Pulmonary Hypertension — Causes, Classification, Diagnosis & PAH Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Pulmonary hypertension (PH) is defined haemodynamically as a mean pulmonary arterial pressure (mPAP) above 20 mmHg at rest measured by right heart catheterisation (RHC) — the gold standard diagnostic procedure. The updated ESC/ERS 2022 definition lowered the diagnostic threshold from the previous mPAP above 25 mmHg to above 20 mmHg, recognising that even modestly elevated pulmonary pressures increase mortality risk. PH is a complex clinical syndrome — not a single disease — with diverse aetiologies, classified by the WHO into 5 groups based on pathophysiology, haemodynamics, and treatment approach. Group 1 (pulmonary arterial hypertension — PAH) is the most studied form, characterised by obliterative remodelling of the small pulmonary arterioles causing progressive increase in pulmonary vascular resistance (PVR) and right ventricular pressure overload leading to right heart failure and death; PAH-specific vasodilator therapies target endothelin, nitric oxide, and prostacyclin pathways. Groups 2-5 represent PH secondary to other conditions — left heart disease (the most common cause of PH overall — Group 2), lung diseases and hypoxia (Group 3), chronic thromboembolic pulmonary hypertension (CTEPH — Group 4), and miscellaneous (Group 5). PAH is rare — approximately 15-60 cases per million — but is severe, progressive, and without modern treatment, has a 3-year survival of approximately 35%. With modern combination targeted therapy, 3-year survival approaches 75-80% in expert centres. All suspected PH should be referred to a designated specialist PH centre.

WHO/ESC Classification Groups: Group 1 — Pulmonary Arterial Hypertension (PAH): characterised by vasoconstriction and obliterative remodelling of pulmonary arterioles, with three pathological pathways — endothelin overproduction (vasoconstriction and proliferation), reduced nitric oxide bioavailability (impaired vasodilation), and reduced prostacyclin (pro-thrombotic and vasoconstrictive); includes idiopathic PAH (iPAH — the most common subgroup, predominantly affecting young women; female-to-male ratio 3:1; peak age 30-50); heritable PAH (BMPR2 mutation — bone morphogenetic protein receptor type 2 — present in 70% of familial PAH and 20% of idiopathic PAH; EIF2AK4, KCNK3, CAV1 mutations also identified); drug and toxin-induced PAH (anorexigens — aminorex, fenfluramine derivatives; now-withdrawn weight-loss drugs; methamphetamine — increasingly recognised; dasatinib — tyrosine kinase inhibitor); connective tissue disease-associated PAH (the most common form of associated PAH — systemic sclerosis/scleroderma: affects 10-15% of SSc patients, particularly limited cutaneous SSc with anti-centromere antibodies; SLE; MCTD; RA); HIV-associated PAH (0.5% of HIV-positive patients); portal hypertension-associated PAH (portopulmonary hypertension — in cirrhosis); and congenital heart disease-associated PAH (Eisenmenger syndrome — left-to-right cardiac shunt reversal from progressive pulmonary arterial remodelling). Group 2 — PH due to left heart disease: the most prevalent form of PH overall; post-capillary PH from elevated left atrial pressure transmitted retrogradely; causes include HFpEF, HFrEF, mitral valve disease, aortic valve disease; characterised by PCWP above 15 mmHg on RHC; targeted PAH therapies are not effective and may be harmful. Group 3 — PH due to chronic lung disease and/or hypoxia: hypoxia-driven pulmonary vasoconstriction in COPD (most common), interstitial lung disease, sleep apnoea, and high-altitude disease; treat underlying lung disease and hypoxia. Group 4 — Chronic thromboembolic PH (CTEPH): organised thrombus after acute PE causing fixed mechanical obstruction; occurs in 0.5-3.8% of PE survivors; uniquely potentially curable with pulmonary endarterectomy (PEA). Group 5 — PH with unclear/multifactorial mechanisms: haematological (myeloproliferative disorders, haemolytic anaemia), systemic (sarcoidosis, Langerhans cell histiocytosis, neurofibromatosis), metabolic (glycogen storage disease, Gaucher disease), and other conditions.

