Single Ventricle BUT Multiple PH treatment in Single Ventricule - - PowerPoint PPT Presentation

3/9/2019 1

PH treatment in Single Ventricule

Marilyne Lévy, Necker- Paris - France UCSF from 2016 to 2019

« Single » Ventricle BUT Multiple…

• Ventricular function: LV? RV?
• Atrial pressure : AV valve ?
• Pulmonary circulation ?

Fontan circulation

• 1971 : Tricuspid Atresia
• Limited indications
• 10 restrictions

– Age > 4 years – mPAP < 15mmHg – PVR < 3 WU – No PA dystorsion – Normal venous return – No arythmia – No right atrial enlargement – No AV regurgitation – No ventricular dysfunction – No previous surgical complications

• Thorax. 1971 May;26:240–248

(Fontan’s Decalogue)

From 10 to 1 restriction pulmonary circulation precapillary PH or post-capillary PH

Technical improvement TCPC Extracardiac tube Fenestration

NO RIGHT V

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The objective

• To maintain low PVR

– Banding we never now : Too high or too low – Blalock shunt : pulmonary artery distorsion – Natural pulmonary stenosis

SaO2 > 85% QP/QS > 2

90 85 3 2

Sa02 QP/QS

Overload

Mario Cazzaniga Rev Esp Cardiol. 2002;55:391-421

PREOPERATIVE MEAN PA PRESSURE : 18 mmHg>>>15mmHg END DIASTOLIC VENTRICULAR PRESSURE : 12 mmHg

> 19 mmHg ≤ 18 mmHg

10 yrs

Early and Late outcome in 124 pts Risk : Normal PAP and PV Reactivity

PAP < 15mmHg 50% distal lesions

Levy et al. J Thorac Cardiovasc Surg. 2003;125:1083-90

eNOS

Targeted treatments on PVR

PDE5 inhibitors ERA

iloprost NO

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Targeted treatments on PVR

PDE5 inhibitors ERA iloprost NO

Many studies but difficult to analyze

PH drugs and SV

• Sildenafil et Fontan : 41 articles (entre 2006 et 2019)
• Bosentan et Fontan : 18 articles (entre 2005 et 2019)
• Prostanoïdes et Fontan : 6 articles (entre 2003 et 2019)

Essentially VO2

Results ?

Médic N etude FU Resultat Hebert 2014 Bosentan 45 Pic VO2 14 sem + 2ml/kg/min Schuuting 2013 Bosentan 42 Exercice 6 mois Ovaert 2009 Bosentan 10 CF, Sa02 16 sem + SaO2 Kouatli 1997 Enalapril 20 Exercice 20 sem Goldberg 2012 Sildenafil 28 Fonction VU 6 sem ≠ 0 Giardini 2008 Sildenafil 27 Exercice 1 jour Augm VO2 Van de Bruaene 2014 Sildenafil 10 KT exercice 1 jour Augm IC Hager 2014 Sildenafil 36 Exercice 1 jour Augm VO2 Rhodes 2013 Iloprost 18° Exercice 2 jours Augm VO2 ° 10/18 effets secondaires (bronchospasme)

Oldenburger et al. Cardiology in the Young 2016;26:842-50

Inclusion of patients 2009-2018

100 200 300 400 500 600

2010 2011 2012 2013 2014 2015 2016 2017 2018

PH biventricular Univentricular P

Spain Registry . Maria Jesus Del Cerro

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When do we need to treat?

• Before surgery ?
• During surgery ?
• Long term ?
• Failing Fontan?

What for ?

• Decrease PAP ?
• Improve FC ?
• Improve exercise capacity ?
• Decrease mortality ?

Before surgery

• Testing PVR before Fontan circulation

YES

Before surgery

• Testing PVR before Fontan circulation YES
• In patients with « limit » PAP in order to
• perate patient with contrindication?

– Mori H et al. Int J Cardiol 2016;221:122-7

• Preop Sildenafil reduced PVR ?

– Tran S et al. Pediatr Cardiol 2018;39:1572-80

• mPAP > 16 Need of preoparative use of sildenafil was

associated with higher morbidity - NO

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During surgery

• In order to facilitate the post-operative course
• Most team use vasodilators in ICU
• Very few published studies

Sildenafil postop after Fontan

Tunks RD et al. Pediatr Crt Care Med 2014;15:28-34

Sildenafil postop after Fontan

• 16 pts Sildenafil + NO • 32 patients without

Pleural effusion NS Ventilation time NS Lenght ICU NS Lenght hospital stay NS

Mendoza A et al. Cardiol Young 2015;25:1136-40

• 19 pts Sildenafil IV
• 84 patients without

Collins JLG et al. Pediatr Cardiol 2017;38:1703-8

After surgery

• To improve PVR?
• To improve FC and excercise capacity?
• Only in Failing Fontan?

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After surgery

Sudye Year TT Npts FU Conclusion Hebert 2014 Bosentan 75 3 months FC; VO2 Schuuring 2013 Bosentan 42 6-9 months NS Ovaert 2009 Bosentan 10 4 months NS Kouatli 1997 Enalapril 21 3 months NS Goldberg 2012 Sildenafil 28 6 weeks SV function Hager 2014 Sildenafil 36 1 day VO2 Rhodes 2013 Iloprost inh 18 2 days VO2 Meta-analysis Oldenburger NJ et al. Cardiol Young 2016;26:842-50 CONCLUSION : Bosentan, Sildenafi and iloprost may improve exercise capacity at the short term in Fontan patients BUT RESLUS NEED TO BE INTERPRETED CAREFULLY

After surgery

• 24 Fontan patients : PRV > 2 UW/m2
• 8 children, 8 adolescents, 8 adults evaluated

before and 6 months after treatment with ERA

Agnoletti G et al. J Thorac Cardiovasc Surg 2017;153:1468-75 PVRi Cardiac Index VO2 max Before After Before After Before After Children 2.3 1.9 Adol 2.3 1.7 2.6 3.6 25 28 Adults 2.8 2.1 2.1 2.8

Sildenafil improves exercise hemodynamics in Fontan patients. N = 10

Van De Bruaene A1, La Gerche A, Claessen G, De Meester P, Devroe S, Gillijns H, Bogaert J, Claus P, Heidbuchel H, Gewillig M, Budts W Circ Cardiovasc Imaging. 2014;7:265- 73.

