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Differentiation


electrocardiographic signs of left atrial dilatation and left ventricular hypertrophy. When pulmonary function testing and the echocardiogram provide insufficient explanation for the presence of PH, further diagnostic testing is warranted and it is advised that it is carried out at a PH expert centre. When pulmonary or cardiac causes of PH are excluded, the next step in the diagnostic algorithm is ventilation/ perfusion scintigraphy. This test still has a higher sensitivity to detect CTEPH than CT angiography.26


An abnormal


perfusion scintigraphy warrants referral to an expert centre for (non-) surgical treatment of CTEPH, where usually a pulmonary angiography will be performed (see Figure 3). This procedure can be combined with a right heart catheterisation. When the ventilation/perfusion scintigram is normal, referral to a PH expert centre is still advised, but in this instance it can be to a centre without facilities to treat CTEPH. In case of a normal ventilation perfusion scan, the expert centre will usually perform a a right heart catheterisation without angiography. During the right heart catheterisation, the pulmonary artery wedge pressure is determined by occluding a small pulmonary artery via inflation of the balloon at the tip of the Swan-Ganz catheter. Through the interruption of bloodflow, it is possible to estimate the left ventricular end- diastolic pressure. A pulmonary artery wedge pressure (PAWP) higher than 15mmHg indicates that left heart failure is the cause of the elevated pressure in the pulmonary artery, no matter the magnitude of the increase. A right heart catheterisation should include measurement of the cardiac output (CO), allowing the calculation of pulmonary vascular resistance (PVR = (mPAP - PAWP)/CO). Because a high CO (for example, in hyperthyroidism or sickle cell disease) can underlie an elevation in pulmonary artery pressure, it was proposed in Nice to add a requirement of a PVR >3 Woods Units (WU) to the definition of PAH.27


This


recommendation was adopted in the 2015 Guidelines. After identification of pre-capillary PH and exclusion of chronic lung disease or CTEPH, a number of additional investigations are required to determine a possible underlying cause to explain the presence of PAH. When a diagnosis of idiopathic


or hereditary PAH is considered, vasoreactivity testing becomes an obligatory part of the right heart catheterisation. This test is preferably performed using inhaled nitric oxide (NO) (20ppm NO in oxygen), by which means a selective dilatation of the pulmonary vascular bed is induced. The outcome of this test determines the subsequent choice of medication. Genetic counselling can be offered to patients with no underlying cause of PAH in order to separate between idiopathic and heritable cases of PAH.


New developments In the last two decades, considerable progress has been made in understanding and treating PAH and CTEPH. Pulmonary vasodilators, including prostacyclins, endothelin receptor antagonists, and type 5 phosphodiesterase 5 inhibitors have activity in PAH whereas soluble guanylyl cyclase stimulators have activity in PAH and CTEPH. Recently, even before publication of the randomised clinical trial in a peer-reviewed journal, the oral prostacyclin IP receptor agonist, selexipag, was also approved for the treatment of PAH. An important recent study showed the superiority of combination treatment over monotherapy, even in patients still in NYHA functional class II.28 While these different therapeutic regimens have doubled the transplantation-free survival of PAH patients,2


PAH is still a deadly disease. A real breakthrough in the treatment of PAH can only come from a therapy that reverses obstructive lung vascular remodelling and/or restores the availability of patent resistance vessels. One of the first studies with a drug to inhibit abnormal cell proliferation in the pulmonary vascular wall (imatinib) showed that such a treatment can reduce pulmonary vascular resistance, but was not associated with clinical improvement.29


Much less improvement has been made when it comes to the treatment of forms of PH other than PAH or CTEPH. No specific treatments are currently available for PH associated with commonly occurring diseases, such as left heart disease, COPD and schistosomiasis. On a global scale, the latter form of PH is perhaps the most prevalent. Long after the recognition that right


heart failure is the most important determinant of patient survival,30 awareness has recently grown that it is important to understand and improve right heart adaptation to the increased afterload in PH.31


Some of the strategies


with proven efficacy in left heart failure, may also prove to be of value in PH- associated right heart failure.32 l


References 1. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998;352:719–25.


2. Humbert M et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 1998;122:156–63.


3. Benza RL et al. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 2012;142:448–56.


4. Galie N et al. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur.Heart J 2009;30:394–403.


5. Savarese G et al. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A meta- analysis of 22 randomized trials. J Am Coll Cardiol 2012;60:1192–201.


6. Galie N et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015;46(4):903–75.


7. Strange G et al. Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The delay study. Pulm Circ 2013;3:89–94.


8. Simonneau G et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34–D41.


9. Handoko ML et al. The rise and fall of endothelin receptor antagonists in congestive heart failure. Eur Respir J 2011;37:484–5.


10. Kessler R et al.”Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med 2001;164:219–24.


11. West JB. High-altitude medicine. Am J Respir Crit Care Med 2012;186:1229–37.


12. Weitzenblum E. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;131:493–8.


13. Vonk-Noordegraaf A, Boerrigter BG. Sildenafil: www.hospitalpharmacyeurope.com 11


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