Journal of the American College of Cardiology
`© 2004 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`Vol. 43, No. 12 Suppl S
`ISSN 0735-1097/04/$30.00
`doi:10.1016/j.jacc.2004.02.037
`
`Clinical Classification of Pulmonary Hypertension
`Gerald Simonneau, MD,* Nazzareno Galie`, MD,† Lewis J. Rubin, MD,‡ David Langleben, MD,§
`Werner Seeger, MD,㛳 Guido Domenighetti, MD,¶ Simon Gibbs, MD,# Didier Lebrec, MD,**
`Rudolf Speich, MD,†† Maurice Beghetti, MD,‡‡ Stuart Rich, MD,§§ Alfred Fishman, MD㛳 㛳
`Paris and Clichy, France; Bologna, Italy; San Diego, California; Montreal, Canada; Giessen, Germany; Locarno,
`Zurich, and Geneva, Switzerland; London, United Kingdom; Chicago, Illinois; and Philadelphia, Pennsylvania
`
`In 1998, during the Second World Symposium on Pulmonary Hypertension (PH) held in
`Evian, France, a clinical classification of PH was proposed. The aim of the Evian classification
`was to individualize different categories sharing similarities in pathophysiological mecha-
`nisms, clinical presentation, and therapeutic options. The Evian classification is now well
`accepted and widely used in clinical practice, especially in specialized centers. In addition, this
`classification has been used by the U.S. Food and Drug Administration and the European
`Agency for Drug Evaluation for the labeling of newly approved medications in PH. In 2003,
`during the Third World Symposium on Pulmonary Arterial Hypertension held in Venice,
`Italy, it was decided to maintain the general architecture and philosophy of the Evian
`classification. However, some modifications have been proposed, mainly to abandon the term
`“primary pulmonary hypertension” and to replace it with “idiopathic pulmonary hyperten-
`sion”; to reclassify pulmonary veno-occlusive disease and pulmonary capillary hemangioma-
`tosis; to update risk factors and associated conditions for pulmonary arterial hypertension and
`to propose guidelines in order to improve the classification of congenital systemic-to-
`pulmonary shunts.
`(J Am Coll Cardiol 2004;43:5S–12S) © 2004 by the American College
`of Cardiology Foundation
`
`Pulmonary hypertension (PH) was previously classified into
`two categories: primary pulmonary hypertension (PPH) or
`secondary pulmonary hypertension, depending on the ab-
`sence or the presence of identifiable causes or risk factors.
`The diagnosis of PPH was one of exclusion after ruling out
`all causes of PH (1,2).
`In 1998, during the Second World Symposium on
`Pulmonary Hypertension held in Evian, France, a clinical
`classification of PH was proposed (3–5). The aim of the
`“Evian classification” was to individualize different catego-
`ries sharing similarities in pathophysiological mechanisms,
`clinical presentation, and therapeutic options. Such a clin-
`ical classification is essential in communicating about indi-
`vidual patients, in standardizing diagnosis and treatment, in
`conducting trials with homogeneous groups of patients, and
`in analyzing novel pathobiological abnormalities in well-
`characterized patient populations. Obviously, a clinical clas-
`sification does not preclude other classifications such as a
`pathological classification based on histological findings, or
`a functional classification based on the severity of symp-
`
`From the *Department of Pulmonary and Critical Medicine, University of Paris
`Sud, Paris, France; †Institute of Cardiology, University of Bologna, Bologna, Italy;
`‡Division of Pulmonary and Critical Care Medicine, University of California, San
`Diego, California; §Department of Medicine, Sir Mortimer B. Davis Jewish General
`Hospital, McGill University, Montreal, Canada; 㛳Department of Internal Medicine
`II, Justus-Liebig-University, Giessen, Germany; ¶Department of Intensive Care and
`Pneumology, Regional Hospital of Locarno, Locarno, Switzerland; #National Heart
`and Lung Institute, Imperial College of Science, Technology and Medicine, London,
`United Kingdom; **Department of Hepatology, INSERM U481, Beaujon Hospital,
`Clichy, France; ††Department of Internal Medicine, University Hospital of Zurich,
`Zurich, Switzerland; ‡‡Pediatric Cardiology Unit, Children’s University Hospital of
`Geneva, Geneva, Switzerland; §§Center for Pulmonary Heart Disease, Rush-
`Presbyterian-St. Luke’s Medical Center, Chicago, Illinois; 㛳 㛳University of Pennsyl-
`vania School of Medicine, Philadelphia, Pennsylvania.
