Download Pulmonary Arterial Hypertension (PAH)

Pulmonary
Arterial
Hypertension
(PAH)
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Contents
Introduction
2
What is PAH?
3
Classification of PAH
5
How common is PAH?
8
Why does PAH develop?
9
What are the symptoms of PAH?
12
How is PAH diagnosed?
13
How is PAH severity classified?
20
How is PAH treated?
21
References
23
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Introduction
Pulmonary arterial hypertension (PAH) is a serious disease of the arteries
connecting the heart to the lungs (the pulmonary arteries). As PAH develops,
blood flow through the pulmonary arteries is restricted and the right side of
the heart is put under increasing strain to pump blood through to the lungs.
This leads to the main symptoms of PAH - breathlessness, chest tightness
limited exercise capacity and fatigue.
Untreated, PAH is a disease with a very poor prognosis.
The early symptoms of PAH (such as breathlessness, chest tightness and
fatigue) can be mild and are common to many other conditions. Reaching the
diagnosis can be delayed and as a consequence patients with PAH may first
present when the disease has already progressed.
This brochure explains how PAH develops, describes the symptoms associated
with this disease and outlines how it can be diagnosed and treated. Treatment
is aimed at improving symptoms, exercise tolerance, long-term outcomes
and quality of life. Until the mid 1980s there were limited treatment options
for patients and PAH was associated with poor prognosis. Today, treatment
options have improved the prognosis for patients with this condition.
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What is PAH?
Pulmonary Arterial Hypertension (PAH) is a syndrome characterised by
a progressive increase in pulmonary vascular resistance leading to right
ventricular overload and eventually to right ventricular failure
and premature death.1
The increase in pulmonary vascular resistance is related to a number of
progressive changes in the pulmonary arterioles, including:
• vasoconstriction
• obstructive remodelling of the pulmonary vessel wall through proliferation
in the various layers of the blood vessel wall (smooth muscle cell and
endothelial cell proliferation)
• inflammation
• in-situ thrombosis.
The main histological features include medial hypertrophy, intimal thickening,
adventitial thickening, plexiform lesions and in-situ thrombosis (Figure 1).
The plexifom lesion represents a focal proliferation of endothelial and smooth
muscle cells and is pathognomonic of PAH.
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Figure 1
PAH is defined as a sustained elevation of mean
pulmonary arterial pressure to more than 25 mmHg at
rest or to more than 30 mmHg while exercising, with a
normal pulmonary wedge pressure (< 15 mmHg).1
In most cases the earliest symptom is dyspnoea on
physical exertion. Other symptoms include syncope
or near syncope, fatigue and peripheral oedema.1
Chest tightness and pain similar to angina may occur,
particularly on physical exertion.
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Classification of PAH
Pulmonary Arterial Hypertension (PAH) represents Group 1 within the Pulmonary
Hypertension WHO clinical classification system (Venice 2003 revision)
and is one of five such groups. The groups are divided based on aetiology.2
Group I.
Pulmonary arterial hypertension (PAH)
Group II.
• Idiopathic (IPAH)
• Familial (FPAH)
• Associated with (APAH):
- Connective tissue disease
- Congenital systemic-to-pulmonary shunts
- Portal hypertension
- HIV infection
- Drugs and toxins
- Other (thyroid disorders, glycogen storage disease,
Gaucher’s disease, hereditary haemorragic telangiectasia,
haemoglobinopathies, myeloproliferative disorders,
splenectomy)
• Associated with significant venous or capillary involvement
- Pulmonary veno-occlusive disease (PVOD)
- Pulmonary capillary haemangiomatosis (PCH)
• Persistent pulmonary hypertension of the newborn (PPHN)
Pulmonary hypertension associated with left heart diseases
Group III. Pulmonary hypertension associated with respiratory diseases and/or
hypoxemia (including chronic obstructive pulmonary disease)
Group IV. Pulmonary hypertension due to chronic thrombotic and/or
embolic disease
Group V.
