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Pulmonary Arterial Hypertension (PAH)
Pulmonary Arterial Hypertension
(PAH)
1
Pulmonary Arterial Hypertension (PAH)
Pulmonary Arterial Hypertension (PAH)
Contents
2
1.Introduction
4
2. What is PAH?
5
3. Classification of PH
4. How common is PAH?
5. Why does PAH develop?
6. What are the symptoms of PAH?
6
8
8
10
7. How is PAH diagnosed?
8.Echocardiography
– Value as a screening tool
9. Right heart catheterisation
– The diagnostic gold standard for PAH
10
10. Screening for PAH
11. How is PAH treated?
12. Treatment guidelines
– Goal-oriented therapy
16
13. The importance of early identification and intervention in PAH
14. Assessing the severity of PAH
– Functional class
– Exercise capacity – six minute walk test (6MWT)
– Cardiopulmonary exercise testing
– Haemodynamic parameters
– Biochemical markers
15. PAH in patients with systemic sclerosis (SSc)
– How is PAH-SSc detected?
– How is PAH-SSc treated?
16.References
19
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Pulmonary Arterial Hypertension (PAH)
1. Introduction
2. What is PAH?
This brochure explains how pulmonary arterial hypertension (PAH) develops, describes the symptoms
associated with the disease and outlines how it can be diagnosed and treated. Treatment is aimed at
improving symptoms, exercise tolerance, long-term outcome 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.
Pulmonary arterial hypertension (PAH) is a progressive disease caused by narrowing or tightening
(constriction) of the pulmonary arteries, which connect the right side of the heart to the lungs. By definition,
PAH is characterised by an increase in mean pulmonary arterial pressure (PAP) to at least 25 mmHg at rest,
and a mean pulmonary capillary wedge pressure (PCWP) of <15 mmHg.1,2 As PAH develops, blood flow
through the pulmonary arteries is restricted and the right side of the heart becomes enlarged due to the
increased strain of pumping blood through the lungs. It is this strain on the heart and the decrease in blood to
the left heart and systemic circulation through the lungs that leads to the common symptoms of PAH, such as
breathlessness, fatigue, weakness, angina, syncope, and abdominal distension.2
The increase in pulmonary vascular resistance observed in patients with PAH is related to a number of
progressive changes in the pulmonary arterioles, including:2
•Vasoconstriction
• Obstructive remodelling of the pulmonary blood vessel walls due to cell proliferation within the various layers
of the vessel wall (smooth muscle cell and endothelial cell proliferation)
•Inflammation
• In situ thrombosis
The most prominent histological feature of PAH is a thickening of the three cellular layers (the intima, media,
and adventitia) that line the blood vessels, which is due to a process of cell enlargement termed hypertrophy.
Other changes include development of plexiform lesions (focal proliferations of endothelial and smooth
muscle cells that are a classic characteristic of PAH), and in situ thromboses (Figure 1).
Figure 1. Histopathological features of PAH
Intima
Endothelium
Media and
smooth muscle
Normal
Collateral flux
Plexifom lesion
Adventitia
Endothelial
proliferation
Intimal and medial thickening
Intimal fibrosis
Medial and
smooth muscle
cell hypertrophy
In situ
thrombosis
Intimal fibrosis
Intimal fibrosis and in situ thrombosis
4
Media
Intimal fibrosis
Direction of blood flow
5
Pulmonary Arterial Hypertension (PAH)
3. Classification of PH
One of the more common forms of PAH is idiopathic PAH (IPAH), which corresponds to sporadic disease
in which there is neither a family history of PAH nor an identified risk factor.3 Heritable PAH (HPAH) accounts
for at least 6% of cases of PAH4 and mutations in the bone morphogenetic protein receptor 2 (BMPR2) have
been identified in the majority of cases.5 PAH is also a rare side effect of certain anorexigenic agents, such as
fenfluramine.2,3 However, the incidence of drug-induced PAH related to fenfluramine is decreasing as this agent
is no longer available.
Pulmonary arterial hypertension (PAH) represents Group 1 within the Pulmonary Hypertension World Health
Organization (WHO) clinical classification system (Dana Point 2008) and is one of five such groups (Figure 2).
The groups are divided based on aetiology.3
Figure 2. Classification of pulmonary hypertension
Group 1
PAH can also be associated with a number of other conditions (associated PAH, APAH), which together account
for most other cases. These conditions include:3
Pulmonary arterial hypertension (PAH)
• Idiopathic (IPAH)
PAH associated with connective tissue disease
PAH is a well-recognised complication of connective tissue diseases, such as systemic sclerosis (SSc) and
systemic lupus erythematosus (SLE). The prevalence of PAH has been well established only for patients with
SSc.3 In recent studies, the prevalence of right heart catheterisation-confirmed PAH in patients with SSc was
between 7% and 12%.6,7 PAH in patients with SSc is discussed in more detail later in this booklet.
