HIPERTENSIUNEA PULMONARA

CIRCULATIA PULMONARA NORMALA PLAMANUL - oxigenare Hb - filtru (particule, bacterii) - eliminarea CO2 – echilibru acido-bazic CIRCULATIA CIRCULATIA PULMONARA BRONSICA Sange venos sange arterial a. pulmonara a. bronsice Capilare Capilare Vene pulmonare Vene sistemice

CIRCULATIA BRONSICA Sunt fiziologic dr-stg (pana la 30% din DC) - bronsiectazii - fibroza chistica - boli congenitale cardio-vasculare

HIPERTENSIUNEA PULMONARA (HTP) NORMAL A SISTEMICE – media 20-25% din diam. vasului A. PULMONARE - media < 10- 5% din diam. vasului Arteriolele pulmonare nu au tunica medie si nu contribuie la rezistenta vasculara VD – fluxul coronarian cel mai mare in sistola - depinde de gradientul pres. pulm. – aorta Pres. VD creste – gradientul scade – fluxul coronar drept scade – ischemie VD

HIPERTENSIUNEA PULMONARA (HTP) NORMAL PRES. A. PULMONARA - sist. 18-25 mm Hg - diast. 6-10 mm Hg - medie 12-16 mm Hg PRES V. PULMONARE – 2-10 mm Hg REZIST. VASC. PULM. = 1/10 din REZIST. SISTEMICA HIPERTENSIUNEA PULMONARA (HTP) PRES. A. PULMONARA - sist. > 30-35 mm Hg - medie > 20-25 mm Hg - diast. > 15 mm Hg Reducerea calibrului vaselor pulmonare Cresterea fluxului

REACTIVITATEA VASCULARA PULMONARA HIPOXIA VASOCONSTRICTIE PULMONARA -histamina – receptori H1 vasculari - endoteliu - echilibru NO – endoteline - patrunderea Ca 2+ in celula musculara neteda HIPOXIA CRONICA Extensia musculaturii netede in peretele arterelor din periferia plamanilor Ingrosarea peretilor arterelor musculare Reducerea nr. arterelor – cresterea raportului alveole/artere

VASOCONSTRICTIE VASODILATATIE Hipoxia Acidoza Prostaglandine F2α si A2 HISTAMINA – H1 SEROTONINA ? ANGIOTENSINA A2 ALTITUDINE VASODILATATIE Alcaloza PROSTAGLANDINE I2 si E BLOCANTI α STIMULARE β (ISOPROTERENOL) ACETILCOLINA (prin EDRF) HISTAMINA (prin H2 ?) INDOMETACIN – creste rezistenta pulmonara La 10 000 m altitudine TA pulmonara medie = 25 mm Hg in repaus > 50 mm Hg in efort

CLASIFICAREA HTP Dana Point, 2008 HTP arteriala 1.1. Idiopatica 1.2. Ereditara 1.3. Indusa de droguri si toxine 1.4. Asociata cu: Boli de colagen HIV Hipertensiune portala Boli cardiace congenitale Schistosomiaza Anemie hemolitica cronica 1.5. HTP persistenta la nou nascut 1’ Boala venoocluziva pulmonara si/sau hemangiomatoza capilara pulmonara

CLASIFICAREA HTP Dana Point, 2008 2. HTP prin suferinta ventriculului stang 2.1. Disfunctie sistolica 2.2. Disfunctie diastolica 2.3. Boli valvulare

CLASIFICAREA HTP Dana Point, 2008 3. HTP prin boli pulmonare sau hipoxie 3.1. BPOC 3.2. Boli interstitiale 3.3. Alte boli cu restrictie si obstructie 3.4. Apneea de somn 3.5. Boli cu hipoventilatie alveolara 3.6. Expunerea cronica la mare altitudine 3.7. Anomalii de dezvoltare fizica

CLASIFICAREA HTP Dana Point, 2008 4. HTP prin tromboembolism 5. HTP prin factori multipli neclari 5.1. Boli hematologice: mieloproliferare, hipersplenism 5.2. Boli sistemice: sarcoidoza, histiocitoza pulmonara cu celule Langerhans 5.3. Boli metabolice: B. Gaucher, glicogenoze, disfunctii tiroidiene 5.4. Altele: obstructii tumorale, mediastinita fibrozanta,, IRC sau dializa

