Hypertrophic Cardiomyopathy

Transcription

1 Hypertrophic Cardiomyopathy From Genetics to ECHO Alexandra A Frogoudaki Second Cardiology Department ATTIKON University Hospital Athens University Athens, Greece EUROECHO 2010, Copenhagen, 11/12/2010

2 Primary cardiomyopathies in which the clinically relevant disease solely or predominantly involve the myocardium Maron, B. J. et al. Circulation 2006;113:

3 Proposed new classification by the ESC Working Group on Myocardial and Pericardial diseases Elliott et al Eur Heart J 2008

4 Hypertrophic Cardiomyopathy Definition Hypertrophic cardiomyopathy is diagnosed clinically by the presence of cardiac hypertrophy in the absence of altered loading conditions that could fully account for the problem A myocardial disorder in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular and congenital heart disease Maron et al JAMA 2002 Elliott et al Eur Heart J 2008

5 What about systemic diseases? Anderson-Fabry, Glycogen Storage Diseases, Mitochondrial Cytopathy, Noonan Syndrome, LEOPARD Syndrome, Friedreich s Ataxia etc It could be considered hypertrophic cardiomyopathy Elliott et al Eur Heart J 2008 It would seem preferable that the myriad of clinically diverse genetic syndromes associated with LV hypertrophy should not be designated as part of the hypertrophic cardiomyopathy disease spectrum. Maron et al Circ Cardiovasc Genet. 2009

6 Elliott et al Eur Heart J 2008

7 Morimoto Cardiovasc Res 2008 The sarcomere

8 The Proteins/Genes ß myosin heavy chain (MYH7) Cardiac myosin binding protein C (MYBPC3) Cardiac troponin I (TNNI3) Troponin-T (TNNT2) a-tropomyosin (TPM1) 10% Cardiac actin (ACTC1) Essential myosin light chain (MYL3) Regulatory myosin light chain (MYL2) a-myosin heavy chain (MHC) Titin (TTN) Troponin C (TNNC1) Muscle LIM protein (MLP, CSRP3) 10 50%

9 Morimoto Cardiovasc Res 2008 The Mutations Thin filament proteins Cardiac troponin T (TNNT2) 27 Cardiac troponin I (TNNI3) 26 Cardiac troponin C (TNNC1) 1 a-tropomyosin (TPM1) 11 a-cardiac actin (ACTC1) 7 Thick filament proteins b-myosin heavy chain (MYH7) 167 Ventricular regulatory light chain (MYL3) 4 Ventricular essential light chain (MYL2) 10 Cardiac myosin-binding protein C (MYBPC3) 134 Titin and Z-disc proteins Titin (TTN) 2 T-cap (TCAP) 4 MLP (CSRP3) 3 Myozenin-2 (MYOZ2) 1 a-actinin (ACTN2) - Obscurin (OBSCN) 2 Cypher (LDB3) -

10 From Mutation to Phenotype Marian Tex Heart Inst J 2010

11 From Genotype to Phenotype Multiple poorly understood mechanisms contribute to heterogeneity of HCM presentation and these include environmental inputs, sex, genetic and epigenetic modifiers Force et al Circulation 2010

12 MYH7 mutations are associated with earlier onset and more extensive hypertrophy 403 mutation: increased risk of heart failure and sudden death 719 mutation: marked increased risk of heart failure TNNT2 mutations are associated with limited hypertrophic response MYBPC3 mutations are associated with incomplete penetrance and relatively later onset Force et al Circulation 2010

13 The importance of family screening 1. Identification of healthy carriers is important as it will lead to identification of subjects at high risk to develop the disease later 2. Genetic counselling Healthy carriers may transmit the gene to offsprings (probability 50%)

14 The Role of Echo Can we <discover> the genetic substrate by echo? Can we identify the carriers? Can we say who is going be diagnosed with HCM later in life? We can definitely say how severe HCM is We can definitely follow-up patients We can definitely say if our management was successful

