Pulmonary hypertension part 1 Flashcards
What is pulmonary hypertension
Narrowing of pulmonary arteries, right ventricular hypertrophy and can lead to right heart failure
What causes pulmonary hypertension
Some common underlying causes of pulmonary hypertension include high blood pressure in the lungs’ arteries due to some types of congenital heart disease, connective tissue disease, coronary artery disease, high blood pressure, liver disease (cirrhosis), blood clots to the lungs, and chronic lung diseases like emphysema. Genetics also play a role.
Pulmonary hypertension can happen in association with many other diseases, such as lung disease and heart disease. Heart failure is common in pulmonary hypertension.
Describe right heart catheterization to measure pulmonary hypertension
The diagnosis of PAH is confirmed by
mPAP (mean pulmonary artery pressure) greater than or equal 25 mmHg at rest
PCWP (pulmonary arterial wedge pressure) less than or equal to 15 mmHg
A thin catheter is inserted into a vein in the groin or in the neck after the skin above the area is cleaned and numbed with medication. Then the catheter is advanced into the heart. The catheter is equipped to take pressure measurements in the chambers of the right heart as will as the pulmonary arteries. The physician is also able to measure how much oxygen is in your blood and your cardiac output (the amount of blood your heart pumps).
Describe vascular remodelling in PH
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 angioproliferative (plexiform) lesions
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
What is PH associated with
≥ 25 mmHg [mean pulmonary arterial pressure (PAP), normal 14 3 mmHg]
Genetic predisposition
Drugs
Heart diseases e.g. aortic valve disease, left heart failure, 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
Describe type 1 PAH
Rare disorder (15-20 cases per million)
Heritable accounts for 15-20% of cases
mutations in bone morphogenetic protein (BMP) type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-β superfamily
Leads to abnormal growth responses to TGF-β
2-4 times more common in women
Mean age of onset 45 y
Prevalence higher in at risk groups (HIV, sickle cell, parasitic infections [developing world])
4 components to vascular remodelling in PH
Vascular obstruction- chronic vasoconstriction, endothelial dysfunction, inflammation, migration and ECM synthesis
Cellular and molecular mechanisms: PGI2, (NO-sGC- cGMP axis), PDE, endothelin, serotonin, K+ and Ca2+ channels
Abnormal proliferation due to TGF B, BMP (type 1), growth factors like PDGF and FGF, MMPs, cytokines and chemokines
Hypoxia induced vasoconstriction and remodelling- HIF, ROS, TRPC
Growth factor signalling in PAH via PDGF and FGF
physiological and pathophysiological stimuli such as genetic factors, hypoxia, toxins and drugs act on pulmonary vascular cells like endothelial cells and vascular smooth muscle cells
PDGF is a strong mitogen for pulmonary vascular smooth muscles, as it prevents them undergoing apoptosis
FGF also binds
goes through PI3K, PKB, AKT pathway
increases survival and proliferation
causes vascular remodelling- through smooth muscle cell proliferation, endothelial cell dysfunction and plexiform lesions
Inflammation mediated vascular remodelling in PAH
Inflammation and infection activate MCP-1, CCL2 and 5, IL 1, IL 6, RANTES, CCR1 etc
Activates macrophages and T cells
All release specific cytokines, chemokines and growth factors associated with PAH
What is Group 3 pulmonary hypertension caused by
Group 3 PH due to lung diseases and hypoxia/hypoxaemia
Chronic lung disease can lead to prolonged exposure to alveolar hypoxia
Remodelling of pulmonary vasculature
Increased pulmonary arterial pressure and right ventricular hypertrophy
What is HIF and its structure
HIF – hypoxia inducible factor
transcription factor regulates hypoxia induced gene transcription
heterodimer, HIF-1α and HIF-1β subunits
HIF-2α
HIF-1/2α levels are tightly regulated by O2 and are degraded in normoxia, but stabilised in hypoxia
3 types:
HIF 1 alpha- bHLH (DNA binding), PAS domain, ODD (O2 dependent stabilisation), NAD (O2 dependent transactivation), CAD
HIF 2 alpha
HIF 1 beta-
bHLH= basic helix loop helix PAS = per-arnt-sim TAD= transactivation domain C-terminus or N-terminus ODD= oxidation dependent degradation domain
Describe HIF-1 regulation by post translational modification
Normoxia - 3 proline hydroxylase enzymes (PHDs) in the presence of O2 and cofactors hydroxylate HIF
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
Describe how HIF is activated by growth factors
Growth factor mediated pathways e.g. insulin, IGF-1, PDGF increase HIF protein synthesis in normoxia
Receptor tyrosine kinase signalling increased
PI3K/AKT/mTOR pathway
Ras/MEK/ERK pathway
mTOR: mammalian target of rapamycin
PI3K: phosphoinositide 3 kinase
AKT: Protein kinase B
ERK : extracellular regulated kinase/MAPK: mitogen activated protein kinase
what are some HIF target genes expressed in pulmonary arterial smooth muscle cells in PH
EDN1- produces endothelin and causes contraction
KCNA5 and KCNB1 code voltage gated K+ channels and increase K+ in the cell
TRPC1 and 6 code transient Ca2+ channels and increase Ca in the cell
NHE1 increase sodium hydrogen exchanger, increasing pHPDK1 codes pyruvate dehydrogenase kinase and causes glycolysis
How does this lead to pulmonary hypertension
Chronic continuous hypoxia acts on the pulmonary artery activating media SMCs.
This activates HIF-1 alpha
Which causes hypertrophy, hyperplasia and contraction, leading to pulmonary hypertension
Chronic continuous hypoxia can also act on the endothelial cells of the intima of the pulmonary artery, increasing HIF 2 alpha, increasing EDN1
This increases hypertrophy, hyperplasia and contraction
Leading to pulmonary hypertension