CATEVA MECANISME FIZIOPATOLOGICE In suferinta inimii stangi PRESIUNE ATRIU STG = 7 mm Hg scade rezistenta pulmonara (recrutare de vase) >7 mmHg – creste presiunea in a. pulmonara (fluxul ramane constant; gradientul ramane constant) > 25 mmHg – crestere disproportionata de presiune in a. pulmonara (gradientul creste; fluxul constant sau scade)

CATEVA MECANISME FIZIOPATOLOGICE Variabilitatea reactivitatii vasculare pulmonare: creste presiunea venoasa – distrugere sau inchidere de cai aeriene – hipoxie – creste presiunea in a. pulmonara creste presiunea venoasa – edem interstitial – rigidizarea vaselor – HTP drenajul limfatic creste starea VD normal hipertrofic insuficient miopatic (+ VS) hipoperfuzat (infarct) Volumul sanguin pulmonar (depinde de debitul celor 2 ventriculi si de distensibilitatea vaselor pulmonare)

MODIFICARI ANATOMICE Celule endoteliale capilare umflate Membrane bazale capilare ingrosate Edem interstitial Rupturi de membrane bazale – transudare de eritrocite – hemosideroza Alveole fibroase Destindere de limfatice

TABLE 73-2   -- Clues for Interpretation of Diagnostic Tests for Pulmonary Hypertension Notable Findings Chest x-ray Enlargement of central pulmonary arteries reflects level of PA pressure and duration. Electrocardiography Right axis deviation and precordial T wave abnormalities are early signs. Pulmonary function tests Elevated pulmonary artery pressure causes restrictive physiology. Perfusion lung scan Nonsegmental perfusion abnormalities can occur from severe pulmonary vascular disease. Chest computed tomography scan Minor interstitial changes may reflect diffuse disease; mosaic perfusion pattern indicates thromboembolism and/or left heart failure. Echocardiography Right ventricular enlargement will parallel the severity of the pulmonary hypertension. Contrast echocardiography Minor right to left shunting rarely produces hypoxemia. Doppler echocardiography This is too unreliable for following serial measurements to monitor therapy. Exercise testing This is very helpful to assess the efficacy of therapy. Severe exercise-induced hypoxemia should cause consideration of a right-to-left shunt.

SINDROM EISENMENGER Toate sunturile sistemico-pulmonare rezultand din mari defecte care duc la cresteri de presiune in VD si la inversarea suntului (pulmonar-sistemic) sau sunt bidirectional cu: cianoza, eritrocitoza si multiple suferinte de organ

MODIFICARI ANATOMICE GR. I : hipertrofia mediei artereor mici musculare GR. II : + proliferarea intimei GR. III: + fibroza concentrica cu obliterare de vase GR. IV: “leziuni plexiforme”, dilatatii, trombi GR. V: complexe plexiforme, leziuni angiomatoase si cavernoase si hialinizaea fibrozei intimale GR. VI: arterita necrozanta

Histopathology of endothelial cell lesions in IPAH. A Histopathology of endothelial cell lesions in IPAH. A. Pulmonary artery showing medial hypertrophy and lined by a single layer of endothelial cells, as outlined by Factor VIII related antigen immunostaining (arrow). Plexiform lesion (outlined by the rim of arrowheads) with the proximal vascular arterial segment with marked intimal and medial thickening by smooth muscle cells (arrow). Note the proliferation of endothelial cells with the outer edge (3–5 o’clock) occupied by dilated blood vessel-like structures. C. Cross section of a plexiform lesion, outlined by arrowheads. Note perilesional inflammatory infiltrate (arrow). D. High magnification histology of plexiform lesions shown slit-like vascular channels lined by hyperchromatic and cuboidal endothelial cells. Cells in the core do not display distinct cytoplamic borders. E. Low magnification immunohistology with Factor VIII related antigen immunohistochemistry of different endothelial cell based vascular lesions. This area has re-vascularized lesions (possibly an organized thrombus), with well-formed and distinct small capillaries/vessels (arrowhead), a plexiform lesion (arrow), and dilated/angiomatoid lesions (between arrowheads). F. High magnification immunohistology of cellular plexiform lesion stained with Factor VIII related antigen (arrowheads). G and H. Histological identification of plexiform and dilation lesions (G) is markedly improved by Factor VIII related antigen immunohistochemistry (H) (arrowheads), while the parent vessel (arrow) shows mild medial remodeling. I. Highlight of vascular dilation/angiomatoid lesions with Factor VIII related antigen immunohistochemistry. J. Endothelial cells in plexiform lesion is highlighted by CD34 immunohisochemistry (arrowheads). Proximal pulmonary artery with marked intima and medial thickening is highlighted by the arrow. K and I. Endothelial cells are highlighted by CD31 immunohistochemistyr (arrowheads). Note that capillary endothelial cells express CD31 as well (arrow in I),

