Pulmonary hypertension is defined on the basis of haemodynamic characteristics as a mean pulmonary arterial pressure >25 mmHg at rest as assessed directly by right heart catheterization, the currently accepted ‘gold standard’ diagnostic method. This is a widely accepted definition that has been used in randomized controlled trials of treatment and in the pulmonary arterial hypertension registry.1 However, recent studies in healthy individuals have shown that mean pulmonary artery pressure is 14 ± 3 mmHg with an upper limit of normal suggested to be 20 mmHg.2 It remains unclear what the implications are for those individuals with pressures between 20 and 24 mmHg. Furthermore, the definition of pulmonary hypertension during exercise is unclear and is set rather arbitrarily at >30 mmHg.

Echocardiography is widely used in individual patients to assess the likelihood of pulmonary hypertension based on findings of impaired right ventricular function, altered haemodynamics and an estimate of pulmonary artery pressure. This is a useful assessment for suspected disease, but is too insensitive to detect mild severity pulmonary hypertension. Therefore, echocardiography is not used to define or screen for pulmonary hypertension.

Pulmonary artery pressure depends on multiple factors, including pulmonary vascular resistance, cardiac output and pulmonary capillary wedge pressure. Using these components, it is possible to classify pulmonary hypertension on a pathophysiological basis into pre- and post-capillary forms. Based on this classification, pulmonary hypertension was previously categorized on clinical grounds into primary and secondary types where the former did not have a clearly defined underlying cause. This classification from the 1950s has been gradually replaced by the findings of research into pulmonary hypertension, which has led to new thinking and the description of mechanisms and management strategies, particularly for primary pulmonary hypertension.

The Evian classification in 1998 grouped categories of pulmonary hypertension on the basis of shared clinical features, pathology and therapeutic options. Five groups were defined which had the effect of stimulating basic and clinical trials work in cohorts of well-defined patient types. The Third World Symposium on Pulmonary Hypertension (2003) refined the Evian scheme to incorporate an expanding understanding of the Group 1 disorder pulmonary arterial hypertension (PAH). In 2008, a further refinement was made at the Fourth World Symposium on Pulmonary Hypertension and is the classification used in this chapter.1, 3

There are few comparative data on the prevalence of different forms of pulmonary hypertension. An echocardiographic survey reported a 10.5% prevalence of pulmonary hypertension, defined as pulmonary artery systolic pressure >40 mmHg, in a group of 4579 patients. Within the group with pulmonary hypertension, ∼79% had left heart disease and 10% had lung disease and hypoxia, while PAH constituted ∼4% and chronic thromboembolic pulmonary hypertension (CTEPH) made up less than 1% of the group.5

Clinical Presentation

The clinical presentation and investigation of pulmonary hypertension are similar for the various groups despite differences in pathology and underlying causes. The symptoms of pulmonary hypertension are non-specific and include breathlessness, a reduced exercise tolerance, weakness, fatigue, angina-like chest pain, syncope and abdominal distension. Initially, symptoms are reported on exertion, but with progression patients will report similar symptoms at rest. Later in the progress of the disorder, physical signs include a left-sided parasternal heave, an accentuated pulmonary valve component to the second heart sound and a pansystolic murmur of tricuspid regurgitation. In addition, a diastolic murmur of pulmonary regurgitation and a right ventricular third sound may be detected. Further features include jugular venous distension, hepatomegaly, peripheral oedema, cyanosis and cool extremities in the more advanced stages of the disease. Examination of the chest usually reveals perfectly normal breath sounds, but hyperinflation, hyper-resonance and a reduced breath sound intensity may indicate the presence of COPD, and fine mid to late inspiratory crackles may indicate pulmonary fibrosis or left ventricular failure. Other peripheral features may give guidance to the cause of pulmonary hypertension, for example, systemic sclerosis with telangectasia, digital ulceration.

Investigations

Electrocardiogram

The electrocardiogram (ECG) may suggest or support the presence of pulmonary hypertension demonstrating right ventricular hypertrophy and strain and right atrial dilatation. In patients with idiopathic PAH (IPAH), right ventricular hypertrophy is present in nearly 90% of subjects with right axis deviation in ∼80%. Hence the absence of such findings does not exclude pulmonary hypertension and does not exclude the potential for underlying haemodynamic abnormalities. The sensitivity and specificity of the ECG makes it a poor screening tool for the detection of significant pulmonary hypertension.

