11th May 2025

Pulmonary Hypertension

Background 

Pulmonary hypertension is a condition of increased vascular resistance within the pulmonary arteries and is defined by a mean pulmonary arterial pressure (mPAP) > 20mmHg at rest. It can be split into primary pulmonary arterial hypertension (PAH) or secondary pulmonary hypertension. Symptoms are non-specific and include breathlessness and fatigue on exertion. Ultimately, right heart failure will manifest in affected patient groups and left untreated carries a median survival of 2.8 years. Whilst there is no cure, management can improve symptoms, reduce morbidity and prolong survival, making early recognition and management key.

Aetiology 

The exact cause of pulmonary hypertension (PH) is unknown, although most cases are associated with an underlying condition and so are secondary in aetiology. The World Health Organization (WHO) has classified PH into five categories, with group one being further subclassified as described below. 

• Group 1: Pulmonary arterial hypertension (PAH) 
  • Idiopathic (IPAH) – commonly presents in females ages 20-50 years 
  • Heritable 
  • Related to an underlying condition:
    • Connective tissues disease – structural lung damage and chronic hypoxaemia: systemic sclerosis (most commonly anti-centromere autoantibodies), rheumatoid arthritis 
    • Congenital heart disease – left-to-right shunt causing Eisenmenger’s syndrome 
    • Portal hypertension
    • HIV infection
    • Drug or toxin induced (cocaine/amphetamines, appetite suppressants such as aminorex)
  • PH of the new-born
• Group 2: PH related to left heart disease – resulting from raised left atrial pressures
  • Left heart systolic/diastolic dysfunction 
  • Valvular disease
• Group 3: PH related to lung disease or chronic hypoxia – resulting from damage lung structure and hypoxic vasoconstriction 
  • Interstitial pulmonary fibrosis (IPF)
  • Chronic Obstructive Pulmonary Disease (COPD)
  • Obstructive Sleep Apnoea 
  • Chronic high-altitude exposure
• Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH) – resulting from chronic arterial obstruction
  • Unresolved thrombus from pulmonary embolism
• Group 5: Unclear or multifactorial 
  • Sickle cell disease
  • Chronic haemolytic anaemia
  • Sarcoidosis 
  • Vasculitis

Pulmonary arterial hypertension pathophysiology

The pathophysiology of PAH remains unclear. Multiple genes have been recognised in the disease pathogenesis. Familial PAH is associated with mutations in BMPR2, and less commonly SMAD9 and ACVRL1; however, penetrance is low and so not all patients with a gene mutation will develop PH across a lifetime. Vascular pathology includes over-proliferation of endothelin-cell and smooth muscle cells within the pulmonary arteries, increased levels of vasoactive mediators and thrombosis. In IPAH levels of endothelin-1 levels are increased and nitric oxide (NO) levels are decreased. Endothelin-1 is a potent vasoconstrictor and pro-proliferative mediator, plasma levels may be used as a marker of severity of IPAH. NO is a potent vasodilator and inhibits smooth muscle proliferation and platelet aggregation. It should also be noted pro-coagulants are elevated within the vasculature of those affected by PAH. Together, these changes contribute to narrowing of the pulmonary vasculature, increasing pulmonary pressures, and ultimately causing right ventricular failure and death.

Diagnosis 

Definitive diagnosis of PH is at right cardiac catheterisation where pulmonary pressures can be measured. PH is defined by a mean pulmonary artery pressure of greater than 20 mmHg at rest. Clinical history, examination and investigations should be utilised to review secondary causes of PH. IPAH is a diagnosis of exclusion once secondary causes of PH have been excluded.

Clinical Manifestations

Most commonly, PH affects females between 20 and 50 years. Presentation may be precipitated by use of stimulants such as cocaine. PH presents with progressive dyspnoea and fatigue on exertion. Other exertional symptoms include cardiac chest pain and presyncope/syncope, which may not appear until the onset of right sided heart failure. Given that the symptoms of PH are not specific, diagnosis is often delayed. 

Symptoms can be classified by WHO functional status. This is useful for marking severity, prognosis and outcome to therapies.

Table 1: WHO functional classification of PH

Examination signs are absent or subtle in early disease and again generally occur after onset of right sided cardiac failure.  