`Manuscript received January 28, 2004; revised manuscript received February 13,
`2004, accepted February 23, 2004.
`
`toms. The 2003 Third World Symposium on Pulmonary
`Arterial Hypertension (PAH) held in Venice, Italy, pro-
`vided the opportunity to assess the impact and the useful-
`ness of the Evian classification and to propose some mod-
`ifications.
`
`EVIAN CLASSIFICATION
`
`The Evian classification (3,4) consisted of five categories
`(Table 1) in which PH diseases were grouped according to
`specific therapeutic interventions directed at dealing with
`the cause of: 1) PAH, 2) pulmonary venous hypertension, 3)
`PH associated with disorders of the respiratory system or
`hypoxemia, 4) PH caused by thrombotic or embolic dis-
`eases, and 5) PH caused by diseases affecting the pulmonary
`vasculature. Within each category are subsets that reflect
`diverse causes and sites of injury.
`Pulmonary arterial hypertension. The first category,
`termed PAH, included a first subgroup without identifiable
`cause, or so-called PPH. It incorporated both the familial
`and sporadic forms of the disease. The second subgroup
`included a number of conditions or diseases of known causes
`that have in common the localization of lesions to the small
`pulmonary muscular arterioles. Among these are drug-
`related PH, porto-pulmonary hypertension, HIV-related
`PH, collagen vascular diseases, congenital systemic-to-
`pulmonary shunts, and persistent PH of the newborn.
`Although the mechanisms responsible for remodeling of
`pulmonary arterioles in these conditions are unknown, they
`share similar morphological findings, clinical presentation,
`and clinical responsiveness to treatment with the continuous
`infusion of epoprostenol (particularly PPH and PAH asso-
`ciated with the scleroderma spectrum of diseases) (6,7).
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`Abbreviations and Acronyms
`ALK1 ⫽ activin-receptor-like kinase-1
`APAH ⫽ pulmonary arterial hypertension related to
`risk factors or associated conditions
`BMPR2 ⫽ bone morphogenetic protein receptor type II
`FPAH ⫽ familial pulmonary arterial hypertension
`IPAH ⫽ idiopathic pulmonary arterial hypertension
`PAH ⫽ pulmonary arterial hypertension
`PCH ⫽ pulmonary capillary hemangiomatosis
`⫽ pulmonary hypertension
`PH
`⫽ primary pulmonary hypertension
`PPH
`PVOD ⫽ pulmonary veno-occlusive disease
`TGF-␤ ⫽ transforming growth factor-␤
`
`Pulmonary venous hypertension. This category consisted
`predominantly of left-sided valvular or myocardial diseases
`requiring therapies directed at improving myocardial per-
`formance or relieving valvular mechanical defects rather
`than pulmonary vasodilator therapy. Indeed, epoprostenol
`therapy in patients with pulmonary venous hypertension can
`be harmful (8). This category also included extrinsic com-
`pression of the pulmonary veins (9) and pulmonary veno-
`occlusive disease (PVOD), which clinically mimics PPH
`(10).
`PH associated with disorders of the respiratory system or
`hypoxemia. Within this category, the predominant cause is
`inadequate oxygenation of arterial blood as a result of either
`lung disease, impaired control of breathing, or residence at
`high altitude. In this category, the increase in mean pulmo-
`nary artery pressure is generally modest (⬍35 mm Hg) (11).
`As a rule, survival depends on the severity of the pulmonary
`disease rather than on pulmonary hemodynamics. Long-
`term oxygen therapy (16 or 24 h/day) improves survival in
`patients with chronic obstructive lung disease (12,13). In
`native residents who develop PH at high altitude, relocation
`to sea level
`rapidly improves PH and its associated
`symptoms.
`PH caused by thrombotic or embolic diseases. This
`category included either chronic thromboembolic PH due
`to proximal organized clot in major pulmonary arteries,
`which can benefit from pulmonary endarterectomy (14,15),
`or more peripheral emboli or thrombi that are indistinguish-
`able from thrombotic lesions observed in PPH and can be
`treated with chronic pulmonary vasodilator therapy (16). In
`all cases, life-long anticoagulation is indicated.
