Curr Hypertens Rep (2013) 15:606–613 DOI 10.1007/s11906-013-0399-3

PULMONARY HYPERTENSION (Z-C JING, SECTION EDITOR)

Pediatric Pulmonary Arterial Hypertension Dan-Chen Wu & Hong-Da Zhang & Zhi-Cheng Jing

Published online: 27 October 2013 # Springer Science+Business Media New York 2013

Abstract Pulmonary arterial hypertension (PAH) can cause morbidity and mortality in children. Although adult and pediatric PAH share many similarities, many differences have been found in children. Thus, a new classification for pediatric pulmonary hypertensive vascular disease has been proposed. Both child and adult gene mutation carriers with PAH tend to have worse prognoses. Pediatric patients present with better preserved functional class, and parents should pay high attention to any children with unexplained shortness of breath, fatigue or syncope, as symptoms of PAH in children are often misleading. Right heart catheterization is necessary for diagnosis. Although there are few medications approved for pediatric PAH and evidence-based treatment algorithms for children are still lacking, the survival of pediatric patients has been improved significantly since targeted therapies approved for adults were introduced to pediatric patients. PAH in children is unique, and further studies are needed to have a better understanding of it.

Introduction Pulmonary arterial hypertension (PAH) is a series of diseases characterized by elevated pulmonary vascular resistance and may lead to right heart failure and death [1]. The etiology of the disease is multifactorial; it can associate with underlying conditions such as congenital heart diseases (APAH-CHD) and connective tissue diseases (APAH-CTD) or be idiopathic. The survival of PAH patients has been improved since targeted therapies came onto the stage. Pediatric PAH and adult PAH have much in common, but also many differences. Like PAH in adults, pediatric PAH is thorny. Limited information is available evaluating the safety and efficacy of the treatment algorithm introduced for adults. While many groundbreaking clinical studies have been performed in adults, more attention should be paid to pediatric patients. The purpose of this article is to describe the classification, pathology and pathogenesis, epidemiology, genetics, epidemiology and survival, clinical features, diagnosis and treatment of pediatric PAH.

Keywords Pulmonary arterial hypertension . Children . Congenital heart disease . Endothelin-receptor antagonist . Phosphodiesterase-5 inhibitor . Prostacyclin Definition and Clinical Classification of PAH

Authors’ Note Dan-Chen Wu and Hong-Da Zhang contributed equally to this article and are the co-first authors. D.3.0 Wood units m 2 or a transpulmonary gradient >6 mmHg is considered pulmonary hypertensive vascular disease. PH in children is heterogeneous; many predisposing factors can contribute to the disorder, including prematurity, congenital heart disease and chromosomal abnormality. To emphasize multifactorial causes of pediatric PH, ten broad categories were listed in this classification.

Pathology and Pathogenesis The pathological changes are similar in all subgroups of PAH [6]. Lung biopsy is no longer reliable to evaluate the operability in CHD patients, although it used to be the “gold standard” to identify the operable patients [7]. Also the pathological changes in children and adult PAH patients are similar by and large. Muscularization of small arteries, intimal fibrosis, medial hypertrophy, plexiform lesions and fibrinoid necrosis occur in consequence. Adult idiopathic PAH (IPAH)/ heritable PAH (HPAH) patients appear to have more plexiform lesions [8], while pediatric patients tend to have more pulmonary vascular medial hypertrophy [9]. A recent study indicated that perivascular inflammation may play an important role in the processes of vascular remodeling, and more plexiform lesions are found in patients treated with prostacyclins and prostacyclin analogs [10•]. Historically, abnormalities in molecular pathways regulating the pulmonary vascular endothelial and smooth muscle cells (SMCs) have been described as underlying causes of PAH. These include inhibition of the voltageregulated potassium channel, mutations in the bone morphogenetic protein receptor-2 (BMPR2), increased serotonin uptake in the SMCs, increased angiopoietin expression in the SMCs and excessive thrombin deposition related to a procoagulant state. As a result, there appears to be loss of apoptosis of the SMCs allowing their proliferation and

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the emergence of apoptosis-resistant endothelial cells, which can obliterate the vascular lumen. Over the past 2 decades, increasing evidence has suggested there are similarities between the cellular processes underlying the pulmonary vascular remodeling in IPAH and those seen in cancer processes. Abnormal cellular metabolism, particularly aerobic glycolysis (the “Warburg effect”), and alterations in mitochondrial function have been recognized as important elements in the pathogenesis of IPAH. Recently, increased rates of pulmonary artery SMC proliferation and depressed rates of apoptosis have been confirmed to be related to normoxic decreases in reactive O 2 species (ROS), pathological activation of hypoxia-inducible factor 1α (HIF1α) and activation of pyruvate dehydrogenase kinase (PDK).