A. Fibrotic, relatively paucicellular intima thickening (outlined by arrowheads) in a pulmonary artery with the media highlighted with the arrow. B. Marked intima remodeling with almost complete obliteration by fibrous tissue with a marked intravascular and perivascular inflammatory infiltrate (arrows). C. Smooth muscle cell hypertrophy, with prominent thickening of medial layer (arrow). D. Highlight of medial hypertrophy with smooth muscle α actin immunohistochemistry. E. Markedly remodeled pulmonary artery with endothelial cell layer highlighted by Factor VIII related antigen immunohistochemistry. Note that the intima and medial smooth muscle cells are negative for Factor VIII related antigen reactivity. F. Ingrowth of smooth muscle cells in a plexiform lesions, highlighted by smooth muscle cell α actin immunohistochemistry (arrow).

Veno-occlusive PH. A. Low-power histological view of thickened pulmonary veins running into the lung parenchyma from the pleural surface (left edge) (arrows). Note marked vein wall thickening and decreased lumen. Adjacent alveoli are filled with blood and show septal thickening with engorged capillaries (arrowhead). B. Marked vein thickening with intimal projection probably representing organized thrombus (arrow). Alveolar hemorrhage and septal thickening are highlighted with arrowhead. C and D. Movat stained pulmonary vein showing arterialization pattern with internal and external elastic layers (arrow). The vein shows marked intima thickening with organized thrombus (arrowheads).

Rx în HTP Normal CRESTEREA FLUXULUI PULMONAR Flux crescut in lobii inferiori Gravitatie Presiuni diferite intra –alveolare Raport A/B = 1,2 : 1 CRESTEREA FLUXULUI PULMONAR FLUX - Φ VASE x 8 (rezerva) + Φ vase - flux + presiune - presiune Creste Φ venos Rx – 1/3 ext. vascularizata - Circ. Inf = circ. sup. N – Φ a. pulm. desc. dr. = 10-15 mm la barbati si 9-14 mm la femei

Rx în HTP Rx HTP arteriala - vasoconstrictie periferica - vasospasm - ingrosarea peretelui vascular Rx scade circulatia (creste transparenta) in 1/3 ext. vasele centrale elastice se largesc calcificari ale vaselor centrale

Rx în HTP HTP de origine venoasa P venoasa > 8 – 12 mm Hg fluxul pulmonar este redistribuit spre lobii superiori Rx – inversare a aspectului normal (cefalizarea fluxului arterial si venos) P venoasa > 25 mm Hg Edem pulmonar

Rx în HTP Mecanisme Sechestrarea de lichid interstitial in lobii inferiori ↓ Presiunea interstitiala ↑ Complianta pulmonara ↓ Fluxul spre lobii inferiori ↓ + Spasm arterial Fluxul este redistribuit spre lobii superiori

HTP IDIOPATICA ETIOLOGIE Embolism pulmonar recurent, asimptomatic Embolism amniotic Tromboza in situ, tulburari de coagulare si fibrinoliza , contraceptive Vasoconstrictie cronica → necroza fibrinoida → leziuni plexiforme Vasculita generala cu fenomen Raynaud Hipersensibilitate la droguri Ingestia de fumarat de aminorex (anorexigen) Hormoni feminini

