1、 The 4th China-Japan Cardiovascular Forum New Classifications of Cardiomyopathies Akira Matsumori, MD, PhD, FACC, FAHA, FESC President, International Society of Cardiomyopathies and Heart Failure Secretary, World Heart Federation Chairman, Scientific Advisory Board 113:1807-1816 Ion Channel Disorder
2、s LQTS Brugada SQTSCPVT Asian SUNDS *Predominantly nongeneticPRKAG2 Danon Glycogen Storage Secondary Cardiomyopathies Infiltrative Storage Toxicity Endomyocardial Inflammatory (granulomatous) Endocrine Cardiofacial Neuromuscular/ neurological Nutritional deficiency Autoimmune/ collagen Electrolyte i
3、mbalance Consequence of Cancer therapy Circulation 2006; 113:1807-1816 Gene Mutations Associated with Multiple Phenotypes of Cardiomyopathies -Myosin heavy chain Cardiac troponin T -Tropomyosin Cardiac myosin binding Protein C Cardiac troponin I Actin Titin Desmin Muscle LIM protein Telethonin Desmo
4、plakin Plakoglobin Gene Phenotypes HCM DCM RCM ARVC/D Sarcomere proteins Z-disc protein Desmosome protein Intermediate filaments Hypertrophic Cardiomyopathy About half of cases show familial occurrence. About half of familial HCM have gene mutations of sarcomere proteins (25% of total HCM). Specific
5、 (Secondary) cardiomyopathies often show HCM phenotype. Storage: Fabrys disease Inflammatory: Sarcoidosis HCV cardiomyopathy Coxsackie B virus Adenovirus Hepatitis C virus Dilated Cardiomyopathy Myocarditis Viral Infection and Phenotypes of Cardiomyopathies Circulation 1995; 92: 2519-2525 Biochem Bi
6、ophys Res Commun 1996; 222: 678-682 Lab Inv. 2000; 80: 1137-1142 Hypertrophic Cardiomyopathy Viral Infection of the Heart Diffuse CHF/DCM Systolic HF Regional Aneurysm Subendocardial RCM Diastolic HFARVC/DLV Aneurysm Random Hypertrophy/HCM Virus Receptor Myocyte Fibroblast Complete recovery Diffuse
7、hypokinesis Regional abnormality Subendocardial lesions Increased wall thickness Unclassified abnormality Viral Myocarditis CHF/DCM Systolic HF HCMRCMARVC/D Diastolic HF Hepatitis C Virus LV Aneurysm ARVCHCMDCMMyocarditis Matsumori A Circ Res 2005;96:144-147 Hypertrophic Obstructive Cardiomyopathy A
8、ssociated with HCV Infection HE CoreA-2 Immunohistochemical Staining of HCV Core Antigen in the Heart of a Patient with HCM Apical Hypertrophic Cardiomyopathy Associated with HCV Infection Endomyocardial Biopsy in Patients with HCM with HCV Infection A Patient with HCM, Hepatitis and Nephritis Assoc
9、iated with HCV Infection Biopsy Finding in a Patient with Hypertropic Cardiomyopathy, Hepatitis and Nephritis Kidney Heart Liver Acute Hepatitis Chronic Hepatitis Liver Cirrhosis MyocardialFibrosis DCM Acute Myocarditis Chronic Inflammation Hepatic Failure HCC HCM 85% 20% 6% 4% HCV Hepatitis HCV Car
10、diomyopathies An Atypical Variant of Fabrys Disease in Men with Left Ventricular Hypertrophy. Nakao S et al NEJM 1995;333:288-293 Fabrys disease is an X-linked recessive disorder that results from a deficiency of -galactosidase. Seven of the 230 patients (3%) of HCM. Fabrys Disease Presented as HCM
11、Alpha-galactosidase activity 0.7 n moles/hr/ml (Normal 4.8-17.6 n moles/hr/ml) IVST 20 mm LVPWT 11 mm LVEDD 58 mm LVESD 45 mm LVEF 45% UCG 201 Tl Scintigraphy Increased uptake at IVS and anterior wall Increased LV cavity compared to those of 1.5 yr before. Heart Disease in Friedreichs Ataxia Observa
12、tion of a Case for Half a Century. Kawai C, Kato S et al Jpn Circ J 2000;64:229-236 IVST 14mm LVPWT 12mm Disarrangement of bizzare-shaped myocardial fibers with hypertrophy and interstitial fibrosis Hypertrophic Cardiomyopathy as a Manifestation of Cardiac Sarcoidosis. Matsumori A et al Jpn Circ J 2
13、000;64:679-683 Six of 82 (7.3%) patients with sarcoidosis have echocardiographic abnormality. Four of 82(4.8%) showed phenotype of HCM. ASH: 2 cases, APH: 1 case Department of Cardiovascular Medicine, Kyoto University LV Aneurysm in a Patient with HCV Cardiomyopathy VT, Hepatitis C (IFN Rx), Lymphad
14、enopathy FH: Hepatitis C, HCC in 2 brothers UCG: IVS 16mm, LVPW 13mm, LVDd 47mm, LVDs 37mm, EF 36% RAO ED ES MT 52 M Detection of HCV RNA in Heart Tissues from Patients with ARVC n Positive n Frequency WHF Council of Cardiomyopathies National Cardiovascular Center, Japan 6 3 9 2 2 4 33.0% 66.7% 44.4
15、%Total Immunohistochemical Staining of HCV Core Protein in the Heart from Patients with ARVC/D Genetic Background of the Host Influences the Phenotype of Cardiomyopathies HLA and HCM HLA-DRW4 antigen linkage in patients with hypertrophic obstructive cardiomyopathy Matsumori A et al. Am Heart J. 1981