Genetics Mutations of several genes, including BMPR2, activin-like kinase type-1 (ALK-1) and endoglin (ENG), have been shown to be present in both adult and pediatric PAH [11] (Table 1). Studies have shown adult BMPR2 carriers may have worse prognoses than noncarriers [12]. In pediatric PAH, the patients with BMPR2 mutations have worse 5-year survival than mutation noncarriers, and ALK1 mutation carriers also have a tendency to have worse outcome than mutation noncarriers [13]. For clinical implication, BMPR2 status appears to predict vasoreactivity during acute vasodilator testing (AVT). A study by Elliott et al. first indicated that the BMPR2 mutation was related to less possibility of being acute responders mostly in adults [14]. Then Rosenzweig et al. extended the observation to a larger cohort including more children and came up with similar results [15]. Recent studies have shown mutations of other genes, such as SMAD-9 [16], caveolin-1 [17] and KCNK3 [18•], are associated with HPAH.

Epidemiology and Survival The true incidence and prevalence of pulmonary arterial hypertension remain unclear. In the overall cohort including both adults and children, IPAH is uncommon, with an estimated incidence of 1-2 cases per million per year [19]. According to some registries done recently by The Netherlands, France, the UK and USA, the annual incidence of IPAH/familial PAH (FPAH) and APAH-CHD ranges from 0.48-0.7 per million, which was lower than that of adults [20–22]. The point prevalences of IPAH and APAH-CHD are 4.4 and 15.6 per million, according to The Netherlands’ registry [20]. Female predominance is less obvious in children than in adult PAH patients, with a ratio of 1.7 to 1 in the TOPP registry and 1.8 to 1 in the REVEAL pediatric registry,

608 Table 1 Gene mutations pediatric/adult patients with PAH

PAH-HTT, pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia; *the only one patient with PAH-HTT had the ALK-1 mutation; #mutation was detected but not found

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Author

Category

Age

BMPR2

ALK-1

Endoglin

Harrison et al Grunig et al Roberts et al Harrison et al Elliott et al

PAH-HTT PAH PAH PAH/PAH-HTT* PAH

Children/adults Children Children/adults Children Children/adults

0 (0 %)# 0 (0 %)# 6 (6 %) 2 (11 %) 27 (40 %)

9 (64 %) 0 (0 %)#

2 (14 %)

1 (6 %)*

1 (6 %)

Fujiwara et al Rosenzweig et al

PAH PAH

Children Children/adults

3 (18 %) 23 (16 %)

compared with 1.9 to 1 in the French registry and 3.5 to 1 in the REVEAL registry [23]. Among all pediatric PAH patients, IPAH and APAH-CHD are the most frequent types in progressive PAH [19]. IPAH/ FPAH accounts for 35-70 % of patients, and PAH associated with CHD is the second most common cause of PAH (2452 %) [21, 24]. Other common causes of PAH include PAH associated with connective tissue diseases (APAH-CTD) and portal hypertension (PoPH). More pediatric patients have chromosomal anomalies (mainly trisomy 21) than adult patients, with a percentage of 13 % [25••]. Besides, a growing population of patients with bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH), sickle cell anemia and other diseases other than IPAH or CHD has been screened out in recent years, thanks to the contribution of multidisciplinary teamwork [26–28]. The natural history of PAH patients varies depending on the etiology. Generally speaking, the outcome of IPAH/FPAH was poorer than APAH in the traditional management era. The survival of IPAH/FPAH patients has been improved dramatically since targeted therapies were introduced. Survival of pediatric IPAH patients at 1, 3 and 5 years has been improved to 86-89 %, 80-84 % and 72-75 %, respectively [22, 29]. The outcome of treated children is now similar to that of adults.