• Heritable (HPAH):
– Bone morphogenetic protein receptor type 2 (BMPR2)
– Activin receptor-like kinase 1 gene (ALK1), endoglin (with or without haemorrhagic telangiectasia)
– Unknown
• Drug- and toxin-induced
• Associated with (APAH):
PAH associated with HIV infection
PAH is a rare but relatively well-documented complication of HIV infection with an estimated prevalence of
around 0.5%.8 Highly active anti-retroviral therapy (HAART) has markedly improved survival rates in HIV patients,
meaning long-term conditions such as PAH are increasingly responsible for HIV-associated morbidity and
poor prognosis.9,10
– Connective tissue diseases
– Human immunodeficiency virus (HIV) infection
– Portal hypertension
– Congenital heart disease (CHD)
– Schistosomiasis
– Chronic haemolytic anaemia
PAH associated with portal hypertension
PAH is a well-recognised complication of chronic liver diseases that develop as a result of portal hypertension
(also called portopulmonary hypertension) and makes up around 10% of the PAH population.11,12
• Persistent pulmonary hypertension of the newborn (PPHN)
Group 1’
Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary haemangiomatosis (PCH)
Group 2
Pulmonary hypertension due to left heart diseases
• Systolic dysfunction
PAH associated with congenital heart disease
Congenital heart disease (CHD) is relatively common and affects around 1% of the population. Approximately
5–10% of adults with CHD will go on to develop PAH.13 The most severe form is Eisenmenger’s syndrome,
which is associated with the reversal of an initial left-to-right shunt to a right-to-left shunt, causing cyanosis
(a blue colouration of the skin due to low oxygen in the blood) and limited exercise capacity.3,14 Patients with
PAH associated with CHD also include those with mild to moderate systemic-to-pulmonary shunts with no
cyanosis at rest, patients with small defects, and those with residual PAH following corrective cardiac surgery.2,3
• Diastolic dysfunction
• Valvular disease
Group 3
Pulmonary hypertension due to lung diseases and/or hypoxemia
• Chronic obstructive pulmonary disease (COPD)
• Interstitial lung disease (ILD)
• Other pulmonary diseases with mixed restrictive and obstructive pattern
• Sleep-disordered breathing
PAH associated with schistosomiasis
Schistosomiasis is a parasitic disease caused by trematode flatworms of the genus Schistosoma. Patients with
schistosomiasis and PAH can have the required specific clinical and pathological characteristics to be included in
the APAH group. The prevalence of PAH in patients with schistosomiasis is around 4.6%.15
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities
Group 4
Chronic thromboembolic pulmonary hypertension (CTEPH)
Group 5
PH with unclear multifactorial mechanisms
PAH associated with sickle cell disease
The prevalence of PAH in patients with sickle cell disease is around 2–3.75%.16,17
• Haematological disorders: myeloproliferative disorders, splenectomy
• Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis,
lymphangioleiomyomatosis, neurofibromatosis, vasculitis
• Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
• Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
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Pulmonary Arterial Hypertension (PAH)
4. How common is PAH?
The role of endothelin
Endothelin-1 (ET-1) is a vasoconstrictive protein produced by endothelial cells lining the blood vessels.
High levels of endothelin are seen in patients with PAH due to various aetiologies24–26 and correlate with
disease severity,27 resulting in a number of detrimental effects, primarily in the vasculature:23
Although PAH is a rare disease, with an overall estimated prevalence of 15–50 cases per million, the
prevalence of PAH in certain at-risk groups (e.g. HIV-infected patients and patients with SSc) is substantially
higher as discussed previously.
18
• Fibrosis
• Hypertrophy and proliferation of cells, which can lead to thickening, narrowing, and occlusion
of blood vessels
• Inflammation
• Vasoconstriction
Idiopathic PAH (IPAH) has an annual incidence of 1–2 cases per million people in the US and Europe and is
2–4 times as common in women as in men.12,19 The mean age at diagnosis is around 45 years, although it can
occur at any age.20 Despite the true relative prevalence of IPAH, heritable PAH (HPAH), and associated PAH
(APAH) being unknown, it is likely that IPAH accounts for at least 40% of cases of PAH, with APAH accounting
for most of the remaining cases.11 PAH associated with the newborn is known as persistent pulmonary
hypertension of the newborn (PPHN). Severe PPHN has been estimated to occur in 0.2% of live-born term
infants, and some degree of pulmonary hypertension complicates the course of more than 10% of all neonates
with respiratory failure.21
ET-1 binds to two receptors, known as ETA and ETB. Both receptors are implicated in PAH and mediate the
deleterious effects of endothelin.23 Endothelin receptor antagonism can either mitigate the effects of only
one (single ETA antagonist) or both (dual ETA and ETB receptor antagonist) receptor types. Therapy with orally
administered endothelin receptor antagonists (ERAs) that block the binding of endothelin to one or both
receptors aims to mitigate the deleterious effects of the high levels of endothelin seen in PAH.28
Due to the non-specific nature of the symptoms, PAH is unfortunately most frequently diagnosed when
patients have reached an advanced stage of disease (WHO Functional Class III and IV).11
The role of prostacyclin
Prostacyclin is a potent vasodilator as well as an inhibitor of platelet activation.29 Patients with PAH have low
levels of prostacyclin,29 which promotes vasoconstriction in the pulmonary vasculature and a tendency for
smooth muscle cell proliferation and platelet activation.23 This may also encourage the formation of thrombi,
which have been found in both the small distal pulmonary arteries and the proximal elastic pulmonary arteries.2
Therapy with prostacyclin or prostacyclin analogues can help to correct this deficiency, although administering
this form of treatment may be complex due to the fact that some prostacyclins are broken down rapidly within
the body; in most cases prostacyclins need to be given as a continuous intravenous or subcutaneous infusion
or by inhalation.30
5. Why does PAH develop?
The exact causes of the development of PAH remain unknown. However, research has led to a better
understanding of underlying pathological mechanisms.
