1. Faculty of Medicine Universitas Brawijaya Malang
Cor Pulmonale
Faculty of Medicine
Universitas Brawijaya
Malang

2. Cor Pulmonale
Right Sided Heart Disease, secondarily caused by abnormalities of lung parenchyme, airways, thorax, or respiratory control mechanisms.
Noevidence of other heart conditions,
Acute vs. Chronic

3. Etiology of Cor Pulmonale ( I )
Vascular Occlusion
Multiple Emboli
Schistosomiasis
Filariasis
Sickle Cell
P. Pulmonary Hypertension
Lung and Airways
COPD
Asthma
Bronchiectasis
DILD
Pulmonary tuberculosis

4. Etiology of Cor Pulmonale ( II )
Thoracic Cage
Kyphosis > 100 o
Scoliosis > 120 o
Thoracoplasty
Pleural fibrosis
N-M Disease
Polio Myelitis
Myasthenia Gravis
ALS
Muscular Dystrophy

5. Etiology of Cor Pulmonale ( III )
Abnormal Respiratory Control
Idiopathic hypoventilation Syndrome
Obesity hypoventilation syndrome (Pick-Wickian syndrome)
Cerebrovascular disease

6. Rt. Ventricular Failure
Hypercapnea H
Anatomic changes
Hypoxia
Acidemia A
Pulmonary Vessel
Restriction
Increased
Viscosity
Increased C.O.
Acidosis C
Chronic Cor Pulmonale
Rt. Ventricular Failure

7. Pathologic Features Lung : consistent with Specific diseases
Common Features: hypertrophy of microvasculatures
Hallmark : Rt. Ventricular Hypertrophy
60g – 200g, > 0.5 CM, RV/LV <2.5
Lt. Ventricular Hypertrophy
Hypertrophy of Carotid Body

8. Natural History Several months to years to develop
All ages from child to old people
Repeated infections aggravate RV strain into RV failure
Initilly respondes well to therapy but progressively becomes refractory

9. Prevalence Emphysema : less frequent Cronic bronchitis : more common
US : 6-7 % of Heart failure
Delhi : 16%
Sheffield in UK : 30 – 40%
Autopsy in Chronic Bronchitis : 50%
More prevalent in pollution area or smokers

10. Lab. Findings
X-Ray : Prominent pulmonary hilum pulmonary artery dilatation
Rt MPA > 20 mm
EKG : P- pulmonale, RAD, RVH
Echocardiography : RVH, TR, Pulm. Hypertension
ABG : Hypoxemia, Hypercapnea, Respiratory acidosis
CBC : polycythemia
Cardiac catheterization

11. Treatment
Treat Underlying Disease : COPD Tx, Steroid, Infection control, theophylline, medroxyprogesterone,
Continuous O2 : < 2-3L/min
Diuretics
Phlebotomy
Digoxin : controversial
Pul. Vasodilators
Beta adrenergic agents
Reduce Ventilation/Perfusion imbalance : Amitrine bimesylate

12. Prognosis 1960-1970 : 3 yr mortality 50-60%
Recent times : years or more

13. Pulmonary Arterial Hypertension (PAH)13

14. PAH explained 14

15. PAH is characterised by;1,2
What is PAH?
Progressive disease caused by narrowing or tightening of the pulmonary arteries
Right side of the heart becomes enlarged due to the increased strain of pumping blood through the lungs
Strain leads to the common symptoms of PAH (breathlessness, fatigue, weakness, angina and syncope)1
PAH is characterised by;1,2
mean PAP ≥ 25mmHg at rest
mean PCWP ≤ 15mmHg
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.
Although symptoms of PAH are non-specific, it is this strain on the heart and lack of blood to the lungs that leads to the common symptoms of PAH, such as breathlessness, fatigue, weakness, angina, syncope, and abdominal distension.1
Galiè N, et al. Eur Heart J 2009;30:2493–537;
Badesch DB, et al. J Am Coll Cardiol 2009;54:S55–66.
1. Galiè N et al. Eur Heart J 2009; 2. Badesch DB et al. J Am Coll Cardiol 2009 15

16. Changes in the pulmonary arteries in PAH
The increase in pulmonary vascular resistance observed in patients with PAH is related to a number of progressive changes in the pulmonary arterioles, including:1
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.
1. Galiè N, et al. Eur Heart J 2009;30:2493–537. 16

17. Classification of PH Group 1. Pulmonary arterial hypertension (PAH)
Idiopathic (IPAH)
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):
connective tissue diseases
Human immunodeficiency virus (HIV) infection
portal hypertension
congenital heart disease (CHD)
schistosomiasis
chronic haemolytic anaemia
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 disease
Systolic dysfunction
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
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental abnormalities
Group 4. Chronic thromboembolic pulmonary
hypertension (CTEPH)
Group 5. PH with unclear multifactorial
mechanisms
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
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. The groups are divided based on aetiology.
Simonneau G, et al. J Am Coll Cardiol 2009;54:S43–S54.
Simonneau G et al. J Am Coll Cardiol 2009 17