Clinical Features Most of the symptoms are nonspecific in pediatric PAH. Dyspnea on exertion (46-65 %) and fatigue (24-41 %) are the most frequently reported symptoms at presentation [25••, 30]. Near-syncope, syncope and chest pain do occur but mainly in children with IPAH/HPAH. Although syncope was reported in 31 % of children with IPAH/HPAH and 18 % with repaired CHD, it was not reported in any child with an unrepaired or residual congenital systemic-topulmonary shunt [29]. Furthermore, severe asthma may be diagnosed with breathlessness, but usually there is absence of wheeze on exertion [31]. Occasionally, cyanosis, hemoptysis

2 (18 %)

or even right heart failure with ankle edema or hepatomegaly may be the first presenting feature [30]. Children with PAH usually have seriously raised mPAP and PVR index scores. Despite severe pulmonary hypertension, the functional class is well preserved (64 % patients graded I or II), which is consistent with preserved right-heart function assessed by the cardiac index (CI). Furthermore, the hemodynamics differ significantly between patients with PAH and PH associated with respiratory disorders or hypoxemia [29].

Diagnosis and Assessment As symptoms of PAH in children are often misleading, parents should pay high attention to any children with unexplained shortness of breath, fatigue or syncope [32]. In children, PAH is usually not diagnosed until a chest radiograph, an electrocardiogram (ECG) or an echocardiogram has been obtained for some occasional reason such as an upper respiratory tract infection or a physical examination. These routine investigations can be the first screening for PAH. After excluding left heart disease and valvular diseases, a chest computed tomographic scan and ventilation-perfusion scan should be performed to rule out thromboembolic disease, pulmonary interstitial lung disease and pulmonary fibrosis in the suspected patients. All pediatric patients suspected of having PAH should undergo right heart catheterization (RHC) to confirm the diagnosis. During RCH, AVT should be performed, usually with inhaled nitric oxide (NO), intravenous (i.v.) epoprostenol, i.v. adenosine or inhaled iloprost [33], to find the “responders” who can be benefit from long-term calcium channel blockers. The WHO functional classification is widely used for assessing functional impairment in PAH patients. It can be applied to adults and older children, but is not suitable for younger children and infants because of its subjectivity and other limitations. In 2011, the PVRI developed a functional classification system for pediatric PH patients [5••]. In this classification, children with PH were stratified by age, and

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more objective indicators were included, such as thriving and need for supplemental feeding. The 6-min walk test (6MWT) is a useful and easy tool for the evaluation of exercise capacity. For children younger than 7 years old, this procedure is no more reliable. Since the normal value of 6MWT is available, adapted from healthy children [34], it could be a reference for children with PAH.

Treatment Based on advantages in the understanding of pulmonary vascular pathophysiology, three main classes of medications have been introduced to treat PAH: prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, ambrisentan) and phosphodiesterase inhibitors (sildenafil, vardenafil, tadalafil). Similar treatment algorithms in children have been established because of the similar pathobiological process. Although a pediatric classification has been developed [5••], no PAH therapies have been stratified to it. All children with PAH need urgent treatment; according to the current guidelines the same therapeutic algorithm is recommended as for adults [33]. The recommendation for considering the therapeutic algorithm proposed for adults in children is class IIa (i.e., the weight of evidence/opinion is in favor of usefulness/efficacy), and the level of evidence is grade C (i.e., it corresponds to a consensus of opinion of the experts and/or small retrospective studies and registries) [33].

Monotherapy of Calcium Channel Blockers for Acute Responders In adults, acute vasodilator responders during AVT are considered the best predictors of long-term response to calcium channel blockers (CCBs) [35]. In children, the criterion of responders is not fixed; three criteria are mostly used: the Barst criterion [36], the Rich criterion [37] and the Sitbon criterion [35]. Douwes et al. assessed the occurrence and prognostic value of acute vasodilator response (AVR) in pediatric and adult PAH, concluding that the proportion of patients with AVR highly depended on the used criteria, but did not differ between pediatric and adult IPAH/HPAH patients [38]. The REVEAL study reported acute vasoreactivity of 13 % and 27 % using the Sitbon criterion and Barst criterion, respectively [30]. Early studies showed both adult and pediatric responders can be benefit from longterm CCB treatment [39, 40], while according to a study in The Netherland, only responders under the Sitbon criterion showed improved survival after treatment with calcium channel blockers [41].

