13.htp Curs Studenti Nou.ppt

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 (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 HTP persistenta a nou-nascutului

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,

1’. - boala veno-ocluziva - hemangiomatoza capilara pulmonara

limfangiomatoza, compresia vaselor pulmonare (adenopatie, tumora, fibroza mediastinala), boli 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 l

celulelor musculare netede

Tromboza

lProliferare

intimala

Patologia HTAP- Modificari Proliferative Intima

Media

Leziune Plexiforma

Adventitia

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 HTP - hipertrofie a mediei VASCULARA - 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, hypertrophy, proliferation 1-2

Endothelial cells Proliferation, dysfunction 3-6

Endotelina Inflammation NF-kB and cytokine release,

increased vascular permeability 10-13

1 Clozel

Fibroblasts Fibrosis 7-9

4 Davie N. M et al. J Pharmacol Exp Ther 1989 ; 2 Yang Z et al. Circulation 1999; 3 Kuhlmann et al. Acta Physiol Scand 2005; 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 • mutatia BMPR2 identificata la 70% in HTAP familiala § penetranta redusa 0.2 § mutatia BMPR2 a fost identificata la 30% din asa zisele HTAP sporadice

Ligan

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 Simptome

Screening

Descoperire intamplatoare

Suspiciune HTP

Detectia

Examen fizic Radiografie pulmonara Electrocardiograma Echocardiograma

HTAP Detectata

Simptomele in HTAP • NU exista simptome precoce in HTAP • Screeningul in populatiile la risc Simptome precoce (sclerodermie, familiile la risc…) Primele simptome

Non-specifice

Tardiv

• Dispnee progresiva la efort ++++ • Fatigabilitate, ameteli, palpitatii • Durere toracica • Sincope • Tuse • Simptome si semne de insuficienta cardiaca dreapta • Edeme, ascita

HTAP: o boala cu evolutie rapida II Simptomatica / Stabila

I Preclinica/ Fara Simptome

Functia VD

presiunea pulm

Nive l

III-IV Progresie / Declin

Index Cardiac

Fereastra Terapeutica AN I T

L UNI

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

Caracterizarea

Teste suplimentare 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 HTAPSCURT ISTORIC • 1980 • 1981 • 1992

Terapie conventionala ( doar masuri suportive) Transplant cardiopulmonar 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)