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Paediatric cardiomyopathy:Paediatric cardiomyopathy:
new developments and insightsnew developments and insights
CardiomyopathiesCardiomyopathiesDefinitionDefinition
!! WHO definition (1996): “Diseases of the myocardium associated WHO definition (1996): “Diseases of the myocardium associated with cardiac dysfunction”with cardiac dysfunction”
–– Dilated cardiomyopathyDilated cardiomyopathy
–– Hypertrophic cardiomyopathyHypertrophic cardiomyopathy
–– Restrictive cardiomyopathyRestrictive cardiomyopathy
–– Unclassified: Arrhythmogenic RVUnclassified: Arrhythmogenic RV dysplasiadysplasia, LV non, LV non--compactioncompaction
Dilated cardiomyopathy:Dilated cardiomyopathy:overviewoverview
!! Characterised by dilatation and impaired ventricular contractionCharacterised by dilatation and impaired ventricular contraction
!! May be familial, genetic, postMay be familial, genetic, post--viral, drug or toxin induced, metabolic, viral, drug or toxin induced, metabolic, mitochondrial, connective tissue associated or due to HIVmitochondrial, connective tissue associated or due to HIV
!! Anomalous coronary origin from a pulmonary artery must be excludAnomalous coronary origin from a pulmonary artery must be excludeded
!! Histology nonHistology non--specific specific
!! Usually presents with heart failureUsually presents with heart failure
!! Accompanying diastolic dysfunction may include impaired ventricuAccompanying diastolic dysfunction may include impaired ventricular lar relaxation and nonrelaxation and non--compliance compliance
Dilated cardiomyopathy:Dilated cardiomyopathy:echocardiogramechocardiogram
Dilated cardiomyopathyDilated cardiomyopathygenetic mutationsgenetic 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:Dilated cardiomyopathy:viral diseaseviral 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:Myocarditis:mouse model mouse model
Acute myocarditis Subacute myocarditis Chronic myocarditis
Viral infection
Myocyte necrosis
Macrophage activation
Infiltrating mononuclear cells
Viraemia Viral clearing Viral absence4 days 14 days
CytokinesNatural killer cells
Nitric oxide
Cytotoxic T lymphocytesB lymphocytes
Neutralising antibodies
Fibrosis
Dilatation
Death
Myocarditis Myocarditis ––histologichistologic variationvariation
Diffuse mononuclear infiltrate
Focal mononuclear infiltrate
Myocardial oedema –no infiltrate Myocardial fibrosis
and hypertrophy
Dilated cardiomyopathyDilated cardiomyopathyinvestigationsinvestigations
!! ECG, CXR, cardiac ultrasoundECG, CXR, cardiac ultrasound
!! Serum carnitine,Serum carnitine, pyruvatepyruvate, lactate, urine metabolic screen , lactate, urine metabolic screen
!! Viral PCR and culture of available tissues/fluidsViral PCR and culture of available tissues/fluids
!! Metabolic consults; consider liver and skeletal muscle biopsyMetabolic consults; consider liver and skeletal muscle biopsy
!! Screen first degree relativesScreen first degree relatives
!! Genotype and skeletal muscle biopsy if no improvementGenotype and skeletal muscle biopsy if no improvement
Mitochondrial diseasesMitochondrial diseasestypical organ involvementtypical organ involvement
Brain: seizures, dementia, infarcts, leukoencephalopathyEye: optic atrophy, pigmentary degeneration, cataractsEar: deafnessMuscle: skeletal myopathyHeart: cardiomyopathy (HCM, DCM), conduction defectsKidney: tubular dysfunctionLiver: hepatic dysfunction, bile stasisBone marrow: pancytopaenia, specific cell line failureBlood, urine, CSF: increased lactate
Mitochondrial diseasesMitochondrial diseases
Respiratory chain Complex 1 deficiencyRespiratory chain Complex 1 deficiencycardiomyopathycardiomyopathy
0
20
40
60
80
100
120
140
160
180
200
220
240
I II II+III III IV CS0
20
40
60
80
100
120
140
160
180
