Pulmonary hypertension and cor pulmonale

• Pulmonary hypertension (PH) is not itself a disease but a haemodynamic state in which the mean pressure in the pulmonary artery is too high; sustained high pressure overloads the right ventricle.
• The current definition is a mean pulmonary artery pressure above 20 mmHg at rest, with pulmonary vascular resistance above 2 Wood units helping to separate true pulmonary vascular disease from other causes of raised pressure.
• PH is grouped into five categories by cause: pulmonary arterial hypertension (including idiopathic and heritable forms, connective tissue disease, HIV, schistosomiasis, congenital shunts and portal hypertension), left heart disease, lung disease and hypoxia, chronic thromboembolic disease, and multifactorial or unclear causes.
• Echocardiography suspects the diagnosis, but the diagnosis is confirmed by right heart catheterisation; a ventilation/perfusion scan points to chronic thromboembolic disease when mismatched defects are present.
• Treatment depends on the group: vasodilator therapies improve life in pulmonary arterial hypertension, pulmonary endarterectomy or balloon angioplasty can cure chronic thromboembolic disease, and treatment of the underlying lung or heart condition is the foundation everywhere else.
• Cor pulmonale is the name for right heart enlargement and failure caused by lung disease, usually by way of pulmonary hypertension; it is most often due to chronic obstructive pulmonary disease (COPD).

By the end of this page you should be able to:

1. State the current haemodynamic definition of pulmonary hypertension and explain how the five WHO groups are separated.
2. Explain, from vascular tone and remodelling, how pulmonary arterial hypertension develops and how the right ventricle responds.
3. Recognise the clinical features and plan first-line, confirmatory and cause-directed investigations.
4. Outline the stepwise treatment of pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension and other groups, including doses, vasoreactivity testing, and when surgery is indicated.
5. Explain cor pulmonale, its causes, prognosis and why long-term oxygen is its key treatment.
6. Adapt the approach in low-resource settings, including schistosomiasis and high-altitude disease.

The 2022 ESC/ERS guidance lowered the diagnostic threshold from the previous 25 mmHg after normative and prognostic data showed that pressures between 21 and 24 mmHg are not benign, and extended pulmonary vascular resistance into the definition so that raised flow or raised wedge pressure is not mistaken for true pulmonary vascular disease. ^[1] The same guidance reintroduced exercise pulmonary hypertension, defined as a mean pulmonary artery pressure to cardiac output slope above 3 mmHg per litre per minute. ^[1]

Almost all randomised trials of pulmonary arterial hypertension drugs used an entry threshold of 25 mmHg with a pulmonary vascular resistance above 3 Wood units, so treatment evidence is strongest for that more severe population; clinicians must be careful not to treat mild haemodynamic changes with the same confidence. ^[1]

The five WHO groups are clinical, not merely haemodynamic, categories:

Pulmonary arterial hypertension (Group 1) is the subgroup with true disease of the small pulmonary arteries. It requires a wedge pressure of 15 mmHg or lower and a pulmonary vascular resistance above 2 Wood units. ^[1] A key split inside idiopathic disease is by acute vasoreactivity testing: patients who drop their mean pressure by at least 10 mmHg to 40 mmHg or lower with an unchanged or increased cardiac output can often be treated with high-dose calcium channel blockers. ^{[1] [5]}

Pulmonary hypertension of all types is commoner than is often assumed; estimates from echocardiography cohorts are much higher than rare-disease figures, although true pulmonary arterial hypertension is rare. Contemporary registries report an incidence of about 2.5 to 7.1 cases per million per year and a prevalence of 5 to 52 per million adults for pulmonary arterial hypertension, with a mean age at diagnosis of 45 to 65 years, a female-to-male ratio of 1.7:1 in the NIH registry and 3 to 4.8:1 in modern US registries, depending on the cohort. ^[5] In contrast to the older NIH registry, where the mean age was 36 years, patients now present older, often with comorbidities such as systemic hypertension, diabetes and coronary disease. ^[5] A serious and unchanged problem is delay: the mean interval from symptom onset to diagnosis is 18 to 32 months in contemporary registries, and most patients are in WHO functional class III or IV when diagnosed. ^[5]