Miscellaneous group
• eg. sarcoidosis, histiocytosis X and lymphangiomatosis
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Idiopathic PAH (IPAH), which by definition has no identifiable underlying
cause, is one of the more common types of PAH. Familial PAH (FPAH)
accounts for at least 6% of cases of IPAH and mutations in the bone
morphogenetic protein receptor 2 (BMPR2) have been identified in the
majority of cases of FPAH.3,4
PAH can also be associated with a number of conditions (Associated
Pulmonary Arterial Hypertension - APAH), which together account for most
other cases of PAH. These conditions include;
1. Connective Tissue Diseases
• including systemic sclerosis (scleroderma) and systemic lupus
erythematosus (SLE)
2. Congenital Heart Disease
• including Eisenmenger’s syndrome
3. Human immunodeficiency virus (HIV) infection
4. Sickle Cell Disease
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PAH is also a rare side effect of certain anorexigenic agents, such as
fenfluramine and dexfenfluramine. However, the incidence of drug-induced
PAH is decreasing as these agents are no longer available.
1. PAH associated with connective tissue disease
PAH is a well-recognised complication of connective tissue diseases such
as systemic sclerosis and SLE and in affected patients may also occur in
association with interstitial lung disease. The prevalence of PAH in patients
with connective tissue disease has been reported to be up to 38%5 and in
systemic sclerosis patients, pulmonary complications, such as interstitial
lung disease and PAH, are now the leading causes of death. Patients with
PAH associated with systemic sclerosis have a particularly poor prognosis
compared to those with systemic sclerosis without PAH.6
2. PAH associated with congenital heart disease
Congenital heart disease is relatively common, affecting around 1% of
the population. Within this population 10% will go on to develop PAH.7 As
determined by the level of pulmonary vascular resistance, the most severe
form of PAH is Eisenmenger’s syndrome, which is associated with the reversal
of an initial left to right shunt causing cyanosis and limited exercise capacity.8
3. PAH associated with HIV infection
PAH is a rare (estimated prevalence in patients with HIV: 0.5%9) but relatively
well-documented complication of HIV infection. With the advent of highly active
anti-retroviral therapy (HAART) and markedly improved survival, PAH and other
non-infectious manifestations of HIV infection are increasingly responsible for
HIV-associated morbidity and poor prognosis. In patients with HIV, the HIV-1
envelope glycoprotein GP120 may stimulate the production of endothelin by
macrophages.10 HIV-associated PAH shows a similar clinical picture to IPAH
and seems to be independent of the degree of immunosuppression.
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4. PAH associated sickle cell disease
Sickle cell disease (SCD) is a genetic disorder of the haemoglobin which
results in a chronic haemolytic anaemia. Over time and due to the chronic
haemolysis the vasculature becomes damaged and pulmonary hypertension
can develop. The prevalence of PAH in sickle cell patients is 20-40%.11 The
two year mortality of pulmonary hypertension related to SCD is reported up to
50% and is one of the leading causes of death in SCD.12
How common is PAH?
Although PAH is a rare disease, with an estimated prevalence of 30-50 cases
per million,13 the prevalence of PAH in certain at-risk groups is substantially
higher. For example, in HIV-infected patients the prevalence is 0.5%9, in
patients with sickle cell disease the prevalence is 20-40%11 and in patients
with systemic sclerosis the prevalence has been reported to be up to 38%.5
Idiopathic PAH is more common in young women with a mean age of
diagnosis of 36 years. However it can occur at any age.1 Idiopathic PAH is
twice as common in women as in men.1,3 Although the true relative prevalence
of IPAH, FPAH and APAH are unknown, it is likely that IPAH accounts for at least
40% of cases, and APAH for most of the remaining cases.14,15
Due to the non-specific nature of the symptoms, PAH is most frequently
diagnosed when patients have reached an advanced
stage of disease (WHO Functional Class III and IV),15
suggesting that the true prevalence may be higher
than documented in the literature.
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Why does PAH develop?