PAH is recognised as a complex, multi-factorial condition involving numerous biochemical pathways and
different cell types.2,22 Endothelial dysfunction, an abnormality of the inner lining of blood vessels, is believed
to occur early in disease pathogenesis, and this leads to endothelial and smooth muscle cell proliferation
followed by structural changes or remodelling of the pulmonary vascular bed, which in turn results in an
increase in pulmonary vascular resistance.
The role of nitric oxide
Nitric oxide (NO) is an endothelial-derived substance that, like prostacyclin, is a potent vasodilator and also
possesses anti-proliferative properties.30 Patients with PAH appear to produce insufficient NO, which could result
in vasoconstriction within the pulmonary vasculature and a tendency for smooth muscle cell proliferation22,23 that
may contribute to the development of PAH. The vasodilatory effect of NO is mediated by cGMP, which is rapidly
degraded by phosphodiesterases (PDEs).23 Orally administered PDE-5 inhibitors reduce the degradation of
cGMP and so promote the accumulation of intracellular cGMP, enhancing NO-mediated vasodilatation.31
Vascular remodelling itself involves every layer of the vessel wall and is characterised by proliferative and
obstructive changes involving many cell types; including endothelial cells, smooth muscle cells, and
fibroblasts.2 Inflammatory cells and platelets may also play a significant role in PAH.
Endothelial dysfunction results in chronically impaired production of vasoactive mediators, such as nitric oxide (NO)
and prostacyclin, along with prolonged overexpression of vasoconstrictors, such as endothelin-1 (ET-1), which
not only affect vascular tone but also promote vascular remodelling. These substances are important therapeutic
targets for new treatment options in PAH.2,23
8
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Pulmonary Arterial Hypertension (PAH)
6. What are the symptoms of PAH?
Figure 3. ACCF/AHA diagnostic approach to PAH22
Pivotal Tests
Changes to the pulmonary vasculature lead to the typical symptoms of PAH. The symptoms are caused by the
high resistance to blood flow through the lungs, which results in increased stress on the heart. This can severely
impact a patient’s ability to exercise or carry out normal daily activities. Common early symptoms include:2,19,32
Contingent Tests
History
Exam
• Index of suspicion
• of PH
CXR
• Breathlessness (dyspnoea), particularly during physical activity
• Fatigue
• Dizziness
• Syncope, also on physical activity (rare)
• Peripheral oedema
• Chest pain, again particularly during physical activity
Contribute to
Assessment of:
ECG
TEE
Echocardiogram
Exercise Echo
• RVE, RAE, RVSP, RV
• Function
• Left Heart Disease
• VHD, CHD
Pulmonary Angiography
VQ Scan
Chest CT Angiogram
• Chronic PE
Coagulopathy Profile
The symptoms may not be obvious at first and are often attributed to more common conditions. 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.
As the early symptoms of PAH are often mild, time from symptom onset to disease diagnosis is estimated to be
more than 2 years.11,12 This means that PAH is frequently not recognised until the disease is relatively advanced.11,19
PFTs
ABGs
Overnight
Oximetry
Polysomnography
Other CTD Serologies
LFTs
7. How is PAH diagnosed?
• Scleroderma, SLE, RA
• Portopulmonary Htn
Functional Test
(6MWT, CPET)
PAH is a challenging disease to diagnose accurately. It requires invasive investigations and significant
experience to manage patients effectively. As such, current guidelines recommend that the diagnosis and
management of PAH is co-ordinated by expert centres (dependent on regional variations).2,33
• Sleep Disorder
• HIV Infection
HIV
ANA
• Ventilatory Function
• Gas Exchange
• Establish Baseline
• Prognosis
Vasodilator Test
RH Cath
Exercise RH Cath
Volume Loading
• Confirmation of PAH
• Haemodynamic Profile
• Vasodilator Response
Left Heart Cath
Once a suspicion of PAH has been raised, the aim is to confirm or exclude the diagnosis of pulmonary
hypertension (PH) and, if present, establish its aetiology, assess disease severity, as well as to decide on
subsequent management and treatment strategies. The non-specific nature of symptoms associated with
PAH means that the diagnosis cannot be made on symptoms alone. The diagnosis of PAH involves a series of
investigations to determine whether there is a likelihood of PAH being present, to confirm the diagnosis based
on initial non-invasive testing, to clarify the specific aetiology, to evaluate the functional and haemodynamic
impairment of the individual patient, and to determine an appropriate treatment category.2,22 These diagnostic
steps have been formalised into clinical practice guidelines for the diagnosis of PAH, both in the US (Figure 3)22
and Europe (Figure 4).2
6MWT, 6-minute walk test; ABGs, arterial blood gases; ANA, antinuclear antibodies; CHD, congenital heart disease; CPET, cardiopulmo6MWT, 6-minute walk test; ABGs, arterial blood gases; ANA, antinuclear antibodies; CHD, congenital heart disease; CPET, cardiopulmonary
nary exercise test; CT, computerised tomography; CTD, connective tissue disease;
exercise test; CT, computerised tomography; CTD, connective tissue disease;CXR, chest x-ray; ECG, electrocardiogram; HIV, human
CXR, chest x-ray; ECG, electrocardiogram; HIV, human immunodeficiency virus screening; Htn, hypertension; LFT, liver function test; PE,
immunodeficiency virus screening; Htn, hypertension; LFT, liver function test; PE, pulmonary embolism; PFT, pulmonary function test; PH,
pulmonary embolism; PFT, pulmonary function test; PH, pulmonary hypertension;
pulmonary hypertension; RA, rheumatoid arthritis; RAE, right atrial enlargement; RH Cath, right heart catheterisation; RVE, right ventricular
RA, rheumatoid arthritis; RAE, right atrial enlargement; RH Cath, right heart catheterisation; RVE, right ventricular enlargement; RVSP, right
enlargement; RVSP, right ventricular systolic pressure; SLE, systemic lupus erythematosus;TEE, transoesophageal echocardiography; VHD,
ventricular systolic pressure; SLE, systemic lupus erythematosus;
valvular heart disease; VQ Scan, ventilation-perfusion scintigram.
