Implications of the new diagnostic criteria for ARVC

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1 EUROECHO 2010 Echocardiographic assessment of cardiomyopathies Implications of the new diagnostic criteria for ARVC Barbara Bauce, MD, PhD Department of Cardiac, Thoracic and Vascular Sciences University of Padova, ITALY

2 Arrhythmogenic Right Ventricular Cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an heart muscle disease characterized by fibrofatty myocardial replacement and ventricular arrhythmias Basso C et al. Lancet 2009;373:

3 ARVC: Anatomo-Clinical Definition Heart muscle disease, often familial ( cardiomyopathy ) Pathology: Fibrofatty replacement of the right ventricular myocardium Clinical presentation: ventricular tachycardia and arrhythmic sudden death ( arrhythmogenic )

4 ARVC: a genetically determined cardiomyopathy The condition was initially believed to be a developmental defect of the RV myocardium, leading to the original designation of dysplasia. However, myocardial atrophy is the consequence of cell death occurring after birth, usually during childhood and is progressive with time. The replacement of the right ventricular myocardium by fibrofatty tissue is progressive, starting from the epicardium or midmyocardium and then extending to become transmural Basso C et al. Lancet 2009;373:

5 ARVC: Pathogenesis Fibro-fatty Replacement Wall thinning and aneurysms Fibro-fatty Replacement Ventricular electrical instability sudden arrhythmic death (any time due the disease course) Progressive loss of RV myocardium and LV involvement heart failure (late in life) Basso C et al. Lancet 2009;373:

6 Genetics of ARVC Familial disease: > 50% Pattern of inheritance: autosomal dominant (except for Naxos disease: autosomal recessive) Prevalence of affected family members: higher in males (gender ratio 1.6 :1) Genetic heterogeneity, variable penetrance Known gene mutations: 40-45%

7 GENES INVOLVED IN ARVC JUP Plakoglobin AR McKoy et al, 2000 RYR2 Cardiac Ryanodine receptor AD Tiso et al, 2001 DSP Desmoplakin AD Rampazzo et al, 2002 PKP2 Plakophilin 2 AD Gerull et al, 2004 TGFB3 Transforming Growth Factor Beta-3 AD Beffagna et al, 2004 DSG2 Desmoglein 2 AD Pilichou et al, 2006 DSC2 Desmocollin 2 AD Syrris et al, 2006

8 Proportion of Mutations in ARVC genes in 110 Italian probands Unknown 52,5% Desmoplakin (DSP) 11% Plakophillin-2 (PKP2) 14,5% Desmoglein-2 (DSG2) Multiple mutations 12% Desmocollin-2 (DSC2) 3% 7%

9 ARVC Common Pathway Cell-to-cell connection protein mutations with impaired intercellular contacts Intercellular dysruption Nuclear signalling Myocyte Death (apoptosis or necrosis) Fibro-genesis and Adipo-genesis Structural changes

10 Br Heart J 1994

11 ARVC : DIAGNOSTIC CRITERIA o Familial history of ARVC and/or sudden death o ECG repolarization abnormalities o ECG depolarization abnormalities o Arrhythmias of right ventricular origin o Global and/or regional dysfunction and structural alterations of the right ventricle o Fibro-fatty replacement of the right ventricular myocardium McKenna et al, Br Heart J 1994

12 ARVC : DIAGNOSTIC CRITERIA o Familial history of ARVC and/or sudden o ECG repolarization abnormalities o ECG depolarization abnormalities o Arrhythmias of right ventricular origin death o Global and/or regional dysfunction and structural alterations of the right ventricle o Fibro-fatty replacement of the right ventricular myocardium McKenna et al, Br Heart J 1994

13 Criteria for diagnosis of ARVC Global and/or regional dysfunction and structural alterations MAJOR Severe dilatation and reduction of right ventricular ejection fraction with no (or only mild) LV impairment Localised right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulging) Severe segmental dilatation of the right ventricle MINOR Mild global right ventricular dilatation and/or ejection fraction reduction with normal left ventricle Mild segmental dilatation of the right ventricle Regional right ventricular hypokinesia Br Heart J 1994

14 Circulation 2010

15 Diagnostic terminology for Revised Criteria Definite Diagnosis: 2 major or 1 major and 2 minor criteria or 4 minor from different categories Borderline: 1 major and 1 minor or 3 minor criteria from different categories Possible: 1 major or 2 minor criteria from different categories

16 Global or regional dysfunction and structural alterations By 2D echo: Major Regional RV akinesia, dyskinesia, or aneurysm and 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) or fractional area change < 33%

17 Global or regional dysfunction and structural alterations By 2D echo: Minor Regional RV akinesia or dyskinesia and 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) or fractional area change >33% to > 40%

18 Global or regional dysfunction and structural alterations By 2D echo: Regional RV akinesia or dyskinesia and 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) or fractional area change >33% to > 40% HYPOKINESIS IS NOT INCLUDED IN THIS DEFINITION!!! RV measures are provided

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26 ARVC/D: Cardiac Imaging Tandri H et al J Am Coll Cardiol 2005;45:98 103

27 Family pedigrees of the four ARVC index cases carrying a DSP mutation. Bauce et al European Heart Journal 2005

28 DSP mutation carrier

29 Female, 12 yrs old PKP2 mutation carrier

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31 What is the role of echocardiography in ARVC diagnosis (in CMR era)?

32 2D-echocardiogram in ARVC diagnosis Non invasive and repeatable tool It allows follow-up evaluation of affected patients and family members But it is important to consider some limitations: Acustic window (retrosternal position of RV) Expertise needed In ARVC diagnosis is based on different tests LV involvement underestimated (compared to CMR) Difficult diagnosis in mild forms

33 2D-echocardiogram in ARVC diagnosis NEW TOOLS

34 Three dimentional echocardiography

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36 Tissue Doppler

37 JACC 2009

38 YES, if: Is there a role for 2D-echocardiogram in ARVC diagnosis? Performed by people with experience on RV evaluation When is a doubt on RV or LV kinesis, need to complete cardiac assessment with CMR Fundamental in family screening, consider its limitation on mild forms of the disease In gene-carriers with negative 2D-echo, CMR can detect tissue abnormalities (late-enhancement) Diagnostic value of new echo tools need to be tested in mild forms of ARVC

39 Thank you for your attention

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