Chest Radiograph

The key findings are central arterial dilatation with pruning or loss of the peripheral pulmonary vessels. There may be evidence of right atrial and right ventricular enlargement, particularly in more advanced disease. The extent of radiographic abnormalities does not correlate with the level of pulmonary hypertension. In the majority of patients with IPAH, ∼90% of chest radiographs will be abnormal from the time of diagnosis. The chest radiograph allows moderate to severe lung disease and pulmonary venous hypertension due to left heart disease to be excluded or considered as the cause of pulmonary hypertension.

Pulmonary Function Tests and Arterial Gas Analysis

These investigations are important as they may help to exclude underlying airways or parenchymal lung disease. Spirometry with reversibility testing or use of the post-bronchodilator FEV1/FVC <70% criterion can be used to rule out the presence of COPD as a cause of hypoxaemia-based pulmonary hypertension. Furthermore, these investigations allow the detection of restrictive lung disease, such as interstitial lung disease. Confirmation of parenchymal lung disease, such as in predominantly emphysematous COPD and interstitial lung disease, can be determined from measurement of static lung volumes and gas transfer indices, including the transfer factor of the lungs for carbon monoxide (TLCO) and the carbon monoxide alveolar volume corrected coefficient (KCO). The physiological implication of such lung disease can be assessed from arterial gas analysis. Further evidence of parenchymal lung disease can be determined by high-resolution computed tomographic (CT) scanning. Overnight oximetry or polysomnography allows the exclusion of a number of sleep-related respiratory problems, such as obstructive sleep apnoea syndrome. Patients with PAH usually have deranged TLCO and mild to moderate reduction of lung volumes. Arterial oxygen tension in PAH is usually normal or only slightly less than normal at rest and carbon dioxide tension is decreased due to alveolar hyperventilation.

Echocardiography

This is a mandatory investigation in suspected pulmonary hypertension because a number of echocardiographic variables relate to right ventricular haemodynamics including pulmonary artery pressure, which can be estimated on the basis of the peak velocity of a tricuspid regurgitant jet. A number of extra measures can be made, such as the right ventricle to pulmonary artery systolic pressure gradient. The detection of pulmonary artery pressure is not accurate enough using this methodology to provide a suitable screening tool for mild or asymptomatic pulmonary hypertension. In the elderly, where left heart disease is likely to be the most common cause of pulmonary hypertension, echocardiographic assessment is a valuable non-invasive method. However, echocardiography can be useful in detecting the cause of suspected or confirmed pulmonary hypertension in that two-dimensional and contrast examinations may identify the presence of congenital heart disease with a shunt or dilatation of the pulmonary artery despite only moderate pulmonary hypertension. Use of transoesophageal echocardiography or cardiac magnetic resonance imaging may help to define further the nature of the problem. Left ventricular diastolic dysfunction can be assessed through the use of Doppler echocardiography.

Ventilation Perfusion Lung Scanning

This is a recommended investigation in all patients with pulmonary hypertension to detect the presence of CTEPH, the potentially curable form of pulmonary hypertension. This is considered to be the screening method of choice for this disorder because of greater sensitivity than CT scans. A normal or low probability V/Q scan excludes CTEPH with a sensitivity of 90–100% and a specificity of 94–100%, whereas in PAH the VQ scan may be normal or show small peripheral unmatched defects in perfusion, a finding which can also occur in pulmonary veno-occlusive disease. Isotopic V/Q scanning is of little or no value in patients with airways obstruction where lung parenchymal changes lead to characteristic matched perfusion and ventilation defects.

High-Resolution Computed Tomographic Scanning

High-resolution CT scanning is useful in defining the presence of lung disease such as the emphysematous changes in COPD and the typical changes in interstitial lung disease including ground-glass shadowing, honeycombing and traction bronchiectasis. It may also be useful when investigating pulmonary veno-occlusive disease where characteristic changes of interstitial oedema with central ground-glass opacification may be seen.

Contrast Computed Tomographic Angiography

This investigation is helpful in determining the presence of surgically accessible thromboemboli in CTEPH and can delineate typical angiographic findings such as complete obstruction or the presence of webs or bands and intimal irregularities. It is also the investigation of choice for suspected pulmonary embolism in the presence of parenchymal lung disease.

Cardiac Magnetic Resonance Imagining

This imaging modality allows a direct assessment of right ventricular size, function and morphology. It also provides an opportunity for the non-invasive assessment of blood flow, which includes stroke volume, cardiac output, distensability of the pulmonary artery and right ventricular mass. It has the advantage of allowing repeated assessment of right heart haemodynamics and left ventricular function.

