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IDIOPATHIC DILATED CARDIOMYOPATHY

IDIOPATHIC DILATED CARDIOMYOPATHY. NEW INSIGHTS INTO PATHOGENESIS AND TREATMENT Dartmouth-Hitchcock Medical Center April 2004. ETIOLOGIES OF DILATED CARDIOMYOPATHY. Felker et al NEJM 2000. IDIOPATHIC DILATED CARDIOMYOPATHY PATHOLOGY. Four chamber dilatation

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IDIOPATHIC DILATED CARDIOMYOPATHY

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  1. IDIOPATHIC DILATED CARDIOMYOPATHY NEW INSIGHTS INTO PATHOGENESIS AND TREATMENT Dartmouth-Hitchcock Medical Center April 2004

  2. ETIOLOGIES OF DILATED CARDIOMYOPATHY Felker et al NEJM 2000

  3. IDIOPATHIC DILATED CARDIOMYOPATHYPATHOLOGY • Four chamber dilatation • Mild to moderate ventricular hypertrophy • Varying degrees of interstitial fibrosis and myocyte hypertrophy • “Functional” atrioventricular regurgitation is common • Normal epicardial coronary arteries

  4. IDIOPATHIC DILATED CARDIOMYOPATHYPATHOLOGIC FINDINGS

  5. IDIOPATHIC DILATED CARDIOMYOPATHYPATHOGENESIS • Familial/genetic factors • Viral myocarditis and cytotoxic insults • Immunologic abnormalities • Beta-receptor auto-antibodies • Abnormal T-cell function • Metabolic, energetic, and contractile abnormalities • Ca2+-ATPase • Myofibrillar ATPase • Creatine Kinase

  6. FAMILIAL DILATED CARDIOMYOPATHY • 767 asymptomatic relatives of 183 consecutive patients were evaluated echocardiographically and clinically between 1992-1998 • 5% had asymptomatic dilated cardiomyopathy • 3% had isolated impaired fractional shortening (FS<25%) • 14% had unsuspected left ventricular enlargement (LVEDD > 112% predicted) • Endomyocardial biopsy of a cohort of asymptomatic relatives with ventricular enlargement (n= 32) demonstrated ICAM-1 expression, endothelial HLA class II (DR) antigen expression, and CD3+ cells in 37%, 64%, and 25%, respectively. Baig MK et al. JACC 1999:31:195-201; Mahon NG et al. JACC 2002;39:455-62

  7. MOLECULAR DEFECTS IN DILATED CARDIOMYOPATHY GENES Lamin A/C δ-sarcoglycan Dystrophin Desmin Vinculin Titin Troponin-T α-tropomyosin ß-myosin heavy chain Actin Mitochondrial DNA mutations Fatkin D, et al. NEJM 1999;341

  8. FAMILIAL DILATED CARDIOMYOPATHYCOMMON ASSOCIATED ABNORMALITIES • Conduction system disease • Skeletal muscle myopathy or muscular dystrophy • X-linked and autosomal dominant inheritance patterns are most common • Extracardiac manifestations: • Sensorineural hearing loss • Neutropenia

  9. HISTOPATHOLOGY OF ACUTE LYMPHOCYTIC MYOCARDITIS

  10. INCIDENCE OF BIOPSY-PROVEN MYOCARDITIS IN PATIENTS WITH DILATED CARDIOMYOPATHY Series Year Patients Positive Biopsy Kunkel et al 1978 66 6% Mason et al 1980 400 3% Noda 1980 52 0.5% Baandrup et al 1981 132 1% O’Connell et al 1981 68 7% Nippoldt et al 1982 170 5% Fenoglio et al 1983 135 25% Unverferth et al 1983 59 6% Parillo et al 1984 74 26% Zee-Cheng et al 1984 35 63% Daly et al 1984 69 17% Bolte et al 1984 91 20% Hosenpud et al 1985 38 16% Mason et al 1995 2233 10% McCarthy et al 1997 1757 14% TOTAL 5379 11.5%

  11. RELATIONS AMONG BIOPSY TIMING, CLINICAL FEATURES, AND BIOPSY POSITIVITY FOR MYOCARDITIS Time from Number of Clinical Positive illness onset patients features biopsy to biopsy score 0-4 weeks 9 2.1* 89%** 4-12 weeks 10 2.3 70% 12-26 weeks 8 0.9* 38%** * p< 0.05; **p<0.02 Dec GW, et al. N Engl J Med 1985;312:885-90.

