The Unencouraged 6-minute Walk Test
The unencouraged 6-minute walk test is a reproducible measure of peak oxygen consumption, is easily performed, is inexpensive and results correlate well with functional status and are an independent prognostic marker.16,17 A value below 300 metres may suggest a worse prognosis and mandate a review to change or initiate treatment,13 although it is not a reliable marker of pulmonary vascular disease progression.18 Cardiopulmonary exercise testing may also be used to functionally evaluate patients with PH and may also assist with prognosis and response to treatment.19,20
Other Radiological Imaging
Other radiological imaging includes ventilation perfusion (VQ) scanning, which is usually applied to investigate patients with PH potentially associated with pulmonary thromboembolism,21,22 but abnormalities are not usually helpful in confirming the diagnosis of PAH.21 However, the historical importance of VQ studies in distinguishing CTEPH from non-CTEPH causes of PH is diminishing with the use of multi-detector computed tomography (CT) (MDCT) scanning1,23 and in its greater resolution and disease-discriminating capacity. In terms of CT scanning, VQ imaging retains a radiation dose advantage and is a pure functional technique. Catheter pulmonary angiography was once considered the gold standard for the determination or exclusion of CTEPH in PH,24 but this is rarely performed now. It is usually limited to occasional cases where further delineation of complex congenital anatomy is required or where there is a concomitant need to perform an image-guided interventional procedure, such as mechanical clot disruption or biopsy of an indeterminate and potentially neoplastic intravascular lesion.1
Computed tomographic pulmonary angiography (CTPA) is the predominant current radiological imaging strategy for the evaluation of patients with suspected PH.25,26 MDCTPA provides the best temporal and spatial resolution providing a high-resolution comprehensive vascular and pulmonary evaluation in less than 5 seconds. Magnetic resonance imaging (MRI) imaging is complex, has limited availability and is associated with poor pulmonary parenchymal evaluation. Therefore, in the near future, this is not likely to replace CT evaluation.1
Right Heart Catheterisation
The gold standard investigation for diagnosing PH is right heart catheterisation.27–29 The procedure is usually performed via the right internal jugular vein although the femoral or subclavian veins are suitable alternatives. A balloon-tipped, triple-lumen Swan-Ganz catheter is connected to a pressure transducer and inserted through the venous sheath. Pressure measurements are then taken in the right atrium, right ventricle and pulmonary artery and the catheter is then advanced carefully with the balloon inflated and wedged in a more distal aspect of the pulmonary artery and the pulmonary capillary wedge pressure is measured. The balloon is then deflated and cardiac output measurements are made using the Fick method or more commonly an indicator dilution method.1 At least three readings of cardiac output should be obtained and the mean value is used to ensure accuracy. It is also routine to measure pulmonary artery oxygen saturation (Sv02) and when intracardiac shunting is suspected oxygen saturations are also measured in the right ventricle, at different points in the right atrium and in the vena cavae. The PVR is calculated as described above and the normal value is less than 2 Wood units (1 Wood unit is 1 mmHg per litre per minute and equates to 80 dynes. second.CM−5). Assessment of PVR is more helpful than mPAP alone when documenting the severity and pathophysiology of PH. As the disease progresses the cardiac output through the lungs falls and this is reflected in a lower pulmonary artery pressure value than is predicted by the patient’s clinical presentation. However when the PVR is calculated it may be demonstrated that the unexpectedly low pulmonary artery pressure is falsely misleading. This has important implications if surgical intervention is being considered for other co-morbidities in these patients.4
Cardiac index (litres per minute per body surface area squared) or PVR index can be calculated by adjusting for body surface. The body surface area is approximated from formulae, such as the Dubois formula, which incorporates height and weight.30 Vaso reactivity testing can be performed during right heart catheter to demonstrate a reduction in mPAP or PVR with an improvement in cardiac output. For some patients with PAH (usually less than 10 %) vaso reactivity testing may indicate a likelihood to respond to long-term calcium channel blockers and these patients may have a better prognosis.31 Those who have a positive response will demonstrate reversibility in mPAP by greater than 10 mmHg to achieve an absolute value of less than 40 mmHg with an unchanged or increased cardiac output during right heart catheterisation when they are given nitric oxide, prostacyclin or adenosine.1 Vaso reactivity testing is not reliable to predict response to treatment for patients who are classified in the other PH groups. It should only be performed by experienced operators cautiously with graded dosing in medically stabilised patients. It should not be performed in patients suspected of having pulmonary veno-occlusive disease as life-threatening pulmonary oedema may be precipitated.13
Most right heart catheter procedures are performed quickly (less than 30 minutes), are well tolerated and have a low complication rate.27 In our unit we also have a special protocol adopted to perform right heart catheter in patients with sickle cell disease.1
Pathophysiology
Our understanding of the molecular biology of the pathobiology of PAH has improved in recent years and this in turn has helped to develop new therapeutic agents against a variety of potential molecular targets. It is possible that vascular injury can occur in patients with PAH who have a genetic pre-disposition e.g. those with bone morphogenetic protein receptor 2 (BMPR2) mutations. Should these mutations occur there may be a loss of the inhibitory (regulatory) action of BMP on vascular smooth muscle growth. Should a subsequent insult occur e.g. as a consequence of autoimmune disease, drugs, HIV infection or toxins (which are not metabolised in patients with liver disease) vascular injury can occur. This may lead to endothelial cell dysfunction with, for example, abnormal production of nitric oxide, prostaglandins, endothelin 1, etc. Smooth muscle cell dysfunction and migration and proliferation due to abnormalities in the production of calcitonin and gastrin-releasing peptide or 5 hydroxytryptamine can follow,5 and lead to inflammation facilitated by a variety of interleukin, chemokines, fract alkaline and many others, which ultimately give rise to vascular remodelling and PPA.4