Pulmonal Hypertensjon Hemodynamikk og Behandling

Hjertesviktforum, høst 2017

Marcel MoufackKlinikk for hjertemedisin

2; 14 April 2013

5th World Symposium on PH:

Modified classification of PH

1. Pulmonary arterial hypertension

1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 Associated with

1.4.1 Connective tissue diseases

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease and/or

pulmonary capillary haemangiomatosis

1’’ Persistent PH of the newborn (PPHN)

2. PH due to LHD

2.1 LV systolic dysfunction

2.2 LV diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart

inflow/outflow obstruction

3. PH due to lung diseases and/or hypoxia

3.1 COPD

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive

and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. CTEPH

5. PH with unclear multifactorial mechanisms

5.1 Haematological disorders: chronic haemolytic

anaemia, myeloproliferative disorders,

splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary

histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease,

Gaucher disease, thyroid disorders

5.4 Others: tumoural obstruction, fibrosing

mediastinitis, chronic renal failure, segmental PH

Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.

COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension;

LHD: left heart disease; LV: left ventricular

Fra ESC/ERS-Guidelines 2015

Fordeling mellom de kliniske klassene

1. Pulmonal arteriell Hypertensjon (PAH)

2. PH assosiert med venstresidig hjertesykdom

3. PH assosiert med lungesykdom og/eller hypoxemi

4. PH pga kronisk tromboembolisk sykdom

5. Øvrige

ESC Pocket Guidelines 2006 (page 5). Adapted from European Heart Journal 2004; 25; 2243-78

6; 14 April 2013

The three pathways in PAH pathogenesis

Adapted from Humbert M, et al. N Engl J Med 2004; 351:1425-36.

Prostacyclin

receptor agonists

Pre-pro-ET pro-ET

ET-1Vasoconstriction

Proliferation

ETA ETB

Endothelin receptor

antagonists (ERA)

L-arginine L-citrulline

Vasodilation

Anti-proliferation

cGMP

Phosphodiesterase 5

inhibitors (PDE-5i)

Vasodilation

Anti-proliferation

cAMP

PGI2NO

Endothelin (ET)

pathwayProstacyclin (PGI2)

pathway

Nitric oxide (NO)-

cGMP pathway

Arachidonic acid PGI2

sGC

GMP

+

+

sGC stimulator

sGC: soluble guanylate cyclase; cAMP: cyclic adenosine

monophosphate; cGMP: cyclic guanosine monophosphate

IP receptor

7; 14 April 2013

Patofysiologi ved PAH

A. Normal B. PAH C. Advanced PAH

Galiè N, et al. Eur Heart J 2010; 31:2080-6.

Hemodynamikk ved PAH

Patofysiologi og hemodynamikk ved PH gr. 3

Gr. 2 PH

Eksempel på venstresidig hjertepatologi som disponerer for PH

Akutt Postkapillar vs prekapillar PH

Blood flowRV

RA

LA

LV

Pointof obstruction

PAH=Pre capillary PH

(mPCWP < 15 mmHg)

Scenario 1

Blood flowRV

RA

LA

LV

Pointof hight pressure

LA

Post capillary PH

(mPCWP > 15mmHg)

PH: scenario 2

Blood flowRV

RA

LA

LV

Hypoxemia leads to vasoconstriction

Pre capillary PH

(mPCWP < 15 mmHg)

ILD

SSc-PH: scenario 3

Blood flowRV

RA

LA

LV

Pointof obstruction

Approval of PAH therapies

Bosentan

2001 – US

2002 – Europe

Epoprostenol i.v.

1995 – US

2001 – Europe

Room-temperature stable epoprostenol i.v.

2012 – US, Switzerland & Canada

2013 – Japan & Europe*

2013

Macitentan†

Treprostinil oral†

US

Riociguat†

2013 – US

2014 – Europe

Iloprost inhaled

2004 – US

2003 – Europe

Iloprost i.v.

Only approved in

New Zealand

2010 201520051995 2000

2009

Treprostinil inhaled†

Tadalafil

2008 – Europe

2009 – US

Sildenafil

2005Beraprost‡†

2007

*End of decentralised procedure in EU; local approvals ongoing†Approval of these therapies varies by country, and thus they

might not be approved in the indications mentioned in your

country. Please refer to your local full SmPC before prescribing.‡Prolonged release derivative

Ambrisentan

2007 – US

2008 – Europe

Beraprost†

1999

Treprostinil i.v. or s.c.

