Risk Factors for Pulmonary Arterial Hypertension

PULMONARY HYPERTENSION 0272-5231/01 $15.00 + .OO

RISK FACTORS FOR PULMONARY ARTERIAL HYPERTENSION

Marc Humbert, MD, Hilario Nunes, MD, Olivier Sitbon, MD, Florence Parent, MD, Philippe Herv6, MD,

and Gerald Simonneau, MD

A new diagnostic classification of pulmonary hypertension was proposed at the 1998 World Health Organization (WHO) Pulmo- nary Hypertension Meeting held in Evian, France (see article on Classification of Pulmo- nary Hypertension by Fishman elsewhere in this issue).88 This classification reflects recent advances in the understanding of pulmonary hypertensive diseases and recognizes the similarity between "unexplained" pulmonary hypertension (primary pulmonary hypertension, PPH) and pulmonary arterial hypertension (PAH) of certain known causes (see Ta- ble 1).

Primary pulmonary hypertension is a rare disease, with an estimated prevalence of one to two per million people.87, 92 It can be sporadic or clustered in families.@* 87, 88, 92 Re- cent genetic studies have identified mutations in the bone morphogenetic protein receptor- 2 (BMPR-2) gene, a receptor member of the transforming growth factor-p family, in most familial cases of PPH.23, Io9 Interestingly, more than 25% of patients displaying sporadic PPH have mutations in the BMPR-2 gene, emphasizing the relevance of genetic susceptibility for this severe condition.l1° Other molecular processes behind the complex vascular changes associated with PAH currently are being investigated, including vasoconstric-

tor-vasodilator imbalance, thrombosis, mis- guided angiogenesis, and inflammation.88, 115

In PPH, the distinctive vascular changes are found in the precapillary arteries. The same pathology is found in PAH of various ori- gins (collagen vascular diseases, human immunodeficiency virus [HIV] infection, portal hypertension, congenital systemic-to-pulmonary shunts, and anorexigen exposure).88

A risk factor for PAH is any factor or condition that is suspected to play a causal or facilitating role in the development of the dis-

Because risk factors relate to the proba- bility of occurrence of the disease, they must be present before the onset of the disease. Risk factors may include drugs, chemical products, diseases, or a clinical state (age, gender). When it is not possible to determine whether a factor was present before the onset of pulmonary hypertension, and it therefore is unclear whether it played a causal role, the term associated condition is used.88 Given the fact that the absolute risk is generally low with the known risk factors of PAH, factors of individual susceptibility are likely to play an important role. Whether mutations of BMPR-2 are implicated in such cases pres- ently is being investigated.

Table 1 describes a number of risk factors and conditions believed to be associated with

From the Service de Pneumologie et Rkanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, HBpital Antoine B&lhre, Universite Paris-Sud, Clamart, France

CLINICS IN CHEST MEDICINE

VOLUME 22 * NUMBER 3 * SEFTEMBER 2001 459

460 HUMBERT et a1

Table 1. RISK FACTORS AND ASSOCIATED CONDITIONS FOR PULMONARY HYPERTENSION

A. Drugs and toxins 1. Definite

Aminorex Fenfluramine . Dexfenfluramine Toxic rapeseed oil

2. Very likely Amphetamines - L-tryptophan

Meta-amphetamines

Chemotherapeutic agents

Antidepressants Oral contraceptives Estrogen therapy Cigarette smoking

3. Possible

Cocaine

4. Unlikely

B. Demographic and medical conditions 1. Definite

2. Possible Gender (female)

Pregnancy Systemic hypertension Splenectomy

3. Unlikely Obesity

C. Diseases 1. Definite

2. Very likely HIV infection

Portal hypertension Collagen vascular diseases Congenital systemic-to-pulmonary cardiac shunts (Eisenmenger 's syndrome)

3. Possible Thyroid disorders Hemoglobinopathies (sickle cell disease,

Type Ia glycogen storage disease (von Gierke's

Lipid storage disorders (Gaucher's disease) Hereditary hemorrhagic telangiectasia (Osler-

thalassemia, spherocytosis)

disease)

Weber-Rendu disease)

pulmonary hypertension. These elements have been classified according to the strength of their association with pulmonary hypertension and their probable facilitating role.88 Definite indicates an association based on several concordant observations, including a major controlled study or a clear epidemic. Definite risk factors are considered to play a causal role in the development of the disease. Very Iikely indicates several concordant observations (including large case series and studies) that are not attributable to considered biases or a general consensus among experts. Possible indicates an association based on case series, registries, or expert opinions. Unlikely indicates risk factors that have been proposed

but have not been found to have any association based on controlled studies.

DRUGS AND TOXINS

Appetite Suppressants

Aminorex Fumarate

The question of a relationship between some drug ingestion and pulmonary hypertension first was raised in the late 1960s, when a 20-fold increase of unexplained pulmonary hypertension was reported in Swit- zerland, Austria, and West Germany.37, 38, 52

This epidemic followed the introduction in these countries of the appetite depressant aminorex fumarate (2-amino-5-phenyl-2-oxa- zoline) and subsided shortly after the drug was banned from the market. Approximately only 2% of the population that had taken aminorex developed pulmonary arterial hypertension, but 61% of the 582 patients who were identified as new cases of PPH gave a history of aminorex intake.37, 38 The relative risk for developing pulmonary hypertension in aminorex users was estimated to be 52:l compared with patients without any exposure to the 38

At that time, controversial conclusions were raised regarding the relationship between the total individual dose and the risk for developing the disease, given that there was no correlation between the disease severity and the number of tablets each individual 'patient had taken.37,38 During follow-up, some authors believed that, after discontinuation of the drug, patients with a history of aminorex intake had a better long-term survival than "unexposed" patients with PPH, whereas other authors did not report differences in survival 38, Aminorex resembles epi- nephrine and amphetamine, and a release of catecholamines from endogenous stores by this drug has been suggested, has a mechanism involving lung serotonin release. All at- tempts based on experimental work to produce chronic pulmonary hypertension and to demonstrate the effect of the chronic adminis- tration of aminorex in any species have failed, however. This failure has been explained first by the low incidence of pulmonary hypertension in test animals and in humans and, second, by the fact that a prerequisite for the pulmonary circulation to constrict or prolifer- ate when exposed to an offending agent is

RISK FACTORS FOR PULMONARY ARTERIAL HYPERTENSION 461

probably attributable to a ity.

