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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.22

perhaps the most prevalent.

Long after the recognition that right heart failure is the most important determinant of patient survival,28 awareness has recently grown that it is important to understand and improve right heart adaptation to the increased afterload in PH.29

Thus, a diagnosis of PAH is made when chronic heart and lung diseases and CTEPH are excluded and when the following hemodynamic criteria are met: mPAP ≥25mmHg, PAWP <15mmHg, PVR >3WU. At this point, 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) (20 ppm 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. While these drugs have doubled the transplantation-free survival of PAH patients,2

patients after acute pulmonary embolism. Haematologica 2010;95:970–5.

16. Guerin L et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost 2014;112:598–605.

Some of the strategies

with proven efficacy in left heart failure, may also prove to be of value in PH- associated right heart failure.30 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, Simonneau G. The Fifth World Symposium on Pulmonary Hypertension. J Am Coll Cardiol 2013;62:D1–D3.

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.

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.27

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

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: a definitive NO in COPD. Eur Respir J 2013;42:893–4.

14. Pengo V et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–64.

15. Klok FA et al. Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in

17. Lang I et al. Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study. Thromb Haemost 2013;110:83–91.

18. Pepke-Zaba J et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011;124:1973–81.

19. Montani D et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:2128–37.

20. Humbert M et al. Pulmonary arterial hypertension in france: results from a national registry. Am J Respir Crit Care Med. 2006;173:1023–30.

21. The 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 the International Society of Heart and Lung Transplantation (ISHLT), Galie N, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009;34:1219–63.

22. Hoeper MM et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013;62:D42–D50.

23. Vonk MC et al. Systemic sclerosis and its pulmonary complications in The Netherlands: an epidemiological study. Ann Rheum Dis 2009;68:961–5.

24. Hachulla E et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52:3792–800.

25. Hofstee H et al. Nailfold capillary density is associated with the presence and severity of pulmonary arterial hypertension in systemic sclerosis. Ann Rheum Dis 2009;68:191–5.

26. Pepke-Zaba J. Diagnostic testing to guide the management of chronic thromboembolic pulmonary hypertension: state of the art. Eur Respir Rev 2010;19:55–8.

27. Hoeper MM et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013;127:1128–38.

28. Sandoval J et al. Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation 1994;89:1733–44.

29. Vonk-Noordegraaf A et al. Right heart adaptation to pulmonary arterial-hypertension: Physiology and Pathobiology. J Am Coll Cardiol 2013;62:D22–D33.

30. Bogaard HJ et al. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med 2010;182:652–60.


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