Download Paediatric cardiomyopathy: new developments and insights

Paediatric cardiomyopathy:
new developments and insights
Cardiomyopathies
Definition
!
WHO definition (1996): “Diseases of the myocardium associated
with cardiac dysfunction”
– Dilated cardiomyopathy
– Hypertrophic cardiomyopathy
– Restrictive cardiomyopathy
– Unclassified: Arrhythmogenic RV dysplasia, LV non-compaction
Dilated cardiomyopathy:
overview
!
Characterised by dilatation and impaired ventricular contraction
!
May be familial, genetic, post-viral, drug or toxin induced, metabolic,
mitochondrial, connective tissue associated or due to HIV
!
Anomalous coronary origin from a pulmonary artery must be excluded
!
Histology non-specific
!
Usually presents with heart failure
!
Accompanying diastolic dysfunction may include impaired ventricular
relaxation and non-compliance
Dilated cardiomyopathy:
echocardiogram
Dilated cardiomyopathy
genetic mutations
!
Up to 25% of dilated CM is caused by genetic mutations
!
1st gene identified was dystrophin (X-linked CM); others include actin,
desmin and lamin A/C (dominant and recessive)
!
Actin, desmin and dystrophin are cytoskeletal proteins with roles in force
transmission, cytoskeletal stability, calcium homeostasis, myocyte
differentiation, myofibrillogenesis
!
Lamin is a nuclear protein; commonest mutation and is associated with
conducting system disease
!
Dystrophin, desmin and lamin mutations can be associated with skeletal
muscle disease
Dilated cardiomyopathy:
viral disease
!
Common pathogenic viruses include adenovirus, enterovirus, CMV,
influenza
!
About 20% of subjects with dilated CM have virus by PCR
!
In subjects with myocarditis, 35-40% viral yield
!
Mechanisms of damage are both acute (dystrophin cleavage) and
delayed (lymphocytic infiltrate)
!
Adenovirus typically causes little lymphocytic infiltrate
Myocarditis:
mouse model
Subacute myocarditis
Acute myocarditis
Viral
infection
Chronic myocarditis
Myocyte necrosis
Macrophage
activation
Infiltrating
mononuclear cells
Natural killer cells
Cytotoxic T lymphocytes
B lymphocytes
Cytokines
Nitric oxide
Viraemia
4 days
Viral clearing
Neutralising antibodies
14 days
Fibrosis
Dilatation
Death
Viral absence
Myocarditis –
histologic variation
Diffuse mononuclear
infiltrate
Myocardial oedema –
no infiltrate
Focal mononuclear
infiltrate
Myocardial fibrosis
and hypertrophy
Dilated cardiomyopathy
investigations
!
ECG, CXR, cardiac ultrasound
!
Serum carnitine, pyruvate, lactate, urine metabolic screen
!
Viral PCR and culture of available tissues/fluids
!
Metabolic consults; consider liver and skeletal muscle biopsy
!
Screen first degree relatives
!
Genotype and skeletal muscle biopsy if no improvement
Mitochondrial diseases
typical organ involvement
Brain:
seizures, dementia, infarcts, leukoencephalopathy
Eye:
optic atrophy, pigmentary degeneration, cataracts
Ear:
deafness
Muscle: skeletal myopathy
Heart:
cardiomyopathy (HCM, DCM), conduction defects
Kidney:
tubular dysfunction
Liver:
hepatic dysfunction, bile stasis
Bone marrow:
pancytopaenia, specific cell line failure
Blood, urine, CSF:
increased lactate
Mitochondrial diseases
Respiratory chain Complex 1 deficiency
cardiomyopathy
%
%
Muscle
%
Liver
240
220
200
180
160
140
120
100
80
Heart
240
240
220
220
200
200
180
180
160
160
140
140
120
120
100
100
80
80
60
60
60
40
40
40
20
20
20
0
0
0
I
II
II+III
III
IV
CS
I
II
II+III
III
IV
CS
I
II
II+III
III
IV
CS
Dilated cardiomyopathy
Drug therapy
!
Diuretics: provide symptomatic relief
!
Digoxin: small effect on symptoms and heart failure admissions; no
benefit with respect to mortality
!
