1. HIPERTENSIUNEA PULMONARA

2. 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

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

4. 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

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

6. 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

7. 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 m altitudine
TA pulmonara medie = 25 mm Hg in repaus
> 50 mm Hg in efort

8. 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

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

10. 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

11. 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

12. 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)

13. 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)

14. 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

15. 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.

16. 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

18. 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

19. 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),

20. 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).

21. 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).

24. 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. = mm la barbati si 9-14 mm la femei

25. 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

26. 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

27. 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

28. 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

29. 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

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

31. 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

32. 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

33. 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)

34. 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

35. 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

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

37. 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

38. 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

39. 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

40. 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

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

42. 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

43. 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

44. 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

45. 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 ( 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

46. 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.

47. Prostanoid analogues
CTD= boala de tesut conjunctiv

48. Epoprostenol Treprostenil
short HL, temp.-dependent , i- v (infusion pump ) , local facilities
2-4ng/kg/min ( tolerance , rebound , adverse reactions: common)
> $ /year
Rubin LJ Ann. Intern.Med. 1990;112:485-92
Barst RJ N.Engl. J Med ;334:
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 )

49. 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 Jun 18;41(12): 2119–25

50. 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.

51. 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 )

52. 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):
mg od : 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

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

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

55. Type 5 Phosphodiesterase inhibitors
Vardenafil HCL ( Levitra ) Br J Pharmacol., 154(4): Apr 21
Tadalafil ( Cialis )
longer half-life (17.50 hours )
marketing approval began in late 2008
J Am Coll Cardiol, 2004; 44:
Circulation. 2004;110:
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).

56. 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

57. 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

58. 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

61. 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

62. 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

63. 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