  12. NON-INVASIVE EVALUATION OF MYOCARDITISMRI IMAGING Unenhanced Enhanced Friedrich MG et al. Circulation 1998;97:1802-9.

  13. MRI ASSESSMENT OF BIOPSY-PROVEN MYOCARDITIS Mahrholdt H, et al. Circulation 2004;109:1253

  14. SURVIVAL IN IDIOPATHIC DILATED CARDIOMOPATHY VERSUS MYOCARDITIS 100 80 60 Survival (%) 40 Myocarditis (n=27) IDCM (n=58) 20 0 0 2 4 6 Years Grogan, et al JACC 1995 CP977755-7

  15. IDIOPATHIC DILATED CARDIOMYPATHYEPIDEMIOLOGY • ANNUAL INCIDENCE 5-8/100,000 • PREVELANCE 36/ 100,000 • INCREASED RISK ASSOCIATED WITH: • MALE GENDER • BLACK RACE • HYPERTENSION • CHRONIC BETA-AGONIST USE

  16. IDIOPATHIC DILATED CARDIOMYPATHYCLINICAL PRESENTATIONS • Heart failure symptoms 75%-85% • Anginal chest pain 8%-20% • Emboli (systemic or pulmonary) 1%-4% • Syncope <1% • Sudden cardiac death <1%

  17. IDIOPATHIC DILATED CARDIOMYOPATHYNATURAL HISTORY Dec GW, Fuster V. NEJM 1994;331:1564-75

  18. SPONTANEOUS IMPROVEMENT IN ACUTE DILATED CARDIOMYOPATHY • PATIENT POPULATION 49 patients with heart failure symptoms of less than 6 months duration were compared to a cohort of 248 chronic dilated cardiomyopathy patients • Improvement was prospectively defined as a rise in LVEF > 0.15 to a final value of > 0.30 -Steimle AE et al. JACC 1994;23:553-9

  19. ACUTE DILATED CARDIOMYOPATHYOUTCOME 49 Patients with Recent Onset Cardiomyopathy 12 Died/10 Tx 16 Alive & Unimproved 11 Improved 18 Died/13 Tx 5 Alive & Unimproved 13 Improved 11±15 mos 27 ± 22 mos 43 ± 29 mos 12 months 9 9 2 5 Steimle et al JACC 1994;23:553-9

  20. SPONTANEOUS IMPROVEMENT IN ACUTE DILATED CARDIOMYOPATHY UNIVARIATE PREDICTORS OF IMPROVEMENT short duration of symptoms higher cardiac output lower NYHA functional classification smaller LV end-diastolic dimension lower filling pressures higher serum sodium concentration STEPWISE REGRESSION MODEL short duration of symptoms higher serum sodium concentration lower right atrial pressure lower pulmonary capillary wedge pressure -Steimle AE, et al. JACC 1994;23:553-9

  21. SURVIVAL IN ACUTE DILATED CARDIOMYOPATHY

  22. CHANGE IN LVEF BY LVEDD: IMAC Trial LVEF LVEDD (cm) N=82 McNamara D, et al. AHA, 2001

  23. IDCM:PROGNOSTIC FEATURES • VENTRICULOGRAPHIC FINDINGS • Degree of impairment in LVEF • Extent of left ventricular enlargement • Coexistent right ventricular dysfunction • Ventricular mass/volume ratio • Global wall motion abnormalities • Left ventricular sphericity • CLINICAL FINDINGS • Favorable prognosis: NYHA < IV, younger age, female sex • Poor prognosis: Syncope, persistent S3 gallop, right-sided heart failure, AV or bundle branch block, hyponatremia, troponin elevation, increased BNP, maximum oxygen uptake < 12 mg/kg/min

