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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
0
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
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
• 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
Kunkel et al
Mason et al
Noda
Baandrup et al
O’Connell 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
Year
1978
1980
1980
1981
1981
1982
1983
1983
1984
1984
1984
1984
1985
1995
1997
Patients
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
9
2.1*
4-12 weeks
10
2.3
12-26 weeks
8
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
2
4
Years
6
Grogan, et al JACC 1995
CP977755-7
IDIOPATHIC DILATED CARDIOMYPATHY
EPIDEMIOLOGY
• 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
• 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
9
2
5
18 Died/13 Tx
11±15 mos
5 Alive & Unimproved
27 ± 22 mos
11 Improved
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
0.6
0.4
LVEF
0.56
0.39
0.32
0.29
0.26
0.2
LVEDD (cm)
0.22
0.20
0.12
< or = 6.0
0.09
>6 to 7.0
0
N=82
> 7.0
Baseline
LVEF
6 months
LVEF
Increase
LVEF
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
Event-Free Rate (%)
N=33
N=10
N=17
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
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 C11 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):
– Fixed defect(s):
– Reversible+ fixed defect(s):
60%
15%
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 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
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
1
2
3
4
5
Survival (yr)
Cooper, et al NEJM 1997
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
Staudt A et al. Circulation 2001;103:2681-8
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
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;107:857-63
ITALIAN UNCONTROLLED TRIAL OF
IMMUNOSUPPRESSIVE THERAPY FOR
MYOCARDITIS
50.00%
40.00%
LVEF
30.00%
20.00%
R
R
6 MO
12 MO
R
10.00%
0.00%
1
BASELINE
2
3
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;
+ Enterovirus
NON-RESPONDERS
(N=20)
17 (85%)
+
0 (0%)
# p < 0.001
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
20.0
10.0
0.0
-10.0
N=
20.0
10.0
0.0
-10.0
-20.0
8
6
6
Low
Moderate
High
Fas gene expression
p=0.002
N =
8
6
6
Low
Moderate
High
Fas gene expression
p=0.006
Sheppard, AHA 2003