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What is PAH?

Assessing the severity of PAH

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 (see section: How is PAH treated?).

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.

Functional classification of pulmonary hypertension

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.1

This system grades PAH severity according to the functional status of the patient. The grades range from Functional Class (FC) I, where the patient's disease does not affect their day-to-day activities, to FC IV, where patients are severely functionally impaired, even at rest. This functional classification system links symptoms with activity limitations, and allows clinicians to quickly predict disease progression and prognosis, as well as the need for specific treatment regimens, irrespective of the underlying aetiology of PAH.

Functional Class

Symptomatic profile

I

Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause dyspnoea or fatigue, chest pain, or near syncope

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.1

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. A prospective study, which aimed to evaluate survival in patients with PAH managed in the modern treatment era, followed 354 consecutive patients with PAH for up to 3 years.2 In this study, lower functional class (I/II) was found to be positively and significantly associated with survival (Figure 1).2 Data from the US REVEAL registry which includes 2716 patients with PAH showed that functional class IV was independently associated with increased mortality (HR, 3.1; 95% CI, 2.2 to 4.4).3

  

Figure 1. Survival according to functional class2 - click to enlarge

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.

 

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 (see section: How is PAH treated?).4

Exercise capacity: Six-minute walk test (6MWT)

The 6-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.5 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 survival. In a prospective study including 43 patients with idiopathic PAH (IPAH) which aimed to compare clinical correlates and prognostic significance of the 6MWT, the distance walked was found to significantly decrease in proportion to the severity of NYHA functional class (Figure 2).6 The patients were followed up for a mean of 21±16 months and it was found that the distance walked in 6 minutes was independently related to mortality by multivariate Cox proportional hazards analysis (risk ratio estimate 0.986, 95% confidence intervals 0.973–0.999; p=0.038).

  

Figure 2. 6MWD compared with functional class 6 - click to enlarge

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 associated with systemic sclerosis (PAH-SSc) (see section: PAH in patients with systemic sclerosis?) who often have accompanying conditions that 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.7

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.8 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 (VO2max), 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.8 CPET with measuring of the VO2max 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.

Haemodynamic parameters

Haemodynamic parameters are measured by right heart catheterisation (RHC) (see section: How is PAH diagnosed?) 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)2,3 and cardiac index (CI).9 Normalisation of haemodynamics may therefore be considered a suitable goal or treatment measure.

Biochemical markers

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.10 However, cut-off levels still need to be verified in controlled trials, and our understanding of the role of this marker is still emerging.

References

  1. Galiè N, Hoeper MM, Humbert M et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493-537.
  2. 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.
  3. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122:164–72.
  4. Barst RJ, Gibbs JS, Ghofrani HA, Hoeper MM, McLaughlin VV, Rubin LJ, Sitbon O, Tapson VF, Galiè N. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S78–84.
  5. Ross RM, Murthy JN, Wollak ID, Jackson AS. The six minute walk test accurately estimates mean peak oxygen uptake. BMC Pulm Med 2010;10:31.
  6. 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. Am J Respir Crit Care Med 2000;161(2 Pt 1):487-92.
  7. ATS statement: guidelines for the 6-minute walk test. Am J Crit Care Med 2002;166:111-7.
  8. Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing. Circulation 2002;106:319-24.
  9. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477-82.
  10. Fijalkowska A, Kurzyna M, Torbicki A, et al. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006;129:1313-21.