PMC:3750932 / 3413-26102 JSONTXT

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and classification\nPulmonary arterial hypertension (PAH) is defined by right-heart catheterization (RHC) showing precapillary pulmonary hypertension with a mean pulmonary artery pressure (mPAP) of \u003e25 mmHg and a normal pulmonary artery wedge pressure (PCWP) of \u003c15 mmHg [1,2]. The classification of pulmonary hypertension (PH) has gone through a series of changes since the first classification proposed in 1973 which designated only two categories, primary pulmonary hypertension or secondary PH, depending on the presence or absence of identifiable causes or risk factors [3,4]. In 1998, a second World Symposium on PH was held in Evian (France) and this classification attempted to create categories of PH that shared similar pathogenesis, clinical features and therapeutic options [5]. This classification allowed defining homogenous groups of patients to conduct clinical trials and to obtain approval for specific PAH therapies worldwide. In 2003, the third World Symposium on PH (Venice, Italy) did not propose major changes. However, the terms idiopathic PAH, familial PAH, and associated PAH were introduced. The other prominent change was to move pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from separate categories into a single subcategory of PAH.\nIn 2008, the fourth World Symposium on PH held in Dana Point (California, USA) and the consensus of an international group of experts was to revise previous classifications in order to accurately reflect published data, as well as to clarify some areas that were unclear. In 2013, the fifth World Symposium on PH held in Nice (France) and proposed only minor modifications, however, since the definite conclusions of this symposium were not yet published, we presented the Dana Point classification of PH (Table 1).\nTable 1 Diagnostic classification of pulmonary hypertension This classification was adapted from (Simonneau et al. [16]).\n\nGroup 1: Pulmonary arterial hypertension\nThe nomenclature of the subgroups and associated conditions has evolved since the first classification, and additional modifications were added in the Dana Point classification.\n\nGroup 1.1/1.2 Idiopathic and heritable PAH \nIdiopathic PAH describes a sporadic disease with neither a family history of PAH nor an identified risk factor. When PAH occurs in a familial context, germline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor beta (TGF- ß) signaling family, can be detected in about 70% of cases [6,7]. More rarely, mutations in activin receptor like kinase type 1 (ACVRL1 or ALK1) or endoglin genes, also coding for members of the TGF-ß signaling family, have been identified in patients with PAH, predominantly with coexistent hereditary hemorrhagic telangiectasia. Some authors suggested that mutations of genes encoding for Smads proteins (Smad8, Smad1 and Smad5), which are other members of the TGF-ß signaling pathway, or mutations in caveolin-1 gene may predispose to PAH [8-10].\nBMPR2 mutations have also been detected in 11–40% of apparently idiopathic cases with no family history [11,12]. Indeed, the distinction between idiopathic and familial PAH with BMPR2 mutations is artificial, as all patients with a BMPR2 mutation have heritable disease. In addition, BMPR2 mutations were identified in only 70-80% families with PAH. Thus, it was decided to abandon the term “familial PAH” in favor of the term “heritable PAH”, including idiopathic PAH with germline mutations and familial cases with or without identified mutations [13,14].\n\nGroup 1.3 Drug- and toxin-induced PAH \nA number of risk factors for the development of PAH have been individualized in the last European Respiratory Society/ European Society of Cardiology (ERS/ESC) conjoint guidelines of PH [15] (Table 2).\nTable 2 Updated risk level of drugs and toxins known to be associated with PAH *This table was adapted from Galiè et al. [15]. Aminorex, fenfluramine derivatives and toxic rapeseed oil represent the only identified “definite” risk factors for PAH [5,16]. Souza et al. have demonstrated that this subgroup of PAH shares clinical, functional, hemodynamic, and genetic features with idiopathic PAH, suggesting that fenfluramine exposure represents a potential trigger for PAH without influencing its clinical course [17].\nTwo prospective epidemiologic investigations, the SNAP (Surveillance of North American Pulmonary Hypertension) and the SOPHIA (Surveillance of Pulmonary Hypertension in America) study, were conducted in the USA [18,19]. These investigations included retrospectively 559 and 1335 patients with PH, respectively, and confirmed the previously described association between idiopathic PAH and the use of fenfluramine. In the SNAP study, the odds ratio of developing PH was 7.5 for the use of fenfluramine more than six months of treatment [18].\nThe agent benfluorex is structurally and pharmacological related to fenfluramine and may be also considered as an anorectic agent. Frachon and co-workers [20] showed a significantly higher prevalence of unexplained valvular heart disease in patients taking benfluorex compared to controls. In addition, Savale and co-workers demonstrated recently that exposure to benfluorex is suggested to be a trigger in the development of PAH [21]. Benfluorex was withdrawn from the market in 2009.\nThe SOPHIA study examined intake of a variety of nonselective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants and anxiolytics. No increased risk of developing PAH was observed [19].