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HIPERTENSIUNEA ARTERIALA PULMONARA (HTAP)

CORDUL PULMONAR CRONIC (CPC)

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

1. Definitia HTAP

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

2. Clasificarea HTAP

1)Hipertensiunea Arteriala Pulmonara


(HTAP) :
Idiopatica (i PAH)
Ereditara (BMPR II, ALK 1)
Droguri si toxine
Asociata cu:
- boli de colagen
- HIV
- hipertensiunea portala
- boli cardiace congenitale
- anemia cronica hemolitica
- schistostomiaza
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HTP persistenta a nou-nascutului


1)
- boala veno-ocluziva
- hemangiomatoza capilara pulmonara
2). Hipertensiunea din bolile cardiace stangi
disfunctie sistolica
disfunctie diastolica
valvulare
3) Hipertensiunea din bolile respiratorii cu hipoxemie
BPOC
Boli interstitiale pulmonare
Sindromul de apnee in somn
Altitudine
Hipoventilatia alveolara
Anomalii de dezvoltare
4) HTAP postembolica
5). Diverse (Sarcoidoza, histiocitoza X, limfangiomatoza, compresia
vaselor pulmonare (adenopatie, tumora, fibroza mediastinala), boli
tiroidiene, boli cu stocaj de glicogen, boala Gaucher, teleangiectazia
hemoragica ereditara, hemoglobinopatii, boli mieloproliferative,
splenectomie, etc)

3. Patogeneza HTAP
Patologia HTAP:
Normal -> flux crescut si rezistenta scazuta; in mod normal, aa. pulm.
asigura prin supletea si elasticitatea lor o hipercomplianta, a.i. in mod
normal, presiunea pulmonara nu creste nici in cursul eforturilor
HTAP -> hipertrofia celulelor musculare netede, tromboza, proliferare
intimala
modificari proliferative ingrosare a tuturor tunicilor aa. pulm.
remodelarea vasculara pulmonara -> lez. plexiforma= stadiu
ireversibil al bolii
[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.]

Clasificarea morfopatologica a vasculopatiei din HTAP


Arteriopatie Pulmonara hipertensiva

- hiperplazie intimala
- hipertrofie a mediei

=> remodelare vasculara => HTAP

- ingrosarea adventitiei
Disfunctia endoteliala
- vasodilatatori si antiproliferativi : prostacicline, NO
- vasoconstrictori si proliferativi: endotheline (ET-1), TxA2
Tromboza ( in situ, TEP)
ET este mediator cheie in HTAP: smooth muscle cells->
vasoconstriction,hypertrophy, proliferation; endothelial cells -> proliferation,
dysfunction; inflammation -> NF-kB and cytokine release, increased vascular
permeability; fibroblasts -> fibrosis.
[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. ]
[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.]

Genetica HTAP: HTAP si mutatiile genei BMPR-II (Bone


Morphogenetic Protein type II Receptor )
-

Mutatie heterozigota a BMPR2, care codifica un receptor TGF-b,


cauza de HTAP familiala; mutatie detectata la ~70% din familie
Asocierea HTAP sporadica cu mutatia BMPR2; 15-26% din
HTAP sporadice au mutatia BMPR-II; transmiterea parentala si
mutatia de novo documentata

HTAP familiala
-

BMPR-II este un membru al superfamiliei receptorului TGF-b


mutatia BMPR2 identificata la 70% in HTAP familiala
penetranta redusa 0.2
mutatia BMPR2 a fost identificata la 30% din asa zisele HTAP
sporadice

4. Algoritmul de diagnostic
Trei pasi in diagnosticul HTAP:
1) Suspicionarea: evaluare simptome, screening, descoperire intamplatoare
2) Detectia: examen fizic, Rx pulmonara, electrocardiograma, echocardiograma
=> HTAP detectata
3) Caracterizarea

1) Suspicionarea
Simptomele in HTAP
-simptome precoce: NU exista simptome precoce in HTAP; screeningul in
populatiile la risc (sclerodermie, familiile la risc)
-primele simptome: dispnee progresiva la efort ++++ ; fatigabilitate, ameteli,
palpitatii
-non-specifice: durere toracica, sincope, tuse
-tardiv : simptome si semne de insuficienta cardiaca dreapta; edeme, ascita

HTAP: o boala cu evolutie rapida

HTP scade prin deteriorarea functiei VD => pres.pulmonara nu apreciaza


severitatea bolii => pres. Nu reprezinta un parametru de monitorizare a bolii
2) Detectia
Examenul clinic: varice; sd. CREST(forma limitata de sclerodermie): calcinoza
(calcificari cutanate), sd. Raynaud (degetele devin albe datorita absentei
fluxului sangvin, apoi albastre prin dilatatia vaselor ce apare pentru a
pastra sangele in tesuturi, in final devin rosii prin reluarea fluxului sangvin),
esofag tulburari de motilitate, sclerodactilie, teleangiectazii
Auscultator: zgomot de IT (evid, prin man. Rivero-Carvallo), zg. II intarit, galop VD
(IC dr), suflu de IP
Rx: dilatare de aa. pulm. In hil, dilatarea trunchiului a. pulm. -> umple golul
parahilar; cardiomegalie index cardio-toracic crescut