Examination findings include: 

• Cyanosis
• Right ventricular heave – indicating right heart hypertrophy
• Loud P2 – accentuated pulmonary component of second heart sound 
• Holosystolic murmur – functional tricuspid regurgitation
• Signs of right heart failure: raised JVP, peripheral oedema, hepatomegaly, ascites.
• Note that the lungs remain clear on auscultation (unless underlying lung disease)

In secondary PH, additional clinical features will depend on the underlying aetiology. When related to systemic sclerosis, one may expect to see sclerodactyly, Reynaud’s, polyarthralgia, telangiectasia, dysphagia and additional rheumatological manifestations associated with this condition. In the presence of left sided cardiac failure, signs of pulmonary congestion may be present, such as coarse bi-basal crackles, orthopnoea and paroxysmal nocturnal dyspnoea. Interstitial lung disease may reveal fine inspiratory bi-basal crackles. 

This illustrates the importance of a thorough history and examination in guiding the clinician towards the cause of suspected PH.

Investigations

PH investigations usually begin when the patient presents with dyspnoea and includes chest x-ray, transthoracic echocardiogram, and possibly pulmonary function tests at this stage (Table 2 describes findings related to PH and its associated conditions). Echocardiogram estimates systolic pulmonary artery pressures and so is useful in raising clinical suspicion but is not considered diagnostic. All patients should go on to have right cardiac catheterisation to accurately measure pulmonary pressures and provide definitive diagnosis. Right heart catheterisation also allows for measurement of haemodynamic parameters (such as cardiac output/index atrial pressures, pulmonary vascular resistance and pulmonary artery saturations) which are important prognostic markers.

Blood tests performed in the initial patient work-up are aimed at alternative causes of dyspnoea and eventually to investigate secondary causes of PH. Labs include full blood count, liver function tests, clotting studies, thyroid function tests, autoantibodies (anti-nuclear, anti-dsDNA, anti-centromere), HIV serology, BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal proBNP). BNP correlates to the severity of right cardiac dysfunction and is used as a marker of prognosis and mortality in patients with PAH.

If obstructive sleep apnoea (OSA) is suspected, overnight oximetry should be performed. 

If no secondary aetiologies are identified, a diagnosis of idiopathic PAH is made.

Table 2: Clinical findings of PH and its associated conditions

In PAH (WHO Group 1), vasodilator testing can be used to identify a small subset of patients who may benefit from treatment with calcium-channel blockers (CCB’s). Pulmonary pressures are measured before and after administration of vasodilators (inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine). If the patient has already progressed to right heart failure, vasodilator testing should not be performed.

A 6-minute-walk-test (6MWT) is performed in all patients with PH and is used to track management and guide prognosis. This test assesses how far the patient can walk in 6-minutes and has an inverse correlation with the functional class of the patient.

Management 

Management of PH should focus on treatment of the underlying condition and general supportive measures, with additional management strategies being considered by a specialist in pulmonary hypertension. Patients with PH in group 1, 4 and 5 should be referred to a specialist centre without delay. 

Most cases of PH are due to underlying left heart disease (Group 2) or lung disease (Group 3), and management is often led by cardiologist and respiratory physicians respectively. 

Treatment aims to prolong survival, improve functional class, improve 6MWT, improve right ventricular function and reduce/normalise BNP.

General Supportive Therapy

General supportive therapy has a role for improving patient’s symptoms and quality of life, although has limited impact on disease progression.

• Anticoagulation therapy – in PAH and CTEPH
• Diuretics (furosemide, spironolactone) – in patients with fluid overload symptoms of right heart failure
• Digoxin – in patients with concurrent arrhythmia (such as atrial fibrillation or atrial flutter)
• Oxygen therapy – in patients with hypoxaemia 
• Avoid pregnancy – woman of childbearing age should be given progesterone-only contraception (to avoid prothrombotic effects of the combined pill) and termination is recommended in the event of pregnancy 
• Annual influenza vaccine
• Encourage low level aerobic exercise, avoid high intensity exercise

Targeted Medical Therapy

Targeted medical therapy is commenced by specialist PH centres. Their aim is to improve exercise capacity and symptoms, haemodynamic parameters and patient quality of life. It is indicated in patients with PAH class II and above who have not responded to general supportive measures. 