Fenfluramine Derivatives

genetic susceptibil-

Fenfluramine derivatives (fenfluramine and dexfenfluramine) are phenylethylanine derivatives that have been prescribed widely as anorectic drugs since the early 1 9 6 0 ~ . ~ ~ Several cases of fenfluramine-associated PAH have been reported since 1981.l”~ 25, loof 116 For some patients, the condition resolved completely after withdrawal of the drug, although re- versibility is debatable.25 Brenot et all3 studied a group of 73 patients with PPH and found that approximately 25% of them had been exposed to fenfluramine. This marked increase followed the large increase in the sales of fenfluramines in France after the introduction of dexfenfluramine in the market (1985- 1992). The International Primary Pulmonary Hypertension Study (IPPHS) found a clear association between appetite suppressants and pulmonary hypertension, with an odds ratio (relative risk estimate) of 6.3 (95% CI = 3-13.2).’ Ninety percent of the cases for whom a defined product could be traced had used a fenfluramine derivative.2 The risk increased markedly with duration of use (relative risk estimate of 23.1 for more than 3 months: 95% CI = 6.9-77.7) and decreased after cessation of intake.’ Similar cases of fenfluramine or dexfenfluramine-induced PAH were reported in the United States after the introduction of these agents in the market or after the large increase in the use of the ”phen-fen” combi-

The Surveillance of North American Pul- monary Hypertension Study recently confirmed a clear association between the use of fenfluramine derivatives and the diagnosis of pulmonary hyperten~ion.~~ The withdrawal of these agents in September 1997 may well have aborted an incipient epidemic in North America, all the more because the risk for developing the condition increases with the duration of use of fenfluramines. Moreover, these anorexigens also may have precipitated the occurrence of PAH in patients with other underlying conditions, such as collagen vascular disease.89

The pathogenetic mechanisms of pulmonary hypertension associated with fenfluramine derivatives remain unknown.loO It seems, however, that alteration of the serotonin (5-hydroxytryptamine) pathway might be

nation.32.67.89 ,

a common denominator.26, loo Serotonin is known to be a powerful pulmonary vasoconstrictor and can induce platelet aggregation.26 Moreover, serotonin is also a potent factor stimulating pulmonary smooth muscle prolif- erationZ6 Recent studies support the hypothesis that fenfluramine derivatives may con- tribute to PPH by increasing serotonin availability or by interacting with serotonin receptors, promoting pulmonary vascular smooth muscle proliferation, PA vasoconstriction, and local microthrombosis. Under normal conditions, the lung vascular bed is not exposed to excessive serotonin levels, because virtually all blood serotonin is stored in the platelets and free serotonin is metabolized rapidly by the endothelial monoamine oxi- dase in the liver and the lung endothelium. By interacting with the serotonin transporter, fenfluramine derivatives release serotonin from platelets and inhibit its reuptake into platelet and pulmonary endothelial cells. As a consequence, free serotonin concentration in the blood increases with fenfluramine treatment. Some evidence indicates that such an abnormality in platelet serotonin storage is a trigger factor in the development of PAH in susceptible patients: (1) A decrease in platelet serotonin storage with enhanced blood concentration of free serotonin has been reported in sporadic cases of PPH and in numerous disorders occasionally associated with PPH, including portal hypertension, Raynaud’s phenomenon, collagen vascular disease, and platelet storage pool disease.26, 42, 43 (2) Platelet serotonin storage remains im- paired in patients with PPH after heart-lung transplantation, whereas it is normal in patients with secondary pulmonary hypertension, indicating that this platelet dysfunction is not secondary to the pulmonary vascular disease.43 (3) The fawn-hooded rat, which has a genetic defect in serotonin platelet storage, develops severe pulmonary hypertension upon exposure to modest hypoxia.26 (4) Fen- fluramine, associated or not with phentermine, recently was shown to induce valvular heart disease in a manner similar to that observed after exposure to serotonin-like drugs such as ergotamine and methysergide and with increased serotonin levels associated with carcinoid disease.18 Interestingly, one third of these patients with valvular heart disease had coexisting pulmonary hypertension.ls All of these observations suggest that fenfluramine may trigger pulmonary hyper-

462 HUMBERT et a1

tension by aggravating or inducing impair- ment in platelet serotonin storage.

Only a minority of patients exposed to fenfluramine derivatives develop pulmonary hypertension, suggesting that this subset of patients could have a genetic susceptibi1ity.l. loo

Whether BMPR-2 mutations are present in patients with fenfluramine-associated pulmonary hypertension has to be determined. Aminorex and fenfluramine derivatives inhibit potassium current in rat pulmonary vascular smooth muscle and stimulate pulmonary vasoconstriction.120 Because inhibition of nitric oxide (NO) synthase markedly potenti- ated the vasoconstrictor effect of fenfluramine in isolated rat lung, it has been speculated that patients who develop PPH while taking an anorectic agent could have a pre-existing diminished NO activity.120 Such a defect has been demonstrated in a small series of patients suffering with severe fenfluramine-associated pulmonary hypertension.6 Finally, poor metabolizers of fenfluramine derivatives may have a more pronounced exposure to the drug and therefore may be more prone to develop the condition, as recently suggested by Higenbottam and col leag~es.~~

Amphetamines

Phentermine has been used as an appetite suppressant since the 1960s. During the aminorex epidemic, a survey found that patients with pulmonary hypertension had used phentermine. In the mid-l990s, a large increase in the use of phentermine occurred in the United States because of the popular phen-fen combina t i~n .~~ Chlorphentermine and phenmetrazine were suggested to con- tribute to the development of pulmonary hypertension, but no report has been issued in humans since 1972. In the authors’ clinic, several patients with an isolated exposure to amphetamine derivatives such as amfepramone and clobenzorex have been identified clearly30 It is not yet clear, however, whether amphetamines alone can cause the di~ease.~

