The mean pressure in the pulmonary artery (mPAP) in a normal resting adult is ∼16 mmHg. Pulmonary hypertension (PH) is defined as a mPAP exceeding 25 mmHg at rest. The increased PAP can be due to a rise in pulmonary vascular resistance (PVR), increased pulmonary blood flow due to a systemic to pulmonary shunt (Eisenmenger’s syndrome; see Chapter 55) or back pressure from the left heart. PH increases right ventricular afterload, eventually leading to right heart failure.
Types of pulmonary hypertension
PH was initially (in 1973) classified as primary if it was idiopathic (without a known cause) and secondary if a cause could be identified. More complex classification schemes designed to group the various manifestations of PH according to their pathological and/ or clinical features and management options were then created in 1998, 2003, and most recently at the 4th World Symposium on PH held in Dana Point in 2008 (Figure 52.1, top). Together, the various forms of PH affect ∼100 million people worldwide.
Group 1 PH, also termed pulmonary arterial hypertension (PAH) comprises heritable (hPAH) and idiopathic PAH (iPAH) and also PH associated with a number of other conditions (aPAH). Patients demonstrate a clinical syndrome indicative of severe PH and an increased PVR associated with a unique set of pulmonary vascular abnormalities (see below). Both hPAH and iPAH are characterized by a decreased expression of bone morphogenetic protein receptor type 2 (BMPR2) which, usually in hPAH and sometimes in iPAH, is associated with mutations in BMPR2, its cognate gene. Group 1′ PH, associated with pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis, has features resembling those of PAH separate clinical entity.
Groups 2–5 are forms of secondary PH. Group 2 PH is due to left heart disease, chiefly ventricular failure or mitral and/or aortic valve disease, which results in increased left atrial pressure that backs up into the pulmonary artery. Group 3 PH is associated with lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis and other conditions such as sleep apnoea, the common factor being the presence of alveolar hypoxia. Group 4 PH is associated with chronic thromboembolic disease, with a persistent blockage of pulmonary arteries arising from venous thromboembolism. Group 5 represents PH associated with a heterogeneous set of conditions such as chronic myeloid leukaemia, sarcoidosis, Gaucher’s disease, and thyroid disease. Secondary PH is generally managed by treating the cause. Group 2 PH is often controlled as a consequence of addressing the underlying left heart disease, whereas Group 3 PH patients with COPD may benefit from O2 therapy. Group 4 PH is treated with anticoagulation and surgical removal of the embolus (thromboembolectomy).
PAH includes hPAH and iPAH, as well as severe PH which for unknown reasons often arises in association with certain condi- tions (aPAH). iPAH and hPAH together affect only ∼15 people per million, whereas aPAH is much more common. PAH prognosis is poor, with a 15% mortality rate after 1 year; the only cure is lung transplant. Right ventricular function is an important deter- minant of prognosis, as patients usually die from progressive right heart failure, and individuals vary with regard to the ability of the right ventricle to compensate for the increased afterload generated as a result of the increased PVR.
Although excessive pulmonary vasoconstriction is an important factor in ∼20% of PAH cases, the main cause of the increased PVR in PAH is pulmonary remodelling characterized by excessive pulmonary artery (PA) smooth muscle cell proliferation. PA remodel- ling typically results in hyperplasia of the intimal layer due to the invasion of myofibroblasts (cells with properties of fibroblasts and smooth muscle), as well as hypertrophy of the medial layer, and adventitial proliferation. These processes cause the muscularization of very small PA, which normally contain little smooth muscle. Thrombosis in situ, inflammation, and the presence of complex vascular lesions (often termed plexiform lesions) compris- ing endothelial cells, lymphocytes and mast cells, are additional features that contribute to raised PVR and blood flow restriction. The causes of remodelling remain controversial, but some of the mechanisms currently thought to contribute to this process are shown in Figure 52b.
Clinical findings and diagnosis
Often the first clinical manifestation of pulmonary hypertension is gradually increasing breathlessness upon exertion and fatigue. As the condition progresses, these symptoms may be present at rest. Other symptoms include chest pain and peripheral oedema.
Physical examination Signs in severe PH include an increased intensity of the pulmonary component of the second heart sound due to the elevated pulmonary pressure that increases the force of closure of the pulmonary valve and a midsystolic ejection murmur indicating turbulent pulmonary outflow.
Diagnosis PH is best diagnosed via right heart catheterization. A Swan–Ganz catheter is inserted via the femoral vein and advanced into the vena cava and then into the right atrium, right ventricle and finally the pulmonary artery, where the mPAP is measured.
Management of PAH includes treatment of symptoms, and newer specific therapies designed to slow disease progression, but which do not afford a cure. Symptomatic therapy includes diuretics to reduce peripheral oedema, anticoagulants to prevent clots, inhaled O2 to increase blood oxygenation and digoxin to provide positive inotropy. Calcium-channel blockers can lower PAP in a small subset of patients. Specific therapies include prostacyclin (PGI2) analogues, endothelin receptor antagonists and phosphodiesterase-5 inhibitors.
Production by PA of PGI2, an endothelium-derived vasodilator and inhibitor of platelet aggregation, is thought to be deficient in PAH, and stable PGI2 analogues have become a mainstay of its treatment. Epoprostenol, the first to be introduced, is used for the intravenous treatment of advanced PAH, and is the only drug that has been shown to lengthen survival in PAH. Iloprost is a synthetic analogue of PGI2 which is delivered by inhalation.
Endothelin-1 (see Chapter 24) is a potent vasoconstrictor and pro-proliferative agent that may contribute to the development of PAH, inhibition of endothelin receptors has shown promise in its treatment. Bosentan is an antagonist of ETA and ETB receptors which was shown in the BREATHE-1 trial to significantly improve exercise tolerance. Ambrisentan, a selective blocker of the ETA receptor is also used, and was shown in the ARIES-1 and ARIES-2 trials to improve the 6-minute walk distance ( a test often used to gauge the severity of PAH) after 12 weeks.
Production by PA of the potent endothelium-derived vasodilator nitric oxide (NO), which acts by increasing smooth muscle cell cyclic guanosine monophosphate (cGMP) levels (see Chapters 15 and 24), is thought to be deficient in PAH. cGMP is broken down by various phosphodiesterases (PDEs), so that PDE inhibition enhances and prolongs the vasodilating effect of NO. PDE-5 is the most important phosphodiesterase in the pulmonary circulation, and PDE-5 inhibitors (sildenafil, vardenafil) have accordingly emerged as an important pillar of therapy. The SUPER-1 study showed that patients taking sildenafil were more likely to show an improvement in symptoms than those taking placebo.