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Ipertensione polmonare: classificazione, fisiopatologia, diagnosi, terapia

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Ipertensione polmonare: inquadramento generale, dalla definizione alla terapia, in base alle linee guida ESC 2009.

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Ipertensione polmonare: classificazione, fisiopatologia, diagnosi, terapia

  1. 1. UOC Pneumologia Ospedale “C e G Mazzoni” - Ascoli Piceno Direttore: Dott. Riccardo Pela <ul><li>Ipertensione Polmonare: </li></ul><ul><li>definizioni e fisiopatologia </li></ul><ul><li>Dott. Gianluca Panella </li></ul>
  2. 2. Ipertensione polmonare (IP) Dana Point 2008
  3. 3. European Heart Journal 2009 IP: classificazione … aumento di PP e RVP in tutti i gruppi clinici ma meccanismi sottostanti, approccio diagnostico ed implicazioni terapeutico/ prognostiche differenti…
  4. 4. IP definizione clinica Ipertensione polmonare (IP): aumento delle resistenze nel circolo polmonare (RVP). Clinica ed emodinamica risultanti dall’aumento del postcarico e dalla capacità di compenso del Ventricolo Destro Farber HW, Loscalzo J. Pulmonary arterial hypertension N Engl J Med 2004;351:1655-1665
  5. 5. Classi Funzionali WHO (NYHA) Barst RJ et al. J Am Coll Cardiol 2004 WHO-FC Symptomatic profile Class I No limitation of physical activity. Ordinary physical activity does not cause dyspnoea or fatigue,chest pain or near-syncope Class II Slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope Class III Marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain or near syncope Class IV Inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest
  6. 6. Time IP PVR CO WHO-FC 0-1 Pre-sintomatico/ Compensato WHO-FC 2-3 Symptomatico/Compensato Symptom Threshold Right Heart Dysfunction WHO-FC 3-4 Scompenso Symptoms Galiè N, Manes A, Palazzini M et al Eur Heart J. Suppl. 9: 68-74, 2007. Rich et al. In: Harrison’s Principles of Internal Medicine. 15th ed. 2001:1506-1507 . Progressione della IP
  7. 7. IP: Cateterismo cardiaco destro (RHC) Gaine et al. Lancet 1998;352:719
  8. 8. IP: definizione emodinamica Pressione arteriosa polmonare media (PAPm) > 25 mmHg a riposo con RHC PH LIEVE : mPAP = 25-35 mmHg PH MODERATA : mPAP = 36-45 mmHg PH SEVERA : mPAP > 45 mmHg European Heart Journal 2004
  9. 9. IP definizioni
  10. 10. IP: classificazione/definizione 1. Ipertensione Arteriosa Polmonare • Idiopatica • Ereditaria • Uso di farmaci e tossine • Associata a : – Malattie del connettivo – Infezione HIV – Ipertensione portale – Cardiopatie congenite • Ipertensione persistente neonato 3. IP secondaria a pneumopatie/ipossiemia • BPCO • Interstiziopatie • Apnee notturne • Alterazioni dello sviluppo 2. IP secondaria a cardiopatie sx • Atriale o ventricolare • Valvulopatie 4. IP secondaria a tromboembolia cronica 5. Miscellanea postcapillare 1’ Malattia veno occlusiva polmonare, emangiomatosi capillare polmonare European Heart Journal 2009 precapillare precapillare precapillare
