Anomalous Pulmonary Veins Coordination of lung and heart development - - PowerPoint PPT Presentation

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Anomalous Pulmonary Veins and Post Repair Pulmonary Vein Stenosis

University of Toronto/ Hospital for Sick Children Rachel Vanderlaan

10TH INTERNATIONAL NEONATAL & CHILDHOOD PULMONARY VASCULAR

DISEASE CONFERENCE

March 10th, 2017

Pulmonary Venous Development

Coordination of lung and heart development

• 1. Formation of the primitive lung
• 2. Formation of the primitive left atrium

Eur J Cardiothorac Surg (2013) 44 (5): 792-799. Posterior view

• Common PV vein; bifurcates and

contributes to left atrium wall

• Septation of atrium
• Involution of systemic venous

connections

Anomalous Pulmonary Venous Connections

Partial Total

Developmental consequence:

• 1. Lack of Myocardial Sleeve
• 2. Abnormal smooth muscle cell and myocardial differentiation in left atrium
• 3. Small left atrium

1.5% of all congenital heart disease Multifactorial etiology

• isolated sporadic cases
• Familial inheritance:
• 1. Identified TAPVC-1 region 4q12

Candidate genes include KDR and PDGFRA

• 2. ANKRD1 overexpression

Associated with syndromes:

• cat eye syndrome
• Holt-Oram
• Right Atrial Isomerism: TAPVC common

~ 40% have PV obstruction

Total Anomalous Pulmonary Venous Connections

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Supracardiac ; Type I ~45% Infracardiac ; Type III ~25% Mixed ; Type IV ~5% Innominate vein (right cardinal veins) Coronary Sinus (left cardinal veins) Cardiac ; Type II ~25% Hepatic vein / IVC (umbilicovitelline)

Kirlin Cardiac Surgery

Types of TAPVC TAPVC : Clinical presentation

• 1. Degree of obstruction to pulmonary venous drainage
• 2. Degree of restriction to the compensatory right-to-left shunt

Neonate- unobstructed Supracardiac/Cardiac Neonate- obstructed Infracardiac/Mixed

Spectrum

Symptoms of RV volume overload Pulm edema, hypoxemia, cardiogenic shock

Definitive Management: Surgery

TAPVC : Risk Factors and Outcomes

Risk Factors

• Preoperative PVO
• 40% of patients
• associated with infracardiac
• Younger age at presentation
• Postoperative PVS

Infracardiac and Mixed Cardiac and Supracardiac Shi G, 2017

TAPVC : Risk Factors and Outcomes Post Repair Pulmonary Vein Stenosis

PVS after TAPV repair

Seale AN, JTCVS 2013

Occurs in ~10-15% Risk factor for death

Intervention for post-repair PVS

(1998-2004)

Recurrence common High mortality

Significant Morbidity: recurrent infections, hemoptysis, pneumonectomy

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Bringing PVS into Focus

• 1. Interventions
• Surgery
• Catheter based interventions
• Transplant
• 2. Medical Therapies/ Experimental therapies
• 3. Enhanced Surveillance- Echo + CTA/MRA/Cath
• 4. Team/ Collaborative Approach
• 5. Research: Understanding mechanisms of disease

Post repair PVS: High mortality and morbidity

Bringing PVS into Focus : PVS Team

PVS Team

• Cardiologists- Echo, MRI, PH, interventionalist , CCCU and surgeons
• Adjunct teams: Lung Transplant, PACT

Clinical Surveillance Protocol- ‘Standard of Care’

• Patients with congenital or post repair PVS
• Children with RAI- small PV confluence
• GOAL: Early detection, Early intervention
• Complementary use of multiple imaging modalities

Echo (Cath) CT/MRI Basic CSP: 1, 6, 12 months post intervention Echo , CTA/MRA (cath) Patient specific: Match surveillance to velocity of disease

Disease Stabilization/Cure Transplantation Palliation

Clinical Impact of PVS Team

Improved performance and surveillance Growth in knowledge of PVS Maturation of team

Surgical repair of PVS Pre–CSP cohort (2010- sept 2015) Post-CSP cohort (Sept 2015-Sept 2016) Number of Patients n=30 n=9 Number of patients with 3D imaging for diagnosis 21/30 (70%) 9/9 ( 100%) * Time from 3D imaging to surgery (median , IQR) 50 days (22-109) 16 days ( 9-40) Number of patients with 3D imaging for follow up 9/16 ( 56%) ( 16 patients with f/u data) 9/9 (100%) * Time from surgery to 3D imaging (median , IQR) 131 days (91-219)

52 days (42-62)*

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Collaboration: PVS Network

PVS

Absence of Clinical Guidelines

Heterogeneous Presentation Diverse Imaging Modalities Multiple Treatment Options Individual Clinician practices Institutional Practices PVS Team Regional/ North American practices PVS Network Practice Based Evidence Evidence based Practice