TEE, transoesophageal echocardiography; VHD, valvular heart disease; VQ Scan, ventilation-perfusion scintigram.
Adapted with permission of Wolters Kluwer Health, from ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the
American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the
American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association, McLaughlin VV, Archer SL, Badesch DB, et al.
Circulation 119:2250–94 Copyright © 2009, permission conveyed through Copyright Clearance Center, Inc.
Interpretation of the results of tests is complex and requires substantial experience in the management and
follow-up of PAH patients.
10
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Pulmonary Arterial Hypertension (PAH)
Diagnosis of PAH
Figure 4. ESC/ERS clinical guidelines for the diagnosis of PAH2
The diagnosis process can be summarised in four general stages as described below. However, the type of
tests used may vary between centres, depending on the individual circumstances and the needs of the patient.
Symptoms/signs/history suggestive of PH
Non-invasive assessment compatible with PH?
YES
Search for
other causes and/or
re-check
1.Clinical suspicion of PAH
• Exertional dyspnoea, syncope, angina, and/or progressive limitation of exercise capacity without apparent
risk factors, symptoms, or signs of common cardiovascular and respiratory disorders
• Patients with associated conditions and/or risk factors (e.g. family history, connective tissue diseases, HIV)
NO
Consider common causes of PH
Group 2: Left heart disease?
Group 3: Lung diseases
and/or hypoxia?
History, Symptoms, Signs
ECG, Chest radiograph
TTE, PFT, HRCT
2.Exclusion of Group 2 (left heart disease) and Group 3 (lung diseases)
• Clinical history, electrocardiogram (ECG), chest radiograph, transthoracic echocardiogram, pulmonary
function tests, and high-resolution computed tomography (HRCT) of the chest are requested in order to
identify the presence of Group 2 (left heart disease) or Group 3 (lung diseases)
Group 2 or 3: diagnosis confirmed
YES
PH “proportionate” to serverity
NO
YES
“out of proportion” PH
Treat underlying disease
and check for progression
Perform V/Q scan
Search for
other causes
Segmental perfusion defects
Consider Group 4:
CTEPH
3.Exclusion of Group 4
• If PH Groups 2 or 3 are not found, less common causes of PH should be looked for. For example,
ventilation/perfusion lung scan is used to exclude Group 4 chronic thromboembolic pulmonary
hypertension (CTEPH)
NO
4.PAH evaluation and characterisation (type, functional class, haemodynamics)
• A range of other tests can be performed to refine the final diagnosis, including CT pulmonary angiography,
cardiac magnetic resonance imaging, haematology, biochemistry, immunology, serology, and ultrasonography
• The diagnostic gold standard for the confirmation of a diagnosis of PAH is right heart catheterisation (RHC)
• The degree of limitation to the patient caused by PAH is assessed by determining functional class and by
exercise tests such as the six-minute walk test (6MWT). This gives both a baseline measure against which to
assess progression or response to treatment, and provides prognostic information
NO
Consider other uncommon causes
YES
Consider
PVOD/PCH
Perform RHC
(PAH probability*)
mPAP ≥ 25 mm Hg
PWP ≤ 15 mm Hg
YES
Specific diagnostic tests
Physical,
Laboratory
analysis
Clinical signs HRCT, ANA
PVOD
PCH
History
CTD
HIV Test
Drugs
Toxins
HIV
TTE,
TEE,
CMR
Physical,
US,
LFT
CHD
Idiopathic or Heritable PAH
Schistosomiasis
Other group 5
Chronic
Haemolysis
PortoPulmonary
BMPR2, ALKI,
Endoglin (HHT)
Family history
ALK-1, activin-receptor-like kinase; ANA, antinuclear antibodies; BMPR2, bone morphogenetic protein receptor 2; CHD, congenital heart
ALK-1,
activin-receptor-like
ANA,CTD,
antinuclear
antibodies;
BMPR2, Group,
bone morphogenetic
protein
receptorhaemorrhagic
2; CHD,
disease;
CMR,
cardiac magnetickinase;
resonance;
connective
tissue disease;
clinical group; HHT,
hereditary
congenital
heart
disease;
CMR,
cardiac
magnetic
resonance;
CTD,
connective
tissue
disease;
Group,
clinical
group;
HHT,, mean
telangiectasia; HIV, human immunodeficiency virus; HRCT, high resolution computed tomography; LFT, liver function test; mPAP
hereditary
telangiectasia;
HIV, human
immunodeficiency
virus; capillary
HRCT, high
resolution computed
LFT,
pulmonary
arteryhaemorrhagic
pressure; PAH,
pulmonary arterial
hypertension;
PCH, pulmonary
haemangiomatosis;
PFT, tomography;
pulmonary function
liverpulmonary
function test;
mPAP, mean
pulmonary
arteryveno-occlusive
pressure; PAH, disease;
pulmonary
arterial
hypertension;
pulmonary
capillary
test; PH,
hypertension;
PVOD,
pulmonary
PWP
, pulmonary
wedge PCH,
pressure;
RHC, right
heart
haemangiomatosis;
PFT, pulmonary
function test; PH, TTE,
pulmonary
hypertension;
PVOD, pulmonary
veno-occlusive V/Q
disease;
catheterisation;
TEE, transoesophageal
echocardiography;
transthoracic
echocardiography;
US, ultrasonography;
Scan,PWP,
pulmonary
wedge
pressure;
RHC,
right
heart
catheterisation;
TEE,
transoesophageal
echocardiography;
TTE,
transthoracic
ventilation/perfusion lung scan.
