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The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)

The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)
Authors:
Lewis J Rubin, MD
William Hopkins, MD
Section Editors:
Jess Mandel, MD, MACP, ATSF, FRCP
Andrew Nicholson, MD
Deputy Editor:
Geraldine Finlay, MD
Literature review current through: Jul 2022. | This topic last updated: Nov 08, 2021.

INTRODUCTION — Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery pressure (mean pulmonary artery pressure ≥20 mmHg at rest with a pulmonary vascular resistance ≥3 Wood units). The World Health Organization (WHO) classifies patients with PH into five groups (table 1) based upon etiology [1]:

Group 1 – Pulmonary arterial hypertension (PAH)

Group 2 – PH due to left heart disease

Group 3 – PH due to chronic lung disease and/or hypoxemia

Group 4 – PH due to pulmonary artery obstructions

Group 5 – PH due to unclear multifactorial mechanisms

The term PAH is used to describe those included in group 1, while the term PH is used when describing all five groups. The pathogenesis of PAH is described in this review. The classification of PH and the pathogenesis of groups 2, 3, and 4 PH are provided separately. (See "Pathophysiology of heart failure with preserved ejection fraction" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Pathogenesis' and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Pathogenesis' and "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Neurohumoral adaptations' and "Pathophysiology of heart failure with reduced ejection fraction: Hemodynamic alterations and remodeling" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

EPIDEMIOLOGY — Pulmonary hypertension (PH) affects individuals of all age, race, and gender. However, because of the broad classification and multiple etiologies (table 1), obtaining accurate estimates of the prevalence of PH and its different forms, including PAH, has been challenging. Nonetheless, idiopathic PAH (IPAH) and heritable PAH (HPAH) are rare in the general population and estimated to be 5 to 15 cases per one million adults [2-4].

Although the prevalence of PAH is unknown in North America, several European registries have reported rates of 5 to 52 per million [5,6].

While schistosomiasis appears to be the most common cause of PAH worldwide, registry data in regions of the world without endemic schistosomiasis, report that over half of cases of PAH are idiopathic (IPAH) and up to 10 percent are heritable (HPAH) [2,5,6]. HPAH may be underdiagnosed. In one study, among five apparently unrelated families, 18 (out of 400) individuals had hereditary bone morphogenetic protein receptor 2 (BMPR2) mutations, 12 of whom were initially classified as IPAH [7]. Among the other associated etiologies of PAH, connective tissue disease and congenital heart disease appear to be the most common, the latter being the predominant cause of PAH in China [2,5,8].

Compared to other groups of PH, IPAH affects younger adults [9]. In contrast, in older populations, group 1 PAH is relatively uncommon. In one series, only 15 percent of 246 adults with PH older than 65 years had PAH, most frequently in association with connective tissue disease [10]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

Although men and women can have PAH, women are more likely to be affected (female:male ratio ranges from 1.7 to 4.8:1.0) as well as symptomatic from PAH [4,9].

While in the past studies suggested that PAH affected young women in their thirties, PAH is now a disease that affects men and women most commonly presenting in midlife. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

One United States registry reported a PAH predominance among White individuals (73 percent of registered cases) but PAH was also seen in African Americans (12 percent), Hispanic Americans (9 percent), and Asian Americans (3 percent) [9].

PAH-related hospitalizations and death may be decreasing. One national database reported that between 2007 and 2011, population-based death rates decreased from 4.6 to 1.7 per million and that the proportion of hospitalizations for PAH reduced from 79 to 38 per 100,000 hospitalizations [11]. Similarly, an analysis of the national inpatient sample database reported an over 50 percent reduction in the number of PAH-related hospitalizations between 2001 and 2012; however, there was no change in in-hospital mortality during that same time period (7.8 versus 6.3 percent) [12].

The epidemiology of other causes of PAH (table 1) are discussed in the followings sections:

Systemic sclerosis (see "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Epidemiology')

Congenital heart disease (see "Clinical manifestations and diagnosis of pulmonary hypertension in adults with congenital heart disease", section on 'Introduction')

Human immunodeficiency virus (see "Pulmonary arterial hypertension associated with human immunodeficiency virus", section on 'Prevalence')

Portopulmonary hypertension (see "Portopulmonary hypertension", section on 'Epidemiology')

Schistosomiasis (see "Schistosomiasis: Epidemiology and clinical manifestations", section on 'Pulmonary complications')

Pulmonary veno-occlusive disease (see "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Epidemiology')

Persistent pulmonary hypertension of the newborn (see "Persistent pulmonary hypertension of the newborn", section on 'Epidemiology')

PATHOGENETIC MECHANISMS — Described in this section is the general physiologic principles behind the development of pulmonary hypertension (see 'General physiologic mechanisms' below) as well as the pathogenetic mechanisms specific to the individual forms of PAH. (See 'Idiopathic and heritable' below and 'Drugs and toxins' below and 'Other conditions' below and 'Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis' below and 'Persistent pulmonary hypertension of the newborn' below.)