18. Drug and toxin-induced
Classification of PH
Idiopathic PAH (IPAH)
sporadic disease in which there is neither a family history of PAH nor an identified risk factor1
Heritable PAH (HPAH)
accounts for at least 6% of cases of PAH2
associated with mutations in the bone morphogenetic protein receptor 2 (BMPR2)3
Drug and toxin-induced
rare side effect of certain anorexigenic agents, such as fenfluramine1,4
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.1
Heritable PAH (HPAH) accounts for at least 6% of cases of PAH2 and mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in the majority of cases.3
PAH is also a rare side effect of certain anorexigenic agents, such as fenfluramine.1,4 However, the incidence of drug-induced PAH related to fenfluramine is decreasing as this agent is no longer available.
Simonneau G, et al. J Am Coll Cardiol 2009;54:S43–S54;
Lane KB, et al. Nat Genet 2000;26:81–4;
Morrell NW. F1000 Biol Rep 2010;2.pii:22;
Galiè N, et al. Eur Heart J 2009;30:2493–537.
1. Simonneau G et al. J Am Coll Cardiol 2009; 2. Lane KB et al. Nat Genet 2000;
3. Morrell NW. F1000 Biol Rep 2010; 4. Galiè N et al. Eur Heart J 2009 18

19. Associated PAH (APAH):1
Classification of PH
Associated PAH (APAH):1
PAH associated with connective tissue disease Well-recognised complication of connective tissue diseases, such as systemic sclerosis (SSc) and systemic lupus erythematosus (SLE)
PAH associated with HIV infection Relatively rare but well documented complication. Long-term conditions such as PAH increasingly responsible for HIV-associated morbidity and poor prognosis2,3
PAH can also be associated with a number of other conditions (associated PAH, APAH), which together account for most other cases. These conditions include:1
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).
2. PAH associated with HIV infection PAH is a rare but relatively well-documented complication of HIV infection. Highly active anti-retroviral therapy (HAART) has markedly improved survival rates in HIV patients, and so long-term conditions such as PAH are increasingly responsible for HIV-associated morbidity and poor prognosis.2,3
Simonneau G, et al. J Am Coll Cardiol 2009;54:S43–S54;
Sitbon O. AIDS 2008;22 Suppl 3:S55–62;
Kanmogne GD. Curr Opin Pulm Med 2005;11:208–12.
1. Simonneau G et al. J Am Coll Cardiol 2009; 2. Sitbon O. AIDS 2008; 3. Kanmogne GD. Curr Opin Pulm Med 2005 19

20. Classification of PH (cont.)
Associated PAH (APAH):1
PAH associated with portal hypertension Well-recognised complication of chronic liver diseases resulting from portal hypertension (portopulmonary hypertension)
PAH associated with congenital heart disease Can arise in patients with a variety of congenital shunts and can persist following corrective surgery. Eisenmenger's syndrome most severe form1,2
PAH associated with schistosomiasis
PAH associated with sickle cell disease
3. 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.1,2
4. 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.3 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 and limited exercise capacity.4,5 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.4,6
6. 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%.7
5. PAH associated with sickle cell disease The prevalence of PAH in patients with sickle cell disease is around 2–3.75%.8,9
Humbert M, et al. Am J Respir Crit Care Med 2006;173:1023–30;
Badesch DB, et al. Chest 2010;137:376–87;
Diller GP, Gatzoulis MA. Circulation 2007;115:1039–1050;
Simonneau G, et al. J Am Coll Cardiol 2009;54:S43–S54;
Diller GP, et al. European Heart Journal Supplements 2007;9(Suppl H):H54–H60;
Galiè N, et al. Eur Heart J 2009;30:2493–537;
Lapa M, et al. Circulation 2009;119:1518–23.
Machado RF, Gladwin MT. Chest 2010;137:30S–38S;
Fonseca GH, et al. Eur Respir J 2011 Sep 8. [Epub ahead of print];
1. Simonneau G et al. J Am Coll Cardiol 2009; 2. Diller GP et al. European Heart Journal Supplements 2007 20