  11. 11. IP: Definizione Ecocardiografica <ul><li>Ecocardiografia doppler transtoracica : stima indiretta </li></ul><ul><li>PAPs = ΔP RT + P Atrio dx (Dimensioni Atrio e Vena Cava Inferiore + sua collassabilità) </li></ul><ul><li>- IP Probabile : PAPs >50 mmHg, V RT >3.4 m/sec </li></ul><ul><li>- IP Improbabile : PAPs ≤ 36 mmHg, V RT ≤ 2.8 m/sec e non </li></ul><ul><li>Elementi Ecografici suggestivi </li></ul><ul><li>- IP Possibile : a) 36 mmHg ≤ PAPs ≤ 50 mmHg e 2.8 m/sec ≤ V RT ≤ 3.4 m/sec </li></ul><ul><li>b) Elementi Ecografici suggestivi e PAPs ≤ 36 mmHg, V RT ≤ 2.8 m/sec </li></ul>Eur Respir J. 2009;34(6):1219
  12. 12. IP: Ecocardiografia <ul><li>Elementi suggestivi di IP: </li></ul><ul><li>Emodinamici e Morfologici </li></ul><ul><li>A. Polmonare: V reflusso e T acc. (< 90 msec), Dilatazione </li></ul><ul><li>TAPSE (< 16 mm) </li></ul><ul><li>Atrio e Ventricolo DX, Setto IV </li></ul><ul><li>Versamento pericardico </li></ul><ul><li>Altri </li></ul><ul><li>Eur Respir J. 2009;34(6):1219, Heart 2011; 97:612-622 </li></ul>
  13. 13. IP: Ecocardiografia
  14. 14. IP: Fisiopatologia
  15. 15. IP: patogenesi multifattoriale Squilibrio mediatori vascolari - Vasocostrittori , mitogeni e protrombotici ( Endotelina, Trombossano A2) vs - Vasodilatatori , inibitori delle crescita cellulare e antitrombotici (Ossido Nitrico, Prostacicline e VIP ) Disfunzione o danno Cellule endoteliali polmonari Genetica (BMPR2, ALK1, Endoglina) <ul><li>Vasculopatia costrittiva </li></ul><ul><li>Proliferazione cellule endoteliali e SMC </li></ul><ul><li>Attività Fibroblasti, Cellule infiammatorie e piastrine </li></ul><ul><li>Vasocostrizione </li></ul><ul><li>Fibrosi </li></ul><ul><li>Trombosi </li></ul>Eur Heart Journal 2009; J Am Med Assoc 2000;284:3160–3168 Stimoli : shear stress, Po2, Virus (HIV, HHV-8) Autoimmunità (SSP,LES), Farmaci
  16. 16. IP: Fisiopatologia
  17. 17. IP: anatomia patologica Gruppi 1-3-4-5 : Arteriole distali (< 500 micron): -ipertrofia media - proliferazione ostruttiva intima con sostituzione fibrotica (concentrica, eccentrica) -ispessimento avventizia e talora flogosi - lesioni complesse (plessiformi, dilatazioni, proliferazione capillare) Eur Heart Journal 2009
  18. 18. IP anatomia patologica Gruppo 1': occlusione fibrotica venosa, edema ed emorragia alveolare Gruppo 2 : dilatazione venosa, capillare e linfatica, edema ed emorragia alveolare, talora arteriopatia tipo gruppo-1 (forme reattive) Gruppo 3 : vasocostrizione ipossica, distruzione letto vascolare (enfisema, ILD), talora arteriopatia tipo gruppo-1 Gruppo 4 : trombi tenaci sostituenti intima, stenosi ed occlusione, reti, bande. Aree a valle delle stenosi con arteriopatia tipo gruppo-1. Aree a valle delle occlusioni con circoli collaterali sistemici (bronchiale, costale, diaframmatico, coronarico). Eur Heart Journal 2009
  19. 19. IP: mediatori principali Major pathways involved in the regulation of PVR
  20. 20. UOC Pneumologia Ospedale “C e G Mazzoni” - Ascoli Piceno Direttore: Dott. Riccardo Pela <ul><li>Ipertensione Polmonare: </li></ul><ul><li>Inibitori Endotelina e Vasodilatatori </li></ul><ul><li>Dott. Gianluca Panella </li></ul>
  21. 21. PAH ( gruppo 1 ): farmaci <ul><li>Calcioantagonisti (CCBS): Diltiazem, Nifedipina, </li></ul><ul><li>Amlodipina </li></ul><ul><li>Antagonisti ET1-R (ERA): Bosentan, Ambrisentan </li></ul><ul><li>Inibitori PDE-5 : Sildenafil, Tadalafil </li></ul><ul><li>Prostanoidi : Epoprostenolo, Iloprost, Treprostinil, Beraprost </li></ul>
