Why does PAH develop?

The exact cause behind the development of Pulmonary arterial hypertension (PAH) remains unknown. However, research has lead to a better understanding of the underlying mechanisms.

Pulmonary Arterial Hypertension (PAH) is recognised as a complex, multi-factorial condition involving numerous biochemical pathways and different cell types. Endothelial dysfunction is believed to occur early on in disease pathogenesis, leading to endothelial and smooth muscle cell proliferation and structural changes or ‘Remodelling' of the pulmonary vascular bed resulting in an increase in pulmonary vascular resistance.

Vascular remodelling itself involves all layers of the vessel wall and is characterised by proliferative and obstructive changes involving many cell types, including endothelial, smooth muscle and Fibroblasts. Inflammatory cells and platelets may also play a significant role in Pulmonary Arterial Hypertension (PAH).

Endothelial cell dysfunction results in reduced production of vasodilators, such as Nitric oxide (NO) and Prostacyclin, and over production of vasoconstrictors, such as thromboxane A2 and endothelin-1 (ET-1).

ET-1, NO and prostacyclin have been the principal focus of research into new treatment options for patients with Pulmonary Arterial Hypertension (PAH).

Click here  for general information about treatment classes for Pulmonary Arterial Hypertension (PAH).

Endothelin

Endothelin is produced by the endothelial cells and is essential for maintenance of normal vascular tone and function.  However, high levels of endothelin are seen in patients with Pulmonary Arterial Hypertension (PAH) due to various aetiologies^1-3 and correlate with disease severity,⁴ resulting in a number of detrimental effects, primarily in the vasculature:⁵

• Fibrosis
• Hypertrophy and proliferation of cells, which can lead to thickening, narrowing and occlusion of blood vessels
• Inflammation
• Vasoconstriction

Endothelin binds to 2 receptors, ET_A and ET_B.

Both receptors are implicated in Pulmonary Arterial Hypertension (PAH) and mediate the deleterious effects of endothelin.⁶  Endothelin receptor antagonism can either mitigate the effects of only one (single ET_A antagonist) or both (dual ET_A and ET_B receptor antagonist) receptor types.

Prostacyclin

Prostacyclin is a potent vasodilator as well as an inhibitor of platelet activation.

It is believed that patients with Pulmonary Arterial Hypertension (PAH) have low levels of prostacyclin, which could result in vasoconstriction in the pulmonary vasculature and a tendency for smooth muscle cell proliferation and platelet activation, encouraging the formation of thrombi in both the micro-circulation and the pulmonary arteries.^7-9 Therapy with synthetic forms of prostacyclin can help to correct this deficiency, although administering this form of treatment is complex.^10-12

Nitric oxide

Nitric oxide is an endothelial-derived substance that, like prostacyclin, it is a potent vasodilator and also possesses anti-proliferative properties.

Pulmonary Arterial Hypertension (PAH) patients appear to produce insufficient NO and this may contribute to the development of Pulmonary Arterial Hypertension (PAH).⁵ The vasodilatory effect of NO is mediated by cGMP, which is rapidly degraded by phosphodiesterases. The inhibition of the degradation of cGMP with phosphodiesterase 5 inhibitors promotes the accumulation of intracellular cGMP, resulting in vasodilatation.¹³

References
1. Stewart DJ, Levy RD, Cernacek P et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Inter Med 1991; 114:464-9.
2. Vancheeswaran R, Magoulas T, Efrat G et al. Circulating endothelin-1 levels in systemic sclerosis subsets--a marker of fibrosis or vascular dysfunction? J Rheum 1994; 21:1838-44
3. Yoshibayashi M, Nishioka K, Nakao K et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation. Circulation 1991; 84:2280-5
4. Galie N, Grigioni F, Bacchi-Reggiani L et al. Relation of endothelin-1 to survival in patients with primary pulmonary hypertension. Eur J Clin Inves 1996 ;26 :A48
5. Gaine SP, Rubin LJ. Primary Pulmonary Hypertension. Lancet  1998; 352: 719-25
6. Channick RN, Simonneau G, Sitbon O et al.  Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.  Lancet 2001; 358:1119-23
7. MacGreggor AJ, Canavan R, Knight C et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001;40(4):453-9
8. Loyd JE, Butler MG, Foround TM et al. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 152: 93-7
9. Rubin LJ. Therapy of pulmonary hypertension: the evolution from vasodilators to antiproliferative agents. Am J Respir Crit Care Med 2002;166: 1308-9
10. Ono F, Nagaya N, Okamura H et al. Effect or orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest  2003;123: 1583-8
11. Galie N, Manes A, Branzi A. Emerging medical therapies for pulmonary arterial hypertension. Prog Cardiov Dis 2003:45: 213-24
12. Clapp LH, Finney P, Turcato S et al. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human Pulmonary artery. Am J Resp Cell Mol Biol 2002;2: 194-201
13. Galiè N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148-57.