\nAmphetamine use represents a “likely” risk factor, although they are frequently used in combination with fenfluramine. A recent retrospective study suggested a relationship with the use of methamphetamine (inhaled, smoked, oral, or intravenous) and the occurrence of PAH [22]. Methamphetamine use is now considered a “very likely” risk factor for the development of PAH.\nRecently published data from the French registry of pulmonary hypertension suggested that dasatinib, a tyrosine kinsase inhibitor (TKI), may induce precapillary PAH [23]. Several cases of precapillary PH in chronic myelogenous leukemia patients treated with dasatinib have been reported.\n\nGroup 1.4.1 PAH associated with connective tissue diseases \nPAH associated with connective tissue diseases (CTD) represents an important clinical subgroup, in which systemic sclerosis represents the major cause of CTD associated PAH. The prevalence of PAH has been well established only for systemic sclerosis (SSc). Prospective studies using echocardiography as a screening method and RHC for confirmation found a prevalence of PAH between 7–12% [24,25]. PH due to lung fibrosis [26], diastolic left heart dysfunction [27] and primary cardiac involvement [28] are also frequent in the setting of pulmonary hypertension in these patients, emphasizing the importance of a systemic evaluation with RHC to accurately classify the underlying mechanism of PH.\n\nGroup 1.4.2 HIV infection \nPAH is a rare complication of HIV infection [29,30]. HIV-associated PAH has clinical, hemodynamic, and histologic characteristics broadly similar to those seen in idiopathic PAH. Epidemiologic data in the early 1990s, a time when therapy with highly active antiretroviral therapy was not yet available, indicated a prevalence of 0.5% [31]. The prevalence of HIV-associated PAH was evaluated more recently and showed a stable prevalence of 0.46% [32].\n\nGroup 1.4.3 Porto-pulmonary hypertension \nPorto-pulmonary hypertension (POPH) is defined by the development of PAH associated with increased pressure in the portal circulation [33,34]. Prospective hemodynamic studies have shown that 2-6% of patients with portal hypertension had PH [35,36]. However, RHC is mandatory for the diagnosis of portal PH, as several mechanisms may increase pulmonary artery pressure in the setting of advanced liver disease: hyperdynamic circulatory state with high cardiac output, fluid overload and diastolic dysfunction. Pulmonary vascular resistance (PVR) is usually normal in these cases.\n\nGroup 1.4.4 Congenital heart diseases \nA significant proportion of patients with congenital heart disease (CHD), in particular those with systemic-to-pulmonary shunts, will develop PAH if left untreated. Eisenmenger's syndrome is defined as CHD with an initial large systemic-to-pulmonary shunt that induces progressive pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis [37,38]. It represents the most advanced form of PAH associated with CHD. It has been reported that a large proportion of patients with CHD develop some degree of PAH [39-41]. The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Europe and North America has been estimated between 1.6 and 12.5 cases per million adults, with 25-50% of this population affected by Eisenmenger’s syndrome.\n\nGroup 1.4.5 Schistosomiasis \nIn the Dana Point classification, PH associated with schistosomiasis was included in Group 1. Recently, it has been demonstrated that PH associated with schistosomiasis may have a similar clinical presentation and histological findings as idiopathic PAH [42,43]. The mechanism of PAH in patients with schistosomiasis is probably multifactorial including portal PH, a frequent complication of this disease [44] and local vascular inflammation, whereas mechanical obstruction by schistosoma eggs seems to play a minor role. More than 200 million people are infected and 4–8% of them will develop hepatosplenic disease. Then, PAH associated with schistosomiasis represents a frequent form of PAH in countries where the infection is endemic. Data from a recent study based on invasive hemodynamics evidenced the prevalence of PAH in patients with hepatosplenic disease of 4.6%; also important was the prevalence of post-capillary hypertension (3%) reinforcing the need of invasive hemodynamics for the specific diagnosis of PAH in schistosomiasis [45].\n\nGroup 1.4.6 Chronic hemolytic anemia \nThe chronic hemolytic anemias represent a subcategory of PAH. There has been increasing evidence that PAH is a complication of chronic hereditary and acquired hemolytic anemias, including sickle cell disease [46,47], thalassemia [48], hereditary spherocytosis [49], stomatocytosis [50], and microangiopathic hemolytic anemia [51].\nPH has been reported most frequently in patients with sickle cell disease, however the prevalence of PAH is not yet clearly established. The prevalence of PH in sickle cell disease is undoubtedly much lower than 32% as suggested by echocardiography [47]. Recently, a prospective epidemiologic studies using echocardiographic screening and direct hemodynamic confirmation were conducted in 398 outpatients with sickle cell disease at referral centers in France [52]. In this study, the prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second measured by echocardiography was 27%. In contrast, the prevalence of pulmonary hypertension confirmed on catheterization was only 6%, suggesting that echocardiographic evaluation alone had a low positive predictive value for PH in this population. Indeed, the precise mechanism of PAH in sickle cell disease remains uncertain.