21. Prevalence is higher in at risk groups:
How common is PAH?
PAH is rare
estimated prevalence of 15–50 cases per million1
IPAH
annual incidence of 1–2 cases per million people in the US and Europe2,3
2-4 times as common in women as men2,3
Prevalence is higher in at risk groups:
systemic sclerosis (~7–12%)4,5
HIV infection (0.5%)6
sickle cell disease (2–3.75%)7,8
schistosomiasis (4.6%)9
Although PAH is a rare disease, with an estimated prevalence of 15–50 cases per million,1 the prevalence of PAH in certain at-risk groups is substantially higher.
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.2,3
Peacock AJ, et al. Eur Respir J 2007;30:104–109;
Gaine SP, Rubin LJ. Lancet 1998;352:719–25;
Badesch DB, et al. Chest 2010;137:376–87.
1.Peacock AJ et al. Eur Respir J 2007; 2. Gaine SP, Rubin LJ. Lancet 1998; 3. Badesch DB et al. Chest 2010; 4. Hachulla E et al. Arthritis Rheum 2005; 5. Mukerjee D et al. Ann Rheum Dis 2003; 6. Sitbon O et al. Am J Respir Crit Care Med 2008; 7. Machado RF, Gladwin MT. Chest 2010; 8.Fonseca GH, et al. Eur Respir J 2011; 9. Lapa M et al. Circulation 2009 21

22. Complex, multi-factorial condition1,2
Why does PAH develop?
Exact causes unknown
Complex, multi-factorial condition1,2
Endothelial dysfunction occurs early in disease pathogenesis and leads to1:
endothelial and smooth muscle proliferation
remodelling of the vessel wall
impaired production of vasodilators (NO, prostacyclin)
overexpression of vasoconstrictors (endothelin-1)
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.1,2 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 (remodelling) of the pulmonary vascular bed, which in turn results in an increase in pulmonary vascular resistance. 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.1 Inflammatory cells and platelets may also play a significant role in PAH.
Endothelial dysfunction results in chronically impaired production of vasodilatory 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.1,3
Galiè N, et al. Eur Heart J 2009;30:2493–537;
McLaughlin VV, et al. Circulation 2009;119:2250–94;
Humbert M, et al. N Engl J Med 2004;351:1425–36.
1. Galiè N, Hoeper M, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009; 30: 2493–537.
2. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: 2009;119:2250–94. 22

23. The role of endothelin Endothelin-1 (ET-1)
elevated levels are seen in PAH patients13
levels correlate with disease severity4
deleterious effects mediated through ETA and ETB receptors5
fibrosis
hypertrophy and cell proliferation
inflammation
vasoconstriction
endothelin receptor antagonists can block these effects6
Endothelin
Endothelin-1 (ET-1) is produced by endothelial cells lining the blood vessels. High levels of endothelin are seen in patients with PAH due to various etiologies1-3 and correlate with disease severity,4 resulting in a number of detrimental effects, primarily in the vasculature:5
Fibrosis
Hypertrophy and proliferation of cells, which can lead to thickening, narrowing, and occlusion of blood vessels
Inflammation
Vasoconstriction
Endothelin binds to two receptors, known as ETA and ETB. Both receptors are implicated in PAH and mediate the deleterious effects of endothelin.5 
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.6
Stewart DJ, et al. Ann Inter Med 1991; 114: 4649;
Vancheeswaran R, et al. J Rheum 1994; 21: 183844;
Yoshibayashi M, et al. Circulation 1991; 84: 228085;
Galiè N, et al. Eur J Clin Invest 1996; 26: A48;
Humbert M, Sitbon O, Simonneau G. N Engl J Med 2004;351:1425–36;
Channick RN, et al. Lancet 2001;358:
1. Stewart DJ et al. Ann Inter Med 1991; 2. Vancheeswaran R et al. J Rheum 1994;
3. Yoshibayashi M et al. Circulation 1991; 4. Galiè N et al. Eur J Clin Invest 1996;
5. Humbert M et al. N Engl J Med 2004; 6. Channick RN et al. Lancet 2001 23

24. The role of prostacyclin
potent vasodilator
inhibitor of platelet activation
low levels in patients with PAH
therapy with prostacyclin or prostacyclin analogues can help to correct this deficiency
Prostacyclin
Prostacyclin is a potent vasodilator as well as an inhibitor of platelet activation.1 Patients with PAH have low levels of prostacyclin,1 which promotes vasoconstriction in the pulmonary vasculature and a tendency for smooth muscle cell proliferation and platelet activation.2 This may also encourage the formation of thrombi, which have been found in both the small distal and the proximal elastic pulmonary arteries.3 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 these substances need to be given as a continuous intravenous or subcutaneous infusion or by inhalation.4
1. McGoon MD, Kane GC. Mayo Clin Proc 2009;84:191–207;
2. Humbert M, et al. N Engl J Med 2004;351:1425–36;
3. Galiè N, et al. Eur Heart J 2009;30:2493–537;
4. Galiè N, et al. Prog Cardiov Dis 2003:45:213–24.
1. Humbert M et al. N Engl J Med 2004; 2. McGoon MD, Kane GC. Mayo Clin Proc 2009;84:191–207 24

