Pulmonary hypertension Normal pulmonary vascular bed highflow lowpressure
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 mm. Hg • Pulmonary hypertension – capacity to dilate is lost resulting in elevated pulmonary artery pressure – pulmonary hypertension 25 mm. Hg rest
Pulmonary hypertension - pathology • Pulmonary arterial hypertrophy – VSM proliferation • luminal narrowing – intimal hyperplasia in small vessels – thrombotic lesions • intrapulmonary venular fibrosis • Hydrostatic oedema
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
Pulmonary vessel hyperplasia in PH Du et al. (2003) NEJM 348: 500
Mechanisms of pulmonary hypertension • Decreased endogenous vasodilator activity – e. NOS reduced in PA of PPH – decreased PGI 2 excretion – Impaired K+ channel activity • Increased vasoconstrictor activities – plasma & tissue ET-1 raised in PH – Increased platelet derived activities • 5 -HT • Tx. A 2
K+ channel abnormalities in Primary PH (PPH) Archer & Rich (2000) Circulation 102: 2782 • Decreased Kv 1. 5 in PPH • Impaired K+ current in PPH SPH – secondary PH Donor and NPH - normals
5 -HT in pulmonary hypertension Mac. Lean (1999) TIPS 20: 490 Blood vessel alveolar lumen
PH 5 -HT 1 TP TP Tx. A 2 and 5 -HT in pulmonary hypertension Mac. Lean (1999) TIPS 20: 490 TP – Tx. A 2 receptor Arterial contraction TP agonist 5 HT 1 agonist
Mechanisms of PH Archer & Rich (2000) Circulation 102: 2782 Genotype, triggers
Angiopoietin-1 • 70 k. Da angiogenic factor essential for lung vascular development – Recruits muscle cells to endothelial tubes, creating arterioles • Produced by smooth-muscle cells and pericytes • Ang-1 k/o die in utero – little arterial development in the lungs and other organs • Ang-1 minimally detectable in normal human lung after development
Angiopoietin-1 levels correlate with PVR in pulmonary hypertension Du et al. (2003) NEJM 348: 500 Ang-1 m. RNA protein
Signalling mechanisms in PH Some PPH : – Mutations in Bone morphogenetic protein receptor (BMPR) • IS BMPR INVOLVED IN OTHER FORMS OF PH?
Angiopoietin decreases BMPR expression in cultured pulmonary artery endothelial cells Du et al. (2003) NEJM 348: 500 + Ang-1 controls
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
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
Pulmonary hypertension therapies • Vasodilators – Ca 2+ channel blockers nifedipine, diltiazem • Less than 30% useful response - reduction in PA pressure without reducing cardiac output – continuous i. v. PGI 2 • • improvement in severe PPH antiplatelet effects? Antiproliferative? Tolerance – inhaled iloprost (stable PGI 2 analog) – inhaled NO
Inhaled Iloprost for Severe Pulmonary Hypertension Olschewski et al. (2002) NEJM 347, 322
Inhaled NO in neonatal PH (full term) Tworetsky et al. (2001) Lancet 357, 118 Pa. O 2 • Improved oxygenation in premature neonates • No increased survival k. Pa PAP/SAP Dose ppm
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
Sildenafil Lowers Pulmonary Vascular Resistance in neonatal pigs Shekerdemian et al. (2000) AJRCCM 165, 1098 -1102 Mean PA pressure (mm. Hg) drug 30 25 control meconium 20 nitric oxide 15 sildenafil 0 60 120 180 Time (min) 240
Endothelin antagonists - Bosentan improves exercise tolerance in severe PH Channick et al. (2001) Lancet 358, 1119 Change in 6 -min walking distance
Simvastatin attenuates pulmonary artery neointimal formation Nishimura et al. (2002) AJRCCM 166, 1403 -1408 (A) Normal rat intra-acinar artery (B) 50% narrowing 4 weeks after injury (C) C +D Injury plus simvastatin
Simvastatin prevents the development of pulmonary arterial hypertension Nishimura et al. (2002) AJRCCM 166, 1403 -1408 PMV – pneumonectomy, monocrotaline plus vehicle PMS – injury plus Statin Numbers indicate treatment days after injury
Decrease in e. NOS m. RNA and its restoration by simvastatin Nishimura et al. (2002) AJRCCM 166, 1403 -1408 PMV – Injury + vehicle control PMS – injury plus Statin
Mechanisms of PH Archer & Rich (2000) Circulation 102: 2782 Genotype, triggers
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