PRINTER-FRIENDLY VERSION AVAILABLE AT ANESTHESIOLOGYNEWS.COM Pulmonary Arterial Hypertension And Pregnancy: An Update ELIZABETH A. M. FROST, MD A ll Department of Anesthesia Mount Sinai Medical Center New York, New York s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 13 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig Dr. Frost reports no relevant financial conflicts of interest. A ny cardiac disease occurring during pregnancy is challenging. As the number and the complexity of cardiac cases increase and maternal age advances, heart disease has become the leading cause of maternal morbidity and mortality in developing countries. Women with s, congenital heart disease comprise most of the cases, owever, although within this group mortality is infrequent. However, ortic pulmonary arterial hypertension (PAH) and severe aortic dilatation remain high-risk conditions.1 Classification of Pulmonary Hypertension Pulmonary hypertension is defined as an increase in pressure in the pulmonary artery, veins, or capillaries in the lungs, leading to dyspnea, dizziness, fainting, and other symptoms, all of which are exacerbated I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G tion. Pulmoby exertion. rtension can be nary hypertension severe, with markedly decreased exercise tolerance and heart failure. First identified by Dr. Ernst von Romberg, a German physician, in 1891,5 PH previously was divided into 2 categories, primary and secondary, based on identifiable etiology. In 1998, the WHO proposed a clinical classification of PH based on similarities in pathophysiology, clinical presentation, and therapeutic options, breaking PH into 5 distinct types: arterial, venous, hypoxic, thromboembolic, and miscellaneous.6 In its 1973 meeting, the WHO divided primary PH into arterial plexiform, veno-occlusive, and thromboembolic forms. At the 1998 meeting, the organization also addressed the causes of secondary PH—those resulting from other medical conditions—and in 2003, the d. The World Health Organization (WHO) organized the first international conference on pulmonary hypertension (PH) in 1973. At that time, no effective therapies existed for the condition, and patients with primary or idiopathic PH survived a median of less than 3 years after diagnosis. Current treatments have more than doubled the survival time, and more patients present for surgery and anesthesia and survive to become pregnant. Nevertheless, pregnancy complicated by PH poses risks to the mother that can prove fatal. At least 3 recent articles have outlined the current treatment modalities and the management of PH during pregnancy.2-4 A N E ST H E S I O LO GY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 0 1 3 77 Pathophysiology Table 1. The Venice 2003 Revised Classification System for PAH Group I. Pulmonary arterial hypertension Idiopathic Familial ll A Associated with other diseases: collagen vascular disease (eg, scleroderma), congenital shunts between the systemic and pulmonary circulation, portal hypertension, HIV infection, drugs, toxins, or other diseases or disorders Co rig Associated with venous or capillary disease ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 13 uc 20 od © pr ht Re rig ed. py rv se re ht Pulmonary arterial hypertension (WHO Group I) is a complex endothelial disorder that causes remodeling of the pulmonary arterial wall with endothelial and smooth muscle proliferation. These changes are consistent with overexpression of the vasoconstrictor endothelin-1 and a reduction in the vasodilators nitric oxide (NO) and prostacyclin.8 Vasoconstriction of blood vessels connected to and within the lungs, and altered vasodilation increase cardiac load. Over time, the affected blood vessels fibrose, further increasing pressure in the lungs and impairing blood flow. The right ventricle hypertrophies (cor pulmonale develops), decreasing the ability of the heart to pump blood through the lungs and ultimately causing right heart failure (Figure). As blood flow through the lungs decreases, the left side of the heart receives not only less blood but blood that is poorly oxygenated, decreasing the ability to supply sufficient oxygen to the rest of the body, especially during physical activity. Normal mean pulmonary pressure is 15 to 20 mm Hg; pulmonary artery wedge pressure is 8 to 12 mm Hg; and pulmonary vascular resistance (PVR) is less than 240 dyn/sec/cm5. Figures greater than these numbers indicate PAH. Pathogenesis of pulmonary venous hypertension (PVH; WHO Group II) differs in that blood flow in the lungs is unobstructed. Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs, followed by pulmonary edema and pleural effusions. In hypoxic pulmonary hypertension (WHO Group III), low levels of oxygen are thought to cause vasoconstriction of pulmonary arteries and a pathophysiology similar to PAH. In chronic thromboembolic pulmonary hypertension (WHO Group IV), vessels are blocked or narrowed by blood clots. Again, the pathology is similar to that seen with PAH. A further classification is made on functional ability, characterized as Class 1 to 4 based on increasing physical limitations. s Group II. Pulmonary hypertension associated with left heart disease Atrial or ventricular disease Valvular disease (eg, mitral stenosis) Group III. Pulmonary hypertension associated with lung diseases and/or hypoxemia Chronic obstructive pulmonary disease, interstitial lung disease Sleep-disordered breathing, alveolar hypoventilation Chronic exposure to high altitude Developmental lung abnormalities Group IV. Pulmonary hypertension due to chronic thrombotic and/or embolic disease Pulmonary embolism in the proximal or distal pulmonary arteries Embolization of other matter, such as tumor cells or parasites Group V. Miscellaneous. Pulmonary hypertension due to direct effect on the pulmonary vasculature of inflammatory diseases such as schistosomiasis,7 sarcoidosis, histiocytosis X, and fibrosing mediastinitis. Epidemiology 78 I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G The overall prevalence of PH in the general population is unknown because of the heterogeneity of the disease (Table 2). The Centers for Disease Control and Prevention (CDC) Pulmonary Hypertension Surveillance reported changes in death rates from PH from 1980 to 2002 are follows: • The age-standardized death rates for the total US population increased from 5.2 to 5.4 deaths per 100,000 population. • The main increase in death rates was seen among women, with 3.3 to 5.5 deaths per 100,000 population, and blacks, with 4.6 to 7.3 deaths per 100,000 population. • The death rate in men decreased during this period, from 8.2 to 5.4 deaths per 100,000 population. d. 3rd World Symposium on Pulmonary Arterial Hypertension convened in Venice to modify the classification based on new understanding of disease mechanisms. The revised system developed by this group provides the current framework for understanding PH. This system includes several improvements over the 1998 classification. Risk factor descriptions were updated, and the classification of congenital systemic-to-pulmonary shunts was revised (Table 1). A new classification of genetic factors in PH was recommended but not implemented because available data were deemed inadequate.6 The classification does not include sickle cell disease, another cause of PH. Infection with human herpesvirus 8, also associated with Kaposi’s sarcoma, has been associated with PAH, suggesting that this virus may play a role in its development. Diagnosis ll A Clinical signs in the early stages of PAH may be few. A physical examination looks for typical signs of PH, including altered heart sounds, such as a widely split S2 or second heart sound, a loud P2 or pulmonic valve closure sound (part of the second heart sound), (para) sternal heave, possible S3 or third heart sound, and pulmonary regurgitation. Other signs include an elevated jugular venous pressure, peripheral edema, ascites, hepatojugular reflux, and clubbing.3,8 Further procedures are required to confirm the presence of PH and exclude other diagnoses. These generally include pulmonary function tests; blood tests to exclude HIV, autoimmune diseases, and liver disease; electrocardiography; measurements of arterial blood gas; chest x-rays followed by high-resolution computed tomography scanning if interstitial lung disease is suspected; and ventilation-perfusion or V/Q scanning to exclude chronic thromboembolic PH. Transthoracic echocardiography (TTE) is used widely as a screening tool for PH. Pulmonary arterial pressures and right ventricular systolic pressure correlate well. However, several factors such as severe lung disease, premature ventricular contractions, and inaccurate estimates of right atrial pressure can lead to misdiagnosis. Studies have found that TTE may overestimate pulmonary artery pressures compared with right heart catheterization (RHC).3 On the other hand, in about one-third of patients, RHC may reveal more severe PH than is estimated from TTE. Thus, both under- and overestimating may occur. However, PH does not mean PAH is present. Therefore, clinicians must assess pulmonary artery occlusion pressures and PVR. Indeed, the diagnosis of PAH must be confirmed with RHC in pregnant patients, given the high morbidity and mortality associated with the combination of the 2 conditions.8 Biopsy of the lung is usually not indicated unless the PH is thought to reflect an