25. The role of nitric oxide
potent vasodilator
possesses anti-proliferative properties
impaired production in PAH3
vasodilatory effect is mediated by cGMP
rapidly degraded by phosphodiesterases (PDEs)
therapy with oral PDE-5 inhibitors reduces degradation4
Nitric oxide
Nitric oxide (NO) is an endothelial-derived substance that, like prostacyclin, is a potent vasodilator and also possesses anti-proliferative properties.1 Patients with PAH appear to produce insufficient NO, which could result in vasoconstriction within the pulmonary vasculature and a tendency for smooth muscle cell proliferation that may contribute to the development of PAH.2 The vasodilatory effect of NO is mediated by cGMP, which is rapidly degraded by phosphodiesterases.3 Orally administered PDE-5 inhibitors reduce the degradation of cGMP and so promote the accumulation of intracellular cGMP, enhancing NO-mediated vasodilation.4
Galiè N, et al. Prog Cardiov Dis 2003;45:213–24;
Humbert M, et al. N Engl J Med 2004;351:1425–36;
McLaughlin W, et al. Circulation 2009;119:2250–94;
Galiè N, et al. N Engl J Med 2005;353:2148–57.
1. Galiè N et al. Prog Cardiov Dis 2003; 2. Humbert M et al. N Engl J Med 2004; 3. McLaughlin VV et al. Circulation 2009; 4. Galiè N et al. N Engl J Med 2005 25

26. What are the symptoms of PAH?
High resistance to blood flow through the lungs causes right heart dysfunction, decreased cardiac output and produces:1–3
dyspnoea
fatigue
dizziness
syncope
peripheral oedema
chest pain, particularly during physical exercise
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 breathlessness (dyspnoea), particularly during physical activity; fatigue; dizziness, syncope, also on physical activity (rare); peripheral oedema and chest pain, again particularly during physical activity.1–3
Galiè N, et al. Eur Heart J 2009;30:2493–537;
Gaine SP, Rubin LJ. Lancet 1998;352:719–25;
Barst RJ, et al. J Am Coll Cardiol 2004;43(Suppl S):40S–47S.
1. Galiè N et al. Eur Heart J 2009; 2. Gaine SP et al. Lancet 1998; 3. Barst RJ et al. J Am Coll Cardiol 2004 26

27. What are the symptoms of PAH?
Early symptoms mild and non-specific
Commonly attributed to other conditions
Over time, symptoms become more severe and limit normal daily activities
Delayed diagnosis common:
symptom onset to disease diagnosis > 2 years1,2,3
frequently not recognised until the disease is relatively advanced1,3
The symptoms of PAH 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, on average, more than 2 years.1,2 This means that PAH is frequently not recognised until the disease is relatively advanced.1,3
Humbert M, et al. Am J Respir Crit Care Med 2006;173:1023–30;
Badesch DB, et al. Chest 2011;137:376–87;
Gaine SP, Rubin LJ. Lancet 1998;352:719–25.
1. Humbert M et al. Am J Respir Crit Care Med 2006; 2. Badesch DB et al. Chest 2010; 3. Gaine SP, Rubin LJ. Lancet 1998 27

28. Diagnosing PAH 28

29. Series of investigations to:1,2
How is PAH diagnosed?
PAH is a challenging disease to diagnose accurately; diagnosis cannot be made on symptoms alone
Series of investigations to:1,2
determine whether there is a likelihood of PAH being present
confirm the diagnosis based on initial non-invasive testing
clarify the specific aetiology
evaluate the functional and haemodynamic impairment of the individual patient
determine an appropriate treatment category
PAH is a challenging disease to diagnose accurately. It also 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).1,2
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.3
1. Galiè N, et al. Eur Heart J 2009;30:2493–537;
2. Barst RJ, et al. J Am Coll Cardiol 2009;54:578–84;
3. McLaughlin VV, et al. Circulation 2009; 119:2250–94.
1. Galiè N et al. Eur Heart J 2009; 2. McLaughlin VV et al. Circulation 2009 29

30. Clinical practice guidelines for the diagnosis of PAH
ESC/ERS clinical guidelines for the diagnosis of PAH1
ACCF/AHA Diagnostic Approach to PAH2
These diagnostic steps have been formalised into clinical practice guidelines for the diagnosis of PAH, both in Europe1 and the US2
1. Galiè N, et al. Eur Heart J 2009;30:2493–537;
2. McLaughlin VV, et al. Circulation 2009; 119:2250–94.
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.
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.
1. Galiè N et al. Eur Heart J 2009; 2. McLaughlin VV et al. Circulation 2009

