Post on 27-Jul-2020
The University of Sydney Page 1
Update in Congenital Heart DiseaseEverything is changing
Professor David WinlawFaculty of Medicine and Health
Heart Centre for ChildrenThe Children’s Hospital at Westmead
The University of Sydney Page 2
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’
The University of Sydney Page 3
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
The University of Sydney Page 4
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
The University of Sydney Page 4
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
The University of Sydney Page 5
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).
The University of Sydney Page 6
Things that we achieve a good long term fix
Simple septal defects
Strategies:Surgery (sternotomy and heart lung machine)
Device closure
The University of Sydney Page 7
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.
The University of Sydney Page 8
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.
The University of Sydney Page 9
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
The University of Sydney Page 10
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
The University of Sydney Page 11
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.
The University of Sydney Page 12
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.
The University of Sydney Page 13
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’
The University of Sydney Page 14
Clinical movers – TAVI as an example of the transition from ‘big surgery’
Aortic Valve replacement – evolution from pulmonary valve replacement techniques
The University of Sydney Page 15
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
The University of Sydney Page 16
Clinical movers – bioengineering solutions
The University of Sydney Page 17
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
The University of Sydney Page 18
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)
The University of Sydney Page 19
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
The University of Sydney Page 20
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
The University of Sydney Page 21
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.
The University of Sydney Page 22
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.
The University of Sydney Page 23
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)
The University of Sydney Page 24
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
The University of Sydney Page 25
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
The University of Sydney Page 26
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
The University of Sydney Page 27The University of Sydney Page 25
Acknowledgements
Clinical group – The Children’s Hospital at WestmeadGillian BlueGary Sholler
Victor Chang Cardiac Research InstituteSally DunwoodieEleni GiannoulatouRichard Harvey
Patients and Parents
Acknowledgements