Pulmonary hypertension

1
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
• 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 348500
5
Mechanisms of pulmonary hypertension

• Decreased endogenous vasodilator activity
• eNOS reduced in PA of PPH
• decreased PGI2 excretion
• 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 1022782

• 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 20490
Blood vessel alveolar lumen
8
TxA2 and 5-HT in pulmonary hypertensionMacLean
(1999) TIPS 20490
TP TxA2 receptor
TP agonist
9
Mechanisms of PHArcher Rich (2000) Circulation
1022782
Genotype, triggers
10
Angiopoietin-1

• 70 kDa 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

11
Angiopoietin-1 levels correlate with PVRin
pulmonary hypertensionDu et al. (2003) NEJM
348500
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 348500
Ang-1 controls
14
Signalling molecules in PH Du et al. (2003) NEJM
348500
PH control
Ang-1 only in PH Ang-2 little
change TIE-2 little change BMPR absent in
PH
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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

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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 360141
20
Sildenafil Lowers Pulmonary Vascular Resistance
in neonatal pigs
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
Endothelin antagonists - Bosentan improves
exercise tolerance in severe PH Channick et al.
(2001) Lancet 358, 1119
22
Simvastatin attenuates pulmonary artery
neointimal formation Nishimura et al. (2002)
AJRCCM 166,1403-1408

• Normal rat intra-acinar artery
• 50 narrowing 4 weeks after injury
• C D Injury plus simvastatin

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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
24
Decrease in eNOS mRNA and its restoration by
simvastatin Nishimura et al. (2002) AJRCCM
166,1403-1408
PMV Injury vehicle control PMS injury plus
Statin
25
Mechanisms of PHArcher Rich (2000) Circulation
1022782
Genotype, triggers