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Prostanoids Prostacyclin (PGI2) is an endogenous vasodilator mediator in the pulmonary vasculature. PGI2 agonists act via cyclic AMPdependent pathways in SMCs. Prostanoids were the earliest targeted drugs used in pediatric PAH patients. Epoprostenol, with a very short half-life of 3-6 min, is an intravenous preparation of the prostacyclin analog first used clinically in the early 1980s and was approved to treat severe IPAH in 1995. It was proved to improve exercise capacity, functional classification, hemodynamic parameters and survival in adults with IPAH and associated PAH [42, 43]. It has also been used in children of all ages with similar safety and efficacy as shown in adult patients, but requires a significantly higher dose of epoprostenol on a per kilogram basis to achieve optimal effects [44, 45]. However, side effects can be severe because the drug is often given at the highest dose the patient can tolerate. Treprostinil, a tricyclic benzidene analog of prostacyclin that has similar biologic actions, with an elimination half-life of 4-5 h and a distribution half-life of 40 min, allows for intravenous or subcutaneous administration or inhalation. A 12-week, double-blind, placebo-controlled trial first demonstrated chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with PAH [46]. Ivy et al. evaluated the effects of intravenous treprostinil on 13 children and found fewer side effects compared to epoprostenol, suggesting treprostinil could be an alternative therapy in children with PAH [47]. Recently, Levy et al. suggested subcutaneous treprostinil may be a potentially valuable rescue therapy in children with refractory PAH [48]. Moreover, inhaled treprostinil was proved to be an effective medication as an addition to background targeted PAH therapy in children and had an acceptable safety profile [49]. Iloprost, a chemically stable prostacyclin analog with a half-life of 20-30 min, is easy to administer, has fewer risks and side effects in its inhaled form, and acts directly on the lung. Iloprost has demonstrated functional improvement in both adults and children with PAH [50, 51]. Recent research shows that inhaled iloprost, with or without concomitant ERA and/or PDE5 inhibitors, is safe and efficacious for the treatment of pediatric PAH patients [52]. However, frequent inhalation leads to poor compliance and limits the use of iloprost in pediatric patients. Beraprost sodium (BPS) is a stable prostacyclin analog with a half-life of 1-2 h, which allows for oral administration. Limsuwan et al. discovered that beraprost can increase the intracardiac left-to-right shunt and reduce the pulmonary-tosystemic vascular resistance ratio in children with severe PAH secondary to CHD [53]. Recently, Nakwan et al. concluded an initial experience of using BPS to treat seven infants with persistent pulmonary hypertension of the newborn (PPHN)

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successfully and suggested BPS may be used as an alternative treatment in PPHN [54]. Furthermore, two cases of PH in Kartagener syndrome and after cord blood transplantation for infantile leukemia treated with BPS were reported [55, 56]. Endothelin Receptor Antagonists High levels of endothelin 1 (ET-1) expression have been found in the lung tissue of patients with PH and thus result in an imbalance between vasodilatation and vasoconstriction [57, 58]. Bosentan is an oral dual endothelin receptor (receptor A and B) antagonist. Its safety and effectiveness were proven in adults and later in children with PAH [59, 60]. In several subsequent studies, it was shown to reduce mPAP and PVR and to improve the hemodynamics, exercise capacity and WHO functional class in both adults and children with PAH [61–63]. In 2009, the FUTURE-1 study suggested a novel formulation of bosentan was well tolerated by pediatric PAH patients [64]. Recently, a 5-year study of bosentan in children with PAH showed an estimated 1-, 2-, 3- and 5-year survival of 96, 89, 83 and 60 %, respectively [65]. Another study by Barst demonstrated outcomes in children with PAH treated with bosentan appeared favorable, with a 4-year survival of 82 % [66]. Ambrisentan, a selective ETA-receptor antagonist, has recently been shown to improve exercise capacity and time to clinical worsening in adults with PAH compared to placebo, and it is well tolerated [67, 68]. Ivy et al. evaluated the clinical safety, pharmacokinetics and efficacy of ambrisentan therapy in children with PAH and suggested that the treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children [69]. Sitaxentan, an oral agent acting predominantly on the ETA receptor, was once approved for use in the EU, Canada and Australia. However, it was withdrawn from the market in 2010 because of severe hepatic toxicity. Before being removed, it was reported to have a more prolonged action than bosentan in children with CHD [70, 71]. Phosphodiesterase type 5 Inhibitors Phosphodiesterase type 5 (PDE5) inhibitors are responsible for pulmonary vasodilation and antiproliferation by preventing the breakdown of cyclic guanosine monophosphate. Sildenafil, a selective PDE5 inhibitor, has an expanding role in the treatment of PAH. Case series and small studies, as well as the first large randomized controlled trial, have demonstrated the safety and efficacy of sildenafil in improving mPAP, PVR, the cardiac index and exercise tolerance in PAH patients [72–75]. In the START-1 study, peak oxygen consumption, functional class and hemodynamic