Toxic Rapeseed Oil

The ”toxic oil syndrome” is an interesting example of the relationships between exposure to chemicals and pulmonary hyperten~i0n.l~. 33* 54, 83 The occurrence of a multisystemic disease, first recognized as a pneumo- nia based on pulmonary symptoms and inter-

stitial infiltrates on chest roentgenograms, suddenly increased in Spain in early 1981.54 The failure of patients to respond to antibiotic therapy, the clustering of the disease within families, without any evidence of a pathogenic agent, and the lack of cases among infants were factors that favored the suggestion of a potential exposure to a toxic agent. These findings led to evidence that the consumption of rapeseed oil was the responsible agent or the vehicle for the epidemic. Hypotheses were made that the oil was contaminated. A WHO Expert Committee defined the condition as the toxic oil syndrome. A total of 20,688 cases were registered officially. Among them, 835 have died. Exposure to toxic oil was defined loosely as the consumption of oil, pre- sumed to be toxic, before the onset of the disease or the occurrence of the disease within the nuclear family, or an epidemic out- break in the community. Pulmonary hypertension was found in approximately 20% of hospitalized patients at the second to fourth month following the onset of the disease.83 Alonso-Ruiz et a15 followed 332 cases of toxic oil syndrome for up to 8 years and found that 8.1% developed pulmonary hypertension. The condition regressed in 74%, and only 2% developed a malignant form of pulmonary hypertension at the end of a follow-up period of 8 years.5 It was estimated that pulmonary hypertension accounted for about 1.6% of all deaths caused by toxic oil. In a group of 40 cases of severe pulmonary hypertension attributable to toxic oil syndrome, aged from 8 to 58 years old and with a female-to-male ratio of 4:1,83% died within 6 years of follow- up. In these patients, microscopic examination of the lungs demonstrated pulmonary hypertensive arteriopathy, including medial hypertrophy, intimal fibrosis, and plexiform lesions.

L-Tryptophan

L-Tryptophan is a food supplement used for ailments such as premenstrual syndrome, insomnia, depression, and drug detoxifica- tion.lo7 Since 1989, it has been linked etiologi- cally with a newly recognized disease, eosinophilia-myalgia syndrome (EMS). More than 1500 cases of EMS have been reported in the United States, and the number of cases has been estimated to be as high as 5000. Of the reported cases, 83% were women, and 94% were non-Hispanic whites, with a median age


of 48 years, data that are believed to reflect the pattern of L-tryptophan users rather than potential risk factors. In its serious, multisystemic, and progressive course, many cases of EMS presented with cough and dyspnea, interstitial infiltrates, and pleural effusion. Pulmonary involvement consists of eosinophilic and vasculitis syndromes, interstitial lung disease, and pulmonary hypertension. Few cases have been reported with pulmonary hype r t ens i~n .~~ . lo7 Biopsy specimens show vasculitis and perivasculitis to be associated with a mild chronic interstitial pneu- monitis and eo~inophi1ia.l~~ Considering multisystemic manifestations of EMS and its linkage with L-tryptophan consumption, pulmonary hypertension related to the intake of L-tryptophan should be considered as a sepa- rate item in the definition criteria of PAH.

Substance Abuse

An association between pulmonary hypertension and substance abuse has been reported in children, young women, and men. Evidence was first obtained from case series, which usually include selected populations. Pulmonary hypertension was found among boys with a history of chronic glue (toluene)

in a case of "crank" and "peanut butter methamphetamine" inhalation, and in young women with a history of smoking crack cocaine.l, 97 Cocaine abuse by a mother also produced signs of persistent pulmonary hypertension in a newborn. In the IPPHS, use of "hard drugs" (intravenous drugs or cocaine) was associated with an increased risk (OR = 2.9), but numbers were small.' The use of hashish and marijuana was not different between cases and contro1s.l In most studies, it is difficult to disentangle the role of the product used (cocaine, heroine) from that of emboli associated with intravenous drug

Moreover, known risk factors for PAH (HIV infection or liver diseases) are prevalent in this patient population.

Herb Toxins

In rats, monocrotaline, a pyrrolizidine alka- loid found in a plant called Crotalaria, and fulvine, found in Crotalaria fiIva, has induced pulmonary hypertension and right-sided heart failure. Bush tea is made with extracts from seeds and leaves from these plants. Pul-

monary hypertension has been described after the ingestion of bush tea.', 26

Chemotherapeutic Agents

Mitomycin-C

Mitomycin-C is used in chemotherapy for malignant tumors. Pulmonary veno-occlusive disease occurred in patients with metastatic cervical carcinoma or with metastatic gastric adenocarcinoma after treatment with mitomycin-C.51.119

Carmustine, Etoposide, and Cyclophosphamide

Pulmonary veno-occlusive disease was reported in two children suffering from acute lymphoblastic leukemia treated with marrow allograft transplant, followed by high doses of carmustine [NN-bis(2-chloroethyl)-N-nitro- sourea], etoposide, and cyc1ophosphamide.l. 39

Open-lung biopsy demonstrated pulmonary veno-occlusive disease. Similarly, some reports seem to incriminate the use of bleomy- cin in some cases.l

Nonsteroidal Anti-inflammatory Drugs

lndomethacin

Indomethacin is used to treat premature labor and polyhydramnios.1° It has been reported that the risk for PPH in the newborn may be increased after prolonged therapy. In a randomized clinical trial, Besinger and col- 1eagues'O found three cases of pulmonary hypertension in newborns whose mothers re- ceived indomethacin in preterm labor.l0 It subsequently has been described that five premature newborns, whose mothers had re- ceived indomethacin, developed clinical and biologic symptoms similar to those of pulmonary hypertension. Findings in the literature, however, are inconsistent.

Naproxen

Naproxen can be used to delay parturition by inhibiting prostaglandin synthesis. Persis- tent pulmonary hypertension was noted in three newborns whose mothers had a history

464 HUMBERT et a1

of exposure to naproxen, which was associated with low plasma concentration of prostaglandin.lz2

Phenformin

Phenformin has been used to treat diabetes mellitus and was reported to be associated with severe lactic acidosis, which could induce pulmonary vasoconstriction in animal experiments. Two cases of pulmonary hypertension, believed to be associated with treatment with phenformin, have been reported.lZ8

Oral Contraceptives

Kleiger and c011eagues~~ and Masi68 reported cases of pulmonary hypertension in women with a history of oral contraceptive use. There was no evidence of thromboembo- lism in the lungs or the veins of the leg. In the IPPHS study, neither oral contraceptive nor estrogen use was associated with a significantly increased risk.z