200
220
240
I II II+III III IV CS0
20
40
60
80
100
120
140
160
180
200
220
240
I II II+III III IV CS
% %%Muscle Liver Heart
Dilated cardiomyopathyDilated cardiomyopathyDrug therapyDrug 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 cardiomyopathyHypertrophic cardiomyopathy
!! Primary cardiac disorder with a heterogeneous expression and Primary cardiac disorder with a heterogeneous expression and diverse clinical coursediverse clinical course
!! Characterised by left ventricular hypertrophy in the absence of Characterised by left ventricular hypertrophy in the absence of dilatation, or conditions capable of producing LVHdilatation, or conditions capable of producing LVH
!! NonNon--obstructive in around 75% of casesobstructive in around 75% of cases
!! Prevalence in the general population is around 0.2%Prevalence in the general population is around 0.2%
Hypertrophic cardiomyopathy:Hypertrophic cardiomyopathy:echocardiogramechocardiogram
Hypertrophic cardiomyopathyHypertrophic cardiomyopathymorphological characteristicsmorphological characteristics
!! Distribution of hypertrophy is usually Distribution of hypertrophy is usually asymmetricasymmetric
!! Any pattern possible but anterior Any pattern possible but anterior ventricular septum predominantly ventricular septum predominantly involvedinvolved
!! Spontaneous LV remodeling with Spontaneous LV remodeling with increase in wall thickness during increase in wall thickness during adolescence, and a decrease in wall adolescence, and a decrease in wall thickness with aging thickness with aging
Hypertrophic cardiomyopathyHypertrophic cardiomyopathygenetic defectsgenetic defects
!! Mendelian trait with autosomal dominant inheritanceMendelian trait with autosomal dominant inheritance
!! Mutations involve genes that encode for sarcomeric proteinsMutations involve genes that encode for sarcomeric proteins
!! 10 different proteins implicated and >200 described mutations 10 different proteins implicated and >200 described mutations (allelic heterogeneity)(allelic heterogeneity)
!! Around 50% of cases represent spontaneous mutationsAround 50% of cases represent spontaneous mutations
!! Hypertrophy may be secondary to altered sensitivity to calcium Hypertrophy may be secondary to altered sensitivity to calcium and impaired contractilityand impaired contractility
Hypertrophic cardiomyopathyHypertrophic cardiomyopathycontractile protein mutationscontractile protein mutations
Paediatric HCMPaediatric HCMaetiological considerationsaetiological 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 deathCauses of sudden cardiac deathin young peoplein young people
Myocarditis 3%
Maron BJ et al. Circulation. 1996;94:850-56.
Hypertrophiccardiomyopathy (36%)
Aortic stenosis 4%
Congenital coronaryanomalies (19%)
Mildly increased cardiac mass (10%)
Ruptured aorta 5%
Tunneled LAD 5%
ARVC 3%MVP 2%
CAD 2%Other 6%
Mortality in HCMMortality in HCMMaron et al; Circulation 2000Maron et al; Circulation 2000
0
2
4
6
8
10
12
14
16StrokeHeart FailureSudden
% M
orta
lity
Age at Death or Most Recent Evaluation (years)
5-15 16-25 26-35 36-45 46-55 56-65 66-75 >75
Hypertrophic cardiomyopathyHypertrophic cardiomyopathysubstrate for SCDsubstrate for SCD
!! Disorganised cellular Disorganised cellular architecturearchitecture
!! Abnormal intramural Abnormal intramural coronary arteries with coronary arteries with thickened walls and narrow thickened walls and narrow lumenslumens
!! Replacement fibrosis Replacement fibrosis adjacent adjacent to adjacent adjacent to intramural vesselsintramural vessels
Maron BJ; Lancet 1997
Adult hypertrophic Adult hypertrophic cardiomyopathycardiomyopathy
risk factors for sudden deathrisk factors for sudden death
Highest
Intermediate
Lowest
Implantable defibrillator
Medical therapy (?)