About half of pulmonary arterial hypertension is idiopathic or heritable, and the rest is associated disease; connective tissue disease and congenital heart disease are the commonest associations in Western registries, congenital heart disease predominates in China, and in francophone registries there are more anorexigen and HIV cases. ^[5] Women are affected more than men, with the most extreme female predominance in US registries. ^[5]

Chronic thromboembolic pulmonary hypertension is rare but important because it is curable. After an acute pulmonary embolism the reported prevalence ranges widely (from about 0.4% to 9.1%), reflecting study design, populations and whether right heart catheterisation was used to confirm the diagnosis. ^[9]

Group 1 (pulmonary arterial hypertension) has no single cause, but several recognised triggers and associations:

• Idiopathic (sporadic, unknown cause in most patients in most series).
• Heritable: about 10% of patients have an inherited form. The commonest mutation is in the BMPR2 gene, which codes for the bone morphogenetic protein receptor type 2 and regulates vascular smooth muscle growth through SMAD and LIM kinase signalling. Loss of function leads to unchecked proliferation of pulmonary artery smooth muscle cells. Other genes include ALK1, endoglin, caveolin-1 and KCNK3, the last a two-pore potassium channel that modulates vascular tone and hypoxic vasoconstriction. ^[5]
• Drugs and toxins: notably appetite suppressants such as fenfluramine and dexfenfluramine, and selected chemotherapy and tyrosine kinase inhibitors.
• Connective tissue disease, especially systemic sclerosis (the commonest associated condition in western registries). ^[5]
• HIV infection, portal hypertension (portopulmonary hypertension), congenital heart disease with systemic-to-pulmonary shunts, and schistosomiasis.
• Pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, now folded into Group 1, which behaves like pulmonary arterial hypertension but has venous and capillary involvement.
• Persistent pulmonary hypertension of the newborn.

Risk factors for poorer outcome include male sex, age above 60 years, systemic sclerosis-associated disease, portopulmonary hypertension and BMPR2 mutations. ^[3]

Group 2 arises from left-sided heart disease (heart failure with preserved or reduced ejection fraction, valvular disease, congenital or acquired post-capillary obstruction). Group 3 arises from lung disease (obstructive, restrictive or mixed), hypoventilation (obesity-hypoventilation, sleep-related hypoventilation) and chronic hypoxia including high altitude. Group 4 follows unresolved pulmonary embolism and thromboembolic obstruction. Group 5 collects unclear or multifactorial causes such as haematological, systemic and metabolic disorders, chronic renal failure, pulmonary tumour thrombotic microangiopathy and fibrosing mediastinitis. ^{[1] [3]}

Pulmonary arterial hypertension has a shared histological picture whatever the trigger. The small resistance arteries show endothelial dysfunction, intimal hyperplasia, medial hypertrophy, adventitial proliferation, in situ thrombosis and inflammation; plexiform arteriopathy, with capillary-like channels inside small muscular arteries, is the pathognomonic lesion. ^[5]

Several interacting pathways are responsible:

• Vasoconstrictor/vasodilator imbalance. In the diseased vessel endothelin-1, thromboxane and serotonin are increased, while nitric oxide, prostacyclin and vasoactive intestinal peptide are reduced. Thromboxane and endothelin also drive proliferation; prostacyclin and nitric oxide restrain it. ^[5]
• Reduced nitric oxide signalling. Even where endothelial nitric oxide synthase expression persists, reactive oxygen species can uncouple the enzyme (tetrahydrobiopterin related), so nitric oxide bioavailability falls and the cyclic GMP vasodilator pathway is quiet.
• Endothelin-1 acts through endothelin A receptors in smooth muscle (vasoconstriction) and, on endothelial endothelin B receptors, can release nitric oxide and prostacyclin (vasodilation); in disease the balance tilts towards vasoconstriction and proliferation.
• Smooth muscle proliferation. Transcription factors such as hypoxia-inducible factor-1 alpha and nuclear factor of activated T-cells are inappropriately active, voltage-gated potassium channels are downregulated, survivin and TRPC6 are upregulated, and there is a glutaminolytic, glycolytic shift similar to cancer; mitochondrial fission is increased.
• Extracellular matrix remodelling. Elastase and matrix metalloproteinase activity disrupt the internal elastic lamina early in animal models, promoting smooth muscle proliferation.
• Inflammation. Interleukin-6 and other cytokines are raised in serum and in vascular infiltrates; raised interleukin-6 promotes a more severe phenotype in experimental models, and interleukin-6 blockade reduced disease in Castleman disease.

