IDIOPATHIC DILATED CARDIOMYOPATHY

NEW INSIGHTS INTO

PATHOGENESIS AND TREATMENT
Dartmouth-Hitchcock Medical Center
April 2004

ETIOLOGIES OF DILATED CARDIOMYOPATHY

50

IDCM

45

Myocarditis

40

Ischmic CM

35
25

Infiltrative
disease
Peripartum CM

20

Hypertension

30

15

HIV

10
5

CTD

Substance
abuse

Disorder

Felker et al NEJM 2000

IDIOPATHIC DILATED CARDIOMYOPATHY

PATHOLOGY
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

PATHOLOGIC FINDINGS

IDIOPATHIC DILATED CARDIOMYOPATHY

PATHOGENESIS
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
GENES
Lamin A/C
-sarcoglycan
Dystrophin
Desmin
Vinculin
Titin
Troponin-T
-tropomyosin
-myosin heavy chain
Actin
Mitochondrial DNA
mutations

Fatkin D, et al. NEJM 1999;341

FAMILIAL DILATED CARDIOMYOPATHY

COMMON 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
Kunkel et al
Mason et al
Noda
Baandrup et al
OConnell et al
Nippoldt et al
Fenoglio et al
Unverferth et al
Parillo et al
Zee-Cheng et al
Daly et al
Bolte et al
Hosenpud et al
Mason et al
McCarthy et al
TOTAL

Patients
1978
1980
1980
1981
1981
1982
1983
1983
1984
1984
1984
1984
1985
1995
1997

66
400
52
132
68
170
135
59
74
35
69
91
38
2233
1757
5379

Positive Biopsy
6%
3%
0.5%
1%
7%
5%
25%
6%
26%
63%
17%
20%
16%
10%
14%
11.5%

RELATIONS AMONG BIOPSY TIMING, CLINICAL

FEATURES, AND BIOPSY POSITIVITY FOR MYOCARDITIS
Time from
illness onset
to biopsy

Number of
patients

Clinical
features
score

0-4 weeks

2.1*

4-12 weeks

10

2.3

12-26 weeks

0.9*

Positive
biopsy

89%**
70%
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
Unenhanced

Enhanced

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

MRI ASSESSMENT OF BIOPSYPROVEN MYOCARDITIS

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

SURVIVAL IN IDIOPATHIC DILATED

CARDIOMOPATHY VERSUS MYOCARDITIS
100

Survival (%)

80
60
40
Myocarditis (n=27)
IDCM (n=58)

20
0
0

Years

Grogan, et al JACC 1995

CP977755-7

IDIOPATHIC DILATED CARDIOMYPATHY

EPIDEMIOLOGY

ANNUAL INCIDENCE
PREVELANCE

5-8/100,000

36/ 100,000

INCREASED RISK ASSOCIATED WITH:

MALE GENDER
BLACK RACE
HYPERTENSION
CHRONIC BETA-AGONIST USE

IDIOPATHIC DILATED CARDIOMYPATHY

CLINICAL PRESENTATIONS
Heart failure symptoms
Anginal chest pain

75%-85%
8%-20%

Emboli (systemic or pulmonary) 1%-4%

Syncope
<1%
Sudden cardiac death
<1%

IDIOPATHIC DILATED CARDIOMYOPATHY

NATURAL 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 CARDIOMYOPATHY

OUTCOME

49 Patients with Recent Onset Cardiomyopathy

12 months

12 Died/10 Tx

16 Alive & Unimproved

9

18 Died/13 Tx
1115 mos

11 Improved

5 Alive & Unimproved

27 22 mos

13 Improved

43 29 mos

Steimle et al JACC 1994;23:553-9

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

SURVIVAL IN ACUTE DILATED

CARDIOMYOPATHY

CHANGE IN LVEF BY LVEDD: IMAC Trial

LVEF

LVEDD (cm)

N=82

McNamara D, et al.
AHA, 2001

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, rightsided 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
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
N=33

Grp 1: TnT < 0.02

ng/mL during
follow-up period

Event-Free Rate (%)

N=10

Grp 2: TnT > 0.02

ng/mL initially but
fell to < 0.02 ng/mL
during follow-up

N=17

Grp 3: TnT > 0.02

ng/mL throughout
follow-up period
Months

Sato Y et al. Circulation 2001;103:372

DILATED CARDIOMYOPATHY
ELECTROCARDIOGRAPHIC 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
akinesis
dyskinesis

(83%)
(11%)
(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 (dipyridamoleinduced) 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 FORCORONARY 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

ENDOMYOCARDIAL BIOPSY IN DILATED CARDIOMYOPATHY

RIGHT
VENTRICULAR
BIOPSY
TECHNIQUE

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
Proportion surviving

1.0

GCM group
LM group

0.8
0.6
0.4
0.2
0.0
0

Survival (yr)

Cooper, et al NEJM 1997

5
CP977755-6

DILATED CARDIOMYOPATHY
PROVEN THERAPEUTIC OPTIONS
TREATMENT
ACE Inhibitors
ARBs
Hydralazine- nitrates
Diuretics
Potassium/Magnesium
Beta-blockers
Digoxin
Warfarin
ICD

INDICATIONS
Symptomatic heart failure and
asymptomatic LV dysfunction
ACE intolerance
ACE intolerance
Volume overload
Diuretic-induced depletion
Symptomatic heart failure in addition to
ACE inhibitor
Persistent heart failure despite
diuretics, ACE inhibitor
Chronic or paroxysmal atrial fibrillation
LV thrombus or prior embolic event
Cardiac arrest; uncontrolled
VT

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
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
Symptom duration
Myocarditis

25 8%
2.0 1.5 months
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

n=12

Effect of
column
effluent on
adult rat
cardiocyte
contractility

Felix SB, et al.

JACC 2002;39:646-52

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

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

IMMUNOABSORPTION AND REPLACEMENT

TREATMENT FOR DILATED CARDIOMYOPATHY
CHANGES 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

A marked
decrease in
myocardial HLAclass II antigen
expression is
evident after 3
months of
treatment

(magnification X
400)

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

CONTROLLED TRIAL OF IMMUNOADSORPTION AND

IMMUNOGLOBULIN SUBSTITUTION IN DILATED
CARDIOMYOPATHY
CHANGE 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
Left Ventricular Ejection Fraction
45%
40%
35%
30%
25%

Placebo
Immuno

20%
15%
10%
5%
0%

Baseline

3 Month

6 Month

12 Month 24 Month

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

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
50.00%
40.00%
LVEF

30.00%
20.00%

6 MO

12 MO

10.00%
0.00%
1

BASELINE

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

IMMUNOSUPPRESSIVE THERAPY FOR

MYOCARDITIS
STUDY DESIGN

RESPONDERS
(N=21)
3 (14%) *

Viral Genome

Cardiac Antibodies 19 (90%)#

* P < 0.001;
+

NON-RESPONDERS

(N=20)
17 (85%)

0 (0%)

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

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

IMAC TRIAL RESULT:APOPTOSIS AND

RECOVERY OF VENTRICULAR FUNCTION

Fas Expression and LV Recovery

Six months
Twelve months
40.0

50.0

40.0
30.0

Change in EF at 12 months (%)

30.0

Change in EF at 6 month (%)

20.0

10.0

0.0

-10.0
N=

Low

Moderate

High

Fas gene expression

20.0

10.0

0.0

-10.0
-20.0
N=

Low

Moderate

High

Fas gene expression

p=0.006

p=0.002

Sheppard, AHA 2003