Antidepressants

The effects of the selective serotonin reuptake inhibitors such as fluoxetine on platelet serotonin uptake are similar to those of fenfluramine.loo Despite large worldwide use, however, no case of pulmonary hypertension or valvular heart disease has been reported yet with these drugs. In contrast to fenfluramine derivatives, which are serotonin receptor agonists in the brain, these antidepressants do not stimulate serotonin receptors. This difference suggests that the increase in serotonin availability is not the unique mechanism of fenfluramine-associated pulmonary hypertension, and that fenfluramine derivatives might induce PAH by interacting with serotonin receptors located in the pulmonary arterial

Alglucerase Replacement Therapy

Patients with symptomatic Gaucher’s disease on enzyme-replacement therapy have shown significant improvement in health-related quality of life.27 The possibility that pulmonary hypertension in patients with

Gaucher ’s disease is triggered, aggravated, or complicated by treatment with placenta- derived alglucerase or the recombinant form, imiglucerase, has been suspected.z* z7 Because these substances have been shown to decrease many signs and symptoms of Gaucher’s disease effectively, this possible side effect is of major concern. Current theoretic explanations include coincidental, unrelated disorders (e.g., micropulmonary emboli or PPH concur- rent with Gaucher’s disease); pulmonary hypertension as a feature of severe Gaucher’s disease, unrelated to and unaffected by enzyme replacement therapy; and drug-induced or drug-aggravated pulmonary hypertension. Elstein and colleaguesz1 recently investigated by echocardiography the rate of pulmonary hypertension among adults with Gaucher ’s disease. Seven percent of the patients studied had pulmonary hypertension (all on enzyme replacement therapy and two thirds with a history of splenectomy). The confounding effects of disease severity and splenectomy in treated patients precluded definitive conclusion of cause and effect.21 There is no consensus regarding replacement therapy withdrawal in treated patients with Gaucher’s disease with pulmonary hypertension. In- deed, withdrawing treatment in symptomatic patients may increase the risk for Gaucher’s disease progression without definitive evidence of the relationship between treatment and pulmonary hypertension.

Cigarette Smoking

Cigarette smoking promotes the occurrence of lung diseases leading to pulmonary hypertension such as chronic obstructive pulmonary disease and histiocytosis X.30, 88 Similarly, cigarette smoking is a major risk factor for ischemic left-sided ventricular heart disease, leading to most of cases of pulmonary venous hypertension in Western countries. Neverthe- less, cigarette smoking by itself has not been shown to increase the risk for developing pulmonary arterial hypertension in the absence of these cardiopulmonary conditions. In the IPPHS study, smoking was reported significantly more often by case patients than by controls, but it was not associated with an increased risk for pulmonary hypertension when other covariates were controlled for.2


DEMOGRAPHIC AND MEDICAL CONDITIONS

Age, Gender, and Race

Primary pulmonary hypertension can occur at any age but most commonly appears in young adults.12, 87 The gender ratio is approximately 1:l in childhood but shows a greater incidence in females in young adults (1.7:l in the US National Institute of Health (NIH) Registry and in the authors' French cohort).12 The mean age at the time of diagnosis is approximately 40 years in most large case series, with a peak of incidence in the third and fourth decades of life. Primary pulmonary hypertension also may occur relatively late in life. Nine percent of the patients in the NIH Registry had the diagnosis established after the age of 60 years (8% in the authors' series).12, 87 No difference ever has been docu- mented definitely in the geographic or racial incidence of the disease. In the NIH Registry and in the authors series, however, there was a greater incidence in black female patients with a (fema1e:male) ratio of 3:l in both co- horts.", 87 The reason for such findings is unclear, although black women might be more susceptible than white women to the development of autoimmune disorders.

Pregnancy and Hormonal Influences

Although many investigators, on the basis of some experimental studies, share the no- tion that hormonal influences on the pulmonary circulation are important, the important findings have yet to come.86 As discussed previously, the increase in incidence of PPH in women of childbearing age is a common finding.lZ Because pregnancy and labor increase the demand on the heart-pulmonary system, they should be contraindicated in patients with pulmonary hypertension. Indeed, pregnancy is a well-known factor that in- duces or aggravates pulmonary hypertension in otherwise well-tolerated systemic-to-pulmonary shunts, such as atrial septa1 defects. Similarly, there are several reports of onset of PPH during pregnancy.21, 31, 76 Whether this indicates that the disease was present earlier and was exacerbated by the hemodynamic changes of pregnancy, or whether pregnancy and hormonal factors may be considered risk factors for PPH remains to be elucidated. Re-

cent pregnancies seemed to be more frequent in the patients than in the controls in the IPPHS study, but IPPHS did not have sufficient numbers of patients to be conclusive in this regard.2

Familial History

Primary pulmonary hypertension has been diagnosed in families worldwide.@ The prevalence of genetic or familial PPH is uncertain but is at least 6% of all PPH cases. Recent studies in well-characterized families suggest that this proportion may be considerably higher.** The transmission of PPH has many unique features that often complicate the diagnosis of familial cases (autosomal dominant transmission with genetic anticipation, variable expression, and a lifetime penetrance of 10% to 20%).63 As described previously, the gene for familial PPH (PPH1 gene) has been localized to chromosome 2q31-32 and subsequently identified as BMPR-2, a receptor member of the transforming growth factor+ (TGF-P) familyz3, 77, lo9 The IPPHS study confirmed that familial cases represent a risk factor for PPH.' It is believed that the likelihood of a first-degree relative being affected when only one person in a family has PPH can be estimated at 0.6% to 1.2%.** If there is a second case in the family, the lifetime risk rises to 5% to 10%.88

Systemic Hypertension

A history of systemic hypertension might occur more frequently in patients with PAH, highlighting the possibility of a systemic rather than compartmentalized propensity of producing vasoconstrictive agents such as en- dothelin-1 or a decreased ability to produce vasodilating agents such as NO in this patient population. The IPPHS study did not have sufficient power to allow any clear conclusion on this possibility, however.

Obesity

Many detractors of the fact that appetite suppressants could play a role in pulmonary hypertension assumed that obesity was a confounding risk factor for this condition. The IPPHS investigators considered whether the

466 HUMBERT et a1

association between the use of appetite suppressants and pulmonary hypertension could be explained by the confounding effect of obesity or of any hidden factor associated with obesity. The effect of appetite suppressants was the same whether or not patients had a high body-mass index.’-3 Neither weight-loss behavior of another type nor the use of thyroid extracts was associated posi- tively with the risk for pulmonary hypertension, as would have been expected if obesity accounted for the odds ratio observed for anorexic agents.’”