Cardiac arrest/sustained VTFamily history of sudden deathRecurrent syncopeMultiple-repetitive NSVTExercise hypotensionMassive LVHMalignant genotype?Coronary bridging?
Relation of wall thickness to sudden deathRelation of wall thickness to sudden deathSpirito P et al, NEJM 2000Spirito P et al, NEJM 2000
02468
101214161820
Maximal Left-Ventricular-Wall Thickness (mm)
02.6
7.4
11.0
18.2
<15 16 - 19 20 - 24 25 - 29 > 30
Inci
denc
e of
Sud
den
Dea
th(p
er 1
000
pers
on –
yr)
HCM HCM -- age related penetranceage related penetranceNimura et al; NEJM 1998Nimura et al; NEJM 1998
0102030405060708090
100
10-19 20-29 30-39 40-49 50-59 >60
Cardiac beta-myosin heavy chainCardiac troponin TCardiac myosin-binding protein C
Myocardial bridgingMyocardial bridging
Hypertrophic cardiomyopathy: Hypertrophic cardiomyopathy: myocardial bridgingmyocardial bridging
Hypertrophic cardiomyopathy: Hypertrophic cardiomyopathy: myocardial bridgingmyocardial bridging
Restrictive cardiomyopathyRestrictive cardiomyopathy
!! Basic defect unknownBasic defect unknown
!! Diastolic dysfunction with normal wall thickness and systolic Diastolic dysfunction with normal wall thickness and systolic functionfunction
!! Primary: endomyocardial fibrosis, Loeffler’s, and primary RCMPrimary: endomyocardial fibrosis, Loeffler’s, and primary RCM
!! Infiltrative: Irradiation, sarcoid, amyloidInfiltrative: Irradiation, sarcoid, amyloid
!! Metabolic: Glyocogen storage disease, Fabry’s disease, Metabolic: Glyocogen storage disease, Fabry’s disease, haemachromatosishaemachromatosis
!! Mixed HCM and RCM may be due to Troponin I mutationMixed HCM and RCM may be due to Troponin I mutation
!! Relentless downhill courseRelentless downhill course
Restrictive cardiomyopathy:Restrictive cardiomyopathy:echocardiogramechocardiogram
Arrhythmogenic right Arrhythmogenic right ventricularventricular dysplasiadysplasia
!! Progressive fibroProgressive fibro--fatty replacement of right ventricular myocardium fatty replacement of right ventricular myocardium with relative septal sparingwith relative septal sparing
!! May be autosomal dominant with incomplete penetrance or May be autosomal dominant with incomplete penetrance or autosomal recessiveautosomal recessive
!! Presentation with arrhythmias and sudden death is common, Presentation with arrhythmias and sudden death is common, particularly in adolescents and young adultsparticularly in adolescents and young adults
Natural history of adult HCMNatural 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
NACCSNACCSdata collectiondata collection
!! 10 year cohort of Australian children aged 010 year cohort of Australian children aged 0--10 years at 10 years at presentation, with primary cardiomyopathypresentation, with primary cardiomyopathy
!! Site visits to paediatric cardiology centres and hospitalsSite visits to paediatric cardiology centres and hospitals
!! All available data reviewed including clinical details and folloAll available data reviewed including clinical details and followw--up, lab results, all cardiac imagingup, lab results, all cardiac imaging
