3/10/2017 SESSION 3: Pulmonary Venous disease Part I NO - - PowerPoint PPT Presentation

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3/10/2017 SESSION 3: Pulmonary Venous disease Part I NO DISCLOSURES Dra. Maria Jess del Cerro Pediatric Pulmonary Hypertension Unit RAMON Y CAJAL University Hospital. Madrid, Spain Q1: Anatomy, Histology of the lesions.

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Dra. Maria Jesús del Cerro

Pediatric Pulmonary Hypertension Unit “RAMON Y CAJAL University Hospital. Madrid, Spain

SESSION 3: Pulmonary Venous disease Part I

NO DISCLOSURES

Q1: Anatomy, Histology of the lesions. Q2: AND CONSEQUENCES of PV Stenosis in preterm Relationship betwen Relationhip between PV stenosis and outcomes of Pretem babies… Q4: WHAT CAN WE LEARN FROM other human PV stenosis entities and from ANIMAL MODELS of PV stenosis? SUMMARY

Benjamin JT

Case report: Ex preterm , 22 weeks GA Surgery PDA Dg Left pulmonary vein stenosis at autopsy performed at 23 months age

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Lumen of the normal, proximal vein Occluded lumen at the stenosis

Spindle shaped Intimal Cells in the ridge

venous congestion Subpleural and interstitial Alveolar simplification Remodelling of small peripheral artery Medium hypertrophy

Mc Connell, Pediatric Cardiology 1994

Case report:

Female,

Birth weight 1.600 gr

TOF, Pda NEC needing surgery At 5 months, diagnosed with PV stenosis of 3 veins..

Autopsy

Obliterative fibromuscular thickening

BOTH IN LARGE VEINS at the venoatrial junction SMALL VEINS Small PV right Lung Small PV left Lung

SEVERE INTERSTITIAL FIBROSIS IN THE LUNG

Q1: anatomy, histology of the lesions

DISCRETE STENOSIS

AT THE VENOATRIAL JUNCTION

DIFFUSE STENOSIS

OF THE “UPSTREAM” PULMONARY VEINS INTO THE LUNG PARECHIMA

ACQUIRED, PROGRESSIVE LESIONS ATRESIA of the VEIN

Pattern at presentation

60% Unilateral 40% Bilateral

86% Left Side

Dressner, Pediatrics 2008

64% Unilateral 36% Bilateral

95% Left Side

Maghoub, Ped Pulmonol 2017

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Maghoub L, et al

Multicentric study :

39 expreterm

with PV stenosis

Q2: AND CONSEQUENCES Of PV Stenosis in preterm infants? Relationship betwen Relationhip between

PV stenosis and outcomes of Pretem babies… PV STENOSIS AND BPD… Pulmonary Vein Stenosis: Prematurity and Associated Conditions 2008 26 pt EVP: 61% prematuridad

EG

42% DBP

88% associated cardiac lesions.

58 cases 38% preterm babies 79% Cardiac Lesions

28% Extracardiac syndromes

Median GA 28 weeks Median Birth Weight 750 gr.

63% BPD

40% documented normal veins at birth PV stenosis DG 7 mo after birth PROGRESSION From Unilateral to Bilateral disease From discrete stenosis to diffuse narrowing and atresia Development of collateral vessels

to unaffected lobes /systemic veins

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Associated Cardiac Lesions: 80%

NEC: 50% 20 preterm

infants diagnosed with PV stenosis

Columbia University

Common embriological origin of Splanchnic Vasculature and Pulmonary Veins VEGF mediated nflammation in NEC affecting P Veins NEC preceded the diagnosis of PV Stenosis… Common embriological origin of Splanchnic Vasculature and Pulmonary Veins VEGF mediated nflammation in NEC affecting P Veins NEC preceded the diagnosis of PV Stenosis…

Maghoub, Ped Pulmonoo 2017 n % preterm % BPD Cardiac lesions NEC 3 y SURVIVAL Dressner

Pediatrics 2008

26 62% 48% 88% 43% Seale

Heart 2009

41/58 38% 63% of pret 79% 49% Heching

Arch Dis Child 2014

20 100%

50% 60% Laux Ped Cardiol 2016 16 100% 87,5% 87,5% 12% 66% Maghoub L Ped Pulmonol 2017 39 100% 74% 100% 23% 55%

2 months age 19 months age 19 months age

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Maghoub L Multicentric study : 39 expreterm with PV stenosis

15/39 (39%) born of Multiple pregnancies, With unaffected siblings EPIGENETIC FACTORS …??? Lung Edema Decreased Lung Compliance

Environmental factors? Genetic factors?

