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Update in Congenital Heart DiseaseEverything is changing

Professor David WinlawFaculty of Medicine and Health

Heart Centre for ChildrenThe Children’s Hospital at Westmead

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What isn’t a congenital form of heart disease?

Origins of some adult onset diseases have fetal risk factors

Should we say genetic heart disease?

And cardiomyopathy? Adult presentations are conceivably ‘wear and tear’ of structural elements

And dysrhythmia?

Clinically used term = ’Structural heart disease’

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CHD Care in Australia

Benefits of a modern health systemAntenatal diagnosis = planned care

Numerous opportunities for diagnosis; baby checks, incidental murmurs.

Paediatric retrieval

Dedicated units

Expensive care

Collaborative Multidisciplinary Care

Lifetime of care

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CHD Care in Myanmar

Multi tier health systemMilitary and civilian facilities

Large number of non-paying unwell

Advanced pathology

Multi-purpose facilities

Shared adult care

Many complex conditions untreated

Procedural focus

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CHD Care in Myanmar

Multi tier health systemMilitary and civilian facilities

Large number of non-paying unwell

Advanced pathology

Multi-purpose facilities

Shared adult care

Many complex conditions untreated

Procedural focus

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Do we have a bad attitude towards genetic disease and critical illness in children generally?

We need to question what impact our introduction of possible genetic causes has on a parent’s understanding (and guilt).

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Things that we achieve a good long term fix

Simple septal defects

Strategies:Surgery (sternotomy and heart lung machine)

Device closure

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Things that we achieve a good medium term fix

Tetralogy of FallotEarly shunt surgery now replaced by ductal and/or outflow stenting

Larger proportion of pulmonary valve preserving operations

Long term morbidity and requirement for pulmonary valve replacement where that removed at initial operation.

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Things that we achieve a good medium term fix

Atrioventricular septal defects

Heart failure before operation is common

Significant operative morbidity

10% left AV valve replacement

Downs and Non-Downs.

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Things that we achieve a good medium term fix

Transposition of the great arteries

Mortality now 1%5% reoperation rate? Late coronary obstruction

Very high diagnostic and technical requirement

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Things that we struggle with

Single Ventricles

Birth Stage 1 Norwood Stage 2 Glenn Stage 3 Fontan2-5 days 3-6 months 3-5 years

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Things that we struggle with

Single Ventricles

Very high attrition during childhood ~ 70% alive and 1 year, 60% alive at 6 years

Many wonderful success stories.

Long term issues related to elevated lower body venous pressure in Fontan circulation.

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Things that we struggle with

Transplants Availability – location of care and donor supply, differences with US.

Transplant for CHD is uncommon but increasing, results are improving.

Sensitisation to previous homograft tissue and blood transfusions make a good match harder to find.

Use of marginal donors may increase pool.

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Clinical movers – ECMO

Bedside Circulatory Support

Post- cardiac surgery – time for the heart to recover

Sepsis and respiratory failure

Post- arrest for reversible cause –‘eCPR’

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Clinical movers – TAVI as an example of the transition from ‘big surgery’

Aortic Valve replacement – evolution from pulmonary valve replacement techniques

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Clinical movers - Bioengineering

Poor maintenance of valve functionNarrowingCalcificationNo growth potentialInfection

Structural deterioration requires replacement.- 4-5 replacements required over a lifetime. - at least the first two replacements require open heart surgery

Mery JTCVS 2016

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Clinical movers – bioengineering solutions

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Clinical movers – cell therapy

Mostly directed at improving heart function not building new structure– During and after first operation for single ventricle pathway

– Apparent clinical benefits but mechanism eludes us

– Likely paracrine effects

Sano Circ Res 201840 patients, 60 controls

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Sceptics – The Problem with ‘Genetics’

We can see the relevance but translation to individuals and resulting modification of treatment remains a work in progress

Few opportunities to act on knowledge about causation of CHD.

Many future opportunities to act on knowledge about how genotype influences outcome of procedures (precision and personalized approach)

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Increased sophistication of bedside care

90s: Directed genetic investigations on the basis of evident dysmorphic features. Karyotype for major syndromes. Mostly ordered by clinical geneticists.

00s: CGH arrays, ordered by primary team, without clinical genetics input, for most structural heart disease presenting as neonate

10s: Recognition that more subtle structural genetic variation contributes to clinical outcomes

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JTCVS 2016

Example – rare/large CNVs and impact on outcome

– Demonstrates worse outcome for those with higher burden of potentially pathogenic copy number variants

– Large difference evident in mortality

– ? Even bigger difference discernible in softer endpoints e.g. ICU stay and complications.

– Likely to see similar outcomes for de novo variants

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Identifying the cause of CHD

Progress in rates of diagnosis in all three of the main groups utilizing exome and whole genome analysis (Eleni G. presenting)

1. Sporadic2. Familial (multiple affected members)3. CHD with additional extra-cardiac anomalies

Cost of WGS and analysis currently prohibitive but likely to find a place for higher risk groups.

Current practice very variable in referral to clinical genetics, thresholds for testing, access to counselling.

Australian Genomics Cardiovascular FlagshipSURVEY coming soon…Establish comparator to approaches that are currently research-based.

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Impact on outcomes e.g. Neurodevelopment

Biggest issue in re-design of CHD care today.Affects 10-20% of all children who have important CHD and around 5% of the general population. Up to 30% of those requiring neonatal surgery.

Spectrum of concerns:Early learning issues; attention, concentration, messy handwritingMotor problems; coordination, gross motor skillsBehavioral concerns; autism, ADHD

Some ’delay’ ie catch up is possible but neurocognitive issues persist in many adolescents and adults. Increased rates of dementia. No major effect on IQ.

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Modifiers of heart and brain outcome

– Procedural factors thought to be associated e.g. use of cardiopulmonary bypass and deep hypothermic circulatory arrest.– Research shows that these account

for a small proportion of the problems (cardiac arrest and use of ECMO stand out)

– Genotype emerges as the most important predictor of neurodevelopmental problems (Gaynor 2015)

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Findings not yet ready for the clinic…

– Enrichment of variants in CHD + NDD group, in genes and gene pathways supporting brain and heart development

– Variant burden well demonstrated and may correlate with incidence and severity of NDD

– Individual-based genetic assessment not well developed

2018

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Moving forward

– Collaborative genotype-phenotype-outcome studies over several decades

– Large patient numbers to associate specific variants with outcome e.g. low cardiac output after neonatal surgery

– $ for sequencing, bioinformatic analysis, statistical geneticists

– Radical increase in clinical genetics and counselling workforce

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Acknowledgements and Appreciation

Clinical Group – The Children’s Hospital at Westmead, Sydney.Gillian Blue, Charlotte Verrall, Gary Sholler

Victor Chang Cardiac Research InstituteSally Dunwoodie, Eleni Giannoulatou, Richard Harvey

Patients and Parents

Funding organisationsWishaw and Hobson Trusts – CHW.HeartKidsNHMRC and NHF

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Acknowledgements

Clinical group – The Children’s Hospital at WestmeadGillian BlueGary Sholler

Victor Chang Cardiac Research InstituteSally DunwoodieEleni GiannoulatouRichard Harvey

Patients and Parents

Acknowledgements