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

Pulmonary hypertension (PH) is a haemodynamic condition defined by elevated mean pulmonary arterial pressure (mPAP) of 20 mmHg or greater at rest, measured by right heart catheterisation — the gold standard diagnostic test. PH causes progressive obstruction to right ventricular outflow, right ventricular hypertrophy, dilation, and ultimately right heart failure. The 2022 ESC/ERS guidelines revised the diagnostic threshold from 25 mmHg to 20 mmHg mPAP, based on evidence that values above 20 mmHg are associated with adverse outcomes. The WHO 2022 classification system organises PH into 5 groups based on aetiology, pathophysiology, and therapeutic approach: Group 1 — Pulmonary arterial hypertension (PAH): idiopathic PAH, heritable PAH (BMPR2, ALK1, ENG gene mutations), drug/toxin-induced PAH (anorexigens — aminorex, fenfluramine; amphetamines; dasatinib), and PAH associated with connective tissue diseases (systemic sclerosis is the leading CTD-associated PAH — prevalence 8-12%), congenital heart disease, HIV infection, or portal hypertension. Group 2 — PH due to left heart disease (the most common group): PH from LV systolic or diastolic dysfunction, mitral stenosis/regurgitation. Group 3 — PH due to lung disease: COPD, ILD (particularly IPF), sleep-disordered breathing. Group 4 — Chronic thromboembolic PH (CTEPH): from unresolved pulmonary emboli. Group 5 — PH with unclear mechanisms: haematological disorders, systemic/metabolic disorders. Accurate group classification is essential because PAH-specific therapies (Group 1) are not effective and may be harmful in Groups 2-3. PAH is the most complex and therapeutically accessible form.

The pathophysiology of PAH (Group 1) involves three pathological processes in the pulmonary vasculature: vasoconstriction (excessive pulmonary arterial smooth muscle constriction — driven by imbalance between vasodilator mediators (nitric oxide — NO, prostacyclin — PGI2) and vasoconstrictors (endothelin-1, thromboxane A2)); vascular remodelling (intimal proliferation, smooth muscle hypertrophy, and adventitial fibrosis — plexiform lesions are pathognomonic for PAH); and thrombosis in situ (thrombotic microangiopathy). The key genetic cause of heritable PAH: BMPR2 (bone morphogenetic protein receptor type 2) mutations — present in 70-80% of familial PAH and 20% of sporadic idiopathic PAH; BMPR2 normally suppresses pulmonary artery smooth muscle proliferation — loss of function leads to uncontrolled smooth muscle and endothelial cell growth. Drug and toxin causes: appetite suppressants (aminorex, fenfluramine — withdrawn from markets in 1990s), methamphetamine, dasatinib (BCR-ABL tyrosine kinase inhibitor — used in CML), and SSRIs (possible association with neonatal PAH). CTD-associated PAH: systemic sclerosis (SSc — particularly in limited cutaneous SSc/CREST syndrome — lcSSc; prevalence 8-12%; anti-centromere antibodies associated); SLE, mixed connective tissue disease, and RA. HIV-associated PAH: occurs in approximately 0.5% of HIV-infected individuals; HAART does not reliably improve PAH but improved overall survival provides the background for longer-duration PAH. Portal hypertension-associated PAH (portopulmonary hypertension): complicates liver cirrhosis in 2-6% — worsens transplant candidacy. Congenital heart disease (CHD-PAH): Eisenmenger syndrome (long-standing large left-to-right shunt — ASD, VSD, PDA — causes pulmonary vascular remodelling and eventual shunt reversal to right-to-left — cyanosis).

PAH is characterised by an insidious onset and a significant diagnostic delay — averaging 2-3 years from first symptoms to diagnosis — because early symptoms are non-specific and mimic more common conditions. Exertional dyspnoea: the most common presenting symptom, present in over 95% of PAH patients; initially present only with moderate exertion, progressively worsening to dyspnoea at rest in advanced disease. WHO functional class (modified NYHA): Class I — no symptoms with ordinary activity; Class II — slight limitation; Class III — marked limitation (comfortable at rest but symptomatic with less than ordinary activity); Class IV — symptoms at rest or with any activity; most patients are diagnosed at Class II or III. Fatigue and weakness: profound fatigue disproportionate to level of dyspnoea. Exertional syncope or near-syncope: a critical warning sign of severe PAH — inability to increase cardiac output with exertion leads to hypotension and cerebral hypoperfusion; represents high risk of sudden death; requires urgent assessment and often hospitalisation. Chest pain: atypical chest discomfort from RV ischaemia — right ventricular angina is common in advanced PAH; not related to left coronary artery disease. Palpitations: sinus tachycardia (compensatory response to low stroke volume); supraventricular arrhythmias (SVT, AF) from right atrial dilation. Lower limb oedema: from right ventricular failure causing increased right atrial pressure, hepatic congestion, and peripheral oedema — bilateral, pitting oedema. Signs on examination: elevated JVP, tricuspid regurgitation murmur (pan-systolic, right-sided — increased on inspiration), palpable RV heave, loud P2 (pulmonary component of second heart sound), right-sided S3 gallop, ascites, and cyanosis in advanced disease or Eisenmenger syndrome. Haemoptysis: from pulmonary artery dilation and rupture in severe PAH — uncommon but serious.

