18th February 2025

Pulmonary hypertension

Overview of pulmonary hypertension

Pulmonary hypertension (PH) is an umbrella term for the pathological condition of raised pressures in the pulmonary vasculature and encompasses numerous aetiological origins. The diagnosis and identification of the underlying cause is vital as it determines the available treatment options.

Classification of PH is into five categories, as per the World Health Organisation (WHO).

Additional categorisation is based on haemodynamic profile, namely whether the disease of the pulmonary vasculature is primarily pre-capillary, post-capillary or combined pre- and post-capillary in origin. Irrespective of the origin, the overarching diagnostic criteria for PH is mean pulmonary artery pressure (mPAP) of >20 mmHg at rest.

Classification of pulmonary hypertension

Table 4 WHO classification of pulmonary hypertension

Cor pulmonale

Cor pulmonale describes the PH-induced structural alteration of the right ventricle (e.g. hypertrophy) associated with chronic lung disease and/or hypoxaemia (i.e. group III PH). Elevation of pulmonary vascular resistance increases pulmonary arterial pressure, which increases right ventricular afterload, resulting in right ventricular dysfunction and failure.

Diagnosis of pulmonary hypertension

Signs and symptoms of pulmonary hypertension

Symptoms are often non-specific and attributed to other conditions, which may themselves have caused the PH (e.g. chronic lung disease or left-sided heart disease). As a result, there is often a delay in diagnosis until the disease becomes severe.

The most common symptoms of PH are:

• Progressive exertional dyspnoea
• Fatigue and weakness
• Substernal chest pain
• Syncope or near syncope on exertion
• Symptoms of right-sided heart failure, e.g. peripheral oedema, abdominal swelling and bloating from ascites

Symptoms such as cough and palpitations can occur but are rarer. A hoarse voice may be a presenting feature of PH from compression of the left recurrent laryngeal nerve by a dilated main pulmonary artery; this is called Ortner’s syndrome.

Early-stage PH may manifest no physical signs. As the disease progresses, signs may develop, such as:

• Elevated JVP with prominent ‘a’ waves and prominent ‘v’ waves in significant tricuspid regurgitation
• Right ventricular heave
• Loud P2 on auscultation, which may be palpable
• Pansystolic murmur of tricuspid regurgitation
• Diastolic murmur of pulmonary regurgitation
• Signs suggestive of tricuspid regurgitation and right heart failure: pulsatile hepatomegaly, peripheral oedema, ascites
• Cyanosis 
• Signs of underlying causative disease, e.g. clubbing in ILD, sclerodactyly in systemic sclerosis

Investigations in pulmonary hypertension

The work up for PH is intended to confirm the diagnosis, assess severity and identify the underlying cause.

Echocardiography is recommended as the first-line non-invasive diagnostic investigation in suspected PH and right heart catheterisation (RHC) is the gold standard for diagnosis. However, there may be suggestive features on other investigations that raise suspicion of PH, and there are numerous other recommended investigations in the work up of PH to identify the cause.

Examples of these include:

• ECG – P pulmonale, right axis deviation, right ventricular hypertrophy, right bundle branch block
• Chest X-ray – right heart enlargement, pulmonary artery enlargement, pruning of peripheral vessels; there may also be signs of left heart disease or underlying lung disease
• Lung function testing – may be normal in early disease or show mild restrictive or obstructive disease in later disease stages; it may be abnormal if underlying lung disease is the cause of the PH
• Arterial blood gas – may show hypoxia and hypocapnia
• High-resolution CT chest – identify any underlying lung disease
• Overnight oximetry or polysomnography – to identify sleep-disordered breathing
• Ventilation-perfusion (VQ) scan – to exclude CTEPH as the cause of PH; a CT pulmonary angiogram may also be used, but VQ scanning is preferred as a normal VQ scan essentially excludes CTEPH with high sensitivity and specificity
• 6-minute walk test (6MWT) – helps establish a baseline and is useful for prognosis; those with a walk distance >440 m have a better prognosis
• Blood tests – there are no specific diagnostic blood tests; bloods may be done to screen for underlying disease such as liver function tests or a connective tissue disease screen; elevated NT-proBNP levels are associated with worse prognosis
• Abdominal/liver ultrasound – if liver cirrhosis/portal hypertension is suspected as the underlying cause

As mentioned, transthoracic echocardiography is the first-line investigation in suspected PH. It helps establish the probability of PH and can also help determine the subsequent required tests. Probability of PH is determined by the peak tricuspid regurgitation velocity (TRV) and presence of other features of PH on echocardiogram, e.g dilated right heart chambers. A peak TRV ≤2.8 m/s with no other features of PH suggests a low probability of PH, and a peak TRV of >3.4 m/s suggests a high probability of PH.