2002 – US

2005 – Europe

Recommendation

(Evidence*)

FC II FC III FC IV

I (A or B) Ambrisentan

Bosentan

Macitentan

Riociguat

Sildenafil

Tadalafil

Ambrisentan, Bosentan,

Epoprostenol i.v.,

Iloprost inhaled, Macitentan

Riociguat, Sildenafil,

Tadalafil,

Treprostinil s.c., inhaled†

Epoprostenol i.v.

IIa (C) Iloprost i.v. †

Treprostinil i.v.

Ambrisentan, Bosentan,

Iloprost inhaled and i.v.†

Macitentan, Riociguat,

Sildenafil, Tadalafil,

Treprostinil s.c., i.v., inhaled†

IIb (B) Beraprost†

IIb (C) Initial combination therapy Initial combination therapy

5th World Symposium on PH: Evidence-based

treatment algorithm Initial therapy with PAH approved drugs

Adapted from Galiè N, et al. J Am Coll Cardiol 2013; 62:D60-72.

Yellow: Morbidity and mortality as primary endpoint in randomised controlled study or reduction in all-cause

mortality (prospectively-defined)

*Level of evidence is based on the functional class (FC) of the majority of the patients of the studies†Approved only: by the FDA (treprostinil inhaled); in New Zealand (iloprost i.v.); in Japan and S. Korea

(beraprost)

Subkutant administrasjon av Remodulin.

I.v. Administrasjon av Remodulin via eksterne pumpe

Ny opsjon ved PAH – implanterbar pumpe

Historikk av implanterbare pumper

.Bruk ved alvorlig muskelspasmer(intrathekal Baklofen) siden 80-tallet.

. Mål om å redusere risiko for infeksjoner

.Bruk rutinemessig fra 90-tallet

Rasjonale for PAH

.Ingen risiko for lokale reaksjoner

.Lav risiko for infeksjon

.Ikke behov for eksterne pumpe

.Økt livskvalitet.

A schematic presentation of LENUSpro®

Operation scar

Catheter 2 isconnected to the pump

Extra length of catheter(behind the pump) -no restriction on activity

Catheters 1 and 2 are connected here

Catheter 1 is immobilized;”usual” procedure

Catheter 2 is tunnelized from below. Extra length to enable the patient to move freely

”Pump pocket” for theLenusPRO®

CTEPH/gr. 4 PH

•Medikamentell behandling indisert som bro til endarterektomi.

•Hos de fleste blir PVR normal etter PEA og med. behandling kan seponeres hvis startet preop..•10% har persisterende PH etter operasjon og må fortsette med. Behandling eller starte.•Kronisk medisisnsk Beh. hvis kontraindikasjon for op.

•Årsak ikke kjent

•45-70% har anamnese på LE

•I en LE-cohort har 3,8% prospektiv utviklet CTEPH ila 2 år

•Diagnostikk: Lungescint bedre enn CT.

•Behandling er kirurgisk ( PEA)

”Fangst” etter PEA

24; 14 April 2013

5th World Symposium on PH:

Modified classification of PH

1. Pulmonary arterial hypertension

1.1 Idiopathic PAH

1.2 Heritable PAH

1.2.1 BMPR2

1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 Associated with

1.4.1 Connective tissue diseases

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1’ Pulmonary veno-occlusive disease and/or

pulmonary capillary haemangiomatosis

1’’ Persistent PH of the newborn (PPHN)

2. PH due to LHD

2.1 LV systolic dysfunction

2.2 LV diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left heart

inflow/outflow obstruction

3. PH due to lung diseases and/or hypoxia

3.1 COPD

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive

and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental lung diseases

4. CTEPH

5. PH with unclear multifactorial mechanisms

5.1 Haematological disorders: chronic haemolytic

anaemia, myeloproliferative disorders,

splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary

histiocytosis, lymphangioleiomyomatosis

5.3 Metabolic disorders: glycogen storage disease,

Gaucher disease, thyroid disorders

5.4 Others: tumoural obstruction, fibrosing

mediastinitis, chronic renal failure, segmental PH

Simonneau G, et al. J Am Coll Cardiol 2013; 62:D34-41.

COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension;

LHD: left heart disease; LV: left ventricular

Fordeling mellom de kliniske klassene

1. Pulmonal arteriell Hypertensjon (PAH)

2. PH assosiert med venstresidig hjertesykdom

3. PH assosiert med lungesykdom og/eller hypoxemi

4. PH pga kronisk tromboembolisk sykdom

5. Øvrige

ESC Pocket Guidelines 2006 (page 5). Adapted from European Heart Journal 2004; 25; 2243-78