  24. ACC/AHA HEART FAILURE EVALUATION GUIDELINESCLASS I & II RECOMMENDATIONS • Laboratory Studies • Blood count, urinalysis, electrolytes, renal function, glucose, LFTs (class I; level C) • Thyroid stimulating hormone (class I; level C) • Fe/TIBC, ferritin (class IIa, level C) • Urinary screening for hemochromatosis (class IIa; level C) • Measurement of ANA, rheumatoid factor, urinary VMA and metanepherines in selected patients (class IIa; level C) • HIV testing (class IIb; level C) • Electrocardiogram (class I; level C) • Chest x-ray (class I; level C) • Echocardiogram/Doppler or radioventriculogram (class I;level C) -Adapted from Hunt SA et al. Circulation 2001;104:2996-3007

  25. OUTCOME IN IDIOPATHIC DILATED CARDIOMYOPATHYPREDICTIVE VALUE OF TROPONIN T N=33 Grp 1: TnT < 0.02 ng/mL during follow-up period Grp 2: TnT > 0.02 ng/mL initially but fell to < 0.02 ng/mL during follow-up Grp 3: TnT > 0.02 ng/mL throughout follow-up period N=10 Event-Free Rate (%) N=17 Months Sato Y et al. Circulation 2001;103:372

  26. DILATED CARDIOMYOPATHYELECTROCARDIOGRAPHIC FINDINGS Disease Etiology Pathologic Q-waves Ischemic cardiomyopathy 10/12 (83%)* (n=15) Idiopathic cardiomyopathy 2/21 (10%)+ # (n=21) *LBBB (n=2); paced rhythm (n=1) + LVH (n=10); IVCD (n=3) # P < 0.003 Feld H, et al. Am J Med 1993;94:547-8

  27. SEGMENTAL WALL MOTION ABNORMALITIES IN DILATED CARDIOMYOPATHY • Regional wall motion abnormalities observed in at least 50% of patients with non-ischemic causes of dilated cardiomyopathy • Most frequent wall motion abnormalities: • anterior wall & apex • Posterior and lateral walls most likely to be preserved • Type of abnormality: • hypokinesis (83%) • akinesis (11%) • dyskinesis (6%) • Heterogeneity in regional oxidative metabolism using C-11 acetate clearance has been demonstrated in DCM AJC 1990;65:364-70; Arch Int Med 1992;152:769-72; JACC 1995;25:1258-62

  28. MYOCARDIAL CONTRACTILE RESERVE PREDICTS IMPROVEMENT IN DILATED CARDIOMYOPATHY Naqvi TS et al. J Am Coll Cardiol 1999;34:1537-44

  29. NONINVASIVE ASSESSMENT OF CORONARY ARTERY DISEASE IN NEW ONSET DILATED CARDIOMYOPATHY • Retrospective studies have shown up to 94% of patients with idiopathic dilated cardiomyopathy will have myocardial perfusion defects • Reversible defect(s): 60% • Fixed defect(s): 15% • Reversible+ fixed defect(s): 25% • Global myocardial blood flow reserve (dipyridamole-induced) is diminished in DCM patients compared to controls using PET imaging • Low myocardial blood flow reserve correlates with high left ventricular wall stress and anaerobic metabolism Ann Inter Med 1992;152:679-72; JACC 2000;35:19-28.

  30. INDICATIONS FORCORONARY ANGIOGRAPHY IN NEW ONSET CARDIOMYOPATHYACC/AHA CONSENSUS GUIDELINES (2001) • Patients with Known Coronary Artery Disease/Angina Pectoris • Revascularization recommended in vast majority of such individuals with multivessel disease. Little role for non-invasive testing. • Coronary angiography considered Class I Recommendation (Level of evidence: B) • Patients with Known Coronary Artery Disease Who Lack Angina • No controlled trials have examined whether coronary revascularization can improve outcomes in this population • Many centers first evaluate patient for myocardial hibernation • Coronary angiography considered Class IIa Recommendation (Level of Evidence:C) • Patients with or without Chest Pain in Whom Coronary Artery Disease has Not Been Evaluated • Approximately 35% of patients with IDCM will report angina-like pain • Coronary angiography should be considered Class IIa recommendation (Level of Evidence: C) Hunt SA,et al. Circulation 2001;104:2996