General physiologic mechanisms — Based upon a variation of Ohm’s Law (ie, change in pressure = flow x resistance), the mean pulmonary arterial pressure is determined by the following formula:

mean pulmonary artery pressure = (right ventricle cardiac output x pulmonary vascular resistance) + pulmonary alveolar occlusion pressure

The primary cause of significant pulmonary hypertension (PH) is almost always increased pulmonary vascular resistance (PVR). Increased flow alone (ie, right ventricle output) does not usually cause significant PH because the pulmonary vascular bed vasodilates and recruits vessels in response to increased flow. Similarly, increased pulmonary venous pressure (represented by the alveolar occlusion pressure) alone does not usually cause significant PH. However, a chronic increase of either flow and/or pulmonary venous pressure can increase pulmonary vascular resistance.

All variables can be altered by numerous medical conditions:

Increased PVR may be due to conditions associated with occlusive vasculopathy (ie remodeling and altered vascular tone) of the small pulmonary arteries and arterioles (eg, conditions associated with PAH), conditions that decrease the cross sectional area of the pulmonary vascular bed (eg, pulmonary emboli, interstitial lung disease), or conditions that induce hypoxic vasoconstriction (eg, hypoventilation syndromes and parenchymal lung disease).

Increased flow through the pulmonary vasculature may be due to congenital heart defects with left-to-right shunt (eg, atrial septal defects, ventricular septal defects, patent ductus arteriosus), liver cirrhosis, anemia, arteriovenous malformations, or arteriovenous fistulas (dialysis). (See "Pulmonary hypertension in patients with end-stage kidney disease".)

Increased pulmonary venous pressure may be due to mitral valve disease, left ventricular systolic or diastolic dysfunction, constrictive pericarditis, restrictive cardiomyopathy or pulmonary venous obstruction (eg, pulmonary veno-occlusive disease).

Idiopathic and heritable — Patients with idiopathic PAH (IPAH) are clinically indistinguishable from patients with heritable PAH (HPAH). Although they share common pathologic and pathogenetic features, heritable PAH exists when heritable genetic defects known to cause PAH can be identified (most often bone morphogenetic protein receptor type II [BMPR2] mutations) while IPAH is sporadic.

Pathology — PAH is a proliferative vasculopathy, characterized by vasoconstriction, cell proliferation, fibrosis, and microthrombosis. Pathologic findings include hyperplasia and hypertrophy of all three layers of the vascular wall (intima, media, adventitia) in pulmonary arteries <50 microns (ie, localizes to the small pulmonary muscular arterioles). In addition, fibrosis and in situ thrombi of the small pulmonary arteries and arterioles (plexiform lesions) can be seen [13,14]. The pathologic appearance of the small pulmonary arteries and arterioles is qualitatively similar in all patients with group 1 PAH.

Pathologic classification of the pulmonary vascular abnormalities (Heath and Edwards classification) was first done using patients with congenital heart disease [15], but are now applied to all patients with PAH and represent increasing severity of PAH (picture 1):

Grade I and II changes are characterized by muscularization of the small pulmonary arterioles, followed by medial hypertrophy and intimal hyperplasia.

Grade III abnormalities are characterized by collagenous replacement of intimal cells, leading to an "onion-skin" appearance.

Grade IV through VI abnormalities overlap, include plexiform lesions, and can be considered one stage [16-18].

Historically, it has been felt that Grade I, II, and III lesions are reversible while Grade IV through VI lesions are not. However, reversibility is poorly understood since no primary data exists as to the reversibility of these lesions in patients on PAH targeted therapy. However, many patients with a positive response to therapy do exhibit a drop in their pulmonary vascular resistance suggesting some degree of reversibility of the occlusive vasculopathy. Grade IV through VI lesions are associated with a poor outcome in patients that undergo surgery for congenital shunts [19,20].

Genetic mutations — Patients with IPAH may have an underlying genetic predisposition to pulmonary vascular disease, while patients with HPAH have PAH due to an inheritable genetic mutation. The most common heritable genetic mutation is BMPR2, which is transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity [21].