PH diagnosis requires haemodynamic confirmation by right heart catheterisation (RHC) — all other investigations are used to assess likelihood and guide the catheterisation protocol. Echocardiography (TTE): the key non-invasive screening investigation — estimates pulmonary arterial systolic pressure (PASP) from tricuspid regurgitant jet velocity (Bernoulli equation); PASP above 40 mmHg warrants further investigation; also identifies RV dilation, RV dysfunction (TAPSE below 18 mm — tricuspid annular plane systolic excursion — indicates RV failure), septal bowing, dilated pulmonary artery (above 29 mm), and pericardial effusion (right heart failure). ESC probability scoring (PH likelihood from echo). ECG: right axis deviation, RV hypertrophy (dominant R-wave in V1), right bundle branch block, P pulmonale (peaked P wave — right atrial enlargement). Chest X-ray: enlarged pulmonary arteries (hilar 'pruning' — prominent central arteries with peripheral vascular pruning), cardiomegaly (right-sided), and pleural effusion. Pulmonary function tests: screen for underlying lung disease (Group 3 PH); typically near-normal FEV1/FVC in PAH; reduced DLCO (gas transfer) — often early and out of proportion to other PFT abnormalities in PAH. CT chest: identify ILD (Group 3), CTEPH (mosaic attenuation on HRCT — Group 4), and CHD. V/Q scan: essential for CTEPH screening — V/Q scan is more sensitive than CTPA for proximal and distal CTEPH; unmatched ventilation-perfusion defects in segmental distribution. Right heart catheterisation (RHC): confirms PH diagnosis (mPAP ≥20 mmHg); measures pulmonary artery wedge pressure (PAWP — normal below 15 mmHg; PAWP above 15 mmHg indicates Group 2/left heart disease as cause); cardiac output (thermodilution or Fick method); pulmonary vascular resistance (PVR = (mPAP - PAWP) / CO — elevated in Group 1 PAH above 3 Wood units); acute vasoreactivity testing with inhaled nitric oxide (NO) or IV adenosine — positive if mPAP falls by ≥10 mmHg to below 40 mmHg; vasoreactors respond to calcium channel blockers (CCBs) and have better prognosis. Genetic testing: BMPR2, ALK1, ENG, SMAD9 mutations for heritable PAH and family counselling. Autoimmune testing: ANA, anti-Scl70, anti-centromere, anti-Ro, anti-La, anti-U1RNP, anti-dsDNA for CTD-associated PAH. Six-minute walk test (6MWT): 6MWT distance and SpO2 nadir are key functional and prognostic markers, used to monitor treatment response.

PAH (Group 1) has the most established targeted therapy — treatment of other PH groups focuses on the underlying cause. Supportive measures for all PH groups: supplemental oxygen for resting hypoxaemia (SpO2 below 90% or PaO2 below 8 kPa); diuretics for right heart failure (furosemide, spironolactone — careful titration to avoid over-diuresis reducing RV preload); supervised exercise training and pulmonary rehabilitation; avoid high altitudes (above 1500-2000 m), vigorous exertion, pregnancy (high mortality in severe PAH — effective contraception mandatory), and drugs worsening PAH (certain stimulants, appetite suppressants). Calcium channel blockers (CCBs): only for vasoreactive PAH patients (10-15% of idiopathic PAH) — high-dose nifedipine, diltiazem, or amlodipine; dramatic, sustained response in true vasoreactors (long-term 5-year survival above 90%); harmful in non-vasoreactors. PAH-specific targeted therapies (via three established pathways): Endothelin receptor antagonists (ERAs) — block endothelin-1 vasoconstriction: bosentan (Tracleer — 125 mg BD; LFT monitoring monthly — hepatotoxicity), ambrisentan (Volibris — 5-10 mg OD; peripheral oedema), macitentan (Opsumit — 10 mg OD; preferred for combination therapy; anaemia). Phosphodiesterase-5 inhibitors (PDE5i) — enhance nitric oxide vasodilation: sildenafil (Revatio — 20-80 mg TDS; effective and widely available), tadalafil (Adcirca — 40 mg OD; once-daily dosing advantage). Soluble guanylate cyclase stimulator: riociguat (Adempas — 0.5-2.5 mg TDS; approved for PAH and CTEPH — the only approved pharmacotherapy for inoperable CTEPH; do not combine with PDE5i — dangerous hypotension). Prostacyclin pathway agonists — promote vasodilation and antiproliferation: epoprostenol (Flolan — continuous IV infusion via Hickman catheter — gold standard for severe PAH; very short half-life of 3-5 minutes requires uninterrupted infusion; heat-stable formulation now available); treprostinil (Remodulin — SC or IV; oral treprostinil — Orenitram; inhaled treprostinil — Tyvaso); iloprost (Ventavis — inhaled 6-9x/day); selexipag (Uptravi — oral prostacyclin IP receptor agonist — GRIPHON trial; reduces mortality/morbidity by 40%). Combination therapy: AMBITION trial showed upfront ambrisentan + tadalafil combination therapy superior to either monotherapy in newly diagnosed PAH — combination therapy is now standard initial treatment for most WHO Class II-III patients; triple combination (ERA + PDE5i + IV epoprostenol or selexipag) for refractory cases. Balloon atrial septostomy (BAS): palliative procedure for refractory right heart failure — creates an atrial septal defect to decompress the right heart; improves cardiac output at the cost of arterial hypoxaemia. Lung transplantation or heart-lung transplantation: reserved for patients with inadequate response to maximal medical therapy; WHO Class III-IV despite optimised therapy; 5-year post-transplant survival approximately 52-55%. Pulmonary endarterectomy (PEA): potentially curative for operable CTEPH (Group 4) — surgical removal of organised thromboembolic material from pulmonary arteries at specialist CTEPH centres.

