Rik De DeckerRed Cross Children’s Hospital

What is paediatric cardiology?

What is paediatric cardiology?

Why is it different to adult cardiology?

Why is it different to adult cardiology?

One fine day…

• You are seeing Mrs Smith and her 2-week old son, John.

• He is very jaundiced.

• She says that his stools are chalky white.

• His lips and tongue also seem cyanosed, and he has an obvious heart murmur.

He looks a little unusual…

Mrs Smith asks 4 crucial questions…

1. What’s wrong?2. What will happen (now and later)?3. Why? 4. Will it happen to our next child?

(or … who’s to blame?)

Paediatric cardiology is different

• Congenital heart abnormalities– genetic

– teratogenic

• Associated abnormalities and syndromes

• Age plays a role– time of onset

– changes over time

• Acquired heart disease– acute rheumatic fever

– myocarditis / cardiomyopathy

– endocarditis

A brave new world…

• Embryology

• Genetics

• Foetal circulation– changes at time of birth

• Anatomy

• Clinical signs (and symptoms)

• Investigation

• Treatment, especially surgery!

1. Function

2. Substrate

3. Aetiology

3 approaches…

1. function• cyanosis or not• heart failure or not• arrhythmia• risk of death

2. substrate• gross structure• cardiomyocytic

What’s wrong?What’s wrong?

What can be done?What can be done?

3. aetiology3. aetiology

congenital abnormality

chromosomal

monogenic

polygenic

multifactorial

environmental

microdeletional

Why?Why?

Next child?Next child?

only a firm diagnosis allows accurate genetic counselling

examinationgenetictesting

pedigree

genetic counselling

diagnosis

clinical management

GENETICS

Spectrum of genetic causes of CHD

• Chromosomal– aneuploidy

– deletions

– other cytogenetic abnormalities

• Single gene disorders

• Other syndromic conditions of unknown genetic aetiology

• Nonsyndromic CHD

The spectrum of

congenital heart disease

GENETIC ENVIRONMENTAL

chromosomal

Trisomy 21

• usually (simple) balanced AVSD

• also VSD, PDA

• AVSD/Tetralogy

• genetic aetiology not well understood

Trisomy 18 & 13

• VSD, ASD, PDA in 80%

• cardiac surgery not usually offered

Turner syndrome

• coarctation of the aorta

• ASD

microdeletion syndromes

1. Tetralogy of Fallot

2. Right aortic arch

3. Laryngeal incompetence

4. Hypocalcaemia

5. Seizures

6. Cerebral atrophy

7. Recurrent infections

8. Feeding difficulties

9. Gastro-oesophageal reflux

10. Hyperactivity

11. Speech difficulty

12. Motor developmental delay

del22q11.2 syndromeaka

DiGeorge, Shprintzen, velocardiofacial, Takao, conotruncal anomaly face, Cayler, Sedlackova, CATCH22, Strong, …

Cardiac findingsCardiac findingsVentricular septal defect

Atrial septal defect

Pulmonic atresia or stenosis

Tetralogy of Fallot

Right sided aorta

Truncus arteriosus

Patent ductus arterious

Interrupted aorta

Coarctation of the aorta

Aortic valve anomalies

Aberrant subclavian arteries

Vascular ring

Anomalous origin of the carotid artery

Transposition of the great vessels

Tricuspid atresia

Genotype-phenotype correlation obscure

Williams syndrome

• supra-valvar aortic stenosis

• peripheral pulmonary stenosis

• elastin gene deletion

• chromosome 7 FISH

single gene disorders

Marfan syndrome

• aortic root dilatation

• MV prolapse

• fibrillin gene mutation

Noonan syndrome

• PTPN11 gene mutation in some (50%)

• pulmonary stenosis

• hypertrophic cardiomyopathy

John Smith has…

– jaundice (resolved)– butterfly vertebrae– Tetralogy of Fallot (repaired)

• JAGGED 1 mutation• sporadic• autosomal dominant

Alagille syndromeAlagille syndrome

EMBRYOLOGY

In the beginning...