echocardiography; US, ultrasonography; V/Q Scan, ventilation/perfusion lung scan.
Adapted with permission of Oxford University Press, from Guidelines for the diagnosis and treatment of pulmonary hypertension, Galiè N, Hoeper MM, Humbert H, et al.
Eur Heart J 2009;30:2493–537 Copyright © 2009, permission conveyed through Copyright Clearance Center, Inc.
12
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Pulmonary Arterial Hypertension (PAH)
8. Echocardiography
9. Right heart catheterisation
Value as a screening tool
The diagnostic gold standard for PAH
Transthoracic Doppler echocardiography (TTE) is a non-invasive screening test for pulmonary hypertension.34
Pulmonary arterial pressure can be estimated from the tricuspid regurgitant (TR) jet measured by TTE (Figure 5)
and a range of other measurements can be obtained which provide information about the cause and
consequences of PH.
Right heart catheterisation (RHC) is required for a definitive diagnosis of PAH (Figures 6 and 7),2,34 to assess
the severity of haemodynamic impairment, and to test the vasoreactivity of the pulmonary circulation. PAH is
defined as a sustained elevation of mean pulmonary arterial pressure (mPAP) to >25 mmHg at rest, and a
mean pulmonary capillary wedge pressure (PCWP) of <15 mmHg.1,2
Figure 5. Echocardiography in PAH
Figure 6. Right heart catheterisation2
Internal jugular vein
Right heart catheterisation
is required to confirm the
diagnosis of PAH.
Tricuspid regurgitation (TR)
Pulmonary artery
Left lung
PAH is defined by
● mPAP ≥25 mmHg at rest
LA
Right ventricle
Brachial vein
● PCWP ≤15 mmHg
RA
RV
LV
Femoral vein
TR jet velocity (v)
Standard approaches for catheter access
Galié et al. Eur Heart J 2009.
Syst PAP = Right ventricular systolic pressure
Right heart catheterization
Figure 7. Right heart catheterisation34
(in absence of pulmonary outflow obstruction)
RVSP = 4v2 + RAP*
Catheter
Aorta
Characteristic intracardiac pressure
waveforms during passage through
the heart
Pulmonary
artery
*ESC guidelines. Eur Heart J 2004.
Left
atrium
RA
RV
PA
PCW
40
mmHg
20
Superior
vena cava
Right
atrium
Pulmonary
valve
Tricuspid
valve
Inferior vena
cava
14
Right
ventricle
Left
ventricle
15
Pulmonary Arterial Hypertension (PAH)
10. Screening for PAH
11. How is PAH treated?
Early diagnosis and therapeutic intervention may offer an improved outlook for patients with PAH.
One method of improving early diagnosis is the introduction of screening programmes for high-risk
patient populations. These programmes screen patients for the presence of PAH while they are not
showing obvious symptoms.
While there is currently no cure for the disease, modern advanced PAH therapies can markedly improve a
patient’s symptoms and slow the rate of clinical deterioration.2,37 The aims of treatment in patients with PAH
are several-fold and range from symptomatic relief to improvement in the physical limitations imposed by
their disease (such as improving functional class; see section: Assessing the severity of PAH), and delaying
disease progression.2,33
High-risk patient populations are those patients with conditions known to be associated with a high risk
of developing PAH, including:
The management of PAH is complex and involves the use of a range of treatment options, which can be
broadly broken down into four main categories:
• Family members of a patient with heritable pulmonary arterial hypertension (HPAH)
• Patients with systemic sclerosis (SSc)
• Patients with HIV
• Patients with portopulmonary hypertension (PoPH)
• Patients with congenital heart disease
1. General measures aim to limit any potentially deleterious effects of the patient’s external circumstances
on their PAH disease, and include avoiding pregnancy, prevention and prompt treatment of chest infections,
and awareness of the potential effects of altitude.2,22,38
2. Conventional or supportive therapy aims to provide symptomatic benefit; however, there is no evidence
that it has an effect on the disease process or prognosis. Such measures include supplemental oxygen,
oral anticoagulants, diuretics, and calcium channel blockers.2,22,38
For example, results from a PAH registry in France, which aimed to describe the clinical and haemodynamic
characteristics of patients with PAH and which included 674 consecutive patients from 17 different centres,
showed that without screening the majority of patients were diagnosed in WHO FC III or IV, and only 24% of
patients were in the less severe WHO FC II (Figure 8).11 The US REVEAL registry was established to define the
characteristics of patients with PAH and their management in current practice, with the aim of helping to improve
diagnosis, treatment and management.12 Data from REVEAL was recently used to validate a quantitative
algorithm for predicting survival and to develop a simplified calculator for everyday clinical use. In this study, of
504 patients newly diagnosed with PAH enrolled in the registry, over 60% were in functional class III.35 However,
PAH was detected at an earlier stage during a national screening program in a high-risk population (Figure 8),
demonstrating the potential value of a screening strategy.6
3. Advanced therapy (also termed PAH-specific therapy)
PAH-specific therapies have been developed to target one of three major pathways known to be involved
in the development of PAH23 and have, to varying degrees, been shown to affect the disease process:
• Endothelin receptor antagonists (ERAs) are oral treatments that act by blocking the binding of endothelin,
which is implicated in the pathogenesis of PAH through its actions on the pulmonary vasculature, to either one
(single antagonist) or both (dual antagonist) of its receptors.23 Clinical trials have shown that treatment with
ERAs has a beneficial effect on exercise capacity, WHO Functional Class (FC), haemodynamics and time to
clinical worsening in patients with PAH23,28,39–42
• Prostacyclins and synthetic prostacyclins (prostacyclin analogues) act by helping to correct the deficiency of
endogenous prostacyclin seen in patients with PAH. The clinical use of prostacyclins in patients with PAH has
been extended by the synthesis of more stable analogues for intravenous infusion,43 as well as those that can
be given by subcutaneous infusion,44,45 or by inhalation46
• Phosphodiesterase-5 (PDE-5) inhibitors are oral agents that act on the nitric oxide (NO) pathway to induce
vasodilation and also have antiproliferative effects on vascular smooth muscle cells. Clinical trials have shown
that treatment with PDE-5 inhibitors has a beneficial effect on exercise capacity, haemodynamic parameters,
and symptoms in patients with PAH.31,47
WHOclass
FCatatdiagnosis
diagnosis,
orscreening
without
6,11 screening
Figure 8. Functional
– with orwith
without
16,27
11
80
Patients (%)
63%
60
With screening
100
75%
80
Patients (%)
6
No screening
100
40
60
50%
40
31%
24%
20
0
12%
1%
I
II
III
WHO FC
N=674
IV
44%
20
0
I
Surgical intervention
13%
6%
II
III
For patients with severe PAH who do not respond to treatment with advanced therapies, surgery may be the only
option. Surgical options include balloon atrial septostomy, which creates a small hole between the right and left
atria to reduce the pressure and therefore the stress on the right heart, and lung or heart and lung transplantation.2
IV
WHO FC
N=16
European and US guidelines now recommend annual screening of high-risk groups with Doppler
echocardiography, which is currently the most effective method for screening.2,36 However, right heart
catheterisation needs to be performed for a definitive diagnosis of PAH.
16
17
Pulmonary Arterial Hypertension (PAH)
12. Treatment guidelines
13. The importance of early identification and intervention in PAH
Goal-oriented therapy
Early diagnosis and therapeutic intervention may offer an improved outlook for patients. Prognosis and response
to treatment have both been shown to be better for patients with less severe disease (i.e. WHO FC I/II) compared
with those who do not begin targeted therapy until their PAH has reached a more severe stage (i.e. WHO FC III/IV).49
Disease progression may be delayed by recognising and treating patients as early as possible.40
Treatment guidelines recommend that patients with PAH receive initial monotherapy.2,33,48 The choice of initial
therapy depends on a variety of factors, including disease severity, route of administration, side effect profiles,
approval and reimbursement status and preferences of patients and clinicians.
Once treatment is initiated, patients should be monitored regularly and their response to therapy assessed
using a range of clinical, exercise, haemodynamic and echocardiographic parameters. Guidelines have
identified factors associated with prognosis which should be used to monitor treatment response, including
functional class, six-minute walk distance, the presence of pericardial effusion on echocardiography, and
haemodynamic parameters such as right atrial pressure.2,22,48
Early diagnosis poses a challenge to healthcare professionals because many of the initial symptoms of
PAH are mild and non-specific meaning many patients are not diagnosed until their disease is already quite
severe.11 Regular screening can improve early detection in those patients with conditions known to be
associated with PAH (e.g. systemic sclerosis or congenital heart disease).
Given the diagnostic challenges, referral to expert centres is recommended to assist in the early identification
of PAH.2,48 Management of patients in such centres also helps to ensure that suitable treatment is provided,
patients are appropriately monitored and treatment adjusted when required, and the complex comorbidities
often associated with PAH are managed optimally.
Treatment guidelines recommend that, if the patient shows an inadequate clinical response to
monotherapy, combination therapy using a combination of PAH-specific therapies from different classes
(i.e. prostacyclin/prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase-5 inhibitors)
should be considered.2,33,48 The type of combination therapy chosen by the healthcare professional will depend
on a variety of factors, including approval and reimbursement status and preferences of patients and clinicians.
A goal-orientated strategy whereby treatment goals are set based on achieving or maintaining particular
thresholds or values in parameters known to be prognostically relevant can be used to assess response.2,22
While this strategy is discussed in international guidelines,1 European guidelines currently give the most
detailed advice as to the use of this strategy.2 According to European guidelines, predetermined goals based
on parameters that have been shown to be associated with better prognosis should be set for the patient,
and regular follow-up visits are recommended in order to ascertain progress towards the treatment goals.