ACE inhibitors: Reduce both hospitalisation and mortality; higher doses
more effective; greatest effect in mild CHF
!
Beta-blockers: good evidence for reduction in mortality and
improvement in ventricular function
Hypertrophic cardiomyopathy
!
Primary cardiac disorder with a heterogeneous expression and
diverse clinical course
!
Characterised by left ventricular hypertrophy in the absence of
dilatation, or conditions capable of producing LVH
!
Non-obstructive in around 75% of cases
!
Prevalence in the general population is around 0.2%
Hypertrophic cardiomyopathy:
echocardiogram
Hypertrophic cardiomyopathy
morphological characteristics
!
Distribution of hypertrophy is usually
asymmetric
!
Any pattern possible but anterior
ventricular septum predominantly
involved
!
Spontaneous LV remodeling with
increase in wall thickness during
adolescence, and a decrease in wall
thickness with aging
Hypertrophic cardiomyopathy
genetic defects
!
Mendelian trait with autosomal dominant inheritance
!
Mutations involve genes that encode for sarcomeric proteins
!
10 different proteins implicated and >200 described mutations
(allelic heterogeneity)
!
Around 50% of cases represent spontaneous mutations
!
Hypertrophy may be secondary to altered sensitivity to calcium
and impaired contractility
Hypertrophic cardiomyopathy
contractile protein mutations
Paediatric HCM
aetiological considerations
!
Contractile protein abnormality
!
Syndromes: Noonan, Beckwith-Wiedemann, LEOPARD,
Friedreich’s ataxia
!
Metabolic: Carnitine deficiency, Fatty acid oxidation defects,
Glycogen storage disease, MPS, Mannosidosis, Fucosidosis,
lipodystrophy
!
Mitochondrial myopathies
!
Neonatal hyperinsulinaemia
Causes of sudden cardiac death
in young people
Maron BJ et al. Circulation. 1996;94:850-56.
Congenital coronary
anomalies (19%)
Mildly increased cardiac
mass (10%)
Ruptured aorta 5%
Tunneled LAD 5%
Aortic stenosis 4%
Myocarditis 3%
Hypertrophic
cardiomyopathy (36%)
ARVC 3%
MVP 2%
CAD 2%
Other 6%
Mortality in HCM
Maron et al; Circulation 2000
16
Stroke
Heart Failure
Sudden
% Mortality
14
12
10
8
6
4
2
0
5-15
16-25
26-35
36-45
46-55
56-65
66-75
Age at Death or Most Recent Evaluation (years)
>75
Hypertrophic cardiomyopathy
substrate for SCD
!
Disorganised cellular
architecture
!
Abnormal intramural
coronary arteries with
thickened walls and narrow
lumens
!
Replacement fibrosis
adjacent adjacent to
intramural vessels
Maron BJ; Lancet 1997
Adult hypertrophic
cardiomyopathy
risk factors for sudden death
Cardiac arrest/sustained VT
Family history of sudden death
Recurrent syncope
Multiple-repetitive NSVT
Exercise hypotension
Massive LVH
Malignant genotype?
Coronary bridging?
Implantable defibrillator
Highest
Intermediate
Lowest
Medical therapy (?)
Relation of wall thickness to sudden death
Incidence of Sudden Death
(per 1000 person – yr)
Spirito P et al, NEJM 2000
20
18
16
14
12
10
8
6
4
2
0
18.2
11.0
7.4
2.6
0
16 - 19
20 - 24
25 - 29
> 30
<15
Maximal Left-Ventricular-Wall Thickness (mm)
HCM - age related penetrance
Nimura et al; NEJM 1998
Cardiac beta-myosin heavy chain
Cardiac troponin T
Cardiac myosin-binding protein C
100
90
80
70
60
50
40
30
20
10
0
10-19
20-29
30-39
40-49
50-59
>60
Myocardial bridging
Hypertrophic cardiomyopathy:
myocardial bridging
Hypertrophic cardiomyopathy:
myocardial bridging
Restrictive cardiomyopathy
!
Basic defect unknown
!
Diastolic dysfunction with normal wall thickness and systolic
function
!
Primary: endomyocardial fibrosis, Loeffler’s, and primary RCM
!
