Extract
For patients with newly diagnosed idiopathic pulmonary arterial hypertension (IPAH) at high risk of death, current guidelines recommend initial triple combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase-5 inhibitor (PDE5i) and a parenteral prostacyclin analogue [1].
Shareable abstract
In this case report of a patient with newly diagnosed, severe idiopathic pulmonary arterial hypertension, near normalisation of haemodynamics was achieved with initial triple combination therapy including the activin signalling inhibitor sotatercept https://bit.ly/48RtbPT
To the Editor:
For patients with newly diagnosed idiopathic pulmonary arterial hypertension (IPAH) at high risk of death, current guidelines recommend initial triple combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase-5 inhibitor (PDE5i) and a parenteral prostacyclin analogue [1].
Recently, the therapeutic landscape for pulmonary arterial hypertension (PAH) has expanded with the approval of sotatercept, an activin signalling inhibitor. Sotatercept has demonstrated efficacy across various patient populations, including those at high risk of mortality [2–4]. However, to date, it has only been studied in patients with prevalent PAH receiving stable background therapy, not as part of the initial treatment regimen in newly diagnosed patients.
We report the case of a patient with high-risk IPAH who achieved significant clinical improvement with near normalisation of haemodynamics within 3 months of treatment with an ERA, a PDE5i and sotatercept.
A 25-year-old woman (height 165 cm, body mass 64 kg, body mass index 23.5 kg·m−2) was transferred from a different hospital in April 2025 after experiencing recurrent syncope over the preceding 2 days. She had delivered a healthy baby 2 weeks earlier and had developed progressive exertional dyspnoea since the third trimester of pregnancy. At the time of admission, she was unable to walk due to severe dyspnoea and light-headedness when trying to get up. Transthoracic echocardiography revealed significant right heart chamber dilation and an estimated systolic pulmonary artery pressure of ∼100 mmHg. Chest computed tomography excluded pulmonary embolism and showed patchy ground-glass opacities without septal thickening or other parenchymal abnormalities.
The patient was immediately transferred to our hospital and admitted to the intensive care unit (ICU), where echocardiographic findings were confirmed. Right heart catheterisation revealed severe pulmonary hypertension with low cardiac output and elevated right-sided filling pressures (table 1). Vasoreactivity testing was negative (data are shown in the table footnote). A working diagnosis of IPAH was made. Alternative causes of PAH were subsequently ruled out; genetic testing has yet to be performed.
TABLE 1.
Echocardiographic and haemodynamic findings
| April 2025 | July 2025 | |
|---|---|---|
| Echocardiography | ||
| sPAP, mmHg | 94 | 28 |
| TAPSE, mm | 0.9 | 2.4 |
| TAPSE/sPAP, mm·mmHg−1 | 0.1 | 0.48 |
| RVEDD, mm | 57 | 32 |
| RA area, cm2 | 18.1 | 14.8 |
| Tricuspid regurgitation | Severe | Mild |
| Pericardial effusion | Trace | None |
| Right heart catheterisation | ||
| HR, beats per min | 97 | 83 |
| RAP, mmHg | 14 | 1 |
| mPAP#, mmHg | 68 | 18 |
| PAWP, mmHg | 6 | 4 |
| CO#, L·min−1 | 2.0 | 4.1 |
| CI, L·min−1·m−2 | 1.2 | 2.5 |
| SVI, mL·m−2 | 13 | 30 |
| PVR, WU | 31 | 3.4 |
| PAC, mL·mmHg−1 | 0.35 | 2.0 |
| SvO2, % | 25 | 73 |
| Haemoglobin, g·dL−1 | 11.0 | 14.5 |
sPAP: systolic pulmonary arterial pressure; TAPSE: tricuspid annular plane systolic excursion; RVEDD: right ventricular end-diastolic diameter; RA: right atrial; HR: heart rate; RAP: right atrial pressure; mPAP: mean pulmonary arterial pressure; PAWP: pulmonary arterial wedge pressure; CO: cardiac output; CI: cardiac index; SVI: stroke volume index; PVR: pulmonary vascular resistance; WU: Wood units; PAC: pulmonary arterial compliance; SvO2: mixed venous oxygen saturation. #: after inhalation of 5 µg iloprost, mPAP was 68 mmHg and CO was 2.7 L·min−1.
