Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43–S54.
PHT is a haemodynamic and pathophysiological state that can be found in multiple clinical conditions (see Box 38.1). It is defined as a mean PAP ≥25mmHg at rest, as assessed by RHC. In clinical groups 1, 3, 4, and 5, the pulmonary capillary wedge pressure is normal at ≤15mmHg. In group 2, this is raised. Resting PHT is significant, as >70% of the vascular bed must be lost for the PAP to rise. Normal resting PAP is around 14mmHg.
Each group has differing characteristic pathological features, but vasoconstriction, remodelling of the pulmonary vessel wall, medial hypertrophy of distal pulmonary arteries ± fibrotic change and thrombosis lead to raised pulmonary vascular resistance and ultimately right heart failure. An imbalance between NO and prostacyclin (a potent vasodilator and platelet inhibitor) and thromboxane A2 (a potent vasoconstrictor and platelet agonist) has been identified in PAH. Unfavourable imbalances between other regulators of vascular tone and smooth muscle cell growth, including endothelin-1, NO, and serotonin, have also been implicated.
The symptoms of PHT are primarily due to RV dysfunction. The symptoms are non-specific, often leading to a delay in diagnosis from first symptoms.
• Exertional breathlessness, due to the inability to increase cardiac output with exercise. WHO functional assessment classification used to quantify; see Box 38.2.
• Chest pain (right heart angina)
• Fatigue and weakness
• Syncope or pre-syncope, due to a fall in systemic BP on exercise
• Peripheral oedema and other signs of right-sided fluid overload.
Reproduced from Galiè N et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493–537, with permission from OUP.
Signs of right heart fluid overload and RVH are associated with advanced disease and include:
• RV heave, RV third sound
• Wide splitting of S2 with loud P2
• Pansystolic murmur of TR, diastolic murmur of pulmonary insufficiency
• Raised JVP, with giant V waves
• Hepatomegaly, ascites, peripheral oedema
• Possible telangiectasia, digital ulceration, and sclerodactyly in PHT associated with scleroderma
• Stigmata of chronic liver disease with portal hypertension
• Clubbing suggests ILD or congenital heart disease
• Lungs normally clear, unless underlying ILD in association with connective tissue disease or if pulmonary oedema associated with pulmonary veno-occlusive disease.
The investigations aim to make a diagnosis of PHT and investigate any possible underlying cause (see Box 38.1). In 85% of patients presenting with symptoms caused by established PHT, a CXR and ECG will be abnormal.
• CXR may show enlarged pulmonary arteries and an enlarged cardiac silhouette, with pruning (loss) of peripheral vessels
• ECG Right atrial dilatation, RAD, RVH and strain
• ABG Slight hypoxia and hypocapnia (correlating with disease severity), with a fall in O2 saturation on exercise
• PFTs The lung volumes may be normal or show a mild restrictive or obstructive defect with a reduced TLCO (late in the disease course). Abnormal if PHT due to underlying lung disease
• HRCT chest to exclude underlying lung disease
• V/Q scanning/CTPA to exclude chronic thromboembolic disease as a cause. V/Q is more sensitive than CTPA. Normal or low probability V/Q scan effectively excludes CTEPH
• Echo The most useful screening tool in PHT. Typically shows enlargement of right-sided cardiac chambers, with paradoxical interventricular septum movement and TR. The systolic PAP can be estimated from the peak velocity of the tricuspid regurgitant jet, using Doppler techniques, and the estimated right atrial pressure from the IVC (assumed to be 5–10mmHg). Pericardial effusions may be present and represent worse prognosis. Bubble echo can help to exclude an intracardiac shunt and also increases the Doppler signal, allowing easier measurement of peak TR velocity
• Cardiac MRI to evaluate RV size, morphology, and function
• Abdominal USS if liver cirrhosis/portal hypertension suspected