Moorman et al. 2007 Phil Trans R Soc B 362: 1257-1265

Gastrula

Moorman et al. 2007 Phil Trans R Soc B 362: 1257-1265

Fo

ldin

g o

f

em

bry

on

ic

dis

k

heart

early development: a tug-of-war

• heart develops from a few mesodermal progenitor cells

• cardiac precursor zone defined by distinct gradients of genetic activity

• competing activating and inhibiting signals

• “all-or-nothing” phase

Harvey RP Nat Rev Genet 2002; 3:554-556

Männer J The Anat Rec 2000;259:248-262

2 heart fields!

• primary heart field develops atrial and left ventricular structures

• under control of NKX2.5

• secondary heart field lies more anteriorly and medially

• not derived from the cardiac crescent

• develops outflow tract and right ventricle

• under control of FGF10 and TBX1

Harvey RP Nat Rev Genet 2002; 3:554-556

The old embryology

arterial trunk

bulbus cordis

ventricle

atrium

sinus venosus

Heart tube

formation

Männer J The Anat Rec 2000;259:248-262

Cardiac loopingthe sequential

model

Männer J The Anat Rec 2000;259:248-262

From…to…Moorman AFM & Christoffels VM Physiol Rev 2003;83:1223-1267.

De la Cruz et al. 1977 and 1985. J Anat.

1. The heart tube contains all the cardiac precursors

2. Looping is the whole story

3. Development is linear

4. The septa are curtains dividing chambers

5. etc...

Some common misconceptions

modular chamber formation - not linear

• complex interplay of overlapping gene products form individual segments

• genes are region-specific• each chamber has intrinsic developmental properties

• chambers can be considered as modularelements

Bruneau BG Clin Genet 2003;63:252-261.Harvey RP Nat Rev Genet 2002; 3:554-556

whole-mount FISH

An explosion of knowledge!

• Recent confluence of:– description of the diverse genetic aetiologies of syndromic CHD

– the completion of the human genome, and– genomes of experimental animals– genetic databases and bioinformatics– molecular embryology, using– knock-in and knock-out animal models– 3D modelling and animation– microvideofluoroscopy

The ballooning model

development of a 4-chamber heart with 2 parallel flow circuitsfrom 1 segmented tube

the ballooning model

• old sequential model was a “fatal assumption” • new model based on:

– morphological,– functional,– flow &– genetic data

• requires the modular concept of chamber development – modules added during evolution– chambers selectively altered by site-specific genes

the linear heart tube

• poorly contractile• peristaltic• poorly coupled • slowly conducting• high automaticity

the fish heart

linear tube NOT folded

ballooning out of myocardium which is:

• rapidly conducting

• fast-contracting• coupled

• low automaticity

RV develops as a new

evolutionary structure

downstream of the P-ring P-ring

the mammalian heart

embryonic blood flow

P ring

blood is highly viscous

flow is laminar andparallel

P ring

How is all this controlled?

Acvr2b (activin A receptor, type IIB)* Laterality defects,* TGA, DORV, PTA

Agpt (angiopoietin 1) Atrial dysgenesis, ASD, venous malformation (cardinal vein obstruction)

Bmp4 (bone morphogenic protein 4) AVSD

Bmpr2 (bone morphogenic protein receptor, type II) PTA, semilunar valve dysgenesis

Cited2 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2)

ASD, VSD, DORV, PTA

CRELD1 (cysteine-rich with EGF-like domains 1)* AVSD*

Cspg2/versican/hdf (chondroitin sulfate proteoglycan 2) CT hypoplasia

Dvl2 (disheveled homologue 2) PTA, TGA

Ece1 (endothelin converting enzyme 1) IAA, VSD, DORV, PTA

Edn1 (endothelin 1) IAA, VSD

Egfr (epidermal growth factor receptor) AS, AI

Erbb2 (erythroblastic leukemia viral oncogene homologue 2) Noncompaction, aberrant trabeculation