PH symptoms develop insidiously — the average delay from symptom onset to diagnosis is 2-3 years. Initial symptoms are non-specific and easily attributed to deconditioning or comorbidities. WHO Functional Class (FC) characterises symptom severity: FC I — no symptoms at rest or ordinary activity; FC II — symptoms during ordinary activity; FC III — symptoms with minimal exertion; FC IV — symptoms at rest or inability to carry out any physical activity. Progressive dyspnoea on exertion is the most common and earliest symptom — worsening over months to years. Fatigue and reduced exercise tolerance (6-minute walk distance below 380 metres is associated with worse prognosis — 6MWD is a key clinical endpoint in PAH trials). Syncope or pre-syncope: exertional dizziness or fainting from inability to increase cardiac output during exercise — an important symptom indicating high-risk disease. Chest pain (exertional): from right ventricular ischaemia — the dilated hypertrophied RV outgrows its coronary blood supply. Palpitations from right heart arrhythmias. Haemoptysis: from rupture of dilated pulmonary arterioles or in situ thrombosis. Signs of right heart failure (cor pulmonale): elevated JVP with prominent V waves (tricuspid regurgitation); right ventricular heave (visible or palpable pulsation at the left parasternal edge); loud accentuated P2 (pulmonary closure sound — audible at the left sternal border and even at the apex in advanced PH — from high pulmonary arterial pressure); tricuspid regurgitation murmur (pansystolic, heard at the left sternal edge); and, in advanced right heart failure: peripheral oedema (ankle swelling, ascites), hepatomegaly (from hepatic venous congestion), and low cardiac output state (cool peripheries, reduced pulse pressure, hypotension). Scleroderma-associated features: skin thickening, Raynaud's phenomenon, telangiectasia, calcinosis, dysphagia — in connective tissue disease-associated PAH.

Echocardiography (transthoracic — TTE): the essential non-invasive screening tool for PH — estimates pulmonary artery systolic pressure (PASP) using the tricuspid regurgitation jet velocity (PASP = 4 x TR velocity squared + right atrial pressure); identifies features of RV dilatation, RV hypertrophy, flattened or D-shaped interventricular septum, pericardial effusion (marker of severe PH), and left heart disease. ESC probability of PH: PASP above 50 mmHg or TR velocity above 3.4 m/s — high probability. Echocardiogram does not provide a haemodynamic diagnosis — right heart catheterisation is mandatory. ECG: right axis deviation, right ventricular hypertrophy (dominant R wave in V1, deep S waves in V5-V6), right bundle branch block, P-pulmonale (peaked P waves in lead II). High-resolution CT chest (HRCT): identifies parenchymal lung disease (ILD, emphysema — Group 3 PH); mosaic attenuation and peripheral vascular pruning (PAH); cardiomegaly and pericardial effusion. CT pulmonary angiography (CTPA): excludes CTEPH (chronic thromboembolic obstruction — persistent filling defects at 3-6 months after anticoagulation for PE). V/Q scan: highly sensitive for CTEPH — preferred over CTPA for detecting organised peripheral thromboembolic disease. Pulmonary function tests (PFTs): spirometry (obstructive — COPD; restrictive — ILD), diffusion capacity (DLCO — reduced in PAH from vascular loss, and in ILD; normal in left heart disease PH). 6-minute walk test (6MWT): standardised functional capacity assessment — 6MWD below 380 metres at diagnosis predicts poorer outcomes; used serially to monitor treatment response; reference endpoint in PAH trials. Biomarkers: NT-proBNP and BNP — reflect right ventricular wall stress; elevated in PAH (NT-proBNP above 300 ng/L is a high-risk marker; target below 300 on treatment); troponin I (elevated in severe RV ischaemia). Blood tests: ANA, anti-dsDNA, anti-Scl-70, anti-centromere (connective tissue disease); HIV; liver function tests and USS abdomen (portopulmonary hypertension); haematology (myeloproliferative disease). Right heart catheterisation (RHC): the definitive diagnostic investigation — mandatory to confirm PH diagnosis before initiating PAH-specific therapy; measures mPAP (above 20 mmHg), PCWP (wedge pressure above 15 mmHg distinguishes post-capillary/Group 2 from pre-capillary/Group 1 PH), cardiac output (Fick or thermodilution), PVR (above 2 Wood units = pre-capillary PH), and mixed venous oxygen saturation. Vasoreactivity testing during RHC (inhaled nitric oxide, adenosine, or epoprostenol): identifies acute vasodilator responders (a positive response — mPAP falls above 10 mmHg to below 40 mmHg) in idiopathic PAH (~10-15% of iPAH patients) who benefit from high-dose calcium channel blockers (amlodipine, diltiazem, nifedipine).

