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HIPERTENSIUNEA ARTERIALA

PULMONARA (HTAP)

Profesor Miron BOGDAN


As. Univ. Mona Sara MITRACHE

UMF “Carol Davila” Bucuresti


Sumar
1. Definitia HTAP - update Dana Point 2008
2. Clasificarea HTAP - Venice 2003, update Dana Point
2008
3. Patogeneza HTAP- genetica in HTAP
4. Algoritmul de diagnostic
5. Tratamentul HTAP
6. CPC in BPOC
7. Tratamentul CPC
Definitie
• Evian- Venice consensus (2003)
- mPAP > 25 mm Hg in repaus (PCP< 15
mm Hg, PVR > 3 uw)
- mPAP > 30 mm Hg la efort

• Dana Point consensus (2008)


- mPAP = 20 – 25 mm Hg – borderline PH
- mPAP > 25 mm Hg –PH manifesta
- nu mai exista criteriul la efort
Clasificarea HTAP - Venetia 2003,
update Dana Point 2008
2. Hipertensiunea Arteriala Pulmonara 2. Hipertensiunea din bolile cardiace stangi
(HTAP) : disfunctie sistolica
• Idiopatica (i PAH) disfunctie diastolica
• Ereditara (BMPR II, ALK 1…) valvulare
• Droguri si toxine 3. Hipertensiunea din bolile respiratorii cu
• Asociata cu: hipoxemie
- boli de colagen • BPOC
- HIV • Boli interstitiale pulmonare
- hipertensiunea portala • Sindromul de apnee in somn
- boli cardiace congenitale • Altitudine
- anemia cronica hemolitica • Hipoventilatia alveolara
- schistostomiaza • Anomalii de dezvoltare
• HTP persistenta a nou-nascutului
4. HTAP postembolica

1’. 5. Diverse (Sarcoidoza, histiocitoza X,


limfangiomatoza, compresia vaselor pulmonare
- boala veno-ocluziva (adenopatie, tumora, fibroza mediastinala), boli
- hemangiomatoza capilara pulmonara tiroidiene, boli cu stocaj de glicogen, boala
Gaucher, teleangiectazia hemoragica ereditara,
hemoglobinopatii, boli mieloproliferative,
Patologia Hipertensiunii Arteriale
Pulmonare

Normal
l flux crescut si rezistenta scazuta

HTAP
lHipertrofia celulelor musculare netede
l Tromboza
lProliferare intimala
Patologia HTAP- Modificari Proliferative
Intima Media Adventitia

Leziune Plexiforma Leziune Colagenotica


•The vascular pathology of PAH is often described as
vasoconstriction; however, it is more complicated than
simply “vasoconstriction”.
•Structural changes occur within the small pulmonary
arteries.
•The development of “plexiform lesions’ is a pathologic
hallmark of PAH.
•The plexiform lesion (seen in the picture on the left), medial
hypertrophy (thickening of the vessel), and intimal fibrosis
(seen in the picture on the right) all eventually lead to the
occlusion of the pulmonary arteries.

Note: Plexiform lesions have been identified in idiopathic


PAH as well as PAH associated with other conditions, such
as CHD & HIV.
Remodelarea Vasculara
Pulmonara

Gaine, S JAMA, 2000


CLASIFICAREA MORPFOPATOLOGICA A
VASCULOPATIEI DIN HTAP
• “Arteriopatie Pulmonara hipertensiva”
- hiperplazie intimala
REMODELARE
- hipertrofie a mediei VASCULARA
HTP

- ingrosarea adventitiei

• DISFUNCTIA ENDOTELIALA
- vasodilatatori si antiproliferativi : prostacicline, NO
- vasoconstrictori si proliferativi: endotheline (ET-1)

• Tromboza ( “in situ”, TEP)


ET este mediator „cheie“ in HTAP
Smooth muscle cells
Vasoconstriction, Endothelial cells
hypertrophy, Proliferation,
proliferation 1-2 dysfunction 3-6

Endotelina

Inflammation
NF-kB and cytokine release,
Fibroblasts
Fibrosis 7-9
increased vascular
permeability 10-13

1 ClozelM et al. J Pharmacol Exp Ther 1989 ; 2 Yang Z et al. Circulation 1999; 3 Kuhlmann et al. Acta Physiol Scand 2005; 4 Davie N.