`PH caused by diseases affecting the pulmonary vascula-
`ture. This category involved PH stemming from inflam-
`matory processes or mechanical obstruction (e.g., schistoso-
`miasis, sarcoidosis). Pulmonary capillary hemangiomatosis
`(17) was also included in this group, although it usually
`presents clinically, as with PVOD (18).
`
`ASSESSMENT OF THE EVIAN CLASSIFICATION
`
`The 2003 World Symposium on PH provided the oppor-
`tunity to evaluate the impact and usefulness of the Evian
`
`Table 1. The Evian Clinical Classification
`
`1. Pulmonary arterial hypertension
`1.1 Primary pulmonary hypertension
`(a) Sporadic
`(b) Familial
`1.2 Related to
`(a) Collagen vascular disease
`(b) Congenital systemic-to-pulmonary shunts
`(c) Portal hypertension
`(d) Human immunodeficiency virus infection
`(e) Drugs/toxins
`(1) Anorexigens
`(2) Other
`(f) Persistent pulmonary hypertension of the newborn
`(g) Other
`2. Pulmonary venous hypertension
`2.1 Left-sided atrial or ventricular heart disease
`2.2 Left-sided valvular heart disease
`2.3 Extrinsic compression of central pulmonary veins
`(a) Fibrosing mediastinitis
`(b) Adenopathy/tumors
`2.4 Pulmonary veno-occlusive disease
`2.5 Other
`3. Pulmonary hypertension associated with disorders of the respiratory
`system or hypoxemia
`3.1 Chronic obstructive pulmonary disease
`3.2 Interstitial lung disease
`3.3 Sleep-disordered breathing
`3.4 Alveolar hypoventilation disorders
`3.5 Chronic exposure to high altitude
`3.6 Neonatal lung disease
`3.7 Alveolar-capillary dysplasia
`3.8 Other
`4. Pulmonary hypertension caused by chronic thrombotic or embolic
`disease
`4.1 Thromboembolic obstruction of proximal pulmonary arteries
`4.2 Obstruction of distal pulmonary arteries
`(a) Pulmonary embolism (thrombus, tumor, ova, or parasites,
`foreign material)
`(b) In situ thrombosis
`(c) Sickle-cell disease
`5. Pulmonary hypertension caused by disorders directly affecting the
`pulmonary vasculature
`5.1 Inflammatory
`(a) Schistosomiasis
`(b) Sarcoidosis
`(c) Other
`5.2 Pulmonary capillary hemangiomatosis
`
`classification and to propose modifications. A questionnaire
`was sent to all the experts (n ⫽ 56) who attended the Venice
`meeting. The first question was: “Do you think the Evian
`classification is now well accepted and widely used in clinical
`practice in place of the previous classification?” Among re-
`sponders (n ⫽ 30), a total of 88% considered the Evian
`classification to be well accepted and widely used in clinical
`practice, especially in centers with the largest clinical expe-
`rience. In contrast, nonexpert physicians apparently still use
`the old classification (primary vs. secondary).
`The second question was: “Do you think the Evian
`classification is useful for drug evaluation and registration,
`clinical practice, basic science?” Respectively, 88%, 96%, and
`66% of experts considered the Evian classification useful for
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`Simonneau et al.
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`drug evaluation and registration, for clinical practice, and for
`basic science.
`Lastly and probably the best evidence of the impact of the
`Evian classification is that both the U.S. Food and Drug
`Administration and the European Agency for Drug Eval-
`uation have recently used this clinical classification for the
`labeling of newly approved drugs: bosentan (19,20), trepro-
`stinil (21), and iloprost (22).
`Considering the globally favorable opinion of the Evian
`classification, the task force on epidemiology and classifica-
`tion decided to maintain the general architecture and
`philosophy of this clinical classification. However, to im-
`prove and to update the Evian classification according to the
`recent advances in our understanding of PH, it was pro-
`posed that some important issues be addressed, including: 1)
`the need to include a genetic classification, 2) discontinuing
`use of the term “primary pulmonary hypertension,” 3) the
`reclassification of PVOD and pulmonary capillary heman-
`giomatosis (PCH), 4) the update on new risk factors for
`PAH, and 5) reassessment of the classification of congenital
`systemic-to-pulmonary shunts.
`
`DO WE NEED A GENETIC CLASSIFICATION OF PH?