EKG: unda P ascutita mai ales in D II si V1; bloc ram drept, chiar BRD major;
deviere ax la dr.; supraincarcare VD -> R inalt precordiale dr., uneori S
adanc precordiale stg.
Eco:

RV

RV

LV

Normal -

LV

HTP -

HTP aplatizare a SIV; VD -> ingrosat


Eco utila in a estima presiunea Eco-Doppler

Se considera ca orice bolnav de HTP are un anumit grad de regurgitare


tricuspidiana (IT): valva T functioneaza in mod normal la diferente de pres.
mici, nu e o valva puternica; la unii indivizi exista o regurgitare T
fiziologica, nesemnificativa hemodinamic } + HTP => creste
regurgitarea.
PAP sistolica : viteza regurgitatiei tricuspidiene (VIT) (PAPS)
PAPmedie : timpul de Accelerare (AT); m PAP = 78 - 0,52 AT
3) Caracterizarea
Teste esentiale: explorarea functionala respiratorie
scintigrafie V/Q
teste sangvine: screening colagenoza (sclerodermie: SCL-70 anticentromer), HIV, enzime hepatice
cateterism cardiac drept cu test vasodilator in acut
Teste suplimentare: ecografie transesofagiana (importanta pt a vedea
malformatii congenitale)
CTSpiral / EBCT / HRCT / MRI
angiografie pulmonara (obstructii, comunicari anormale)
teste sangvine : clotting study, SaO2, acid uric , BNP
studiul somnului
biopsie pulmonara

HTP detectata si caracterizata


Explorarea functionala respiratorie: spirometrie -> debite pulmonare
pletismografie -> CPT, VR. etc
capacitatea de difuziune -> schimbul de
gaze
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 computerizata : 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 vasodilatotor: agenti: oxid nitric (NO), prostaciclina, adenozina

Severitatea bolii: clasa NYHA; test de mers 6 minute; corelatie intre TM6M si clasa
NYHA; hemodinamica

5. Tratamentul HTAP
1) Tratamentul conventional (la toti pacientii)
2) Tratament specific HTAP (cls III-IV NYHA)
1) Tratamentul conventional
Limitarea agresiunilor

limitarea efortului fizic

interzicerea sarcinii

atentie la interventiile chururgicale (precautii privind anestezia


generala)

hipoxia (altitudine > 2000 m, avioane nepresurizate) pot agrava


vasoconstrictia

Anticoagulare orala (INR = 2.0-3.0)


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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 acut)
- in insuficienta cardiaca dreapta decompensata
- uneori in admin continua iv in HTAP avansata
(Blocante canale calciu -> pentru acei 1 din 15 cu HTP idiopatica la care apare
vasodilatatie la anumite substante medicamentoase, DOAR pt. ei. Se considera
ca acestia au o boala diferita de HTP)
[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) ]
Analogi de prostaciclina:
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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.

6. CPC in BPOC
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 acute predomina 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: centriculografia isotopica,


scintigrafia miocardica (Thaliu, Tc)
speciale pt circulatia pulmonara : cateterism cardiac drept /
angiografie, scintigrafie ventilatie-perfu zie, biopsie pulmonara

Clasificarea clinica a cordului pulmonar: latent, compensate, decompensat

7. Tratamentul CPC din BPOC


1) Tratament specific al BPOC
2) Digitalice
3) Diuretice
4) Antibiotice
5) Oxigenoterapie
6) Anticoagulante
7) Antiaritmice
8) Transplant pulmonar

1) Tratamentul BPOC:
- incetarea fumatului
- bronhodilatatoare: anticolinergice (bromura de ipratropium,
tiotropium )
beta 2 agonisti de lunga durata (salmeterol,
formoterol)
teofilina retard

2)
3)
4)
5)

- 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
Oxigenoterapia cronica:
CEA MAI IMPORTANTA TERAPIE
extractor O2
debit: 2-3 l/min
15-16 h/zi
rezultate: imbunatatirea calitatii vietii, scaderea ratei de morti subite,
scaderea progresiva a ratei de agravare a HTP ( cordul pulmonar), probabil
creste supravietuirea

6) Anticoagulante: daca se suspecteza tromboza venoasa profunda sau


agravare datorita unor tromboze in situ
7) Antiaritmice: aritmie simptomatica; tratament profilactic la pacientii cu
aritmii supraventriculare recurente; propafenon, amiodaron, verapamil
8) 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 (xceptand oxigenoterapia)


-

DOAR in hipertensiunea pulmonara severa (disproportionata)

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