Inflammation citokines

Shunts

flow in PVs Lung infection, Sepsis NEC Chorioamnionitis Lung infection, Sepsis NEC Chorioamnionitis Disrupted angiogenesis

HYPOPERFUSION OF THE AFFECTED LOBE/LUNG
OVERFLOW TO THE UNAFFECTED LUNG/LOBES
HYPOPLASIA OF THE AFFECTED LUNG
LUNG EDEMA
VENOUS COLLATERALS DEVELOPMENT
PULMONARY HYPERTENSION

INFLUENCE ON THE PATIENTS OUTCOMES

HYPOPERFUSION OF THE AFFECTED LUNG/LOBE OVERFLOW TO UNAFFECTED LOBES

intrapulmonary hypoplasia

f the left pulmonary artery

in left Pv stenosis/Hypoplasia

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VENOUS Collaterals to systemic veins

Courtesy of Dr Lina Caicedo and Diana M. Nuñez, Shaio Clinic, Bogotá

CONSEQUENCES OF PV STENOSIS

INCREASE IN PULMONARY CAPILLARY WEDGE PRESSURE OVERFLOW TO UNAFFECTED LOBES ARTERIOLAR REMODELLING

IN THE AFFECTED & UNAFFECTED LOBES

REFLEX ARTERIOLAR VASCONSTRICTION?

LUNG EDEMA, DECREASED COMPLIANCE,

INCREASE IN HYPERCAPNIA AND HYPOXIA

PAH ?

PH LEFT HEART DISEASE? PH DUE TO LUNG DISEASE?

Maghoub L Multicentric study :

39 expreterm

with PV stenosis

CONSEQUENCES OF PV STENOSIS

PULMONARY HYPERTENSION

4.7 % in a retrospective

ECHOcardiographic Review

f 213 pts with severe BPD

At Ohio´s Children´s hospital

Cerro et al, Pediatric Pulmonology, 2014

27% in a cohort of BPD with moderate/severe PH

referred to a PH Unit

DG: CT scan /cath

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3/10/2017 7 PV stenosis and outcomes of Pretem babies…

n % preterm % BPD Cardiac lesions NEC

3 y SURVIVAL

Dressner

Pediatrics 2008

26 62% 48% 88%

43%

Seale

Heart 2009

41/58 38% 63% of pret 79%

49%

Heching

Arch Dis Child 2014

20 100%

50%

60%

Laux Ped Cardiol 2016 16 100% 87,5% 87,5% 12%

66%

Maghoub L Ped Pulmonol 2017 39 100% 74% 100% 23%

55% 20 preterm infants

diagnosed with PV stenosis

NEC no NEC

58 cases

38% preterm babies 79% associated cardiac lesions

Median GA 28 weeks
Median Birth Weight 750 gr.
63% BPD

Seale et al

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58 cases

38% preterm babies

79% associated cardiac lesions Maghoub L AGA/LGA Small for GA Multicentric study :

39 expreterm

with PV stenosis Survival 76% Survival 61% 3 or more veins Bilateral disease Dg < 6 months age

16 expreterm infants from 2 French institutions

Laux D, et al Pts with bilateral disease and 3 or more veins Pts with Unilateral disease and 1 or 2 veins

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SEVERE PULMONARY HYPERTENSION Angioplasty & stenting pulmonary veins ,

RSPV Pre stent RSPV POST stent

stent implantation in RSPV Balloon Angioplasty Left PVs

PROGRESSION TO Restenosis of RSPV stent Complete occlussion of left PVs Died in right heart failure ANOUAR LOUBANI BPD Right heart failure PV stenosis at 18 months

f Left inferior and

Right superior PVs

Daily sincopal episodes Failure to thrive Progressive Ph In spite of sildenafil Pericardial effusion

