PAH Pathophysiology

Endothelin-1 (ET-1) is thought to play a critical role in the pathogenesis and progression of PAH1,2

Three major pathways are involved in abnormal cell proliferation and function associated with PAH.3

ET-1 is a powerful vasoconstrictor and mitogen for smooth muscle tissue1,3-4

Plasma levels of ET-1 are elevated in patients with idiopathic PAH (IPAH)1-2,4

Plus signs denote an increase in the intracellular concentration.
Minus signs denote blockage of a receptor, inhibition of an enzyme, or a decrease in the intracellular concentration.
cGMP=cyclic guanosine monophosphate; cAMP=cyclic adenosine monophosphate.
Adapted from Humbert M, et al. N Engl J Med. 2004;351(14):1425-1436.

Prostacyclin is an endogenous vasodilator, inhibitor of platelet aggregation, and suppressor of vascular smooth muscle cell proliferation2

Prostacyclin levels and activity are diminished in patients with PAH5

Plus signs denote an increase in the intracellular concentration.
Minus signs denote blockage of a receptor, inhibition of an enzyme, or a decrease in the intracellular concentration.
cGMP=cyclic guanosine monophosphate; cAMP=cyclic adenosine monophosphate.
Adapted from Humbert M, et al. N Engl J Med. 2004;351(14):1425-1436.

NO is a potent pulmonary vasodilator and an inhibitor of pulmonary vascular smooth
muscle proliferation2

NO synthase expression and levels of NO are diminished in patients with PAH5

Plus signs denote an increase in the intracellular concentration.
Minus signs denote blockage of a receptor, inhibition of an enzyme, or a decrease in the intracellular concentration.
cGMP=cyclic guanosine monophosphate; cAMP=cyclic adenosine monophosphate.
Adapted from Humbert M, et al. N Engl J Med. 2004;351(14):1425-1436.

References:
  1. 1. Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12, suppl5):62S-67S.
  2. 2. Austin ED, Lloyd JE. Genetics and mediators in pulmonary arterial hypertension. Clin Chest Med. 2007;28(1):43-57.
  3. 3. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol. 2009;53(17):1573-1619.
  4. 4. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351(16):1655-1665.
  5. 5. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114(13):1417-1431.