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parameters were improved with medium and high doses of sildenafil [76]. Unfortunately, a higher risk of mortality occurred among patients randomized to high-dose compared with lower-dose sildenafil in the START-2 study [76]. Although approved by the European Medicines Agency (EMA), the American Food and Drug administration (FDA) recommended not to use sildenafil in children with PAH in August 2012. However, Abman et al. held the opinion that the warning by the FDA was based on extremely limited data, with monotherapy and inadequate treatment time [77]. They suggested its use in pediatric patients with PAH under close surveillance and frequent monitoring. In addition, persistent sildenafil monotherapy is likely insufficient with disease progression [77]. Tadalafil, a long-acting selective PDE5 inhibitor, is an efficacious drug with a favorable side-effect profile and convenient mode of administration. It was approved by the US FDA for adults with chronic PAH in 2009 and may improve the clinical course in adults with severe PAH on intravenous prostacyclin therapy [78–80]. A retrospective study showed tadalafil can be safely used for pediatric patients with PAH and may prevent disease progression [81]. Vardenafil, another PDE 5 inhibitor, has been proved to be more effective than sildenafil in vitro [82, 83]. Vardenafil induced pulmonary vasodilatation via inhibition of extracellular calcium entry in addition to NO-cGMP pathway activation in rats, and it could prevent impaired arterial relaxation in PAH [84]. A multicenter, open-label study in China first showed long-term treatment with vardenafil was associated with improvements in hemodynamic parameters and WHO functional classification [85]. Then the same group reported that vardenafil was effective and well tolerated in patients with PAH at a dose of 5 mg twice daily, and it could reduce clinical worsening events [86]. However, the safety and efficacy of vardenafil in pediatric PAH need further investigation.

Combination Therapy Several studies have suggested that the use of various combinations may improve exercise capacity, hemodynamics, time to clinical worsening and quality of life in PAH patients [87, 88]. However, the most effective and safe combinations are unclear and controversial. In adults, combination therapy is recommended for monotherapy patients who remain in WHO functional class III, while continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients [89]. In a UK registry of pediatric PAH patients, combination therapy of intravenous epoprostenol with either bosentan or sildenafil, or both, appeared to achieve better outcomes than monotherapy [29].

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Advances in Treatment Recent progress from basic studies on the pathobiology of PAH has suggested novel targets for the development of new therapies, particularly target cell growth, proliferation and apoptosis [90]. Approaches including apoptosis and gene therapy, Rho-kinase inhibitors [91], vasoactive intestinal peptide, estradiol derivatives, serotonin pathways and Larginine are providing novel strategies. The results of researches on the soluble guanylate cyclase stimulator riociguat [92] and platelet-derived growth factor inhibitor imatinib [93] may shed light on novel therapeutic approaches to PAH.