Thrombotic Risk Factors

Thrombotic lesions are observed consis- tently in chronic thromboembolic pulmonary hypertension and frequently found in PPHFs It remains unknown, however, whether thrombosis is related to defects of the anti- thrombotic pathway or to previous vascular injury. The authors recently analyzed the frequency of thrombotic risk factors in patients displaying chronic thromboembolic pulmonary hypertension or PPH.’23 The prevalence of hereditary thrombotic risk factors was not increased in either patient population (anti- thrombin, protein C and protein S activities, mutations of factor V and factor 1I).l3 In contrast, a high frequency of phospholipid-de- pendent antibodies was observed in PPH (10%) and, more notably, in chronic thromboembolic pulmonary hypertension (20%).123 In PPH, these antibodies in low titer may reflect endothelial dysfunction, whereas in chronic thromboembolic pulmonary hypertension, the presence of antibodies in high titer associated with lupus anticoagulant underlines the role of thrombosis in the pathogenesis of this condition.

Splenectomy

An increased risk for pulmonary hypertension previously has been suggested in patients with certain hemolytic disorders such as thalassemia or hereditary stomat~cytosis.~~ 47, 70 In this patient population, splenectomy may be a risk factor for thromboembolic complications and pulmonary hyperten~ion.4~ The underlying pathogenetic mechanisms are unclear but it has been hypothesized that because of loss of the filter function of the

spleen, abnormal erythrocytes remain in the circulatory system longer and may trigger platelet activation. These activated platelets then could become trapped in the pulmonary vascular bed. Such mechanisms could be ac- tive in any patient who has had splenectomy but would be aggravated in the presence of hemolytic disorders. Hoeper and c011eagues~~ recently reported that the prevalence of asplenia in patients with pulmonary hypertension was 11.5% (7 of 61) compared with 0% in 151 lung transplant recipients referred to the same clinic at the same peri0d.4~ Causes of asplenia in these seven patients included spherocytosis, idiopathic thrombopenic pur- pura, and trauma. Histopathologic examination of lung specimens from patients with postsplenectomy pulmonary hypertension showed intimal fibrosis, plexiform lesions, and abundant thrombotic lesions. Similarly, splenectomy is present in more than 5% of patients referred to the authors’ center for severe pulmonary hypertension. Interestingly, asplenia is associated with classical PPH but also with chronic thromboembolic pulmonary hypertension that sometimes is accessible to surgical cure (pulmonary thromboendarter- iectomy),

Altitude

Residents of highland areas usually show some signs of pulmonary vascular reaction to chronic alveolar h y p o ~ i a . ~ ~ In the Himalayas, at altitudes 3000 to 5000 meters, 5% of subjects present with right ventricular hypertrophy, whereas 27% of those living between 4500 and 5000 meters have clinical evidence35 of pulmonary hypertension. It has been suggested that immigrants from lowlands to high altitude may be more likely to react to chronic hypoxia than lifelong re~idents.3~ Recreational or frequent stays in high altitude are not associated with the risk for developing pulmonary hypertension, although such stays may reveal what was at sea level an otherwise paucisymptomatic condition.

DISEASES

Human Immunodeficiency Virus Infection

Several cases of HIV-1-infected patients with pulmonary hypertension have been re-


ported, raising the question of a causal relationship between these two condition^.'^, 71,

79-82, 85, Io2 The first case of HIV infection-associated pulmonary hypertension was described in 1987 by Kim and FactoP in a homosexual patient who also had membranoproliferative glomerulonephritis. This complication of HIV infection then was reported in patients with hemophilia, suggesting a possible role for factor VIII concentrates. It subsequently was observed that PAH occurred in HIV-infected patients regardless of the risk category for the condition, supporting the concept that it could be related to HIV infection itself. Al- though every risk group for HIV infection can be affected, intravenous drug addicts seem to

In a recent review7’ and in the authors’ intravenous drug use represents 42% and 56% of the cases of HIV-associated PAH, whereas this risk factor is observed in approximately one third of the overall HIV population in developed countries.71* 79 In intravenous drug addicts, some additional risk factors for pulmonary hypertension, such as foreign particle pulmonary emboli,gO coin- fection (including viral hepatitis),44 liver diseases,44 portal hypertensionjU and substance abuse (such as amphetamines and cocaine),g7 also could play a part in the occurrence of pulmonary hypertension.

Since 1987, fewer than 200 cases of HIV- associated pulmonary hypertension have been reported in the 1iteratu1-e.~~ Pulmonary hypertension therefore is regarded as an uncommon complication of HIV infection and it surprisingly is omitted in many reviews on pulmonary aspects of HIV infection. The incidence of pulmonary hypertension in patients with HIV infection is too high for the association to be considered as coincidental, however. In a prospective study from a cohort of 1200 HIV-infected patients, six cases of pulmonary hypertension were detected by echocardiography, giving a cumulative incidence of 0.5%.102 A Swiss survey of a large cohort of 3349 HIV-infected subjects found pulmonary hypertension in 19 patients over a period of 5.2 years, representing a cumulative incidence of 0.57%. In the authors’ center, 56 cases of HIV-associated pulmonary hypertension were observed between 1986 and 1998, leading to an estimated number of 150 to 300 French cases during the same period of time, suggesting a cumulative incidence of HIV- associated pulmonary hypertension ranging from 0.1% to 0.2% in France. The IPPHS study

confirmed that HIV infection is a risk factor for pulmonary hypertension.2

Histopathologic findings of HIV associated- pulmonary hypertension includes classical pulmonary hypertensive arteriopathy and veno-occlusive disease.71 In intravenous drug users, pulmonary vascular obstruction from embolic material or talc granulomatosis rarely is observed.s2 The hypothesis of a direct infection of the pulmonary vascular wall has not been confirmed in two studies, supporting the concept that HIV may play a role through mediator release associated with retroviral infection rather than by direct endothelial infec- t i ~ n . ~ ~ , 72 The authors69 and others72 have suggested an indirect role for HIV on the production of cytokines and growth factors such as PDGF by activated macrophages and lymphocyte^.^^, 72 Similarly, human herpes virus 8 (HHVB) has been implicated in HIV- related Kaposi sarcoma pathogenesis, another HIV-associated condition characterized by abnormal angiogenesis. The authors were un- able to demonstrate evidence of HHV8 infection in their patients by means of enzyme- linked immunosorbent assay and Western blot analysis, however.49 Interestingly, only a minority of HIV-infected individuals develop pulmonary hypertension, suggesting that displaying this condition in the context of an HIV infection requires some predisposition. A recent report74 indicates that HIV-associated PPH may reflect a host response to HIV determined by one or more human leukocyte anti- gen-DR alleles located within the major his- tocompatibility complex.74 Similarly, the involvement of mutations affecting the PPHl gene are being evaluated. Indeed, genetically predisposed individuals may have abnormal growth factor signaling in response to HIV, which, in turn, promotes abnormal cell proliferation.