Univ. Colorado Health Sciences Center. With permission; 5 Girgis et al. Am J Respir Crit Care Med 2005 ; 6 Amiri et al. Circulation 2004;
7Cambrey et al. Am J Respir Cell Mol Biol 1994; 8 Shi-Wen et al. J Invest Dermatol 2001; 9 Shi-Wen et al. Mol Biol Cell 2004; 10 Yang et al.
11 12 13
Circulation 2004; Wilson et al. Biochem Piophys Res Comm 2001; Helset et al. Am J Physiol 1996; Salani et al. Am J Pathol 2000
ET is a driver of the structural changes that occur and lead to the
pathogenesis of PAH.
These pathological changes are due to the direct effects of ET.
On smooth muscle cells, ET has mitogenic effects and causes vascular
hypertrophy & proliferation, in addition to potent vasoconstriction.
On endothelial cells, ET causes structural remodeling, promotes cell
growth (resulting in arterial wall thickening) and causes ET cell
dysfunction (resulting in decreased levels of NO).
ET stimulates fibroblast collagen production, down-regulates MMP-1
(matrix metalloproteinase 1; responsible for the degradation of
extracellular matrix proteins), and promotes contraction of FPLC
(fibroblast-populated collagen lattices), all leading to fibrosis.
In addition, data has demonstrated that increased ET triggers an
inflammatory cascade, causing an increase in inflammatory cytokines.
The result of the multiple effects of ET are the key elements in the
pathogenesis of PAH: vascular hypertrophy, fibrosis, inflammation, and
vasoconstriction.
These findings clearly support the need to block ET.
Tinta terapiilor curente in
Hipertensiunea Arteriala Pulmonara

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


Figure 1. Targets for Current or Emerging Therapies in
Pulmonary Arterial Hypertension. Three major pathways
involved in abnormal proliferation and contraction of the
smooth-muscle cells of the pulmonary artery in patients
with pulmonary arterial hypertension are shown. These
pathways correspond to important therapeutic targets in
this condition and play a role in determining which of four
classes of drugs -- endothelin-receptor antagonists, nitric
oxide, phosphodiesterase type 5 inhibitors, and
prostacyclin derivatives -- will be used. At the top of the
figure, a transverse section of a small pulmonary artery (
HTAP si mutatiile genei BMPR-II (Bone
Morphogenetic Protein type II Receptor )

• Mutatie heterozigota a BMPR2, care codifica un receptor TGF-,


cauza de HTAP familiala
– Mutatie detectata la ~70% din familie
(The International PPH Consortium, Nat. Genetics 2000;
Deng et al. Am J. Hum. Genetics 2000)

• Asocierea HTAP “sporadica” cu mutatia BMPR2


– 15-26% din HTAP sporadice au mutatia BMPR-II
– transmiterea parentala si mutatia de novo documentata
(Thomson et al. J. Med. Genet. 2000
Newman et al. N. Engl. J. Med. 2001)
HTAP Familiala
• BMPR-II este un
membru al
superfamiliei
receptorului TGF-b Ligan

• mutatia BMPR2
identificata la 70% in
HTAP familiala
§ penetranta redusa 0.2
§ mutatia BMPR2 a
fost identificata la
30% din asa zisele
HTAP sporadice
Proposed Mechanism of Action
of Bone Morphogenetic
Proteins on Pulmonary
Circulatory Cells.

John H Newman N Engl J Med 345,5


Trei pasi in Diagnosticul
Hipertensiunii Arteriale Pulmonare

1.
Suspicionarea
2.
Detectia
3.
Caracterizarea
Diagnosticul Hipertensiunii Pulmonare :
Suspicionare, detectie si caracterizare

Evaluare Screening Descoperire


Simptome intamplatoare

Suspiciune HTP

Examen fizic
Radiografie pulmonara
Electrocardiograma
Echocardiograma
Detectia

HTAP Detectata
Simptomele in HTAP

• NU exista simptome precoce in HTAP


• Screeningul in populatiile la risc
Simptome precoce
(sclerodermie, familiile la risc…)

• Dispnee progresiva la efort ++++


Primele simptome
• Fatigabilitate, ameteli, palpitatii

• Durere toracica
Non-specifice • Sincope
• Tuse
• Simptome si semne de insuficienta cardiaca
Tardiv dreapta
• Edeme, ascita
HTAP: o boala cu evolutie rapida
I II III-IV
Preclinica/ Simptomatica Progresie /
Fara / Declin
Simptome Stabila
Functia
presiunea VD
pulm
Nive