underlying interstitial lung disease. Lung biopsies carry risks for bleeding from high intrapulmonary blood pressure. Clinical improvement often is measured by a “6-minute walk test”—the distance that a patient can walk in 6 minutes. Stability and improvement in this measurement correlate with better survival. Levels of brain natriuetic peptide may be used to follow the progress of patients with PH.14 A combination of echocardiography and biomarkers seems to offer the best means to accurately screen for PAH. Diagnosis of PAH requires the presence of PH with 2 other conditions. Pulmonary artery occlusion pressure (PAOP or PCWP) must be less than 15 mm Hg (2,000 Pa), and PVR must be greater than 3 Wood units (240 dyn/sec/cm–5 or 2.4 mN/s/cm–5). Pulmonary hypertension is present when mean pulmonary artery pressure (mPAP) exceeds 25 mm Hg (3,300 Pa) at rest or 30 mm Hg (4,000 Pa) with exercise. Mean pulmonary artery pressure should not be confused with systolic pulmonary artery pressure (sPAP), which often appears on echocardiogram reports. A systolic pressure of 40 mm Hg typically implies an mPAP of more than 25 mm Hg. s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 13 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig Figure. Chest x-ray of a patient with ASD and PH. The main pulmonary artery (long arrow) and its main branches are enlarged, and the peripheral pulmonary vessels by comparison are “pruned.” The heart is enlarged and the shape suggests right heart enlargement. Reprinted with permission from Scognamilio G, et al. The essential role of imaging in the evaluation of patients with pulmonary arterial hypertension in association with congenital heart disease. Advances in Pulmonary Hypertension. 2012;11:171-182. Physiologic Changes of Pregnancy d. Several cardiopulmonary physiologic changes with pregnancy exacerbate PH. In the pulmonary system, minute ventilation increases by 50% at term. Arterial carbon dioxide decreases to about 34 mm Hg. Functional residual capacity, expiratory reserve volume, and residual volume all decrease. Total lung capacity remains the same because of an increase in chest circumference. The smooth muscle relaxation effects of progesterone may decrease airway resistance and improve function. Cardiac changes include a 50% increase in cardiac output, with early increases in blood volume that increase stroke volume. Afterload is reduced secondary to decreased peripheral vascular resistance. Later, cardiac output is augmented by tachycardia. Normally, PVR decreases to allow these changes of pregnancy, an accommodation that is not possible in patients with PH. As afterload increases from the higher PVR, the right ventricle cannot manage the increased cardiac output and begins to fail. Sudden death from dysrhythmias may occur. Peak plasma volumes develop at about 22 to 24 weeks of pregnancy, and cardiac output peaks around 32 weeks. At the time of delivery, pain stimulates the sympathetic nervous system with sudden significant increases A N E ST H E S I O LO GY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 0 1 3 79 Table 2. Prevalence of Pulmonary Hypertension in Specific Subgroups An observational study of 277 patients with HIV infection found that 46% of patients had PH.9 A systematic review of several studies of patients with obstructive sleep apnea estimated the prevalence of PH at 15% to 20%.10 ll A Studies of patients with chronic obstructive pulmonary disease estimated the prevalence of PH at 10% to 30%.11 TREATMENT AND MANAGEMENT Untreated PAH has 1-, 3-, and 5-year survival rates of 68%, 48%, and 34%, respectively. The addition of pregnancy worsens the prognosis significantly.21 As soon as a diagnosis of PH is made, patients should be followed with regular assessment of right ventricular (RV) function with TTE. If dysfunction is detected, early delivery is recommended.3 Close follow-up using a multidisciplinary approach is essential, including obstetricians, anesthesiologists, cardiologists, hematologists, and neonatologists. Hospitalization by the second trimester is appropriate, given the high risk for hemodynamic changes and preterm delivery.8 Monitoring is done by echocardiography. Compression of the inferior vena cava must be prevented. The patient’s paO2 should be maintained above 70 mm Hg. Loop diuretics should be used to treat right heart failure. Low-molecular-weight heparin is indicated prior to delivery, and warfarin should be used in the postpartum period. Short of lung transplantation, no curative therapy exists for PH. However, several treatments have shown potential for improving outcome in patients with this condition. Therapy is dictated in part by the cause, whether arterial, venous, hypoxic, thromboembolic, or