History, presentation, and investigations
A 19-year-old female university student with congenital heart disease–associated pulmonary arterial hypertension (PAH-CHD), who was on triple therapy and used home and portable oxygen, was referred to us for adult CHD management in July 2025. She had been referred earlier for lung transplantation due to severe PAH.
At initial presentation in January 2023, she reported shortness of breath (SoB) and decreased exercise tolerance, but her overall past health was good. Electrocardiography showed right-axis deviation and right ventricular (RV) hypertrophy. Echocardiography revealed enlarged right atrium (RA) and RV and severe tricuspid regurgitation with a high jet gradient of 100 mm Hg, highly suggestive of pulmonary hypertension (PH). Additionally, there was a large secundum atrial septal defect (ASD) measuring up to 2.1 cm with bidirectional shunting, consistent with CHD.
Chest CT showed a large ASD and enlarged RA/RV without evidence of pulmonary embolism. Airway was partly compressed by dilated pulmonary arteries. Spirometry showed fixed airflow obstruction, consistent with the CT findings of dilated pulmonary arteries causing airway compression. Diffusion studies were normal.
All rheumatology tests were negative. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was elevated at 2,431 pg/mL. Her 6-minute walk distance (6MWD) was 235 m on room air. (Figure)
Right heart catheterization (RHC) in late January 2023 confirmed severe PAH, with mean pulmonary artery pressure (mPAP) of 52 mm Hg, systolic pulmonary artery pressure (sPAP) at 95 percent of systemic systolic pressure, pulmonary vascular resistance (PVR) of 16.2 WU, PVR index (PVRi) of 22.30 WU·m2, and reduced cardiac output at 3.38 L/min/m2. Vasoreactivity test was negative. These findings led to a diagnosis of PAH-CHD. (Figure)
Dual therapy for PAH-CHD with sildenafil and bosentan was started in January 2023, along with furosemide, spironolactone, and warfarin. Her peripheral oxygen saturation was 92 percent while receiving supplemental O2 at 0.5 L/min. Home and portable oxygen concentrators were arranged at that time.
After a joint cardiac-surgical meeting in February 2023, the patient was deemed high-risk and was started on pulmonary vasodilators with early referral for lung transplantation. (Figure)
After 2 months of dual therapy, the patient’s response was suboptimal, with relatively unchanged SoB, poor exercise tolerance, and persistent need to sleep propped up on three pillows. Subsequently, selexipag 200 mcg BID was added and uptitrated to 600 mcg BID between March and April 2023. (Figure)
In August 2023, another RHC showed similar findings to the previous RHC. The patient was ineligible for ASD repair after a negative acute vasoreactivity test (PVRi, 13.26 WU·m2; PVR/systemic vascular resistance ratio [PVR/SVR], 0.49). Selexipag was further uptitrated to 800 mcg BID, which resulted in slight improvements in NT-proBNP to 1,129/mL and 6MWD to 415 m on supplemental O2 at 2 L/min. In November 2023, she reported significant gastrointestinal side effects from selexipag, which prevented further uptitration. Her New York Heart Association (NYHA) functional class (FC) was II–III. (Figure)
In July 2024, after 1.5 years of triple therapy, the patient had further improvements in NT-proBNP to 543 pg/mL, and 6MWD to 456 m. Selexipag was uptitrated to 800/ 1,000 mcg BID. In January 2025, RHC showed a PVR of 9.52 WU. (Figure)
In July 2025, the patient remained in NYHA FC II–III, but both NT‑proBNP and 6MWD showed a worsening trend. She was therefore referred to our adult CHD team to evaluate the possibility of ASD management. The patient failed to switch from bosentan to macitentan due to dizziness. (Figure)
Add-on treatment with sotatercept
At the first assessment at our centre in September 2025, the patient’s NYHA FC was II–III, NT‑proBNP was 1,128 pg/mL, 6MWD was 456 m, risk status by the REVEAL Lite 2 calculator was high (score 10), and risk status by the COMPERA 2.0 four‑strata model was intermediate–high (score 3). (Figure) Add‑on treatment with sotatercept, a first-in-class activin signalling inhibitor approved in Hong Kong in August 2025, was discussed.