  31. ENDOMYOCARDIAL BIOPSY IN DILATED CARDIOMYOPATHY RIGHT VENTRICULAR BIOPSY TECHNIQUE

  32. INDICATIONS FOR ENDOMYOCARDIAL BIOPSY • Acute dilated cardiomyopathy with refractory heart failure symptoms • Rapidly progressive ventricular dysfunction in an unexplained cardiomyopathy of recent onset • New onset cardiomyopathy with recurrent ventricular tachycardia or high grade heart block • Heart failure in the setting of fever, rash, and peripheral eosinophilia • Dilated cardiomyopathy in setting of systemic diseases known to affect the myocardium (systemic lupus erythematosus, polymyositis, sarcoidosis) Wu LA, et al. Mayo Clin Proc 2001;76:1030-8

  33. GCM group LM group SURVIVAL BY HISTOPATHOLOGICAL TYPE OF MYOCARDITIS Proportion surviving Survival (yr) Cooper, et al NEJM 1997 CP977755-6

  34. DILATED CARDIOMYOPATHYPROVEN THERAPEUTIC OPTIONS TREATMENT INDICATIONS ACE Inhibitors Symptomatic heart failure and asymptomatic LV dysfunction ARBs ACE intolerance Hydralazine- nitrates ACE intolerance Diuretics Volume overload Potassium/Magnesium Diuretic-induced depletion Beta-blockers Symptomatic heart failure in addition to ACE inhibitor Digoxin Persistent heart failure despite diuretics, ACE inhibitor Warfarin Chronic or paroxysmal atrial fibrillation LV thrombus or prior embolic event ICD Cardiac arrest; uncontrolled VT

  35. STATIN THERAPY IMPROVES VENTRICULAR FUNCTION IN DILATED CARDIOMYOPATHY Node K, et al. Circulation 2003;108:839-43

  36. CONTROLLED TRIAL OF IMMUNE GLOBULIN IN RECENT ONSET DILATED CARDIOMYOPATHY Purpose: To determine whether intravenous immunoglobulin G (IVIG) improves ejection fraction in adults with recent onset idiopathic dilated cardiomyopathy or myocarditis Methods: 62 patients with symptomatic DCM < 6 months and LVEF < 40% were randomized to receive IVIG 2 g/kg or placebo Study Population: Age (mean) 43 ± 12 yrs LVEF 25 ± 8% Symptom duration 2.0 ± 1.5 months Myocarditis 16% McNamara et al. Circulation 2001;103:2254-9

  37. IMMUNOGLOBULIN THERAPY FOR ACUTE DILATED CARDIOMYOPATHY:IMAC TRIAL RESULTS McNamara et al. Circulation 2001;103:2254-9

  38. IMMUNOADSORPTION THERAPY FOR DILATED CARDIOMYOPATHY12 MONTH AUTOANTIBODY LEVELS BY TREATMENT GROUP Muller J et al. Circulation 2000;101: 385 - 391

  39. IMMUNOADSORPTION THERAPY FOR DILATED CARDIOMYOPATHY12 MONTH CHANGE IN EJECTION FRACTION BY TREATMENT GROUP Muller J et al. Circulation 2000;101: 385 - 391

  40. EFFECT OF REMOVAL OF ANTIBODIES BY IMMUNOADSORPTION IN DILATED CARDIOMYOPATHY Effect of column effluent on adult rat cardiocyte contractility n=12 Felix SB, et al. JACC 2002;39:646-52

  41. CONTROLLED TRIAL OF IMMUNOADSORPTION AND IMMUNOGLOBULIN SUBSTITUTION IN DILATED CARDIOMYOPATHY Hypothesis: Immunomodulatory therapy may decrease myocardial inflammation and improve ventricular systolic function Methods: 25 patients with DCM were randomized to immunoabsorption (IA) followed by IgG (0.5 gm/kg) replacement for 3 consecutive months (n=12) or conventional therapy (n=13): Age: 50 ± 11 years LVEF: 20% ± 6% Symptom Duration: 4.0 years Fibrosis: 8.7% Primary End-points: Change in LVEF (3 month) Change in CD3+, CD4+ & CD8+ cells Staudt A et al. Circulation 2001;103:2681-8

