activation duration of QRS >=55 ms measured from the nadir of the S wave to the end of the QRS, including R, in V1, V2, or V3, in the absence of complete right bundle-branch block Circulation 2010; EHJ 2010
18 ECG from a proband with ARVC Prolongation of terminal activation >=55 ms from S to end of QRS T-wave inversion Frank I. Marcus et al. Circulation. 2010;121:
19 ECG from a proband with ARVC epsilon wave Prolongation of terminal activation >=55 ms from nadir of S to end of QRS epsilon wave T-wave inversion epsilon wave
20 Chiara Calore EHJ 2015
21 Jan Novak Europace 2017
22 Diagnostic Criteria V. Arrhythmias Major Criteria NSVT or sustained VT of LBBB morphology with superior axis (negative or indeterminate QRS in lead II, III, & avf and positive in lead avl) Minor Criteria NSVT or sustained VT of RVOT configuration, LBBB morphology with inferior axis (positive QRS in lead II, III, & avf and negative in lead avl) or of unknown axis > 500 PVC per 24 hours (Holter) Circulation 2010; EHJ 2010
23 Major Criteria Diagnostic Criteria: VI. Family History ARVC/D confirmed in a 1 st degree relative who meets current Task Force criteria ARCV/D confirmed pathologically at autopsy or surgery in a 2 nd degree relative Identification of a pathologically mutation categorized as associated or probably associated with ARVC/D in patient under evaluation Minor Criteria History of ARVC/D in a 1 st degree relative in whom it is not possible or practical to determine whether the family member meets current Task Force criteria Premature sudden death (<35 years of age) due to suspected ARVC/D in 1 st degree relative ARCV/D confirmed pathologically or by current Task Force Criteria in a 2 nd degree relative Circulation 2010; EHJ 2010
24 Diagnostic Criteria for ARVC/D Definite ARVC/D 2 major (2 x 2 points) 1 major and 2 minor criteria (2 + (2 x 1) points) or 4 minor from different categories (4 x 1 points) Borderline 1 major and 1 minor (2 + 1 points) or 3 minor criteria from different categories (3 x 1 points) Possible 1 major (2 points) or 2 minor criteria from different categories (2 x1 points) Circulation 2010; EHJ 2010
25 78 carriers Male: 46 Mean age: 44 years Regular physical activity from 10 years of age. Cynthia A. James JACC 2013
26 Impacts of Exercise on ARVC Presentation & Arrhythmic Outcomes Cynthia A. James JACC 2013
27 Threshold model for phenotypic expression of Arrhythmogenic Cardiomyopahty E.T. Hoorntje. Cardiovascular Research 2017
28 Gabriela M. Orgeron et al. JAHA 2017 Risk Stratification for Ventricular Arrhythmic events 312 patients with definite ARVC with ICD 163 men (52%) Age at presentation: 33.6±13.9 years Cumulative survival from first appropriate ICD intervention (VT/VF) Increased Risk with Inducible VT on EPS Male >= 3 TWIs >1,000PVCs/day VT at presentation Secondary prevention
29 Risk Stratification: Meta-analysis Arrhythmic outcome: Definite ARVC: 10.6%/yr Borderline ARVC: 10.0%/yr Mutation carriers: 3.7%/yr Bosman Laurens Heart Rhythm 2018
30 Risk Stratification: Meta-analysis Bosman Laurens Heart Rhythm 2018
31 Risk Factors for Arrhythmic Events Definite ARVC patients Male gender Syncope T-wave inversion >V3 RV dysfunction Prior (non) sustained VT/VF; Borderline ARVC patients All factors in Definite ARVC patients Inducibility at EPS and Inducibility during strenuous exercise Mutation carriers regardless of ARVC phenotypes All aforementioned predictors Ventricular ectopy, Multiple ARVC-related pathogenic mutations LV dysfunction Palpitations/pre-syncope determined arrhythmic risk. Bosman Laurens Heart Rhythm 2018
32 Flow chart of risk stratification and indications to ICD implantation in ARVC/D High Risk >10%/yr arrhythmic events Intermediate Risk 1-10%/yr arrhythmic events Low Risk <1%/yr arrhythmic events - Aborted SCD due to VF - Sustained VT - Severe RV dysfunction (RVEF <36%) - Severe LV dysfunction (LVEF <36%) >=1 major risk factors - Syncope - NSVT - Moderate RV dysfunction (RVEF 36-46%) - Moderate LV dysfunction (LVEF ) >= 1 minor risk factors: complex genotype, male sex, proband, positive EPS, T-wave inversion in 2/3 inferior leads, and T- wave inversion in >=V3 - No risk factors - Healthy gene carriers ICD indicated (Class I) ICD should be considered (Class IIa) ICD May be considered (Class IIb) ICD not indicated (Class III) Corrado Domenico, Circulation
33 Management: AAD AADs are recommended as an adjunct therapy to ICD in ARVC/D patients with frequent appropriate device discharges (class I). The use of AADs should be considered to improve symptoms in patients with frequent premature ventricular beats and/or nonsustained VT (class IIa).
34 Management: Beta-blocker Beta-blocker therapy is recommended in ARVC/D patients with recurrent VT, appropriate ICD therapies, or inappropriate ICD interventions resulting from sinus tachycardia, supraventricular tachycardia, or atrial fibrillation/flutter with high-ventricular rate (class I). Beta-blocker therapy should be considered in all patients with ARVD/C irrespective of arrhythmias (class IIa). The prophylactic use of β-blockers in healthy gene carriers is not recommended (class III).
35 Management: Ablation Catheter ablation of VT is recommended in ARVC/D patients with incessant VT or frequent appropriate ICD interventions on VT despite maximal pharmacological therapy, including amiodarone (class I). Catheter ablation of VT should be considered in ARVC/D patients with incessant VT or frequent appropriate ICD interventions on VT who have failed pharmacological therapy other than amiodarone (class IIa).
36 Conclusions ARVC is associated with risk of SCD in young adult The arrhythmic risk ranges from % per years Common factors for arrhythmic risk have been identified including gender, presentation, symptom, cardiac function, ECG features, and so on Strenuous exercise hastens development of cardiac phenotype, therefor should be avoided For high risk patients, ICD should be considered Future studies are needed to develop risk models to tailor individual patient management.
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