Infiltrative: Irradiation, sarcoid, amyloid
!
Metabolic: Glyocogen storage disease, Fabry’s disease,
haemachromatosis
!
Mixed HCM and RCM may be due to Troponin I mutation
!
Relentless downhill course
Restrictive cardiomyopathy:
echocardiogram
Arrhythmogenic right
ventricular dysplasia
!
Progressive fibro-fatty replacement of right ventricular myocardium
with relative septal sparing
!
May be autosomal dominant with incomplete penetrance or
autosomal recessive
!
Presentation with arrhythmias and sudden death is common,
particularly in adolescents and young adults
Natural history of adult HCM
!
Initial reports suggested a 3-5% mortality per year in adults with
HCM being followed at tertiary care institutions
!
In 1989, Spirito et al (NEJM) pointed out that of 3404 subjects
with HCM in a total of 78 published studies, 73% were from
two referral institutions!
!
More recent population based data suggests that the outcome for
most subjects is good, with 10 year survival rates of 85%
reported
NACCS
data collection
!
10 year cohort of Australian children aged 0-10 years at
presentation, with primary cardiomyopathy
!
Site visits to paediatric cardiology centres and hospitals
!
All available data reviewed including clinical details and followup, lab results, all cardiac imaging
!
Cases sought from regional paediatricians and adult
cardiologists, transplant centres and coroners’ courts
!
Available cardiac histology reviewed centrally
NACCS - epidemiology
Incidence per 100,000 at risk/year
0-<1 year
1-<2 years
2-<5 years
5-10 years Total
Dilated CM
4.76
1.14
0.24
0.13
0.73
Hypertrophic CM
1.89
0.36
0.13
0.10
0.32
Restrictive CM
0
0.04
0.05
0.02
0.03
Unclassified CM
1.18
0.20
0.05
0.02
0.17
Total
7.84
1.73
0.47
0.28
1.24
Cumulative frequency histogram
of age at presentation
UCM
1
DCM
.9
HCM
.8
RCM
.7
.6
.5
.4
.3
.2
.1
0
0
1
2
3
4
5
6
Age (years)
7
8
9
10
Racial differences
!
Indigenous children had a higher incidence of dilated CM than
remaining subjects (relative risk 2.67; 95% CI 1.42, 4.63)
!
Sudden death was the presenting symptom in 11 (3.5%) cases
including 4.9% of dilated CM cases, and 4.8% of unclassified
CM cases
!
Indigenous children had a higher rate of death as the
presenting symptom 16.7% vs 2.6%; p=0.02)
Proportion of DCM subjects with
known/likely aetiology
%
40
35
30
Myocarditis
Viral
Familial
Consang
Metabolic
25
20
15
10
5
0
Myocarditis
Viral
Familial
Consang
Metabolic
Prevalence of lymphocytic
myocarditis among DCM subjects
Time from
presentation
0–7
days
1–4
weeks
4–8
weeks
>8 weeks
Total
Lymphocytic
myocarditis
22
2
1
0
25
Total
44
10
8
8
70
Proportion (%)
50
20
12.5
0
37
p = 0.009 Kruskall-Wallis
Viral aetiologies in DCM subjects
A probable or definite viral aetiology was identified in 59
of 184 (32.1%) subjects, including
– 30 of 44 (68.2%) subjects with available histology
within 1 week of presentation
– 8 of 9 subjects who presented with sudden death
Dilated cardiomyopathy:
risk factors for death/transplant
Variable
Hazard
ratio
95% CI
P-value
Presentation above 5 years
5.6
2.6, 12.0
<0.0001
Familial cardiomyopathy
2.9
1.5, 5.6.2
0.001
F.S. Z score at presentation*
0.75
0.65, 0.87 <0.0001
Change in F.S. Z score*
0.68
0.58, 0.79 <0.0001
* Per unit Z score
DCM: survival according to
patient characteristics
