Pulmonary Hypertension
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
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.
