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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

IDIOPATHIC DILATED CARDIOMYOPATHY

NEW INSIGHTS INTO PATHOGENESIS AND TREATMENT

Dartmouth-Hitchcock Medical Center

April 2004

idiopathic dilated cardiomyopathy pathology
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
idiopathic dilated cardiomyopathy pathogenesis
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
familial dilated cardiomyopathy
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

molecular defects in dilated cardiomyopathy
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

familial dilated cardiomyopathy common associated abnormalities
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
incidence of biopsy proven myocarditis in patients with dilated cardiomyopathy
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%

relations among biopsy timing clinical features and biopsy positivity for myocarditis
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.

non invasive evaluation of myocarditis mri imaging
NON-INVASIVE EVALUATION OF MYOCARDITISMRI IMAGING

Unenhanced

Enhanced

Friedrich MG et al. Circulation 1998;97:1802-9.

mri assessment of biopsy proven myocarditis
MRI ASSESSMENT OF BIOPSY-PROVEN MYOCARDITIS

Mahrholdt H, et al. Circulation 2004;109:1253

survival in idiopathic dilated cardiomopathy versus myocarditis
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

idiopathic dilated cardiomypathy epidemiology
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
idiopathic dilated cardiomypathy clinical presentations
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%
idiopathic dilated cardiomyopathy natural history
IDIOPATHIC DILATED CARDIOMYOPATHYNATURAL HISTORY

Dec GW, Fuster V. NEJM 1994;331:1564-75

spontaneous improvement in acute dilated cardiomyopathy
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

acute dilated cardiomyopathy outcome
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

spontaneous improvement in acute dilated cardiomyopathy20
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

slide22

CHANGE IN LVEF BY LVEDD: IMAC Trial

LVEF

LVEDD (cm)

N=82

McNamara D, et al. AHA, 2001

idcm prognostic features
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
acc aha heart failure evaluation guidelines class i ii recommendations
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

outcome in idiopathic dilated cardiomyopathy predictive value of troponin t
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

dilated cardiomyopathy electrocardiographic findings
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

segmental wall motion abnormalities in dilated cardiomyopathy
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

myocardial contractile reserve predicts improvement in dilated cardiomyopathy
MYOCARDIAL CONTRACTILE RESERVE PREDICTS IMPROVEMENT IN DILATED CARDIOMYOPATHY

Naqvi TS et al. J Am Coll Cardiol 1999;34:1537-44

noninvasive assessment of coronary artery disease in new onset dilated cardiomyopathy
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.

indications for coronary angiography in new onset cardiomyopathy acc aha consensus guidelines 2001
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

slide31

ENDOMYOCARDIAL BIOPSY IN DILATED CARDIOMYOPATHY

RIGHT VENTRICULAR BIOPSY TECHNIQUE

indications for endomyocardial biopsy
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

survival by histopathological type of myocarditis

GCM group

LM group

SURVIVAL BY HISTOPATHOLOGICAL TYPE OF MYOCARDITIS

Proportion surviving

Survival (yr)

Cooper, et al NEJM 1997

CP977755-6

dilated cardiomyopathy proven therapeutic options
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

statin therapy improves ventricular function in dilated cardiomyopathy
STATIN THERAPY IMPROVES VENTRICULAR FUNCTION IN DILATED CARDIOMYOPATHY

Node K, et al. Circulation 2003;108:839-43

controlled trial of immune globulin in recent onset dilated cardiomyopathy
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

immunoglobulin therapy for acute dilated cardiomyopathy imac trial results
IMMUNOGLOBULIN THERAPY FOR ACUTE DILATED CARDIOMYOPATHY:IMAC TRIAL RESULTS

McNamara et al. Circulation 2001;103:2254-9

immunoadsorption therapy for dilated cardiomyopathy 12 month autoantibody levels by treatment group
IMMUNOADSORPTION THERAPY FOR DILATED CARDIOMYOPATHY12 MONTH AUTOANTIBODY LEVELS BY TREATMENT GROUP

Muller J et al. Circulation 2000;101: 385 - 391

slide39
IMMUNOADSORPTION THERAPY FOR DILATED CARDIOMYOPATHY12 MONTH CHANGE IN EJECTION FRACTION BY TREATMENT GROUP

Muller J et al. Circulation 2000;101: 385 - 391

effect of removal of antibodies by immunoadsorption in dilated cardiomyopathy
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

controlled trial of immunoadsorption and immunoglobulin substitution in dilated cardiomyopathy
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

slide42
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

immunoabsorption and replacement treatment for dilated cardiomyopathy
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

slide44

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

immunosuppressive therapy for inflammatory dilated cardiomyopathy
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

immunosuppressive therapy for dilated cardiomyopathy change in ventricular function
IMMUNOSUPPRESSIVE THERAPY FOR DILATED CARDIOMYOPATHYCHANGE IN VENTRICULAR FUNCTION

Left Ventricular Ejection Fraction

Wojnicz R, et al. Circulation 2001;104:39-45

italian uncontrolled immunosuppressive trial for myocarditis
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

italian uncontrolled trial of immunosuppressive therapy for myocarditis
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

immunosuppressive therapy for myocarditis study design
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

treatment for idiopathic dilated cardiomyopathy 2004 and beyond
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
fas expression and lv recovery

IMAC TRIAL RESULT:APOPTOSIS AND RECOVERY OF VENTRICULAR FUNCTION

Fas Expression and LV Recovery

Six months

Twelve months

p=0.006

p=0.002

Sheppard, AHA 2003

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