Clinical and hemodynamic features of HIV associated-pulmonary hypertension are similar to those of PPH. In a comparison of 56 patients with HIV-associated pulmonary hypertension with 112 patients with PPH observed during the same period of time, survival rate was lower in patients with HIV, presumably because of less frequent use of continuous intravenous epoprostenol in these patients.79 In HIV-associated pulmonary hypertension, prognosis is related mainly to pulmonary hypertension itself rather than to other complications of HIV infection and it is the direct cause of death in approximately 75% of reported cases. In the Swiss cohort,

468 HUMBERT et a1

the survival rate in HIV-associated pulmonary hypertension is significantly lower than in patients with HIV without pulmonary hypertension. Recent improvement in survival in this patient populations coincides with major improvement in therapies, including new antiretroviral drugs and vasodilator agents such as epoprostenolso (Nunes H, Humbert M, and Simonneau G, submitted).

Portal Hypertension and Liver Diseases

Pulmonary hypertension is a well-recognized complication of chronic liver diseases.16, 40, 44, 65, 75, 98 Portal hypertension rather than the hepatic disorder itself seems to be the main determining risk factor for developing pulmonary hypertension, leading to the concept of portopulmonary hypertension.4* Ini- tially described by Mantz and Craige66 in 1951, portopulmonary hypertension is suffi- ciently infrequent so that it was debated for a long time whether this association was coincidental or causally related. Several lines of evidence suggest that the existence of portal hypertension and the development of pulmonary hypertension is noncoincidental. Indeed, the incidence of pulmonary hypertension in patients with portal hypertension is much higher than the estimated incidence of PPH in the general population. A large retrospective autopsy study0 showed that pulmonary hypertension occurred in 0.13% of overall unse- lected autopsied patients, versus 0.73% of patients with cirrhosis and portal hypertension. Two prospective hemodynamic studies40 showed that 2% of patients with cirrhosis and portal hypertension had significant pulmonary hypertension. Two recent studies carried out in patients undergoing liver transplanta- tionM, loM found an incidence of pulmonary hypertension of 4% and 3.5%, respectively. Finally, the IPPHS study confirmed that cirrhosis was a risk factor for pulmonary hypertension. Portal hypertension is not a rare cause of pulmonary hypertension; the proportion of patients with portopulmonary hypertension was 8% in the NIH registry and 13% in the authors’ series.

The mechanism whereby portal hypertension facilitates the development of pulmonary hypertension remains unknown. The presence of porto-systemic shunt might allow vasoconstrictive and vasoproliferative substances, normally cleared by the liver, to reach

the pulmonary circulation. Serotonin produced by the enterochromaffin cells of the intestine may be one of these substances. His- topathologic findings of portopulmonary hypertension are indistinguishable from those commonly observed in PPH. Hemodynami- cally, compared with patients with PPH, patients with portopulmonary hypertension have a significantly higher cardiac output and significantly lower systemic vascular resistances and pulmonary vascular resistances. In a retrospective study, patients with portopulmonary hypertension had a better rate of survival than patients with primary pulmonary hypertension, although there is some debate on this issue.44, 6o Continuous intravenous epoprostenol infusion may be effective against portopulmonary hype r t en~ ion .~~ In- terestingly, liver transplantation has been shown to reverse the pulmonary vascular disorder in selected ind iv id~als .~~

Collagen Vascular Diseases

Pulmonary hypertension is a well-known complication of collagen vascular diseases such as systemic scler0sis,5~, 93, lo4, 114 systemic lupus erythematosus,6, lol mixed connective tissue disease,lo5< lZ1 and to a lesser extent, rheumatoid arthritis,73 dermatopolymyo- sitis,14, and primary Sjogren’s 96

In these patients, pulmonary hypertension may occur in association with interstitial fibrosis or as a result of direct proliferative vascular involvement in the absence of significant parenchymal disease or chronic hypoxia. Estimation of the prevalence of pulmonary hypertension in patients with collagen vascular diseases is difficult because of the lack of consistent epidemiologic data. Esti- mated prevalence of pulmonary hypertension in these patients is highly variable, according to the definition of pulmonary hypertension and the method used for assessing PA pres- sure and potential bias concerning the study population.

Systemic sclerosis, particularly in its CREST (calcinosis, Raynaud’s disease, esophageal dysmotility, sclerodactyly, and telangiectasia) variant, represents the main collagen vascular disease associated with pulmonary hyperten- ~ i o n . ~ ~ , lo4, 114 In a large study of 673 patients with the CREST variant of systemic sclerosis, 9% were noted to have significant pulmonary hypertension. In the NIH registry, among 236 cases of unexplained pulmonary hyperten-


sion, 18 were associated with collagen vascular diseases In the authors' center, more than 10% of the patients displaying severe PAH have an associated collagen vascular disease, most often the CREST variant of scleroderma. Histopathologic changes in pulmonary hypertension associated with collagen vascular diseases are generally undistin- guishable from those of classical PPH.lZ4 Moreover, the whole spectrum of pulmonary vascular pathology has been described in these patients, including veno-occlusive disease and pulmonary capillary hemangio-

The mechanisms leading to pulmonary hypertension in patients with collagen vascular diseases remain unknown. A pulmonary va- sospasm, the so-called pulmonary Raynaud phenomenon, hypothetically could play a role. The presence of antinuclear antibody, rheumatoid factor, immunoglobulin-G, and com- plement fractions deposits in the pulmonary wall vessels suggests a role for an immuno- logic mechanism. Compared with patients with PPH, patients with pulmonary hypertension and collagen vascular diseases are mainly women, are older, have a significantly lower cardiac output, and show a trend toward a shorter survival. In the authors' experience, survival was significantly lower in the patients suffering from scleroderma compared with other collagen vascular disease.5o, 94