The exact cause behind the development of PAH remains unknown. However,
research has led to a better understanding of the underlying mechanisms.
PAH is recognised as a complex, multi-factorial condition involving numerous
biochemical pathways and different cell types. Endothelial dysfunction is
believed to occur early on in disease pathogenesis, leading to endothelial and
smooth muscle cell proliferation and structural changes or ‘remodelling’ of
the pulmonary vascular bed resulting in an increase in pulmonary vascular
resistance.
Vascular remodelling itself involves all layers of the vessel wall and is
characterised by proliferative and obstructive changes involving many cell
types, including endothelial, smooth muscle and fibroblasts. Inflammatory cells
and platelets may also play a significant role in PAH.
Endothelial cell dysfunction results in reduced production of vasodilators,
such as nitric oxide (NO) and prostacyclin, and over production of
vasoconstrictors, such as thromboxane A2 and endothelin-1 (ET-1).
ET-1, NO and prostacyclin have been the principal focus of research into new
treatment options for patients with PAH.
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Endothelin
Endothelin is produced by the endothelial cells and is essential for
maintenance of normal vascular tone and function. However, high levels of
endothelin are seen in patients with PAH due to various aetiologies16-18 and
correlate with disease severity,19 resulting in a number of detrimental effects,
primarily in the vasculature1:
• Fibrosis
• Hypertrophy and proliferation of cells, which can lead to thickening,
narrowing and occlusion of blood vessels.
• Inflammation
• Vasoconstriction
Endothelin binds to 2 receptors, ETA and ETB. Both receptors are implicated in
PAH and mediate the deleterious effects of endothelin20. Endothelin receptor
antagonism can either mitigate the effects of only one (single ETA antagonist)
or both (dual ETA and ETB receptor antagonist) receptor types.
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Prostacyclin
Prostacyclin is a potent vasodilator as well as an inhibitor of platelet activation.
It is believed that patients with PAH have low levels of prostacyclin, which
could result in vasoconstriction in the pulmonary vasculature and a tendency
for smooth muscle cell proliferation and platelet activation, encouraging
the formation of thrombi in both the micro-circulation and the pulmonary
arteries.21-23 Therapy with synthetic forms of prostacyclin can help to correct
this deficiency, although administering this form of treatment is complex.29-31
Nitric oxide
Nitric oxide is an endothelial-derived substance that, like prostacyclin,
is a potent vasodilator and also possesses anti-proliferative properties.
PAH patients appear to produce insufficient NO and this may contribute
to the development of PAH.1 The vasodilatory effect of NO is mediated by
cGMP, which is rapidly degraded by phosphodiesterases. The inhibition of
the degradation of cGMP with phosphodiesterase 5 inhibitors promotes the
accumulation of intracellular cGMP, resulting in vasodilatation.27
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What are the symptoms of PAH?
The changes to the pulmonary vasculature described above lead to the typical
symptoms of PAH. The symptoms are caused by the high resistance to blood
flow through the lungs and result in increased stress on the heart. This can
severely impact the ability to exercise or carry out normal daily activities.
Common early symptoms include:23-25
• Breathlessness (dyspnoea), particularly on physical activity
• Fatigue
• Dizziness
• Syncope, also on physical activity (rare)
• Peripheral oedema
• Chest pain, again particularly during physical activity.
The symptoms may not be obvious at first and are often attributed to more
common conditions such as asthma, general fatigue, or lack of physical
fitness. Over time, however, they can become more severe and begin to limit
normal activities. As the disease progresses, some patients may experience
constant dyspnoea and fatigue so that even simple
tasks such as getting dressed and walking short
distances become difficult.
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How is PAH diagnosed?
The early symptoms of PAH (such as dyspnoea, dizziness and fatigue) are
often mild and are common to many other conditions. At rest there are often
no symptoms and no apparent signs of illness. As a result, diagnosis can
be delayed for months or even years meaning that PAH is frequently not
recognised until the disease is relatively advanced.1 PAH is often diagnosed
only once other conditions have been investigated and ruled out.