31. Four stage approach to diagnosis
Clinical suspicion of PAH
symptoms, known risk factors
Exclusion of Group 2 (left heart disease) and Group 3 (lung disease) PH
ECG, chest radiograph, echocardiography, PFTs, HRCT
Exclusion of Group 4 (CTEPH) PH
ventilation/perfusion lung scan
PAH evaluation and characterisation
CT pulmonary angiography, CMRI, haematology, biochemistry, serology, and ultrasonography
functional class and exercise capacity
right heart catheterisation (RHC)
The diagnosis process can be summarised in four general stages, although the type of tests used may vary between centres, depending on the individual circumstances and the needs of the patient.
1. Clinical suspicion of PAH: Symptoms such as exertional dyspnoea, syncope, angina, and/or progressive limitation of exercise capacity without apparent risk factors, symptoms, or signs of common cardiovascular and respiratory disorders, or patients with associated conditions and/or risk factors (e.g. family history, connective tissue diseases, HIV)
2. Exclusion of Group 2 and Group 3 PH: Clinical history, electrocardiogram (ECG), chest radiograph, transthoracic echocardiogram, pulmonary function tests (PFTs), 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)
3. Exclusion of Group 4 PH: 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)
4. PAH evaluation and characterisation: A range of other tests can be performed to refine the final diagnosis, including CT pulmonary angiography, cardiac magnetic resonance imaging (CMRI), haematology, biochemistry, immunology, serology, and ultrasonography. 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). However, the diagnostic gold standard for the confirmation of a diagnosis of PAH is right heart catheterisation (RHC).
Galiè N, et al. Eur Heart J 2009;30:2493–537.
Note: Not all tests may be performed at all centres
Galiè N et al. Eur Heart J 2009 31

32. Echocardiography – value as a screening tool
Transthoracic Doppler echocardiography (TTE) can be used as a non-invasive screening test for pulmonary hypertension. Pulmonary arterial pressure (PAP) can be estimated from the tricuspid regurgitant (TR) jet measured by TTE and a range of other measures can be obtained which provide information about the cause and consequences of PH.
Habib G, Torbicki A. Eur Respir Rev 2010;19:1–12. 32

33. Right heart catheterisation – the diagnostic gold standard1
Right heart catheterisation (RHC) is required for a definitive diagnosis of PAH,1,2 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.1,3
Galiè N, et al. Eur Heart J 2009;30:2493–537;
Habib G, Horbicki A. Eur Respir Rev 2010;19:1–12;
Badesch DB, et al. J Am Coll Cardiol 2009;54:S55–66.
1. Galiè N et al. Eur Heart J 2009 33

34. Right heart catheterisation – the diagnostic gold standard
This diagram shows how the catheter is placed in the heart during RHC, and the relative positions of the catheter used to record standard haemodynamic measurements such as right atrial pressure (RAP), pulmonary artery pressure (PAP) and pulmonary capillary wedge pressure (PCWP). 34

35. Improving early diagnosis – screening high risk populations:
Screening for PAH
Improving early diagnosis – screening high risk populations:
family members of a patient with heritable PAH (HPAH)
patients with systemic sclerosis (SSc)
patients with HIV
patients with portopulmonary hypertension (PoPH)
patients with congenital heart disease
European and US guidelines recommend annual screening with Doppler echocardiography1,2
Right heart catheterisation required for definitive diagnosis
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.
High-risk patient populations are those patients with conditions known to be associated with a high risk of developing PAH, including: • 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
European and US guidelines now recommend annual screening of high-risk groups with Doppler echocardiography, which is currently the most effective method for screening.1,2 However, right heart catheterisation needs to be performed for a definitive diagnosis of PAH.
1. Galiè N, et al. Eur Heart J 2009;30:2493–537;
2. McGoon M, et al. Chest 2004;126:14S–34S.
1. Galiè N et al. Eur Heart J 2009; 2. McGoon M et al. Chest 2004 35

36. Results of a disease registry in France
The value of screening
Results of a disease registry in France
without screening, the majority of patients were diagnosed in WHO FC III or FC IV and only 24% of patients were in WHO FC II at diagnosis1
with screening, PAH was detected at an earlier stage2
Results from a PAH registry in France, for example, 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.1 In the US, over 60% of newly diagnosed patients with PAH enrolled in the REVEAL registry were in functional class III.2 However, PAH was detected at an earlier stage during a national screening programme in a high-risk population, demonstrating the potential value of a screening strategy.3
Humbert M, et al. Am J Respir Crit Care Med 2006;173:1023–30;
Benza RL, et al. Chest 2011 Jun 16. [Epub ahead of print];
Hachulla E, et al. Arthritis Rheum 2005;52:
1. Humbert M et al. Am J Respir Crit Care Med 2006; 2. Hachulla E et al. Arthritis Rheum 2005 36