Right heart catheterisation (RHC) is the gold standard for diagnosing PH. RHC also allows for determining the contribution of left heart disease to PH and allows assessment of baseline severity and vasoreactivity testing, which is important for choosing treatment and monitoring the subsequent response. However, it is not always necessary to carry out RHC to confirm a diagnosis of PH: for example, in patients with severe left heart disease or severe lung disease with a high probability of PH on echocardiogram, a clinical diagnosis would suffice. However, RHC would be indicated if there is a discrepancy between echocardiogram and clinic suspicion of PH, where the contribution of left heart disease to PH is uncertain if the aetiology of PH remains undetermined after extensive non-invasive testing or where mixed aetiologies are suspected.

Management of pulmonary hypertension

All patients with PH should be referred to a specialist centre with expertise in managing the condition. There are supportive and disease-specific treatments available in PH.

Supportive therapies are non specific and can be employed in the management of all cases of PH.

Disease-specific medical treatments are available for group I PH (PAH) and there are specific interventional treatments for group IV PH. The treatments used in PAH have been shown to have variable and sometimes negative effects on patients with groups II and III PH. As a result, the primary medical management of groups II and III PH focuses on optimisation of the underlying left heart (group II) or pulmonary disease (group III). Given the heterogeneous aetiology of group V PH, PAH-specific therapy is also not utilised in this.

Supportive therapies are similar to those utilised in any patient with a chronic respiratory condition:

• Smoking cessation advice and support
• Pulmonary rehabilitation
• Vaccinations (influenza, coronavirus, pneumococcal)
• Optimising nutrition
• Oxygen therapy if hypoxic
• Diuretics in treating fluid overload from right ventricular failure from PH
• Treating underlying comorbidities
• Psychosocial support

Management of group I PH (PAH)

Patients with suspected PAH will generally have undergone RHC in order to confirm the diagnosis. Vasoreactivity testing at the time of RHC is recommended in those with suspected idiopathic PAH, hereditary PAH and PAH associated with drugs and toxins. PAH associated with other conditions is often not vasoreactive and so testing is not indicated. 

Vasoreactivity testing involves administration of a short-acting vasodilator (e.g. inhaled nitric oxide or intravenous epoprostenol) and assessment of haemodynamic response. A test is positive (‘vasoreactive’) if there is a ≥10 mmHg reduction in mPAP to a value ≤40 mmHg, with increased/unchanged cardiac output and minimally reduced/unchanged systolic blood pressure.

Initial treatment is guided by whether vasoreactivity testing is positive or not:

• For those that are vasoreactive, a trial of calcium channel blockers is indicated
  • Options include amlodipine, nifedipine, felodipine and diltiazem
  • Response to treatment is assessed after three to six months with repeat RHC
• For those who are not vasoreactive or where there is an inadequate response to calcium channel blockers there are other targeted therapies available
  • Endothelin receptor antagonists (ERA): ambrisentan (oral), bosentan (oral), macitentan (oral)
  • Phosphodiesterase 5 inhibitors (PDE5I): sildenafil (oral), tadalafil (oral)
  • Soluble guanylate cyclase stimulators (SGCS): riociguat (oral)
  • Prostacyclin receptor agonists (PRA): selexipag (oral)
  • Prostacyclin analogues: beraprost (oral), treprostinil (oral, inhaled, subcutaneous or intravenous), iloprost (inhaled), epoprostenol (intravenous)

Treatment decisions are based on WHO functional class (WHO-FC) grade and patient risk (determined by numerous factors including 6MWT distance and NT-proBNP level). WHO-FC ranges from grade I (no limitation in physical activity) to grade IV, where patients are unable to carry out physical activity without symptoms.

Oral monotherapy, often with ERAs,  may be appropriate for patients with WHO-FC class I/early class II and low-risk PH.

WHO-FC class II and III disease with low or intermediate risk is usually treated with a combination of ERA and PDE5I, most commonly ambrisentan and tadalafil.

Rapid or progressive disease or WHO-FC class IV or high-risk PH should be treated with a regime containing a parenteral prostacyclin analogue; intravenous epoprostenol is the preferred agent. This is often in addition to the ERA and PDE5I combination.

Inadequate response to combination medical therapy should prompt referral for consideration and work up for lung transplantation.

Management of CTEPH (group IV PH)

All patients with CTEPH should be on lifelong therapeutic anticoagulation, most commonly warfarin.

First-line management is consideration of pulmonary endarterectomy if the patient is an operative candidate.

If the patient is not an operative candidate or has persistent/recurrent PH following endarterectomy, medical therapies used in PAH can be used. Riociguat and parenteral prostacyclin analogues are used based on WHO-FC class at the time of initiation of treatment. ERAs and PDE5Is are also regularly used in clinical practice, albeit off-label currently. An alternative to medical therapy is balloon pulmonary angioplasty in patients who are not operative candidates or have persistent/recurrent PH following endarterectomy.

Prognosis in pulmonary hypertension

Prognosis is variable depending on PH group, WHO-FC class, aetiological origin, sex, age and other factors. In the absence of therapy, group I PH shows worse survival than the rest of the groups. However, with the advent of disease-specific treatment, survival in group I PH is improving and comparable to other groups. Group III PH now appears to have the least favourable prognosis, with a 1-year survival rate of 80% compared to 89% in group I PH and a 5-year survival rate of 38% compared to 59% in group I PH.

References

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