`
`In light of the recent advances in our understanding of the
`genetic basis of PPH, it has been suggested that a genetic
`classification of PH be considered. Before addressing this
`question further it may be worthwhile to outline briefly
`what is known and unknown regarding the genetics of
`severe PH. Mutations in the gene encoding the bone
`morphogenetic protein receptor type II (BMPR2), localized
`to chromosome 2q33, have been suggested to underlie
`approximately 50% of cases of familial PPH (23). Although
`many of the other 50% of families show some evidence of
`linkage to the BMPR2 locus, specific mutations have not
`been identified in the coding region, or the promoter region
`(R. Trembath, personal communication, June 2003). More-
`over, mutations in BMPR2 have been identified in up to
`26% of sporadic cases of PPH (24). Although some of these
`cases may arise de novo by mutation, the majority represent
`familial transmission of mutant BMPR2, with low pen-
`etrance of the gene for the disease (25). However, the
`frequency of mutation has not yet been reproduced in larger
`studies, and so far fewer than 70 BMPR2 mutations have
`been reported. In addition, there is some evidence for a
`second locus mapping to 2q31, although this locus has been
`mapped using a phenotype that includes an abnormal
`pulmonary vascular response to exercise, rather than mani-
`fest PPH.
`So far, mutations in BMPR2 gene seem to be quite
`specific for so-called PPH; however, mutations in BMPR2
`have also been identified in rare cases of PAH associated
`with appetite-suppressant drugs (26) and one patient with
`PVOD (27). Thus far, a search for BMPR2 mutations in
`other forms of PH has been negative (28).
`Genetic studies have demonstrated that mutations in
`
`BMPR2 are not sufficient per se to cause clinical disease.
`Hence, the chance of a disease gene carrier developing
`clinical PPH is as low as 20%. This observation highlights
`the critical role of other genetic/environmental factors in
`conferring susceptibility to PH (29).
`In summary, because our knowledge of the role of genes
`in various forms of PH remains at an early stage it is
`probably premature to recommend a classification of PH
`based on genetic defects. Further studies are needed to
`identify other genes, modifiers, and regulatory genes of PH
`and to determine whether PAH patients with BMPR2
`mutations differ from PAH patients without identified
`mutations with respect to response to treatment, age of
`onset, severity, and natural course of the disease.
`
`TO ABANDON THE TERM
`“PRIMARY PULMONARY HYPERTENSION”
`
`Primary pulmonary hypertension means unexplained or
`idiopathic PH.
`Initially described by Romberg (30) as “sclerosis of
`pulmonary arteries” more than a century ago this disease has
`been the subject of great interest and has successively
`undergone several name changes. The term “primary pul-
`monary hypertension” was coined by Dresdale et al. (31)
`more than 50 years ago, to characterize a condition in which
`hypertensive vasculopathy existed exclusively in the pulmo-
`nary vasculature without a demonstrable cause.
`In the last 20 years, it has become recognized that several
`conditions or diseases, including the intake of appetite-
`suppressant medications, connective tissue disease, portal
`hypertension, or HIV infection, may be associated with
`pulmonary vascular disease, and that they share similar
`pathologic and clinical features with PPH. These conditions
`were commonly grouped as “secondary pulmonary hyper-
`tension” in contrast with primary forms. As a result, the
`term “secondary pulmonary hypertension” comprised very
`heterogeneous forms of diseases including other intrinsic
`pulmonary vascular diseases that resemble PPH as well as
`disorders that either affect the pulmonary venous circulation
`or conditions that affect
`the pulmonary circulation by
`altering respiratory structure or function.
`Thus, the term “secondary pulmonary hypertension” in
`the Evian classification was abandoned because it was found
`confusing and without value for diagnosis and treatment. In
`contrast, the term “primary pulmonary hypertension” was
`retained because of its common use and familiarity, and
`because it was emblematic of 50 years of intense scientific
`and clinical research. However, the main problem with the
`term “primary” is that it requires use of the modifier
`“secondary” to distinguish this condition from others. Thus,
`during the Venice meeting, it was proposed to abandon
`“primary pulmonary hypertension” and to replace it with
`“idiopathic pulmonary arterial hypertension.” The first cat-
`egory in the modified Evian classification termed “pulmo-
`nary arterial hypertension” now consist of
`three main
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`subgroups: 1) idiopathic pulmonary arterial hypertension
`(IPAH), 2)
`familial pulmonary arterial hypertension
`(FPAH), and 3) pulmonary arterial hypertension related to
`risk factors or associated conditions (APAH).