  42. IMMUNOABSORPTION AND REPLACEMENT TREATMENT FOR DILATED CARDIOMYOPATHYCHANGES IN CELLULAR INFILTRATION (3 months) IA/IgG treatment resulted in a significant decline in all subtypes of infiltrating lymphocytes ** p < 0.05 vs baseline ++ p < 0.05 vs controls Staudt A et al. Circulation 2001;103:2681-8

  43. IMMUNOABSORPTION AND REPLACEMENT TREATMENT FOR DILATED CARDIOMYOPATHY A marked decrease in myocardial HLA-class II antigen expression is evident after 3 months of treatment (magnification X 400) Staudt A et al. Circulation 2001;103:2681-8

  44. CONTROLLED TRIAL OF IMMUNOADSORPTION AND IMMUNOGLOBULIN SUBSTITUTION IN DILATED CARDIOMYOPATHYCHANGE IN LEFT VENTRICULAR FUNCTION (3 Months) **p <0.05 vs baseline ++p < 0.01vs controls Staudt A et al. Circulation 2001;103:2681-8

  45. IMMUNOSUPPRESSIVE THERAPY FOR INFLAMMATORY DILATED CARDIOMYOPATHY Purpose:To assess the efficacy of immunosuppressive therapy in patients with dilated cardiomyopathy and HLA up-regulation on biopsy. Study Population:84 (of 202 DCM) patients had HLA class I or II expression on myocytes, endothelium or interstitial cells and were randomized to 24 months of conventional therapy [digoxin, furosemide, spironolactone, ACE inhibitor, beta-blocker, nitrates, and amiodarone] alone or with concomitant immunosuppression [prednisone 1mg/kg/day taper to 0.2 mg/kg/day for 90 days + azathioprine 1 mg/kg/day for 100 days]. Primary Endpoint: Death, transplantation or hospital readmission Secondary Endpoints: LVEF, LVEDD, LVESD, NYHA class Wojnicz R, et al. Circulation 2001;104:39-45

  46. IMMUNOSUPPRESSIVE THERAPY FOR DILATED CARDIOMYOPATHYCHANGE IN VENTRICULAR FUNCTION Left Ventricular Ejection Fraction Wojnicz R, et al. Circulation 2001;104:39-45

  47. ITALIAN UNCONTROLLED IMMUNOSUPPRESSIVE TRIAL FOR MYOCARDITIS 112 patients had biopsy-proven lymphocytic myocarditis 41 patients had progressive symptoms for > 3 months duration and were treated with 6 months with prednisone (1 mg/kg/day x 4 wks; 0.33 mg/kg/day x 5 months) and azathioprine (2 mg/kg/day x 6 months) Efficacy of therapy was evaluated at 6 & 12 months Responders demonstrated: Decrease in NYHA class Increase in LVEF > 10 Units Frustaci A, et al. Circulation 2003;107:857-63

  48. ITALIAN UNCONTROLLED TRIAL OF IMMUNOSUPPRESSIVE THERAPY FOR MYOCARDITIS R R R BASELINE 6 MO 12 MO Frustaci A, et al. Circulation 2003;107:857-63

  49. IMMUNOSUPPRESSIVE THERAPY FOR MYOCARDITISSTUDY DESIGN RESPONDERS NON-RESPONDERS (N=21) (N=20) Viral Genome 3 (14%) * 17 (85%)+ Cardiac Antibodies19 (90%)#0 (0%) * P < 0.001; # p < 0.001 + Enterovirus 5; EB virus 5; adenovirus 4; influenza 1; parvovirus 1 Frustaci A, et al. Circulation 2003;107:857-63

  50. TREATMENT FOR IDIOPATHIC DILATED CARDIOMYOPATHY 2004 AND BEYOND • Conventional neurohormonal antagonists • ? Anticoagulation (WATCH; WARCEF) • ? ICD implantation (DEFINITE & SCD-HeFT) • ? Immunosuppression vs immunomodulation • Gene therapy (SERCA2a, phospholamban) • Cellular transplantation • Fetal cardiomyocytes • Skeletal myoblasts • Adult (tissue) stem cells • Embryonic stem cells

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