5 YEARS LATER: alive, FC I-II , severe PH with triple therapy

PRET 27+4 WEEKS . Birth weight: 880 gr. Multiple pregnacy . PDA surgically closed NEC (several surgeries), Short bowel syndrome Severe BPD

DG with severe left PV stenosis at age 7 months ECO: big ASD severe PH severe gradient in left Pulmonary veins

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7 m. HTP Limitation of agressive therapies decided…. The girl started tolerating enteral feeding.. Discharged home... Favourable evolution of the BPD…

7 years age

Functional class I NO PH Left PV remain patent but stenotic in the CT scan REEVALUATED IN CARDIOLOGY AT 18 months ASD surgically closed at 20 months age No residual PH Left PV remained stenotic

7 m. HTP Age 2 y.o.: left PV stenosis (superior and inferior) Corrected TOF Severe PH , severe GERD, still depending on Oxygen therapy Surgery for GERD Sildenafil therapy NO intervention on the left Pvs

9 years age

Functional class I-II Mild PH (40% systemic), Sildenafil therapy Left PV remain patent but stenotic in the CT scan

Autopsies of 10 infants Dg PV stenosis in first year life Simple shunts Abnormal intimal spindle- shaped cellular proliferation

Electron microscopic images

Inmunohistochemical stainig

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Ussia GP. Eur J Cardiothorac Surg 2002;22:465-7

3 infants developing left pulmonary vein stenosis/atresia In the months after open heart surgery for complex heart disease: TA+Tga+IIA type B----Norwood+Glenn DORV +mitral stenosis– banding--Fontan D- TGA+ Ao coartation--- atrial switch+Co repair

All of them had documented normal veins before surgery…

Neointimal fibromuscular proliferation In the large central pulmonary vein Intimal Hyperplasia in the small intrapulmonary veins Arterioles : Intimal proliferation Medial hypertrphy 55 years old men , PH with PV stenosis, needing lower left lobectomy for recurrent hemoptisis with PV stenosis after AF radiofrecuency ablation… angioplasty, stents, surgery… Pereda D, et al, J Cardiovasc Tras Res 2014

4 weks old piglets Sham group N=3 PV banding N=12

CT scan 2 months after intervention

PV Banding Sham

right Antero Lateral thoracotomy

RVEDV RVEDV RVEF RVEF RVEDV RVEF

mPAP PVRI

Pereda D, et al, J Cardiovasc Tras Res 2014

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PV banding

LUNG HISTOLOGY IN PV BANDING

Remodelling in small arterioles

(intimal thickening, medial hypertrophy, adventitial fibrosis & linfocitic infiltration

IN ALL LOBES OF BOTH LUNGS

In spite of the fact that only the inferior lobes vein were banded

Increased lung weight without increased water content Increased extracellular connective tissue

Pereda D, et al, J Cardiovasc Tras Res 2014

RIGHT VENTRICULAR HYPERTROPHY AND DILATATION INTERVENTRICULAR SEPTAL BOWING LEFT VENTRICULAR DEFORMATION

MASSON´S TRICHROME STAINIG HEART:

HYPERTROPHY, DISARRAY OF MUSCULAR FIBERS INTERSTITIAL FIBROSIS Increase in collagen tIssue INTHE RV MYOCARDIUM PV BANDING PV BANDING SHAM SHAM

Masson´s Trichrome Stainig Heart

Li S, et al Sham

Atrial fibrilation AF Radiofrecuency RF

AF + RF Increased expression of b-TGF protein in stenotic Pulmonary veins

Endothelial-Mesenchymal transition EndMT contributes to the upstream propagatation of the disease

Piglet model of bilateral Pulmonary veins BANDING Human PV tissue: Infants dead with PV stenosis Heart TX donors infants

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IN VITRO INDUCTION OF ENDOTHELIAL TO MESENCHYMAL TRANSITION BY ADITION OF BETA TRANSFROMING GROWTH FACTOR (TGF) in a cell culture of both

CELLS FROM BANDED PIGLET PULMONARY VEINS CELLS from HUMAN FETAL UMBILICAL VEINS

Acquired, Progressive Disease Related To BPD And PH Multifactorial Model of PH Influence on Expreterm babies outcomes Better prognosis in Unilateral disease