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What is PAH?

How is PAH diagnosed?

The early symptoms of pulmonary arterial hypertension (PAH), such as dyspnoea, dizziness, and fatigue, are often mild and are common to many other conditions. At rest there are often no symptoms and no apparent signs of illness. As a result, 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 In addition, 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 patients should be referred to expert centres experienced in the management of pulmonary vascular diseases.4,5 The organisation of delivery of healthcare services for PAH varies across countries, therefore it is recommended that you contact your national healthcare service or PAH patient organisation to understand how recommendations from the guidelines are being implemented in your region.

Once a suspicion of PAH has been raised, the aim is to confirm or exclude a 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. Diagnosis involves a logical sequence of steps. These diagnostic steps have been formalised into clinical practice guidelines for the diagnosis of PAH, both in the US (Figure 1)6 and Europe (Figure 2).5 The evaluation process of a patient with suspected 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.5,6 Although there are slight differences in the sequence of tests performed, the nature and overall flow is similar in both sets of guidelines. Interpretation of the results of tests described below is complex and requires substantial experience in the management and follow-up of PAH patients.

Screening and diagnosis in PAH - Click this image to enlarge.  

Figure 1. ACCF/AHA Diagnostic Approach to PAH6 - click to enlarge

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.

Click this image to enlarge.  

Figure 2. ESC/ERS clinical guidlines for the diagnosis of PAH5 - click to enlarge

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.

Chest radiograph in PAH - Click this image to enlarge.  

Figure 3. Radiography in PAH - click to enlarge

 

Diagnosis of PAH

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.

1.

Clinical suspicion of PAH

 
  • PAH should be considered in the differential diagnosis of exertional dyspnoea, syncope, angina, and/or progressive limitation of exercise capacity, particularly in patients without apparent risk factors, symptoms, or signs of common cardiovascular and respiratory disorders
  • Special awareness should be directed towards patients with associated conditions and/or risk factors, such as family history, connective tissue diseases, congenital heart disease, or a history of intake of drugs or toxins known to induce PAH

2.

Exclusion of Group 2 (left heart disease) and Group 3 (lung diseases)

 
  • Clinical history, symptoms, signs, electrocardiogram (ECG), chest radiograph, echocardiogram, pulmonary function tests, and high-resolution computed tomography (HRCT) of the chest are requested in order to exclude the presence of Group 2 (left heart disease) or Group 3 (lung diseases):
    • ECG may provide suggestive or supportive evidence of PH by demonstrating right ventricular (RV) hypertrophy and strain, and right atrial dilatation
    • Doppler echocardiography provides several variables that correlate with right heart haemodynamics — Doppler echocardiography should always be performed in the case of suspected PH
    • Chest radiography may show evidence of cardiomegaly and enlarged pulmonary arteries (Figure 3) and allows the reasonable exclusion of associated moderate to severe lung diseases (Group 3) or pulmonary venous hypertension due to left heart disease (Group 2)
    • Pulmonary function tests and arterial blood gas samples will identify the contribution of underlying airway or parenchymal lung disease
    • HRCT provides detailed views of the lung parenchyma and facilitates the diagnosis of interstitial lung disease and emphysema

3.

Exclusion of Group 4

 
  • If PH Groups 2 or 3 are not found less common causes of PH should be looked for:
    • A ventilation/perfusion lung scan is used to exclude Group 4 chronic thromboembolic pulmonary hypertension (CTEPH); where there is evidence of multiple segmental perfusion defects, a diagnosis of CTEPH should be suspected
    • The final diagnosis of CTEPH requires CT pulmonary angiography, right heart catheterisation, and selective pulmonary angiography

4.