Conclusion Significant progress has been achieved in pediatric PAH in the last 15 years. Mortality seems to have significantly decreased. However, pediatric PAH is still complicated and is extremely challenging to manage, partly due to the relatively small numbers of patients and limited data. There are many challenges we must face: (1) pediatric patients tend to have other factors that may cause PAH, resulting in more complicated conditions; (2) choosing the clinically related event so as to evaluate the severity of the patients’ condition may be difficult; (3) as a special population different from adults, pediatric PAH patients need optimized treatment strategies. We believe increased medical awareness and novel mechanisms will further improve the survival and quality of life in children with PAH.

Compliance with Ethics Guidelines Conflict of Interest Dan-Chen Wu, Hong-Da Zhang and Zhi-Cheng Jing declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular importance, published recently, have been highlighted as: • Of importance •• Of major importance 1. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(Suppl):S43–54.

611 2. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(Suppl):S55–66. 3. Adatia I, Beghetti M. Immediate postoperative care. Cardiol Young. 2009;19 Suppl 1:23–7. 4. Hatano S, Strasser T. Primary pulmonary hypertension: Report on a WHO Meeting, Geneva, 15-17 October 1973. 5. •• Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: report from the PVRI pediatric taskforce. Pulm Circ. 2011;1:286–98. This is the first classification especially for pediatric pulmonary hypertensive vascular disease. In this classification, pediatric pulmonary hypertensive vascular diseases are divided into ten categories. The concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia are highlighted as causative factors of pediatric PH. 6. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):25S–32S. 7. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 1958;18:533–47. 8. Haworth SG. Pulmonary hypertension in the young. Heart. 2002;88: 658–64. 9. Wagenvoort C, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation. 1970;42:1163–84. 10. • Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261–72. This research reveals the pathological changes in pulmonary vasculature after applying targeted therapies. It emphasizes the role of inflammation in the processes of vascular remodeling. 11. Newman JH, Trembath RC, Morse JA, et al. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol. 2004;43(12Suppl.S):33S–9S. 12. Sztrymf B, Coulet F, Girard B, et al. Clinical outcomes of pulmonary artery hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med. 2008;177:1377–83. 13. Chida A, Shintani M, Yagi H, et al. Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers. Am J Cardiol. 2012;110:586–93. 14. Elliott CG, Glissmeyer EW, Havlena GT, et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation. 2006;113:2509–15. 15. Rosenzweig EB, Morse JH, Knowles JA, et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant. 2008;27:668–74. 16. Drake KM, Zygmunt D, Mavrakis L, et al. Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med. 2011;184:1400–8. 17. Austin ED, Ma L, LeDuc C, et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet. 2012;5:336–43. 18. • Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med. 2013;369:351–61. The gene was newly found to be associated with PAH. 19. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336:111–7. 20. van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011;124:1755–64. 21. Fraisse A, Jais X, Schleich J-M, et al. Characteristics and prospective 2 year follow-up of children with pulmonary arterial hypertension in France. Arch Cardiovasc Dis. 2010;103:66–74.

