pediatric cardiac surgery: past, present, and future · pediatric cardiac surgery: past, present,...
TRANSCRIPT
![Page 1: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/1.jpg)
Pediatric Cardiac Surgery: Past, Present, and Future
Peter J. Gruber, MD, PhD
Johan Ehrenhaft Professor and Chair
Department of Cardiothoracic Surgery
Carver College of Medicine
University of Iowa
![Page 2: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/2.jpg)
![Page 3: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/3.jpg)
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![Page 5: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/5.jpg)
Carver School of Medicine- Iowa
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CHOI
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“Any surgeon who wishes to preserve the respect of his colleagues would never attempt to
operate on the heart.”
(Theodore Billroth)
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Evolution of Congenital Cardiac Surgery
4 eras complete, 1 in process, more to come
Closed extra-cardiac operations
Early closed or semi-closed intra-cardiac operations
Complete intra-cardiac repair
Refinement of technique
Management of unforeseen co-morbidities
Disease causality risk assessment and surgical planning
?
1937
1944
1952
1971
2000
2015
?
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Evolution of Cardiac Surgery
4 historical eras
1. Closed extra-cardiac operations
1937/8 - Ligation of patent ductus arteriosus (Strider and Gross)
2. Early closed or semi-closed intra-cardiac operations
1944 - Coarctation repair (Craaford)
1944 - Blalock-Taussig shunt
1946 - Potts’ shunt
1946 - Closed pulmonary valvotomy (Sellors)
1948 - Blalock-Hanlon atrial septectomy
1952 - Pulmonary artery band (Muller and Dammann)
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Evolution of Cardiac Surgery
4 historical eras
3. Complete intra-cardiac repair
1952 - Atrial well for ASD closure (Gross)
1952 - ASD closure with inflow occlusion and hypothermia (Lewis)
1954 - Controlled cross-circulation (Lillehei)
1958 - Superior cavopulmonary anastomosis (Glenn)
1962 - Waterston’s shunt
1966 - Balloon atrial septostomy (Rashkind)
1968 - Atriopulmonary connection (Fontan and Baudet)
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Evolution of Cardiac Surgery
4 historical eras
4. Refinement of technique
1971 - Complex repair in neonates and infants with DHCA (Barratt-Boyes)
1975 - Arterial switch operation (Jatene)
1976 - Introduction of PGE1 (Elliott)
1981 –Stage I palliation of hypoplastic left heart syndrome (Norwood)
1984 - Neonatal heart transplantation (Bailey)
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PGE1
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PGE1
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PGE1
Surgeon
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Ligation of patent ductus arteriosus
• 1937 John Stridor
• 1938 Robert Gross
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Ligation of patent ductus arteriosus
• 1937 John Stridor
• 1938 Robert Gross
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Coarctation of the aorta repair
• 1944 Blalock-Park
• 1944 Craaford
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Coarctation of the aorta repair
• 1944 Blalock-Park
• 1944 Craaford
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Johns Hopkins Hospital, 1945
• Alfred Blalock
• Vivien Thomas
• William Longmire
• Denton Cooley
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Palliation of cyanotic heart disease
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B-H atrial septectomy
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Rashkind
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Atrial well technique of ASD closure- the wild west (Gross)
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Evolution of ASD closure
Date Surgeon Technique Institution Mortality
1948 Murray External suturing
1952 Gross Atrial well- blind! Boston Children’s 30.2%
1952 Lewis Inflow occlusion Mayo 12.1%
1953 Gibbon Direct closure with CPB Penn
today all CPB everywhere <1%
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Cardiopulmonary Bypass Circuit
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Cross circulation- Mayo experience
L
G
S
F
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Cross circulation
• 1 y.o. 6.9 kg VSD, 11d survival
• support Owen Wangenstein
• 4 y.o. girl with a VSD
• 45 operations
• TOF, AVSD, VSD
• No operative deaths were directly attributable due to the cross circulation technique
• post-operative heart block was the real killer
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Risk in Congenital Heart Surgery: Chronological improvement
0
25
50
75
100
1990 2003 2012
5
4
3
2
1
RACHS
Year
Mortality
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How do we crack the final percentage?