\n\nGroup 1’: Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis\nPVOD and PCH are uncommon conditions, but they are increasingly recognized as causes of PH [53]. A recent clinicopathologic study [54] analyzed specimens from 35 patients diagnosed as having either PVOD (n = 30) or PCH (n = 5). PCH was identified in 24 (73%) cases diagnosed as PVOD. Indeed, venous involvement was present in 4/5 cases initially diagnosed as PCH. These findings suggest that PCH may be an angioproliferative process frequently associated with PVOD. Similarities in pathologic features and clinical presentation suggest that these disorders may be two different presentation of the same disease [54].\nAlthough PVOD and PCH may present similarly to idiopathic PAH, there are a number of important differences. These include the presence of crackles on examination, radiologic abnormalities on high-resolution computed tomography of the chest (ground glass opacities, septal thickening, mediastinal adenopathy) [55-58], hemosiderin-laden macrophages on bronchoalveolar lavage [59], and a lower DLCO and PaO2 in patients with PVOD or PCH [58]. PVOD/PCH remains a difficult disorder to categorize, as it shares characteristics with idiopathic PAH but also has a number of distinct differences. Given the current evidence, it was decided that PVOD/PCH should be a distinct category but not completely separated from PAH and PVOD/PCH are designated as 1’ in the current classification.\n\nGroup 2: Pulmonary hypertension due to left heart disease\nLeft-sided ventricular or valvular diseases may produce an increase of left atrial pressure, leading to a backward transmission of the pressure and a passive increase of pulmonary arterial pressure. Left heart disease, probably represents the most frequent cause of PH [60]. In this situation, PVR is normal or near normal (\u003c3.0 Wood units) and there is no gradient between mean PAP and pulmonary wedge pressure (transpulmonary gradient \u003c12 mm Hg). In the Dana Point classification, the increasing recognition of left-sided heart dysfunction with preserved ejection fraction leads to changes in the subcategories of Group 2 and now this group include three distinct etiologies: left heart systolic dysfunction, left heart diastolic dysfunction, and left heart valvular disease. In some patients with left heart disease, the elevation of pulmonary arterial pressure is out of proportion to that expected from the elevation of left arterial pressure (transpulmonary gradient \u003e12 mm Hg), and PVR is increased to \u003e3.0 Wood units (19–35% of patients) [60]. However, there is no widely accepted hemodynamic definition of transpulmonary gradient, and future recommendations may propose new definition and threshold of this gradient. Some patients with left heart valvular disease or even left heart dysfunction can develop severe PH of the same magnitude as that seen in PAH [61-63]. The elevation of PAP and PVR may be due to either the increase of pulmonary artery vasomotor tone and/or pulmonary vascular remodeling [64,65].\n\nGroup 3: Pulmonary hypertension due to lung diseases and/or hypoxia\nIn this group, the predominant cause of PH is alveolar hypoxia as a result of either chronic lung disease, impaired control of breathing, or residence at high altitude. However, the precise prevalence of PH in all these conditions remains largely unknown. In the revised classification, the heading has been modified to reinforce the link with the development of PH. A category of lung disease characterized by a mixed obstructive and restrictive pattern was added, including chronic bronchiectasis, cystic fibrosis and the recently described syndrome of combined pulmonary fibrosis and emphysema in which the prevalence of PH is almost 50% [66,67]. In PAH associated with parenchymal lung disease, the increase of pulmonary arterial pressure is usually modest (mean PAP lower than 35 mmHg) [68]. Interestingly, in some patients, increase of PAP is out of proportion and be higher than 35 mmHg [69]. In a retrospective study of 998 patients with chronic obstructive pulmonary disease who underwent RHC, only 1% had severe PH [70]. These patients with more severe PH were characterized by mild-to-moderate airway obstruction, severe hypoxemia, hypocapnia, and a very low diffusing capacity for carbon monoxide.\n\nGroup 4: Chronic thromboembolic pulmonary hypertension\nChronic thromboembolic pulmonary hypertension (CTEPH) was included in Group 4. The incidence of CTEPH is uncertain. CTEPH represents however a frequent cause of PH and occurs in up to 4% of patients after an acute pulmonary embolism [71,72]. In the classification from the third World Symposium on PH, CTEPH was divided into 2 subgroups: proximal CTEPH and distal CTEPH, depending on the feasibility of performing pulmonary thromboendarterectomy. Currently, there is no consensus about the definitions of proximal and distal CTEPH and the decision of surgery may vary depending on individual centers [73]. Thus, the Dana Point Classification propose only one group irrespectively of proximal or distal obstruction. Patients with suspected or confirmed CTEPH need to be referred to expert centers with experience in the management of CTEPH, to consider the feasibility of performing surgery. The indication for surgery depends on the location of the obstruction, the correlation between hemodynamics and the degree of obstruction assessed by angiography, comorbidities, the willingness of the patient, and the experience of the surgeon [74,75]. Patients who are not candidates for surgery may benefit from PAH-specific medical therapy [76,77]; however, further evaluation of these therapies in randomized control trials are needed [78].