Pulmonary hypertension causes serious, life-threatening complications predominantly related to progressive right ventricular failure. Right heart failure: the fundamental complication of PAH and CTEPH — as RV afterload increases from pulmonary vascular resistance, the RV first hypertrophies then dilates and fails; features include peripheral oedema, hepatic congestion (congestive hepatopathy), ascites, pleural effusions, and fatigue at rest (WHO Class IV); right heart failure significantly reduces cardiac output. Supraventricular arrhythmias: atrial flutter and atrial fibrillation develop from right atrial dilation in advanced PH — they cause haemodynamic deterioration and syncope; urgent cardioversion may be required; arrhythmia is an independent predictor of mortality in PAH. Haemoptysis: pulmonary artery dilation and in situ thrombosis can cause significant haemoptysis in advanced PH — occasionally massive and life-threatening; anticoagulation decisions must balance thromboembolism prevention against haemoptysis risk. Treatment-related complications: IV epoprostenol catheter-related complications (bloodstream infection, catheter thrombosis — life-threatening if infusion interrupted as acute PH rebound crisis can occur); ERA hepatotoxicity (monthly LFT monitoring required for bosentan); PDE5i-related hypotension; selexipag GI side effects (nausea, diarrhoea, jaw pain from prostacyclin receptor activation). Pregnancy: PAH is associated with 30-50% maternal mortality in pregnancy — pregnancy is absolutely contraindicated in severe PAH; effective contraception mandatory. Sudden death: risk of sudden cardiac death from arrhythmia or acute pulmonary vascular crisis — particularly with exertion, infection, or invasive procedures.

Prevention of PAH focuses on early detection of at-risk groups and screening for connective tissue disease-associated PAH — where early treatment can significantly alter prognosis. Systemic sclerosis (SSc) screening: annual echocardiography and PFTs for all SSc patients — detection of isolated DLCO reduction and elevated echo PASP triggers echocardiography-based and DETECT algorithm assessment; DETECT algorithm (incorporating 6 clinical variables) risk-stratifies SSc patients for RHC; early PAH detection and treatment initiation is associated with significantly improved outcomes in SSc-PAH. HIV patients: echocardiographic screening for patients with advanced HIV disease or unexplained dyspnoea. Genetic counselling: BMPR2 mutation carriers should be offered regular echocardiographic screening given lifetime risk of developing PAH. Drug avoidance: avoid anorexigens, stimulants, and dasatinib where clinically feasible in patients with pulmonary hypertension risk factors. Management monitoring at PH centre: 3-4 monthly assessments including 6MWT, NT-proBNP, WHO functional class, and echocardiography; RHC repeated when clinical deterioration or treatment change; risk stratification at each visit (low/intermediate/high) using validated risk calculators (COMPERA, REVEAL 2.0) guides treatment escalation decisions; treatment should target achieving 'low-risk' status on these tools. Vaccination: influenza and pneumococcal vaccination annually — respiratory infections are a common cause of acute deterioration in PH; COVID-19 vaccination strongly recommended.

See your GP promptly for unexplained progressive breathlessness on exertion — particularly if it has developed over weeks to months without obvious cause in a person with systemic sclerosis, other connective tissue disease, congenital heart disease, HIV, or a family history of pulmonary hypertension. Request referral to a designated pulmonary hypertension centre for any patient with suspected PAH — NICE requires all PAH management at specialist centres. Go to an Emergency Department immediately or call 999 for: syncope or pre-syncope on exertion in a patient with known or suspected PH — this represents a life-threatening crisis; severe acute breathlessness with cyanosis in a PH patient; haemoptysis in a PH patient; and acute severe right heart failure (gross peripheral oedema, ascites, and profound dyspnoea at rest). For patients already established on PAH treatment: contact your PH specialist centre urgently for any sudden deterioration in functional class or 6MWT distance — this represents treatment failure requiring urgent escalation; interruption of IV epoprostenol infusion (Flolan) is a MEDICAL EMERGENCY — the rebound pulmonary vasoconstriction can be rapidly fatal — seek emergency assistance immediately if this occurs. Patients with PAH should carry an emergency card indicating their condition, current medications (especially IV prostanoids), and the 24-hour emergency contact number for their PH centre.