  22. 22. Terapia PAH (gruppo 1) Eur Heart Journal 2009 Cateterismo destro e test di vasoreattività acuta ( Ossido Nitrico inalato , epoprostenolo e adenosina e.v.) Non - responder Responder (<15%) ERA : Bosentan, Ambrisentan PDE-5 I : Sildenafil, Tadalafil Prostanoids : Iloprost, Treprostinil, Beraprost Epoprostenol CCBs Nifedipina 120-240 mg/die Diltiazem 240-720 mg/die (con controllo ECG/emodinamico) mPAP  10 mmHg  mPAP < 40 mmHg
  23. 23. Terapia PAH(gruppo 1) Major pathways involved in the regulation of pulmonary vascular tone Peinado V. I. et.al. Chest 2008;134:808-814 ECE = endothelin-converting enzyme; ETA = endothelin receptor A; ETB = endothelin receptor B; sGC = soluble guanylate cyclase; GTP = guanosine triphosphate; GMP = guanosine monophosphate; cGMP = cyclic GMP; PDE = phosphodiesterase; PGH2 = prostaglandin H2; PGI2 = prostacyclin; PGI2S = prostacyclin synthase; ATP = adenosine triphosphate; AC = adenylate cyclase; AMP = adenosine monophosphate; cAMP = cyclic AMP.
  24. 24. Via metabolica Endotelina Via metabolica NO Via metabolica Prostaciclina Lume del vaso Cellule endoteliali Pre-proendotelina Proendotelina Endotelina-1 Antagonisti Recettoriali dell’ endotelina Cellule muscolari liscie Vasodilatazione e antiproliferazione Recettore ET B Recettore ET A Inibitori della PDA 5 Ossido Nitrico esogeno Vasodilatazione e antiproliferazione Fosfodiesterasi 5 L-arginina L-citrullina Ossido Nitrico Acido arachidonico Prostaglandina I 2 Derivati della prostaciclina Vasodilatazione e antiproliferazione AMP ciclico Prostaciclina (prostaglandina I 2) PROSTANOIDI
  25. 25. Epoprostenolo ( Flolan  ) <ul><li>- Prostaciclina sintetica per infusione </li></ul><ul><li>e.v continua con CV tunnellizzato </li></ul><ul><li>- Brevissima emivita (t 1/2 3-5 minuti) </li></ul><ul><li>Efficacia in IPAH (APAH e CTEPH): </li></ul><ul><li>NYHA 3-4 </li></ul><ul><li>- Efficacia : sintomi, esercizio, emodinamica </li></ul><ul><li> CO,  RAPm) e sopravvivenza </li></ul><ul><li>- L’interruzione improvvisa può essere </li></ul><ul><li>fatale (rebound PH); problemi per CV </li></ul>Ann Intern Med 1990;112:485–491. N Engl J Med 1996;334:296–302. Ann Intern Med 2000;132:425–434.Circulation 1999;99:1858–1865. Hepatology 1999;30:641–648.Am J Respir Crit Care Med 2003;167:1433–1439.J Heart Lung Transplant 2007;26:357–362.
  26. 26. Iloprost ( Ventavis  ) <ul><li>-Prostaciclina sintetica (inalatoria, endovena) </li></ul><ul><li>-Inalato: azione selettiva per polmone </li></ul><ul><li>-Endovena: simile a epoprostenolo </li></ul><ul><li>-PAH in classe III e IV </li></ul><ul><li>-Efficacia: studio AIR </li></ul><ul><li>-Effetti indesiderati: vasodilatazione, </li></ul><ul><li>ipotensione, tosse, dolori articolari, cefalea, </li></ul><ul><li>Sindrome influenzale </li></ul><ul><li>Eur Heart Jou 2009 </li></ul>Prodose® AAD® system only 2.5 mcg initial dose increase to 5 mcg if 2.5 mcg dose is tolerated maintain at maximum tolerable dose (2.5 mcg or 5 mcg): 6-9 inhalations daily during waking hours
  27. 27. Inhaled Placebo 2.5 or 5.0 ug (6 or 9 x/d, median 30ug/d) Inhaled Iloprost 12 weeks Baseline AIR STUDY N=203 NYHA III-IV PAH, CTPH Risultati Aumento della distanza percorsa (36 m, p=0.004) Miglioramento classe funz. NYHA (p=0.03) Miglioramento Dispnea (p=0.015) Minimo miglioramento dell’emodinamica: PVR (n.s.) N Engl J Med 2002;347:322–329.