Erbb3 (erythroblastic leukemia viral oncogene homologue 3) AV hypoplasia

Endra (endothelin receptor type A) IAA, VSD, DORV, PTA, TGA

Fgf8 (fibroblast growth factor 8) DORV, PTA, ASD, VSD, AV valve atresia, arch hypoplasia

Foxc1 (Fkh1/forkhead box C1) Aortic arch abnormalities

Foxc2 (Mfh1/Fkh14/forkhead box C2) Aortic arch abnormalities

Gata4 (GATA binding protein 4)* ASD,* VSD, cardia bifida, ventral morphogenesis

Gja1 (connexin43/gap junction membrane channel protein 1)* RVOT obstruction, aberrant coronary patterning; heterotaxy*

Hand1 (eHand/heart and neural crest derivatives expressed 1) Looping abnormality

Hand2 (dHand/heart and neural crest derivatives expressed 2) RV hypoplasia, Ao arch hypoplasia, trabecular abnormality

Has2 (hyaluron synthase 2) Absent AV cushions and trabeculae

Hoxa3 (Hox-1.5/homeobox A3) CT abnormalities

Hspg2 (perlecan/heparin sulfate proteoglycan of basement membrane)

TGA/IVS, coronary anomalies

Jag1 (jagged 1)* PS, VSD, TOF, Alagille’s syndrome*

Madh6 (Smad6/mothers against decapentaplegic homologue 6) CT septation defects

Nf1 (neurofibromatosis 1) EC cushion defect, DORV

Nfatc (nuclear factor of activated T cells, cytoplasmic 1) VSD, valve defects

Nkx2–5 (Csx/NK2 transcription factor related, locus 5)* ASD,* VSD, TOF, EP

Nr2f2 (COUP-TFII/nuclear receptor subfamily 2, group F, member 2)

Atrial dysgenesis, ASD, venous malformation (cardinal vein obstruction)

Nrg1 (neuregulin 1) Noncompaction, dysmorphic trabeculae

Nrp (neuropilin-1) TGA, PTA

Ntf3 (neurotrophin 3) PTA, IAA, CT defects

Pax3 (paired box gene 3) PTA, CT defects

Pcaf (p300/CBP-associated factor) PTA, CT defects

Pdgfr (platelet-derived growth factor receptor, polypeptide) PTA, DORV, VSD, noncompaction

Pitx2 (paired-like homeodomain transcription factor 2) Laterality, AVSD, PTA, TGA, DORV

Rar (retinoic acid receptor, ; RAR1/ß2, /ß2, compound mutants similar)

IAA, VSD, PTA, DORV

Rarß (retinoic acid receptor, ß) CT defects, VSD

Rar (retinoic acid receptor, ) CT defects, VSD

Rxr (retinoid X receptor, ) ASD, VSD, AVSD, noncompaction, PTA, AP window

Sema3c (semaphoring 3C/sema domain, immunoglobulin domain, short basic domain, secreted)

IAA, PTA

Sox4 ([sex determining region Y]-box 4) AVSD, TGA, semilunar valve defects, PTA

Tbx1 (T-box 1)* DGS*

Tbx5 (T-box 5)* HOS*, ASD, VSD, TOF, EP

Tead1 (Tef-1/TEA domain family member 1) Noncompaction, trabecular abnormality

Tek (Tie2/endothelial-specific receptor tyrosine kinase)* Venous malformations*

Tgfß2 (transforming growth factor, ß2) VSD, DORV

Tgfßr3 (transforming growth factor, ß receptor III/ß glycan) Decreased cushion mesenchyme transformation

Vcam1 (vascular cell adhesion molecule 1) Noncompaction, VSD

Zfpm2 (FOG2 [friend of GATA] 2/zinc finger protein, multitype 2)

TA, ASD, VSD, PS, TOF, AVSD

Gene CHD

Gruber PJ & Ebstein JA Circ Res 2004;94:273-283.

Aetiology leads to control…?

Can we manipulate heart development?Canadian mandatory folate fortification 1998

The foetal circulation

Attitudinally Appropriate

ANATOMY

The Valentine Heart