In these patients, immunosuppressive therapy seems to be effective only in a minority of patients mainly suffering from conditions other than ~cleroderma.~~ Continuous intravenous epoprostenol therapy has produced interesting results in this indication, although less than in age- and severity-matched PPH.50,94

matosis.36, 4650 . 76. 124

Congenital Systemic-to-pulmonary Cardiac Shunts (Eisenmenger's Syndrome)

In 1897, Viktor Ei~enmenger'~~ described a patient with cyanosis and dyspnea since infancy who died of massive hemoptysis at 32 years of age. Postmortem examination showed a ventricular septal defect and severe pulmonary vascular disease.l17 In 1958, Wood coined the term Eisenmenger complex to describe pulmonary hypertension at the systemic level caused by high pulmonary vascular resistance, with reversed or bidirectional shunting through a large ventricular septal

defect. Subsequently, the term Eisenmenger's syndrome has been used to describe pulmonary vascular disease and cyanosis resulting from any systemic-to-pulmonary circulation connection, such as atrial septal defect, ventricular septal defect, patent ductus arteriosus, or aortopulmonary window.l17 The likelihood of developing Eisenmenger's syndrome depends on the size and location of the intra- cardiac defect. Among patients with ventricular septal defects, 3% of patients who have a small or moderate-sized (51.5 cm in diameter) defect and approximately half the patients who have a large (>1.5 cm diameter) defect will develop Eisenmenger's syndrome.l17 Among the patients who have a large defect, the syndrome develops in half of those with ventricular septal defects or patent ductus arteriosus and only in about 10% of those with atrial septal defects.lo3! 117

Moreover, patients with patent ductus arteriosus or ventricular septal defects who develop the syndrome have an earlier onset (80% during infancy) than do patients with atrial septal defects (goo/, during adult-

The reason that some children develop pulmonary hypertension in the context of atrial septal defect remains poorly under- stood. It seems likely that factors other than congenital heart disease are necessary to ex- plain the occurrence of pulmonary hypertension in a minority of patients suffering from an otherwise well-tolerated atrial septal defect.

The pulmonary vascular involvement from congenital heart disease usually follows a period of decreased pulmonary resistance and high pulmonary blood flow but may occur in patients who never manifest a large left-to- right shunt, further suggesting that the pulmonary hypertension in these individuals might be "primary," rather than "secondary" to congenital heart disease. Support for this comes from reported cases of severe pulmonary hypertension in children with small atrial septal defects whose mothers had PPH, suggesting that congenital heart disease may play an additional role in people predisposed to develop pulmonary hypertension or may be a misleading risk factor in individuals genetically predisposed to develop PPH.88 Moreover, histopathologic examination of the lungs of these patients is usually indistinguishable from that of PPH.

Thyroid Disorders

An association between PPH and hypothy- roidism9, 2o or hyperthyroidismll' has been

470 HUMBERT et a1

suggested by some authors on the basis of a limited number of case reports. The present authors recently evaluated the prevalence of autoimmune thyroid diseases in the South Paris University PPH Registry and compared this prevalence with that of autoimmune thyroid diseases reported in Whickham, UK, a representative sample of Western Europe pop~lation.”~ Fourteen patients (13 females) met all the criteria of autoimmune thyroid diseases in the authors’ Registry (eight Hashi- moto’s diseases and six Graves’ diseases). When compared with the Whickham population, the authors’ female PPH population was characterized by a higher prevalence of Hashimoto’s disease (2.8% versus 19’0) but not Graves’ disease (1.8% in both series). Isolated PPH and PPH associated with autoimmune thyroid diseases were similar in terms of hemodynamics and survival. The only clinical difference was the higher rate of Raynaud’s phenomenon in PPH associated with autoimmune thyroid diseases (50% versus 14%). This finding raises the question of the respective roles of autoimmunity and the hemodynamic consequences of hypothyroidism in severe pulmonary hyperten~ion.~

Hematologic Conditions

Hemoglobinopathies such as sickle cell disease, thalassemia, or spherocytosis, may result in pulmonary hypertension alone or in combination with another known risk factor such as splenectomy, liver disease, or chronic thromboembolic pulmonary hyperten~ion.~, 70

Myeloproliferative disorders (e.g., polycythe- mia Vera, idiopathic myelofibrosis, essential thrombocytosis) have been described as possible conditions leading to pulmonary hyper- tension34 although several cofactors (high blood flow attributable to splenomegaly or chronic anemia, hematopoietic infiltration of the pulmonary parenchyma and alveolar capillary plugging by malignant cells, thrombocytosis, hypercoagulability, chemotherapeutic agents, portal hypertension, splenectomy) may play a part in these patients.&, 47 More- over, it is of utmost importance to evaluate, in detail, the left side of the heart because left ventricular failure is a common feature in this setting. Other hematologic conditions, including lymphomas, have been associated with PAH and pulmonary veno-occlusive disease.lo6 In these patients, several cofactors (mediastinal compression, chemotherapy, ra-

diotherapy, bone marrow transplantation, vascular plugging) may act in synergy to pro- mote the occurrence of PAH.

Rare Diseases

Unexplained pulmonary hypertension in patients with rare diseases provides valuable tools to analyze possible relevant pathobio- logic hypotheses in PAH. Development of severe PAH with no identifiable cause in a patient with a rare familial platelet storage deficiency, for instance, allowed the authors to hypothesize that serotonin-a pulmonary vasoconstrictor and growth factor for vascular smooth muscle cells stored in platelets- could play a role in PAH. This observation subsequently led to the description of altered serotonin turnover leading to an increased availability of free serotonin in patients with PPH.43, 53 Similarly, the authors believe that identification of PAH in rare but well-characterized genetic or metabolic diseases will pro- vide new hypotheses in the field of pulmonary vascular diseases (e.g., alternative role of a known mutated gene, genetic defects in chromosomic regions adjacent to a mutated gene, role of a new metabolic pathway).