other. Because PVH is synonymous with congestive heart failure, treatment attempts to optimize left ventricular function by the use of diuretics, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or other agents, or to repair or replace the mitral or aortic valves. Digoxin, diuretics, and oxygen have been advocated, but results are inconsistent unless for the specific indication of preventing hypoxia. High-dose calcium channel blockers (CCBs) are useful in 5% of patients with idiopathic PAH who are vasoreactive by pulmonary artery catheter measurements. Yet, these drugs have been prescribed to many patients with non-vasoreactive PAH, leading to excessive morbidity and mortality. The criteria for vasoreactivity have changed: Only those patients whose mPAP falls by more than 10 mm Hg to below 40 mm Hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or NO are considered vasoreactive.22 Of these, only half are responsive to CCBs in the long term.23 Vasoconstriction results from the overexpression of endothelial-1 and the reduction of NO and prostacyclin. Thus, therapy is targeted to these factors. Several s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 13 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig The incidence of PH in patients with scleroderma is estimated at 6% to 60%, with the variance based on the extent of disease.12 results of 26 pregnancies at 13 centers over a 3-year period.19 Eight pregnancies ended in abortion; 3 women died; and 1 required urgent heart–lung transplantation. Among the 16 successful pregnancies, mothers who survived had a lower PVR, 500 dyn/sec/cm5 versus 1,667 dyn/sec/cm5 for non-survivors. A retrospective report, in the United States, of outcomes at 5 PH centers included 18 pregnancies over 2 years. Of those, 6 ended in abortion and 13 continued, all on sildenafil and IV prostacyclins with cesarean delivery at 34 weeks.20 Three patients died, for a mortality rate of 16.7%. In patients who took the diet medication fenfluramine/phentermine, there was a 23-fold increase in the development of PH, often long after ingestion of the drug combination.13 PH, pulmonary hypertension in heart rate, blood pressure, and myocardial oxygen consumption. Contractions during labor increase blood volume by 300 to 500 mL and cause a 50% increase in cardiac output. Cardiac output remains high for 48 hours or longer after delivery, and may require up to 6 months to return to prepregnancy levels.8 Maternal vagal responses also may occur, leading to hypotension and possibly sudden death.15 Valsalva maneuvers may further increase blood pressure and myocardial oxygen consumption. Pregnancy is associated with a hypercoagulable state due to increased fibrin levels, reduced fibrinolytic activity, and increased procoagulant activity with higher resistance to activated protein C, lower protein S, and increased clotting factor activity (I, II, V,VII, VIII, X, and XII).16 Any degree of thromboembolism contributes to a poor outcome in pregnant patients with PH. Pulmonary Hypertension and Pregnancy 80 I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G d. Undiagnosed PH may manifest first with the stress of pregnancy. Pulmonary hypertension also can develop acutely during pregnancy. Sudden onset of dyspnea, syncope, or chest pain should be investigated immediately. Differential diagnosis includes sleep apnea, asthma, arteriovenous malformations, atrial myxoma, amniotic fluid embolism, atrial septal defect, cardiomyopathy (dilated, hypertrophic, or restrictive), chronic obstructive pulmonary disease, emphysema, mitral regurgitation and stenosis, restrictive and interstitial lung disease, and systemic lupus erythematosis. Pulmonary hypertension affects a relatively small number of pregnancies (approximately 0.0003%).17 Recent studies indicate a decline in mortality from approximately 50% to 25%, with patients in the idiopathic PAH group showing the most improvement (17%), perhaps the result of specific therapy that now is more likely to be used in these patients.4,18 A multinational, prospective registry in Europe reported the ll A agents have been introduced recently for primary and secondary PAH. The clinical trials supporting the use of these agents have been relatively small, and the only measure consistently used to compare their effectiveness is the walk test. Many trials lack data on mortality, clinical benefit, or time to progression.21,24 The most common cause of death in pregnant patients with PH is RV failure. Treatment therefore has aimed at reducing PVR. Three of the many vasoactive pathways involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries have been targeted with drugs—endothelin receptor antagonists, phosphodiesterase type 5 (PDE5) inhibitors, and prostacyclin derivatives.24 The dual (ETA and ETB) endothelin receptor antagonist bosentan (Tracleer, T.A.P.) was approved in 2001. Sitaxentan (Thelin, Pfizer), a selective endothelin receptor antagonist that blocks only the action of ETA, was approved for use in Canada, Australia, and the European Union, but not by the FDA. In 2010, Pfizer withdrew the drug from the market because of its severe side effects. Both agents, although effective, are teratogenic and should not be used if the pregnancy is to be continued.8 A similar drug, ambrisentan (Letairis, Gilead Sciences) is available in the United States. Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH.4,24 Epoprostenol (Flolan, GlaxoSmithKline) is given by continuous infusion that requires a semipermanent central venous catheter. This delivery system can cause sepsis and thrombosis. Epoprostenol is unstable, and therefore must be kept cold during administration. Because epoprostenol has a half-life of 3 to 5 minutes, the infusion must be continuous and interruption can be fatal. Other prostanoids have been developed. Treprostinil (Remodulin, United Therapeutics Corporation) can be given intravenously or subcutaneously, but the subcutaneous injection can be painful and increases the patient’s risk for sepsis. Studies establishing the effectiveness of the inhaled form of treprostinil (Tyvaso, United Therapeutics Corporation) included mainly New York Heart Association functional Class III patients, those with symptoms and etiologies of idiopathic or heritable PAH (56%), or PAH associated with connective tissue diseases (33%).25 Iloprost (Ilomedin, Bayer Schering Pharma) also is used in Europe intravenously and has a longer half-life. Iloprost (Ventavis, Bayer Schering Pharma AG/Actelion Pharmaceuticals) was the only inhaled form of prostacyclin approved for use in the United States and Europe, until the inhaled form of treprostinil was approved by the FDA in July 2009. Administration by inhalation has the advantage of selective deposition in the lungs with less systemic side effects; however, cough and throat irritation commonly occur. Beraprost is an oral prostanoid available in South Korea and Japan. A combination therapy is usually advised.24 An investigational prostacyclin, selexipeg, is now in Phase II trials. A study of 43 patients showed a 30% reduction in PVR.26 s ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 13 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig Sildenafil (Revatio, Pfizer), a selective inhibitor of cGMP-specific PDE5, was approved for the treatment of PAH in 2005, and has been shown to be effective in a selected subset of patients. In 2009, tadalafil (Adcirca, Eli Lilly), another PDE5 inhibitor, also was approved.24 The NO signaling pathway is important for many physiologic functions including vascular smooth muscle relaxation, neuronal signal transduction, and inhibition of platelet aggregation. The source of NO in vivo is the enzyme NO synthase. The principal receptor for NO is soluble guanylate cyclase (sGC), Several sGC activators are undergoing clinical trials. Data on the fetal effects of these medications are conflicting; however, anecdotal reports indicate safe use for most of them.3 In contrast, a recent large study of 30,000 women who had used selective serotonin reuptake inhibitors late in pregnancy showed a 2-fold risk for persistent PH in newborns.27 Numerous surgical procedures have been described for the treatment of PH. Atrial septostomy creates a communication between the right and left atria and relieves pressure on the right side of the heart, but at the cost of relative hypoxia. Lung transplantation cures PAH but leaves the patient with the complications associated with transplantation, and a postsurgical median survival of just over 5 years.28 Pulmonary thromboendarterectomy is a difficult, major procedure that currently is performed in a few centers but with apparent good results in selected patients. Anesthetic Considerations d. Even in the first 20 weeks of pregnancy, patients with PAH may experience severe cardiorespiratory problems. Successful management of these patients depends especially on a team approach with obstetricians, cardiologists, cardiac surgeons, and anesthesiologists all in attendance and informed about the patient’s history and clinical status. Starting with preanesthetic care, hemodynamic status should be assessed by clinical, radiological, and echocardiographic means. The goals of intraoperative management are to decrease the pulmonary blood flow and PVR while maintaining cardiovascular and respiratory stability. Invasive monitoring is recommended, even with pulmonary artery