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Mechanisms and Genetics of Dilated Cardiomyopathy
- 1. Cardiomyopathies: what are the mechanisms? Dilated Cardiomyopathy (DCM) Andre Keren MD Assuta Hospitals, Clalit Health Services and Hadassah University Hospital, Israel
- 3. a malignant diseaseCM -Dilated
- 4. Clinical Presentation of DCM • Isolated DCM/Familial DCM • DCM associated with peripheral muscle disease • DCM associated with conduction disturbances • DCM associated with multisystem disease
- 5. Elliott P, Eur Heart J 2008;29:270-276
- 7. DCM: Prevalence • Incidence 5-8/100,000 • Prevalence 1:2,700 (Olmstead County Minnesota)* • Gender (>men), Racial (>black) differences * HCM estimated at 1:5,000 Gillum RF. (United States, 1970-1982) Am Heart J 1986;111:752-755 Bagger JP et al. (Western Denmark). Br Heart J 1984;52:327-331 Williams DG et al. (England). Br Heart J 1985;54:153-155 Codd MB et al. (Minnesota, 1975-1984). Circulation 1989;80:564-572
- 9. FAMILIAL DCM (FDCM) PREVALENCE • 20-50% of DCM are familial & 30% of asympt fam members are clinically affected (LVE, dFS) • 10-20% of those affected develop within 2-3 years symptomatic DCM Michels VV-NEJM 1992; Keeling PJ- Br Heart J 1995; Gruning E-JACC 1998; Baig MK-JACC 1998; Crispell KA- JACC 1999; Mestroni L - JACC 1999.;Mahon NG Ann Int Med 2005
- 10. DCMDCM Prospective CardiovascularProspective Cardiovascular Evaluation of AsymptomaticEvaluation of Asymptomatic RelativesRelatives N=767N=767
- 11. Autoimmunity in DCM HLA DR4 MHC Class II expression Cytokines Cardiac autoantibodies Familial aggregation of autoimmune diseases
- 12. Antibodies in DCM Antibody DCM(%) Controls(%) Muscle specific Antifibrillary 24 41 Antiinterfibrillary 6 3 Cardiac specifc 26 3 Antia/ß 46 0 Antilaminin 78 6 Antimitochondrial M7 31 0 ANT 57 0 Anti ß Inhibiting 31 12 Stimulating 35 0
- 15. 2013Caforio ALP et al. Eur Heart J
- 16. • The inflammation is due to infectious, toxic or an autoimmune process • The most common etiology appears to be the viral infection Definition by the WHO/ISFC* : Inflammatory disease of the myocardium diagnosed by established histological, immunological and immunohistochemical criteria Richardson P, McKenna WJ et al. Ciculation 1996;93:841-842 Caforio ALP et al. Eur Heart J 2013, Jul 3, ahead of print
- 17. populationthe 2010 worldcaused by myocarditis infailureHeart The burden of myocarditis as a percentage of prevalent heart failure varied by age and region from 0.5% - 4%
- 18. Kindermann I, Boehm M, et al. J Am Coll Cardiol 2012;59:779-792
- 19. Keren A, Caforio ALP. ACCA 18.10.2013
- 20. Schultz JC, Hilliard AA, Cooper LT. Mayo Clin Proc 2009;84:1001-1009
- 21. Viral infectionViral infection myocardialmyocardial inflammationinflammation Immune response virus persistencevirus persistence ± inflammation± inflammation Inflammatory cardiomyopathy virus clearance +virus clearance + inflammationinflammation (autoimmune)(autoimmune) Genetic factors virus clearancevirus clearance no inflammationno inflammation Healed myocarditis DCM Keren A
- 22. Caforio ALP et al. Eur Heart J 2013
- 23. Kindermann I, Boehm M et al. Circulation 2008;118:639-648
- 24. Changes in LVEF% Mortality 20% 56% Mason JW et al. NEJM 1995 CONCLUSION: Routine immunosuppressive therapy is not indicated in histologically proven myocarditis
- 25. McCarthy RE, NEJM 2000;342:690-696; Mason JW NEJM 1995;333:269-275 Fulminant N=15, Acute N=132 93% 45%
- 26. 7.8.2013 VT+ SA blocks VTs Early +Late Arrhythmias
- 27. Mason JW N Engl J Med 1995;333:269-275; Cooper LT N Engl J Med 1997;336:1860-1866;
- 28. Kandolin R. Circ Heart Fail 2013;6:15-22
- 29. Kandolin R et al
- 30. ● Gene profiling in 28 candidate genes included: Genes for cytokines, cytokine and chemokine receptors, TLR’s, apoptosis and mitochondrial respiratory chain ● Gene profiling performed on 1-2 EMB’s ● Patients:
- 31. Distinctive gene expression profiles in active myocarditis (MCA), cardiac sarcoidosis (CS) and idiopathic giant cell myocarditis (IGCM)
- 32. Take Home Messages GCM and CS Gene expression profiling might be useful to overcome high sampling error due to patchy distribution, such as giant cells Krasniqi N, Eriksson U Eur Heart J 2014;35:2138-2139 • The first attempt to define and use “inflammatory cardiac microenvironment” for diagnostic purposes • Possible insights into the pathogenesis of ALL inflamm CM including GCM and CS Limitations: - Small number of pts - Highly specialized procedure - This patented gene expression needs to be reproduced in larger studies
- 33. Caforio ALP et al. Eur Heart J 2013