Mutations in the following genes have been variably associated with familial, idiopathic, or hereditary hemorrhagic telangiectasia (HHT)-associated PAH (table 2):

Bone morphogenetic protein receptor type II – BMPR2 is a member of the transforming growth factor (TGF)-beta family. Several lines of evidence support a role for abnormal BMPR2 in PAH:

Human – Up to 25 percent of patients with IPAH have abnormal BMPR2 structure or function [22-27], while up to 80 percent of hereditary PAH is due to mutations in BMPR2 [28].

Animal – Transgenic mice with smooth muscle specific deletion of BMPR2 have pulmonary hypertension [29].

Cellular – The BMPR2 pathway induces apoptosis, which when mutated, may permit excess endothelial cell proliferation in response to a variety of injuries (figure 1) [30].

Activin-like kinase type 1 receptor (ALK1; ACVRL1; also known as serine/threonine-protein kinase receptor R3) – The ALK1 receptor is also a member of the TGF-beta family. Mutations have been identified in some patients with HHT and PAH [31-33].

5-hydroxytryptamine (serotonin) transporter (5HTT) – Increased 5HTT activity may induce pulmonary artery smooth muscle hypertrophy. The L-allelic variant of the 5HTT gene promoter is associated with increased activity of 5HTT and is found in a greater percentage of patients with idiopathic PAH compared to controls [34,35].

Endoglin (ENG) – ENG is a protein involved in vasculogenesis. Mutations of the ENG gene have been associated with HHT and idiopathic PAH [36,37].

Mothers against decapentaplegic homologue 9 (SMAD9) – SMAD9 is an important intracellular signaling molecule downstream of the TGF-beta receptor. Rare mutations of SMAD9 have been found in patients with idiopathic PAH [38].

Caveolin 1 (CAV1) – CAV1 is a scaffolding plasma membrane-associated protein involved in cell cycle progression, mutations of which have been described in familial and idiopathic PAH [39].

Potassium channel subfamily K member 3 (KCNK3) – KCNK3 encodes a potassium channel, which can be remedied by pharmacologic manipulation. Mutations in KCNK3 were identified in familial and idiopathic PAH [40,41].

Mutations in the eukaryotic translation initiation factor 2-alpha kinase (EIF2AK4) gene are predominantly found in PAH associated with pulmonary veno-occlusive disease (PVOD). They have also been rarely found in patients with IPAH/HPAH [42,43]. However, one study reported that although EIF2AK4 mutations were found in 1 percent of patients clinically classified as having IPAH/HPAH, their clinical features and pathology suggested they were likely misclassified and probably had PVOD [42]; for example these patients tended to be younger (<50 years), had a low diffusing capacity (<50 percent predicted), and had a worse prognosis (ie, clinical features consistent with PVOD). (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Genetic factors'.)

Vascular mediators — In addition, to a genetic cause or predisposition, superimposed modifying factors activate or perpetuate the disease, thereby explaining the progressive nature of PAH.

Modifying factors involved in the pathogenesis of PAH include one or more of the following [13,44-56]:

Increased endothelin levels (endothelin is a vasoconstrictor and mitogen)

Decreased nitric oxide levels (nitric oxide is a vasodilator and is antiproliferative)

Decreased prostacyclin levels (prostacyclin is a vasodilator, is antiproliferative, and inhibits platelet function)

Studies implicating these molecules in the pathogenesis of PH have resulted in the development of drugs that augment prostanoid-mediated pathways, block endothelin receptors, or augment NO signaling by inhibiting breakdown of cGMP (eg, phosphodiesterase inhibitors), by directly activating guanylate cyclase(eg, riociguat), or by NO replacement (eg, inhaled NO). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Potassium channel dysfunction — Some data suggest that IPAH may result from functional impairment of the voltage-gated potassium channel (Kv) in pulmonary artery smooth muscle cells [57]. Such impairment could lead sequentially to a change in resting membrane potential, elevation of the intracytoplasmic free calcium concentration, and an increase in pulmonary vascular tone [58]. Kv dysfunction may also play an important role in the development of PAH due to anorectic agents (eg, fenfluramine, dexfenfluramine, and aminorex) or PH due to hypoxia [59].

Estrogen — Estrogen is considered a risk factor for the development of PAH. As an example, one preclinical study reported that estrogen inhibition prevented and treated PAH in BMPR2 mutant mice [60]. Human studies are lacking.

Drugs and toxins — The mechanism by which drugs cause pulmonary hypertension is unknown but thought to be due to altered growth factor biology (eg, serotonin, platelet derived growth factor). The following drugs are considered definite risk factors for PAH: appetite suppressants, toxic rapeseed oil, and benfluorex [1]. Drugs that are considered possible risk factors for PAH include the following: amphetamines, L-tryptophan, methamphetamines, cocaine, phenylpropanolamine, St. John's Wort, dasatinib, and interferon.

