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Pulmonale Hypertonie: Warum gerade ich? Risikofaktoren und Krankheitsmechanismen Ralph Schermuly Department of Pulmonary Pharmacotherapy University of Giessen and Marburg Lung Center

Pulmonale Hypertonie: Warum gerade ich? Risikofaktoren und ... · Pulmonale Hypertonie: Warum gerade ich? Risikofaktoren und Krankheitsmechanismen . Ralph Schermuly . Department of

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Pulmonale Hypertonie:

Warum gerade ich?

Risikofaktoren und Krankheitsmechanismen

Ralph Schermuly

Department of Pulmonary Pharmacotherapy

University of Giessen and Marburg Lung Center

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PAP [mm Hg ]

Pulmonalarterieller Druckverlauf unter Belastung

Mechanismen der vaskulären Widerstandsreduktion unter Belastung

Distension (druckpassiv)

Recruitment (druckpassiv)

aktive Vasodilatation

Zunahme des Gefäßquerschnitts durch elastische Dehnung

Zunahme des Querschnitts durch Rekrutierung von Reservegefäßen

NO, PGI2

Pulmonalvaskuläre Erkrankungen

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PAP [ mm Hg ]

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PAP [ mm Hg ]

Latente PH: COPD Fibrose Linksherzinsuff. Aging

Manifeste PH Kollagenosen

PAH

80 µm

15 µm

normal

De novo Muscularization / distal Migration

pulmonary vascular disease

Remodeling: Definition

Strukturelle Veränderungen der Gefäßwand,

charakterisiert durch endotheliale, mediale und

adventitielle Proliferation als Antwort auf Hypoxie,

Druckveränderungen oder Gefäßerkrankungen

Pulmonalarterielles Remodeling umfaßt alle

Schichten der Gefäßwand

Remodeling affects all vascular layers

Endothelium

Media (smooth muscle cells)

Adventitia (connective tissue)

Mediahypertrophie

Neointimabildung

Lumenverengung

Rarefizierung

(‚Pruning‘)

Plexiforme Läsionen

(PAH)

Was sind die Charakteristika von ‚Remodeling‘?

De novo Muskularisierung

Ursachen des Lungenhochdrucks

Entzündung Linksherz- versagen

Sauerstoff- mangel

Idiopathic = rare disease

Different variants up to 100 million people worldwide

Mean survival rate - without therapy 2 - 4 years - < 3 months in right heart decompensation

chest-X-ray small pulmonary artery

Pulmonary Hypertension

I Preclinical/

No symptoms

II Symptomatic /

Stable

III Progression /

declining

Pulm pressure

Cardiac output

Leve

l

Time

PAH : a rapidly evolving disease

Years Months

Therapeutic window

RV function

Pathophysiology of PAH genet. Predisposition Environment Local Factors

Vascular Dysfunction

Vasoconstrictors Growth Factors

(ET1, PDGF, Serotonin)

Vasodilators antiprolif. Mediators (PGI2, NO…)

Pulmonary Arteriopathy = ‚Remodeling‘

constrictive Lesions

complex Lesions

According to Dandel et. al., 2006

Pulmonary Hypertension

Infection

Molecular Pathology: Imbalance of vasoactive mediators

Humbert et. al., NEJM 2004

Deficient PGI2-synthase in PH

• reduced PGI2- excretion (Christman et al., 1992)

Normal PPH SPH

600

0

6-keto-PGF1α

• reduced PGI2-synthase expression in a model of PAH (Voelkel et al., 1997)

• PGI2-synthase transfection reverses hypoxia-induced PH (Voelkel et al., 1997)

• PGI2-inhalation/infusion reduces PAH (Olschewski et al., 1996; Olschewski et al., 2002)

• reduced PGI2-synthase expression in PAH (Tuder et al., 1999)

Endothelin-1 bei pulmonaler Hypertonie

Expression von ET-1 in plexiformen Läsionen

Giaid A et al; N Engl J Med 1993;328:1732-1739

Expression von ET-1 korreliert mit hämodynamischenWerten bei PAH

Endothelin Rezeptoren in Pulmonalarterien

Migneault A et al. Am J Respir Crit Care Med 2005

Sowohl ETA als auch ETB sind in der Media hoch exprimiert

Endothelin-Rezeptor A Endothelin-Rezeptor B

In Rot: Immunfluoreszenz-Markierung der Verteilung der ET-R in den kleinen Lungenarterien

Grün: Markierung Grenze von Endothel (E) und Media (M)

IEL interne elastische Lamina EEL externe elastische Lamina

1.Clozel M, et al. J Pharmacol Exp Ther 1989; 2.Yang Z, et al. Circulation 1999; 3.Kuhlmann, et al. Acta Physiol Scand 2005; 4.Girgis RE, et al. Am J Respir Crit Care Med 2005; 5.Amiri, et al. Circulation 2004; 6.Cambrey AD, et al. Am J Respir Cell Mol Biol 1994; 7.Shi-Wen X, et al. J Invest Dermatol 2001; 8.Yang, et al. Circulation 2004.

