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  1. Cardiomyopathies Andre Keren, MD דר' ישראל גוטסמן מערך הלב, הדסה עין כרם

  2. Cardiomyopathies • Cardiomyopathies: Heart muscle disease • A myocardial disorder in which the heart muscle is structurally and functionally abnormal in the absence of: coronary artery disease, hypertension, valvular disease and congenital heart disease

  3. Cardiomyopathies • Dilated CM(DCM) • Hypertrophic CM (HCM) • Restrictive CM (RCM) • Arrhythmogenic RV dysplasia (ARVD)

  4. Classification of Cardiomyopathies Hypertrophic Dilated Arrhythmogenic RV dysplasia Restrictive

  5. Normal • Dilated CM • (DCM) Hypertrophic CM (HCM) • Restrictive CM • (RCM)

  6. ממצאים מורפולוגיים

  7. קליניקה עיקרית

  8. Pathogenesis

  9. SarcomereBasic Unit of The Muscle

  10. Genetics of CMP • Genes encoding: • Cytoskeletal proteins – DCM: • Beta/delta-sarcoglycan • Dystrophin • desmin and lamin A/C (intermediate filament) • Sarcomeric proteins – • DCM/HCM: • Actin • b-myosin heavy chain • a-tropomyosin • cardiac troponin T • HCM: • cardiac troponinI • titin • myosin light chains

  11. Genetics of CMP

  12. Genetics of CMP HCM DCM Functional alterations caused by Z-disc mutations

  13. Hypertrophic Cardiomyopathy (HCM)

  14. Hypertrophic Cardiomyopathy (HCM) • Most common genetic cardiovascular disease • Prevalence 0.2% (1:500) • Autosomal dominant trait • Gene mutations of cardiac sarcomere proteins • 18 genes and >500 individual mutations have been identified…

  15. Genetic Mutations in HCM Spirito P, Seidman CE, McKenna WJ, Maron BJ. NEJM 1997;336:775

  16. Major Mutations in HCM:Risk of sudden death • Beta myosin heavy chain (35%): Typical features, both malignant and benign types • Myosin binding protein C (15%): Late appearance, usually benign • Troponin T (15%): Mild hypertrophy, malignant

  17. Non-Sarcomeric mutations that causeStorage diseases and mimic LV Hypertophy • Anderson-Fabry disease: X-linked lysosomal storage disease (a-galactosidase A) • PRKAG2 mutation Glycogen accumulation • Danon disease: LAMP2 mutation X-linked Massive hypertrophy, preexitation, malignant prognosis

  18. Hypertrophic Cardiomyopathy (HCM) LV Hypertrophy LVOT obstruction

  19. LV Hypertrophy HCM AO SEPTUM LV

  20. Natural History of LV Hypertrophy Increase in LV hypertrophy after adolescence

  21. HCM - Histopathology Normal • Myocardial Disarray • Fibrosis Small-vessel disease: Remodeled intramural coronary arteriole with thickened media and narrowed lumen

  22. Pathophysiology Mitral valve Abnormalities Mitral Regurgitation SAM Systolic Anterior Motion of MV ASH Asymmetric septal hypertrophy LVOT obstruction Left Ventricular Outflow Obstruction (Dynamic) Diastolic dysfunction

  23. Clinical Presentation • Sudden death – ventricular tachyarrhythmias • Asymptomatic • Chest Pain • Limited functional capacity • Progressive heart failure • Embolic stroke

  24. Symptoms • Exertionaldyspnea, Exercise intolerance • Fatigue • Chest pain • Syncope Pathophysiology • LV outflow obstruction - elevated LV pressures and wall stress • Diastolic dysfunction - impaired LV filling due to noncompliant and thickened wall • Myocardial ischemia from the small vessel disease

  25. Diagnosis • Examination: Characteristic findings • ECG: LVH • Echo: Most useful diagnostic tool • ECG Holter: Arrhythmias • Stress test: Blood pressure response • Catheterization: rule out associated CAD

  26. Physical findings in HOCM Bisferiens LVOT 4 Triple MR

  27. Maneuvers and HOCM Murmur • Murmur increase: • Valsalva maneuver • Exercise • Standing

  28. ECG in HCM • Abnormal in 90% of patients LVH, ST-T changes, T wave inversion

  29. Echocardiography in HCM LVH, ASH, SAM, MR

  30. Natural History of HCM

  31. Mortality in HCMHigher in younger patients - SCD

  32. Functional Capacity and SCD

  33. Causes of SCD in young athletes HCM is the major cause of SCD in young & in athletes

  34. LV Hypertrophy and SCD Significant increase in SCD risk if Max Wall thickness >30mm

  35. Risk Stratification • Risk Factors: • Cardiac arrest/sustained VT • Multiple familial SD • Unexplained syncope • Massive LVH (>3cm) • Multiple-repetitive NSVT • Abnormal blood pressure on exercise • Malignant genotype (troponinT) • End stage disease • Extensive delayed enhancement on MRI • Marked LVOT outflow obstruction (rest) ICD 11%/yr Highest (>2) 4%/yr ? Intermediate (1) Lowest (0)

  36. Therapy • Reduce LVOT obstruction • Alleviate elevated diastolic pressures • Reduce microvascular ischemia Beta Blockers, Verapamil, Disopyramide • Atrial Fibrillation Amiodorone, Anticoagulants • Heart Failure HF therapy

  37. Therapy Interventions to reduce LVOT obstruction: • Pacemaker (DDD): Reduces obstruction • Alcohol septal ablation • Surgical myomectomy

  38. Septal Myomectomy in HOCM Nishimura RA. NEJM 2004;350:1320-7

  39. Septal Ablation in HOCM NEJM 347:1307,2002 A. Keren

  40. Septal Ablation in HOCMAcute Hemodynamic Result

  41. Dilated Cardiomyopathy (DCM) Dilated Cardiomyopathy (DCM) Normal Heart

  42. Dilated Cardiomyopathy (DCM)

  43. Dilated Cardiomyopathy (DCM) • Myocarditis: Viral/ Inflammatory • Idiopathic (50%) • Genetic

  44. Dilated Cardiomyopathy (DCM) • Sensitivity and toxins: alcohol, catecholamines, anthracyclines, irradiation • Metabolic cardiomyopathy: endocrine abnormalities, glycogen storage disease, deficiencies (hypokalemia), and nutritional disorders • General systemic disease: connective tissue disorders and infiltrative diseases: sarcoidosis and leukemia • Muscular dystrophies: Duchenne, Becker-type, myotonic dystrophies • Neuromuscular disorders: Friedreich ataxia, Noonan syndrome, lentiginosis

  45. Dilated Cardiomyopathy (DCM) • Peripartum • Tachycardia-mediated • Sarcoidosis

  46. Dilated Cardiomyopathy (DCM)Familial Genetic (~50%): • Family history • Genetic testing: low yield even in familial DCM (20-30%) • Promising future (?) with deep sequencing

  47. Myocarditis Genetics Immune Response Virus Dilated Cardiomyopathy

  48. Clinical Presentation Development of symptoms and signs of heart failure • Gradual symptoms or incidental finding • Progressive symptoms for periods varying from weeks to months with acute HF due to intercurrent illnesses • Aggressive, life-threatening fulminant heart failure (fulminant lymphocytic myocarditis, giant cell myocarditis)