Some patients with IPAH may benefit from calcium channel blockade. To isolate this subgroup, patients with IPAH without right sided cardiac failure undergo vasodilator testing to identify those whose pulmonary arterial pressures fall following the administration of vasodilators. The minority of patients (10-15%) have a positive response to vasodilators (fall in mean pulmonary artery pressure of >20% with an increased or unchanged cardiac output during acute challenge) and can commence treatment on CCB’s. CCB’s are aimed at reducing pulmonary vascular resistance. Choice of CCB is dependent on the patient’s baseline heart rate. If heart rate is less than 100 beats per minute nifedipine or amlodipine would be first line, however if the patient’s heart rate is greater than 100 beats per minutes then diltiazem would be the preferred drug for its negatively chronotropic effect. 

Most patients with PAH have a negative response to vasodilator testing. These patients should be considered for alternative targeted medical therapy, which consists of 4 drug classes shown in Table 3 below. 

Table 3: PAH targeted medical therapy drug classes

Treatment decision is dependent on risk stratification of patients into either low, intermediate or high risk. This risk stratification is based on clinical judgement and the following criteria defined in Table 4.

Table 4: PH risk stratification criteria

Low or intermediate risk patients can be commenced on an oral agent from one of the above classes or on multiple in the form of oral combination therapy. If the patient is unresponsive to oral combination therapy, they are then considered for parenteral prostanoids, such as epoprostenol, with the option of adding an endothelin receptor antagonist or phosphodiesterase-5 inhibitor or soluble guanylate cyclase stimulator.

Patients within the high-risk group should be immediately started on an intravenous epoprostenol, which can prolong survival. If treatment goals are not achieved, combination therapy with an endothelin receptor antagonist or phosphodiesterase-5 inhibitor is indicated.

Surgical Management 

Patients’ refractory to targeted therapies with severe symptomatic PAH may be considered for transplantation. This includes a single or double lung transplant or a heart-lung transplant. 

In Group 4 patients with CTEPH, pulmonary endarterectomy (PEA) surgery can be performed to remove old blood clots from the lungs. This is recommended alongside life-long anticoagulation and can potentially cure CTEPH with > 90% 5-year-survival.

Complications

• Right heart failure – the most common and ultimately inevitable complication of PH is right cardiac failure. Raised pulmonary pressures effectively ‘obstruct’ the right outflow tract and so increase afterload of the right heart, this in turn causes right sided cardiac hypertrophy and failure.
• Supraventricular tachyarrhythmias – right sided heart failure may lead to right atrial dilatation, which can predispose patients to atrial fibrillation and atrial flutter
• Pneumonia – patients with PH are at greater risk of developing pneumonia and is associated with the mortality of this patient group. 
• Mortality – historically, prior to development in management of PH mortality was high, with an untreated median survival was 2.8 years. Since the introduction of targeted therapies, 3-year survival has risen to 87%
• Pregnancy mortality – pregnancy is associated with a high maternal mortality (17-33%) and should be avoided. 
• Treatment related side effects – prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors all commonly cause headache as an adverse side effect.

References

BMJ Best Practice – Topic 292 Idiopathic Pulmonary Hypertension – https://bestpractice.bmj.com/topics/en-gb/292/

Humbert, M. et al. (August 2022) ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. https://academic.oup.com/eurheartj/article/43/38/3618/6673929?login=false#384349191 

Kiely, D.G. et al. (2013) Pulmonary hypertension: Diagnosis and management, The BMJ. British Medical Journal Publishing Group. https://www.bmj.com/content/346/bmj.f2028.full 

Morrell, N.W. et al. (2018) Genetics and genomics of Pulmonary Arterial Hypertension, European Respiratory Society. European Respiratory Society. https://erj.ersjournals.com/content/early/2018/10/11/13993003.01899-2018

Pulmonary Hypertension Association UK (May 2007) Appraisal of the drug treatments used in pulmonary arterial hypertension – National Institute for Health & Clinical Excellence https://www.nice.org.uk/guidance/GID-TAG382/documents/pulmonary-arterial-hypertension-association-uk4