Basic Science of PAH Flashcards
What are the different types of PH?
Pulmonary Arterial HTN–rare progressive severe syndrome, low prognosis for survival
left sided congenital heart disease
COPD & lung disease
thromboembolic PH-patients need anticoagulant therapy
What are the subclassifications of PAH, the rare & severe syndrome?
- idiopathic PAH
- heritable/familial PAH
- Drug or Toxin induced PAH
- Atypical
- Persistent PAH of newborn
What falls into the category of atypical PH?
HIV infection, portal hypertension, congenital heart diseases, connective tissue disease, Schistosomiasis chronic hemolytic anemia
What are some mutations that can contribute to heritable/familial PAH?
- Type 2 Bone Morphogenetic Receptor (BMPR2)
- Mutation of Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1)
- 5-HT Transporter Polymorphisms
- microRNA controlling gene expression
T/F Patients with PH often need anticoagulant therapy.
True. Can promote thromboembolism b/c of the remodeling of the pulmonary arteries.
How does ASD lead to PH?
atrial septal defect
get shunting of blood from left–>right.
right heart gets overwhelmed, get a ton of blood in the pulmonary arteries
get HTN & remodeling of these arteries.
What is an example of a drug/toxin that induced pulmonary arterial hypertension?
anorexigens…drugs that people were taking for a period of time to kill the appetite & lose weight.
1/1000 were affected.
What is a new treatment for persistent PH of a newborn, a form of severe PAH?
inhaled NO
Type 2 bone morphogenic receptor is a part of what family of receptors?
transforming growth factor beta family of receptors
What happens with the BMPR2 mutation?
if this is normally stimulated it decreases proliferation & enhances apoptosis.
When it is downregulated in idiopathic or heritable PAH….it can’t decrease these things…get thicker arteries & hypertension.
What is alteration in microRNA expression a deal with PH?
this controls expression of proteins, binds mRNA.
How does the regulation of ventilation/perfusion work in the lungs?
- when an alveolus is open & filled with oxgyen…more blood will be directed there.
- when an alveolus is more closed or holding less oxygen–>the capillaries will constrict & redirect blood flow elsewhere.
What is hypoxic pulmonary vasoconstriction? When does this occur?
this when blood vessels will constrict in the absence of oxygen
sorta like what happens in skeletal muscle
happens in the lung at high altitudes
What are the 3 mechanisms proposed for hypoxic pulmonary vasoconstriction?
- Redox hypothesis
- ROS hypothesis
- Energy state/AMPK hypothesis
Describe the redox hypothesis for HPV.
hypoxia affects mitochondria & you get activation of NADPH oxidase
ROS decreases, more reduced redox state
inhibition of K+ channels
membrane depolarization, opening of Ca++ channels.
More calcium–>vasoconstriction
Describe the ROS hypothesis.
inhibition of mitochondrial oxidative phosphorylation
ROS increases
get more release of calcium from SR
increase in calcium & vasoconstriction
Describe the Energy state/ampk hypothesis.
inhibition of mitochondrial oxidative phosphorylation due to the hypoxia
increased activation of AMPK
increased release of Ca++ from SR via RyR
What are the factors contributing to the elevated Pulmonary Arterial Pressure in PAH patients?
- vasoconstriction
- remodeling–luminal obstruction
- propensity of thrombosis
Note: can see pulmonary arteries inflated on chest xray often
What is required for diagnosis of PAH?
catheterization to see right heart & pulmonary arteries–assess pulmonary artery pressure:
>25 mmHg at rest
capillary wedge pressure: 3 wood units
What is the equation for peripheral vascular resistance?
PVR=(Mean PAP-PA Wedge Pressure)/CO
Is there a less invasive method for diagnosing PAH?
they are moving towards only requiring echocardiography as it is less invasive, but still required catheterization
Is there a PAP during exercise required for diagnosis?
no, b/c even tho RV will contract vigorously during exercise the pulmonary arteries may dilate as a compensation
may or may not go up.
technically: >30 mmHg during exercise
What is involved in capillary wedge pressure? What must it be for a diagnosis of PAH?
cardiac catheter is used & a balloon is inflated in a pulmonary vessel to block the flow & measure residual flow.
**need a low CWP b/c you need to exclude left heart disease induced PH
How do you measure cardiac output?
via doppler flow
What are the most important current therapies for PAH?
- prostanoids
- endothelin receptor blockers
- phosphodiesterase inhibitors
Other therapies for PAH?
L-type Ca++ channel blockers
drugs targeting NO & cGMP signaling pathways
What is an endothelin receptor blocker? What does it do?
Ex: Bosentan
improves QOL & survival
nonselective ET1A & ET1B type receptor
**helps with remodeling of pulmonary vasculature & diameter of the arterial wall
What is an example of a phosphodiesterase inhibitor?
sildenafil
How do endothelin receptor blockers work in the pathway?
Block ET1A & ET1B receptors on smooth muscle cells.
These receptors when activated cause vasoconstriction.
BLock this–>treat PAH
How do prostanoids work in the pathway to treat PAH?
Prostacyclin triggers receptor on smooth muscle cell
adenylate cyclase activated & you get more cAMP.
protein kinase is activated & vasodilation is promoted.
How do phosphodiesterase inhibitors work to cause vasodilation in PAH?
PDE5 inhibitors stop the breakdown of cGMP.
This promotes thea ctivation of protein kinase A & vasodilation.
What is used to induce PAH in a rat?
monocrotaline-single subcu injection
What is the way you can get plexiform lesions in a mouse?
only way–>induce chronic hypoxia + sugen (VEGF inhibitor)
How do you induce chronic hypoxia in a rat or mouse?
10% O2 for the mouse for 2-4 weeks.