`
`TO RECLASSIFY PVOD AND PCH
`
`Both PVOD and PCH are uncommon conditions, but they
`are increasingly recognized as causes for PH. In the Evian
`classification, these two entities were included in separate
`groups, both distinct from the PAH category: PVOD was
`included in the pulmonary venous hypertension category,
`which consists predominantly of left-sided valvular or myo-
`cardial diseases; PCH was included in the last and heter-
`ogenous group of PH caused by diseases directly affecting
`the pulmonary vasculature.
`As discussed in the pathology report by Pietra et al. (32)
`in this supplement, PVOD and PCH are similar in some
`respects, particularly in relation to the changes in the
`pulmonary parenchyma (i.e., pulmonary hemosiderosis, in-
`terstitial edema, and lymphatic dilation) and to pulmonary
`arterial intimal fibrosis and medial hypertrophy (18, 33, 34).
`Similarities in the pathological features and clinical presen-
`tation, along with the possible occurrence of pulmonary
`edema during epoprostenol therapy (35,36), suggest that
`these disorders may overlap. Accordingly, it seems logical to
`include PVOD and PCH within the same group, most
`appropriately within the category of PAH. Indeed, PVOD
`and PCH, as well as PAH, show similar histological
`changes in the small pulmonary arteries, including intimal
`fibrosis, medial hypertrophy, and plexiform lesions. More-
`over, the clinical presentation of PVOD and PCH is
`generally similar to that of PPH.
`Finally, the risk factors or conditions associated with
`PAH and PVOD/PCH are similar and include the sclero-
`derma spectrum of the disease (37), HIV infection (38,39),
`and the use of anorexigens (F. Capron, personal communi-
`cation, June 2003). Of particular interest are reports of a
`familial occurrence in both PVOD (40) and PCH (41) as
`well as in PAH. Lastly, BMPR2 mutation,
`the gene
`associated with familial and IPAH, has been documented in
`a patient with PVOD (27). These findings suggest that
`PVOD, PCH, and PAH may represent components of a
`spectrum of a single disease. Thus, in the new classification,
`the PAH category comprises another subgroup termed
`“PAH associated with significant venous or capillary in-
`volvement.” This subgroup probably requires similar man-
`agement to the other PAH subgroups. However, the prog-
`nosis seems worse, with a more rapid downhill course. In
`addition, vasodilators and especially epoprostenol have to be
`used with great caution because of the high risk of pulmo-
`nary edema. As a result, as soon as recognized, these
`patients should be placed on the list for lung transplanta-
`tion.
`
`UPDATED RISK FACTORS AND
`ASSOCIATED CONDITIONS FOR
`PULMONARY ARTERIAL HYPERTENSION
`
`A risk factor for PAH is any factor or condition that is
`suspected to play a predisposing or facilitating role in the
`development of the disease. Risk factors may include drugs
`and chemicals, diseases, or phenotype (age, gender). The
`term “associated conditions” is used when it is not possible
`to determine whether a predisposing factor was present
`before PH onset. Because the absolute risk of known risk
`factors for PAH is generally low, individual susceptibility or
`genetic predisposition is likely to play an important role.
`During the Evian meeting, different risk factors and asso-
`ciated conditions were categorized according to the strength
`of their association with PH and their probable causal role.
`“Definite” indicates an association based on several concor-
`dant observations including a major controlled study or an
`unequivocal epidemic. “Very likely” indicates several con-
`cordant observations (including large case series and studies)
`that are not attributable to identified bases. “Possible”
`indicates an association based on case series, registries, or
`expert opinions. “Unlikely” indicates risk factors that were
`suspected but for which controlled studies failed to demon-
`strate any association. According to the strength of the
`evidence, Table 2 summarizes, risk factors and associated
`conditions that were identified during the Evian meeting.
`
`RECENT EPIDEMIOLOGIC STUDIES
`
`Ever since the Evian meeting, two prospective epidemio-
`logic studies have been performed in the United States.
`The SNAP (Surveillance of North American Pulmonary
`Hypertension) study was a voluntary collaborative survey
`conducted on 559 patients with PH over a 14-month period
`(42). This study confirmed the causal role of fenfluramine
`derivatives in the development of PAH. It showed a clear
`association between the use of fenfluramine and the diag-
`nosis of PPH but not secondary PH. The adjusted odds
`ratio (OR) for the use of fenfluramine for more than six
`months was 7.5. Another interesting observation in the
`SNAP study was the unexpectedly high reported rate of
`anorexigen use in secondary PH (11.4%). This finding
`suggested that the use of anorexigens increased the likeli-
`hood of developing PH in patients with other conditions
`that cause secondary PH.