Group 1 PAH — targeted vasodilator therapy (targeting the three key pathways): Endothelin receptor antagonists (ERA): ambrisentan (5-10 mg daily); macitentan (10 mg daily — SERAPHIN trial: 45% reduction in morbidity-mortality); bosentan (62.5-125 mg twice daily). Phosphodiesterase-5 (PDE5) inhibitors: sildenafil (20 mg three times daily); tadalafil (40 mg once daily — PHIRST trial). Soluble guanylate cyclase (sGC) stimulator: riociguat (1-2.5 mg three times daily — PATENT trial; also licensed for CTEPH — approved by FDA; only therapy licensed for both Group 1 PAH and Group 4 CTEPH). Prostacyclin pathway agonists: epoprostenol (IV continuous infusion — the only treatment proven to improve survival in RCT in PAH; gold standard for WHO FC IV and high-risk PAH; central venous catheter required; dose titrated from 2 ng/kg/min); iloprost (inhaled 6-9 times daily); treprostinil (subcutaneous infusion or IV); selexipag (Uptravi — oral IP prostacyclin receptor agonist; GRIPHON trial: 40% reduction in morbidity-mortality composite endpoint; approved for PAH as an add-on). ESC/ERS 2022 guidelines recommend risk stratification at diagnosis (low, intermediate-low, intermediate-high, high risk based on WHO FC, 6MWT, NT-proBNP, haemodynamics, imaging): initial combination therapy recommended for most patients. Upfront dual combination therapy (ERA plus PDE5 inhibitor): ambrisentan plus tadalafil (AMBITION trial — 50% reduction in clinical failure vs. either monotherapy) is the most evidence-supported first-line combination for Group 1 PAH. Triple therapy (ERA plus PDE5i plus selexipag or prostacyclin) for high-risk or intermediate-risk patients not meeting treatment goals. Urgent listing for lung transplantation for PAH patients with WHO FC III-IV despite maximal medical therapy — bilateral sequential lung transplantation or heart-lung transplantation; 5-year post-transplant survival approximately 50-55%. Group 2 PH (left heart disease): treat underlying left heart disease — optimise diuresis, ACE inhibitor/ARNI (sacubitril/valsartan — PARADIGM-HF), beta-blockers for HFrEF; PAH-specific vasodilators are not indicated and may cause pulmonary oedema by unmasking increased PCWP. Group 3 PH (lung disease): treat underlying lung disease; supplemental oxygen (target SpO2 above 92%); CPAP/NIV for sleep-disordered breathing; PAH drugs not indicated in most cases. Group 4 CTEPH: pulmonary endarterectomy (PEA) is the curative treatment — removes organised thromboembolic material from proximal pulmonary arteries; performed at specialist CTEPH centres; perioperative mortality approximately 2-3% in expert centres; 5-year survival above 80% after PEA. For inoperable or residual CTEPH: riociguat (the only approved medical therapy — improves 6MWT and PVR); balloon pulmonary angioplasty (BPA) — repeated catheter-based dilation of organised thromboembolic lesions in distal vessels; complementary to riociguat.