• RHC The ‘gold standard’ test to confirm the diagnosis, assess the PAP, pulmonary capillary wedge pressure, and cardiac output (with a Swann–Ganz catheter, by thermodilution or Fick). Also can exclude a left-to-right intracardiac shunt. Vasodilator responsiveness is measured with incremental doses of a short-acting vasodilator such as inhaled NO or IV epoprostenol or adenosine. A positive vasodilator response is defined as a drop in mean PAP by >10mmHg to <40mmHg, with an unchanged or increased cardiac output. Only about 5–10% of patients are responders
• 6MWT for objective assessment of exercise capacity. Walking distances of <300m and O2 desaturation of >10% indicate worse prognosis in PAH. Increase in 6MWT distance following treatment often used in assessment and in trials but may not be best outcome measure for PHT subgroups
• CPET (see p. [link]) O2 uptake at the anaerobic threshold and peak exercise are reduced in relation to disease severity
• Selective pulmonary angiography is rarely required, as CTPA and V/Q can detect nearly all cases of thromboembolic disease
• Blood tests Routine tests, including HIV test, TSH, ACE, autoantibodies (anti-centromere antibody, anti Scl-70, and RNP) if connective tissue disease suspected; thrombophilia screen in CTEPH
• BNP/NT-proBNP plasma levels If elevated, associated with worse prognosis in PAH.
A National Pulmonary Hypertension Service was established in the UK in 2001 to coordinate diagnosis and treatment in five regional centres, recognizing the need to provide best care (with complex interventions) and optimize funding for expensive treatments. The five UK centres are:
• London—Hammersmith Hospital (general)
• Royal Brompton Hospital (adult congenital heart disease)
• Royal Free Hospital (connective tissue disease)
• Great Ormond Street Hospital for Children (children)
• Cambridge—Papworth Hospital
• Sheffield—Royal Hallamshire Hospital
• Newcastle—Freeman Hospital
• Glasgow—Western Infirmary, Scottish Pulmonary Vascular Unit, Golden Jubilee National Hospital.
Recent guidelines suggest referral to a specialist centre after CXR, ECG, simple spirometry, and echo (but not cardiac catheterization, as this should be done in parallel with a vasodilator study in a specialist centre).
PH centre will: confirm/refine diagnosis, assess severity and prognosis, plan treatment, review progress 3–6-monthly, with appropriate investigations repeated, and gather data for national database to facilitate audit and research.
Recommendations on the management of pulmonary hypertension in clinical practice. Heart 2001;86:S1.
Pathological lesions affect the distal pulmonary arteries, with medial hypertrophy, intimal proliferative and fibrotic changes, adventitial thickening with moderate perivascular inflammatory infiltrates, and thrombotic lesions. Pulmonary veins are unaffected.
The incidence of IPAH in Europe and the USA is 1–2 cases per million population per year. The mean age at diagnosis is 36, with a ♀ preponderance of about 2:1. Although rare, it is important to diagnose, as it affects a young age group and has an extremely poor outcome without treatment
A familial predisposition is seen in 6–10% of IPAH cases where the disease is transmitted in an autosomal dominant fashion. Incomplete penetrance and anticipation are seen, with presentation at a younger age in successive generations. The responsible gene has been localized to Chr 2 (locus 2q 31–32). Abnormal cardiovascular responses to exercise have been demonstrated in asymptomatic carriers of BMPR2.
1.2.1 Bone morphogenetic protein receptor type II (BMPR2) is a receptor in the transforming growth factor beta (TGF-β) receptor superfamily and is an important regulator of apoptosis and proliferation. The identification of a mutation in BMPR2, present in 70% of familial PAH, has improved understanding. It is hypothesized that defective signalling via this pathway may result in abnormal endothelial proliferation and cell growth in response to various insults, with an inability to terminate the proliferative response to injury. Due to incomplete disease penetrance in the presence of a mutation in BMPR2 (15–20%), it is thought that the genetic abnormality may have to be accompanied by some additional environmental factor, e.g. hypoxia, to cause PAH.