HTP IDIOPATICA MODIFICARI HISTOLOGICE Ingrosarea intimala a a. mici si arteriole cu fibroza in “foi de ceapa” Ingrosarea mediei a. musculare si muscularizarea arteriolelor Arterita necrozanta cu necroza fibrinoida Leziuni plexiforme → arteriopatie pulmonara plexogenica → umbre vasculare → reducerea patului vascular

HTP IDIOPATICA HIPOXIE → raspuns anormal → disfunctie endoteliala Modificarea raportului EDRF - endoteline Distrugeri de endoteliu Tromboza Vasoconstrictie → necroza fibrinoida Leziuni plexiforme

HTP IDIOPATICA ASPECTE CLINICE 4 simptome principale Dispnee de efort Femei tinere 4 simptome principale Dispnee de efort Accentuarea zgomotului II Modificari Rx – cardiomegalie - a. pulmonara proeminenta Modificari ECG : - HVD - deviatie axiala dr. - HAD Mai rar: - Ameteli si sincope de efort - Dureri toracice de efort - Edeme - Fenomene Raynaud - Istoric de tromboflebita superficiala

HTP IDIOPATICA PROGNOSTIC MOARTEA HEMOPTIZIA IN STADII TARDIVE Prost (supravietuire peste 5 ani – 21%) Anticoagulantele imbunatatesc prognosticul MOARTEA Insuficienta cardiaca congestiva Pneumonie Moarte subita Moarte la cateterism Disectie de a pulmonara HEMOPTIZIA IN STADII TARDIVE Ruptura de leziuni plexiforme Tromboze in situ Embolism pulmonar DUREREA TORACICA Ischemia subendocardului VD Distensia a pulmonare

HTP IDIOPATICA SEMNE CLINICE Zgomot II intarit la pulmonara Suflu sistolic la pulmonara Semne de insuficienta cardiaca dreapta Semne de regurgitare triscuspidiana Cianoza - tardiv prin deschidere de foramen ovale Paralizie de recurent (rara)

HTP IDIOPATICA LABORATOR - Uneori defecte de coagulare si fibrinoliza ECG: HVD, HAD Rx: largirea a pulmonare; marirea atriului si ventriculului dr CT – Φ a pulmonare TESTE FUNCTIONALE - Disfunctie restrictiva ECHOCARDIOGRAFIA Marirea atriului si ventriculului drept Cavitati stangi normale Ingrosarea septului Regurgitare tricuspidiana si prolaps de valva mitrala secundare dilatatiei de VD

HTP IDIOPATICA SCINTIGRAFIA PULMONARA - normala In stadii avansate poate fi daunatoare – trasorul legat de albumina – procoagulant CATETERISMUL CARDIAC SI ANGIOGRAFIA RISCANTE Presiunea in VD egala sau chiar mai mare decit presiunea sistemica Rezistenta vasculara pulmonara depaseste uneori pe cea sistemica Uneori foramen ovale este patent Presiunile stg. sunt normale sau mici, dar uneori greu de determinat BIOPSIA PULMONARA

HTP IDIOPATICA DIAGNOSTIC DIFERENTIAL HTP secundara (mai benigna si mai tratabila)

TESTUL VASODILATATOR In sala de cateterism cardiac PAPm dupa administrarea de NO inhalator (sau adenozina iv, epoprostenol iv sau inhalator) Test + = reducerea cu 20% a PAPm sau a rezistentei vasculare pulmonare – bolnavul va primi vasodilatator indelungat

PROGNOSTICUL Supravietuirea medie in HTP netratata = 2,8 ani Factori de prognostic: Varsta < 14 ani sau 65 ani – prognostic prost Clasa NYHA: I – II: supravietuire 6 ani in medie III: supravietuire 2,5 ani in medie IV: supravietuire 0,5 ani in medie Scaderea capacitatii de efort Sincopa Hemoptizie Semne de insuficienta ventriculara dreapta O2 in a pulmonara > 63 – 55% supravietuire la 5 ani < 63 – 17% supravietuire la 5 ani Indexul cardiac < 2,1 l/min/m2 supravietuire medie 17 luni Presiunea in AD < 10 mmHg - supravietuire 4 ani in medie > 20 mmHg - supravietuire medie o luna Test de vasodilatatie negativ

