Pulmonary hypertension - primary
Description
Haemodynamic definition (ESC/ERS 2022 - thresholds were lowered)
| Criterion | |
|---|---|
| Pulmonary hypertension | mPAP >20 mmHg at rest (was >=25) |
| Pre-capillary PH | mPAP >20 + PAWP <=15 + PVR >2 WU (was >3) |
| Isolated post-capillary | mPAP >20 + PAWP >15 + PVR <=2 |
| Combined pre- and post-capillary | mPAP >20 + PAWP >15 + PVR >2 |
| Exercise PH | mPAP/cardiac output slope >3 mmHg/L/min |
- *Requires right heart catheterisation. Echo estimates probability, it does not diagnose*
Clinical groups - the classification that decides treatment
| Group | Entity | Key point |
|---|---|---|
| 1 | Pulmonary arterial hypertension - idiopathic, heritable, drug/toxin-induced, CTD, HIV, portal hypertension, congenital heart disease, schistosomiasis | The only group with PAH-specific drug therapy |
| 1' | PVOD / PCH (pulmonary veno-occlusive disease) | *Vasodilators cause fulminant pulmonary oedema* |
| 2 | Left heart disease | Commonest group overall - treat the left heart |
| 3 | Lung disease / hypoxia - COPD, ILD, OSA, high altitude | Treat the lung; oxygen |
| 4 | CTEPH and other pulmonary artery obstruction | *Potentially curable by endarterectomy - never miss it* |
| 5 | Unclear/multifactorial - sarcoid, haematological (MPN, splenectomy), metabolic (Gaucher), CKD, fibrosing mediastinitis |
- *"Primary pulmonary hypertension" is an obsolete term - it is now idiopathic PAH (Group 1)*
- The single commonest error is treating Group 2 or 3 PH with PAH drugs - harmful, worsening V/Q matching and precipitating pulmonary oedema
Epidemiology
- PAH (Group 1): prevalence ~15-50/million; incidence ~5-10/million/yr
- Idiopathic PAH: F>M ~2-4:1, mean age at diagnosis has risen from ~35 to ~50-65 yr
- Heritable PAH ~6-10% - BMPR2 mutation in ~70-80% of familial and ~20% of "idiopathic" cases
- Autosomal dominant, incomplete penetrance (~20%), genetic anticipation; males have worse haemodynamics but are less often affected
- Systemic sclerosis - PAH in ~8-12%; the leading cause of death in limited cutaneous SSc
- CTEPH in ~2-4% after acute PE
- Groups 2 and 3 are far commoner than Group 1 in unselected practice
Aetiopathogenesis
PAH vasculopathy - three interacting processes
- Vasoconstriction - reversible early; the target of vasodilators
- Proliferative remodelling - intimal, medial and adventitial thickening, plexiform lesions; largely irreversible
- In-situ thrombosis
The three targetable pathways - and their drugs
| Pathway | Abnormality | Drug class |
|---|---|---|
| Nitric oxide | dec NO -> dec cGMP | PDE5 inhibitors (sildenafil, tadalafil), sGC stimulator (riociguat) |
| Prostacyclin | dec prostacyclin | Epoprostenol, treprostinil, iloprost, selexipag (IP receptor agonist) |
| Endothelin | inc endothelin-1 | ERAs - bosentan, ambrisentan, macitentan |
| BMP/activin (new) | BMPR2 loss -> unopposed activin/TGF-beta signalling -> proliferation | Sotatercept (activin signalling inhibitor) |
- BMPR2 loss-of-function removes the anti-proliferative brake on pulmonary artery smooth muscle and endothelium
- Sotatercept restores the BMPR2/activin balance - the first agent that targets remodelling rather than tone
Causes and triggers
- Drugs/toxins: dexfenfluramine/fenfluramine, aminorex, benfluorex, methamphetamine, dasatinib, toluene, interferon
- CTD: systemic sclerosis (esp. limited/CREST), MCTD, SLE, Sjogren
- HIV, portal hypertension (portopulmonary), congenital left-to-right shunt (Eisenmenger), schistosomiasis
- PVOD - EIF2AK4 biallelic mutation, chemotherapy, organic solvent exposure
Physiological consequence
- inc PVR -> inc RV afterload -> RV hypertrophy -> dilatation -> TR -> RV failure
- Septal bowing -> dec LV filling -> dec cardiac output
- Fixed cardiac output -> exertional syncope and inability to increase output on exercise
- *RV function, not pulmonary pressure, determines survival*
Diagnosis
Clinical - late and non-specific
- Exertional dyspnoea (>95%), fatigue; median 2 years from symptom onset to diagnosis
- Exertional syncope or presyncope, exertional chest pain (RV ischaemia) - both indicate advanced disease
- Later: peripheral oedema, ascites, abdominal distension
Signs
- Loud P2, palpable P2, left parasternal (RV) heave
- Prominent a wave in the JVP; giant v wave with TR
- Pansystolic murmur of TR (louder on inspiration), Graham Steell murmur of PR
- Right-sided S4 then S3; pulsatile liver, ascites, oedema