1.2.2 ALK1, endoglin (with or without HHT) PAH occurs in around 15% of patients with HHT, an autosomal dominant vascular dysplasia. Mutations in the ALK1 receptor (also in the TGF-β receptor superfamily) are implicated.
1.3 Drug- and toxin-induced
Damage to the pulmonary artery endothelium can be caused by drugs, e.g. Aminorex, fenfluramine, dexfenfluramine, toxic rapeseed oil, benfluorex, amphetamines, methamphetamines, L-tryptophan, cocaine, phenylpropanolamine, St John’s Wort, chemotherapeutic agents, selective serotonin reuptake inhibitors, pergolide. A careful history must be taken. PHT can develop within 4 weeks of starting the drug, with increasing incidence with longer use.
1.4 Associated with (APAH)
Conditions which have a similar clinical presentation to IPAH, with identical histological findings. This group accounts for about half the patients looked after in specialist centres.
1.4.1 Connective tissue diseases
PAH develops in about 15% of patients with systemic sclerosis and is most frequently seen as an isolated phenomenon in patients with limited cutaneous disease. Also occurs 2° to ILD, with a very poor prognosis. Life expectancy is <1y in patients with systemic sclerosis, isolated PHT, and a gas transfer of <25% of normal. Patients with systemic sclerosis should be screened annually with echo for PHT, even if no symptoms are present. Obliteration of the alveolar capillaries and arteriolar narrowing are induced by both the 1° vascular disease and any interstitial fibrosis. Other connective tissue diseases, including RA, SLE, Sjögren’s syndrome, dermatomyositis, can also lead to 2° PHT. There is a strong association with Raynaud’s phenomenon, and a ♀ predominance is seen. Immunosuppressive therapy can improve PAH associated with SLE or mixed connective tissue disease.
1.4.2 HIV infection
PAH is found in up to 1 in 200 HIV-positive people, more common in men and IVDUs. The incidence is about 0.1%, 6–12 times higher than the general population. The development of PAH is independent of CD4 cell count but is associated with duration of infection. The mechanism is unclear. It is hypothesized that HIV-infected macrophages release vasoactive cytokines that lead to endothelial damage and proliferation.
1.4.3 Portal hypertension
PAH is seen in up to 5% of patients with portal hypertension of whatever cause, increasing with duration of liver disease. Porto-pulmonary hypertension is probably due to the failure of the liver to remove vasoactive substances from the portal circulation, with their resultant accumulation and presentation to the pulmonary arterial endothelium (see p. [link]).
1.4.4 Congenital heart disease
Pressure overload caused by systemic to pulmonary shunts. Includes large defects (Eisenmenger’s syndrome), moderate to large defects, small defects (small ventricular and atrial septal defects). Detailed subclassifications available, based on clinical and anatomical-pathophysiological features, allow individual patients to be better defined.
Portal hypertension along with local vascular inflammation caused by Schistosoma eggs.
1.4.6 Chronic haemolytic anaemia,
such as sickle cell disease, thalassaemia, hereditary spherocytosis, stomatocytosis, and microangiopathic haemolytic anaemia, may result in PAH. The mechanism is related to a high rate of NO consumption, leading to a state of resistance to NO bioactivity
1’ Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
Difficult disorders to classify; share some characteristics with IPAH, but also a number of differences. HRCT helpful in diagnosis; characteristic interstitial oedema with diffuse central ground-glass opacification and thickening of interlobular septa. Possible lymphadenopathy and pleural effusion also. Pulmonary capillary haemangiomatosis suggested by diffuse bilateral thickening of interlobular septa and the presence of small, centrilobular, poorly circumscribed nodular opacities. Biopsy is the gold standard for diagnosis but may not be necessary.