TRATAMENTUL MEDICAL 1. Anticoagulantele 2. Oxigenoterapia Warfarina dubleaza supravietuirea in HPP Indicatiile anticoagularii permanente: toti pacientii cu HTPI Tromboembolismul pulmonar (INR = 2-3) HTP secundare, daca nu exista contraindicatii 2. Oxigenoterapia Se recomanda monitorizarea Sat O2 nocturna, Sat O2 < 90% in aerul atmosferic corectabila la administrarea de O2, indica oxigenoterapia nocturna 3. Tratamentul insuficientei ventriculare drepte: - Diuretice - Digoxinul creste DC in administrarea acuta in HTPI, efectul sau in administrarea cronica este discutabil

TRATAMENTUL MEDICAL 4. Tratamentul vasodilatator Antagonistii de Ca (diltiazem sau nifedipina): HTP de tip arterial cu test vasodilatator pozitiv CI in : HTP venoasa (precipita EPA) HTP hipoxica din bolile cronice pulmonare cu Sat O2 in sangele venos < 63% (agraveaza hipoxemia) PAD > 10 mm Hg Index cardiac < 2,1 l/min/m2

Responders: Ca.-blockers (if bradicardic) Nifedipine :120 -240 mg (if tahicardic) Diltiazem 240-720 mg Begin low dosage , increase weekly Less than ½ of pts tolerate maximum dosage

TRATAMENTUL MEDICAL (PG) 5. Prostaglandinele – efectele pozitive ale tratamentului indelungat (min 3 luni) Reducerea rezistentei vasculare pulmonare Cresterea indexului cardiac Dublarea supravietuirii la 5 ani Reducerea riscului si ameliorarea evolutiei dupa transplantul pulmonar

TRATAMENTUL MEDICAL Indicatii Bolnavii cu ICC cl III – IV, index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mmHg, indiferent de testul vasodilatator Toti bolnavii care nu raspund la tratamentul medical conventional, in asteptarea transplantului pulmonar

TRATAMENTUL MEDICAL (PG) Efecte adverse: Diaree, dureri abdominale, cefalee, flush, artralgii, dureri musculare Ascita, edem pumonar (prin cresterea permeabilitatii vasculare) Toleranta ce necesita cresterea dozelor Rebound al HTP la intreruperea brusca a tratamentului Infectii de cateter

TRATAMENTUL MEDICAL (PG) Preparate folosite: Epoprostenol = PGI2 iv. Se incepe cu 2 ng/kc/min in pev continua si se creste doza dupa o saptamana pana la doza maxima tolerata de pacient Iloprost = analog al epoprostenolului, mai puternic iv (pev continua) sau in aerosoli, 6-9 inhalatii/zi (50 -200 μg/zi) Trepostenil (UT – 15) este analog de PGI2. Doza initiala este de 1,25 ng/kc/min si se creste cu 1,25 ng/kc/min la 7 zile pana la 9,3 ng/kc/min

TRATAMENTUL MEDICAL (PG) Beraprost: derivat stabil de PGI2, poate fi adminisrat p.o. 1 tb = 20μg. Se incepe cu 1 tb/zi si dupa 6 saptamani de titrare, se ajunge la 6 tb/zi (studiul ALPHABET). Rezultate bune in HTPI, neconcludente in HTP sec. Se pare ca nu este eficient in stadiile avansate de boala.

Prostanoid analogues CTD= boala de tesut conjunctiv

Epoprostenol Treprostenil short HL, temp.-dependent , i- v (infusion pump ) , local facilities 2-4ng/kg/min ..20-40 ( tolerance , rebound , adverse reactions: common) >100.000 $ /year Rubin LJ Ann. Intern.Med. 1990;112:485-92 Barst RJ N.Engl. J Med 1996;334:296-304 Badesch DB Ann. Intern.Med. 2000;132:425-34 3 month results: indic. surv/altern Conversion to oral agents ?? Treprostenil sufficient chemical stability to be administered at ambient temperature allow iv / subcutaneous /oral ( bid ) and inhalatory adm.(6-9 d )

Beraprost Iloprost Orally :40-80microg qid/zi efficacy does not appear to be sustained with extended duration of therapy Iloprost Inhalations 6-12 times/d (20-40 microg/d.) Advant: selective to pulm.circ. J Am CollCardiol. 2003 Jun 18;41(12): 2119–25

TRATAMENTUL MEDICAL (ARE) 6. Antagonistii receptorilor de endotelina Bosentan (ET1RA) po. Doze: 62,5 mg de 2 ori/zi, pana la 125 mg de 2 ori/zi, timp de 16 saptamani.