The first subcutaneous dose of sotatercept 0.3 mg/kg was added to her regimen in October 2025. In November 2025, the second sotatercept dose was given, and selexipag was uptitrated to 800/1,200 mcg BID. (Figure)
At the latest follow-up on 1 December 2025, after two doses of sotatercept, the patient reported a subjective improvement in exercise tolerance. She was able to walk on level ground without supplemental O2. Her NYHA FC improved to II, 6MWD increased to 490 m, and NT‑proBNP decreased to 440 pg/mL. Importantly, she reached low‑risk status based on both REVEAL Lite 2 (score 5) and COMPERA 2.0 four‑strata (score 1) models. The third dose of sotatercept was administered on the same day. (Figure)
Discussion
Patients with CHD are at risk of developing PAH. Approximately 4–15 percent of patients with CHD will eventually develop PAH.1
PAH-CHD is a subtype of PAH and represents a heterogeneous patient population. It can be classified into four groups: 1) Eisenmenger syndrome; 2) PAH associated with prevalent systemic-to-pulmonary shunts; 3) PAH with small or coincidental defects; 4) PAH after defect correction.2 Because of variable anatomy and haemodynamics, standard echocardiographic criteria for detecting PH are often not directly applicable to patients with CHD and should be adjusted to the underlying anatomy. RHC should always be performed for correct diagnosis (mPAP >20 mm Hg and PVR >2 WU).3
A core concept of PAH-CHD management is choosing between a “treat-and-repair” and a “repair-and-treat” approach, which requires individualized, multidisciplinary decision-making. Acute vasoreactivity testing during cardiac catheterization is often required to guide treatment. For example, our patient was deemed ineligible for surgical repair as her PVRi was not <6 WU·m2 and PVR/SVR was not <0.3 on acute vasoreactivity testing.4
Patients with PAH-CHD are at moderate-to-high risk and therefore require a proactive, risk-based strategy involving either initial or sequential combination therapy. Evidence for standardized treatment is limited. Pharmacological treatment generally mirrors that for PAH.5 Both macitentan’s SERAPHIN trial and selexipag’s GRIPHON trial included PAH patients with repaired congenital shunts (8.4 percent in SERAPHIN and 9.5 percent in GRIPHON) and both trials met their primary endpoints.6,7
The decision to add sotatercept to our patient’s regimen was based on the phase III STELLAR trial. In STELLAR, 323 patients with PAH with repaired congenital shunts (5 percent) on stable background therapy (triple therapy, 61.3 percent; prostacyclin infusion therapy, 39.9 percent; double therapy, 34.7 percent; monotherapy, 4.0 percent) were randomized 1:1 to receive subcutaneous sotatercept (starting dose, 0.3 mg/kg of body weight; target dose, 0.7 mg/kg) or placebo Q3W.8
STELLAR met its primary endpoint by demonstrating a significant improvement from baseline in 6MWD at week 24 with sotatercept vs placebo (+40.8 m; 95 percent confidence interval [CI], 27.5–54.1; p<0.001).8 The benefit was consistent across most prespecified subgroups, including patients with repaired congenital shunts (+92.4 m; 95 percent CI, -22.49 to 207.26).8
Notably, sotatercept led to an 84 percent lower risk of a composite secondary endpoint of death from any cause or nonfatal clinical worsening event vs placebo (5.5 vs 26.2 percent; hazard ratio, 0.16; 95 percent CI, 0.08–0.35; p<0.001).8
Consistently, after two doses of sotatercept, our patient’s 6MWD increased by 120 m (from 370 to 490 m without requiring supplemental O2), NYHA FC improved from II–III to II, and NT-proBNP level decreased from 1,128 to 440 pg/mL. Importantly, she transitioned to low-risk status based on both REVEAL Lite 2 & COMPERA 2.0 models. (Figure)
In STELLAR, rates of overall, severe, and serious adverse events (AEs) at week 24 were lower with sotatercept vs placebo. Although not experienced by our patient, increased haemoglobin level, a known AE of sotatercept, was reported in 5.5 percent of patients at week 24. This was manageable with dose interruptions or reductions and was not associated with treatment discontinuations.8
Apart from PAH (group I PH, pre-capillary), sotatercept holds potential for treatment of group II PH, such as combined pre- and post- PH (CpcPH) due to heart failure with preserved ejection fraction (HFpEF). Topline results from the phase II CADENCE trial showed that sotatercept led to a statistically significant reduction in PVR at 24 weeks vs placebo in patients with CpcPH due to HFpEF.2,9
In summary, PAH-CHD, a subgroup of PAH, comprises a heterogeneous patient population. Management generally follows PAH care.2,5 Our case and the STELLAR trial demonstrated that sotatercept is an effective add-on treatment for PAH-CHD, improving 6MWD, NYHA FC, NT-proBNP and risk status, with a favourable safety profile. Sotatercept may also have potential in treatment of group II PH.8-9