\n\nGroup 5: PH with unclear or multifactorial etiologies\n\nGroup 5.1 Hematologic disorders \nPH has been reported in chronic myeloproliferative disorders including polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia [79,80]. Several mechanisms may be implicated in PH associated with chronic myeloproliferative disorders including high cardiac output, asplenia, direct obstruction of pulmonary arteries by circulating megakaryocytes [81], CTEPH [82], portal PH, and congestive heart failure. Splenectomy as a result of trauma or as a treatment for hematologic disorders may increase the risk of developing PH [83]. As described above, dasatinib use may be one cause of PAH, particularly in chronic myeloid leukemia [23].\n\nGroup 5.2 Systemic disorders \nThe second subgroup includes systemic disorders, including sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis or vasculitis.\nPH is a well recognized complication of sarcoidosis [84], with a reported prevalence of 1–28% [84]. PH is multifactorial and usually attributed to the destruction of capillary bed by the fibrotic process and/or the result of chronic hypoxemia [85]. However, the severity of PH is frequently out of proportion to the degree of parenchymal lung disease and blood gas abnormalities, suggesting specific pulmonary vascular involvement [86]. Such mechanisms may include extrinsic compression of large pulmonary arteries by lymph node enlargement, and granulomatous infiltration of the pulmonary vasculature, especially the pulmonary veins, which sometimes mimic PVOD [87].\nPulmonary Langerhans cell histiocytosis is an uncommon cause of infiltrative and destructive lung disease. Severe PH is a common feature in patients with end stage disease [88] and PH in these patients is usually related to chronic hypoxemia and/or abnormal pulmonary mechanics. Histopathologic examination has shown severe diffuse pulmonary vasculopathy involving predominantly intralobular pulmonary veins and, to a lesser extent, muscular pulmonary arteries [89].\nLymphangioleiomyomatosis is a rare multisystem disorder predominantly affecting women, characterized by cystic lung destruction, lymphatic abnormalities, and abdominal tumors. PH is relatively uncommon in patients with lymphangioleiomyomatosis [90]. Recently, a series of 20 cases of lymphangioleiomyomatosis associated PH has been reported showing that PH is usually moderate in this setting and associated with pulmonary function impairment [91].\nNeurofibromatosis type 1, also known as von Recklinghausen’s disease, is an autosomal-dominant disease. The disease is occasionally complicated by systemic vasculopathy. A series of cases of PH have been reported in the setting of Neurofibromatosis type-1 [92].\n\nGroup 5.3 Metabolic disorders \nPH has been reported in a few cases of type Ia glycogen storage disease, a rare autosomal-recessive disorder caused by a deficiency of glucose-6-phosphatase [93-95]. The mechanisms of PH are uncertain but portocaval shunts, atrial septal defects, severe restrictive pulmonary function defects or thrombosis are thought to play a role. In one case, autopsy findings revealed the presence of plexiform lesions [96].\nGaucher’s disease is a rare disorder characterized by a deficiency of lysosomal B glucosidase, which results in an accumulation of glucocerebroside in reticuloendothelial cells. In a study of 134 patients with Gaucher’s disease who were systematically screened by echocardiography, PH was not uncommon [97]. In this setting, several potential mechanisms for PH have been suggested, including interstitial lung disease, chronic hypoxemia, capillary plugging by Gaucher cells and splenectomy [97,98].\nThe association between thyroid diseases and PH has been reported in some studies [99]. A prospective study of 63 consecutive adult patients with PAH found a prevalence of autoimmune thyroid disease, including both hypothyroidism and hyperthyroidism, in 49%, suggesting that these conditions may share a common immunogenetic susceptibility [100].\n\nGroup 5.4 Miscellaneous conditions \nThe last subgroup includes a number of miscellaneous conditions, including tumoral obstruction, fibrosing mediastinitis or chronic renal failure on dialysis.\nA progressive obstruction of proximal pulmonary arteries leading to PH may be observed in tumor obstruction when a tumor grows into the central pulmonary arteries with additional thrombosis. Such cases are due principally to pulmonary artery sarcomas, which occur rarely but are usually rapidly fatal [101-103]. The differential diagnosis with CTEPH can be difficult and CT angiography may be useful to differenciate an obstruction by tumor or thrombotic material. Occlusion of the microvasculature by metastatic tumor emboli represents a cause of rapidly progressive PH.\nFibrosing mediastinitis have been mainly reported in sarcoidosis, tuberculosis, histoplasmosis and after radiotherapy. Fibrosing mediastinitis may be associated with severe PH due to compression of both pulmonary arteries and veins.\nLastly, PH has been reported in patients with end-stage renal disease maintained on long-term hemodialysis. Based on echocardiographic studies, the prevalence of PH in this patient population is estimated up to 40% [104]. PH in these patients may be explained by high cardiac output (resulting from the arteriovenous access, anemia and fluid overload) and potential diastolic and systolic left heart dysfunctions. Furthermore, hormonal and metabolic modification associated with end-stage renal disease might lead to dysfunction of normal pulmonary vascular tone.\n\n"}

