Hypertension pulmonaire

associée aux pathologies

cardiaques gauches: Une

nouvelle cible thérapeutique?

Jocelyn Dupuis MD, PhD

Pas de conflits d’intérêts à déclarer

Association des cardioloques du Québec,

Florence, 1er Mai 2017

L’Insuffisance

cardiaque entraine

avec elle d’autres

organes…

Thérapies de l’HTP

post-capillaire

Aucune !

Pourquoi les

insuffisants cardiaque

sont-ils dyspnéiques?

Parce que l’IC est aussi

une maladie

pulmonaire...

Plan 1. Classification et définition

2. Importance du problème

3. Pathophysiologie

4. Impact pronostique

5. Comment mesurer et évaluer Rx

6. Le futur…

Hypertension pulmonaire (PH)

VS

Hypertension artérielle pulmonaire (PAH)

VS

Hypertension pulmonaire post-capillaire (pc-

PH)

Updated PH

Classification 5th World PH Symposium, 2013 1. Pulmonary arterial hypertension

(PAH)

2. PH due to left heart disease

3. PH due to lung disease and/or

hypoxia

4. Chronic thromboebolic PH (CTEPH)

5. PH with unclear multifactorial

mechanisms JACC 2013 62(25):D34-D41.

Group 2 PH:

Due to left heart disease

2.1 Left ventricular systolic dysfunction

2.2 Left ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart inflow/

outflow obstruction and congenital

cardiomyopathies

Definition of PH

• Mean pulmonary arterial pressure ≥25

mmHg

Cardiac cath.

Echocardiographic screening

• Systolic pulmonary arterial pressure of 36-50 mmHg

Group II PH: confusion with

definitions

Proportionate vs Out-of-

proportion

Passive vs Reactive

Venous vs Arterial

Pre-capillary vs Post-capillary

Reversible vs Irreversible

Définition de l’HTP du groupe II:

HTP post-capillaire

Terminology Abbreviation Mean

PAP PAWP

TPG

or PVR* DPG**

Isolated

post-capillary Ipc-PH ≥25 mmHg >15 mmHg

≤15 mmHg

or

≤3 WU

< 7 mmHg

or

≤3 WU

Combined

pre and post-capillary

Cpc-PH ≥25 mmHg >15 mmHg

>15 mmHg

or

>3 WU

≥7 mmHg

or

>3 WU

*J Heart Lung Transplant 2012;31:913–33

**JACC 2013 62(25);D100-D108

TPG: Mean PAP - PAWP

DPG: diast PAP - PAWP

Gradient pulmonaire

diastolique

J Am Coll Cardiol. 2013;62(25_S):. doi:10.1016/j.jacc.2013.10.033

Effect of PAWP and SV on Pulmonary Pressures

Pulmonary artery wedge pressure (PAWP) is transmitted in a 1:1 ratio to diastolic pulmonary artery pressure (dPpa) and PAWP, both

pressures being within a 3-mm Hg range. If PAWP is directly transmitted to dPpa, there is a non-proportional increase in systolic (sPpa)

and mean (mPpa) pulmonary artery pressure, depending on (SV) (left graph). The transpulmonary gradient (TPG) increases, but the

dPpa-PAWP gradient is independent of both PAWP and SV (right graph). If dPpa increases more than PAWP, the TPG increases. The

dPpa-Ppw gradient increases linearly but slightly with PAWP but is independent of SV.

Définition de la reversibilité

TPG PVR DPD

Reversible, reactive or

vasoreactive PH <12 mmHg <3 WU ?