612 22. Moledina S, Hislop AA, Foster H, et al. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96:1401–6. 23. Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and non-US Contemporary Registries. Chest. 2011;139:128–37. 24. Fasnacht MS, Tolsa JF, Beghetti M. The Swiss registry for pulmonary arterial hypertension: the paediatric experience. Swiss Med Wkly. 2007;137:510–3. 25. •• Berger RM, Beghetti M, Humpl T, et al. Clinical features of pediatric pulmonary hypertension: The Global Registry Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP). Lancet. 2012;379:537–46. This is the first global registry on pediatric pulmonary hypertension and provides data on the clinical features of childhood PH. 26. Mourani PM, Abman SH. Pulmonary vascular disease in BPD: physiology, diagnosis and treatment. In: Abman SH, editor. Bronchopulmonary dysplasia. New York: Informa; 2010. p. 347–63. 27. Ivy DD, Feinstein JA, Humpl T, Rosenzweig EB. Noncongenital heart disease associated pediatric pulmonary arterial hypertension. Prog Pediatr Cardiol. 2009;27:13–23. 28. Mourani PM, Mullen M, Abman SH. Pulmonary hypertension in bronchopulmonary dysplasia. Prog Pediatr Cardiol. 2009;27:43–8. 29. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001-2006. Heart. 2009;95:312–7. 30. Barst RJ, McGoon MD, Elliott CG, et al. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term PAH disease management. Circulation. 2012;125:113–22. 31. Rosenzweig EB, Barst RJ. Idiopathic pulmonary arterial hypertension in children. Curr Opin Pediatr. 2005;17:372–80. 32. Rosenzweig EB, Feinstein JA, Humpl T, et al. Pulmonary arterial hypertension in children: diagnostic work-up and challenges. Prog Pediatr Cardiol. 2009;27:4–11. 33. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: 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). Eur Heart J. 2009;30:2493–537. 34. Lammers AE, Hislop AA, Flynn Y, et al. The 6-minute walk test: normal values for children of 4-11 years of age. Arch Dis Child. 2008;93:464–8. 35. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105–11. 36. Barst RJ. Pharmacologically induced pulmonary vasodilatation in children and young adults with primary pulmonary hypertension. Chest. 1986;89:497–503. 37. Rich S, Kaufmann E, Levy PS. The effect of high doses of calciumchannel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76–81. 38. Douwes JM, van Loon RL, Hoendermis ES, et al. Acute pulmonary vasodilator response in paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value when comparing three response criteria. Eur Heart J. 2011;32:3137–46. 39. Yung D, Widlitz AC, Rosenzweig EB, Kerstein D, Maislin G, Barst RJ. Outcomes in children with idiopathic pulmonary arterial hypertension. Circulation. 2004;110:660–5. 40. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197–208. 41. J Menno Douwes, Rosa Laura E van Loon, Elke S Hoendermis, et al. Paediatric Pulmonary Hypertension: Epidemiology, Characterisation and Treatment. Chapter 6. Prevalence and prognostic value of acute

Curr Hypertens Rep (2013) 15:606–613

42.

43.

44. 45.

46.

47.

48.

49.

50.

51. 52.

53.

54.

55.

56.

57.

58. 59.

60.

61.

pulmonary vasodilator response in adults versus children with pulmonary arterial hypertension: which criteria to use? Edited by Rosa Laura Elisabeth van Loon. Rotterdam: Optima Grafische Communicatie; 2010:100-17. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival. J Am Coll Cardiol. 2002;40:780–8. McLaughlin VV, Genthner DE, Panella MM, et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998;338:273–7. Lammers AE, Hislop AA, Flynn Y, et al. Epoprostenol treatment in children with severe pulmonary hypertension. Heart. 2007;93:739–43. Nakayama T, Shimada H, Takatsuki S, et al. Efficacy and limitations of continuous intravenous epoprostenol therapy for idiopathic pulmonary arterial hypertension in Japanese children. Circ J. 2007;71:1785–90. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165: 800–4. Ivy DD, Claussen L, Doran A. Transition of stable pediatric patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil. Am J Cardiol. 2007;99:696–8. Levy M, Celermajer DS, Bourges-Petit E, et al. Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr. 2011;158:584–8. Krishnan U, Takatsuki S, Ivy DD, et al. Effectiveness and safety of inhaled treprostinil for the treatment of pulmonary arterial hypertension in children. Am J Cardiol. 2012;110:1704–9. Ivy DD, Doran AK, Smith KJ, et al. Short-and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51:161–9. Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322–9. Alehan D, Yildirim I, Sahin M, et al. Long-term inhaled iloprost use in children with pulmonary arterial hypertension. Cardiol Young. 2012;22:396–403. Limsuwan A, Pienvichit P, Khowsathit P. Beraprost therapy in children with pulmonary hypertension secondary to congenital heart disease. Pediatr Cardiol. 2005;26:787–91. Nakwan N, Wannaro J. Persistent pulmonary hypertension of the newborn successfully treated with beraprost sodium: a retrospective chart review. Neonatology. 2011;99:32–7. Shen YC, Wen FQ, Yi Q. Pulmonary arterial hypertension in a Kartagener syndrome patient: treatment with beraprost sodium. Int J Cardiol. 2012;159:e9–e10. Kawashima N, Ikoma M, Sekiya Y, et al. Successful treatment of pulmonary hypertension with beraprost and sildenafil after cord blood transplantation for infantile leukemia. Int J Hematol. 2013;97:147–50. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732–9. Lang IM, Bonderman D, Kneussl M, et al. Paediatric pulmonary vascular disease. Paediatr Respir Rev. 2004;5:238–48. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119–23. Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2003;73:372–82. Maiya S, Hislop AA, Flynn Y, et al. Response to bosentan in children with pulmonary hypertension. Heart. 2006;92:664–70.