Index
Cardiac
l

Fereastra
Terapeutica
AN L
I UNI
T
Examenul Clinic
Examenul Clinic
Radiografia pulmonara
Radiografia pulmonara
Radiografia pulmonara
Electrocardiograma
Echocardiografia
RV
RV
LV
LV

PAP sistolica : viteza regurgitatiei


tricuspidiene (VIT)

PAPmedie : timpul de Accelerare (AT)

m PAP = 78 - 0,52 AT (Beard JT. 1991)


Hipertrofie ventriculara dreapta
Diagnosticul Hipertensiunii Pulmonare :
Suspicionare, detectie si caracterizare
Teste Esentiale
Explorarea Functionala Respiratorie
Sintigrafie V/Q
Teste sangvine
- Screening colagenoza
- HIV
- enzime hepatice
Cateterism cardiac drept cu test
vasodilator in acut

Teste suplimentare
Caracterizarea Ecografie transesofagiana
CTSpiral / EBCT / HRCT / MRI
Angiografie Pulmonara
Teste sangvine
- Clotting study
- SaO2, acid uric - BNP
Studiul Somnului
Biopsie pulmonara

PH Detectata si
caracterizata
Explorarea functionala

• Spirometrie
– Debite pulmonare
• Pletismografie
– CPT, VR. etc
• Capacitatea de difuziune
– Schimbul de gaze
Scintigrafia de Ventilatie-Perfuzie
Boala tromboembolica cronica
Conditii
• Boala tromboembolica
cronica
Tratament
• Medical
– Anticoagulare
– Filtru vena cava
• Chirurgical
– Tromboendarterectomie
Analize sangvine
• Anticorpi Antinucleari
• Enzime hepatice
• HIV

• BNP
• Acid uric
Tomografia

Conditii
• Boli de parenchim
pulmonar
– Emfizem
– Fibroza pulmonara
• Emboli in vasele pulm
– Angiograma
• Adenopatii
– Mediastin
Cateterism cardiac drept

Indicatii

• Confirmarea diagnosticului

• Determinarea prognosticului

• Decizia de tratament
Testul Vasodilatator

Agenti
• Oxid Nitric (NO)
• Prostaciclina
• Adenozina

Harris, P. Br Heart J 1957; 19:272-286


SEVERITATEA BOLII
CLASA NYHA

TEST DE MERS 6 MINUTE


• CorelatiE INTRE TM6M si clasa NYHA

HEMODINAMICA
TRATAMENTUL HTAP

• Tratamentul conventional (la toti pacientii)

• Tratament specific HTAP (cls III-IV NYHA)


TERAPIA CONVENTIONALA
• LIMITAREA AGRESIUNILOR

– LIMITAREA EFORTULUI FIZIC


– Interzicerea sarcinii
– Atentie la interventiile chururgicale (precautii privind anestezia
generala)
– Hipoxia (altitudine > 2000 m, avioane nepresurizate) – pot
agrava vasoconstrictia

• ANTICOAGULAREA ORALA
(INR = 2.0-3.0)
CONVENTIONAL THERAPY
• DIURETICE
- scad hipervolemia
- in decompensarea insuficientei cardiace drepte
- natriuretic + antialdosteronic ( Furosemid + Spironolactona)

• OXIGENOTERAPIE
- daca exista hipoxemie
- NU la pacientii cu sunturi cardiace

• DIGITALICE – NU sunt utilizate in HTAP

• DOBUTAMINA
- in insuficienta cardiaca dreapta decompensata
- uneori in admin continua iv in HTAP avansata
Tinta terapiilor curente in
Hipertensiunea Arteriala Pulmonara

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


Figure 1. Targets for Current or Emerging Therapies in
Pulmonary Arterial Hypertension. Three major pathways
involved in abnormal proliferation and contraction of the
smooth-muscle cells of the pulmonary artery in patients
with pulmonary arterial hypertension are shown. These
pathways correspond to important therapeutic targets
in this condition and play a role in determining which of
four classes of drugs -- endothelin-receptor antagonists,
nitric oxide, phosphodiesterase type 5 inhibitors, and
prostacyclin derivatives -- will be used. At the top of the
figure, a transverse section of a small pulmonary artery
STRATEGIA TERAPEUTICA IN HTAP-
SCURT ISTORIC
• 1980 Terapie conventionala ( doar masuri suportive)
• 1981 Transplant cardiopulmonar
• 1992 Doze mari de blocanti ai canalelor de calciu

• 1996 Analogi de prostaglandine IV (Epoprostenol - FLOLAN®)