Right ventricular failure (cor pulmonale): the primary driver of morbidity and mortality in PAH — progressive RV pressure overload leads to RV dilatation, hypertrophy, and ultimately failure with reduced cardiac output, elevated filling pressures, and backward failure causing hepatic congestion (congestive hepatopathy — elevated bilirubin, coagulopathy from hepatic synthetic dysfunction), peripheral oedema, ascites, and anasarca. Arrhythmias: atrial flutter and atrial fibrillation are particularly poorly tolerated in PH — sudden loss of right atrial kick dramatically reduces cardiac output; urgent cardioversion or rate control with careful drug selection (avoid drugs reducing RV contractility or causing hypotension). Haemoptysis: from rupture of dilated pulmonary arterioles, in situ pulmonary arterial thrombosis, or bronchial artery aneurysms — life-threatening massive haemoptysis requires immediate bronchial artery embolisation. Paradoxical embolism through a patent foramen ovale (PFO) — which dilates in the context of elevated right atrial pressure — causing systemic thromboembolism and stroke; closure not routinely recommended. Sudden death: particularly in World Functional Class IV or during exercise; from fatal arrhythmia, haemoptysis, or hypoxaemia. Pregnancy: PAH is associated with a maternal mortality of 30-56% in pregnancy — pregnancy is strongly contraindicated in all PAH patients; reliable contraception is essential. Central line complications (for IV prostacyclin): line infection, catheter blockage, and device-related bloodstream infection causing sepsis from epoprostenol or treprostinil IV therapy — pump failure or accidental cessation can cause fatal acute haemodynamic deterioration — patients and carers must be trained in emergency procedures.

Prevention of PAH: avoidance of established risk factors — particularly anorexigenic drugs and amphetamine derivatives (eliminated from the market but illicit methamphetamine use is an emerging risk); prompt treatment of HIV infection (ART reduces but does not eliminate HIV-PAH risk); adequate management of connective tissue diseases with regular echocardiographic screening for early PAH detection (annual echo in all patients with systemic sclerosis — limited cutaneous particularly, as anti-centromere antibody positivity and reduced DLCO identify high-risk individuals for developing PAH). Prevention of Group 4 CTEPH: adequate anticoagulation for acute PE (minimum 3 months; consider longer for unprovoked events); investigating persistent dyspnoea at 3-6 months after PE with V/Q scan to detect subclinical CTEPH early. Monitoring in established PAH (every 3-6 months in specialist centres): 6MWT; NT-proBNP; RV function on echocardiography; clinical assessment of WHO FC; right heart catheterisation (every 6-12 months in high-risk or therapy-escalating patients — the only way to reliably measure haemodynamics); assessment of treatment goals (low-risk or intermediate-low-risk status on all three risk assessment criteria: WHO FC I-II, 6MWT above 440 metres, NT-proBNP below 300 ng/L). Supportive management: diuretics for volume overload; supplemental oxygen for SpO2 below 92%; supervised pulmonary rehabilitation (safe and beneficial in stable compensated PAH); anticoagulation (warfarin INR 2-3 for iPAH with no contraindication — reduces in situ thrombosis; less clear evidence for other PAH subgroups — use clinical judgement and patient preference). Influenza and pneumococcal vaccination for all PAH patients — infections precipitate acute clinical decompensation.

Go to A&E immediately for: acute clinical deterioration in a known PH patient — sudden worsening breathlessness, pre-syncope or syncope (low cardiac output), haemoptysis, or symptoms of right heart failure with haemodynamic instability; any acute infection in a PH patient (fever, worsening breathlessness, worsening oedema) — infections precipitate acute on chronic right heart failure and may require IV diuretic therapy, antibiotic treatment, and haemodynamic monitoring. Report device alarms immediately: patients on IV prostacyclin (epoprostenol, treprostinil) must contact their specialist PH centre immediately if the pump alarm activates or if the infusion stops — accidental discontinuation of IV prostacyclin can cause fatal acute haemodynamic deterioration within minutes to hours. See a GP urgently for assessment and specialist referral if: progressive unexplained breathlessness on exertion despite normal cardiac and respiratory investigations — particularly in young women, patients with connective tissue diseases, or anyone with a strong family history of PH; exertional pre-syncope or syncope; or unexplained elevated JVP and peripheral oedema in a young to middle-aged patient. All suspected PH should be referred to a designated NHS PH specialist centre for echocardiography and right heart catheterisation — delay in diagnosis is common and associated with more advanced disease at presentation.