What is pulmonary hypertension?

Pulmonary hypertension (PH) is high blood pressure in the pulmonary arteries (the blood vessels from the heart to the lungs). Formally defined as mean pulmonary arterial pressure (mPAP) ≥20 mmHg measured by right heart catheterisation (updated ESC 2022 threshold — previously 25 mmHg). PH is not a single disease — the WHO classification has 5 groups: Group 1 (PAH): primary disease of pulmonary arterioles — rare, specific treatments. Groups 2-5: PH secondary to left heart disease, lung disease, thromboemboli or miscellaneous causes. The distinction matters clinically: PAH-specific drugs (Group 1) can worsen outcomes if given to patients with Group 2 PH (left heart disease) — they increase pulmonary blood flow but the backed-up left ventricle cannot handle it, causing flash pulmonary oedema.

What is pulmonary arterial hypertension (PAH)?

PAH (WHO Group 1) is a rare, devastating vasculopathy of the pulmonary arterioles — not explained by left heart disease or lung disease. Pathology: endothelial dysfunction → vasoconstriction + smooth muscle cell proliferation + vascular remodelling → progressive increase in pulmonary vascular resistance (PVR) → right ventricular pressure overload → right heart failure → death. Causes: idiopathic (no identifiable cause); heritable (BMPR2 mutations — ~70% of familial PAH); drugs (fenfluramine appetite suppressants — now withdrawn; methamphetamine; dasatinib); associated conditions (systemic sclerosis — most common; HIV; portal hypertension; congenital heart disease). Untreated, median survival was 2.8 years. Modern targeted therapy has substantially improved this.

What treatments exist for PAH?

Three molecular pathways are therapeutically targeted: (1) Prostacyclin pathway (prostacyclin is deficient in PAH): IV epoprostenol (gold standard for severe PAH — continuous infusion; oldest and most proven drug); SC/IV treprostinil; inhaled iloprost; oral selexipag (GRIPHON trial: 40% morbidity/mortality reduction). (2) Endothelin pathway (endothelin-1 is elevated — promotes vasoconstriction and proliferation): bosentan, ambrisentan, macitentan (SERAPHIN: 45% morbidity/mortality reduction). (3) Nitric oxide pathway (NO is deficient — normally causes vasodilation via cGMP): sildenafil, tadalafil (PDE5 inhibitors); riociguat (sGC stimulator). ESC/ERS 2022 recommends initial triple combination for most incident PAH — maximising all three pathways from the start.

Why is epoprostenol so dangerous to interrupt?

Epoprostenol (Flolan and generic) is an intravenous infusion with a half-life of approximately 3-5 minutes. If the infusion is interrupted — pump battery failure, line occlusion, accidental disconnection, kinking of the infusion tubing — patients experience rebound pulmonary vasoconstriction within minutes. The pulmonary arteries, accustomed to the vasodilating drug, constrict dramatically → immediate, catastrophic rise in PVR → right heart failure → cardiac arrest. This is called rebound pulmonary hypertension and it can be fatal within minutes. Patients and their carers must understand this risk. Backup pumps, extra medication and emergency plans are essential. Patients with epoprostenol infusions cannot travel without careful planning.

What is CTEPH and can it be cured?

Chronic thromboembolic pulmonary hypertension (CTEPH, WHO Group 4) occurs when pulmonary emboli (clots) are not completely dissolved but organise into fibrotic obstructive material in the pulmonary arteries — unlike typical PE which resolves completely. CTEPH occurs in approximately 2-4% of patients after acute PE. The critical distinction from PAH: CTEPH has a potential cure — surgical pulmonary endarterectomy (PEA), which physically removes the organized thromboembolic material via open heart surgery under deep hypothermic circulatory arrest at specialised centres. PEA achieves normal or near-normal pressures in approximately 70-80% of operated patients. For inoperable cases (distal disease): riociguat (Adempas) — the only drug approved specifically for CTEPH — and balloon pulmonary angioplasty (BPA) at specialised centres.

How does GMJ News cover pulmonary hypertension?