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and classification\nPulmonary arterial hypertension (PAH) is defined by right-heart catheterization (RHC) showing precapillary pulmonary hypertension with a mean pulmonary artery pressure (mPAP) of \u003e25 mmHg and a normal pulmonary artery wedge pressure (PCWP) of \u003c15 mmHg [1,2]. The classification of pulmonary hypertension (PH) has gone through a series of changes since the first classification proposed in 1973 which designated only two categories, primary pulmonary hypertension or secondary PH, depending on the presence or absence of identifiable causes or risk factors [3,4]. In 1998, a second World Symposium on PH was held in Evian (France) and this classification attempted to create categories of PH that shared similar pathogenesis, clinical features and therapeutic options [5]. This classification allowed defining homogenous groups of patients to conduct clinical trials and to obtain approval for specific PAH therapies worldwide. In 2003, the third World Symposium on PH (Venice, Italy) did not propose major changes. However, the terms idiopathic PAH, familial PAH, and associated PAH were introduced. The other prominent change was to move pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from separate categories into a single subcategory of PAH.\nIn 2008, the fourth World Symposium on PH held in Dana Point (California, USA) and the consensus of an international group of experts was to revise previous classifications in order to accurately reflect published data, as well as to clarify some areas that were unclear. In 2013, the fifth World Symposium on PH held in Nice (France) and proposed only minor modifications, however, since the definite conclusions of this symposium were not yet published, we presented the Dana Point classification of PH (Table 1).\nTable 1 Diagnostic classification of pulmonary hypertension This classification was adapted from (Simonneau et al. [16]).\n\nGroup 1: Pulmonary arterial hypertension\nThe nomenclature of the subgroups and associated conditions has evolved since the first classification, and additional modifications were added in the Dana Point classification.\n\nGroup 1.1/1.2 Idiopathic and heritable PAH \nIdiopathic PAH describes a sporadic disease with neither a family history of PAH nor an identified risk factor. When PAH occurs in a familial context, germline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor beta (TGF- ß) signaling family, can be detected in about 70% of cases [6,7]. More rarely, mutations in activin receptor like kinase type 1 (ACVRL1 or ALK1) or endoglin genes, also coding for members of the TGF-ß signaling family, have been identified in patients with PAH, predominantly with coexistent hereditary hemorrhagic telangiectasia. Some authors suggested that mutations of genes encoding for Smads proteins (Smad8, Smad1 and Smad5), which are other members of the TGF-ß signaling pathway, or mutations in caveolin-1 gene may predispose to PAH [8-10].\nBMPR2 mutations have also been detected in 11–40% of apparently idiopathic cases with no family history [11,12]. Indeed, the distinction between idiopathic and familial PAH with BMPR2 mutations is artificial, as all patients with a BMPR2 mutation have heritable disease. In addition, BMPR2 mutations were identified in only 70-80% families with PAH. Thus, it was decided to abandon the term “familial PAH” in favor of the term “heritable PAH”, including idiopathic PAH with germline mutations and familial cases with or without identified mutations [13,14].\n\nGroup 1.3 Drug- and toxin-induced PAH \nA number of risk factors for the development of PAH have been individualized in the last European Respiratory Society/ European Society of Cardiology (ERS/ESC) conjoint guidelines of PH [15] (Table 2).\nTable 2 Updated risk level of drugs and toxins known to be associated with PAH *This table was adapted from Galiè et al. [15]. Aminorex, fenfluramine derivatives and toxic rapeseed oil represent the only identified “definite” risk factors for PAH [5,16]. Souza et al. have demonstrated that this subgroup of PAH shares clinical, functional, hemodynamic, and genetic features with idiopathic PAH, suggesting that fenfluramine exposure represents a potential trigger for PAH without influencing its clinical course [17].\nTwo prospective epidemiologic investigations, the SNAP (Surveillance of North American Pulmonary Hypertension) and the SOPHIA (Surveillance of Pulmonary Hypertension in America) study, were conducted in the USA [18,19]. These investigations included retrospectively 559 and 1335 patients with PH, respectively, and confirmed the previously described association between idiopathic PAH and the use of fenfluramine. In the SNAP study, the odds ratio of developing PH was 7.5 for the use of fenfluramine more than six months of treatment [18].\nThe agent benfluorex is structurally and pharmacological related to fenfluramine and may be also considered as an anorectic agent. Frachon and co-workers [20] showed a significantly higher prevalence of unexplained valvular heart disease in patients taking benfluorex compared to controls. In addition, Savale and co-workers demonstrated recently that exposure to benfluorex is suggested to be a trigger in the development of PAH [21]. Benfluorex was withdrawn from the market in 2009.\nThe SOPHIA study examined intake of a variety of nonselective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants and anxiolytics. No increased risk of developing PAH was observed [19].