Definite:

Appetite suppressants (eg, aminorex, fenfluramine, dexfenfluramine, and methamphetamines ) increase the risk of developing PAH [61-66]. While the reason for this is largely unknown, altered serotonin biology may play a role. Serotonin has been shown to induce growth of pulmonary artery smooth muscle cells from patients with PAH; fenfluramine derivatives can interact directly with the serotonin transporter [67-70]. In a case control study that compared 95 patients with PAH to 335 control patients, appetite suppressants increased the risk of PAH (odds ratio [OR] 6.3, 95% CI 3-13) [62]. The risk was particularly high when the appetite suppressants were used in the preceding year or for more than three months (OR 10, 95% CI 3-30). Appetite suppressant use reported by patients with all types of PH is greater than that reported by the general population, suggesting that appetite suppressants may initiate PH in patients with underlying conditions that are associated with PH, or that obesity is associated with PH [71].

Rapeseed oil, when consumed in excess amounts, has been reported in the past to be associated with PAH, although amounts in commercially available vegetable oil are safe [72].

Benfluorex, a drug that is used in Europe for the treatment of diabetes and metabolic syndrome, shares an active metabolite with fenfluramine and has also been associated with the development of PAH with and without coexistent valvular heart disease [73-75].

Dasatinib, a tyrosine kinase inhibitor (TKI) used for the treatment of chronic myelogenous leukemia has been reported to cause PAH [76]. TKIs are known inhibitors of platelet derived growth factor (PDGF) receptor and its downstream signaling molecules (eg, Src kinase). PDGF has a well-defined role in the pathogenesis of PAH so the association between TKIs and PAH is somewhat paradoxical and unexplained. Prior treatment with imatinib (another TKI that is less potent than dasatinib) and female gender appear to be risk factors for the development of dasatinib-induced PAH. Dasatinib-associated PAH may be partially reversible upon discontinuation of the drug. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

Several drugs have also been associated with the development of pulmonary veno-occlusive disease (mostly chemotherapeutic agents), which are discussed separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Drugs and toxins'.)

Possible:

Chronic use of cocaine or amphetamines or use of diethylpropion either inhaled or intravenous, has also been associated with PAH [62,77-79]. The mechanism is thought to relate to the shared pharmacologic properties with fenfluramine. In one study, cocaine or amphetamine use tripled the risk of developing PAH [62].

PAH has also been associated with amphetamine use and with recreational use of the designer amphetamine analog, 4-methyl-aminorex (ie, ice, euphoria, U-4-E-uh), as well as with leflunomide, phentermine, and mazindol (used for the treatment of narcolepsy and obesity) [71,80-82]. Several drugs that have mechanisms of action that are similar to amphetamines (eg, methylphenidate and ropinirole) have no clear association with PAH. However, clinicians should be aware in case patients develop symptoms of PAH .

PAH has been reported in a small number of patients receiving interferon (IFN) therapy for hepatitis (IFN-alpha) and multiple sclerosis (IFN-beta) through an unknown mechanism [83-86]. IFN-associated PAH may be partially reversible upon discontinuation of the drug. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

Other drugs that have been listed as possible agents associated with PAH include phenylpropanolamine, L-tryptophan, St. John’s wort, alkylating agents, bosutinib, direct-acting antiviral agents against hepatitis C virus, and indirubin (chinese herb Qing-Dai) [1,87-89].

While no clear association with adult PAH has been demonstrated with selective serotonin reuptake inhibitors (SSRIs), they are associated with a poor prognosis in those with established PAH [90]. They have also been associated with the development of persistent pulmonary hypertension of the newborn when taken by pregnant mothers [91-95]. (See "Persistent pulmonary hypertension of the newborn".)

Other conditions — There are several other conditions that can be complicated by PAH, the pathogenesis of which is less clear.

Connective tissue diseases — While several connective tissue diseases (systemic sclerosis, Raynaud’s disease, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis) can be complicated by PAH alone they can also be complicated by other forms of pulmonary hypertension (eg, PH from interstitial lung disease and from heart failure, or both), the pathogenesis of which is poorly understood. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Pulmonary vascular disease'.)

Congenital heart disease — The pathogenesis of pulmonary hypertension in patients with congenital heart disease (eg, septal defects, Eisenmenger syndrome) is discussed separately. (See "Clinical manifestations and diagnosis of pulmonary hypertension in adults with congenital heart disease".)