`The Sophia (Surveillance Of Pulmonary Hypertension In
`America) study enrolled 13 tertiary-care PH centers within
`the U.S. and included 1,335 patients with newly diagnosed
`PH between January 1998 and June 2001 (43). This study
`demonstrated that the use of fenfluramine during the past
`five years was preferentially associated with PPH rather than
`chronic thromboembolic PH (OR, 2.7; 95% confidence
`interval [CI]: 1.5 to 4.8); Interestingly, this study also
`showed an unanticipated association between PPH and
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`Table 2. Risk Factors and Associated Conditions for PAH
`Identified During the Evian Meeting (1998) and Classified
`According to the Strength of Evidence
`
`A. Drugs and Toxins
`1. Definite
`● Aminorex
`● Fenfluramine
`● Dexfenfluramine
`● Toxic rapeseed oil
`2. Very likely
`● Amphetamines
`● L-tryptophan
`3. Possible
`● Meta-amphetamines
`● Cocaine
`● Chemotherapeutic agents
`4. Unlikely
`● Antidepressants
`● Oral contraceptives
`● Estrogen therapy
`● Cigarette smoking
`B. Demographic and Medical Conditions
`1. Definite
`● Gender
`2. Possible
`● Pregnancy
`● Systemic hypertension
`3. Unlikely
`● Obesity
`C. Diseases
`1. Definite
`● HIV infection
`2. Very likely
`● Portal hypertension/liver disease
`● Collagen vascular diseases
`● Congenital systemic-pulmonary-cardiac shunts
`3. Possible
`● Thyroid disorders
`
`both “St. John’s wort” and over-the-counter antiobesity
`agents that contain phenylpropanolamine.
`
`CASE SERIES AND CASE REPORTS
`
`Ever since the Evian meeting, several case series or case
`reports have been published that provide some evidence of
`novel “possible” risk factors for PAH.
`Hematologic conditions. Recently, a high prevalence
`(11.5%) of asplenia secondary to surgical splenectomy has been
`reported in a series of 61 patients with unexplained PAH,
`suggesting that patients with splenectomy may be at in-
`creased risk for developing PAH (44). At the time of
`diagnosis, PAH was generally severe, and the interval
`between splenectomy and diagnosis ranged from 4 to 32
`years. Histological examination of the lungs in three pa-
`tients showed pulmonary vascular changes similar to those
`of IPAH. However, these patients also had many throm-
`botic lesions in small pulmonary arteries. The underlying
`pathogenetic mechanisms are unclear; it was hypothesized
`that because of the loss of the filter function of the spleen,
`abnormal erythrocytes remained longer in the circulation
`and might have triggered platelet activation.
`
`Certain hemoglobinopathies represent other possible risk
`factors for PAH. Pulmonary hypertension is a well-
`recognized complication of sickle-cell disease. It is a severe
`complication that significantly reduces the survival rate of
`these patients as compared with those without PH. It
`represents the cause of death in 3% of patients with
`sickle-cell disease. Classically, in situ thrombosis of elastic
`and small pulmonary arteries was considered to be the
`predominant finding at autopsy. Recently, a clinical-
`pathologic study of 20 patients reported pulmonary vascular
`abnormalities consistent with those of PAH,
`including
`plexiform lesions, in 60% of patients (45). Increased shear
`stress from deformed erythrocytes passing through the
`pulmonary microvasculature has been proposed as the un-
`derlying mechanism of vascular injury. In addition, the
`bioavailability of nitric oxide is reported to be decreased in
`these patients (46,47).
`Other hemoglobin abnormalities may be associated with
`PAH, especially beta-thalassemia (48). In some patients,
`histologic examination at postmortem has found the lesions
`of IPAH and/or thrombotic pulmonary arteriopathy. The
`mechanism of PAH in patients with hemoglobinopathy is
`unclear, but a possible role has been suggested for liver
`disease, splenectomy, and thrombosis.
`The possible association of PAH with chronic myelopro-
`liferative disorders has been reported by several case reports
`(49,50) and in one cohort of six patients (51). A recent
`report from the Mayo Clinic dealt with 26 patients seen in
`that institution between 1987 and 2000 (52). The chronic
`myeloproliferative disorders included polycythemia vera,
`essential thrombocytosis, and myelofibrosis with myeloid
`metaplasia accompanying chronic myeloid leukemia or the
`myelodysplastic syndrome. In all patients, PH was moderate
`or severe at diagnosis. In these patients, the main causes of
`PH, particularly chronic thromboembolism, were excluded
`on clinical grounds and ventilation-perfusion lung scan.