B
1 .0
0 .9
0 .9
0 .8
0 .8
Proportion surviving
Proportion surviving
A
1 .0
0 .7
0 .6
0 .5
0 .4
0 .3
0 .2
0 .6
0 .5
0 .4
0 .3
0 .1
0
0
0
1
N o . a t r is k 1 7 5
2
126
3
108
4
5
6
Y e a r s f r o m p r e s e n t a t io n
92
77
60
48
7
8
37
26
9
15
10
8
0
N o . a t r is k
0 -5 y rs
159
> 5 y rs
16
C
1
2
3
120
104
89
74
58
47
6
4
3
3
2
1
4
5
6
7
Y e a r s f r o m p r e s e n t a t io n
8
9
10
36
25
14
7
1
1
1
1
8
9
10
D
1 .0
1 .0
0 .9
0 .9
0 .8
0 .8
N o fa m ilia l c a r d io m y o p a th y
Proportion surviving
Proportion surviving
P r e s e n tin g a g e > 5 y e a r s
0 .2
0 .1
0 .7
0 .6
0 .5
F a m ilia l c a rd io m y o p a th y
0 .4
0 .3
L y m p h o c y tic m y o c a r d itis
0 .7
0 .6
N o L y m p h o c y tic m y o c a r d itis
0 .5
0 .4
0 .3
0 .2
0 .2
0 .1
0 .1
0
0
0
N o . a t r is k
No
149
Yes
P r e s e n tin g a g e 0 -5 y e a r s
0 .7
26
1
2
3
4
5
6
7
Y e a r s f r o m p r e s e n t a t io n
8
9
10
114
98
83
68
52
41
32
22
12
6
12
10
9
9
8
7
5
4
3
2
0
N o . a t r is k
No
26
Yes
13
1
2
3
4
5
6
7
Y e a r s f r o m p r e s e n t a t io n
20
17
14
13
10
9
6
5
2
1
13
13
12
11
8
4
3
2
2
1
Adult vs. pediatric myocarditis
- comaparison
Frequency
Non-viral etiology
Chronic symptoms
Potential for recovery
Speed of recovery
Progression to end-stage CM
Adult
5-10%
Pediatric
30-40%
35%
++
<5%
-
+
+
+++
+++
30-40%
<5%
Proportion of HCM subjects with
known/likely aetiology
%
30
25
20
Noonan
Other syndrome
Familial
Consang
Metabolic
15
10
5
0
Noonan
Other
syndrome
Familial
Consang
Metabolic
Hypertrophic cardiomyopathy:
risk factors for death/transplant
Variable
Hazard
ratio
95% CI
P-value
Presentation below 1 year
6.16
1.44, 26.3
0.014
Concentric LVH
8.01
1.33, 48.2
0.02
Increase in post wall Z score*
1.36
1.03, 1.81
0.03
Fractional shortening Z at
presentation*
1.32
1.08, 1.60
0.006
* Per unit Z score
HCM: freedom from death
and LV myectomy
Surgery
Survival
1
1
0.9
Proportion surviving
Proportion surviving
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.1
0
0
0
0
1
2
3
4
5
6
7
8
9
10
22
17
14
1
2
80
66
64
56
51
44
37
26
4
5
6
7
8
9
10
Years from presentation
Years from presentation
No at risk
3
No. at risk
80
59
53
48
42
36
28
18
17
14
11
LV non-compaction
Left ventricular
non-compaction
!
Poorly characterised
!
Persistance of foetal spongiform myocardium
!
Mitochondrial basis
!
Can be associated with restrictive or dilated physiology
!
Undulating phenotype
!
9.2% of all paediatric cardiomyopathy cases
NACCS
Survival probability
Survival for all CM
1
.9
.8
.7
.6
.5
.4
.3
.2
.1
0
HCM
DCM
LVNC
RCM
0
1
2
3
4
5
6
Years
7
8
9
10
11
12
Paediatric cardiomyopathies:
conclusions
!
!
!
!
!
Heterogenous group of disorders with genetic, infectious,
mitochondrial and metabolic aetiologies
Behaviour can be predicted by morphological and functional
characteristics, and underlying patient characteristics
Sudden death may occur at presentation and during follow-up
Require a multidisciplinary approach to diagnosis and
management
If aetiology is unclear, remaining first degree family members
should be screened periodically
Paediatric cardiomyopathy
underutilised investigations
!
Post mortem with light and electron microscopy of the heart
!
Genetic testing and DNA storage
!
Viral PCR of the myocardium
!
Respiratory chain enzyme assay