17th January 2024

Pulmonary Hypertension

Background

Epidemiology

Pulmonary hypertension is defined as an increase in pulmonary artery pressure (PAP) to more than 25mmHg at rest when measured on right heart catheterisation studies. Comparatively, the average PAP in a healthy individual is around 14mmHg (1). Due to formal diagnosis relying on this invasive testing, we can assume that case numbers are largely underreported on a global scale. In the U.K., incidence is reported as 97 cases per million, with a slightly increased prevalence in females.

Pathophysiology

Pulmonary hypertension is a broad term which encompasses five distinct aetiological categories. The pathophysiology of all subcategories is defined by an increased pulmonary vascular resistance, resulting in progressively increased pulmonary artery pressures and eventually right ventricular failure and death. The disease course generally follows a progressive deterioration interspersed with acute episodes of decompensation.

The World Health Organisation (WHO) has classified pulmonary hypertension into five groups (2):

• Group 1 – Pulmonary Arterial Hypertension (PAH) – defined by sustained vascular remodelling of the pulmonary arteries. There are a range of causes, including:
  • Idiopathic
  • Inherited – account for approximately 10% of cases, most commonly associated with a mutation in the BMPR2 gene
  • Drugs and toxins, such as fenfluramine
  • Congenital heart disease associated with left-right shunting, e.g., ASD, VSD
  • Connective tissue diseases
  • Vasculitis
  • Human Immunodeficiency Virus (HIV)
  • Schistosomiasis
  • Pulmonary veno-occlusive disease
• Group 2 – Pulmonary hypertension secondary to left heart disease is thought to be the most common subgroup due to the frequency of left heart disease. Pathophysiology involves the passive backflow of blood from a poorly functioning left-sided system (due to either systolic, diastolic or valvular dysfunction), causing increased right-sided pressures. Causes include:
  • Left ventricular systolic dysfunction
  • Left ventricular diastolic dysfunction
  • Valvular disease
  • Congenital or acquired left ventricular inflow or outflow tract obstruction, such as hypertrophic obstructive cardiomyopathy (HOCM)
  • Congenital or acquired pulmonary venous stenosis
• Group 3 – Pulmonary hypertension due to lung diseases and/or hypoxaemia. Hypoxia induces vasoconstriction and endothelial cell damage and remodelling via neo-muscularisation and collagen deposition. Causes include:
  • Interstitial lung disease – often associated with severe PH
  • Chronic Obstructive Pulmonary Disease (COPD) – commonly associated with mild PH
  • Obstructive sleep apnoea
  • Alveolar hypoventilation disorders
  • Chronic exposure to high-altitude
  • Neuromuscular causes such as myasthenia gravis and motor neurone disease
• Group 4 – Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with prolonged occlusion of the pulmonary vasculature, most typically by a thrombus. Sometimes occurs when a pulmonary embolism has not been diagnosed and treated in the acute setting, but can also be due to poor resolution of thrombi despite anticoagulant treatment. Rarely, can also occur with other pulmonary artery obstructions such as angiosarcoma or hydatid cyst disease.
• Group 5 – Pulmonary hypertension with unclear and/or multifactorial mechanism, including:
  • Haematological, e.g., sickle cell disease, myeloproliferative diseases, chronic haemolytic anaemia
  • Systemic, e.g., sarcoidosis, neurofibromatosis, pulmonary histiocytosis
  • Metabolic disorders, e.g., Gaucher’s disease, thyroid disease, disorders of glycogen storage
  • Others, e.g., pulmonary capillary haemangiomatosis, fibrosing mediastinitis, chronic renal failure

Presentation 

Symptoms

Symptoms of pulmonary hypertension can be non-specific and most commonly include fatigue, shortness of breath, angina and syncope. These symptoms are all classically worse on exertion, and severity of symptom burden is often assessed for these patients by calculating their MRC Dyspnoea Scale score (grading breathlessness on a scale of 0-4). Structural complications of the disease can also result in further symptoms such as haemoptysis (due to bronchial artery rupture) and hoarseness of voice (due to compression of the left recurrent laryngeal nerve).