Curr Hypertens Rep (2013) 15:606–613 62. Rosenzweig EB, Ivy DD, Widlitz A, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46:697–704. 63. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903. 64. Beghetti M, Haworth SG, Bonnet D, et al. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study. Br J Clin Pharmacol. 2009;68:948–55. 65. Hislop AA, Moledina S, Foster H, et al. Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children. Eur Respir J. 2011;38:70–7. 66. Ivy DD, Rosenzweig EB, Lemarie JC, et al. Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings. Am J Cardiol. 2010;106:1332–8. 67. Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008;117:3010–9. 68. Oudiz RJ, Galiè N, Olschewski H, et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:1971–81. 69. Takatsuki S, Rosenzweig EB, Zuckerman W, et al. Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension. Pediatr Pulmonol. 2013;48:27–34. 70. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441–7. 71. Barst RJ, Rich S, Widlitz A, et al. Clinical efficacy of sitaxsentan, an endothelin-a receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest. 2002;121:1860–8. 72. Alaeddini J, Uber PA, Park MH, et al. Efficacy and safety of sildenafil in the evaluation of pulmonary hypertension in severe heart failure. Am J Cardiol. 2004;94:1475–7. 73. Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as longterm adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol. 2003;42:158–64. 74. Humpl T, Reyes JT, Holtby H, et al. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation. 2005;111:3274–80. 75. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360:895–900. 76. Barst RJ, Ivy DD, Gaitan G, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation. 2012;125:324–34. 77. Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. food and drug administration warning against the use of

613 sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med. 2012;187:572–5. 78. Udeoji DU, Schwarz ER. Tadalafil as monotherapy and in combination regimens for the treatment of pulmonary arterial hypertension. Ther Adv Respir Dis. 2013;7:39–49. 79. Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119: 2894–903. 80. Arif SA, Poon H. Tadalafil: A long-acting phosphodiesterase-5 inhibitor for the treatment of pulmonary arterial hypertension. Clin Ther. 2011;33:993–1004. 81. Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. Pediatr Cardiol. 2012;33:683–8. 82. Teixeira CE, Priviero FB, Webb RC. Differential effects of the phosphodiesterase type 5 inhibitors sildenafil, vardenafil, and tadalafil in rat aorta. J Pharmacol Exp Ther. 2006;316:654–61. 83. Toque HA, Teixeira CE, Priviero FB, et al. Vardenafil, but not sildenafil or tadalafil, has calcium-channel blocking activity in rabbit isolated pulmonary artery and human washed platelets. Br J Pharmacol. 2008;154:787–96. 84. Karasu-Minareci E, Ozbudak IH, Ozbilim G, et al. Acute effects of vardenafil on pulmonary artery responsiveness in pulmonary hypertension. Sci World J. 2012;2012:718279. 85. Jing ZC, Jiang X, Wu BX, et al. Vardenafil treatment for patients with pulmonary arterial hypertension: a multicentre, open-label study. Heart. 2009;95:1531–6. 86. Jing ZC, Yu ZX, Shen JY, et al. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011;183:1723–9. 87. Driscoll JA, Chakinala MM. Medical therapy for pulmonary arterial hypertension. Expert Opin Pharmacother. 2008;9:65–81. 88. Mogollon MV, Lage E, Cabezon S, et al. Combination therapy with sildenafil and bosentan reverts severe pulmonary hypertension and allows heart transplantation: case report. Transplant Proc. 2006;38: 2522–3. 89. Barst RJ, Gibbs JS, Ghofrani HA, et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S78–84. 90. Erzurum S, Rounds SI, Stevens T, et al. Strategic plan for lung vascular research: an NHLBI-ORDR workshop report. Am J Respir Crit Care Med. 2010;182:1554–62. 91. Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol. 2011;301:H287–96. 92. Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–40. 93. Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127:1128–38.