Treatment of Pulmonary arterial hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a rare and severe disease that continues to progress over time.1 Although there is no cure, recent advances in treatment strategies with increased therapeutic options have offered an improvement in prognosis and survival.2,3

The prognosis of PAH depends on a number of modifiable clinical, functional, exercise, biochemical, echocardiographic and haemodynamic variables. Comprehensive assessment based on these parameters can determine prognosis by classifying patients as low-risk, intermediate-risk or high-risk for clinical worsening or death.4 Patients across all risk categories have poor survival;5 therefore, treatment strategies should target the improvement of long-term outcomes, with the ultimate goal of achieving a low-risk status.4


Adapted from Hoeper et al. 20175
PAH, pulmonary arterial hypertension

Given the progressive nature of PAH, the overall aim of treatment is to achieve and/or maintain a low-risk status in order to reduce the risk of clinical deterioration.4 In a retrospective study of an incident cohort of patients with PAH, patients with more low-risk parameters at follow-up had considerably better long-term outcomes.6


Adapted from Boucly et al. 20176

PAH-specific therapies have been developed to target one of three major pathways known to be involved in the development of PAH. Combination therapy (using two or more classes of drugs together) is an option in the management of PAH to simultaneously target multiple pathways involved in the disease pathogenesis. Evidence to support combination therapy is growing.4,7 The 2015 European Society of Cardiology and European Respiratory Society (ESC/ERS) guidelines recommend initial combination therapy for PAH or double or triple sequential combination therapy in cases of inadequate clinical results or in cases of deterioration.4


Adapted from Humbert et al. 20147
cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET, endothelin; GMP, guanosine monophosphate; GTP, guanosine triphosphate; IP, prostacyclin; NO, nitric oxide; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type 5; PGl2, prostacyclin; sGC, soluble guanylate cyclase

Endothelin pathway

The endothelin-1 expression level is upregulated in patients with PAH, causing potent vasoconstriction and smooth muscle cell proliferation. Endothelin receptor antagonists (ERAs) act by blocking the binding of endothelin to its receptors to prevent this process.8

Nitric oxide pathway

Phosphodiesterase type-5 (PDE-5) inhibitors and guanylate cyclase stimulators act on the nitric oxide pathway to promote vasodilation and have antiproliferative effects on vascular smooth muscle cells.4

Prostacyclin pathway

Prostacyclin induces potent vasodilation and inhibition of platelet aggregation and has both cytoprotective and antiproliferative effects. Prostacyclin receptor agonists and prostacyclin analogues act by helping to correct the deficiency in endogenous prostacyclin seen in patients with PAH.4

Recent advances in our understanding of the mechanisms behind the development of PAH have led to major progress in treatment options for patients. Management of PAH has evolved towards a focus on optimising treatment strategies.8


Adapted from Lajoie et al. 20179
PAH, pulmonary arterial hypertension



Diagnosis of PAH

Clinical guidelines set out the diagnostic pathway so patients can be referred and treated as quickly as possible.


Pathophysiology of PAH

While the exact cause of PAH is uncertain, a clearer picture of the underlying pathological mechanisms is emerging.



  1. D’Alonzo GE et al. Ann Intern Med  1991; 115:343–349.
  2. Benza RL et al. Chest  2012; 142:448–456.
  3. Montani D et al. Orphanet J Rare Dis  2013; 8:97.
  4. Galiè N et al. Eur Heart J  2016; 37:67–119.
  5. Hoeper MM et al. Eur Respir J  2017; 50:1700740.
  6. Boucly A et al. Eur Respir J  2017; 50:1700889.
  7. Humbert M et al. Circulation  2014; 130:2189–2208.
  8. Rosenkranz S, Dumitrescu D. Rev Esp Cardiol (Engl Ed)  2017; 70:901–904.
  9. Lajoie A et al. Pulm Circ  2017; 7:312–325.

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