Based on these parameters, a patient’s condition can be categorised as:2
• Stable and satisfactory: A patient fulfilling the majority of goals or targets
• Stable but not satisfactory: A patient who, although stable, has not achieved the status that the patient and
treating physician would consider desirable and some of the treatment goals have not been met
• Unstable and deteriorating: A patient not meeting goals or targets, and exhibiting a number of parameters
associated with a worse prognosis
Patients in the ‘stable but not satisfactory’ or ‘unstable and deteriorating’ categories require re-evaluation and
consideration for escalation of treatment.
The management of patients with PAH is complex. Given these complexities, referral of patients with PAH to an
expert centre is recommended wherever possible.2,33,48
18
19
Pulmonary Arterial Hypertension (PAH)
Survival according to functional class5
14. Assessing the severity of PAH
Figure 10. Survival according to functional class37
100
Survival (%)
Assessing patients with pulmonary arterial hypertension (PAH) involves evaluating the severity of their disease
using a range of clinical assessments, exercise tests, biochemical markers, and echocardiographic and
haemodynamic assessments. The clinical assessment of the patient has a pivotal role in the choice of the
initial treatment, the evaluation of the response to therapy, and the possible escalation of therapy if needed.
A number of parameters have been proven to have prognostic significance in PAH, although their value in a
given patient may vary depending on the underlying aetiology of the disease. Some of the most important and
widely-used parameters are discussed below.
80
WHO FC II
60
WHO FC III
40
WHO FC IV
20
0
Functional class
24
36
No. at risk
12
15
19
23
24
26
27
37
48
70
79
86
88
89
7
6
9
11
10
13
17
Reproduced with permission from: Wolters Kluwer Health. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated
pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156–63.
Figure 9. WHO functional classification of pulmonary hypertension (modified from the New York Heart
Association functional classification for heart failure)
I
12
Time (months)
The clinical severity of PAH is classified according to a system originally developed for heart failure by the
New York Heart Association (NYHA) and then modified by the World Health Organization (WHO) for patients with
PAH.2 This system grades PAH severity according to the functional status of the patient, linking symptoms with
activity limitations, and allows clinicians to quickly and accurately predict disease progression and prognosis,
as well as the need for specific treatment regimens, irrespective of the underlying aetiology of PAH (Figure 9).
Functional class
0
Given this link with prognosis, improvement from WHO FC III/IV to WHO FC II and improvement or
maintenance of patients with early signs at WHO FC I/II are very important goals of therapy.33
Symptomatic profile
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
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
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
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
Functional class is a powerful predictor of outcomes in patients with PAH.2
Even with advanced medical treatment (see section: How is PAH treated?), patients in WHO FC IV continue to
have extremely poor outcomes relative to those patients in lower functional classes. In a recent French study,
lower functional class (I/II) was found to be positively and significantly associated with survival (Figure 10),37 while
data from the US REVEAL registry showed that functional class IV was independently associated with increased
mortality in patients with PAH (HR, 3.1; 95% CI, 2.2 to 4.4).50
20
21
Pulmonary Arterial Hypertension (PAH)
Exercise capacity: six-minute walk test (6MWT)
CPET with measuring of the VO2 max offers some advantages over the 6MWT, for example in terms of sensitivity,
but these tests are more difficult to perform and require specialist equipment. As they are a maximal stress test,
they are not suitable for more severe patients who may not be able to tolerate the exercise and may be exposed
to risk of syncope and discomfort.
The six-minute walk test (6MWT) is a key test in PAH management because it is a measure of the patient’s
functional limitation and correlates with peak aerobic capacity.51 It is also a simple test to perform,
which is inexpensive and convenient. In addition to distance walked, dyspnoea on exertion, and O2 saturation
can also be recorded, which can provide further information regarding the patient’s condition.
Haemodynamic parameters
Results of the 6MWT have been shown to correlate with functional class and the distance walked significantly
decreases in proportion to the severity of NYHA FC (Figure 11).52
Haemodynamic parameters are measured by right heart catheterisation (RHC) and are important diagnostic
and prognostic markers in the assessment of PAH; correlating with clinical status, WHO FC, exercise capacity,
and prognosis. They are also used to assess treatment effect. Prognosis is significantly correlated with markers
of right ventricular function, including mean right atrial pressure (mRAP)37,50 and mean cardiac index (CI).55
Normalisation of haemodynamics may therefore be considered a suitable goal or treatment measure.
Figure 11. 6MWD compared with functional class52
800
* p<0.05 vs. control subjects
† p<0.05 vs. NYHA FC II
700
Serum levels of a protein known as N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) have
been shown to be associated with prognosis in PAH.2 A level of serum NT-proBNP below 1400 pg/mL seems
to identify patients with good prognosis and who are unlikely to need escalation of treatment in the immediate
future.56 However, cut-off levels still need to be verified in controlled trials, and our understanding of the role of
this marker is still emerging.
*
600
6MWD (m)
Biochemical markers
‡ p<0.05 vs. NYHA FC III
500
*†
400
300
*†‡
200
100
0
Control
NYHA FC II
NYHA FC III
NYHA FC IV
Reprinted with permission of the American Thoracic Society. Copyright © American Thoracic Society. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates
and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing.
