*3.3.4 Treatment*

PAH treatment is based on the severity of disease at diagnosis and on the evaluation of how the individual will respond to treatment, using a multiparametric risk stratification approach. Clinical, exercise, right ventricular function, and hemodynamic parameters are combined to outline a low-, intermediate- or high-risk status, according to the expected 1-year mortality. PAH remains a severe clinical condition, despite the availability over the past 15 years of multiple drugs interfering with the ET1, NO, and prostacyclin pathways (**Figure 2**). Therefore, the current progress observed in the medical therapy of PAH is not related to the detection of new pathways, but the development of new strategies of combination therapy and escalation of treatments based on clinical response.

The current treatment algorithm provides the most appropriate initial strategy, including monotherapy, or double or triple combination therapy. Additionally, treatment escalation is required in case low-risk status is not achieved in planned follow-up assessments. Usually, treatment starts with general supportive therapies: these

#### **Figure 2.**

*Biological pathways involved in the pathogenesis of PAH. Pre-pro-ET: Pre-pro-endothelin; pro-ET: Proendothelin; ET > 1: Endothelin-1ETA/ETB: ET receptor subtypes A and B; ERA: Endothelin receptor agonist; sGC: Soluble guanylate cyclase; sGCs: sGCs stimulator; PDE5: Phosphodiesterase type 5; PDE-5-i: PDE5 inhibitors; cGMP: Cyclic guanosine monophosphate (GMP); cAMP: Cyclic adenosine monophosphate; PGI2 analogues: Prostaglandin I2 analogues.*

measurements, include oxygen supplementation, supervised physical exercise, respiratory rehabilitation, diuretic therapy, and psychosocial support for the patient and his family [37]. Moreover, the fundamental milestone of the treatment is the specific therapy that address the three main specific pathways altered in PAH.
