Idiopathic PAH in a young woman — case discussion

Presentation

Practice case (not a real patient). A 38-year-old woman in Australia has 18 months of breathlessness on progressively less exertion, now with less than ordinary activity, and has had two episodes of near syncope on stairs.^[1] She has no known heart or lung disease, no history of pulmonary embolism, no family history of PAH and takes no regular medicines.

Step 1 — Is this an emergency, and where does she go?

Discussion:

• ESC/ERS 2022 names dyspnoea on progressively minor exertion as the cardinal symptom, and the time from symptom onset to diagnosis remains over 2 years, with most patients presenting with advanced disease.^[1]
• Warning signs listed with Figure 6 include rapid progression of symptoms, severely reduced exercise capacity, pre-syncope or syncope on mild exertion, and signs of right heart failure.^[1]
• ESC/ERS 2022 warning signs include rapidly evolving or severe symptoms (WHO-FC III/IV), clinical signs of RV failure, syncope, signs of a low cardiac output state, poorly tolerated arrhythmias and compromised or deteriorated haemodynamic status (hypotension, tachycardia); such patients must be managed immediately as inpatients for initial work-up at a nearby hospital or PH centre, and RV dysfunction on echocardiography, elevated cardiac biomarkers and/or haemodynamic instability must prompt referral to a PH centre for immediate assessment.^[1]
• Her breathlessness with less than ordinary activity (WHO-FC III) counts as severe symptoms (WHO-FC III/IV), a warning sign, so she must be managed immediately as an inpatient for initial work-up, not as a routine outpatient.^[1]

Step 2 — Non-invasive work-up

Her ECG shows right axis deviation and her NT-proBNP is raised. Echocardiography shows a peak TRV of 3.6 m/s, a flattened interventricular septum (LV eccentricity index 1.3 in systole) and a right atrial area of 22 cm².^[1]

Discussion:

• In adults with suspected PH, right axis deviation has a high predictive value for PH.^[1]
• ESC/ERS 2022: echocardiography is recommended as the first-line, non-invasive diagnostic investigation in suspected PH (Class I, Level B), and it is recommended to assign an echocardiographic probability of PH based on an abnormal TRV and other echocardiographic signs suggestive of PH (Class I, Level B).^[2]
• Her TRV lies in the above 3.4 m/s band of Figure 5, and her septal flattening with an LV eccentricity index above 1.1 (category A) and RA area above 18 cm² (category C) are signs from two Table 10 categories.^[1]
• With an intermediate/high probability of PH, warning signs and a raised NT-proBNP, she should be referred to a PH centre for immediate assessment; the PH centre performs an invasive assessment according to the clinical scenario.^[1]
• A V/Q or perfusion lung scan is recommended in unexplained PH to assess for CTEPH (ESC/ERS 2022, Class I, Level C); hers is normal.^[2]
• Routine biochemistry, haematology, immunology, HIV testing and thyroid function tests are recommended in all patients with PAH to identify associated conditions (ESC/ERS 2022, Class I, Level C); hers find none.^[2]

Step 3 — Right heart catheterisation and vasoreactivity

At the PH centre, RHC shows mPAP 46 mmHg, PAWP 10 mmHg, right atrial pressure 9 mmHg, cardiac index 2.3 L/min/m² and PVR 9 WU. With inhaled nitric oxide, mPAP falls to 44 mmHg with unchanged cardiac output.^[1][2]

Discussion:

• RHC is recommended to confirm the diagnosis of PH (especially PAH or CTEPH) and to support treatment decisions (ESC/ERS 2022, Class I, Level B); her values meet pre-capillary PH (mPAP >20 mmHg, PAWP ≤15 mmHg, PVR >2 WU).^[2][1]
• PAH is pre-capillary PH in the absence of other causes of pre-capillary PH; Table 6 lists idiopathic PAH alongside heritable, drug- and toxin-associated and associated forms, and with none of those features found she is treated here as idiopathic PAH.^[1]
• ESC/ERS 2022: vasoreactivity testing is recommended in idiopathic, heritable or drug-associated PAH (her idiopathic PAH is one of these) to detect patients who can be treated with high doses of a CCB (Class I, Level B), and a positive response needs a fall in mPAP of 10 mmHg or more to 40 mmHg or less with an increased or unchanged cardiac output (Class I, Level C); her 2 mmHg fall is negative.^[2]
• CCBs are therefore not recommended for her, unless prescribed for other indications (ESC/ERS 2022, Class III, Level C).^[2]