Eisenmenger syndrome is the most severe and end-stage form of shunt-related PAH. This group also includes patients that have PAH with coincidental or small defects and those with persistent or worsening PAH despite closure of the defect. (See "Pathophysiology of left-to-right shunts", section on 'Pulmonary hypertension' and "Clinical manifestations and diagnosis of pulmonary hypertension in adults with congenital heart disease", section on 'Pathogenesis'.)

Human immunodeficiency virus — A small proportion of patients with human immunodeficiency virus (HIV) develop PAH, the pathogenesis of which is discussed separately. (See "Pulmonary arterial hypertension associated with human immunodeficiency virus", section on 'Pathogenesis'.)

Portopulmonary hypertension — Patients with portal hypertension, typically from chronic liver disease, may develop PAH, the pathogenesis of which is discussed separately. (See "Portopulmonary hypertension", section on 'Pathogenesis'.)

Schistosomiasis — PAH can develop in patients infected with schistosomiasis species, particularly those with hepatosplenic involvement, the details of which are provided separately. (See "Schistosomiasis: Epidemiology and clinical manifestations", section on 'Pathogenesis' and "Schistosomiasis: Epidemiology and clinical manifestations", section on 'Pulmonary complications'.)

Miscellaneous — One case of PAH has been reported to be induced by profound vitamin C-deficiency [96].

Vasoreactivity to calcium channel blockers — A small subset (5 to 10 percent) of patients with significant PAH exhibit an acute response to pulmonary vasodilators (usually calcium channel blockers; "responders") [97]. This population may be physiologically different to the remaining majority who do not respond to vasodilators ("non-responders"). Limited data suggest that recruitment of pulmonary flow from the precapillary microvessels (ie, functional capillary surface area [FCSA]) to distal capillary microvessels is different between responders and non-responders. One observational study of 14 drug-naïve patients with PAH measured FCSA before and after vasodilator testing in responders (12 patients) and non-responders (two patients) at the time of diagnosis [98]. Responders had a higher resting FCSA that readily increased during vasodilator testing when compared with non-responders. In contrast, non-responders were unable to recruit FCSA flow during vasodilator testing. These observations suggested that the primary pathology in vasodilator-responsive patients is vasoconstriction at the precapillary level, compared with non-responders who may be unable to recruit flow due to obstructed vessels at the precapillary level. Further exploration of this theory is warranted with the inclusion of larger numbers of responders. Measurement of the vasodilator response is discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients'.)

Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis — Pulmonary veno-occlusive disease-associated PH (classified as group 1’) (table 1) has a pathophysiology that appears to be distinct from other forms of PAH, the details of which are provided separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Pathogenesis and risk factors'.)

Persistent pulmonary hypertension of the newborn — Persistent pulmonary hypertension of the newborn (PPHN) is classified as group 1’’. Details regarding the pathogenesis of PPHN are provided separately. (See "Persistent pulmonary hypertension of the newborn", section on 'Pathogenesis'.)

SUMMARY AND RECOMMENDATIONS

Pulmonary hypertension (PH) is classified into five groups based on the World Health Organization (WHO) classification system. The term PAH is used to describe those included in WHO group 1, while the term PH is used when collectively describing all five groups. (See 'Introduction' above.)

Idiopathic PAH (IPAH) and heritable PAH (HPAH) are rare in the general population and estimated to be 5 to 15 cases per one million adults, although schistosomiasis is the most common cause worldwide. PAH affects younger adults and although it occurs in both genders, women are affected more often and are generally more symptomatic than men. (See 'Epidemiology' above.)

PAH is a proliferative vasculopathy of the small pulmonary muscular arterioles (<50 microns). It is characterized by vasoconstriction, hyperplasia, hypertrophy, fibrosis, and thrombosis that involves all three layers of the vascular wall (intima, media, adventitia). Patients with IPAH and heritable variants may have a genetic predisposition to PAH (eg, bone morphogenetic protein receptor 2 mutations) with additional contributing mechanisms including vasoactive mediators, potassium channel dysfunction and abnormal response to estrogen. (See 'Pathogenetic mechanisms' above and 'Idiopathic and heritable' above.)

The pathogenesis of other forms of PAH (eg, drugs and toxins, connective tissue disease, congenital heart disease, human immunodeficiency virus, portopulmonary hypertension, schistosomiasis, pulmonary venoocclusive disease, persistent pulmonary hypertension of the newborn) is poorly understood. (See 'Pathogenetic mechanisms' above and 'Drugs and toxins' above and 'Other conditions' above and 'Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis' above and 'Persistent pulmonary hypertension of the newborn' above.)

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Topic 8247 Version 35.0

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