\nAmphetamine use represents a “likely” risk factor, although they are frequently used in combination with fenfluramine. A recent retrospective study suggested a relationship with the use of methamphetamine (inhaled, smoked, oral, or intravenous) and the occurrence of PAH [22]. Methamphetamine use is now considered a “very likely” risk factor for the development of PAH.\nRecently published data from the French registry of pulmonary hypertension suggested that dasatinib, a tyrosine kinsase inhibitor (TKI), may induce precapillary PAH [23]. Several cases of precapillary PH in chronic myelogenous leukemia patients treated with dasatinib have been reported.\n\nGroup 1.4.1 PAH associated with connective tissue diseases \nPAH associated with connective tissue diseases (CTD) represents an important clinical subgroup, in which systemic sclerosis represents the major cause of CTD associated PAH. The prevalence of PAH has been well established only for systemic sclerosis (SSc). Prospective studies using echocardiography as a screening method and RHC for confirmation found a prevalence of PAH between 7–12% [24,25]. PH due to lung fibrosis [26], diastolic left heart dysfunction [27] and primary cardiac involvement [28] are also frequent in the setting of pulmonary hypertension in these patients, emphasizing the importance of a systemic evaluation with RHC to accurately classify the underlying mechanism of PH.\n\nGroup 1.4.2 HIV infection \nPAH is a rare complication of HIV infection [29,30]. HIV-associated PAH has clinical, hemodynamic, and histologic characteristics broadly similar to those seen in idiopathic PAH. Epidemiologic data in the early 1990s, a time when therapy with highly active antiretroviral therapy was not yet available, indicated a prevalence of 0.5% [31]. The prevalence of HIV-associated PAH was evaluated more recently and showed a stable prevalence of 0.46% [32].\n\nGroup 1.4.3 Porto-pulmonary hypertension \nPorto-pulmonary hypertension (POPH) is defined by the development of PAH associated with increased pressure in the portal circulation [33,34]. Prospective hemodynamic studies have shown that 2-6% of patients with portal hypertension had PH [35,36]. However, RHC is mandatory for the diagnosis of portal PH, as several mechanisms may increase pulmonary artery pressure in the setting of advanced liver disease: hyperdynamic circulatory state with high cardiac output, fluid overload and diastolic dysfunction. Pulmonary vascular resistance (PVR) is usually normal in these cases.\n\nGroup 1.4.4 Congenital heart diseases \nA significant proportion of patients with congenital heart disease (CHD), in particular those with systemic-to-pulmonary shunts, will develop PAH if left untreated. Eisenmenger's syndrome is defined as CHD with an initial large systemic-to-pulmonary shunt that induces progressive pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis [37,38]. It represents the most advanced form of PAH associated with CHD. It has been reported that a large proportion of patients with CHD develop some degree of PAH [39-41]. The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Europe and North America has been estimated between 1.6 and 12.5 cases per million adults, with 25-50% of this population affected by Eisenmenger’s syndrome.\n\nGroup 1.4.5 Schistosomiasis \nIn the Dana Point classification, PH associated with schistosomiasis was included in Group 1. Recently, it has been demonstrated that PH associated with schistosomiasis may have a similar clinical presentation and histological findings as idiopathic PAH [42,43]. The mechanism of PAH in patients with schistosomiasis is probably multifactorial including portal PH, a frequent complication of this disease [44] and local vascular inflammation, whereas mechanical obstruction by schistosoma eggs seems to play a minor role. More than 200 million people are infected and 4–8% of them will develop hepatosplenic disease. Then, PAH associated with schistosomiasis represents a frequent form of PAH in countries where the infection is endemic. Data from a recent study based on invasive hemodynamics evidenced the prevalence of PAH in patients with hepatosplenic disease of 4.6%; also important was the prevalence of post-capillary hypertension (3%) reinforcing the need of invasive hemodynamics for the specific diagnosis of PAH in schistosomiasis [45].\n\nGroup 1.4.6 Chronic hemolytic anemia \nThe chronic hemolytic anemias represent a subcategory of PAH. There has been increasing evidence that PAH is a complication of chronic hereditary and acquired hemolytic anemias, including sickle cell disease [46,47], thalassemia [48], hereditary spherocytosis [49], stomatocytosis [50], and microangiopathic hemolytic anemia [51].\nPH has been reported most frequently in patients with sickle cell disease, however the prevalence of PAH is not yet clearly established. The prevalence of PH in sickle cell disease is undoubtedly much lower than 32% as suggested by echocardiography [47]. Recently, a prospective epidemiologic studies using echocardiographic screening and direct hemodynamic confirmation were conducted in 398 outpatients with sickle cell disease at referral centers in France [52]. In this study, the prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second measured by echocardiography was 27%. In contrast, the prevalence of pulmonary hypertension confirmed on catheterization was only 6%, suggesting that echocardiographic evaluation alone had a low positive predictive value for PH in this population. Indeed, the precise mechanism of PAH in sickle cell disease remains uncertain.