The right ventricle first compensates for rising afterload by hypertrophying concentrically, preserving ejection fraction (adaptive remodelling). With continued load it remodels eccentrically with fibrosis, capillary rarefaction, glycolytic metabolism, calcium mishandling and ischaemia, leading to dilatation and failure (maladaptive remodelling). Maladaptive remodelling is particularly early in scleroderma-associated disease, while congenital heart disease cases may remain stable in the adaptive state for years. ^[5] Long-term outcomes in pulmonary arterial hypertension are determined far more by the right ventricle than by the lung vessels. ^[5]

Congenital shunt disease and HIV and schistosomiasis (discussed below) share the same vascular remodelling once the shunt or immune drive is established.

Most patients present with breathlessness on exertion, initially only on steep climbs and later on flat ground. ^[4] Other common symptoms are fatigue, chest discomfort, light-headedness, syncope and, less frequently, cough. Signs of right-sided heart failure appear as the disease progresses. ^[4]

Physical findings include an augmented second heart sound (loud P2), a right ventricular heave or lift, jugular venous distension with hepatojugular reflux, ascites, hepatomegaly or splenomegaly, peripheral oedema, and systolic murmurs of tricuspid or pulmonary regurgitation. ^[4] A third heart sound gallop may be heard. ^[4] These signs reflect pressure and volume overload of the right ventricle. ^{[4] [5]}

The clinical course also depends on the underlying group. Group 1 pulmonary arterial hypertension tends to present in relatively younger patients; Group 2 presents with the symptoms and signs of left heart failure (orthopnoea, paroxysmal nocturnal dyspnoea, third heart sound from the left, basal crepitations); Group 3 presents with the symptoms of chronic lung disease (wheeze, copious sputum, finger clubbing, hyperinflation); Group 4 may follow a recognised venous thromboembolic event; and Group 5 carries the features of the associated systemic disorder. ^{[1] [3]}

Pulmonary hypertension is a sign, not a diagnosis. The differential is really the differential of each WHO group, and of the common presentations.

• Left heart disease (Group 2) can mimic pulmonary arterial hypertension clinically. It is separated by a raised pulmonary artery wedge pressure above 15 mmHg, left-sided signs and a consistent cardiac history or imaging.
• Chronic lung disease and hypoxia (Group 3) is the commonest overall context for high pulmonary pressures. Spirometry, imaging and blood gases distinguish it.
• Chronic thromboembolic disease (Group 4) must be excluded in every patient with unexplained pulmonary hypertension, because it is treatable. A normal ventilation/perfusion scan makes it very unlikely. ^{[4] [9]}
• Cardiovascular causes of breathlessness (coronary disease, arrhythmia, anaemia, deconditioning) should be excluded.
• Pulmonary veno-occlusive disease belongs to Group 1 but presents with severe breathlessness and can be missed if pulmonary vascular resistance is interpreted in isolation.

Investigations answer three questions: is pulmonary hypertension present, how severe is it, and why is it there.

Transthoracic echocardiography is the best non-invasive screening test. ^[4] It estimates pulmonary artery systolic pressure from the tricuspid regurgitant jet velocity and adds right ventricular size, septal shape, right atrial area, inferior vena cava size and collapse, acceleration time of right ventricular outflow and early diastolic pulmonary regurgitant velocity. ^[4] The level of echocardiographic probability is generated from these variables, and an echocardiography probability table is used rather than a single threshold. ^[4] Supporting signs include right ventricular dilation and hypertrophy, right atrial dilation and abnormal septal bowing. ^[4] Echocardiography also screens for congenital shunts and left ventricular or valvular disease. It is not a diagnostic test on its own.