- Look for the cause: sclerodactyly, telangiectasia, Raynaud, calcinosis; clubbing (ILD, shunt); cyanosis and differential clubbing (PDA); stigmata of liver disease; obesity/OSA
Investigations
- ECG - right axis deviation, RVH (dominant R in V1), P pulmonale, RV strain (T inversion V1-V4), RBBB
- CXR - enlarged central pulmonary arteries with peripheral pruning, RV enlargement
- Echocardiography - the screening test
- Estimates peak TR velocity -> PH probability (low / intermediate / high)
- Adverse prognostic features: pericardial effusion, RA enlargement, dec TAPSE, septal flattening / D-shaped LV
- Estimated systolic PAP is unreliable - do not diagnose or grade PH on echo alone
- Lung function + DLCO - isolated dec DLCO with normal volumes is characteristic of PAH; also seen in CPFE and SSc
- HRCT chest - lung disease; PVOD signs: septal lines, centrilobular ground glass, mediastinal adenopathy
- *V/Q scan in EVERY patient - the mandatory step to exclude CTEPH (far more sensitive than CTPA for chronic thromboembolic disease*)
- Bloods: ANA/ENA/scleroderma serology, HIV, hepatitis, LFTs, TFTs, NT-proBNP
- Overnight oximetry/PSG; abdominal ultrasound for portal hypertension
- Genetic testing and counselling for heritable PAH (BMPR2, EIF2AK4)
Right heart catheterisation - mandatory to confirm and characterise
- Measures mPAP, PAWP, PVR, cardiac output, RA pressure, SvO2
- Acute vasoreactivity testing with inhaled NO (or iloprost/adenosine) - in idiopathic, heritable and drug-induced PAH only
- Positive = dec mPAP by >=10 mmHg to an absolute <=40 mmHg with preserved or increased cardiac output
- Only ~5-10% are responders - but they are the group who benefit from calcium channel blockers
- *Do NOT perform in CTD-associated, congenital or portopulmonary PAH - a positive result does not predict CCB benefit there*
Risk stratification - the driver of treatment decisions
ESC/ERS three-strata at diagnosis, four-strata (low/intermediate-low/intermediate-high/high) at follow-up
- WHO functional class, 6-minute walk distance, NT-proBNP
- Haemodynamics: RA pressure, cardiac index, SvO2
- Imaging: RA area, pericardial effusion
- *The goal of treatment is to reach and stay in the low-risk category*
- REVEAL 2.0/Lite is the alternative validated score
Management
All PAH should be managed at, or in partnership with, a designated pulmonary hypertension centre.
1. Confirm the group first
- *PAH-specific therapy is for Group 1 (and riociguat for inoperable Group 4). It is harmful or useless in Groups 2, 3 and 5*
- Group 2 (left heart): treat the left heart; vasodilators cause pulmonary oedema
- Group 3 (lung disease): oxygen, treat the lung; inhaled treprostinil is the one agent with positive evidence in PH-ILD (INCREASE)
- Group 4 (CTEPH): refer for pulmonary endarterectomy assessment - potentially curative; balloon pulmonary angioplasty and riociguat if inoperable or residual; lifelong anticoagulation
2. Vasoreactive responders (~5-10% of idiopathic/heritable/drug-induced)
- High-dose calcium channel blocker - amlodipine, nifedipine, or diltiazem up to 120-900 mg/day
- Long-term survival benefit, but only in this small group
- *Verapamil is avoided - negative inotropy*
- Reassess at 3-6 months; only ~half sustain the response - switch to standard PAH therapy if not low-risk
- *No benefit in CTD-associated PAH - do not use this strategy there*
3. Non-vasoreactive PAH - combination therapy by risk
| Risk at diagnosis | Initial therapy |
|---|---|
| Low or intermediate | Initial dual oral combination: ERA + PDE5 inhibitor (ambrisentan + tadalafil, or macitentan + tadalafil) |
| High | Initial triple therapy including a parenteral prostacyclin - IV epoprostenol or SC/IV treprostinil |
- Reassess at 3-6 months and escalate if not low-risk
- Add selexipag (oral IP agonist) or switch to riociguat
- *Never combine riociguat with a PDE5 inhibitor - severe hypotension*
- Escalate to parenteral prostacyclin if intermediate-high or high risk
- Sotatercept - activin signalling inhibitor; added to background therapy in intermediate/high-risk PAH
- STELLAR: improved 6MWD, haemodynamics and risk profile; ZENITH: reduced morbidity/mortality events in high-risk disease
- Adverse effects: erythrocytosis, thrombocytopenia, epistaxis, telangiectasia; monitor FBC
- Epoprostenol is the only therapy with a demonstrated survival benefit in a randomised trial (idiopathic PAH)
- Continuous IV via tunnelled line; abrupt interruption is life-threatening - line infection, pump failure
