1. health and fitness
2. disease

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Pulmonary
Arterial
Hypertension
(PAH)
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Contents
1.
Introduction
3
2.
What is PAH?
4
3.
Classification of PAH
5
4.
How is PAH severity classified?
7
5.
How common is PAH?
7
6.
Why does PAH develop?
8
7.
What are the symptoms of PAH?
9
8.
Early diagnosis and intervention is crucial
9
9.
How is PAH diagnosed?
10
10. Screening in PAH: key to early diagnosis
12
11. Echocardiography – value as a screening tool
13
12. Right heart catheterisation – the diagnostic gold standard
14
13. Assessing PAH:
6-minute walk test – an evaluation of exercise capacity
15
14. How is PAH treated?
16
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1. 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.
3
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2. 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.
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).2 In
most cases the earliest symptom is dyspnoea on physical exertion. Other symptoms include syncope or
near syncope, fatigue and peripheral oedema.3,4 Chest tightness and pain similar to angina may occur,
particularly on physical exertion.
Figure 1.
4
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3. 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.5
Group I. Pulmonary arterial hypertension (PAH)
• 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)
Group II. 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
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.6,7
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
5
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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 systemic sclerosis has been reported to be up to 16%8 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.9
2. PAH associated with congenital heart disease
Congenital heart disease is relatively common, affecting around 1% of the population. Within this population
15% will go on to develop PAH.10 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.11
3. PAH associated with HIV infection
PAH is a rare (estimated prevalence in patients with HIV: 0.5%)12 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.13 HIV-associated PAH shows a similar
clinical picture to IPAH and seems to be independent of the degree of immunosuppression.
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%.14 The two year mortality
rate of pulmonary hypertension related to SCD is reported up to 50% and is one of the leading causes of
death in SCD.15
6
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4. How is PAH severity classified?
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 Organisation
(WHO). WHO functional class (WHO FC) 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; class I being the least severe and
class IV being the most advanced (Table 1).4
Table 1.
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.
5. How common is PAH?
Although PAH is a rare disease, with an estimated prevalence of 30–50 cases per million,16 the prevalence
of PAH in certain at-risk groups is substantially higher. For example, in HIV-infected patients the prevalence
is 0.5%,12 in patients with sickle cell disease the prevalence is 20–40%14 and in patients with systemic
sclerosis the prevalence has been reported to be up to 16%.8
Idiopathic PAH is more common in young women with a mean age of diagnosis of 36 years.3 However it
can occur at any age.3 Idiopathic PAH is twice as common in women as in men.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.17
Due to the non-specific nature of the symptoms, PAH is most frequently diagnosed when patients have
reached a more advanced stage of disease (WHO Functional Class III and IV),17 suggesting that the true
prevalence may be higher than documented in the literature.
7
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6. 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 remodeling 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.
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 aetiologies18–20 and
correlate with disease severity,21 resulting in a number of detrimental effects, primarily in the vasculature:3
•
•
•
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 endothelin.22 Endothelin receptor antagonism can either mitigate the effects of only
one (single ETA antagonist) or both (dual ETA and ETB receptor antagonist) receptor types.
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.23–25 Therapy
with synthetic forms of prostacyclin can help to correct this deficiency, although administering this form of
treatment is complex.26–28
8
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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.3 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.29
7. 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:3,4
•
•
•
•
•
•
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.
8. Early diagnosis and intervention is crucial
Early diagnosis and intervention is important in PAH as without treatment the median survival of patients is
2.8 years, which is comparable with some malignancies.30–32 However, diagnosis is complex and can be
delayed for months or even years as early PAH symptoms are mild and non-specific. This means that PAH
is frequently not recognised until the disease is relatively advanced.3 In fact, the average time from onset to
diagnosis is estimated to be approximately 2 years.17
Although patients progress at different rates, mildly symptomatic PAH patients still have a devastating
condition, which can progress rapidly. Recognising and treating PAH early is therefore crucial to changing
the course of the disease. Marked improvements in prognosis and survival have been shown for patients
who begin targeted therapy in less severe stages of PAH (WHO FCI/II) compared with those in a more
severe stage (WHO FCIII/IV).33
9
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9. How is PAH diagnosed?
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:
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)
•
•
•
10
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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10. Screening in PAH: key to early diagnosis
The key to early diagnosis is introducing screening for high risk patient populations if they are
asymptomatic. High risk patient populations include:
•
•
•
•
Family members of a patient with familial Pulmonary Arterial Hypertension (FPAH)
Patients with systemic sclerosis (SSc)
Patients with HIV
Patients with portopulmonary hypertension (PoPH)
The results of a disease registry in France indicated that without screening, the majority of patients were
diagnosed in a more severe stage of PAH (WHO FC III/IV), and only 25% of patients were in early stage PAH
(WHO FC I/II).17 Furthermore, the results of a French national screening program in a high-risk population
indicated that it is possible to detect Pulmonary Arterial Hypertension (PAH) in an earlier stage in a high-risk
population34 (Figure 4).
International guidelines now recommend annual screening high-risk groups with Doppler
echocardiography.2,8,35 Doppler echocardiography is currently the most effective method for screening,
however, for a definitive diagnosis right heart catheterisation has to be performed.
Figure 4.
No screening17
12
With screening34
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11. Echocardiography – value as a screening tool
Transthoracic Doppler-echocardiography (TTE) is a non-invasive screening test for pulmonary arterial
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 5).
Figure 5.
13
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12. Right heart catheterisation – the diagnostic gold standard
Right heart catheterisation is required for a definitive diagnosis of PAH (Figure 6 and 7)3,4 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.2 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%).1
Figure 6.
14
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Figure 7.
13. Assessing PAH:
6-minute walk test – an evaluation of exercise capacity
In patients with PAH, the 6-MWT to evaluate exercise capacity is reflective of activities of daily living;36 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.37
•
•
•
•
•
•
•
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
15
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14. 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.
Prognosis is influenced by the status of WHO FC when treatment is started – patients who start therapy in
functional class I or II demonstrate a better prognosis than those whose therapy is started in more severe
stages (WHO FC III or IV).33
Early treatment may delay disease progression
By recognising and treating patients as early as possible, disease progression may be delayed. Without
treatment, patients in WHO FC II can rapidly deteriorate within 6 months to more advanced Pulmonary
Arterial Hypertension (PAH) as evidenced by progression of symptoms.38
Treatment options have progressed considerably in the last decade, especially those which target the
underlying mechanisms of the disease. The main medical treatment options for patients with PAH are:39
Treatments that are routinely used but with little evidence of a positive impact on the
disease progression
•
•
•
•
16
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 deleterious1
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 receptors22
Phosphodiesterase 5 inhibitors – oral agents which induce relaxation and antiproliferative effects on
vascular smooth muscle cells by preventing the reduction in levels of cGMP29
Prostacyclin analogues – may be delivered by continuous intravenous or subcutaneous infusion or
via an intermittent nebuliser39
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.
17
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