PAH evaluation and classification (type, functional capacity, haemodynamics)

 
  • If a ventilation/perfusion scan is normal, or shows only subsegmental patchy perfusion defects, a tentative diagnosis of Group 1 (PAH) or the rarer condition of Group 5 PH is made
  • A CT pulmonary angiography may also show signs suggestive of Group 1' pulmonary veno-occlusive disease (PVOD)
  • Additional specific diagnostic tests including haematology, biochemistry, immunology, serology, and ultrasonography will allow the final diagnosis to be refined:
    • Cardiac magnetic resonance (CMR) imaging provides a direct evaluation of RV size, morphology, and function, and allows non-invasive assessment of blood flow including stroke volume, cardiac output (CO), distensibility of pulmonary artery, and RV mass; CMR is also used to distinguish PAH associated with congenital heart disease
    • Blood, immunology, and serological tests are important to detect underlying connective tissue disease, human immunodeficiency virus (HIV) infection, and hepatitis; liver function tests and hepatitis serology should be examined if clinical abnormalities are noted
    • An abdominal ultrasound scan can reliably exclude liver cirrhosis and/or portal hypertension
    • Right heart catheterisation (RHC) represents the diagnostic gold standard for the confirmation of a diagnosis of PAH, and usually includes vasoreactivity testing
    • 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.

Echocardiography — value as a screening tool

Click this image to enlarge.  

Figure 4. Echocardiography in PAH - click to enlarge

Transthoracic Doppler echocardiography (TTE) is a non-invasive screening test for pulmonary hypertension.7 In the absence of pulmonary outflow obstruction, TTE provides an estimate of the right ventricular systolic pressure, which is equivalent to the systolic pulmonary arterial pressure. The systolic right ventricular pressure, and thus the pulmonary arterial pressure, can be estimated from the tricuspid regurgitant (TR) jet velocity (Figure 4).

TTE can also provide information about the cause and consequences of PH, including right and left ventricular dimensions and function, heart valve abnormalities, right ventricular ejection and left ventricular filling characteristics, and presence of a pericardial effusion.7 In the initial investigation of patients with PAH it is important to obtain adequate images of the right heart.

Right heart catheterisation — the diagnostic gold standard for PAH

Right heart catheterisation (RHC) is required for a definitive diagnosis of PAH (Figure 5 and 6)5,7 to assess the severity of haemodynamic impairment, and to test the vasoreactivity of the pulmonary circulation. The following parameters should always be assessed: right atrial pressure (RAP), pulmonary arterial pressure (PAP [systolic, diastolic and mean]), pulmonary capillary wedge pressure (PCWP), cardiac output/index, pulmonary (PVR) and systemic vascular resistance (SVR), systemic blood pressure, and arterial and mixed venous oxygen saturation.

PAH is defined as a sustained elevation of mean PAP (mPAP) to ≥25 mmHg at rest, and a mean PCWP of ≤15 mmHg.5,8 Vasoreactivity testing is performed during RHC to help delineate the specific haemodynamic profile of the patient and to identify those patients who might respond to treatment with calcium channel blockers (CCBs).5,6 A positive vasoreactive response is defined as a reduction in mPAP ≥10 mmHg to reach an absolute value of mPAP ≤40 mmHg, with an increased or unchanged cardiac output.6,9 A positive response is shown in only 10% of patients.5

Figure 5. Right Heart Catheterisation5 - click to enlarge

Right heart catheterisation - Click this image to enlarge.  

Figure 6. Right Heart Catheterisation - click to enlarge

 

References

  1. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023–30.
  2. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry. Chest 2011;137:376–87.
  3. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998;352:719–25.
  4. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S78–84.
  5. Galiè N, Hoeper MM, Humbert H, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493–537.
  6. McLaughlin VV, Archer SL, Badesch DB, et al. ; 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. Circulation 2009;119:2250–94.
  7. Habib G, Torbicki A. The role of echocardiography in the diagnosis and management of patients with pulmonary hypertension. Eur Respir Rev 2010;19(118):1–12.
  8. Badesch DB, Champion HC, Sanchez MAG et al. Diagnosis and assessment of pulmonary arterial hypertension. JACC 2009;54:S55–66.
  9. Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;11:3105–11.