Step 4 — Risk and initial therapy

She is in WHO-FC III, with a 6-minute walk distance of 380 m and an NT-proBNP of 700 ng/L. She has no signs of right heart failure.^[1]

Discussion:

• At diagnosis a three-strata model is recommended, using all available data including haemodynamics (ESC/ERS 2022, Class I, Level B).^[2]
• On Table 16 her WHO-FC III, 6MWD of 380 m (165–440 m), NT-proBNP of 700 ng/L (300–1100 ng/L), RAP of 9 mmHg (8–14 mmHg) and cardiac index of 2.3 L/min/m² (2.0–2.4) all sit in the intermediate-risk column (estimated 1-year mortality 5–20%).^[1]
• She has no cardiopulmonary comorbidities and is at intermediate risk, so initial combination therapy with a PDE5i and an ERA is recommended (ESC/ERS 2022, Class I, Level B; GRADE: low quality, conditional); ambrisentan with tadalafil is one Class I, Level B combination.^[2]
• Her RAP, cardiac index and PVR do not reach the examples of severe haemodynamic impairment (RAP ≥20 mmHg, cardiac index <2.0 L/min/m², SVI <31 mL/m² and/or PVR ≥12 WU) that would bring initial triple therapy into consideration at intermediate risk.^[1]
• ESC/ERS 2022 Table 19 gives ambrisentan 5 mg once daily rising to 10 mg once daily, and tadalafil 20 or 40 mg once daily with a target of 40 mg once daily.^[1]
• The general measures recommended by ESC/ERS 2022 include supervised exercise training under medical therapy (Class I, Level A), psychosocial support (Class I, Level C) and immunisation against SARS-CoV-2, influenza and Streptococcus pneumoniae (Class I, Level C).^[2]

Step 5 — Follow-up

After 4 months she is in WHO-FC II, walks 400 m in 6 minutes and her NT-proBNP is 450 ng/L.^[1]

Discussion:

• During follow-up a four-strata model based on WHO-FC, 6MWD and BNP/NT-proBNP is recommended, with additional variables taken into account as necessary (ESC/ERS 2022, Class I, Level B).^[2]
• Her grades are 1 (WHO-FC II), 2 (6MWD 320–440 m) and 2 (NT-proBNP 300–649 ng/L); dividing the sum by the number of variables and rounding to the next integer gives 2, intermediate–low risk.^[1]
• ESC/ERS 2022: at intermediate–low risk on ERA/PDE5i therapy, addition of selexipag should be considered (Class IIa, Level B), and switching from PDE5i to riociguat may be considered (Class IIb, Level B).^[2]
• The 2026 ERS update recommends add-on sotatercept in PAH patients already receiving PAH drugs at intermediate–low, intermediate–high or high risk of death during follow-up, with treatment in PH centres.^[15]
• Achieving and maintaining a low-risk profile on optimised medical therapy is recommended as a treatment goal in PAH (ESC/ERS 2022, Class I, Level B).^[2]

Step 6 — Contraception and pregnancy

Discussion:

• The 2025 ESC pregnancy guideline recommends clear contraceptive advice for women of childbearing potential with PAH (Class I, Level C).^[3]
• If she wishes to become pregnant, multidisciplinary counselling about the very high risk of pregnancy-related adverse events, with shared decision-making, is recommended (ESC 2025, Class I, Level C).^[3]
• ERAs, riociguat and selexipag are not recommended during pregnancy (ESC 2025, Class III, Level C), so her ambrisentan matters here; PAH therapies that can be used during pregnancy include PDE5 inhibitors and prostacyclin analogues.^[3]

Step 7 — The Australian context

Discussion:

• No Australian or New Zealand PH guideline was found in the census for this topic.
• In a cohort study of PAH patients from the PHSANZ registry diagnosed from 2004 to 2017 (2044 included in the analysis), the median diagnostic interval was 1.2 years, and a longer interval was associated with lower 5-year survival.^[11]