American Journal of Critical Care Medicine 2000;161(2 Pt 1):487–92. Official Journal of the American Thoracic Society
It should be noted that, despite these advantages, the 6MWT is only properly validated for patients with IPAH. It is not
yet clear whether it is appropriate for the assessment of treatment success in patients with, for example, PAH-SSc
where accompanying conditions can make the 6MWT difficult. It also has not been standardised for all populations,
and it is important that the test is performed under supervision according to a standardised protocol in order to allow
meaningful comparisons.53
Cardiopulmonary exercise testing
Cardiopulmonary exercise testing (CPET) assesses lung gas exchange and gives a more sensitive and
comprehensive measure of exercise capacity than the 6MWT.51 It is a maximal stress test – the patient
exercises at a workload that progressively increases to their symptom tolerance (i.e. the maximum workload
the patient can tolerate). As such, it is difficult to perform in patients with severe disease.
One important measure assessed using CPET is peak O2 consumption (VO2 max), which is a measure of the
ability of the cardiovascular system to transport oxygen to the tissues and the ability of the cells to use oxygen.
It has become the gold standard for assessing a patient’s exercise capacity and maximal cardiovascular
response. PAH patients show reduced peak VO2 and this measurement correlates with a patient’s prognosis.54
22
23
Pulmonary Arterial Hypertension (PAH)
Suggested screening protocol for the detection
of PAH in SSc patients53
Figure 12. Suggested screening protocol for the detection of PAH in SSc patients61
15. PAH in patients with systemic sclerosis (SSc)
SSc patients without severe pulmonary function
abnormalities or severe cardiac disease
Around 15% of all cases of pulmonary arterial hypertension (PAH) in a recent French PAH registry11 and 25% in
a US PAH registry12 were associated with connective tissue disease, and particularly with SSc (also known as
scleroderma).
Doppler echocardiography
Patients with SSc who develop PAH have poorer prognosis than those who do not,57,58 and PAH has become one
of the leading causes of mortality in SSc patients, accounting for more than 25% of all SSc-related deaths.59
VTR <2.8 m/s
NO DYSPNOEA
(or dyspnoea explained
by another cause)
Given the significant incidence of PAH in patients with SSc and the high mortality associated with this complication
if untreated, there is a clear need for early detection and timely treatment before patients show marked clinical and
haemodynamic deterioration.6
VTR ≥3.0 m/s
VTR 2.8–3.0 m/s
DYSPNOEA
(not explained by
another cause)
Suspected PAH
NO PAH
How is PAH-SSc detected?
The diagnosis of PAH in patients with SSc can be particularly challenging, especially in its early stages. SSc affects
a number of organs, including the lungs, and can be associated with symptoms such as fatigue and dyspnoea,
which are also symptoms of PAH. As a result, detection of PAH in SSc is often delayed and patients are only
diagnosed when they have advanced disease with severe clinical and haemodynamic impairment.60
Right heart catheterisation
mPAP at rest <25 mmHg
mPAP during exercise
<30 mmHg and
mPCWP <15 mmHg
However, given the known high incidence of PAH in SSc, echocardiography screening is recommended in all
symptomatic patients and screening by echocardiography may also be considered in all SSc patients according
to the treatment guidelines.2,22 Recent studies have also shown that screening for PAH in asymptomatic SSc
patients is associated with improved outcomes.60
NO PAH
mPAP at rest ≥25 mmHg
and mPCWP <15 mmHg
mPAP during exercise
≥30 mmHg
Confirmed PAH
VTR, peak velocity of tricuspid regurgitation; mPAP, mean pulmonary artery pressure; mPCWP, mean pulmonary capillary wedge pressure.
Figure adapted from: The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in
France. Hachulla E, de Groote P, Gressin V, et al. Copyright © 2009, John Wiley and Sons, Inc. Reproduced with permission of John Wiley and Sons, Inc.
In this example of a screening algorithm,61 it is recommended that patients with SSc are regularly assessed using
Doppler echocardiography (Figure 12). The parameter assessed is peak velocity of tricuspid regurgitation (VTR);
patients with low VTR (<2.8 m/s) do not have PAH, whereas a high VTR (>3.0 m/s), or moderate VTR (2.8–3.0 m/s)
together with dyspnoea, raises the suspicion of PAH. To confirm the diagnosis, patients must then undergo right
heart catheterisation (RHC).
How is PAH-SSc treated?
PAH-SSc is associated with poor outcome if untreated. Data suggest that available therapies may improve quality
of life and exercise capacity, and slow disease progression.62–66 Overall, patients with PAH-SSc should be treated,
followed and assessed in the same way as patients with IPAH, taking into account some additional considerations.2
For example, the six-minute walk test (6MWT) used routinely to evaluate exercise capacity is not validated in
patients with PAH-SSc, and complications of SSc, such as other cardiopulmonary disorders, musculoskeletal pain,
fatigue, arthritis/tendonitis, and muscle weakness and contractures, can interfere with a patient’s ability to perform
the test and therefore affect results.67 Treatment of patients with PAH-SSc is particularly complicated by the need
to manage other problems associated with SSc, such as skin, renal, and gastrointestinal complications.68 As with
other forms of PAH, patients should therefore be referred to an expert centre for PAH diagnosis and management.
24
25
Pulmonary Arterial Hypertension (PAH)
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28
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Notes
30
31
Pulmonary Arterial Hypertension (PAH)
For further information visit www.pah-info.com
© 2012 Actelion Pharmaceuticals Ltd.
Gewerbestrasse 16 – CH-4123 Allschwil – Switzerland – www.actelion.com
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Pulmonary Arterial Hypertension (PAH)