Cardiomiopatia Dilatativa (DCM) • Dilatazione e depressa funzione di pompa del ventricolo sinistro/e destro • EF < 45%, LVEDD > 117% corretto per eta’ e BSA • Causa di of CHF, aritmie, sudden death, trapianto • Prevalenza: 1 in 500-2500 individui • 2-3 millioni di pazienti negli US • mortalita’: 28,807 nel 1998 (American Heart Association website) • Causa? CU VI CMPD IDIOPATICA: EZIOPATOGENESI 2 FATTORI GENETICI MUTAZIONI DEL DNA MH C ALTERAZIONI DEL SISTEMA IMMUNITARIO AUTOANTICORP I ANTI T-linfociti INFEZIONE VIRALE MIOCARDITE INTERFERENZA CON LA RISPOSTA IMMUNE PROTEINE ALTERATE FUNZIONE MIOCARDICA ALTERATA PERSISTENZ A VIRALE CARDIOMIOPATIA DILATATIVA CMPD: SINTOMI • • • • • • Nessuno (scoperta occasionale: ECGG, ECO, RX) dispnea astenia palpitazioni angina sincopi/presincopi CMPD: esame obiettivo • Polso piccolo/alternante • itto esteso e sollevante, spostato sull’AA, in VI spazio • turgore giugulare (onda “a” e “v” ++) • II tono polmonare ++ • 3° e 4° tono • rigurgito mitralico/tricuspidale • epatomegali • edemi Pedigrees of Families With Different Forms of Familial Dilated Cardiomyopathy: Phenotypic Heterogeneity Mestroni,Sinagra et al., JACC 1999 CU VI Components of Myocyte Cytoarchitecture Desmin Titin Dystrophin Dystrophin-associated glycoprotein complex Actin-associated cytoskeleton Actin Beta MHC Troponin T Z band Alpha-tropomyosin Sarcolemma Sarcomere Emerin Lamins A and C Nuclear membranes Nucleus Nuclear envelope Nuclear pore Cytoplasm Fatkin,et al. N Eng J Med 1999 ;341:1715 (modified) CU VI DCM: molecular epidemiology GENE •cardiac troponin T • titin PHENOTYPE DCM DCM FREQUENCY ? 5% ? • desmin DCM, CDDC, MD ? 0-1% (exon 8) • b-myosin heavy chain DCM ? 5% • cardiac actin DCM < 1% • a-tropomyosin DCM ? < 1% • dystrophin XLDC ~ 37% • lamin A/C DCM, CDDC, EDMD, LGMD ? (~ 40% in CDDC) • metavinculin DCM < 1% • d-sarcoglycan DCM (~CK) 4%, pediatric pts • G4.5 (tafazzin) congenital DCM, LVNC ? ⇧CK pediatric pts CU VI DCM: molecular epidemiology Phenotype Chromosomal location 6q12-q16 LOCUS OMIM 9q13 CMD1B 600884 (with mitral prolapse) 10q21-q23 CMD1C 601493 Autosomal recessive FDC unknown Autosomal dominant FDC with 6q23 CMD1F Autosomal dominant FDC with 2q14-q22 CMD1H 604288 conduction defects 3p22-p25 CMD1E 601154 Autosomal recessive with retinitis 6q23-q24 CMD1J 605362 Autosomal dominant FDC 605582 212110 602067 skeletal muscle disease pigmentosa and deafness CU VI Genes associated with DCM •Cardiac troponin T •Titin •Tinin-cap (teletonin) •Cardiac Myosin-Binding Protein C •Cardiac b-myosin heavy chain •Cardiac actin a-tropomyosin Cypher/ZASP MLP a-actinin 2 Cysteine-glycine-rich protein 3 (MLP) Cardiac a-myosin heavy chain •Desmin •Dystrophin • d-sarcoglycan a-dystrobrevin •Desmoplakin •Metavinculin •Lamin A/C •LAP2 Pospholamban •G4.5 (tafazzin) Changing Mortality in DCM Heart Muscle Disease Registry - Trieste Deaths/HTx 1,0 ,8 p<0.0001 ,6 Cohort 1988-1994 (n=249) ,4 Cohort 1978-1987 (n=99) ,2 p<0,0001 0,0 0 36 72 108 follow-up (months) 144 180