Accurate diagnosis of Eisenmenger syndrome and exclusion of other potential con- tributors to right-to-left shunting or pulmonary hypertension by means of advanced imaging and cardiac catheterization are crucial prerequisites to optimize therapy for adults with Eisenmenger syndrome. 2. In adults with Eisenmenger syndrome associated with ASD or VSD in World Health Organization functional class III or IV, RCTs demonstrate improved 6-minute walk distance, hemody- namics, and subjective functional ability after 4 months of oral bosentan.S4.4.6.2-17 Longer-term benefit has been demonstrated through open- label extension of this initial RCTS4.4.6.2-1 and in single-center registry cohorts.S4.4.6.2-1,S4.4.6.2-17 There may be a class effect for endothelin receptor antagonists, but others have not been studied in this population. 3. A randomized crossover trial of combination PAH therapy (PDE-5 inhibitor therapy and endothelin receptor antagonist therapy) enrolled adults with Eisenmenger syndrome or with idiopathic PAH and demonstrated improvement in systemic ar- terial saturation but not in functional ability or Use of combination PAH therapy for adults with Eisenmenger syndrome was further supported by a single-center co- hort series suggesting improvement in 6-minute walk testing and hemodynamics in adults with Eisenmenger syndrome using combined PDE-5 in- hibitory therapy and endothelin receptor antago- 4. Open-label single-center registries and cohort studies of adults with Eisenmenger syndrome, attributable to shunts other than ASD/VSD or with complex congenital heart lesions, suggest benefit in functional capacity or hemodynamics after months of endothelin receptor antagonist Patients with ACHD and Down syndrome have greater likelihood to de- velop pulmonary hypertension, and they have unique comorbidities that influence the nature of their pulmonary hypertension, the metrics used in follow-up, and the potential for benefit from as well as adverse response to therapy. 