JACC: HEART FAILURE VOL. 3, NO. 1, 2015

Les pathologies cardiaques

gauches: la cause la plus

fréquente d’HTP

• Incidence de 20% à 60%

• Dépend de la population étudiée

• Dépend de la définition utilisée…

1. Ghio S, J Am Coll Cardiol. 2001; 37:183-188.

2. Butler J, J Am Coll Cardiol. 1999; 34:1802-1806.

JACC Vol. 59, No. 3, 2012

J Am Heart Assoc. 2014;3:e000363 doi

N = 417 mean age 54, HFpEF 24.9%

L’HTP pré-capillaire et la

dysfonction VD déterminent le

pronostique

JACC: Heart Failure Vol. 2, No. 3, 2014

J Thorac Cardiovasc Surg 2016;152:394-400

Circ Cardiovasc Interv.2015;8:e002358

Couplage VD-AP:

Compliance

pulmonaire

TAPSE/PAPs

J Am Coll Cardiol 2017;69:1718–34

Un paradoxe de l’IC…

• Un sujet préalablement sain développe de

l’œdème pulmonaire critique quand sa PCPB

augmente à 25 mmHg de façon aigue

• Plusieurs patients avec IC chronique stable sont

ambulatoire avec des pressions encore plus

élevées…

Manifestations pulmonaires de

l’insuffisance cardiaque

• Physiologie restrictive: dimimution des volume et

de la compliance

• Reduction de la Dlco: surtout par réduction de

perméabilité capillaire

• Pas amélioré par: diurèse, ultra-filtration et même

transplantation

• Corrélé avec capacité d’exercice et facteur

pronostique indépendant The pulmonary manifestations of left heart failure. Chest. 2004;125:669-82.

Alveolar–capillary membrane gas conductance:

a novel prognostic indicator in chronic heart

failure 106 CHF patients, LVEF 33 ± 1%

Eur Heart J. 2002;23:467-76.

Gas diffusion and alveolar–capillary

unit in chronic heart failure

European Heart Journal (2006) 27, 2538–2543

Cardiopulmonary Exercise Testing as a Diagnostic Tool for

the Detection of Left-sided Pulmonary Hypertension in

Heart Failure

Journal of Cardiac Failure Vol. 19 No. 7 2013

Oscillatory Breathing and Exercise Gas Exchange Abnormalities

Prognosticate Early Mortality and Morbidity in Heart Failure

J. Am. Coll. Cardiol.2010;55;1814-1823

Qu’est-ce qui cause le

remodelage alvéolaire

pulmonaire ?

Human lungs Rat lungs

Control

Left heart disease

Clinical Science 2014, 127; 65-76

Prolifération de Myofibroblastes

MI MI + Irbe

Smooth muscle α-actin

Cardiovascular Research 58 (2003) 621-631

Alveolar remodelling in left heart disease

Increased lung capillary

pressure

Alveolar-capillary stress failure

TGF-ß

Cytokines

PDGF

CTGF

TGF-ß

Angiotensin II

Endothelin

Aldosterone

Osteopontin

Systemic neurohumoral activation

Reduced cardiac output

Endothelial mesenchymal transition

Epithelial mesenchymal transition

Resident mesenchymal cells

Circulating fibrocytes

Myofibroblasts Differentiation and proliferation

α-SMA

Desmin

Cadherin

Extracellular matrix deposition: Elastin

Collagen

Reticulin

Basement membrane-like material

Thickening of alveolar

septa

Protective: Reduced pulmonary oedema

Maladaptive: Reduce oxygen diffusing capacity

increased lung weight and stiffness

Restrictive lung syndrome

Contribution to pulmonary hypertension

Reduced exercise tolerance

Genetic

predisposition?

Clinical Science 2014, 127; 65-76

Capillary stress failure

Congestion of bronchial

circulation

Reduced alveolar fluid clearance

Alveolar wall remodelling

Pulmonary vascular remodelling

Pulmonary oedema

Restrictive lung syndrome

Gas diffusion abnormalities

Passive: reversible

Reactive: irreversible

Clinical Science 2014, 127; 65-76

Failure of trials in

LHD

JACC 2013 62(25);D100-D108

.