\n\nGroup 1’: Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis\nPVOD and PCH are uncommon conditions, but they are increasingly recognized as causes of PH [53]. A recent clinicopathologic study [54] analyzed specimens from 35 patients diagnosed as having either PVOD (n = 30) or PCH (n = 5). PCH was identified in 24 (73%) cases diagnosed as PVOD. Indeed, venous involvement was present in 4/5 cases initially diagnosed as PCH. These findings suggest that PCH may be an angioproliferative process frequently associated with PVOD. Similarities in pathologic features and clinical presentation suggest that these disorders may be two different presentation of the same disease [54].\nAlthough PVOD and PCH may present similarly to idiopathic PAH, there are a number of important differences. These include the presence of crackles on examination, radiologic abnormalities on high-resolution computed tomography of the chest (ground glass opacities, septal thickening, mediastinal adenopathy) [55-58], hemosiderin-laden macrophages on bronchoalveolar lavage [59], and a lower DLCO and PaO2 in patients with PVOD or PCH [58]. PVOD/PCH remains a difficult disorder to categorize, as it shares characteristics with idiopathic PAH but also has a number of distinct differences. Given the current evidence, it was decided that PVOD/PCH should be a distinct category but not completely separated from PAH and PVOD/PCH are designated as 1’ in the current classification.\n\nGroup 2: Pulmonary hypertension due to left heart disease\nLeft-sided ventricular or valvular diseases may produce an increase of left atrial pressure, leading to a backward transmission of the pressure and a passive increase of pulmonary arterial pressure. Left heart disease, probably represents the most frequent cause of PH [60]. In this situation, PVR is normal or near normal (\u003c3.0 Wood units) and there is no gradient between mean PAP and pulmonary wedge pressure (transpulmonary gradient \u003c12 mm Hg). In the Dana Point classification, the increasing recognition of left-sided heart dysfunction with preserved ejection fraction leads to changes in the subcategories of Group 2 and now this group include three distinct etiologies: left heart systolic dysfunction, left heart diastolic dysfunction, and left heart valvular disease. In some patients with left heart disease, the elevation of pulmonary arterial pressure is out of proportion to that expected from the elevation of left arterial pressure (transpulmonary gradient \u003e12 mm Hg), and PVR is increased to \u003e3.0 Wood units (19–35% of patients) [60]. However, there is no widely accepted hemodynamic definition of transpulmonary gradient, and future recommendations may propose new definition and threshold of this gradient. Some patients with left heart valvular disease or even left heart dysfunction can develop severe PH of the same magnitude as that seen in PAH [61-63]. The elevation of PAP and PVR may be due to either the increase of pulmonary artery vasomotor tone and/or pulmonary vascular remodeling [64,65].\n\nGroup 3: Pulmonary hypertension due to lung diseases and/or hypoxia\nIn this group, the predominant cause of PH is alveolar hypoxia as a result of either chronic lung disease, impaired control of breathing, or residence at high altitude. However, the precise prevalence of PH in all these conditions remains largely unknown. In the revised classification, the heading has been modified to reinforce the link with the development of PH. A category of lung disease characterized by a mixed obstructive and restrictive pattern was added, including chronic bronchiectasis, cystic fibrosis and the recently described syndrome of combined pulmonary fibrosis and emphysema in which the prevalence of PH is almost 50% [66,67]. In PAH associated with parenchymal lung disease, the increase of pulmonary arterial pressure is usually modest (mean PAP lower than 35 mmHg) [68]. Interestingly, in some patients, increase of PAP is out of proportion and be higher than 35 mmHg [69]. In a retrospective study of 998 patients with chronic obstructive pulmonary disease who underwent RHC, only 1% had severe PH [70]. These patients with more severe PH were characterized by mild-to-moderate airway obstruction, severe hypoxemia, hypocapnia, and a very low diffusing capacity for carbon monoxide.\n\nGroup 4: Chronic thromboembolic pulmonary hypertension\nChronic thromboembolic pulmonary hypertension (CTEPH) was included in Group 4. The incidence of CTEPH is uncertain. CTEPH represents however a frequent cause of PH and occurs in up to 4% of patients after an acute pulmonary embolism [71,72]. In the classification from the third World Symposium on PH, CTEPH was divided into 2 subgroups: proximal CTEPH and distal CTEPH, depending on the feasibility of performing pulmonary thromboendarterectomy. Currently, there is no consensus about the definitions of proximal and distal CTEPH and the decision of surgery may vary depending on individual centers [73]. Thus, the Dana Point Classification propose only one group irrespectively of proximal or distal obstruction. Patients with suspected or confirmed CTEPH need to be referred to expert centers with experience in the management of CTEPH, to consider the feasibility of performing surgery. The indication for surgery depends on the location of the obstruction, the correlation between hemodynamics and the degree of obstruction assessed by angiography, comorbidities, the willingness of the patient, and the experience of the surgeon [74,75]. Patients who are not candidates for surgery may benefit from PAH-specific medical therapy [76,77]; however, further evaluation of these therapies in randomized control trials are needed [78].