37. Treating PAH 37

38. Currently no cure for PAH
How is PAH treated?
Currently no cure for PAH
Modern advanced PAH therapies can markedly improve a patient’s symptoms and slow the rate of clinical deterioration1,2
Management is complex, involving use of a range of treatment options:
general measures
conventional or supportive therapy
advanced therapy (PAH-specific therapy)
surgical intervention
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.1,2 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:
1. General measures
2. Conventional or supportive therapy
3. Advanced therapy (also called PAH-specific therapy)
4. Surgical intervention
1. Galiè N, et al. Eur Heart J 2009;30:2493–537;
2. Humbert M, et al. Circulation 2010;122:156–63.
1. Galiè N et al. Eur Heart J 2009; 2. Humbert M et al. Circulation 2010 38

39. General measures and supportive therapy
limit effects of external circumstances
avoid pregnancy
prevention and prompt treatment of chest infections
awareness of the potential effects of altitude
Conventional or supportive therapy1–3
provide symptomatic benefit
supplemental oxygen
oral anticoagulants
diuretics
CCBs
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.1,2
Conventional or supportive therapy aims to provide symptomatic benefit. Such measures include supplemental oxygen, oral anticoagulants, diuretics, and calcium channel blockers.
1. Galiè N, et al. Eur Heart J 2009;30:2493–537;
2. McLaughlin VV, et al. Circulation 2009;119:2250–94;
3. Badesch DB, et al. Chest 2004;126(1 Suppl):35S–62S.
1. Galiè N et al. Eur Heart J 2009; 2. McLaughlin VV et al. Circulation 2009; 3. Badesch DB et al. Chest 2004 39

40. Advanced (PAH-specific) therapy
Endothelin receptor antagonists (ERAs)
oral treatments that act by blocking the binding of ET to either one (single antagonist) or both (dual antagonist) of its receptors1
Synthetic prostacyclins and prostacyclin analogues
act by helping to correct the deficiency of endogenous prostacyclin seen in patients with PAH
may be administered by intravenous infusion,2 by subcutaneous infusion,3,4 or by inhalation5
Phosphodiesterase-5 (PDE-5) inhibitors
oral agents which act on NO pathway
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 PAH 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. 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 PAH.1-6
Synthetic prostacyclins and 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,7 as well as those that can be given by subcutaneous infusion,8,9 or by inhalation.10
Phosphodiesterase-5 (PDE-5) inhibitors are oral agents which 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.11,12
Humbert M, et al. N Engl J Med 2004;351:1425–36;
Channick RN, et al. Lancet 2001;358:119–23;
Rubin LJ, et al. N Engl J Med 2002;346:896–903;
Galiè N, et al. Lancet 2008;371:2093–100;
Galiè N, et al. Circulation 2006;114:48–54;
Galiè N, et al. Circulation 2008;117:3010–9;
Nicolas LB, et al. Am J Respir Crit Care Med 2011;183:A5902;
Simonneau G, et al. Am J Respir Crit Care Med 2002;165:800–4;
Barst RJ, et al. Eur Respir J 2006;28:1195–203;
Olschewski H, et al. N Eng J Med 2002;347:322-9;
Galiè N, et al. N Engl J Med 2005;353:2148–57;
Galiè N, et al. Circulation 2009;119:2894–903.
1. Humbert M et al. N Engl J Med 2004; 2. Nicolas LB et al. Am J Respir Crit Care Med 2011; 3. Simonneau G et al. Am J Respir Crit Care Med 2002; 4. Barst RJ et al. Eur Respir J 2006; 5. Olschewski H et al. N Eng J Med 2002 40

41. Surgical intervention
balloon atrial septostomy
lung or heart and lung transplantation
Surgical intervention
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.
Galiè N, et al. Eur Heart J 2009;30:2493–537.
1. Galiè N et al. Eur Heart J 2009 41

42. Treatment guidelines: Goal-oriented therapy
Patients should be monitored regularly and response to therapy assessed using a range of parameters
Based on set goals, a patient’s condition at follow-up may be1:
stable and satisfactory
stable but not satisfactory
unstable and deteriorating
‘Stable but not satisfactory’ or ‘unstable and deteriorating’ → re-evaluation and consideration for escalation of treatment
Treatment guidelines recommend that patients with PAH receive initial monotherapy.1–3
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. 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. prostanoids, endothelial receptor antagonists, phosphodiesterase-5 inhibitors) should be considered.2–4
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:3
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.
Barst RJ, et al. J Am Coll Cardiol 2009;54:578–84;
Badesch DB, et al. Chest 2004;126(1 Suppl):35S–62S;
Galiè N, et al. Eur Heart J 2009;30:2493–537;
McLaughlin VV, et al. Circulation 2009;119:2250–94.
1. Galiè N et al. Eur Heart J 2009 42