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Today
• team oriented approach
• importance of co-morbidities
• operations for single ventricle physiology
• neurodevelopment
• fetal interventions
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Tetralogy of Fallot
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Patients with same disease have different responses
Post operative day 5, TOF
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Aorta
RV
RPA
HLHS
PA
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HLHS- Classic Norwood
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HLHS- Classic Norwood
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Are surgeons to blame for everything?
Time (min)
Anesthesia
CPB
AXC
DHCA
CICU
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↓ Substrate delivery
↓ Oxygen delivery
↑↓ Cerebral resistance
Placental abnormalities
Genetic syndromes
Delayed diagnosis
Preoperative Modifiers Low Cerebral Blood Flow
Low Cerebral O2 Content
ICU Morbidity (emboli, fever, etc.)
Anesthesia
Opiates
Benzodiazepines
CPB
Hypothermia
Circulatory Arrest
Early Modifiers
Genetic Polymorphisms
Alterations in CBF
Hypoxemia, hypocarbia, hypotension
Hyperthermia
Seizures Stroke
Late Modifiers
Hypoxemia
Reoperations
Socioeconomic Status
PTSD, maternal depression
Poor nutrition
Abnormal Brain at Birth ↓ head circumference
Structural abnormalities
PVL
CNS immaturity
Middle School Behavior problems
Inattention/Hyperactivity
↓ Handwriting
↓ Visual motor integration
Pre-School Delayed motor skills
Delayed language
Microcephaly
Adolescence-Transition to ACHD Depression and behavior problems
Inattention/hyperactivity
↓ Visual motor integration
↓ Planning and executive function
Neurodevelopmental (Early and Latent) Outcomes
Fetus → Birth → Surgery → ICU → Stepdown → → → Home → → → → → →
Causes of adverse neurodevelopmental outcomes: Multifactorial, interactive, and ongoing
Infancy Seizures (cortex)
↑ PVL (white matter)
Delayed motor skills
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↓ Substrate delivery
↓ Oxygen delivery
↑↓ Cerebral resistance
Placental abnormalities
Genetic syndromes
Delayed diagnosis
Preoperative Modifiers Low Cerebral Blood Flow
Low Cerebral O2 Content
ICU Morbidity (emboli, fever, etc.)
Anesthesia
Opiates
Benzodiazepines
CPB
Hypothermia
Circulatory Arrest
Early Modifiers
Genetic polymorphisms
Alterations in CBF
Hypoxemia, hypocarbia, hypotension
Hyperthermia
Seizures Stroke
Late Modifiers
Hypoxemia
Reoperations
Socioeconomic status
PTSD, maternal depression
Poor nutrition
Abnormal Brain at Birth ↓ head circumference
Structural abnormalities
PVL
CNS immaturity
Middle School Behavior problems
Inattention/Hyperactivity
↓ Handwriting
↓ Visual motor integration
Pre-School Delayed motor skills
Delayed language
Microcephaly
Adolescence-Transition to ACHD Depression and behavior problems
Inattention/hyperactivity
↓ Visual motor integration
↓ Planning and executive function
Neurodevelopmental (Early and Latent) Outcomes
Fetus → Birth → Surgery → ICU → Stepdown → → → Home → → → → → →
Causes of adverse neurodevelopmental outcomes: Multifactorial, interactive, and ongoing
Infancy Seizures (cortex)
↑ PVL (white matter)
Delayed motor skills
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Collaborative Model of Care
Cardiothoracic Surgery
Cardiac Critical Care
Cardiac Anesthesia
Cardiac Nursing
Cardiology
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What’s next
• precision therapies guided by genetics
• new and nano technology introduced drugs, devices, and materials
• robotic manipulations
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What’s next
• precision therapies guided by genetics
• new and nano technology introduced drugs, devices, and materials
• robotic manipulations
![Page 42: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/42.jpg)
What tools are in place
• patients and clinical data
• sequencing and bioinformatic tools
• biologic tools for variant verification
• ontologies that speak to each other
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What tools are in place
• patients and clinical data
• sequencing and bioinformatic tools
• biologic tools for variant verification
• ontologies that speak to each other
![Page 44: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/44.jpg)
How do we get many thousands of samples to analyze?