  28. 28. Treprostinil ( Remodulin   ) <ul><li>-Analogo epoprostenolo stabile </li></ul><ul><li>a temperatura ambiente </li></ul><ul><li>- Sottocute, endovena , inalato </li></ul><ul><li>(F3) </li></ul><ul><li>- Efficacia : sintomi, esercizio, </li></ul><ul><li>Emodinamica </li></ul><ul><li>-NYHA III e IV </li></ul><ul><li>- Effetti indesiderati : dolore sito </li></ul><ul><li>infusione , effetti vasodilatazione </li></ul>Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension. A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800–804.
  29. 29. Beraprost <ul><li>-Analogo della prostaciclina somministrabile per </li></ul><ul><li>via orale </li></ul><ul><li>-Emivita: 30 - 60 minuti </li></ul><ul><li>-Dosaggio: BID or QUID (20 - 80  g al giorno) </li></ul><ul><li>-Causa tachifilassi  dosaggi crescenti fino a dose max </li></ul><ul><li>-RCTs: miglioramento capacità funzionale non oltre i 6 mesi </li></ul><ul><li>di trattamento, nessun miglioramento emodinamico </li></ul>ALPHABET STUDY: J Am Coll Cardiol 2002;39:1496–1502 .
  30. 30. Via metabolica Endotelina Via metabolica NO Via metabolica Prostaciclina Lume del vaso Cellule endoteliali Pre-proendotelina Proendotelina Endotelina-1 Antagonisti Recettoriali dell’ endotelina Cellule muscolari liscie Vasodilatazione e antiproliferazione Recettore ET B Recettore ET A Inibitori della PDA 5 Ossido Nitrico esogeno Vasodilatazione e antiproliferazione Fosfodiesterasi 5 L-arginina L-citrullina Ossido Nitrico Acido arachidonico Prostaglandina I 2 Derivati della prostaciclina Vasodilatazione e antiproliferazione AMP ciclico Prostaciclina (prostaglandina I 2) Inibitori PDE5 GMP cGMP vasodilatazione Guanylate cyclase NO PDE-5 PDE-5 causa le degradazione di GMP, inibendo la vasodilazione sildenafil promuove vasodilatazione prevendo al degradazione di GMP
  31. 31. <ul><li>- Inibitore selettivo della (cGMP type) PDE-5 </li></ul><ul><li>- Dosaggio : 20-80 mg TID (approvato 20 mg TID) </li></ul><ul><li>-NYHA III e IV (studi non controllati: IPAH, APAH-CTD, </li></ul><ul><li>CHD, CTEPH) </li></ul><ul><li>- Efficacia : SUPER-1 (RCT in PAH: 278 pts -> 20, 40, 80 mg TID) </li></ul><ul><li>miglioramento esercizio, sintomi ed emodinamica </li></ul><ul><li>- Effetti indesiderati: vasodilatazione, cefalea, flushing, epistassi </li></ul>(SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. New Engl J Med 2005;353:2148–2157. Sildenafil ( Revatio  )
  32. 32. Tadalafil ( Adcirca  ) <ul><li>- Inibitore selettivo PDE-5 (cGMP type) </li></ul><ul><li>- Dosaggio : 40 mg (approvato in monosomministrazione) </li></ul><ul><li>- PHIRST-RCT: 406 pts NYHA I-IV (I-HPAH, APAH-CTD,-CHD, -HIV, -anorex.) –> 5, 10, 20 e 40 mg/day </li></ul><ul><li>-Efficacia : miglioramento esercizio, sintomi, emodinamica e </li></ul><ul><li>tempo di peggioramento clinico (40 mg/day) </li></ul><ul><li>- Effetti indesiderati: vasodilatazione, cefalea, flushing, epistassi </li></ul>Galie` N, Brundage B, Ghofrani A, Oudiz R, Simonneau G, Safdar Z, Shapiro RS, White J, Chan M, Beardsworth A, Frumkin LR, Barst R. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119:2894–2903.