Right heart catheterisation is mandatory for the diagnosis and provides the definitive haemodynamic classification. ^{[4] [1]} Mean pulmonary artery pressure, pulmonary artery wedge pressure, pulmonary vascular resistance, cardiac output and mixed venous oxygen saturation are recorded; wedge pressure 15 mmHg or lower defines pre-capillary disease. ^[1] The procedure also allows acute vasoreactivity testing (see below) and rules out significant left heart or shunt contributions.

Ventilation/perfusion scanning is the preferred screening test for chronic thromboembolic pulmonary hypertension. ^[9] The hallmark is mismatched segmental perfusion defects with preserved ventilation. ^[9] Chronic thromboembolic disease often produces large segmental defects, whereas pulmonary arterial hypertension may give a normal scan or small non-segmental unmatched defects. ^[9] A normal ventilation/perfusion scan effectively excludes chronic thromboembolic disease. ^[4]

Contrast-enhanced chest CT shows right-sided chamber enlargement, an enlarged main pulmonary artery (diameter 29 mm or greater) and a main pulmonary artery to ascending aorta ratio of 1 or more; high-resolution studies identify parenchymal lung disease and allow CTPA for thrombus in proximal vessels. ^[4] CT pulmonary angiography and conventional pulmonary angiography are used for operative planning in chronic thromboembolic disease. ^[9]

Pulmonary function testing is required in all patients. In pulmonary arterial hypertension the pattern is a mild restrictive defect with a markedly reduced diffusing capacity for carbon monoxide (below 60% of predicted) or severe exertional hypoxaemia suggesting pulmonary veno-occlusive disease. ^[4] Arterial blood gases establish resting oxygen and carbon dioxide levels and point to hypoventilation syndromes. Cardiopulmonary exercise testing helps quantify exercise limitation and estimate prognosis, and is particularly useful in high-risk or screening populations. ^[4]

Blood testing is not diagnostic but excludes and follows complications: full blood count, renal and hepatic function, thyroid function, iron studies, BNP or NT-proBNP, HIV, viral hepatitis and autoantibody screening (with ANA by immunofluorescence at a titre of 1:160 or above where scleroderma is suspected). ^[4] An ECG is a supportive clue but a normal tracing does not exclude pulmonary hypertension. ^[4] Chest radiography is non-specific. Risk stratification uses BNP/NT-proBNP, six-minute walk distance, functional class, echocardiography and haemodynamics; a published risk table stratifies one-year mortality into under 5%, 5 to 20% and above 20%. ^{[2] [3]}

Acute vasoreactivity testing is performed during right heart catheterisation with a short-acting vasodilator (inhaled nitric oxide, intravenous adenosine or inhaled iloprost) while haemodynamics are monitored. ^[2] A positive result is a fall in mean pulmonary artery pressure of at least 10 mmHg to 40 mmHg or lower with an unchanged or increased cardiac output. ^{[1] [2]} Positivity occurs in roughly 10% of patients with idiopathic, heritable and drug-associated pulmonary arterial hypertension (one review reports about 12%), with only about half of those showing a persistent response at one year on a calcium channel blocker, and about 7% showing long-term benefit. ^{[1] [2]} Acute vasoreactivity testing should not be used in other pulmonary arterial hypertension types because it does not predict long-term benefit. ^[2]

The diagnosis requires haemodynamic confirmation: a mean pulmonary artery pressure above 20 mmHg, and, for pre-capillary disease, a wedge pressure of 15 mmHg or lower and a pulmonary vascular resistance above 2 Wood units. ^[1] Pulmonary arterial hypertension is often defined in trials with the stricter entry criterion of 25 mmHg and above 3 Wood units, which is worth remembering when reading evidence. ^[1]

WHO functional class I to IV grades breathlessness and limitations, analogous to NYHA class. Six-minute walk distance, NT-proBNP and cardiopulmonary exercise testing provide objective severity.