Dobutamine was initiated for inotropic support. PAH therapy was started with tadalafil (20 mg once daily), macitentan (10 mg once daily) and intravenous treprostinil. However, treprostinil could not be titrated beyond 4 ng·kg−1·min−1 due to intolerable side-effects, including severe headache, vomiting and diarrhoea. It was discontinued after 7 days. At that time, the patient remained in the ICU, continued to require inotropic support, showed no clinical improvement and had persistently elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (peak 2206 ng·L−1). Consequently, we initiated sotatercept at a starting dose of 0.3 mg·kg−1 administered subcutaneously.
The patient improved steadily over the following week, and was weaned off dobutamine and transferred to a non-ICU ward, then discharged home a few days later. In May 2025, ∼4 weeks after the initial presentation and 3 weeks after the first sotatercept dose, she presented to our outpatient clinic in World Health Organization (WHO) functional class II with a 6-min walk distance (6MWD) of 343 m. NT-proBNP had decreased to 118 ng·L−1. Treatment with macitentan and tadalafil was continued at the same dosages, and sotatercept was escalated to 0.7 mg·kg−1 subcutaneously every 3 weeks.
In July 2025, the patient was readmitted for a scheduled right heart catheterisation. She remained in WHO functional class II with a 6MWD of 363 m. NT-proBNP had normalised (<50 ng·L−1). Echocardiography showed recovery of right heart function and haemodynamic parameters had almost normalised (table 1). No adverse events occurred during treatment.
This is, of course, a single case report. It remains possible that similar outcomes might have been achieved with more conventional treatment strategies and this case does not prove the efficacy of sotatercept as part of initial combination therapy in patients with newly diagnosed IPAH. However, the fact that clinical improvement began only after initiating sotatercept suggests that the drug may have significantly contributed to the marked clinical and haemodynamic response observed in this patient.
While these observations should be interpreted cautiously, they align with the emerging concept of achieving remission in PAH through early use of effective combination regimens [5, 6]. Sotatercept appears to exert reverse remodelling effects, as demonstrated in pre-clinical models suggesting induction of apoptosis of cells obstructing the pulmonary vascular lumen [7]. If this mechanism is also active in human disease, it could explain the rapid haemodynamic and clinical improvement observed in our patient. Thus, sotatercept may have a valuable role when used as part of an initial treatment strategy, especially in patients with a short disease duration and rapidly progressing symptoms, as illustrated by this case. A prospective multicentre study is currently being planned to further explore this hypothesis.
Footnotes
Provenance: Submitted article, peer reviewed.
Conflict of interest: D-H. Park reports support from PRACTIS – the Clinician Scientist Program at Hannover Medical School, funded by the German Research Foundation (DFG, ME 3696/3-1). J-C. Kamp reports no conflicts of interest. B. Seeliger reports consultancy fees from Boehringer Ingelheim, GlaxoSmithKline and AstraZeneca, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, GlaxoSmithKline and AstraZeneca. M.M. Hoeper reports consultancy fees from Acceleron, Actelion, AOP Health, Bayer, Ferrer, GossamerBio, Inhibikase, Janssen, Keros, MSD and Novartis, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Actelion, AOP Health, Bayer, Ferrer, Janssen and MSD. K.M. Olsson reports consultancy fees from Acceleron, Actelion, AOP Health, Bayer, Ferrer, Janssen and MSD, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Actelion, AOP Health, Bayer, Ferrer, Janssen and MSD.
Support statement: This work was funded by Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH), Hannover, Germany, a member of the German Center for Lung Research (DZL).
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