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

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I II II+III III IV CS0

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I II II+III III IV CS0

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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

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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

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<15 16 - 19 20 - 24 25 - 29 > 30

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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

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RCMHCM

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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

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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

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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

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Noonan Othersyndrome

Familial Consang Metabolic

NoonanOther syndromeFamilialConsangMetabolic

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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

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80 66 64 56 51 44 37 26 22 17 14No at risk

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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

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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