Group 1: Pulmonary arterial hypertension
The nomenclature of the subgroups and associated conditions has evolved since the first classification, and additional modifications were added in the Dana Point classification.

Group 1.1/1.2 Idiopathic and heritable PAH 
Idiopathic 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].
BMPR2 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].

Group 1.3 Drug- and toxin-induced PAH 
A 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).
Table 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].
Two 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].
The 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.
The 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].
Amphetamine 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.
Recently 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.

Group 1.4.1 PAH associated with connective tissue diseases 
PAH 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.

Group 1.4.2 HIV infection 
PAH 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].

Group 1.4.3 Porto-pulmonary hypertension 
Porto-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.

Group 1.4.4 Congenital heart diseases 
A 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.

Group 1.4.5 Schistosomiasis 
In 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].

Group 1.4.6 Chronic hemolytic anemia 
The 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].
PH 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.