16、;101:14-16. HLA in hypertrophic cardiomyopathy and rheumatic heart disease Matsumori A et al. Jpn Circ J 1979;43:445-449 HL-A and Hypertrophic Cardiomyopathy Matsumori A et al. Am Heart J 1979;97:428-431 Frequencies of DPB1 Alleles in Patients With HCV-Associated Cardiomyopathy and Controls Both DPB
17、1*0401 and DPB*0901 was significantly associated with HCV-HCM (* P0.05), whereas none of DPB1 allele demonstrated significant association with HCV-DCM Shichi D, Matsumori A, et al. Int J Immunogenet 2008;35:37-43 DPB1 allele HCV-HCM (2n=76) HCV-DCM (2n=42) Control (2n=264) *0201 0.145 0.143 0.205 *0
18、301 0.053 0.095 0.057 *0401 0.079* 0.024 0.023 *0501 0.368 0.381 0.413 *0601 0.013 0.004 *0901 0.184* 0.119 0.095 Association with Polymorphic of DP-Chain in HCV-HCM Shichi D, Matsumori A, et al. Int J Immunogenet 2008;35:37-43 Position Amino acidresidue Cases (n=38)+ - DP 8 DP 9 DP 11 DP 36 DP 55 D
19、P 57 DP 76 Leu Phe Gly Ala Ala Glu Met Controls (n=132) + - OR (95% CI) P Pc 6 6 6 31 31 6 6 129 129 129 7 7 129 129 3 3 3 125 125 3 3 32 32 32 7 7 32 32 0.12 (0.03-0.52) 0.12 (0.03-0.52) 0.12 (0.03-0.52) 4.03 (1.32-12.35) 4.03 (1.32-12.35) 0.12 (0.03-0.52) 0.12 (0.03-0.52) 0.004 0.004 0.004 0.017 0
20、.017 0.004 0.004 0.008 0.012 0.008 0.034 0.051 0.008 0.012 (Pockets) (6) (9) (6) (9) (9) (-) (4) The polymorphic residues from DPB1 alleles located in P9 pockets (at position 36A and 55A) showed positive associations with HCV-HCM. In contrast, five polymorphic residues showed significant negative as
21、sociations: 76M in P4 pockets; 8L and 11G in P6 pockets; 9F in P9 pockets and 57E adjacent to P9 pocket. Quite interestingly, all the residues showing significant positive or negative associations composed of DPB1*0401. The Susceptible Gene Mapping for HCV-DCM and HCM with Microsatellite Markers thr
22、oughout the HLA region Odds Ratio Corrected P Susceptibility to HCV-DCM was mapped at the locus spanning from NFKBlL1 to BAT1 loci within the HLA class III subregion. HCV-HCM was associated with DPB1 alleles. The candidate genes may encode molecules involved in the immunity and inflammation. Shichi
23、D et al Tissue Antigen 2005:66:200 HCM DCM HLA and HCV Infection Our study provides new and suggestive information on the immunological involvement of DPB1 gene in the HCV-HCM development. The polymorphic amino acids residues by which the DP chain adopt specificity pocket appear to influence on dise
24、ase-susceptibility at the allelic manner level. The existence of different risk alleles among HCV-related diseases including chronic liver disease, asymptomatic carrier and HCV- DCM suggests that each clinical outcome may arise from distinct pathogenic conditions on the basis of differential HLA-med
25、iated immune responses. Etiology of HCM HCM Genetic Inflammatory Sarcomere Storage Virus Unknown Etiology of DCM DCM Genetic Inflammatory Sarcomere Storage Virus Unknown Etiology of ARVC/D ARVC/D Genetic Inflammatory Virus Unknown Definition and Classifications of Cardiomyopathies I. Etiological Cla
26、ssification II. A. Genetic III. B. Infectious IV. C. Nutritional V. D. Unknown VI.II. Anatomical (Structural) Classification A. Dilated a. LV b. RV B. Hypertrophic a. Septum b. Diffuse c. Free wall d. Apex III. Physiological (mechanical) Classification A. Systolic failure/dysfunction B. Diastolic fa
27、ilure/dysfunction C. Both D. Normal function IV. Electrical Classification A. Ion channel disorders B. Conduction system disease C. Others Definition and Classifications of Cardiomyopathies ISFC Classification Proposed Classification DCM (with viral infection) DCM (with gene mutation) HCM (with gene
28、 mutation and outflow obstruction) Apical HCM (with unknown causes) Apical HCM (with HCV infection) ARVC/D (with gene mutation) ARVC/D (with HCV infection) Long QT Syndrome I B, II A a, III A I A, II A a, III A I A, II B a, III B I D, II B d, III B I B, II B d, III B I A, II A b, III A I B, II A b,
29、III A I A, ，IV A I. Etiological II. A. Genetic III. B. Infections IV. C. Nutritional V. D. Unknown VI. II. Anatomical (Structural) A. Dilated a. LV b. RV B. Hypertrophic a. Septum b. Diffuse c. Free wall d. Apex III. Physiological (mechanical) A. Systolic failure/dysfunction B. Diastolic failure/dysfunction C. Both D. Normal Function IV. Electrical Classification A. Ion channel disorders B. Conduction system disease C. Others