  33. 33. Endotelina mediatore chiave nella patogenesi della PAH Via metabolica Endotelina Via metabolica NO Via metabolica Prostaciclina Lume del vaso Cellule endoteliali Pre-proendotelina Proendotelina Endotelina-1 Antagonisti Recettoriali dell’ endotelina Cellule muscolari liscie Vasodilatazione e antiproliferazione Recettore ET B Recettore ET A Inibitori della PDA 5 Ossido Nitrico esogeno Vasodilatazione e antiproliferazione Fosfodiesterasi 5 L-arginina L-citrullina Ossido Nitrico Acido arachidonico Prostaglandina I 2 Derivati della prostaciclina Vasodilatazione e antiproliferazione AMP ciclico Prostaciclina (prostaglandina I 2) Antagonisti recettoriali Endotelina Vasocostrizione Prolifera zione Fibrosi Infiammazione Ipertrofia ET Trp Ile Ile Asp Leu His Cys Tyr Val Phe Cys Cys Cys Ser Glu Ser Ser Leu Met Asp Lys N C
  34. 34. Recettori ET Opitz CF, Ewert R, Kirch W et al Eur Heart J 2008; 29(16):1936-1948
  35. 35. Recettori ET
  36. 36. Bosentan ( Tracleer  ) Black. Circulation 2003; Bauer. Circulation 2002; Cardillo. Hypertension 1999; Clozel M. J Cardiovasc Pharmacol 1995; Chen. J Appl Physiol 1995 ET B ET A Cellula muscolare liscia ET Effetti ET bloccati Duplice blocco con bosentan ET B ET A bosentan ET B ET A Cellula endoteliale ET Vasocostrizione, proliferazione, ipertrofia. PAH ET B ET A Cellula endoteliale Cellula muscolare liscia
  37. 37. Bosentan ( Tracleer  ) <ul><li>-Antagonista recettoriale ET (A e B) </li></ul><ul><li>-RCTs in IPAH, APAH (CTD, HIV e CHD): Pilot, BREATHE 1->5, EARLY </li></ul><ul><li>-Efficacia: sintomi (WHO-FC), esercizio, emodinamica, variabili Ecocardio e Tempo </li></ul><ul><li>di peggioramento clinico </li></ul><ul><li>-Orale bid (62,5 mg x 2 per 1 mese. Poi 125 mg x 2), WHO-FC 2 -> 4 </li></ul><ul><li>-Effetti indesiderati: funzione epatica (max 10% dose dipendente), </li></ul><ul><li>diminuzione Hb e Spermatogenesi </li></ul>Lancet 2001;358:1119–1123. N Engl J Med 2002;346:896–903. Eur Respir J 2004;24:353–359. Circulation 2006;114 Lancet 2008;371:2093–2100.
  38. 38. Ambrisentan ( Volibris  ) Dupuis J. Lancet 2001; 358(9288):1113-1114
  39. 39. <ul><li>- Antagonista recettoriale selettivo ET-A (SM-Cells) </li></ul><ul><li>- RCTs ARIES 1 e ARIES 2 (IPAH, APAH-CTD e HIV) </li></ul><ul><li>- Efficacia: sintomi, esercizio, emodinamica, tempo di peggioramento clinico </li></ul><ul><li>-WHO-FC 2 e 3: orale monodose (5 mg e 10 mg) </li></ul><ul><li>-Bassa incidenza di anomalie funzione epatica (max 3%) </li></ul>J Am Coll Card 2005;46: 529-35 - Circulation 2008;117:3010–3019. Dupuis J. Lancet 2001; 358(9288):1113-1114 Ambrisentan ( Volibris  )
  40. 40. Ipertensione polmonare <ul><li>GRAZIE </li></ul>

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