4. Supportive care
- Diuretics for RV failure and congestion - often the most symptomatically effective drug
- Oxygen if PaO2 <60 mmHg / SpO2 <90%
- Anticoagulation - indicated in CTEPH (lifelong); controversial and not routine in idiopathic PAH; avoid in CTD-PAH and portopulmonary
- Iron studies and IV iron - deficiency is common and worsens exercise capacity
- Supervised exercise training / rehabilitation - now recommended
- Vaccination; treat anaemia and thyroid disease
- *Avoid pregnancy - maternal mortality 10-30%. Effective contraception is mandatory; avoid oestrogen-containing methods with ERA (hepatic and teratogenic issues) - bosentan reduces oral contraceptive efficacy*
- Counsel every woman of childbearing age at every visit; offer termination if pregnancy occurs
- Avoid: high altitude without oxygen, decongestants, non-essential surgery, beta blockers unless another indication
- Psychosocial support and advance care planning
5. Interventional and surgical
- Balloon atrial septostomy - creates a right-to-left shunt to decompress the RV and augment systemic output at the cost of desaturation
- Palliative/bridging only, in refractory syncope or RV failure; contraindicated if RA pressure >20 mmHg or SaO2 <90% on air
- Lung or heart-lung transplantation - WHO class III-IV refractory to maximal therapy including parenteral prostacyclin
- *Refer early - deterioration is unpredictable and waitlist mortality is high*
- Pulmonary endarterectomy for operable CTEPH - the only curative operation in this field
6. Managing decompensated RV failure
- Treat the trigger - sepsis, arrhythmia (loss of atrial kick is poorly tolerated - restore sinus rhythm), anaemia, non-adherence, PE
- Diurese carefully; avoid fluid boluses
- Noradrenaline for perfusion pressure; dobutamine or milrinone for RV inotropy
- Avoid intubation if at all possible - induction and positive pressure ventilation frequently precipitate arrest
- Inhaled NO or prostacyclin; ECMO as a bridge to transplant
Associations
- Systemic sclerosis (esp. limited/CREST) - annual screening with echo, DLCO and NT-proBNP (DETECT algorithm)
- MCTD, SLE, Sjogren, RA
- HIV, portal hypertension (portopulmonary), congenital heart disease/Eisenmenger
- Schistosomiasis - the commonest cause of PAH worldwide
- Drugs: fenfluramine derivatives, methamphetamine, dasatinib, interferon
- Hereditary haemorrhagic telangiectasia (ALK1/ENG - overlapping BMP pathway)
- Thyroid disease (autoimmune), splenectomy, myeloproliferative neoplasms, sickle cell disease, thalassaemia
- Sarcoidosis, Gaucher disease, glycogen storage disease, CKD/dialysis, fibrosing mediastinitis
- OSA and obesity hypoventilation, chronic lung disease
- Iron deficiency - very common, independently worsens function
Natural history & complications
- Historically: median survival 2.8 years from diagnosis in untreated idiopathic PAH
- With modern combination therapy: ~65-75% 5-year survival in registries; better still in vasoreactive responders
- *Death is from progressive right ventricular failure or sudden death*
Prognostic markers - what actually predicts outcome
- WHO functional class and change in it
- 6MWD <165 m (poor) vs >440 m (good)
- NT-proBNP - level and trend
- RA pressure >14 mmHg, cardiac index <2.0 L/min/m2, SvO2 <60%
- Pericardial effusion, dec TAPSE, RA enlargement
- Failure to reach low-risk status at reassessment
- Aetiology: SSc-PAH has the worst prognosis; congenital heart disease-associated the best
- RV adaptation, not pulmonary artery pressure, drives outcome - a falling mPAP with a failing RV is an ominous sign, not an improving one**
Complications
- Progressive RV failure, cardiac cachexia
- Arrhythmia - atrial flutter/AF; poorly tolerated, restore sinus rhythm
- Haemoptysis - bronchial artery hypertrophy; can be massive
- Pulmonary artery dissection or rupture; compression of the left main coronary by a dilated PA
- Hoarseness (Ortner syndrome - left recurrent laryngeal nerve compression)
- Line sepsis and pump failure on parenteral prostacyclin
- Sudden cardiac death - especially with syncope
Monitor
- 3-6 monthly: WHO class, 6MWD, NT-proBNP, echo; RHC if escalating or deteriorating
- Iron studies, FBC (sotatercept - erythrocytosis and thrombocytopenia; ERA - transaminitis, anaemia)
- Monthly LFTs on bosentan; ERAs are teratogenic - monthly pregnancy testing in women of childbearing potential
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