Basic Science of Pulmonary HTN-Leblanc

Question 1

(blank) is a rare progressive and severe syndrome (1-50/1,000,000) with a very low prognosis for survival

Answer 1

Pulmonary Arterial Hypertension (PAH)

Question 2

Pulmonary hypertension is associated with (blank) heart disease such as congenital heart disease.

Answer 2

left

Question 3

Pulmonary hypertension is associated with (blank) disease and or (blank)

Answer 3

lung disease

hypoxia

Question 4

What are the 5 PAH classifications?

Answer 4

1. Idiopathic PAH (iPAH)
2 Heritable or Familial PAH
3. Drug or toxin induced
4. Atypical  (HIV inection, portal HTN, Congential heart disease, CT disease, Schistosomiasis chronic hemolytic anemia)
5. Persistent PH of the newborn

Question 5

What is down regulated in >80% of patients with familial/Heritable PAH?

Answer 5

BMPR2 (type 2 bone morphogenic receptor), type of growth factor B family receptor)

Question 6

How common is it to find BMPR2 downregulated in idiopathic PAH?

Answer 6

10-20%

Question 7

What does BMPR2 do?

Answer 7

decreases vascular smooth muscle proliferation and increases apoptosis. SO when you lose this you have thicker walls and increased hypertension

Question 8

What are some other ways (besides BMPR2) cause familial PAH?

Answer 8

• mutation of activin A receptor type II
• 5-HT transporter polymorphisms
• MicroRNAs controlling Gene expression

Question 9

In hypoxic pulmonary hypertension, what happens in response to low 02 levels in the lungs?
What mediates this?

Answer 9

decreased blood flow (i.e vasoconstriction) in respose to low O2 levels (only occurs in the lungs)

K channels (directly sensitive to O2 levels) and non voltage gate Ca-channels (one of the reasons you get altitude sickness)

Question 10

What are the three postulated mechanisms for Hypoxic pulmonary vasoconstriction?

Answer 10

Redox hypothesis
ROS hypothesia
Energy State/AMPK hypothesis

Question 11

What is the redox hypothesis?

Answer 11

inhibition of mitochondrial oxidative phosphorylation -> more reduced redox state-> inhibition of Kv channels-> activation of L-type Ca2+ channels

Question 12

What is the ROS hypothesis?

Answer 12

inhibition of mitochondrial oxidative phosphorylation-> increased generation of O2 for complex III-> multiple potential targets

Question 13

What is the energy state/AMPK hypothesis?

Answer 13

inhibition of mitochondrial oxidative phosphorylation -> increased AMP/ATP activation of AMPK-> cADPR-mediated Ca2+ release from SR RyR

Question 14

What are factors contributing to elevating pulmonary arterial pressure in PAH patients?

Answer 14

1. Enhanced vasoconstriction
2. Partial or complete luminal obstruction due to remodeling of all layers of proximal and distal pulmonary arteries characterized by enhanced proliferation, reduced apoptosis, and infiltration of inflammatory and progenitor cells
3. propensity for thrombosis

Question 15

How do you diagnose PAH?

Answer 15

-right heart and pulmonary arterial catheterization or less invasive echocardiography

Question 16

A pumonary arterial catherization of more than (blank) mm HG at rest and (blank) mmHg during exercise inicates PAH.

Answer 16

25

30

Question 17

A capillary wedge pressure of less than (blank) mm Hg indicates PAH

Answer 17

15 mm Hg

Question 18

A PVR greater than (blank) wood units indicates PAH

Answer 18

3 wood units

Question 19

What is the equation for pulmonary vascular pressure?

Answer 19

PVR= (mean PAP - PA wedge pressure)/ CO

Question 20

How can you treat PAH?

Answer 20

Prostanoids (PGI2 analogues)
Endothelin receptor blockers (Bosentan)
Phosphodiesterase Inhibitors (PDE5 blocker AKA Sildenafil)
L-type Ca2+ channel blockers (nifedipine, diltiazem)
Drugs targeting the NO and cGMP signaling pathways

Question 21

What are the effects of prostanoids?

Answer 21

Causes vasodilation

GI tract side effects

Question 22

What are the effects of endothelin receptor blockers (bosentan)?

Answer 22

endothelin causes vasoconstriction and has effects on cellular proliferation
-first to prove improved QOL and survival

Question 23

What are the effects of phosphodiesterase inhibitors (PDE5 blockers such as Sildenafil)?

Answer 23

improve morbidity and mortality rate

Question 24

Why are L-type Ca2+ channel blockers not used as much for PAH?

Answer 24

because only a small fraction (10-20%) of pnts respond to CCB’s
You have to worry about systemic hypotension

Question 25

Nearly all the PAH therapies target the enhanced (blank) properties of small (blank) and the benefits are extremely limited in the terms of survival and morbidity rates.

Answer 25

vasoactive properties

PA

Question 26

How do we tackle treatment of PAH?

Answer 26

• preclinical studies with validated animal
• studies w/ human pulmonary arterial tissues and lungs
• Gene research
• clinical multi-center trials
• test hypotheses that target both pulmonary arterial modeling and right heart failure

Question 27

Increased (blank) causes contraction and proliferation to cause sustained pulmonary vasoconstriction and pulmonary vascular remodeling

Answer 27

intracellular calcium

Question 28

How do you make animal models with PAH?

Answer 28

• monocrotaline in rat (REVERSIBLE)
• Chronic hypoxia in rat or mouse (10% for 2-4 weeks) (REVERSIBLE)
• Chronic hypoxia + sugen (an ihibitor of VEGF)
• genetic: Fawn-hooded rat model: spontaneously pulmonary hypertensive
• Genetically-engineered mice

Question 29

What is the only animal model that causes plexiform lesions in PAH?

Answer 29

chronic hypoxia + sugen