43. The importance of early identification and intervention in PAH
Early diagnosis and therapeutic intervention may offer an improved outlook for patients
Prognosis and response to treatment both shown to be better for patients with less severe disease (i.e. WHO Functional Class I/II)1
Early diagnosis challenging: initial symptoms mild and non-specific
Many patients are not diagnosed until their disease is already quite severe2
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 Functional Class 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).1
Early diagnosis poses a challenge to healthcare professionals because many of the initial symptoms of PAH are mild and non-specific and so many patients are not diagnosed until their disease is already quite severe.2
Sitbon O, et al. J Am Coll Cardiol 2002;40:780–8;
Humbert M, et al. Am J Respir Crit Care Med 2006;173:1023–30.
1. Sitbon O et al. J Am Coll Cardiol 2002; 2. Humbert M et al. Am J Respir Crit Care Med 2006 43

44. Assessing the patient 44

45. Assessing the severity of PAH
Assessment involves:
clinical assessment
exercise tests
biochemical markers
echocardiographic assessment
haemodynamic assessments
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. 45

46. Functional class Functional Class 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
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 Organisation (WHO) for patients with PAH. 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 .
Galiè N, et al. Eur Heart J 2009;30:2493–537.
Adapted from guidelines for the diagnosis and treatment of pulmonary hypertension1
1. Galiè N et al. Eur Heart J 2009 46

47. Functional class and survival
Even with advanced medical therapy, patients in WHO FC IV continue to have extremely poor survival rates 1
WHO FC is a powerful predictor of survival in patients with PAH. In a recent French study, lower functional class (I/II) was found to be positively and significantly associated with survival (Figure);1 while data from the US REVEAL registry showed that functional class IV was independently associated with increased mortality.2
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.3
Humbert M, et al. Circulation 2010;122:156–63;
Benza RL, et al. Circulation 2010;122:164–72;
Barst RJ, et al. J Am Coll Cardiol 2009;54:S78–84.
1. Humbert M et al. Circulation 2010 47

48. Measure of patients’ functional limitations
6 minute walk test (6MWT)
Measure of patients’ functional limitations
Simple, inexpensive, convenient
Correlate with WHO FC 1
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.1 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.
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.2
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.3
Ross RM, et al. BMC Pulm Med 2010;10:31;
Miyamoto S, et al. Am J Respir Crit Care Med 2000;161(2 Pt 1):487–92;
ATS statement: guidelines for the 6-minute walk test. Am J Crit Care Med 2002;166:111–7.
1. Miyamoto S et al. Am J Respir Crit Care Med 2000 48

49. Cardiopulmonary exercise testing
More sensitive and comprehensive measure of exercise capacity than the 6MWT1
Maximal stress test
Peak O2 consumption (VO2 max)1:
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
More difficult to perform and require specialist equipment
Not suitable for more severely affected patients
Cardiopulmonary exercise testing (CPET) assesses lung gas exchange and gives a more sensitive and comprehensive measure of exercise capacity than the 6MWT. 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.
Despite offering some advantages over the 6MWT in terms of sensitivity, these tests are more difficult to perform and require specialist equipment. As they are a maximal stress test, they are not suitable for more severely affected patients who may not be able to tolerate the exercise and may be exposed to risk of syncope and discomfort.
Wensel R, et al. Circulation 2002;106:319–24.
1. Wensel R, et al. Circulation 2002 49

50. Haemodynamic parameters
Measured by RHC
Correlate with clinical status, WHO FC, exercise capacity, and prognosis
Prognosis is significantly correlated with markers of right ventricular function1,2,3
Normalisation of haemodynamics may therefore be considered a suitable goal or treatment measure
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)1,2 and mean cardiac index (CI).3 Normalisation of haemodynamics may therefore be considered a suitable goal or treatment measure.
Humbert M, et al. Circulation 2010; 122:156–63;
Benza RL, et al. Circulation 2010;122:164–72;
McLaughlin VV, et al. Circulation 2002;106:1477–82.
1. Humbert M et al. Circulation 2010; 2. McLaughlin VV et al. Circulation 2002; 3. Benza RL et al. Circulation 2010 50

51. Cut-off levels still need to be verified in controlled trials
Biochemical markers
Increases in serum NT-proBNP shown to be associated with prognosis in PAH1
Serum NT-proBNP < 1400 pg/mL seems to identify patients with good prognosis1,2
Cut-off levels still need to be verified in controlled trials
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.1 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.2 However, cut-off levels still need to be verified in controlled trials, and our understanding of the role of this marker is still emerging.
Galiè N, et al. Eur Heart J 2009;30:2493–537;
2. Fijalkowska A, et al. Chest 2006;129:1313–21.
1. Galiè N et al. Eur Heart J 2009; 2. Fijalkowska A et al. Chest 2006 51

