Pulmonary Hypertension I Flashcards
Define Pulmonary Hypertension
Narrowing of pulmonary arteries (increased vasocon), right ventricular hypertrophy (due to backflow pressure into right ventricle) = high BP of pulmonary artery in the lungs
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What can Pulmonary Hypertension lead to?
can lead to right heart failure
what is a Right Heart Catheterisation and why is it done? (4)
-BP measured through cuffs - in GP’s or at home
-Cannot measure the BP in lungs like this so
-Right Heart Catheterisation is required to confirm the diagnosis of PAH
- not done routinely: need to put in a catheter in femoral/jugular vein to feed it into pulmonary artery (minimally invasive - but still invasive) = not many diagnoses of PAH since it is diff to carry out
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What is PAH defined by? (2)
meanPAP =/greater than 25mmHG at rest
PCWP =/less than 15mmHg
(changes in america)
Vascular Remodelling in PH + underlying causes (5)
- PH is characterised by sustained vasoconstriction and a progressive obliteration of small resistance pulmonary arteries and arterioles
- Medial thickening, intimal fibrosis and the formation of (concentric remodelling - area of wall has equal thickness) or angioproliferative
(plexiform) lesions
Plexiform =type 1 PAH/classic lesion
- Inflammation and endothelial dysfunction and pulmonary artery endothelial cell apoptosis/dysfunction are thought to play an important early role in disease pathogenesis
- Subsequent proliferation and migration of medial cells including smooth muscle cells, fibroblasts and PA-EC drives the pulmonary vascular remodelling
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Pulmonary Hypertension causes (8)
- ≥ 25 mmHg [mean pulmonary arterial pressure (PAP), normal 14 +/- 3 mmHg]
- Genetic predisposition
- Drugs
- Heart diseases e.g. aortic valve disease, LHF, mitral valve disease
- Liver diseases, rheumatic disorders, lung conditions e.g. COPD, pulmonary fibrosis
- Thromboembolic disease
- High altitude living (low oxygen conditions)
-PH found in multiple clinical conditions – clinically classified into 5 groups
How many types of PAH? - WHO classification (5)
5 groups
1) Pulmonary Arterial Hypertension PAH
- idiopathic
-heritable
-drugs + toxins
- HIV etc.
-newborn
1) Pulmonary veno-occulsive disease and/or pulmonary capillary haemangiomatosis
2) Pulmory HT due to LH disease
3) PHT due to lung diseases and or/hypoxaemia
4) Chronic thromboembolic PHT
5) P HT w/unclear and/or multifactorial mechanisms
Group 1 PAH (5)
- Rare disorder (15-20 cases per million)
- Heritable accounts for 15-20% of cases
– mutations in bone morphogenetic protein (BMPR-II), a receptor for the (TGF)-β superfamily
– Leads to abnormal growth responses to TGF-β - 2-4 times more common in women (esp younger women)
- Mean age of onset 45 y
- Prevalence higher in at risk groups (HIV, sickle cell, parasitic infections [developing world])
Vascular remodelling in PAH from healthy to PAH (3)
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(-chronic vasocon
-prolif + apoptosis
-Migration + ECM synth
-Disturbed metabolism
-Endothelial Dysfun
-in-situ thrombosis
-inflam)
basically dysreg of vascular tone = imbalance of vasocons’s + dilators , abnormal prolif (upreg of genes), and hypoxia-induced vasomotion + remodelling (because reduced lumen = red o2)
Growth factor signalling in PAH (3)
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PDGF + FGF - activate tyrosine kinase r = PI3K = PKB Akt cascade
(basically transcription + genes activated that affect cellular processes)
= increased PROLIFERATION, SURVIVAL + MIGRATION caused
Inflammation-mediated vascular remodelling in PAH (3)
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1) infection/inflammation = cytokine release
2) = Activation of immune cells
3) immune cell infiltration(e.g. macrophages, monocytes, T cells) in vessel wall
Group 3 PH (4)
Chronic lung disease can lead to prolonged exposure to alveolar hypoxia
due to lung diseases and hypoxia/hypoxaemia (response to this)
Remodelling of pulmonary vasculature
=
Increased pulmonary arterial pressure and right ventricular hypertrophy
HIF – hypoxia inducible factor (5)
mediates the hypoxic response
– TF regulates hypoxia induced gene transcription
– heterodimer, HIF-1α and HIF-1β subunits
– HIF-2α (isoform) - so 1a or 2a can bind to 1b
– HIF-1/2α levels are tightly regulated by O2 and are degraded in normoxia, but stabilised in hypoxia
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HIF subunits binding domains (4)
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bHLH= basic helix loop helix
PAS = per-arnt-sim
TAD= transactivation domain C-terminus or N-terminus
ODD= oxidation dependent degradation domain
KEY SLIDE: HIF-1 regulation by postranslational modification in normoxia + hypoxia (4)
Normoxia
1) 3 proline hydroxylase enzymes (PHDs) in the presence of O2 and cofactors hydroxylate HIF-1apha
2) Recognition by von Hippel Lindau (VHL) protein – an E3 ligase which targets HIF for degradation via ubiquitination
Hypoxia – PHDs inactive, HIF translocates to nucleus
= Activates genes involved in angiogenesis, cell migration and metabolism
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