Pts at risk 804 615 542 393 123 0

807 655 577 388 113 0

ENABLE: Death or CHF

hospitalization

Bosentan = 312 events

Placebo = 321 events

Logrank p-value: 0.8986

0 26 52 78 104 130 Weeks

Bosentan

Placebo

% o

f patients

(event-

free)

0

25

50

75

100

JACC: HEART FAILURE VOL. 5, NO. 5, 2017

Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical

Status in Heart Failure With Preserved Ejection Fraction: RELAX trial

JAMA 2013 309, 1268–1277

Circulation. 2017;135:1509–1517

Future trials should… • Evaluate the presence of PH and select subjects

accordingly

• combined PH

• reversible vs not reversible

• Incorporate evaluation of RV function and coupling

• Incorporate evaluation of lung remodeling

• Lung function testing

• CPX testing with VE/VCO2

• Novel markers of lung damage

Dynamic lung uptake of PulmoBind

in human

Mol Imaging 2015: 14: 1535-1538.

1) Hagner S. et al. Cell Tissue

Res (2002) 310:41–50

Effet sélectif du PBI-4050 sur le remodelage pulmonaire

post-infarctus

43 Circulation. 2016; 134 (Suppl 1), A12654

44

PBI-4050 Reduced RV Hypertrophy and Improved RV Function in Heart Failure with Reduced Ejection Fraction

Circulation. 2016; 134 (Suppl 1), A12654

Conclusion • LHD is the most frequent cause of PH

• Pathophysiology different form PAH: Capillary injury with MYF proliferation

• Restrictive lung syndrome with reduced gas exchange

• Effects of PAH treatments cannot be extrapolated to group II PH (ERAs, PDE5 inh etc)

• Properly sized studies need to be performed with better phenotyping:

• Combined pre-post capillary PH

• Reversibility vs no reversibility

• RV function

• Restrictive lung syndrome

• Gaz exchange (VE/VCO2)

• Markers of lung remodeling

La pyramide MVP

Maladie Vasculaire

Pulmonaires

RV

Failure

Pulmonary Hypertension

Lung structural and vascular

remodelling

Inflammation, proliferation, fibrosis

Myofibroblasts

Environmental or pathologic triggers: infection, inflammation,

injury

Genetic predisposition

References

• J Am Coll Cardiol 2013, 62(25); D100 -

D108

• J Heart Lung Transplant 2012, 31;913–33

• Clinical Science 2014, 127; 65-76

• Can J Cardiol 2015, 31; 416-429

HFrEF PH Trials Trial Agent n

Inclusion

criteria Duration Endpoint Results

LEPHT1 Riociguat 201 LVEF ≤ 40%

mPAP ≥ 25 mmHg 16w

Change in

mPAP

No change

improved CI,

PVR, SVR

PITCH-

HF2 Tadalafil 2102

LVEF ≤ 40%

Documented PH

(echo or cath)

54m

Time to CV

death or HF

hops.

Terminated by

funding agency

Sil-HF3 Sildenafil 210

LVEF ≤ 40%

sPAP > 40 mmHg

echo

24w global ass.

and 6mwd recruiting

Corean4 Sildenafil 140

LVEF ≤ 40%

sPAP ≥ 40 mmHg

echo

12w 6 mwd recruiting

Melody-15 Macitentan 60

Combined pre-

post PH due to

LVD

12w safety Recruiting

1) Circulation. 2013;128:502-511 2) NCT01910389 3) Eur J Heart Fail (2013) 15, 119–122 4)NCT01913847 5)NCT02070991

Trial Agent n Inclusion

criteria Duration Endpoint Results

DILATE1 Riociguat 39

LVEF > 50%

mPAP ≥ 25 mmHg

wedge > 15 mmHg

acute

6hr Mean PAP No effect

BADDHY2 Bosentan 20

NYHA II-IV

mPAP ≥ 25

DD by echo

12w 6 mwd completed

U Texas

SW3 Ambrisentan 20

NYHA II-IV

mPAP ≥ 25

DD by echo

16w PVR ?

HFpEF PH Trials

1) Chest. 2014 Nov;146(5):1274-85 2 )NCT00820352 3) NCT00840463

Plasma Surfactant Protein-B:

A Novel Biomarker in Chronic Heart

Failure

Circulation. 2004;110:1091-1096 Circ Heart Fail. 2009;2:175-180

Jpn Heart J 1984