Over 12 Institutions and growing

1. Registry study First analysis: clinical practice patterns and contemporary

• utcomes

2. Resources: parents and clinicians www.pvsnetwork.org

• 3. Generation of consensus guidelines

Collaboration: PVS Network

Advancing Research and Clinical Care for Children with Pulmonary Vein Stenosis

Collaboration to improve outcomes for children with PVS

Bringing PVS into focus: Understanding Disease Mechanisms PVS Research

Molecular mechanism Therapies

Genomics Clinical Trial Surveillance PVS Team

Laboratory Model of PVS

Modified model from LaBourene, Circ Res 1990; Kato et al. JTCVS 2012

10 20 30 40 50

Sham B7

PA systolic pressure

mmHg

*

50 100

Sham B7

RV weight- indexed * SHAM B3 B5 B7 7 wk

Sequential bilateral PV banding

Sacrifice 3 wk 5 wk losartan LB7

Pig Surgical Model: Disease Mechanisms in PVS

3/10/2017 5 Progressive Disease: Myofibroblast Deposition

Gapdh

Fibronectin

S B3 B5 B7

Fold Increase in mRNA expression

* * * * * *

1 2 3 4 5 6 7 B3 B5 B7 MMP2 Col1A1

α-SMA/CD31

SHAM

Stage 1 Stage 2 Stage 3

Progressive Disease: Myofibroblast Deposition

• 1. Proliferating Cells
• Fibroblasts, SMC
• 2. Endothelial to mesenchymal transition
• 3. Circulating Progenitors

Proliferation contributes to neointimal lesions

* * 0.5 1 1.5 2

B3 B5 B7

Ki 67

Fold Increase in mRNA expression

% Ki-67 positive cells

p=0.06

* 5 10 15

Sham B3 B5 B7

Intima

2 4 6 8 10

Sham B3 B5 B7

Media

* * 5 10 15

Sham B3 B5 B7

Adventitia

Enhanced proliferation in the intimal and adventitial compartments

Sham B5

EndMT CD31 VE Cadherin α-SMA, FSP-1 FN EC markers Fibroblast markers

SNAIL

TGF-B MET

Endothelial to mesenchymal transition : source of myofibroblasts

Mechanical Stress Growth factors

* * * * *

1 2 3 4 5 TGFB Veh

Fold Increase in mRNA expression

Veh TGFB PV Endothelial cells

FN/DAPI/VE FN/DAPI/VE Sham

Fold Increase in mRNA expression

* * * * * *

1 2 3 4 5 6 7 8

B3 B5 B7

Snail Twist

α-SMA\CD31

B5

Supportive of EndMT in PVS neointimal formation

3/10/2017 6 Altered vasoreactivity in upstream pulm veins

% Relaxation

* * * 0.06

• 140
• 120
• 100
• 80
• 60
• 40
• 20

20 Banded Sham 10-9 10-8 10-7 10-6 10-510-4

Acetylcholine

* * * * * * * * 1 2 3 4 5 6 7

B3 B5 B7

Nox 2 Nox4 p22phox p47phox

Fold Increase in mRNA expression

Protein Carbonylation Sham B7 Anti- DNP B- actin

Early upstream endothelial dysfunction prior to overt neointimal lesions

Myofibroblasts ECM deposition Adventitial fibroblast proliferation and activation EndMT ↑TGF B and AngII signaling

Losartan

Sham Banded Losartan + Banded

Zhu J et al. JTCVS 2014

Therapeutic Adjuncts in PVS

• > Health Canada Safety and Feasibility Trial

Post repair PVS has significant impact on survival following TAPVC primary repair Post repair PVS and congenital PVS : Many Tools

• requires team approach and sharing of knowledge
• multi-institutional collaboration key for progress

Research will insights into disease mechanisms

• Identification of targets for developing therapeutic adjuncts

Summary

Acknowledgements

PVS team Christopher Caldarone Andreea Dragulescu Lars Grosse-Wortmann Tilman Humpl Hartmut Grasemann Jennifer Russell Luc Mertens Andrea Wan Rachel Vanderlaan PVS Research Program Christopher Caldarone Rachel Vanderlaan Members/ Trainees Anouk Martine-Teichert Yana Fu Yanting Wang Mauro Lo Rito Haruki Ide Jiaquan Zhu Hideyuki Kato Collaborators John Coles Jason Maynes Richard Wiesel Jaques Belik Boris Hinz PVS Network Site investigators and research coordinators Donor Families

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Post Repair PVS

• Histological neointimal lesions

similar to primary PVS

• Can be progressive into upstream

intraparenchymal veins

• Unilateral / bilateral

Diffuse NeoIntimal lesions and fibrosis