Endothelin induziert Dysfunktion von Endothelzellen, glatten Muskelzellen und

Fibroblasten und Zytokin-Freisetzung

glatte Muskelzellen Vasokonstriktion,

Hypertrophie, Proliferation1-2

Fibroblasten Fibrose6-7

Endothelin

Endotheliale Zellen Proliferation,

Dysfunktion3-5

Inflammation NF-kB und cytokine

Freisetzung, Erhöhte

Gefäßpermeabilität8

Ghofrani et al. Nat Rev Drug Discovery 2006

NO-sGC-PDE Pathway

Alveoläre Distension führt zur

NO Freisetzung

Stretch

Stretch

Stretch Stretch

NO

NO

NO

NO

NO

Expression of Phosphodiesterase 5 in pulmonary vascular diseases

Wharton et al. AJRCCM 2005

α - Actin

PDE 5A

Schermuly et al., Circulation 2007

cGMP sGC (Fe2+) NO Vasodilatation

Anti-aggregation

Anti-remodeling

Anti-inflammation

O2-

sGC (Fe3+) (inactive)

ONOO-

Oxidative Stress inactivates NO

NO-sGC-PDE Pathway in PAH

RISK FACTOR (autoimmunity, HIV,

drugs,toxins…)

GENETIC PREDISPOSITION

(BMPR2, ALK-1, 5-HTT..)

PULMONARY VASCULAR DYSFUNCTION

Endothelial cell dysfunction

(NO, PgI2, ET-1…)

Smooth muscle cell dysfunction

(Kv1.5…)

INFLAMMATION/REMODELING (IL-1, IL-6, PDGF,

Chemokines…)

PULMONARY VASCULAR REMODELING DISEASE PROGRESSION

BMPR2 mutations: genetic basis for familial PAH

Machado et al. JACC 2009

Genetics

Mutation in gene encoding for bone morphogenetic protein receptor 2 (BMPR2) in 16 of 27 IPAH families

Deng et al, Am J Human Genet 2000;67:737-44, and Internat PPH Consortium Nat Genet 2000;26:81-4

BMP’s are members of the TGFβ superfamily BMPR2-smad signalling inhibits proliferation

BMPR2 mutations as a cause of PAH

Estimated < 10 – 20 % incidence of PAH in carriers of BMPR2 mutations

Not all familial PAH have detectable BMPR2 mutations

Incidence of BMPR2 mutations 5 % in sporadic IPAH BMPR2 mutations uncommon in other PAH

categories (anorexigens, CHD) BMPR2 mutations neither necessary nor sufficient

Genetics in PAH

Machado et al. JACC 2009

Decreased BMPR2 protein in IPAH with BMPR2 mutations > IPAH > CHD or CTD - PAH

Atkinson et al, Circulation 2002;105: 1672-78

Risk factor: HIV

• HIV infection is an established risk factor for PH • The use of highly active antiretroviral therapy (HAART) has

increased the life expectancy of HIV-infected patients. • With prolonged survival and improved control of infectious

susceptibility, vascular complications have emerged as a significant source of morbidity and mortality in HIV-infected patients

• These vascular complications, affecting >10% of those with HIV infections, include myocardial and pericardial tumours, cardiomyopathy, peripheral vasculitides, ischaemic heart disease and pulmonary arterial hypertension

• HIV-infected patients have a 2500-fold increased risk of developing PAH

• Mechanismsm unknown (evidence that the HIV proteins Env, Tat and Nef are implicated in cardiopulmomary complications)

UPDATED CLINICAL CLASSIFICATION (2008)

1. Pulmonary Arterial Hypertension 1. Pulmonary Arterial Hypertension • Idiopathic PAH • Heritable BMPR2 ALK1,endoglin unknown • drugs and toxins induced • associated with: – Connective tissue diseases – HIV infection – Portal hypertension – systemic to pulmonary shunts - Schistosomiasis - Chronic hemolytic anaemia