Endothelin receptor antagonists Type A receptor : vasoconstriction, proliferation, fibrosis. Type B receptor (endotelial): increases the synthesis of nitric oxide ( vasodilation ) Type B receptor (SMC): activates aldosterone, thromboxane, norepinephrine. ( vasoconstriction )

Bosentan ( Tracleer ) available in Romania dual ETA and ETB-receptor antagonist 125 mg bid BREATHE-1 BREATHE-3 (children ) 10% liver enzimes > BREATHE -5 EARLY Sitaxsentan 6500 times greater affinity for the ETA STRIDE I and II Chest , 2008; 134(4): 775 - 782. 100-300 mg od 2004 : Level of evidence : B Incl .HTP in congenitals/CTD aproved in Europe Warfarine interference Ambrisentan ARIES-2 . Am J Respir Cirt Care Med. 2006;173: lower incidence of liver enzyme abnormality Ann. Pharmacother, 2008; 42(11): 1653 absence of significant drug interactions - 2004 : Level of evidence : C

TRATAMENTUL MEDICAL (IFD) 7. Inhibitori de fosfodiesteraza (Sildenafil)

Phosphodiesterase inhibitors Sildenafil ( REVATIO ) 25 mg t.i.d. Available in Romania Humbert M N Engl J Med 2004;351: 1425–36.

Type 5 Phosphodiesterase inhibitors Vardenafil HCL ( Levitra ) Br J Pharmacol., 154(4):787-96. 2008 Apr 21 Tadalafil ( Cialis ) longer half-life (17.50 hours ) marketing approval began in late 2008 J Am Coll Cardiol, 2004; 44:1488-1496 Circulation. 2004;110:3149-3155 The three PDE5 inhibitors differ markedly in : kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil) selectivity for the pulmonary circulation (sildenafil and tadalafil, but not vardenafil), impact on arterial oxygenation (improvement with sildenafil only).

TRATAMENTE CHIRURGICALE Septostomie atriala. Procedeu paleativ ce scade presiunea in inima dreapta. Indicatii: HTP severa, care nu raspunde la prostaglandine Se exclud pacientii cu Insuf Ventr dr severa, disfunctie de VS sau in stare critica Trombendarterectomie Transplant pulmonar

TRATAMENTE CHIRURGICALE Indicatii transplant HTPI simptomatica, progresiva in ciuda tratamentului medical optim, cu test de mers de 6 min < 400 m, cu index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mm Hg sau PAP m > 55 mmHg

Test vasodilatator acut Raspuns - NYHA I/II, Sv O2>63%, IC > 2,1 NYHA III/IV, Sv O2<63%, IC < 2,1 Raspuns + Sv O2>63%, IC > 2,1 Warfarina + diuretic + digoxin Prostaglandine +/- transplant Blocanti de Ca Nu raspund la tratament

Frequently asked questions At which level of pulm .pressure should we begin pharmacological treatment in sec. PHT ? Adapted to etiology ! Unknown borderline ! Is it harmful to use CCB in nonresponders ? Yes , at least for high doses ACCP Gd.: Level of evidence: expert opinion; benefit: substantial; grade of recommendation: E/A. Would it be better to use the more active drugs for responders also ? Probably yes , but economically unwise

Frequently asked questions How useful is multiple drug therapy Which order of introduction /doses ? BREATHE -2 Is atrial septostomy an option ? Rarely (bridge to… ) ; 5-15% mortality

CONCLUSIONS PPHT pts to be treated in dedicated centers New therapies available ; debate on results Combination therapy in developpement Rapid change of recomandations /guidelines Cost –effectiveness analysis vital Hard end points-including mortality may be influenced