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1	Heritable Cardiomyopathies: The Role of Genetics in Heart Failure Michael Arad MD Heart Failure Service and Heart Institute Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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5	The Clinical Spectrum of familial Cardiomyopathies Familial Hypertrophic Cardiomyopathy Familial Dilated Cardiomyopathy Arrhythmogenic Cardiomyopathy (ARVD) Metabolic Cardiomyopathy Restrictive Cardiomyopathy Amyloidosis Non-Compaction
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8	Phenotypic variability in HCM 1. Asymmetric septal hypertrophy, SAM and outflow obstruction
9	2. Cavity obliteration and Diastolic failure in distal (“apical”) hypertrophy
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18	Noonan Syndrome Common congenital anomaly 1: 1000-2500 Short stature, webbed neck, facial dysmorphia and heart defects Congenital heart disease 136/157 (87%) Autosomal dominant, PTPN11 mutations Tyrosine phosphatase playing a role in embryogenesis and hematogenesis M/F ratio 2:1, ~ 50% de novo mutations
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20	Endocardial enhancement in Fabry
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23	Causes of Dilated Cardiomyopathy
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27	Different mutations in Nuclear Lamina Protein (Lamin A/C) cause: Muscular dystrophy DCM with conduction system disease Lipodystrophy Charcot-Marie-Tooth disease Progeria
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29	DCM & Myopathy: Dystrophin Mutations
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32	Arrhythmogenic Right Ventricular Cardiomyopathy (Dysplasia)
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35	Left Ventricular Non-Compaction
36	Clinical and Genetic Features of LVNC Murphy et al, Eur Heart J, 2005 Disorder of endomyocardial morphogenesis resulting in multiple trabeculations in LV myocardium. High prevalence of left ventricular dysfunction, ventricular arrhythmia and systemic emboli. 2/3 of LVNC patients had LV dilatation and systolic Dx. and 40% were initially diagnosed as DCM Familial disease in > 50%. Phenotypic variability including excessive trabeculations, contractile dysfunction and ventricular arrhythmia. Mutations in a-dystrobrevin and Cypher/ZASP – proteins linking the cytoskeleton to extracellular matrix
37	Left Ventricular Non-Compaction
38	ACTC Glu101Lys mutation in the Spanish families with apical HCM (Arad et al, Circulation 2005)
39	ACTC mutation causes apical HCM, non-compaction and septal defects (Monserrat et al, Eur Heart J, 2007)
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41	Etiology of Restrictive Cardiomyopathy Sporadic Hypereosinophilia, Endomyocardial fibrosis, Irradiation etc. Infiltrative Amyloidosis, Sarcoidosis, Iron overload Familial Phenotypic variant of familial HCM (troponin I) Desmin mutations (± skeletal myopathy) Metabolic cardiomyopathies (Fabry, Gaucher’s, etc.)
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43	Potential roles of genetic diagnosis in familial cardiomyopathies Define the disease causing gene mutation - Establish genetic diagnosis Genotype the family - Diagnose borderline cases - Identify asymptomatic carriers - Prenatal/preimplantation diagnosis Understand the molecular mechanisms - Develop specific therapy
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47	Linkage to genomic locus
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49	מהו פולימורפיזם, מהי מוטציה? פולימורפיזם – שינוי גנטי הקיים באוכלוסיה רגילה תפוצה > 1% אינו גורם מחלה יכול להוות גורם סיכון למחלה מוטציה – שינוי גנטי הגורם מחלה נדיר אינו נמצא באוכלוסיה רגילה גורם לשינוי משמעותי בחלבון המקודד
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54	Treating Asymptomatic LV Dysfunction Evidence based drug therapy