\n\nGroup 5: PH with unclear or multifactorial etiologies\n\nGroup 5.1 Hematologic disorders \nPH has been reported in chronic myeloproliferative disorders including polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia [79,80]. Several mechanisms may be implicated in PH associated with chronic myeloproliferative disorders including high cardiac output, asplenia, direct obstruction of pulmonary arteries by circulating megakaryocytes [81], CTEPH [82], portal PH, and congestive heart failure. Splenectomy as a result of trauma or as a treatment for hematologic disorders may increase the risk of developing PH [83]. As described above, dasatinib use may be one cause of PAH, particularly in chronic myeloid leukemia [23].\n\nGroup 5.2 Systemic disorders \nThe second subgroup includes systemic disorders, including sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis or vasculitis.\nPH is a well recognized complication of sarcoidosis [84], with a reported prevalence of 1–28% [84]. PH is multifactorial and usually attributed to the destruction of capillary bed by the fibrotic process and/or the result of chronic hypoxemia [85]. However, the severity of PH is frequently out of proportion to the degree of parenchymal lung disease and blood gas abnormalities, suggesting specific pulmonary vascular involvement [86]. Such mechanisms may include extrinsic compression of large pulmonary arteries by lymph node enlargement, and granulomatous infiltration of the pulmonary vasculature, especially the pulmonary veins, which sometimes mimic PVOD [87].\nPulmonary Langerhans cell histiocytosis is an uncommon cause of infiltrative and destructive lung disease. Severe PH is a common feature in patients with end stage disease [88] and PH in these patients is usually related to chronic hypoxemia and/or abnormal pulmonary mechanics. Histopathologic examination has shown severe diffuse pulmonary vasculopathy involving predominantly intralobular pulmonary veins and, to a lesser extent, muscular pulmonary arteries [89].\nLymphangioleiomyomatosis is a rare multisystem disorder predominantly affecting women, characterized by cystic lung destruction, lymphatic abnormalities, and abdominal tumors. PH is relatively uncommon in patients with lymphangioleiomyomatosis [90]. Recently, a series of 20 cases of lymphangioleiomyomatosis associated PH has been reported showing that PH is usually moderate in this setting and associated with pulmonary function impairment [91].\nNeurofibromatosis type 1, also known as von Recklinghausen’s disease, is an autosomal-dominant disease. The disease is occasionally complicated by systemic vasculopathy. A series of cases of PH have been reported in the setting of Neurofibromatosis type-1 [92].\n\nGroup 5.3 Metabolic disorders \nPH has been reported in a few cases of type Ia glycogen storage disease, a rare autosomal-recessive disorder caused by a deficiency of glucose-6-phosphatase [93-95]. The mechanisms of PH are uncertain but portocaval shunts, atrial septal defects, severe restrictive pulmonary function defects or thrombosis are thought to play a role. In one case, autopsy findings revealed the presence of plexiform lesions [96].\nGaucher’s disease is a rare disorder characterized by a deficiency of lysosomal B glucosidase, which results in an accumulation of glucocerebroside in reticuloendothelial cells. In a study of 134 patients with Gaucher’s disease who were systematically screened by echocardiography, PH was not uncommon [97]. In this setting, several potential mechanisms for PH have been suggested, including interstitial lung disease, chronic hypoxemia, capillary plugging by Gaucher cells and splenectomy [97,98].\nThe association between thyroid diseases and PH has been reported in some studies [99]. A prospective study of 63 consecutive adult patients with PAH found a prevalence of autoimmune thyroid disease, including both hypothyroidism and hyperthyroidism, in 49%, suggesting that these conditions may share a common immunogenetic susceptibility [100].\n\nGroup 5.4 Miscellaneous conditions \nThe last subgroup includes a number of miscellaneous conditions, including tumoral obstruction, fibrosing mediastinitis or chronic renal failure on dialysis.\nA progressive obstruction of proximal pulmonary arteries leading to PH may be observed in tumor obstruction when a tumor grows into the central pulmonary arteries with additional thrombosis. Such cases are due principally to pulmonary artery sarcomas, which occur rarely but are usually rapidly fatal [101-103]. The differential diagnosis with CTEPH can be difficult and CT angiography may be useful to differenciate an obstruction by tumor or thrombotic material. Occlusion of the microvasculature by metastatic tumor emboli represents a cause of rapidly progressive PH.\nFibrosing mediastinitis have been mainly reported in sarcoidosis, tuberculosis, histoplasmosis and after radiotherapy. Fibrosing mediastinitis may be associated with severe PH due to compression of both pulmonary arteries and veins.\nLastly, PH has been reported in patients with end-stage renal disease maintained on long-term hemodialysis. Based on echocardiographic studies, the prevalence of PH in this patient population is estimated up to 40% [104]. PH in these patients may be explained by high cardiac output (resulting from the arteriovenous access, anemia and fluid overload) and potential diastolic and systolic left heart dysfunctions. Furthermore, hormonal and metabolic modification associated with end-stage renal disease might lead to dysfunction of normal pulmonary vascular tone.\n\n"}