LeBlanc: Basic Science of Pulmonary Hypertension

Question 1

What are the 5 classifications of pulmonary hypertension?

Answer 1

1. pulmonary arterial hypertension
2. PH associated with left heart disease
3. PH associated with lung disease and/or hypoxia
4. Thromboembolic PC
5. Misc

Question 2

What are 5 sub-classifications of pulmonary arterial hypertension?

Answer 2

1. idiopathic PAH
2. heritable or familial PAH
3. drug or toxin induced (anorexigens)
4. atypical (HIV infection, portal hypertension, congenital heart diseases CT diseases, Schistosomiasis)
5. persistent PH of the newborn

Question 3

What are some genes that are mutated in the heritable or familial cases of PAH?

Answer 3

BMPR2

• *part of the TGFbeta family of receptors
• *stimulation decreases proliferation and enhances apoptosis
• *Down-regulated in more than 80% of pts in this subclass

Activin A receptor type II-like kinase-1 (ALK1)
**less common

5HT transporter polymorphisms

Question 4

Describe how the lungs respond to ventilation-perfusion mismatch

Answer 4

When a group of alveoli in the lung are poorly oxygenated, the surrounding blood vessels in this region will constrict to shunt blood away from the poorly ventilated region

**this is opposite to the effect seen in other parts of the body, like in skeletal muscle (hypoxia –> vasodilation)

Question 5

Why is the ventilation-perfusion mismatch a problem at high altitude?

Answer 5

there is not enough oxygen in any area of the lung –> so the blood vessels think they must constrict to shunt blood away from poorly perfused areas, but all of the areas are poorly perfused!

**this leads to pulmonary hypertension –> all the blood vessels are constricting

Question 6

What are 3 postulated mechanisms for hypoxic pulmonary vasoconstriction?

Answer 6

1. Redox hypothesis
2. Ros hypothesis
3. Energy state/AMPK hypothesis

Question 7

Factors Contributing to Elevating Pulmonary Arterial Pressure in PAH Patients

Answer 7

1. enhanced vasoconstriction
2. partial or complete remodeling of the intimal, medial, and adventitial layers of the pulmonary arteries –> enhances proliferation, reduces apoptosis
3. propensity for thrombosis

Question 8

What would you see histologically in PAH?

Answer 8

plexiform lesions

vessel almost completely occluded due to hypertrophy of all vessel layers

Question 9

What must you use to diagnose PAH?

Answer 9

right heart and pulmonary arterial catheterization

or

less invasive echocardiography

Question 10

What pressure defines pulmonary arterial hypertension at rest? During exercise?

Answer 10

greater than 25mmHg;

greater than 30mmHg

Question 11

What capillary wedge pressure is diagnostic for PAH?

Answer 11

less than 15mmHg

**this rules out left sided causes

Question 12

What pulmonary vascular resistance (PVR) is diagnostic for PAH?

Answer 12

greater than 3 wood units

Question 13

Current therapies for pulmonary arterial hypertension?

Answer 13

prostanoids (prostaglandin analogues - proinflammatory)
endothelin receptor blockers (Bosentan) - block vasoconstriction in blood vessels
PDE5 blockers (Sildenafil)
Ca++ channel blockers
drugs that target NO and cGMP signaling pathways

Question 14

How do prostanoids lead to vasodilation?

Answer 14

prostanoids activate AC, which increases cAMP, which acts on PKA to cause vasodilation

Question 15

How do endothelin receptor blockers work to decrease PAH?

Answer 15

endothelin-1 binds to ETA and ETB receptors on smooth muscle cells to cause vasoconstriction - by blocking these receptors, less vasoconstriction

Question 16

How do we tackle a multifactorial very rare disease like PAH?

Answer 16

start with animal models

studies with human pulmonary arterial tissues and lungs