GMJ News covers WHO Group 1-5 classification, PAH epidemiology and prognosis, right heart catheterisation diagnosis, triple combination therapy, epoprostenol (lifesaving and lethal if interrupted), BMPR2 genetics, systemic sclerosis PAH screening, CTEPH and pulmonary endarterectomy, REVEAL risk stratification, and CTEPH balloon pulmonary angioplasty. Pulmonary hypertension — rare but devastating — is directly relevant to PHIG's cardiovascular medicine programme and Georgia's rare disease policy.

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Pulmonary Hypertension

GMJ News knowledge hub · last reviewed September 2026 · Georgian Medical Journal

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Pulmonary hypertension (PH) — defined as a mean pulmonary arterial pressure ≥20 mmHg at rest on right heart catheterisation (updated ESC/ERS 2022 criteria) — ranges from the common secondary forms (WHO Group 2: left heart disease; Group 3: chronic lung disease) to the devastating and specifically treatable pulmonary arterial hypertension (PAH, WHO Group 1), where progressive proliferative vasculopathy of the pulmonary arterioles causes right heart failure and death with a median untreated survival of approximately 2.8 years (WHO). IV epoprostenol — the first approved PAH therapy (FDA 1995) — remains the gold standard for severe/refractory PAH, while the modern era of triple combination therapy targeting all three pathways (prostacyclin, endothelin and nitric oxide) has transformed PAH from a uniformly fatal diagnosis into a chronic manageable condition for many patients.

Key messages

PAH — untreated median survival 2.8 years — now a manageable chronic condition

Untreated pulmonary arterial hypertension (PAH) carried a median survival of approximately 2.8 years (D'Alonzo 1991 NIH registry). Modern triple combination therapy targeting all three pathways has dramatically improved survival — with 3-year survival in treated PAH now exceeding 70% in specialised centres.

Right heart catheterisation — the diagnostic gold standard

PAH can only be definitively diagnosed by right heart catheterisation (RHC): mPAP ≥20 mmHg + PAWP ≤15 mmHg + PVR ≥2 Wood units (updated ESC 2022 criteria). Echocardiography is a screening tool — it cannot diagnose PAH. Any patient with echocardiographic evidence of pulmonary hypertension requires RHC for definitive diagnosis.

Triple combination therapy — the modern standard

ESC/ERS 2022 PAH guidelines recommend initial oral triple combination for most incident PAH patients: ERA (endothelin receptor antagonist) + PDE5i (phosphodiesterase-5 inhibitor) + prostacyclin pathway agonist. Triple therapy produces superior outcomes vs sequential monotherapy/dual therapy. For high-risk patients: IV/subcutaneous prostanoid (epoprostenol or treprostinil) must be included.

Epoprostenol — the lifesaving IV drug you cannot stop

IV epoprostenol (Flolan) — FDA approved 1995 as the first PAH-specific drug — remains the gold standard for WHO functional class III-IV PAH and is the only PAH drug with a mortality benefit from an RCT. The critical safety issue: epoprostenol has a half-life of approximately 3-5 minutes. Abrupt discontinuation causes fatal rebound pulmonary hypertension. Pump failure, line occlusion or accidental disconnection can kill within minutes.

WHO groups 1-5 — not all PH is PAH

WHO Group 1 (PAH): specific vasoproliferative disease — idiopathic, heritable (BMPR2), drug-induced, connective tissue disease, HIV, portopulmonary. Group 2: left heart disease (the most common cause of PH — these patients should NOT receive PAH-specific drugs, which can cause pulmonary oedema). Group 3: lung disease/hypoxia. Group 4: CTEPH (chronic thromboembolic PH — potentially curable by pulmonary endarterectomy; riociguat for inoperable). Group 5: multifactorial.

BMPR2 mutations — the genetic basis of heritable PAH

Approximately 70% of heritable PAH (hPAH) cases are caused by mutations in BMPR2 (bone morphogenetic protein receptor type 2) — which normally suppresses pulmonary vascular smooth muscle cell proliferation. Female carriers have approximately 20% lifetime penetrance; male carriers approximately 14%. Other hPAH genes: ACVRL1 (hereditary haemorrhagic telangiectasia), ENG, SMAD1/4/8/9, KCNK3, TBX4.