3. Pulmonary hypertension due to lung diseases and/or hypoxia

2. Pulmonary hypertension due to left heart disease

4. Chronic Thromboembolic pulmonary hypertension (CTEPH)

• Chronic obstructive pulmonary disease • Interstitial lung disease • Sleep-disordered breathing • Chronic exposure to high altitude • Broncho pulmonary dysplasia (BPD) • Developmental abnormalities

•Systolic dysfunction •Diastolic dysfunction •Valvular disease

5. Pulmonary Hypertension with unclear and/or mulifactorial mechanisms

•Hematologic disorders myeloproliferative disorders ;splenectomy

•Systemic disorders Vasculitis Sarcoidosis, Pulmonary Langerhans cell histiocytosis LAM ,Neurofibromatosis. •Metabolic disorders Glycogen storage disease, Gaucher disease, Thyroid disorders •Congenital Heart Disease other than systemic to pulmonary shunt •Others: obstruction by tumors, fibrosing mediastinitis,Chronic Renal failure on dialysis

1’Pulm. veno- occlusive disease(PVO) and/or pulmonary capillary hemangiomatosis(PCH)

Vascular obstruction Chronic vasoconstriction Proliferation/Apoptosis

Migration/ECM synthesis Disturbed metabolism

Endothelial Dysfunction In-situ thrombosis

Inflammation

disease

Respiratory unit with pre-capillary resistance vessel

alveolus

endothelium

alveolus

Type II AEC

Type I AEC

Vascular lumen

smooth muscle fibroblasts

health

Cellular and molecular mechanisms of disease induction

Dysregulation of vascular tone PGI2 NO-sGC-cGMP axis PDE Endothelin Serotonin K- and Ca-channels

Abnormal proliferation TGF-beta, BMP Growth factors (PDGF, FGF) Transcription factors (Notch3) Metabolic changes Elastases / MMPs Cytokines and chemokines Hypoxia-induced vasomotion and remodeling HIF ROS Channles (e.g. Kv, TRPC) Mitochondria NADPH Oxidase

Clinical trials Tki, sGC, PDE, Rho-Ki, EPC,…

Schermuly et al. Nat Rev Cardiol 2011

Serotonin (5-HT) abnormalities in PAH

MacLean et al. British Journal of Pharmacology (2000) 131, 161 - 168

Serotonin (5-HT) receptor inhibition with Terguride inhibits MCT-PH

Dumitrascu et al. Eur Respir J 2011; 37: 1104–1118

Ion channels in PAH

Kuhr F K et al. Am J Physiol Heart Circ Physiol 2012;302:H1546-H1562

Vascular obstruction Chronic vasoconstriction Proliferation/Apoptosis

Migration/ECM synthesis Disturbed metabolism

Endothelial Dysfunction In-situ thrombosis

Inflammation

disease

Respiratory unit with pre-capillary resistance vessel

alveolus

endothelium

alveolus

Type II AEC

Type I AEC

Vascular lumen

smooth muscle fibroblasts

health

Cellular and molecular mechanisms of disease induction

Dysregulation of vascular tone PGI2 NO-sGC-cGMP axis PDE Endothelin Serotonin K- and Ca-channels

Abnormal proliferation TGF-beta, BMP Growth factors (PDGF, FGF) Transcription factors (Notch3) Metabolic changes Elastases / MMPs Cytokines and chemokines Hypoxia-induced vasomotion and remodeling HIF ROS Channles (e.g. Kv, TRPC) Mitochondria NADPH Oxidase

Clinical trials Tki, sGC, PDE, Rho-Ki, EPC,…

Schermuly et al. Nat Rev Cardiol 2011

Disordered elastin metabolism and deposition in PAH

Growth factors in PAH

Hassoun et al., J Am Coll Cardiol 2009

Inflammation in PH

Summary

• Vasodilator – vasoconstrictor dysbalance – Endothelin – Prostacyclin – Nitric oxide – Serotonin

• Risk factors: Genetic predisposition (BMPR2, others), HIV infection, drugs, toxins, infections, autoimmune diseases, hypoxia

• Excessive vascular cell growth and inflammation • Proproliferative signaling pathways: growth factors,

cytokines, ion channels, elastases • New treatments: Prostanoids, ET antagonists, sGC

stimulators, RTKi, Metabolic modulators