Clinical signs

• Right ventricular heave
• Central cyanosis
• Peripheral oedema
• Ascites
• Loud P2
• Pansystolic murmur heard loudest at the left lower sternal edge (secondary to tricuspid regurgitation)
• Elevated jugular venous pressure
• Lancisi’s sign (giant C-V waves seen in tricuspid regurgitation)

Take care to also observe for clinical signs on examination that may point you towards the underlying diagnostic cause of the pulmonary hypertension, such as digital clubbing or telangiectasia (3).

Diagnosis 

Once there is clinical suspicion of pulmonary hypertension, patients are often referred to a regional specialist pulmonary hypertension centre for focused investigation and access to a multidisciplinary approach. Depending on the level of clinical suspicion, there are many investigations that can be undertaken.

Investigations

• Blood tests, including FBC, U&E, LFT, TFTs, a full autoimmune screen and thrombophilia screening – whilst these are not diagnostic, they can point towards the aetiology. NT-proBNP is also measured and used as an independent marker of severity in pulmonary hypertension.
• Electrocardiogram (ECG) – can often be normal, but ECG changes associated with right ventricular strain are common, including p pulmonale, right axis deviation, right bundle branch block and QTc prolongation. In advanced disease, there is often also an association with atrial arrhythmias.
• Chest radiograph – can show features of right atrial and ventricular enlargement, pulmonary arterial dilatation as well as clues to the underlying cause of the pulmonary hypertension.
• Pulmonary function tests – most commonly, patients with pulmonary hypertension have a reduced carbon monoxide lung diffusion capacity (transfer factor, or TLCO). Obstructive and restrictive defects from co-existing or related airways or interstitial lung disease can also aid with diagnosis but are best interpreted in the context of cross-sectional imaging.
• Arterial blood gas
• Transthoracic echocardiography – can be used to support a diagnosis of pulmonary hypertension, but, like all of the above tests, is not strictly diagnostic. Peak tricuspid regurgitation velocity is used as a substitute marker for pulmonary arterial pressures – a value of >3.4m/s is highly suggestive of the diagnosis. Other suggestive features include right atrial and ventricular dilatation, pulmonary regurgitation and flattening of the interventricular septum.
• Ventilation/perfusion scan – identifies patients with unmatched perfusion defects as the underlying cause of pulmonary hypertension, indicating CTEPH
• High-resolution computed tomography and pulmonary angiography (HRCT/CTPA) – cross-sectional imaging can reveal features of pulmonary hypertension, such as right ventricular or pulmonary artery dilatation, but is also essential in investigating the underlying cause, such as lung disease or CTEPH. CTPA can help identify the subset of patients with CTEPH who may benefit from intervention with pulmonary endarterectomy.
• Cardiac magnetic resonance imaging (CMRI) – provides detailed assessment of the right ventricular structure as well as function, which can strongly support a diagnosis of pulmonary hypertension but cannot be used to exclude it.
• Abdominal ultrasound scan – to look for the complication of portal hypertension
• Right heart catheterisation – this is the gold standard test for diagnosis. It allows for direct measurement of pulmonary arterial pressures and oxygen saturation levels within the internal vena cava. Left heart catheterisation is often performed at the same time, as it is a requirement for patients likely to proceed to pulmonary endarterectomy, and can be useful diagnostically in patients where left heart disease is a suspected cause.
• 6-minute walking test – used as a marker of severity once the diagnosis has been made. Measures simply the maximum walking distance a patient achieves in the set 6-minute time frame.
• Cardiopulmonary exercise testing (CPET)

Management

Group 1 – Pulmonary Arterial Hypertension 

Supportive

• Oral anticoagulation is indicated due to increased risk of VTE in this patient group
• Supplemental oxygen as required to aim of pO2 >8kPa
• Correct iron deficiency anaemia
• Diuretic therapy for clinically fluid-overloaded patients
• Treatment of co-existing atrial arrhythmias; digoxin is often the drug of choice
• Counsel patients regarding substantial mortality associated with pregnancy and offer appropriate birth control
• Offer routine influenza and pneumococcal vaccinations
• Encourage physical activity within symptom limits

Disease-modifying pharmacological therapy, used as both monotherapy and in combination:

