IDIOPATHIC DILATED CARDIOMYOPATHY

NEW INSIGHTS INTO PATHOGENESIS AND TREATMENT

Dartmouth-Hitchcock Medical Center

April 2004

ETIOLOGIES OF DILATED CARDIOMYOPATHY

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IDCM

Myocarditis

Ischmic CM

InfiltrativediseasePeripartum CM

Hypertension

HIV

CTD

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Felker et al NEJM 2000

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 CARDIOMYOPATHYPATHOLOGIC FINDINGS

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

• 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

Fatkin D, et al. NEJM 1999;341Fatkin D, et al. NEJM 1999;341

GENESLamin A/Cδ-sarcoglycanDystrophinDesminVinculinTitinTroponin-Tα-tropomyosinß-myosin heavy chainActin

Mitochondrial DNA mutations

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

HISTOPATHOLOGY OF ACUTE LYMPHOCYTIC MYOCARDITIS

INCIDENCE OF BIOPSY-PROVEN MYOCARDITIS IN PATIENTS WITH DILATED CARDIOMYOPATHY

Series Year Patients Positive BiopsyKunkel 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

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 MYOCARDITISMRI IMAGING

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

UnenhancedUnenhanced EnhancedEnhanced

MRI ASSESSMENT OF BIOPSY-PROVEN MYOCARDITIS

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

SURVIVAL IN IDIOPATHIC DILATED CARDIOMOPATHY VERSUS MYOCARDITIS

CP977755-7

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Myocarditis (n=27)Myocarditis (n=27)IDCM (n=58)IDCM (n=58)

Grogan, et al JACC 1995

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 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 CARDIOMYOPATHYNATURAL HISTORY

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

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 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

Steimle et al JACC 1994;23:553-9

295

9

SPONTANEOUS IMPROVEMENT IN ACUTE DILATED CARDIOMYOPATHY

UNIVARIATE PREDICTORS OF IMPROVEMENTshort duration of symptomshigher cardiac outputlower NYHA functional classificationsmaller LV end-diastolic dimensionlower filling pressureshigher serum sodium concentration

STEPWISE REGRESSION MODELshort duration of symptomshigher serum sodium concentrationlower right atrial pressurelower pulmonary capillary wedge pressure

-Steimle AE, et al. JACC 1994;23:553-9

SURVIVAL IN ACUTE DILATED CARDIOMYOPATHY

CHANGE IN LVEF BY LVEDD: IMAC Trial

0.32

0.56

0.220.26

0.39

0.12

0.20

0.29

0.09

0

0.2

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0.6

BaselineLVEF

6 monthsLVEF

IncreaseLVEF

< or = 6.0

>6 to 7.0

> 7.0

LVEDD (cm) LVEF

McNamara D, et al. AHA, 2001

N=82

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 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

Months

Eve

nt-

Fre

e R

ate

(%

)

Sato Y et al. Circulation 2001;103:372

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=33

N=10

N=17

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

• 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

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

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)

• 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

RIGHT VENTRICULAR BIOPSY TECHNIQUE

ENDOMYOCARDIAL BIOPSY IN DILATED CARDIOMYOPATHY

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

CP977755-6

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Cooper, et al NEJM 1997

DILATED CARDIOMYOPATHYPROVEN THERAPEUTIC OPTIONS

TREATMENT INDICATIONSACE Inhibitors Symptomatic heart failure and

asymptomatic LV dysfunctionARBs ACE intoleranceHydralazine- nitrates ACE intoleranceDiuretics Volume overloadPotassium/MagnesiumDiuretic-induced depletionBeta-blockers Symptomatic heart failure in addition to

ACE inhibitorDigoxin Persistent heart failure despite

diuretics, ACE inhibitorWarfarin Chronic or paroxysmal atrial fibrillation

LV thrombus or prior embolic eventICD Cardiac arrest; uncontrolled VT

STATIN THERAPY IMPROVES VENTRICULAR FUNCTION IN DILATED CARDIOMYOPATHY

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

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

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

IMMUNOADSORPTION THERAPY FOR DILATED CARDIOMYOPATHY

12 MONTH AUTOANTIBODY LEVELS BY TREATMENT GROUP

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

IMMUNOADSORPTION THERAPY FOR DILATED CARDIOMYOPATHY

12 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

Felix SB, et al. JACC 2002;39:646-52

n=12

Effect of column effluent on adult rat cardiocyte contractility

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

IMMUNOABSORPTION AND REPLACEMENT TREATMENT FOR DILATED CARDIOMYOPATHY

CHANGES IN CELLULAR INFILTRATION (3 months)

Staudt A et al. Circulation 2001;103:2681-8

IA/IgG treatment resulted in a significant decline in all subtypes of infiltrating lymphocytes

** p < 0.05 vs baseline

++ p < 0.05 vs controls

IMMUNOABSORPTION AND REPLACEMENT TREATMENT FOR DILATED CARDIOMYOPATHY

Staudt A et al. Circulation 2001;103:2681-8

A marked decrease in myocardial HLA-class II antigen expression is evident after 3 months of treatment

(magnification X 400)

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

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

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Baseline 3 Month 6 Month 12 Month 24 Month

Placebo

Immuno

Left Ventricular Ejection Fraction

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

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;107:857-63Frustaci A, et al. Circulation 2003;107:857-63

ITALIAN UNCONTROLLED TRIAL OF IMMUNOSUPPRESSIVE THERAPY FOR

MYOCARDITIS

0.00%

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50.00%

LVEF

1 2 3

Frustaci A, et al. Circulation 2003;107:857-63

BASELINE 6 MO 12 MOBASELINE 6 MO 12 MO

RRRR RR

IMMUNOSUPPRESSIVE THERAPY FOR MYOCARDITISSTUDY DESIGN

RESPONDERS NON-RESPONDERS

(N=21) (N=20)

Frustaci A, et al. Circulation 2003;107:857-63Frustaci A, et al. Circulation 2003;107:857-63

Viral Genome 3 (14%) * 17 (85%) +

Cardiac Antibodies 19 (90%)# 0 (0%)

* P < 0.001; # p < 0.001

+ Enterovirus 5; EB virus 5; adenovirus 4; influenza 1; parvovirus 1

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

668N =

Fas gene expression

HighModerateLowC

ha

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EF

at

12

mo

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s (%

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50.0

40.0

30.0

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-10.0

-20.0668N =

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HighModerateLow

Cha

nge

in E

F a

t 6 m

onth

(%

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40.0

30.0

20.0

10.0

0.0

-10.0

Fas Expression and LV Recovery

p=0.002 p=0.006

Six months Twelve months

Sheppard, AHA 2003

IMAC TRIAL RESULT:APOPTOSIS AND IMAC TRIAL RESULT:APOPTOSIS AND RECOVERY OF VENTRICULAR FUNCTIONRECOVERY OF VENTRICULAR FUNCTION