• 2000 - 2005 Analogi de prostacicline


Treprostinil (SC,IV) - REMODULIN®
Iloprost (inhaled) - VENTAVIS®
Beraprost (oral)

Antagonisti de receptor de endotelina


Bosentan ( TRACLEER®)
Sitaxsentan ( THELIN®), Ambrisentan (VOLIBRIS®)

Inhibitori de fosfodiesteraza V
Sildenafil ( REVATIO®)
ACTIUNE: vasodilatatie, antiagregant, scaderea
proliferarii musculaturii netede
CI: Boala veno ocluziva (edem pulmonar)

Efecte secundare: hipotensiune, rush, cefalee,


diaree, dureri ososase, discomfort
abdominal, greata

Complicatii : locale ale administrarii IV sau SC.


ADMINISTRAREA ANALOGILOR DE
PROSTAGLANDINE
In contrast, treprostinil is premixed into a small syringe and 
changed once daily into this Minimedpump, about the size of a 
pager or small cell phone.  Only aseptic technique is necessary at 
the injection site which is changed every 3 days.  The needle is 

similar to a small 25 gauge, 4 mm tuberculin needle.
CORDUL PULMONAR
CRONIC
DEFINITIE

• Cordul pulmonar cronic reprezinta o


modificare a structurii si functiei ventricului
drept ca urmare a unei boli respiratorii

• Hipertrofia ventriculara dreapta (HVD) este


modificarea predominenta in cordul pulmonar
cronic, in timp ce in cazurile acutepredomina
dilatatia.

• Atat hipertrofia cat si dilatatis sunt rezultatul unei


cresteri a presiunii in ventricului drept.
Ipoteza Clasica
Hipoxia alveolara cronica

Vasculopatie Pulmonara

Hipertensiune Pulmonara

Cord Pulmonar

Deces
INVESTIGATII

• Speciale pt ventriculul drept:


– Ventriculografia Isotopica
– Scintigrafia Miocardica (Thaliu, Tc)

lSpeciale pt circulatia pulmonara


–Cateterism Cardiac Drept / Angiografie
–Scintigrafie Ventilatie-Perfuzie
–biopsie pulmonara
CLASIFICAREA CLINICA A
CORDULUI PULMONAR

• Latent
• Compensat
• Decompensat
TRATAMENTUL CORDULUI PULMONAR
DIN BPOC
1. Tratament specific al BPOC
2. Digitalice
3. Diuretice
4. Antibiotice
5. Oxigenoterapie
6. Anticoagulante
7. Antiaritmice
8. Transplant pulmonar
Tratamentul BPOC

• Incetarea fumatului
• Bronhodilatatoare
– anticolinergice (bromura de ipratropium, tiotropium )
– beta 2 agonisti de lunga durata (salmeterol, formoterol)
– teofilina retard
• Corticosteroizi inhalatori ( daca are cel putin 3 exacerbari
in 2 ani)
• Ventilatie Noninvaziva CPAP/ BiPAP (daca este necesar?
cronic?)
Digitalice

• De obicei NU

• Eventual la pacientii cu insuficienta VD asociata

• Doze mici (5-6 cp digoxin/saptamana)


Diuretice

• Natriuretice and antialdosteronice

• Evitarea dozelor mari

• risc alcaloza hipocloremica (accentueaza deprimarea


centrului respirator)
Antibiotice

• Doar in exacerbari
Despre oxigenoterapia cronica …

• CEA MAI IMPORTANTA TERAPIE


• extractor O2
• debit: 2-3 l/min
• 15-16 h/zi

• Resultate:
– Imbunatatirea calitatii vietii
– Scaderea ratei de morti subite
– Scaderea progresiva a ratei de agravare a HTP ( cordul pulmonar)
– Probabil creste supravietuirea
Anticoagulante

Daca se suspecteza tromboza venoasa profunda sau agravare


datorita unor tromboze “in situ”
Antiaritmice

• aritmie simptomatica

• Tratament profilactic la pacientii cu aritmii


supraventriculare recurente

• propafenon, amiodaron, verapamil


TRANSPLANT PULMONAR

• Rar in BPOC

• Mortalitate mare (supravietuire 5 ani - 40%)


Terapie specifica a HTAP

Hipertensiunea pulmonara din BPOC


• Este in general usoara sau moderata (mPAP < 30 mmHg)
• este marker de severitate a bolii respiratorii
• NU necesita tratament specific(exceptand oxigenoterapia)

DOAR in Hipertensiunea Pulmonara severa (disproportionata)

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