Type la Glycogen Storage Disease (von Gierke 3 Disease)

Type Ia glycogen storage disease is an autosomal recessive disorder caused by a deficiency of glucose-6-phosphatase (von Gierke’s disease). Its estimated incidence is 1 per 100,000. Since the pioneer description of Pizzo in 1980, seven cases of severe pulmonary hypertension have been described in von Gierke’s disease.”, 84 In all but one case, this condition was severe, leading to the patients’ deaths within a few months of cardiopulmonary arrest or untractable congestive right heart failure. When available, postmortem examination of the lungs demonstrated pulmonary hypertensive arteriopathy, indistinguishable from classical PPH.84

The only case occurring before the age of 10 years was in a young girl with atrial septal defect of the secundum type and type Ia glycogen storage disease.” Interestingly, neither atrial septal defect nor type Ia glycogen storage disease usually lead to severe pulmonary hypertension in the first decade, suggesting that these conditions could have cumulative negative effects, with a faster progression of

RISK FACTORS FOR PUQMONARY ARTERIAL HYPERTENSION 471

the pulmonary vascular disease.'lfs4, 117 The six remaining cases of severe PAH complicating the course of type Ia glycogen storage disease occurred in the second or third decade, suggesting that long-term metabolic abnormalities may be necessary to lead to pulmonary hypertension. The authors recently hypothesized that the occurrence of PAH in type I glycogen storage disease could be caused by abnormal production of vasoconstrictive amines such as serotonin. As a first step to study the serotonin hypothesis in this rare condition, the authors prospectively mea- sured plasma serotonin in a series of patients displaying type Ia glycogen storage disease with or without pulmonary hypertension. Demonstration of elevated plasma serotonin in most patients, irrespective of PAH, suggested that this mediator could be involved in the development of this condition in susceptible individuals with type Ia glycogen storage disease (Humbert M, Labrune P, Si- monneau G, submitted). As described previously, familial and sporadic PPH may be caused by mutations in the BMPR-2 gene.23, lo9, 110 Other genes predisposing to PPH presumably will be identified in the near future. The gene responsible for type Ia glycogen storage disease has been cloned on the long arm of chromosome 17 in position 17q21. Fur- ther studies should be performed to investi- gate a possible gene linked to pulmonary hypertension in the same chromosomic region.

Lipid Storage Disorders (Gaucher's Disease)

Gaucher's disease is another rare autoso- ma1 recessive disorder characterized by a deficiency of lysosomal P-glucosidase, resulting in the accumulation of glucocerobroside in reticuloendothelial cells. The typical manifestations of this lipid storage disorder include hepatosplenomegaly and bone marrow infiltration with dysfunctional monocytes. With the exception of splenectomy, few options were available for treating this disorder until enzyme replacement therapy with alglucerase became available. Lung involvement in Gaucher's disease has been reported to occur in the following three distinct patterns: interstitial infiltrates of Gaucher cells with associated fibrosis; alveolar consolidation by Gaucher cells, filling alveolar spaces; and pulmonary hypertension.22 Pulmonary hypertension may result from capillary plugging by Gaucher liver splene~tomy,~~ enzyme replacement therapy (alglucerase or

imiglucerase),22 or closure of intrapulmonary vascular dilatations following the reduction of hepatomegaly by enzymatic treatment,22 resulting in increased blood flow through a pre-existing restriction of the pulmonary vascular bed. As discussed previously, there is no consensus regarding replacement therapy wi thd rawa l i n t rea ted pa t ien ts wi th Gaucher 's disease with pulmonary hyperten- s i ~ n . ~ ~

Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

The classic patient with hereditary hemorrhagic telangiectasia has nose bleeds, dilated vessels over the lips and fingertips, and gas- trointestinal bleeding in later life.99 Arteriove- nous malformations in the pulmonary, cere- bral, and hepatic circulations account for some of the most devastating clinical complications of the disease.99 This condition has an autosomal-dominant inheritance pattern. Mutations in at least two genes have been shown to be associated with hereditary hemorrhagic telangiectasia in different families-endoglin on chromosome 9 and ALK-1 (activin receptor-like kinase-1) on chromosome 12-although there is now evidence that a third hereditary hemorrhagic telangiectasia gene accounts for the disease in some patients with hereditary hemorrhagic telangiectasia with pulmonary inv~lvement .~~ Interestingly, endoglin and ALK-1 encode endothelial cell transmembrane proteins that can be defined as components of the receptor complexes for growth factors of the TGF-P ~uperfamily.~~ This occurrence suggests that disease pathogenesis is likely to result from perturbation of physiologic effects of growth factors in vascular development or hemosta- sis.

The main physiologic features of patients with pulmonary arteriovenous malformations are pulmonary hypotension and a right-to- left intrapulmonary shunt.11s There have been occasional reports of pulmonary hypertension, however.95, In 1969, Sapru and col- l e a g u e ~ ~ ~ described two patients with hereditary hemorrhagic telangiectasia and mild- to-moderate PAH.95 In the same report, they described an additional case of PAH occurring in a patient with a single, large arteriovenous fistula in the right middle In another report, Trell and colleagues112a described two sisters with severe pulmonary

472 HUMBERT et a1

hypertension and hereditary hemorrhagic telangiectasia, emphasizing the possibility of a genetic predisposition of developing pulmonary hypertension in a subset of patients with Osler-Weber-Rendu syndrome. Moreover, two patients with large arteriovenous pulmonary fistula recently were referred to the authors' institution for end-stage PAH, emphasizing the fact that a minority of patients with arteriovenous pulmonary malformations may develop pulmonary hypertension rather than pulmonary hypotension. The reasons for this uncommon presentation are being investigated.

Finally, the authors and others are following up several members of families in which patients with isolated so-called PPH have a familial history of hereditary hemorrhagic telangiectasia without evidence of PAH. The authors strongly believe that analyzing in detail the clinical and genetic characteristics of these patients and families will help in understanding the reasons why diseases characterized by an abnormal TFG-P signaling pathway may lead to uncommon vascular disorders such as hereditary hemorrhagic telangiectasia and PPH.'lZb

SUMMARY

The present limitations in knowledge of the potential risk factors for PPH undoubtedly are attributable to the facts that PPH is a rare disease with an unknown pathogenesis and lacking large case series. Moreover, definite epidemiologic data are rare and ideally should be obtained from epidemiologic sur- veys such as large case-control studies. The increased incidence of the disease in young women, the familial cases, the association with autoimmune disorders, and the recent discovery that mutation of the PPHl gene may not be restricted to familial PPH support the hypothesis that the development of pulmonary hypertension likely implies an individual susceptibility or predisposition, which is probably genetically determined. It is also now commonly believed that the development of pulmonary hypertension in some of these predisposed individuals could be has- tened or precipitated by various expression factors (some of them yet unrecognized), such as ingestion of certain drugs or diets, portal hypertension, or HIV infection.

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