- 34. ACUTE MYOCARDITIS: DIAGNOSTIC AND MANAGEMENT PROTOCOL Clinically Suspected Myocarditis Haemodynamically stable PreservedLV function No eosinophilia No significant rhythm or conduction disturbances Not associated with systemic immune disease# History, Examination, ECG, Echo, Laboratory tests: Troponin, CRP, ESR, Blood Cell Count, BNP, Consider CMR & if Available, Serum Cardiac Autoantibodies Consider coronary angiography and EMB No coronary disease General Supportive Therapy unstable, DecreasedHaemodynamically LV Function, Cardiogenic Shock Pharmacological & if needed Mechanical supportECMO, LVAD/Bi-VAD, Bridge to( heart transplant or to recovery) Lymphocytic Giant cell, Eosinophilic, Sarcoidosis (acute decompensation) General Supportive Therapy Immunosuppression if unresponsive & virus negative EMB Immunosuppression if infection negative EMB If myocarditis is associated with systemic immune disease exacerbation, therapy overlaps with treatment of the background disease (usually# immunosuppression).Keren A, Caforio ALP. ACCA 18.10.2013
- 36. 36 Familial Genetic DCM • 25-50% OF DCM cases • DISEASE TRANSMISSION: - AUTOSOMAL DOMINANT - BUT also autosomal recessive, X-linked and matrilineal (mitochondrial) • > 30 genes account for 40-50% of familial DCM
- 37. Graham RM, Owens WA. NEJM 1999;341:1759
- 38. van Spaendonck-Zwarts KY 2008; Jongbloed JD 2011; Van Tintelen JP; Cardiovasc Research 2014;101:571-578 Overlap of genes involved in different cardiomyopathies
- 39. 39 Seidman GS& Seidman C, Cell 2001:104:557
- 40. 40 DCM MOLECULAR MECHANISMS • Force generation and transmission • Decreased myocyte viability (lamins) • Calcium cycle dysregulation (mainly through SERCA, Phospholamban and Ca binding proteins)
- 41. Dystrophin • Severe dilated cardiomyopathy • Elevated CK • Mutations in 5’ end or promoter region of dystrophin gene cause cardiomyopathy Muntoni, Melacini 1993, Milasin 1996
- 43. Truncated Titin mutations in DCM: the rise of a Titan - Found in 25% of familial and 18% of sporadic forms of DCM - Found in 3% of controls
- 46. Keren A, BillinghamME, Popp RL. J Am Soc Echo 1988;1:78-87 LVEDP 28mmHg LVEDP 29mmHg LVEDP 26mmHg
- 47. A/C mutationLamin Fatkin D, NEJM 1999;341:1715-1724 DCM Atrial arrhythmias, sinus bradycardia, heart block Sudden death
- 48. LMNA Gene Defects : Nuclear Membrane Fragmentation and Pathologic Degeneration of the AV Junction Arbustini E et al. JACC 2002;39:981-90
- 49. Survival in Lamin A/C Mutation 75% 30% Taylor M et al. JACC 2003;41:771-80 Familial DCM Registry Rresearch Group
- 50. KY European J Heart Fail 2013;15:628-636 Spaendonck-Zwartsvan Pinto YM, ESC Congress 2014 LMNA mutations are associated with worst survival in large cohorts of DCM
- 51. van Berlo JH, Pinto YM et al. J Mol Med 2005;83:79-83 * * Same proportion of SD in neuromuscular type (43%) as in the isolated cardiac type* (50%) Carriers of LMNA Gene Mutations299Meta-analysis of Clinical Characteristics of
- 52. Primary prevention of sudden death in Lamin A/C gene mutations • 19 pts with LMNA, conduction defect & LVEF 58+12% had ICD instead of pacemaker implant • 9 of 19 (45%) received an appropriate ICD intervention for VT/VF during 39 mo’s fup • The data suggest that these pts are at high risk of SCD before onset of clinical featured of DCM Meune C et al. N Engl J Med. 2006; 354: 209-210
- 54. Risk factors - NSVT, LVEF< 45%, male (3) - Non-missense mutations (ins-del/truncating, or mutations affecting splicing) (4). Risk factors - NSVT, LVEF< 45%, male (3) Risk of malignant arrhythmias in 269 LMNA mutation carriers van Rijsingen IAW, JACC 2012;59:493-500
- 55. In pts with Lamin A/C mutations institution of early treatment including ICD is recommended
- 56. Left Ventricular ARVC (Arrhythmmogenic Cardiomyopathy - AC) Thiene G et al. Cardiovasc Path 2005;14:165 UCLH London, UK
- 58. LEFT VENTRICULAR INVOLVEMENT IN ARVC 76% WITH LV INVOLVEMENT
- 59. Domain Binding to DesminDesmoplakinMutation in LV ARVCCauses - 2034insA mutation 10 individuals: ARVC+LV involvement 7 Inf/Lat T wave changes 8 RBBB ventricular arrhythmia 3 exercise syncope Norman M et al. Circulation 2005;112:636-642Norman M et al. Circulation 2005;112:636-642
- 60. Fibrofatty Replacement on LV Histology X 10 X 20
- 61. Atlas of the clinical genetics of human dilated cardiomyopathy Haas J et al. European Heart Journal 2015; 36:1123–1135 pts with DCM, 8 countries- 639 (46%) with known disease causing - 294 mutation % compound or combined mutations (2)- 38 3 mutations>% - 13
- 62. In 2003 the human genome project was completed. It took 13 years, involved 20.000 researchers at a cost of $3 billions nextUsing NGS, the sequencing of human genome requires a laboratory technician, generation sequencing device and about $5.000
- 63. Spaendonck-Zwarts KY EuropeanJ Heart Fail 2013;15:628-636 van Mutations found in 20% of 418 probands with DCM evaluated by standard genotyping techniques
- 65. Conclusions • DCM is the most common and malignant cardiomyopathy • Etiology can be genetic, infectious, autoimmune or toxic • The genetic forms represent up to 50% of cases • In virus negative inflammatory cardiomyopathy trial of immunosuppressive treatment has to be considered