52. PAH-SSc explained 52

53. PAH in patients with SSc (PAH-SSc)
~15-25% of all cases of PAH are associated with connective tissue disease, particularly with SSc1,2
Patients with SSc who develop PAH have poorer prognosis than those who do not3,4
PAH accounts for more than 25% of all SSc-related deaths5
Need for early detection and timely treatment before patients show marked clinical and haemodynamic deterioration6
Around 15% of all cases of pulmonary arterial hypertension (PAH) in a recent French PAH registry1 and 25% in a US PAH registry2 were associated with connective tissue disease, and particularly with SSc (also known as scleroderma).
Patients with SSc who develop PAH have poorer prognosis than those who do not;3,4 and PAH has become one of the leading causes of mortality in SSc patients, accounting for more than 25% of all SSc-related deaths.5
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
Humbert M, et al. Am J Respir Crit Care Med 2006;173:1023–30;
Badesch DB, et al. Chest 2010;137:376–87;
Hachulla E, et al. Rheumatology (Oxford) 2009;48:304–8;
Steen VD, Medsger TA. Arthritis Rheum 2003;48:516–22;
Steen VD, Medsger TA. Ann Rheum Dis 2007;66:940–4;
Hachulla E, et al. Arthritis Rheum 2005;52:3792–800.
Humbert M et al. Am J Respir Crit Care Med 2006; 2.Badesch DB et al. Chest 2010; 3.Hachulla E et al. Rheumatology (Oxford) 2009; 4.Steen VD, Medsger TA. Arthritis Rheum 2003; 5.Steen VD, Medsger TA. Ann Rheum Dis 2007.; 6. Hachulla E et al. Arthritis Rheum 2005 53

54. How is PAH-SSc detected?
Diagnosis particularly challenging, especially in early stages
Symptoms of SSc such as fatigue and dyspnoea are also symptoms of PAH
Patients are often diagnosed late when they have advanced disease with severe clinical and haemodynamic impairment1
Screening for PAH in SSc is associated with improved outcomes1
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.1
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.2,3 Recent studies have also shown that screening for PAH in asymptomatic SSc patients is associated with improved outcomes.1
1. Humbert M, et al. Arthritis Rheum 2011;63:3522–30;
2. Galiè N, et al. Eur Heart J 2009;30:2493–537;
3. McLaughlin VV, et al. Circulation 2009;119:2250–94.
1. Humbert M et al. Arthritis Rheum 2011 54

55. Screening for PAH in SSc: suggested screening protocol for the detection of PAH in SSc patients
In this example of a screening algorithm, it is recommended that patients with SSc are regularly assessed using Doppler echocardiography.
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 (>3.0 m/s) VTR, 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)
Hachulla E, et al. Arthritis Rheum 2009;60:1831–9.
Figure adapted from: The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicentre nationwide longitudinal study in France1. 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.
1. Hachulla E et al. Arthritis Rheum 2009 55

56. Treatment and reassessment of PAH-SSc largely the same as for IPAH6
How is PAH-SSc treated?
Available therapies may improve quality of life and exercise capacity, and slow disease progression1–5
Treatment and reassessment of PAH-SSc largely the same as for IPAH6
Some special consideration required:
complications of SSc may affect ability to perform exercise tests (e.g. 6MWT)7
potential need to manage multiple complications (e.g. renal, skin, gastrointestinal)8
Referral to expert centres recommended
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.1–5
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.6 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.7
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.8 As with other forms of PAH, patients should therefore be referred to an expert centre for PAH diagnosis and management.
Denton CP, et al. Ann Rheum Dis 2006;65:1336–40;
Launay D, et al. Rheumatology (Oxford) 2010;49:490–500;
Badesch DB, et al. J Rheumatol 2007;34:2417–22;
Badesch DB, et al. J Rheumatol 2009;36:2244–9;
Oudiz RJ, et al. Chest 2004;126:420–7;
Galiè N, et al. Eur Heart J 2009;30:2493–537;
Garin MC, et al. J Rheumatol 2009;36:330–6;
Kowal-Bielecka O et al. Ann Rheum Dis 2009;68:620–628.
Denton CP et al. Ann Rheum Dis 2006; 2. Launay D et al. Rheumatology (Oxford) 2010; 3. Badesch DB et al. J Rheumatol 2007; 4. Badesch DB et al. J Rheumatol 2009; 5. Oudiz RJ et al. Chest 2004; 6. Galiè N et al. Eur Heart J 2009; 7.Garin MC et al. J Rheumatol  2009; 8. Kowal-Bielecka O et al. Ann Rheum Dis 2009 56