Key statistics

~15-50/million

PAH prevalence in HICs — rare but devastating

ESC/ERS 2022

2.8 years

median untreated PAH survival (NIH registry 1991)

NEJM 1991

>70%

3-year survival with modern PAH therapy in specialised centres

ESC/REVEAL 2.0

FDA 1995

IV epoprostenol — first approved PAH drug; still gold standard for severe disease

FDA

3-5min

epoprostenol half-life — rebound PH = death if infusion interrupted acutely

Pharmacology

~70%

of hereditary PAH caused by BMPR2 mutations

ESC/Genetics

PAH treatment — three pathway targets and approved drug classes

Source: ESC/ERS 2022. All three pathways should be targeted; triple combination is now the standard of care.

Glossary of key terms

Prostacyclin and the prostacyclin pathway
PharmacologyProstacyclin (PGI2) is produced by pulmonary vascular endothelial cells — causing vasodilation and inhibiting smooth muscle cell proliferation and platelet aggregation. In PAH, prostacyclin production is reduced and thromboxane A2 (pro-constrictive, pro-proliferative) is increased — shifting the balance toward vasoconstriction and proliferation. PAH prostacyclin drugs: epoprostenol (IV only, short half-life); iloprost (inhaled, 6-9 times daily); treprostinil (IV, SQ, inhaled, oral — Orenitram); selexipag (Uptravi, oral IP receptor agonist — GRIPHON trial: 40% reduction in morbidity/mortality composite).

REVEAL 2.0 risk calculator
ESC/ChestThe REVEAL (Registry to Evaluate Early And Long-term PAH disease management) 2.0 risk calculator: assesses low/intermediate/high 1-year mortality risk from: 6MWD; WHO functional class; NT-proBNP; mRAP; mPAP; PAWP; cardiac index; eGFR; mean systolic BP; echocardiographic parameters; DLCO. ESC/ERS 2022 guidelines embed risk-stratification into treatment algorithms: target low-risk status; escalate therapy if intermediate or high risk.

Pulmonary endarterectomy (PEA) for CTEPH
ESCChronic thromboembolic pulmonary hypertension (CTEPH, WHO Group 4): obstructive organized thromboembolic material in pulmonary arteries — potentially curable by surgical pulmonary endarterectomy (PEA). PEA removes chronic thromboembolic material from the pulmonary arteries via median sternotomy under deep hypothermic circulatory arrest — a highly specialised operation offering potential cure. For inoperable or residual CTEPH: riociguat (Adempas, sGC stimulator — only PAH drug approved specifically for CTEPH) and balloon pulmonary angioplasty (BPA).

Macitentan (Opsumit)
FDA/EMA 2013A dual endothelin receptor antagonist (ERA) — blocking both ETA and ETB receptors; improved tissue penetration vs older ERAs. SERAPHIN trial (NEJM 2013): macitentan 10mg reduced time to first morbidity/mortality event by 45% vs placebo (long-term event-driven trial — the first PAH trial with morbidity/mortality primary endpoint). Teratogenic — requires double contraception (REMS programme). Hepatotoxicity monitoring required.

Vasoreactivity testing in PAH
ESC/AHAAt the time of diagnostic RHC, acute vasodilator challenge (adenosine, epoprostenol or inh. NO) is performed in idiopathic/heritable PAH. A positive response: mPAP fall >10 mmHg to an absolute mPAP <40 mmHg with increased/unchanged cardiac output. Approximately 10-15% of iPAH are vasoreactive (predominantly KCNK3 mutations). Vasoreactive patients can be treated with oral calcium channel blockers (amlodipine, diltiazem — NOT verapamil) alone initially — potentially normalising pressures (rare but possible).

Connective tissue disease PAH (CTD-PAH)
ESC/RheumatologySystemic sclerosis (SSc, scleroderma) is the most common connective tissue disease causing PAH — approximately 10% of systemic sclerosis patients develop PAH (the main cause of mortality in limited cutaneous SSc). SSc-PAH has a poorer prognosis than iPAH, even with treatment, due to concurrent ILD, cardiac involvement and reduced vasoreactivity. Annual echocardiographic screening for PAH is recommended for all systemic sclerosis patients.