• Calcium channel blocker therapy
  • Both dihydropyridine (amlodipine; nifedipine) and non-dihydropyridine (diltiazem) CCBs are used, depending on baseline heart rate.
  • Can be used only in patients shown to be responsive to vasodilator therapy when tested during right heart catheterization
• Endothelin receptor antagonists
  • Work by interfering with the endothelin pathway, blocking pulmonary vascular smooth muscle vasoconstriction
  • Taken as oral agents, they have been shown to improve exercise capacity as well as echocardiographic and haemodynamic measurements.
  • Examples include bosentan, ambrisentan (both of which require monthly liver function test monitoring) and macitentan
• Phosphodiesterase type 5 inhibitors
  • Work by preventing degradation of the enzyme cyclic guanosine monophosphate (cGMP), resulting in pulmonary vasodilation
  • Examples include sildenafil, tadalafil and vardenafil, all of which are oral agents originally approved for use in erectile dysfunction.
  • Shown to improve exercise tolerance as well as echocardiographic and haemodynamic measurements
• Prostacyclin analogues and prostacyclin receptor agonists
  • Endothelial cells produce prostacyclin, which acts as a potent vasodilator of the pulmonary vascular bed. Synthetic prostacyclins have the same effect.
  • Epoprostenol is a synthetic prostacyclin, which is the only treatment shown to have a mortality benefit when used in idiopathic PAH (although other similar agents include iloprost and treprostinil). The half-life of epoprostenol is very short, at only 3-5 minutes, necessitating it to be administered as a continuous IV infusion, which should not be abruptly stopped. This is associated with infection risks of having a long-term central venous catheter in situ, as well as a side effect profile of flushing, diarrhoea, headache and jaw pain.
  • Selexipag is an oral prostacyclin receptor agonist proven to reduce pulmonary arterial hypertension.

Interventional

• Balloon atrial septostomy – the intentional creation of an atrial septal defect to allow for right-to-left shunting and decompression of the high-pressure right heart and increase cardiac output. This procedure is used very rarely, either as a palliative measure or bridge to lung transplant.
• Lung transplantation – bilateral lung transplantation in PAH patients can have up to 75% 5-year survival rates.
• Bronchial artery embolisation – can be used to symptomatically control severe haemoptysis.

Group 2 – pulmonary hypertension due to left heart disease

The primary goal of treatment here is to optimise the underlying condition, for example, valve replacements or heart failure therapies where indicated. The use of specific therapies approved in PAH is not evidenced in group 2 disease.

Group 3 – pulmonary hypertension due to lung disease

Appropriate treatment of the primary lung disease, with additional oxygen supplementation for hypoxaemia, is the goal of treatment. Similarly to group 2 disease, there is no evidence for the effectiveness of any disease-modifying therapy in this subtype.

Group 4 – chronic thromboembolic pulmonary hypertension 

Medical

Lifelong anticoagulation is the mainstay of medical management for CTEPH, even if surgical intervention takes place. In patients deemed not fit for surgical intervention, anticoagulation alone is recommended.

Surgical

Pulmonary endarterectomy is the gold-standard treatment of choice for CTEPH. There is proven to be a substantial benefit both symptomatically and haemodynamically post-operatively, with patients debilitated by breathlessness often able to return to normal functioning. However, the procedure is performed with the patient in a hypothermic state under induced circulatory arrest, so not all CTEPH patients would be appropriate candidates. In patients with co-existing coronary artery disease, bypass grafting can be performed simultaneously.

Group 5 – pulmonary hypertension with unclear or multifactorial aetiology

Like with group 2 and group 3 cases, the primary aim should be rigorous diagnostic investigations to try and establish the underlying cause and treat this accordingly. There are no specific disease-modifying therapies in this group.

References

• Galiè N, Humbert M, Vachiery J, Gibbs S, Lang I, Torbicki A et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. 2022.
• Sysol J, Machado R. Classification and pathophysiology of pulmonary hypertension. Continuing Cardiology Education. 2018;4(1):2-12.
• Kalra P. Essential revision notes for MRCP. Knutsford, Cheshire: PasTest; 2014.