!! Cases sought from regional paediatricians and adult Cases sought from regional paediatricians and adult cardiologists, transplant centres and coroners’ courtscardiologists, transplant centres and coroners’ courts
!! Available cardiac histology reviewed centrallyAvailable cardiac histology reviewed centrally
NACCS NACCS -- epidemiologyepidemiologyIncidence per 100,000 at risk/yearIncidence per 100,000 at risk/year
1.241.240.280.280.470.471.731.737.847.84TotalTotal
0.170.170.020.020.050.050.200.201.181.18Unclassified CMUnclassified CM
0.030.030.020.020.050.050.040.0400Restrictive CMRestrictive CM
0.320.320.100.100.130.130.360.361.891.89Hypertrophic CMHypertrophic CM
0.730.730.130.130.240.241.141.144.764.76Dilated CMDilated CM
TotalTotal55--10 years10 years22--<5 years<5 years11--<2 years<2 years00--<1 year<1 year
Cumulative frequency histogram Cumulative frequency histogram of age at presentationof age at presentation
Age (years) 0 1 2 3 4 5 6 7 8 9 10
0
.1
.2
.3
.4
.5
.6
.7
.8
.9
1 UCM
RCMHCM
DCM
Racial differencesRacial 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 Proportion of DCM subjects with known/likely aetiologyknown/likely aetiology
0
5
10
15
20
25
30
35
40
Myocarditis Viral Familial Consang Metabolic
MyocarditisViralFamilialConsangMetabolic
%
Prevalence of lymphocytic Prevalence of lymphocytic myocarditis among DCM subjectsmyocarditis among DCM subjects
37370012.512.520205050Proportion (%)Proportion (%)
7070888810104444TotalTotal
25250011222222Lymphocytic Lymphocytic myocarditismyocarditis
TotalTotal>8 weeks>8 weeks4 4 –– 8 8 weeksweeks
1 1 –– 4 4 weeksweeks
0 0 –– 7 7 daysdays
Time from Time from presentationpresentation
p = 0.009 Kruskall-Wallis
Viral Viral aetiologies aetiologies in DCM subjectsin 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: Dilated cardiomyopathy: risk factors for death/transplantrisk 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 DCM: survival according to patient characteristicspatient characteristics
1
0
0 .1
0 .2
0 .3
0 .4
0 .5
0 .6
0 .7
0 .8
0 .9
1 .0
Prop
ortio
n su
rviv
ing
0 1 2 3 4 5 6 7 8 9 1 0Y e a rs fro m p re s e n ta t io n
A
0
0 .1
0 .2
0 .3
0 .4
0 .5
0 .6
0 .7
0 .8
0 .9
1 .0
Prop
ortio
n su
rviv
ing
0 2 3 4 5 6 7 8 9 1 0Y e a rs f ro m p re s e n ta t io n
P re s e n tin g a g e 0 -5 y e a rs
P re s e n tin g a g e > 5 y e a rs
B
0
0 .1
0 .2
0 .3
0 .4
0 .5
0 .6
0 .7
0 .8
0 .9
1 .0
Prop
ortio
n su
rviv
ing
0 1 2 3 4 5 6 7 8 9 1 0Y e a rs fro m p re s e n ta t io n
N o fa m ilia l c a rd io m y o p a th y
F a m ilia l c a rd io m y o p a th y
C
0
0 .1
0 .2
0 .3
0 .4
0 .5
0 .6
0 .7
0 .8
0 .9
1 .0
Prop
ortio
n su
rviv
ing
0 1 2 3 4 5 6 7 8 9 1 0Y e a rs fro m p re s e n ta t io n
N o L y m p h o c y tic m y o c a rd itis
L y m p h o c y tic m y o c a rd it is
D
1 7 5 1 2 6 1 0 8 9 2 7 7 6 0 4 8 3 7 2 6 1 5 8 N o . a t r is k 1 5 9
1 6
1 2 0
6
1 0 4
4
8 9
3
7 4
3
5 8
2
4 7
1
3 6
1
2 5
1
1 4
1
7
1
0 -5 y rs
> 5 y rs
N o . a t r is k
1 4 9
2 6
1 1 4
1 2
9 8
1 0
8 3
9
6 8
9
5 2
8
4 1
7
3 2
5
2 2
4
1 2
3
6
2
2 6
1 3
2 0
1 3
1 7
1 3
1 4
1 2
1 3
1 1
1 0
8
9
4
6
3
5
2
2
2
1
1
N o
Y e s
N o . a t r is k N o . a t r is kN o
Y e s
Adult vs. pediatric myocarditisAdult vs. pediatric myocarditis-- comaparisoncomaparison