Right Heart Catheterization

This is necessary to confirm the diagnosis of PAH and to assess the severity of the haemodynamic impairment. Important variables that need to be assessed include the systolic, diastolic and mean pulmonary artery pressure, right atrial pressure, the pulmonary capillary wedge pressure and the right ventricular pressure. Patients with pulmonary hypertension from other causes likely to under go transplantation should also have a right heart study. In the majority of older patients with pulmonary hypertension, the underlying cause is clear-cut and treatment is not dependent on right heart catheterization and precise knowledge of their pulmonary haemodynamic status.

Other Investigations

Routine biochemistry, haematology and thyroid function tests are recommended in all patients in addition to determining their hepatitis and HIV status. Antinuclear antibodies are present in ∼40% of IPAH patients, although usually at a low titre, and a number of autoantibodies should be looked for in an attempt to determine the presence of systemic sclerosis. A thrombophilia screen is important and should be performed in all patients where CTEPH is suspected. An abdominal ultrasound should be carried out to demonstrate or exclude cirrhosis or portal hypertension.

Management

There are general measures that apply to the management of most cases of pulmonary hypertension, irrespective of cause. Specific aspects of management will be discussed in the consideration of the each clinical group.

Lifestyle

General advice on activities of daily living, physical activity and diet are important in terms of general support and will help individuals adapt to and cope with the changes imposed by progressive disability. Additionally, contact with support groups may help to address the issue of increasing social isolation and the risk of anxiety or depression which commonly occur in such patients. Patients should be advised to remain active within the limitations imposed by their symptoms. In COPD, interstitial lung disease, chronic heart failure and PAH, there is evidence that supervised programmes of exercise reconditioning or full rehabilitation can improve control of breathing, exercise performance and quality of life. Combined with dietary advice, rehabilitation programmes may have an impact on the loss of peripheral skeletal muscle mass, which occurs fairly commonly in PAH, left heart disease and respiratory causes of pulmonary hypertension.6

Travel

There are clear guidelines regarding the assessment for and the prescription of supplementary in-flight oxygen in respiratory conditions. In general, any patient receiving oxygen therapy while living at sea level is likely to need supplementary oxygen at routine cabin pressure to maintain arterial oxygen tension and saturation. In general, a flow rate of 1–2 l min−1 will be sufficient.7

Infection

Patients with chronic lung conditions, chronic heart failure and PAH are at heightened risk of respiratory infection and pneumonia. Although there is a lack of trial evidence for all groups of pulmonary hypertension, it is generally recommended that patients receive influenza and pneumococcal immunization.

Surgery

Either elective or emergency surgical intervention in patients with pulmonary hypertension is likely to carry an increased risk of death or significant postoperative morbidity. In general, elective procedures should be undertaken with local anaesthesia whenever possible and be planned with anaesthetist colleagues.

Medical Treatment

In addition to specific pharmacological treatments, especially for PAH, there are some general options that may be needed across the spectrum of pulmonary hypertension. These include the prescription of diuretics, digoxin, anticoagulants and oxygen, which may be needed intermittently or long term as background problems, such as COPD or left heart disease progress.

Group 1. Pulmonary Arterial Hypertension

The underlying mechanisms that lead to the pathological picture in this group are still largely unknown, but it is likely to be of a multifactorial origin in which there is an interaction between functional and structural components of the pulmonary vasculature. The key feature of increased pulmonary vascular resistance is likely to be due to mechanisms that lead to enhanced vasoconstriction. Much of the excessive vasoconstriction has been related to endothelial dysfunction with impaired production of vasodilator and antiproliferative factors such as nitric oxide and prostacyclin. There is also evidence of simultaneous over-expression of vasoconstrictor and proliferative substances such as thromboxane A2 and endothelin-1. This change in the balance of vasodilator and vasoconstrictor agents both leads to an elevation of vascular tone and may promote vascular remodelling by proliferative changes which enhance injury and healing mechanisms, including cellular proliferation and obstructive remodelling of the pulmonary wall, and the presence of inflammation and the development of local thrombosis. It is probable that inflammation also has a key mechanistic role and involves complex cellular inactions between vessel wall cell populations, which is associated with a increased production of extracellular matrix proteins in the adventitia of the vessel walls. As part of the activation of the inflammatory pathways, it is likely that prothrombotic abnormalities occur that lead to the presence of thrombi in the small distal pulmonary arteries.

The characteristic pathological changes in this group are medial hypertrophy, proliferative and fibrotic changes in the intima with adventitial thickening with varying degrees of perivascular inflammatory infiltration. Complex lesions, including dilatation and plexiform formation, and thrombotic lesions may also occur. The predominant site for pathological lesions in this group of pulmonary hypertension is in the distal pulmonary arteries, generally <500 μm in diameter. The pulmonary veins are not usually affected in this group.

Group 1′. Pulmonary Veno-Occlusive Disease (PVOD)