PAP PVRi

After surgery

Hebert A et al. Circulation 2014;130:2021-30 Bosentan Improves Exercise Capacity in Adolescents and Adults After Fontan Operation The TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) Study Fontan at 4 years. Mean age 20 y – Bosentan 3 months 28.7 to 30.7

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Failing Fontan

Morchi GS et al. Congenit Heart Dis 2019;4:107-111

Failing Fontan

• 13 failing Fontan

– 3 protein-losing enteropathy – 4 bronchial cast – 2 severe cyanosis after fenestration – 2 prolonged chylous effusion – 1 take down – 1 arythmia and end stage cardiac failure

• 2 years Sidenafil
• All improved BUT 5 patients had concomittent

fenestration

Reinhardt et al. Cardiol Young 2010;20:522-5

What about Long Term Fontan?

• Few publications on VO2
• Long term results are very poor

Decreased aerobic capacity in Fontan patients

Fredriksen P et al. Heart Heart. 2001 Mar; 85(3): 295–299

52 patients At late follow up (median 10 years, range 1 to 26 years)

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PDE5 in adolescent after Fontan Palliation

Phase I/II Muticenter Investigation. Goldberg JG et al. Am Heart J 2017;188:42-52

Late Fontan and Quality of life

• 30% free of events à 20 ans

Rychik J, Goldberg DJ.Circulation 2014;130:1525-8 d’Udekem Y et al. Circulation 2014;130:32-8 Rychic et al.Pediatr Cardiol. 2012; 33:1001–1012 Kiesewetter et al. Heart 2007;93: 579–584

Paris 1990-2018 – Poor results

• 344 TCPC – 160 FU 10-35yrs (med 20)

– 57 lost : Alive? Dead?

• 110 adults FU more than 20 years FU

– Death 6* – Tx 5 – Tx list 5** – NYHA 3 24 – Severe arythmia 13 – Neurologic cpcs 5 – Treated arythmia 21 36% 53% * Cirrhosis at autopsy 72% ** liver cancer

Patients > 30 years old

• 49 patients
• 5 deaths
• 5 tranplantations
• 4 Tx list*
• 3 Strokes
• 9 FC 2 18%

– 3 non operated patients – 1 IVC valuvulation

• 7 FC 2-3 (fistulae; arythmia)

35% Severe events 32% in FC 2or3

* hepatocarcinoma

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Long term Fontan

• Loss of pulsatile pulmonary blood flow after

the Fontan procedure has been suggested to increase PVR through vascular remodeling

Zongtao Y et al. J Thorac Cardiovasc Surg. 2010;58:468–472 Henaine R et al. J Thorac Cardiovasc Surg. 2013;146:522-9

• Severe intimal damage at autopsy that

correlate with age at death and duration of Fontan circulation

Ridderbos FJ et al. Heart Lung Transplant 2015;34:404-13

Long term Fontan

• Loss of pulsatile pulmonary blood flow after

the Fontan procedure has been suggested to increase PVR through vascular remodeling

Zongtao Y et al. J Thorac Cardiovasc Surg. 2010;58:468–472 Henaine R et al. J Thorac Cardiovasc Surg. 2013;146:522-9

• Severe intimal damage at autopsy that

correlate with age at death and duration of Fontan circulation

Ridderbos FJ et al. Heart Lung Transplant 2015;34:404-13

Protection of pulmonary endothelial function from birth Our attitude in Paris

• 344 Fontan patients
• Since 2002 almost all the patients have

fenestrated fontan (extracardiac tube)

• ccluded 6 months later if possible
• Except aorto-pulmonary collaterals, all receive

sildenafil in the post-operative course

• Sildenafil is not continued
• Treatment in the perioperative course
• No preventive treatment
• In case of complications : sildenafil
• According to my talk, illogical….
• We need to improve the management of this

population according to the long-term results

Our attitude in Paris

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Conclusion

• PVR are crucial before TCPC
• PVR are crucial after TCPC
• No real effect of PH treatments ?
• What about lack of pulsatility ?

What Future ?

• even with the technical adapations and use of

PH treatments

• Fontan circulation is not a good option

(arythmia, liver, brain, kidney..)

• Less than 20% in FC 2 at the age of 30!!!
• Other options?

What Future ?

• Less than 20% in FC 2 at the age of 30!!!
• Other options? To « create » the physiological

circulation

Next generation PH training

Cardiologist Pneumologist Neonatologist

1h/week ?

genticien

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Next generation

Cardiologist Pneumologist Neonatologist

Thank you for your attention Thank you for your attention Fontan et dysfonction endothéliale

NO caused a significant drop of mean PVRI late after Fontan (*P=0.016).

Khambadkone S et al. Circulation. 2003;107:3204-8 Kurotobi S et al. J Thorac Cardiovasc Surg. 2001;121:1161-8

Perte de pulsatilité et altération de la réponse endothéliale

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Résultats à 25 ans (n=1089)

d’Udekem Y et al. Circulation 2014;130:32-8 Registre Australie et Nouvelle Zelande