Risk assessment places patients into low (under 5%), intermediate (5 to 20%) or high (above 20%) one-year mortality categories from clinical features, functional class, walk distance, biomarkers, imaging and haemodynamics. ^{[2] [3]} The variables include functional class, six-minute walk distance, NT-proBNP, imaging of the right atrium and right ventricle and haemodynamic parameters such as right atrial pressure, cardiac index, stroke volume and mixed venous saturation. ^[2]

All patients need education, vaccination against influenza, COVID-19 and pneumococcal infection, psychological support, avoidance of pregnancy, and contraception advice (endothelin receptor antagonists are teratogenic). Physical activity within symptom limits and rehabilitation are encouraged, while heavy exertion and dehydration are avoided. ^[2]

In acute decompensated right heart failure, diuretics reduce volume overload and inotropes and vasopressors (dobutamine, milrinone, levosimendan, norepinephrine, vasopressin) support cardiac output and perfusion; digoxin has a limited role and should be used cautiously with renal impairment and diuretic-induced electrolyte disturbance. ^[2] Oxygen is given if the patient is hypoxaemic. Intravenous iron is used for iron deficiency (oral iron is poorly absorbed). ^[2]

Vasoreactive patients. Only patients with idiopathic, heritable or drug-associated pulmonary arterial hypertension and a positive acute vasoreactivity test should receive high-dose calcium channel blockers (nifedipine or amlodipine if the heart rate is slow, diltiazem if it is fast), started low and titrated to the highest tolerated dose. Partial or lost responders need targeted therapy. ^{[1] [2]}

Targeted therapy. Three classical pathways are addressed:

• Endothelin receptor antagonists block endothelin-1. Bosentan is started at 62.5 mg twice daily for 4 weeks and increased to 125 mg twice daily (range 62.5 to 125 mg twice daily) with monthly liver function monitoring; hepatotoxicity and peripheral oedema are dose-dependent. Ambrisentan is 5 mg once daily, increased to 10 mg once daily if tolerated, and is contraindicated in idiopathic pulmonary fibrosis. Macitentan is 10 mg once daily and requires routine blood monitoring for anaemia rather than liver tests. ^[2]
• Phosphodiesterase-5 inhibitors preserve cyclic GMP. Sildenafil 20 mg three times daily (titrated to 20 to 80 mg three times daily), tadalafil 20 to 40 mg once daily, and vardenafil 5 mg twice daily are used. ^[2]
• Soluble guanylate cyclase stimulators: riociguat is started at 1 mg three times daily and titrated by 0.5 mg every 2 weeks to a maximum of 2.5 mg three times daily. It is the only targeted drug also licensed for chronic thromboembolic pulmonary hypertension. Combination with phosphodiesterase-5 inhibitors is contraindicated because of hypotension. ^[2]
• Prostacyclin analogues and receptor agonists. Epoprostenol (2 to 4 ng/kg/min initially, target 20 to 40 ng/kg/min, continuous intravenous infusion), iloprost (inhaled 10 to 20 microg six to nine times daily, or 0.5 to 4 ng/kg/min intravenously), treprostinil (1.25 ng/kg/min intravenous or subcutaneous initially, with oral and inhaled forms), beraprost (20 to 80 microg three to four times daily), and selexipag (200 microg twice daily, increased weekly by 200 microg to a maximum of 1600 microg twice daily). ^[2]
• Sotatercept, a newer transforming growth factor-beta pathway inhibitor (activin receptor ligand trap), is given at 0.3 mg/kg subcutaneously every 3 weeks and uptitrated to 0.7 mg/kg if haemoglobin and platelets are stable; in trials it improved six-minute walk distance by about 41 m compared with placebo at 24 weeks. ^{[3] [10]}
• Tyrosine kinase inhibition: imatinib reduced pulmonary vascular resistance in trials but caused a high rate of serious adverse events (including subdural haematoma) and is not licensed. ^[3]

Combination therapy is standard for intermediate and high risk patients: dual oral therapy (endothelin receptor antagonist plus phosphodiesterase-5 inhibitor) for low or intermediate risk, and triple therapy including a parenteral prostacyclin for high risk. ^{[2] [1]} Escalation or transplantation is considered if intermediate or high risk persists at follow-up, and de-escalation to monotherapy may be used for genuinely low-risk patients. ^[2]

