OBJECTIVES This study was conducted to investigate the combined use of fenestrated atrial septal occluder (F-ASO) and targeted medical therapy (TMT) in patients with secundum atrial septat defect (ASD) and severe pulmonary arterial hypertension (PAH). BACKGROUND Treatment of patients with ASD and severe PAH is still challenging. METHODS After ethical approval was obtained, 56 consecutive patients with ASD with severe PAH were included (7 men, 49 women; median age 50.5 years; mean ASD size 26.9 +/- 4.6 mm). After 3 months of TMT, transcatheter dosure was performed using F-ASO in patients with ratios of pulmonary to systemic blood flow >= 1.5. TMT was continued postoperatively together with 6 months of dual-antiplatelet therapy. The hemodynamic variables during baseline, TMT atone, and combined treatment with F-ASO were compared. RESULTS After only TMT, systolic pulmonary arterial pressure (-14.5 mm Hg; p < 0.001), pulmonary vascular resistance (-3.9 Wood units; p < 0.001), and exercise capacity (+72.0 m; p < 0.001) improved. Ratio of pulmonary to systemic blood flow increased by 0.9 (p < 0.001), with adverse cardiac remodeling (right ventricular dimension +3.5 mm; p < 0.001). Closure with F-ASO (median size 34.0 mm) led to further decrease in systolic pulmonary artery pressure (6.0 mm Hg; p < 0.001). Follow-up (median duration 10 months) revealed further improvement in exercise capacity (+60.5 m; p < 0.001), with favorable cardiac remodeling (right ventricular dimension -9.9 mm; p < 0.001). In addition, all fenestrations were stable (p < 0.699), with negligible shunt (median ratio of pulmonary to systemic blood flow 1.1) and no complications. One year later, pulmonary artery pressure was normalized in 8 of 19 patients, and PAH recurred in 5 patients after discontinuation of TMT. CONCLUSIONS In patients with ASD and severe PAH, combination of F-ASO and TMT was a safe and effective procedure. Compared with TMT alone, the combined treatment further improved exercise capacity, with favorable cardiac remodeling. (C) 2020 by the American College of Cardiology Foundation.