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IDIOPATHIC DILATED CARDIOMYOPATHY
NEW INSIGHTS INTO PATHOGENESIS AND TREATMENT
Dartmouth-Hitchcock Medical Center
April 2004
ETIOLOGIES OF DILATED CARDIOMYOPATHY
0
5
10
15
20
25
30
35
40
45
50
Disorder
IDCM
Myocarditis
Ischmic CM
InfiltrativediseasePeripartum CM
Hypertension
HIV
CTD
Substanceabuse
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
0
20
40
60
80
100
0 2 4 6YearsYears
Su
rviv
al (
%)
Su
rviv
al (
%)
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
0.4
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
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5
Survival (yr)Survival (yr)
Pro
po
rtio
n s
urv
ivin
gP
rop
ort
ion
su
rviv
ing
GCM groupGCM groupLM groupLM group
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%
10.00%
20.00%
30.00%
40.00%
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
ng
e in
EF
at
12
mo
nth
s (%
)
50.0
40.0
30.0
20.0
10.0
0.0
-10.0
-20.0668N =
Fas gene expression
HighModerateLow
Cha
nge
in E
F a
t 6 m
onth
(%
)
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