3. PHT due to lung diseases and/or hypoxia
The majority of patients with PHT seen by a respiratory specialist will have PHT due to chronic hypoxic lung disease such as COPD. Chronic hypoxia causes pulmonary vasoconstriction and, in the longer term, vascular remodelling. Inflammation, mechanical stress of hyperinflated lungs, loss of capillaries, and toxic effects of cigarette smoke all contribute to the pathophysiological mechanisms. Patients with ‘out of proportion’ PHT due to underlying lung disease should be referred to a specialist centre—that is dyspnoea insufficiently explained by mechanical disturbances, mean PAP ≥40–45mmHg at rest.
In this case, the PHT is often an incidental finding in a patient with a chronic respiratory disease.
• A significant proportion of COPD patients will develop PHT, possibly up to 25%. The level of PAP in these patients is much lower than that seen in patients with PAH
• COPD with PHT has a much poorer prognosis than COPD without PHT. In patients with a PAP <25mmHg, the 5y survival is >90%. In those with a PAP >45mmHg, the 5y survival is <10%. Whether this is due to the PHT itself or whether the PHT is a marker of worse hypoxia and disease severity is unclear.
PHT in COPD was thought to be due to hypoxia and emphysematous destruction of the vascular bed, but neither of these factors correlates well with PAP. Cigarette smoke may have a direct effect on the intrapulmonary vessels, with the upregulation of mediators leading to aberrant vascular structural remodelling and physiological changes in vascular function
3.4 Sleep-disordered breathing
with the obesity hypoventilation syndrome, not just OSA (see p. [link]).
3.5 Alveolar hypoventilation disorders,
e.g. due to neuromuscular disease. Both alveolar hypoxia and hypercapnia produce pulmonary vasoconstriction, thereby increasing PAPs.
is a frequent cause of PHT, with both proximal and distal clot. Recent data suggest that CTEPH occurs in up to 4% of cases of acute non-fatal PE, higher than previously thought. Pathogenesis is unclear, but abnormalities in the clotting cascade, endothelial cells, or platelets may all contribute. Natural history of pulmonary thromboemboli is resolution or near-total resolution of clot, with restoration of normal pulmonary haemodynamics within 30 days in 90% of patients. Right-sided pressures return to normal in most patients by 2 weeks. In CTEPH, thromboemboli do not resolve, forming endothelialized fibrotic obstructions of the pulmonary vascular bed. In situ thrombosis and vascular remodelling of small distal pulmonary arteries also contribute. Peripheral PAH-like arteriopathic changes are also seen in the distal pulmonary arteries in non-obstructed areas. Collateral vessels from bronchial, intercostal, diaphragmatic, and coronary arteries can develop to partially reperfuse areas distal to complete obstruction. The clinical deterioration parallels the loss of RV functional capacity. Risk factors for CTEPH include increasing age, idiopathic PE, and a larger perfusion defect. Splenectomy is associated possibly by inducing a pro-thrombotic state due to loss of filtering function of the spleen. Antiphospholipid antibodies are present in 10–20% of patients. The diagnosis is not usually made until advanced PHT is present. Progressive PHT seems to result from changes in the small peripheral resistance vessels in the vascular bed, as opposed to being due to progressive pulmonary events. 2° hypertensive changes, probably induced by high PAPs, lead to incremental increases in RV afterload, with increasing PHT, ultimately leading to RV failure. Patients with CTEPH have a 5y survival of <10% if the PAP >50mmHg. CTPA helps determine whether there is any surgically accessible CTEPH.
5. PHT with unclear and/or multifactorial mechanisms
Calcium channel blockers (CCBs)
• Vasoresponders at RHC should be considered for therapy with CCBs. They should not be used in those with a negative vasodilator challenge, as they may increase mortality
• Only a small number of patients with IPAH and vasodilator response at RHC do well with CCBs. High-dose nifedipine (120–240mg daily) and diltiazem (240–720mg daily) are recommended in patients with IPAH with a positive vasodilator response. They should then be followed closely to determine if they are long-term CCB responders, with repeat RHC after 3–4 months of treatment. If their response is inadequate, further PAH therapy should be started
• Vasodilator responsiveness does not predict a favourable long-term response to CCB therapy in patients with APAH and connective tissue disease; high-dose CCBs are often not well tolerated in these patients
• Amlodipine has more selective vasodilating properties and, at doses of up to 20mg daily, may be useful in those intolerant of the other agents or if RV function is impaired
• Calcium antagonists should be started in hospital and titrated with careful monitoring
• Verapamil is not used, because of its negative inotropic effects
• Side effects include hypotension and oedema, which may limit use.