15 Our Job Confirm the presence of LVH Assess mitral valve Assess the severity of LVOTO if present Assess systolic function Assess diastolic function Identify the carriers? 2D The Tools Doppler (PW, CW, Color) Tissue Doppler Imaging Contrast 2D Strain

16 Diagnostic criteria for HCM McKenna et al. Heart 1997

17 Diagnostic value of diagnostic criteria in a genotyped population 109 patients and family members All genotyped Low sensitivity High specificity Charron et al. Inter J Cardiol 2003

18 Intraventricular septum morphology and genes sigmoid reverse curve apical neutral 388 patients 8 genes Binder J, et al. Mayo Clin Proc 2006

19 Hypertrophy- Obstruction

20 Contrast

21 Systemic Diseases Danon Disease Tada et al Circulation 2010 Fabry Disease Kovacevic et al Eur J Echocard 2007 Danon Disease Erickson e-medicine

22 Systolic Function? Tissue Doppler Imaging Consistently Detects Myocardial Abnormalities in Patients With Hypertrophic Cardiomyopathy and Provides a Novel Means for an Early Diagnosis Before and Independently of Hypertrophy Nagueh et al Circulation 2001 Burnt-out HCM means low ejection fraction and it is associated with increased risk of SCD and increased mortality (11%) Harris et al Circulation 2006

23 Contractility in myectomy samples resembles the hypocontractile phenotype found in endstage failing heart muscle in vitro Jaques et al Cardiovascular Research 2008

24 Diastolic Dysfunction Extensive myocardial fibrosis Stiff ventricle Dilated left atrium Diastolic dysfunction is characteristic of the disease Losi et al Cardiovascular Ultrasound 2010

25 Strain Non sustained ventricular tachycardia in hypertrophic cardiomyopathy can be predicted with the use of strain Carasso et al. J Am Soc Echocardiogr 2008 Di Salvo et al. J Am Soc Echocardiogr 2010

26 Atrial Strain NORMAL Reservoir Conduit Contraction

27 Hypertrophic Cardiomyopathy Reservoir Conduit Contraction

28 Left ventricular 2D strain and left atrial 2D strain is lower in patients with HCM than in patients with non HCM LVH LA longitudinal function in HCM 2D strain : Additive value in the D/D of Hypertrophy Contractile atrial strain : >-10,8% (sens:82%,spec:81%) for D/D Paraskevaidis I, Panou F, Papadopoulos C et al. Heart 2009

29 Left atrium strain carries prognostic value in HCM total left atrial strain 21% total left atrial strain 21% In patients with HCM and preserved systolic function, total LA strain predicts 12-month outcome in terms of death and/or hospitalization 90% sensitivity 86% specificity Paraskevaidis, Farmakis, Papadopoulos et al. Am Heart J 2009

30 Early identification of mutation carriers in familial hypertrophic cardiomyopathy by combined echocardiography and tissue Doppler imaging Tissue Doppler imaging velocities alone were not reliable enough to identify LVH-free mutation carriers in HCM. In contrast, abnormal LV remodelling was a frequent early manifestation of HCM Echo/TDI score combined three parameters It was defined as the probability to be affected: P= IVS/LPW RWT septal E/Ea Gandjbakhch E et al Eur Heart J 2010

31 Guide to treatment

32 Septal Ablation

33 7 days post septal ablation

34 2.5 years post septal ablation

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36 Daughter 16yrs old E/E =6 E/E =4.7 Do we know she is safe?

37 More information? Son 14yrs old

38 E/E =6 E/E =4

39 Does he have HCM?

40 HCM diagnosis is a puzzle and we need to use carefully every piece of the jigsaw in patients with HCM family history

41 Conclusion Echo is required for the diagnosis and followup of patients with hypertrophic cardiomyopathy There are echo-derived indices with prognostic value Some attempts were made in the past to decode HCM genes using the echo phenotype New diagnostic strategies are continuing to evolve in order to identify affected individuals earlier and with greater accuracy As clinical genetic testing for HCM is deploying in concert with advanced imaging modalities we will be able to discern more precise genotype-phenotype correlations

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