The exact cause behind the development of Pulmonary arterial hypertension (PAH) remains unknown. However, research has led to a better understanding of underlying pathological mechanisms.
PAH is recognized as a complex, multi-factorial condition involving numerous biochemical pathways and different cell types.1,2
Endothelial dysfunction, an abnormality of the inner lining of blood vessels, is believed to occur early in disease pathogenesis, and this leads to endothelial and smooth muscle cell proliferation followed by structural changes or remodeling of the pulmonary vascular bed, which in turn results in an increase in pulmonary vascular resistance.
Vascular remodeling itself involves every layer of the vessel wall and is characterised by proliferative and obstructive changes involving many cell types, including endothelial cells, smooth muscle cells and fibroblasts.1 Inflammatory cells and platelets may also play a significant role in PAH.
Endothelial dysfunction results in chronically impaired production of vasoactive mediators, such as nitric oxide (NO) and prostacyclin, along with prolonged overexpression of vasoconstrictors, such as endothelin-1 (ET-1),which not only affect vascular tone but also promote vascular remodeling.1 These substances are important therapeutic targets for new treatment options in PAH.1,3
Click here for general information about treatment classes for PAH.
The role of endothelin
Endothelin-1 (ET-1) is a vasoconstrictive protein produced by endothelial cells. Little is known about the physiological role of ET-1, although animal models have demonstrated that it is essential for normal development, for example of the thyroid and thymus, and may also play a role in cardiovascular homeostasis.4,5 Our current understanding of the endothelin system is based on information gathered from pathological conditions such as PAH. High levels of ET-1 are seen in patients with PAH due to various aetiologies6–8 and correlate with disease severity,9 resulting in a number of detrimental effects, primarily in the vasculature:3
ET-1 binds to two receptors, known as ETA and ETB. Both receptors are implicated in PAH and mediate the deleterious effects of endothelin.3 Endothelin receptor antagonism can either mitigate the effects of only one (single ETA antagonist) or both (dual ETA and ETB receptor antagonist) receptor types. Therapy with orally administered endothelin receptor antagonists (ERAs) that block the binding of endothelin to one or both receptors aims to mitigate the deleterious effects of the high levels of endothelin seen in PAH.10
The role of prostacyclin
Prostacyclin is a potent vasodilator as well as an inhibitor of platelet activation.11 Patients with PAH have low levels of prostacyclin,11 which promotes vasoconstriction in the pulmonary vasculature and a tendency for smooth muscle cell proliferation and platelet activation.3 This may also encourage the formation of thrombi, which have been found in both the small distal and the proximal elastic pulmonary arteries.1 Therapy with prostacyclin or prostacyclin analogues can help to correct this deficiency, although administering this form of treatment may be complex due to the fact that some prostacyclins are broken down rapidly within the body; in most cases these substances need to be given as a continuous intravenous or subcutaneous infusion or by inhalation.12
The role of nitric oxide
Nitric oxide (NO) is an endothelial-derived substance that, like prostacyclin, is a potent vasodilator and also possesses anti-proliferative properties.12 Patients with PAH appear to produce insufficient NO, which could result in vasoconstriction within the pulmonary vasculature and a tendency for smooth muscle cell proliferation2,3 that may contribute to the development of PAH. The vasodilatory effect of NO is mediated by cGMP, which is rapidly degraded by phosphodiesterases (PDEs).3 Orally administered PDE-5 inhibitors inhibit the degradation of cGMP and so promote the accumulation of intracellular cGMP, enhancing NO-mediated vasodilatation.13
- Galiè N, Hoeper M, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493–537.
- McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009;119:2250–94.
- Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–36.
- Kurihara Y, Kurihara H, Maemura K, et al. Impaired development of the thyroid and thymus in endothelin-1 knockout mice. J Cardiovasc Pharmacol. 1995;26 Suppl 3:S13.
- Kurihara Y, Kurihara H, Suzuki H, et al. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 1994;368:703–10
- 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.
- 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.
- 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.
- Galiè 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.
- 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;358:119–23.
- McGoon MD, Kane GC. Pulmonary hypertension: diagnosis and management. Mayo Clin Proc 2009;84:191–207. Erratum in Mayo Clin Proc 2009;84:386.
- Galiè N, Manes A, Branzi A. Emerging medical therapies for pulmonary arterial hypertension. Prog Cardiov Dis 2003:45:213–24.
- Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–57.