• I have thousands of DNA, hundreds of tissue, and tens of stem cells lines- not enough
• Collaboration to get the rest
– single investigators
– institutional BioBanks
– larger initiatives
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CHSS collaborative sites
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CHSS enrolling institutions
11 12 16 15
19 20 19 17
13
19 22
28 30
0
5
10
15
20
25
30
35
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CHSS study enrollment
895
494
903
457
613
489
349
634
767
298
105
0
200
400
600
800
1000
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Samples by diagnosis
Arrhyth
AS
ASD
AVSD
CoA
DORV
HLHS
IAA
TGA
TOF
VSDn = 12,000
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What tools are in place
• patients and clinical data
• sequencing and bioinformatic tools
• biologic tools for variant verification
• ontologies that speak to each other
![Page 50: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/50.jpg)
Turn to development for answers
• Fish- transgenic zebrafish
• Mice- gene-targeted mice
• Human- genome sequencing and iPSC production
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Chr 5 variation in the ISL1 region
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Chr 5 variation in the ISL1 region
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ISL1 risk by ethnicity
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ISL1 risk by ethnicity
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ISL1 risk by ethnicity
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Total # SNPs by chromosome
Total=3,754,214 Total=3,169,270 Total=3,147,463
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What’s next
• precision therapies guided by genetics
• new and nano technology introduced drugs, devices, and materials
• robotic manipulations
![Page 58: Pediatric Cardiac Surgery: Past, Present, and Future · Pediatric Cardiac Surgery: Past, Present, and Future Peter J. Gruber, MD, PhD Johan Ehrenhaft Professor and Chair Department](https://reader033.vdocuments.us/reader033/viewer/2022053017/5f1c432c2196ee5609561190/html5/thumbnails/58.jpg)
2 y.o. TOF/AVC
• 2 y.o. female with transitional AVC, dysplastic RAVV, and PV stenosis.
• primary repair in infancy
• secondary repair at 1 year with RAVV repair and RV-PA conduit.
• now with PA stenosis and severe RAVV regurgitation
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Complete common AV canal
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Native valve function- pre
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Heimlich valve principal
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ECM TV creation
• completed cylinder valve
• ends are tacked to ventricular wall
• other cylindrical end is sewed to annulus
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ECM TV function- post
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In vitro images
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Risk in Congenital Heart Surgery: Chronological improvement
0
25
50
75
100
1990 2003 2012
5
4
3
2
1
RACHS
Year
Mortality
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Generation of human iPS cells of patient specific tissue
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Patient-specific cellular reprogramming in CHD
-11 lines of AF: gest age 3@19, 3@20, 1@22, 1@25, 1@32, 1@33 weeks - average reprogramming time with clonal selection = 3 weeks - creation of >100 stable iPS cell lines
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Reprogramming using amniocentesis-derived fibroblasts
Experimental Time (Gest. Age)
0 (14-20 weeks)
1 day (14-20 weeks)
1 week (15-21 weeks)
2 weeks (17-23 weeks)
1 week (18-24 weeks)
1 week (19-25 weeks)
3 weeks (22-28 weeks)
2-6 weeks (24-32 weeks)
4-8 weeks (28-40 weeks)
Procedure
Amniocentesis
Purification of amniotic fluid fibroblasts
Expansion of fibroblasts
Transduction of fibroblasts (4XF/miR)
Selection of iPSC clones
Screen iPSC clones
Expansion iPSC clones
Directed differentiation
Assay of differentiated cell types
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Cardiac differentiation of human iPS cells
iPS-1
iPS-2
iPS-3
iPS-4
iPS-5
Days post-directed differentiation
ISL1
exp
ress
ion
0 2 4 6 8 10 12 0.0
0.2
0.4
0.6
0.8
1.0
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Neuronal differentiation
iPS precursor
Neural induction
Neural differentiation
0.1
1
10
100
1000
10000
d0 d2 d4 d6 d8 d10 d15 d20
Expanded iPS clones of two different patient with congenital heart disease and hES as a control (beta III tubulin)
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Directed differentiation of patient-specific iPS cells may eventually help predict responses
iPS/progenitor cell
cardiomyocyte neuron etceterocyte
mechanical load EP
drug responses
hypoxia tolerance drug responses
etc.
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“This isn’t rocket science, it’s much harder” (A. Spiegel)
Portion of G1-S transition (Korn, 1999)
Portion of propulsion and altitude control, system from Cassini- Saturn mission (NASA)