Anticoagulation in pulmonary arterial hypertension is nuanced. Historical meta-analysis supported warfarin in idiopathic disease, but more recent registry data do not show a survival benefit in all subtypes. Anticoagulation should be individualised: it is reasonable in idiopathic and heritable disease and after selected risk-benefit assessment, but it is not beneficial and may be harmful in systemic sclerosis-associated disease, and it is contraindicated with frequent haemoptysis, high bleeding risk, portopulmonary hypertension, Eisenmenger syndrome with haemoptysis, hereditary haemorrhagic telangiectasia or pulmonary veno-occlusive disease. ^[2] Patients with CTEPH receive lifelong anticoagulation unless contraindicated. ^[2]

The foundation is treatment of the left heart problem: heart failure therapy, rate and rhythm control, valvular intervention. Routine pulmonary arterial hypertension vasodilators are not beneficial and can worsen pulmonary oedema; they are reserved for selected patients within trials or specialised protocols. ^[1]

Treat the underlying lung condition and hypoxaemia. Long-term oxygen therapy is the key intervention that improves pulmonary haemodynamics in hypoxaemic patients. Pulmonary arterial hypertension drugs have not shown consistent benefit in pure Group 3 disease and are used only cautiously in specialist practice. ^[6] For high-altitude residents, descent to lower elevation leads to substantial reversal over time. ^[8]

Pulmonary endarterectomy is the treatment of choice for suitable patients and can be curative; it removes organised thrombus from proximal and segmental arteries during deep hypothermic circulatory arrest and is performed in specialist centres. ^[9] For those who are inoperable, have distal disease, or have residual disease after surgery, balloon pulmonary angioplasty relieves obstructions and improves haemodynamics. ^[9] Riociguat is the licensed medical therapy for inoperable or persistent/recurrent disease. ^[9] General measures include lifelong anticoagulation after exclusion of contraindications and management of risk factors.

Management is directed at the underlying disorder; specialist advice is needed and evidence for pulmonary arterial hypertension drugs is limited.

Risk is reassessed 3 to 6 months after starting or escalating therapy using functional class, six-minute walk distance, NT-proBNP, imaging and, when needed, repeat catheterisation, with the aim of reaching a low-risk category. ^{[2] [1]}

Every patient with suspected pulmonary hypertension should be discussed with or transferred to a specialist pulmonary hypertension centre, because diagnosis, risk stratification and therapy all need expert input. Expedite referral when there is high-risk haemodynamics (right atrial pressure above 14 mmHg, cardiac index below 2.0 L/min/m2, mixed venous saturation below 60%), syncope, rapid progression, or suspected chronic thromboembolic disease. ^[2]

• Right ventricular dilation and failure, tricuspid regurgitation, right-sided gallop sounds.
• Cardiac dysrhythmias (notably atrial fibrillation, which is often poorly tolerated).
• Hepatic congestion and malabsorption, which interfere with drug absorption.
• Recurrent haemoptysis and pulmonary arterial thrombosis.
• Complications of therapy: transaminase elevation, anaemia, systemic hypotension, infusion-site pain, catheter infection.
• In Group 3, acute exacerbations can cause rapid rises in pressure and acute right heart failure.

Pulmonary arterial hypertension remains serious despite treatment: a 7-year survival around 50% has been reported in a recent review, and mortality is higher in men over 60, systemic sclerosis-associated disease, portopulmonary hypertension and BMPR2 mutation carriers. ^[3] In a systematic review of risk tables, the intermediate and high risk one-year mortality brackets are 5 to 20% and above 20%. ^{[2] [3]}

Schistosomiasis-associated pulmonary arterial hypertension has a more benign course: treated patients have 89% versus 69% survival at 5 years compared with untreated, and treatment-naive one, two and three year survival rates of 95%, 95% and 86%. Schistosoma disease is unlikely to show an acute vasoreactivity response. ^[7]

Chronic thromboembolic pulmonary hypertension untreated has a poor prognosis that correlates with pulmonary artery pressure; outcomes after endarterectomy are substantially better. ^[9]