<5%<5%3030--40%40%Progression to endProgression to end--stage CMstage CM++++++++Speed of recoverySpeed of recovery++++++++Potential for recoveryPotential for recovery
--++++Chronic symptomsChronic symptoms<5%<5%35%35%NonNon--viral etiologyviral etiology
3030--40%40%55--10%10%FrequencyFrequencyPediatricPediatricAdultAdult
Proportion of HCM subjects with Proportion of HCM subjects with known/likely aetiologyknown/likely aetiology
0
5
10
15
20
25
30
Noonan Othersyndrome
Familial Consang Metabolic
NoonanOther syndromeFamilialConsangMetabolic
%
Hypertrophic cardiomyopathy: Hypertrophic cardiomyopathy: risk factors for death/transplantrisk 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 HCM: freedom from death and LV myectomyand LV myectomy
Prop
ortio
n su
rviv
ing
Years from presentation0 1 2 3 4 5 6 7 8 9 10
0
0.1 0.2 0.3 0.4 0.5 0.6
0.7
0.8
0.9 1
80 66 64 56 51 44 37 26 22 17 14No at risk
Prop
ortio
n su
rviv
ing
Years from presentation 0 1 2 3 4 5 6 7 8 9 10
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
80 59 53 48 42 36 28 18 17 14 11No. at risk
Survival Surgery
LV nonLV non--compactioncompaction
Left ventricular Left ventricular nonnon--compactioncompaction
!! Poorly characterisedPoorly characterised
!! PersistancePersistance ofof foetal spongiformfoetal spongiform myocardiummyocardium
!! Mitochondrial basisMitochondrial basis
!! Can be associated with restrictive or dilated physiologyCan be associated with restrictive or dilated physiology
!! Undulating phenotypeUndulating phenotype
!! 9.2% of all paediatric cardiomyopathy cases9.2% of all paediatric cardiomyopathy cases
Surv
ival
pro
babi
lity
Surv
ival
pro
babi
lity
YearsYears0 1 2 3 4 5 6 7 8 9 10 11 12
0.1.2.3.4.5.6.7.8.91
DCM
HCM
RCM
LVNC
NACCSNACCSSurvival for all CMSurvival for all CM
Paediatric cardiomyopathies:Paediatric cardiomyopathies:conclusionsconclusions
!! Heterogenous Heterogenous group of disorders with genetic, infectious, group of disorders with genetic, infectious, mitochondrial and metabolic mitochondrial and metabolic aetiologiesaetiologies
!! BehaviourBehaviour can be predicted by morphological and functional can be predicted by morphological and functional characteristics, and underlying patient characteristicscharacteristics, and underlying patient characteristics
!! Sudden death may occur at presentation and during followSudden death may occur at presentation and during follow--upup!! Require a multidisciplinary approach to diagnosis and Require a multidisciplinary approach to diagnosis and
managementmanagement!! If aetiology is unclear, remaining first degree family members If aetiology is unclear, remaining first degree family members
should be screened periodically should be screened periodically
Paediatric cardiomyopathyPaediatric cardiomyopathyunderutilisedunderutilised investigationsinvestigations
!! Post mortem with light and electron microscopy of the heartPost mortem with light and electron microscopy of the heart
!! Genetic testing and DNA storageGenetic testing and DNA storage
!! Viral PCR of the myocardiumViral PCR of the myocardium
!! Respiratory chain enzyme assayRespiratory chain enzyme assay