Phosphodiesterase type-5 inhibitors (PDE-5),
e.g. sildenafil and tadalafil. Augment the vasodilatory effects of NO, causing pulmonary vasodilatation, and improve exercise capacity and haemodynamics in PAH in patients in functional classes II and III. Common side effects: headache, flushing, epistaxis, nasal congestion
• Sildenafil is taken orally tds and has proven benefits in IPAH, APAH with connective tissue disease, congenital heart disease, and CTEPH
• Tadalafil oral, once a day.
Prostacylin is produced predominantly by endothelial cells and is a potent vasodilator. It inhibits platelet aggregation and has antiproliferative and cytoprotective properties. Side effects include headache, jaw pain, diarrhoea, flushing, nausea, and arthralgia and are usually dose-related. Prostaglandin treatment doubles the time on the lung transplantation waiting list and improves transplantation outcomes. Improved haemodynamics may lead to some patients coming off transplant waiting lists. Tolerance develops to IV prostaglandin therapy, with increasing dose requirements over time. The mechanism for this is unclear.
• Epoprostenol A synthetic prostacyclin analogue potent vasodilator, acting via increasing intracellular cAMP. It is the only drug shown to improve survival in IPAH in RCTs. It probably has its effects as a selective pulmonary vasodilator and potentially through vascular remodelling and platelet adhesion. It also improves symptoms, exercise capacity, and haemodynamics in IPAH and PAH associated with scleroderma. It is inactive in the circulation after 5min and given therefore by continuous IV infusion via a portable pump and tunnelled central venous catheter. Pump failure can be life-threatening
• Treprostinil is a prostacyclin analogue that can be given as a continuous subcutaneous or IV infusion, as it has greater in vivo stability than epoprostenol. It improves symptoms, exercise capacity, and pulmonary haemodynamics. Pain at the subcutaneous infusion site is the major side effect. Due to its current pricing structure, treprostinil is not routinely prescribed for new patients
• Iloprost is a prostacyclin analogue and is more potent than epoprostenol. It has a half-life of 25min and can be given by continuous IV infusion or nebulizer (6–9 times a day). Side effects: headache, cough, mild diarrhoea, and nausea.
Endothelin receptor antagonists (ERA)
Endothelin is a powerful vasoconstrictor and pro-inflammatory mediator and causes smooth muscle cell proliferation. Plasma levels raised in some forms of PHT.
• Bosentan is an oral endothelin receptor A and B antagonist that has been shown to improve exercise capacity, haemodynamics, functional class, and time to clinical worsening in patients with IPAH, APAH with connective tissue disease, and Eisenmenger’s syndrome. It was the first oral therapy approved for the treatment of PHT. 3y survival for a cohort of mainly WHO functional class III patients starting on bosentan was >85%. The major side effect is reversible liver transaminitis, causing discontinuation in ~3%. LFTs should be monitored monthly during treatment. Other side effects include headache and peripheral oedema
• Ambrisentan is a selective type A blocker, with a better liver safety profile. Improvements in symptoms, exercise capacity, haemodynamics, and time to clinical worsening in patients with IPAH and APAH with HIV and connective tissue disease.
