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Pulmonary hypertension

Pulmonary hypertension. Normal pulmonary vascular bed high-flow low-pressure capacity to dilate and recruit unused vasculature in order to accommodate increases in blood flow normal resting 14 mmHg Pulmonary hypertension

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Pulmonary hypertension

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  1. Pulmonary hypertension • Normal pulmonary vascular bed • high-flow • low-pressure • capacity to dilate and recruit unused vasculaturein order to accommodate increases in blood flow • normal resting 14 mmHg • Pulmonaryhypertension • capacity to dilate is lost resulting in elevated pulmonary artery pressure • pulmonary hypertension 25 mmHg rest

  2. Pulmonary hypertension - pathology • Pulmonary arterial hypertrophy • VSM proliferation • luminal narrowing • intimal hyperplasia in small vessels • thrombotic lesions • intrapulmonary venular fibrosis • Hydrostatic oedema

  3. Pulmonary Hypertension • primary pulmonary hypertension (PPH) • Familial or idiopathic • Very rare • secondary PH • COPD, emphysema, pulmonary fibrosis, immune diseases, preterm birth • Not clear if mechanisms common

  4. Pulmonary vessel hyperplasia in PHDu et al. (2003) NEJM 348:500

  5. Mechanisms of pulmonary hypertension • Decreased endogenous vasodilator activity • eNOS reduced in PA of PPH • decreased PGI2excretion • Impaired K+ channel activity • Increased vasoconstrictor activities • plasma & tissue ET-1 raised in PH • Increased platelet derived activities • 5-HT • TxA2

  6. K+ channel abnormalities in Primary PH (PPH)Archer & Rich (2000) Circulation 102:2782 • Decreased Kv1.5 in PPH • Impaired K+ current in PPH SPH – secondary PH Donor and NPH - normals

  7. 5-HT in pulmonary hypertensionMacLean (1999) TIPS 20:490 Blood vessel alveolar lumen

  8. TxA2 and 5-HT in pulmonary hypertensionMacLean (1999) TIPS 20:490 PH TP TP 5-HT1 Arterial contraction Arterial contraction 5HT1 agonist TP – TxA2 receptor TP agonist

  9. Mechanisms of PHArcher & Rich (2000) Circulation 102:2782 Genotype, triggers

  10. Angiopoietin-1 • 70 kDa angiogenic factor essential for lungvascular development • Recruits muscle cells to endothelial tubes, creating arterioles • Produced by smooth-muscle cells and pericytes • Ang-1 k/o die in utero • little arterialdevelopment in the lungs and other organs • Ang-1 minimally detectablein normal human lung after development

  11. Angiopoietin-1 levels correlate with PVRin pulmonary hypertensionDu et al. (2003) NEJM 348:500 Ang-1 mRNA protein

  12. Signalling mechanisms in PH Some PPH : • Mutations in Bone morphogenetic protein receptor (BMPR) • IS BMPR INVOLVED IN OTHER FORMS OF PH?

  13. Angiopoietin decreases BMPR expressionin cultured pulmonary artery endothelial cellsDu et al. (2003) NEJM 348:500 + Ang-1 controls

  14. Signalling molecules in PH Du et al. (2003) NEJM 348:500 PH control Ang-1 – only in PH Ang-2 – little change TIE-2 – little change BMPR – absent in PH

  15. Signalling - summary • BMPR suppressive in PH • Mutation associated with PH • Angiopoetin-1 implicated as causal in pulmonary hypertension • Induces tissue growth and remodelling • Expressed in PH • Suppresses BMPR expression

  16. Pulmonary hypertension therapies • Vasodilators • Ca2+ channel blockers nifedipine, diltiazem • Less than 30% useful response - reduction in PA pressure without reducing cardiac output • continuous i.v. PGI2 • improvement in severe PPH • antiplatelet effects? • Antiproliferative? • Tolerance • inhaled iloprost (stable PGI2 analog) • inhaled NO

  17. Inhaled Iloprost for Severe Pulmonary Hypertension Olschewski et al. (2002) NEJM 347, 322

  18. Inhaled NO in neonatal PH (full term)Tworetsky et al. (2001) Lancet 357, 118 PaO2 kPa • Improved oxygenation in premature neonates • No increased survival PAP/SAP Dose ppm

  19. Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn Moya et al. (2002) Lancet; 360:141 Changes in postductal oxygen saturation during dose escalation of o-nitrosoethanol gas, maintenance, and shut off

  20. Sildenafil Lowers Pulmonary Vascular Resistance in neonatalpigs Shekerdemian et al. (2000) AJRCCM 165, 1098-1102 drug 30 25 20 15 control meconium Mean PA pressure (mmHg) nitric oxide sildenafil 0 60 120 180 240 Time (min)

  21. Change in 6-min walking distance Endothelin antagonists - Bosentan improves exercise tolerance in severe PHChannick et al. (2001) Lancet 358, 1119

  22. Simvastatin attenuates pulmonary artery neointimal formationNishimura et al. (2002) AJRCCM 166,1403-1408 • Normal rat intra-acinar artery • 50% narrowing 4 weeks after injury • C +D Injury plus simvastatin

  23. Simvastatin prevents the development of pulmonary arterial hypertensionNishimura et al. (2002) AJRCCM 166,1403-1408 PMV – pneumonectomy, monocrotaline plus vehicle PMS – injury plus Statin Numbers indicate treatment days after injury

  24. Decrease in eNOS mRNA and its restoration by simvastatinNishimura et al. (2002) AJRCCM 166,1403-1408 PMV – Injury + vehicle control PMS – injury plus Statin

  25. Mechanisms of PHArcher & Rich (2000) Circulation 102:2782 Genotype, triggers

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