The non-specific nature of symptoms associated with PAH means that the
diagnosis cannot be made on symptoms alone. A series of investigations
is required to make an initial diagnosis, to refine that diagnosis in terms
of clinical class of pulmonary hypertension and to evaluate the degree of
functional and haemodynamic impairment (Figure 2). Consequently, it can be
useful to adopt a four stage approach:
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1. Clinical suspicion of pulmonary hypertension
• Breathlessness (dyspnoea) without overt signs of specific heart or lung
disease
• Screening of patients with associated conditions (Connective Tissue
Disease, Congenital Heart Disease, HIV, Sickle Cell Disease)
• Incidental findings on examination for other clinical reasons
2. Detection of pulmonary hypertension
• ECG (echocardiogram)
• Doppler echocardiogram (Figure 2)
• Chest radiograph, may show evidence of cardiomegaly and enlarged
pulmonary arteries (Figure 3)
3. Identify other causes of pulmonary hypertension
• Pulmonary function tests (PFTs) and arterial blood gas samples
• Ventilation and perfusion lung scan
• High resolution computed tomography (HRCT)
• Pulmonary angiography
4. PAH evaluation and classification (type, functional capacity,
haemodynamics)
• Blood tests and immunology, HIV test, abdominal ultrasound scan
• 6 minute walk test (6-MWT) and peak VO2
• Right heart catheterisation and vasoreactivity testing
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Figure 2
Figure 3
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Echocardiography - value as a screening tool
Transthoracic Doppler-echocardiography (TTE) is a non-invasive screening
test for pulmonary hypertension. TTE is able to estimate pulmonary arterial
systolic pressure, which is equivalent to right ventricular systolic pressure
in the absence of pulmonary outflow obstruction. It can provide additional
information about the cause and consequences of PH, including right and
left ventricular dimensions and function, heart valve abnormalities, right
ventricular ejection and left ventricular filling characteristics and presence of
a pericardial effusion. In the initial investigation of patients with PAH it is
important to obtain adequate images of the right heart. Pulmonary arterial
pressure can be estimated from the tricuspid regurgitant (TR) jet (Figure 4).
Figure 4
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Right heart catheterisation - the diagnostic
gold standard
Right heart catheterisation is required for a definitive diagnosis of PAH
(Figure 5 and 6)1,26 to assess the severity of haemodynamic impairment
and to test the vasoreactivity of the pulmonary circulation. The following
parameters should always be assessed: right atrial pressure (RAP), pulmonary
arterial pressure (PAP [systolic, diastolic and mean]), pulmonary capillary
wedge pressure (PCWP), cardiac output / index, pulmonary (PVR) and
systemic vascular resistance, blood pressure and arterial and mixed venous
oxygen saturation.
PAH is defined as a sustained elevation of mean pulmonary arterial pressure
to > 25 mmHg at rest or to > 30 mmHg while exercising, with a mean
pulmonary wedge pressure or left ventricular end-diastolic pressure of
< 15 mmHg and pulmonary vascular resistance of ≥3 woods units.1 A positive
vasoreactive response is defined as a reduction in mean pulmonary artery
pressure (mPAP) ≥ 10 mmHg to reach an absolute value of mPAP ≤ 40 mmHg
with an increase or unchanged cardiac output. A positive response is shown
in only 10-15% of patients, and sustained response is shown in even fewer
(less than 7%).27
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Figure 5
Figure 6
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6-minute walk test - evaluation of exercise
capacity
In patients with PAH, the 6-MWT to evaluate exercise capacity is reflective of
activities of daily living;28 the distance a PAH patient can walk in 6 minutes
is a critical endpoint in studies evaluating the benefit of different therapeutic
options.