Cor pulmonale: a mild level of pressure (20 to 35 mmHg) at rest in COPD is common, but five-year survival in this group is about 50%; long-term oxygen therapy greatly improves survival. ^[6]

There is no population screening for pulmonary hypertension. Prevention means treating causes: left heart disease and hypoxia aggressively, anticoagulation after deep vein thrombosis and pulmonary embolism, control of HIV and schistosomiasis, and avoidance of appetite suppressant exposure. Screening high-risk groups (systemic sclerosis, HIV with additional risk factors, portal hypertension, congenital heart disease after surgery, known mutation carriers) with echocardiography and NT-proBNP can find disease earlier; in systemic sclerosis, annual screening is recommended. ^[4]

Pregnancy. Pregnancy in pulmonary arterial hypertension carries a high maternal mortality and is generally contraindicated. Endothelin receptor antagonists and riociguat are contraindicated in pregnancy. Management must be in a specialist centre with a planned delivery and multidisciplinary team.

Children. Paediatric pulmonary hypertension includes idiopathic, heritable, congenital heart disease and persistent pulmonary hypertension of the newborn; drug doses are weight based and specialist paediatric centres are essential. Vasoreactivity testing and calcium channel blockers are also used in idiopathic childhood disease.

Older adults. The idiopathic phenotype now includes older patients with cardiopulmonary comorbidities and low diffusing capacity; such patients receive initial monotherapy regardless of risk, are more prone to side effects, and require assessment for left heart and lung disease before targeted therapy. ^[1]

Immunocompromised patients. HIV-associated disease is Group 1 and responds to targeted therapy; screening is recommended when additional risk factors are present. ^[4]

Cor pulmonale is the Group 3 end of pulmonary hypertension. COPD accounts for roughly 80 to 90% of cases, and counts as one of the commonest forms of heart disease in absolute terms. ^[6] Other causes include restrictive lung disease (interstitial fibrosis, pneumoconiosis, kyphoscoliosis), cystic fibrosis, bronchiectasis, asthma with irreversible obstruction, neuromuscular disease, sleep apnoea and obesity-hypoventilation syndromes, and chronic exposure to high altitude. ^[6]

Mechanism: alveolar hypoxia is the main driver. Acute hypoxia causes hypoxic pulmonary vasoconstriction (localised to small pre-capillary arteries, maximising ventilation-perfusion matching); chronic hypoxia induces structural remodelling (medial hypertrophy, muscularisation of arterioles, intimal fibrosis) that persists. ^[6] Hypercapnic acidosis, polycythaemia and hyperviscosity contribute but are minor. In interstitial fibrosis the rise in resistance is anatomical (loss or compression of the vascular bed). ^[6]

At rest in chronic respiratory disease the pressure is usually only mildly elevated, between 20 and 35 mmHg, much less than in idiopathic pulmonary arterial hypertension, where pressures are typically above 40 to 50 mmHg. ^[6] This modest pressure means right heart failure develops late or during exacerbations, and non-invasive diagnosis is difficult. Importantly, pressures rise markedly during exercise, sleep desaturation and exacerbations, and those acute afterload surges contribute to right heart failure episodes. ^[6]

Clinical assessment is relatively insensitive: peripheral oedema is the best sign of right heart failure but is neither specific nor universal, tricuspid regurgitation murmur is a very late sign, and P2 accentuation occurs only in severe disease. The ECG has high specificity but very low sensitivity for right ventricular hypertrophy. Echocardiography is the practical diagnostic tool but is technically difficult in hyperinflated patients. ^[6]

Management of cor pulmonale is mostly management of the lung disease and hypoxia, not targeted pulmonary arterial hypertension therapy: long-term oxygen in hypoxaemic patients is the best treatment and attenuates or reverses the rise in pressure through the NOTT/MRC mechanisms of correction of hypoxia; digoxin only for associated left heart disease or arrhythmia; diuretics (especially loop diuretics) for fluid overload; no specific vasodilators justified long term in most COPD patients at the time of that review. ^[6]

Five-year survival in mild cor pulmonale (pressures 20 to 35 mmHg) is about 50%, and the pressure level remains a powerful prognostic marker even on long-term oxygen. The prevalence of clinical right heart failure has fallen with long-term oxygen therapy. ^[6]

Pulmonary hypertension and cor pulmonale are major causes of heart failure in low-resource regions. Diagnostics should focus on the plausible group: echocardiography, ECG, spirometry or peak flow, pulse oximetry and basic serology are high-yield; right heart catheterisation and advanced imaging are often unavailable, so treatment follows the most likely group.