There are very clear nationally agreed guidelines on starting treatment for PHT. Disease-targeted drug therapies should only be commenced by a designated specialist PHT centre. Non-specialist clinicians should not routinely prescribe these therapies. Use CCBs in vasodilator responders, but only continue if there is a sustained response. Otherwise—first-line therapy: start monotherapy with PDE inhibitor. If this is not clinically appropriate, an endothelin receptor antagonist may be substituted. Second-line therapy: patients who have failed to respond to a trial of therapy of adequate dose and duration (typically 8–12 weeks) or failed to tolerate one of the oral therapies should be switched to an alternative oral product as monotherapy. Patients who have initially responded to first-line therapy but then deteriorated despite dose escalation may be considered for dual therapy. Patients with a suboptimal response to first-line therapy may be considered for dual therapy. Dual therapy: for patients with progressive disease who have failed to respond to first- and second-line monotherapy or who have initially responded to monotherapy but subsequently deteriorated despite dose escalation or who have had a suboptimal response to monotherapy. Triple therapy: only for patients who have been accepted as suitable for transplant.
• Anticoagulation All patients with PHT are at risk of VTE and in situ pulmonary arterial thrombosis and therefore should be considered for lifelong warfarin. A small thrombus can have catastrophic effects in a patient who is already severely compromised. Studies show an increased survival with warfarin in PHT, which may reflect reversal of an underlying pro-thrombotic state, as well as the prevention of in situ thrombus formation. Additional beneficial effects are seen when combined with a vasodilator
• Long-term O2 Hypoxaemia is due to reduced cardiac output, V/Q mismatching, and right-to-left shunting through a patent foramen ovale. Added O2 may reduce any further rise in PAP resulting from additional hypoxic pulmonary vasoconstriction. Supplemental O2 should achieve a pO2 of >8kPa during rest, exercise, and sleep
• Diuretics and digoxin Diuretics may be useful for the treatment of oedema, but excess pre-load reduction may limit their usefulness. Digoxin has been shown to improve cardiac output acutely in IPAH, though its longer-term effects are not known
• Treatment of arrhythmias
• Immunization Annual influenza and one-off pneumococcal vaccination
• Contraception may be required, as pregnancy is poorly tolerated in IPAH, with a 30–50% mortality.
• Pulmonary thromboendarterectomy is the treatment of choice in CTEPH for proximal obstructive disease. This is the surgical removal of organized thrombotic material and aims to strip away the pulmonary arterial endothelium, starting proximally and extending out to remove all clot in the subsegmental levels. It is done on cardiopulmonary bypass with circulatory arrest. The PAP usually falls within 48h of surgery. Operative mortality is <10% in experienced hands. Longer-term effects are not known
• Atrial septostomy Creation of a right-to-left shunt by balloon atrial septostomy aims to increase systemic blood flow by bypassing the pulmonary circulation, particularly in patients with syncope or severe right heart failure. It is a palliative procedure and can be used for symptom control prior to transplantation, with the defect being closed at the time of transplant. Also used in people receiving prostanoid therapy having syncope. Arterial desaturation occurs following the procedure but is normally offset by the increased cardiac output seen with increased O2 delivery. It is not indicated in severe left heart failure or in patients with impaired LV function
• Transplantation Improves survival and QoL in patients with PHT. In those with preserved LV function, lung transplant is the procedure of choice. Return of normal RV function is found after transplantation. As for all diseases needing transplantation, timing of referral and operation is crucial, as organ availability is limited. The incidence of obliterative bronchiolitis appears to be higher post-transplantation for PHT than in transplantation for other diseases, although the reason for this is uncertain.
in PHT is variable, depending on functional class, haemodynamic compromise with cardiac index, right atrial pressure, and prognosis is linked to mean PAP at presentation. The clinical course is one of progressive deterioration with episodes of acute decompensation. The median survival in NYHA functional class III (symptomatic on mild exertion) is 2.8y and 6 months in NYHA class IV (symptomatic at rest) without treatment.
A number of agents are currently being investigated, including inhaled treprostinil, riociguat, a soluble guanylate cyclase stimulator, and drugs with antiproliferative effects such as simvastatin, imatinib, and sirolimus.
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