To allow meaningful comparisons, it is important that the 6-MWT be
performed under supervision according to a standardised protocol.29
• A 30 m corridor should be available, marked at 3 m intervals
• The patient should rest for at least 10 minutes prior to the test and should
not have performed any rigorous exercise within the previous 2 hours
• The patient should be asked to rate their baseline dyspnoea
• The patient should be instructed to walk to their maximum capacity but not
to run or jog; they should be permitted to rest as necessary
• The supervisor should count each lap as the patient finishes it
• The patient should be asked to rate their dyspnoea at the end of the test
• The test should be repeated at approximately the same time of day on
each occasion
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How is PAH severity classified?
Once diagnosed, PAH is usually classified according to a functional class
system initially devised by the New York Heart Association (NYHA) for Chronic
Heart Failure and then adapted for PAH by the World Health Organization
(WHO). This functional class measures the severity of PAH and reflects the
impact on a patient’s life in terms of physical activity and symptoms. There
are four classes, with class I being the least severe and class IV being the
most advanced (Table 1).26
Table 1. NYHA/WHO Classification of Functional Status of Patients With
Pulmonary Hypertension26
Class
Symptomatic profile
Class I
Patients with pulmonary hypertension but without resulting
limitation of physical activity. Ordinary physical activity does not
cause dyspnoea or fatigue, chest pain or near syncope.
Class II
Patients with pulmonary hypertension resulting in slight limitation
of physical activity. They are comfortable at rest. Ordinary
physical activity causes undue dyspnoea or fatigue, chest pain or
near syncope.
Class III
Patients with pulmonary hypertension resulting in marked
limitation of physical activity. They are comfortable at rest. Less
than ordinary activity causes undue dyspnoea or fatigue, chest
pain or near syncope.
Class IV
Patients with pulmonary hypertension with inability to carry out
any physical activity without symptoms. These patients manifest
signs of right heart failure. Dyspnoea and/or fatigue may even be
present at rest. Discomfort is increased by any physical activity.
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How is PAH treated?
There is currently no cure for PAH but advances in understanding how the
disease develops (see section: Why does PAH develop?) means that there are
now treatments available which have helped to improve prognosis for patients
with this disease.
The main treatment options for patients with PAH are:26
Treatments that are routinely used but with little evidence of a positive
impact on the disease progression.
• anticoagulants, such as warfarin, to address the observed thrombotic
changes and potential predisposition in the pulmonary microcirculation for
in-situ thrombosis.
• calcium-channel blockers (CCBs). Less than 10% of IPAH patients benefit
from CCB therapy. This figure is even lower in other forms of PAH. If not used
in appropriate candidates (patients with demonstrated vasoreactivity during
right heart catheterisation), CCBs can decrease cardiac output and systemic
vascular resistance without any improvement in PAP and PVR and therefore
may be deleterious.27
• diuretics, for treatment of right heart failure.
• oxygen therapy, to maintain oxygen saturation at > 90% at all times.
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Treatments that have been specifically studied in PAH
• endothelin receptor antagonists - endothelin is implicated in the
pathogenesis of PAH through actions on the pulmonary vasculature.
Endothelin is found to be elevated in patients with PAH and levels of
endothelin are directly related to disease severity and prognosis. Endothelin
receptor antagonists (ERAs) are oral treatments that either block the ETA
receptor alone or both the ETA and ETB receptors.30,31
• phosphodiesterase 5 inhibitors - Oral agents which induce relaxation and
antiproliferative effects on vascular smooth muscle cells by preventing the
reduction in levels of cGMP.
• prostacyclin analogues - may be delivered by continuous intravenous or
subcutaneous infusion or via an intermittent nebuliser. To date, oral agents
have shown limited effectiveness.
In very severe cases surgical options may be considered:
• balloon atrial septostomy
• heart and lung transplantation
However, the use of transplantation is constrained by the limited number
of donor organs.
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19. Galie N, Grigioni F, Bacchi-Reggiani L et al. Relation of endothelin-1 to survival in patients with primary
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For further information visit www.pah-info.com
© 2007 Actelion Pharmaceuticals Ltd.
Gewerbestrasse 16 – CH-4123 Allschwil – Switzerland – www.actelion.com
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