Schistosomiasis. Hepatosplenic schistosomiasis is a precursor to pulmonary arterial hypertension. Pulmonary arterial hypertension occurs in about 5 to 10% of patients with hepatosplenic disease, usually after years of infection and portal hypertension. ^[7] Diagnosis combines non-invasive evidence of periportal fibrosis and splenomegaly on ultrasound with echocardiographic probability, and (where available) right heart catheterisation. Antihelminthic treatment with praziquantel is safe and helps arrest progression, even if it does not reverse established vascular disease; pulmonary vasodilator therapy is often limited to sildenafil because of cost, yet improves symptoms and survival. ^[7] Beta-blockers used for variceal bleeding should be used with caution once pulmonary arterial hypertension is present. ^[7]

High altitude. High-altitude pulmonary hypertension is WHO Group 3.5 and is diagnosed by a mean pulmonary artery pressure of 30 mmHg or more measured at altitude, in someone without chronic lung or cardiac disease; prevalence varies widely (5% to 18% depending on population) but is roughly 10 to 15% by consensus. ^[8] Descent to sea level reverses it over time; drugs have not been shown to treat it long-term. ^[8] Sleep apnoea and nocturnal hypoxaemia contribute and should be addressed.

In all low-resource settings, long-term oxygen, diuretics, iron repletion and meticulous treatment of TB, HIV, schistosomiasis and COPD are the interventions most likely to help; expensive targeted therapies should be directed to those with confirmed Group 1 disease and prioritised by risk.

• Pulmonary hypertension is a haemodynamic state, currently defined as mean pulmonary artery pressure above 20 mmHg at rest, with pulmonary vascular resistance above 2 Wood units separating pre-capillary disease.
• Heart failure from left heart disease is the commonest overall context; pulmonary arterial hypertension is rarer but the target of specific therapy.
• Pulmonary arterial hypertension is driven by endothelin, nitric oxide, prostacyclin and thromboxane imbalance, medial hypertrophy and inflammation, with plexiform lesions on pathology, and is determined in the end by the right ventricle.
• Clinically look for exertional dyspnoea, a loud P2, right ventricular heave, tricuspid regurgitation murmur, raised JVP and peripheral oedema.
• Echocardiography screens and right heart catheterisation confirms; every case needs a ventilation/perfusion scan to exclude chronic thromboembolic disease.
• Treat the group: calcium channel blockers only in vasoreactive idiopathic/heritable disease; endothelin antagonists, phosphodiesterase-5 inhibitors, riociguat, prostanoids, selexipag and sotatercept in pulmonary arterial hypertension; endarterectomy or angioplasty for chronic thromboembolic disease; oxygen for hypoxaemic lung disease; transplant for refractory disease.
• Anticoagulation is individualised in pulmonary arterial hypertension but lifelong in chronic thromboembolic disease.
• Portopulmonary hypertension (0.85 per million in one registry, 2 to 6% of portal hypertensive patients) and schistosomiasis are important worldwide causes. ^[4]
• Cor pulmonale is lung-driven pulmonary hypertension and right ventricular enlargement, most often from COPD; long-term oxygen is the best treatment.
• Schistosomiasis and high-altitude disease illustrate Group 1 and Group 3 disease in endemic settings; praziquantel and descent to lower altitude matter more than expensive vasodilators.

• Chronic obstructive pulmonary disease and cor pulmonale.
• Interstitial lung disease.
• Chronic thromboembolic disease and pulmonary embolism.
• Left heart failure and valvular heart disease.
• Connective tissue disease and systemic sclerosis.
• HIV infection and schistosomiasis.
• Hypoxaemia and respiratory failure.
• Long-term oxygen therapy.
• Echocardiography and right heart catheterisation.