catheterization and transesophageal echocardiography. Although percutaneous cardiopulmonary bypass often is not necessary, a setup should be available in critical cases. Although no anesthetic technique has proven superior, most patients are delivered under spinal or epidural anesthesia.3 Propofol has been shown to decrease leftto-right flow and increase right-to-left flow, thus reducing the pulmonary-to-systemic flow ratio.29 Inhaled iloprost (prostaglandin) has been shown to decrease both pulmonary artery pressure and PVR in most patients.29 One report has been published of successful delivery at 30 weeks by cesarean under epidural anesthesia with central monitoring and a continuous infusion of prostaglandin E1.30 Another case using the same A N E ST H E S I O LO GY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 0 1 3 81 ll A anesthetic technique ended in sudden collapse after delivery and death of the patient about 16 hours later.31 Because ACEs are present in high concentrations in lung tissue with increased susceptibility for PAH, use of ACE inhibitors, such as enalapril or captopril, may prove beneficial.29 Factors as hypoxia, airway obstruction, and hypoventilation can induce failure. Of note, hypotension may develop during delivery from the several medications used to treat PH, including oxytocin, pulmonary vasodilator drugs, inotropes (dobutamine), and analgesics, as well as blood loss. Vasopressin preferentially increases systemic vascular resistance without increasing PVR, and is a viable option to support blood pressure without compromising RV function. Maternal death is most likely to occur in the postpartum period when maximum fluid shifts s 1. Conclusion Mortality from PAH during pregnancy has decreased in recent years, but remains high well into the postpartum period. In patients who become pregnant either with preexisting PAH or who develop the condition during pregnancy, abortion is still the recommended course of action. For patients who do not elect to terminate their pregnancy, second-trimester admission to the hospital is warranted, with early operative delivery. Several drugs are approved or are currently undergoing trials to attempt to decrease pulmonary pressures. ite d. ib te oh no pr e is is rw on si he is ot m er ss le tp un ou up ith ro w G rt ng pa hi in is bl or Pu le ho on ah in w cM n M tio 13 uc 20 od © pr ht Re rig ed. py rv se re ht Co rig References occur. Very careful fluid management, especially with goal-directed therapy, should be used. Both under- and over-resuscitation can be disastrous. Postoperative surveillance in a monitored care setting for at least 1 to 2 days should be provided. Roos-Hesselink JW, Ruys PT, Johnson MR. Pregnancy in adult congenital heart disease. Curr Cardiol Rep. 2013;15(9):401. 2. Pritts CD, Pearl RG. Anesthesia for patients with pulmonary hypertension. Curr Opin Anaesthesiol. 2010;23(3):411-416. 3. Lane CR, Trow TK. Pregnancy and pulmonary hypertension. Clin Chest Med. 2011;32(1):165-174. 4. Bartolome SD. Clinical advances in pulmonary arterial hypertension: the year in review. 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Pulmonary arterial hypertension: new insights into the optimal role of current and emerging prostacyclin therapies. Am J Cardiol. 2013;111(5 suppl):1A-16A. 7. Armstrong AC, Bandeira AM, Correia LC, et al. Pulmonary artery pressure, gender, menopause and pregnancy in schistosomiasisassociated pulmonary hypertension. Arg Bras Cardio. 2013; Jul 2. [Epub ahead of print] 22. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 suppl S):40S-47S. 8. Terek D, Kayikcioglu M, Kultursay H, et al. Pulmonary arterial hypertension and pregnancy. J Res Med Sci. 2013;18(1):73-76. 23. Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111(23):3105-3111. 9. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIVrelated pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;177(1):108-113. 24. Torres F. Systematic review of randomised, double-blind clinical trials of oral agents conducted in patients with pulmonary arterial hypertension. Int J Clin Pract. 2007;61(10):1756-1765. 10. Kessler R, Chaouat A, Weitzenblum E, et al. Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences. Eur Respir J. 1996;9(4):787-794. 11. Elwing J, Panos RJ. Pulmonary hypertension associated with COPD. Int J Chron Obstruct Pulmon Dis. 2008;3(1):55-70. 25. Channick RN, Voswinckel R, Rubin LJ. Inhaled treprostinil: a therapeutic review. Drug Des Devel Ther. 2012;6:19-28. 26. Simoneau G, Torbicki A, Hoeper MM, et al. Selexipeg: an oral selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012; 40(4);874-880. 27. Kieler H, Artama M, Engeland A, et al. 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