`Unfortunately, autopsies were not performed. The etiology
`of PAH in these patients is probably multifactorial, includ-
`ing splenectomy, portal hypertension, chemotherapy-
`induced PVOD, and infiltration of the pulmonary paren-
`chyma by hematopoietic cells and extramedullary
`hemopoiesis.
`Rare genetic or metabolic diseases. Unexplained PAH
`has been reported in patients with certain rare genetic or
`metabolic diseases. These observations suggest new patho-
`biologic mechanisms for the pulmonary hypertension (e.g.,
`an alternative role for a known mutated gene, genetic
`defects in chromosomal regions adjacent to a mutated gene,
`or a consequence of a new metabolic pathway).
`Pulmonary arterial hypertension has been associated with
`type Ia glycogen storage disease (Von Gierke disease) in fewer
`than 10 patients since the initial description (53). It is a rare
`autosomal recessive disorder caused by a deficiency of glucose-
`6-phosphatase (54). Pulmonary histology is typical of PAH,
`and the clinical course is that of rapidly developing right heart
`failure. It has been suggested that in these patients PAH could
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`be due to an abnormal production of serotonin (55); in some
`patients, a surgical porto-caval shunt might represent an
`additional risk factor. The gene responsible for type Ia glyco-
`gen storage disease has been cloned on the long arm of
`chromosome 17 in position 17q21. Further studies should be
`performed to investigate a possible gene linked to PH in the
`same chromosomal region.
`Gaucher disease is another rare autosomal recessive disorder
`characterized by a deficiency of lysosomal beta-glycosidase,
`which results 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. Several
`cases of unexplained PAH have been reported in association
`with Gaucher disease (56). In these patients, liver disease,
`splenectomy, capillary plugging by Gaucher cells, and en-
`zyme replacement therapy could play a role in the develop-
`ment of PH. Interestingly, a polymorphism in exon 13 of
`BMPR2 has been found in a patient with Gaucher disease
`and unexplained PAH (57).
`Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu
`disease) is a rare autosomal-dominant disorder characterized
`by the presence of multiple arteriovenous malformations
`particularly in the pulmonary hepatic and cerebral circula-
`tions. Mutations in two genes encoding transforming
`growth factor-beta (TGF-␤) receptor superfamily, namely
`endoglin and activin-receptor-like kinase-1 (ALK1), which
`are located on chromosomes 9 and 12, respectively, underlie
`this disorder. Recently, individual cases (58,59) and one case
`series of 10 patients (60) with hereditary hemorrhagic
`telangiectasia associated with PH were reported. These
`patients were clinically and histologically indistinguishable
`from PPH. In these patients, mutations in ALK1 (60), or
`more rarely in endoglin (61), were identified, suggesting
`that these mutations can give rise to diverse effects, includ-
`ing the vascular dilation characteristic of hereditary hemor-
`rhagic telangiectasia and the occlusion of small pulmonary
`arteries typical of PPH.
`
`CLASSIFICATION OF CONGENITAL
`SYSTEMIC-TO-PULMONARY SHUNTS
`
`In 1897, Vicktor Eisenmenger first described a patient with
`ventricular septal defect and severe pulmonary vascular
`disease (62). The term “Eisenmenger syndrome” was coined
`by Paul Wood, and it is now commonly used to include all
`systemic-to-pulmonary arterial shunts leading to PH and
`resulting in a right-to-left or bidirectional shunt (63).
`Pulmonary vascular histopathologic changes that accom-
`pany congenital heart disease are usually indistinguishable
`from those of IPAH; the lesions include medial hypertro-
`phy, intimal proliferation fibrosis, and, in more severe PH,
`plexiform lesions and necrotizing arteritis (64). The pulmo-
`nary vascular involvement from congenital heart disease
`usually follows a period in which pulmonary resistance is
`low and pulmonary blood flow is high. In these patients, it
`
`Table 3. Revised Clinical Classification of Pulmonary
`Hypertension (Venice 2003)
`
`1. Pulmonary arterial hypertension (PAH)
`1.1. Idiopathic (IPAH)
`1.2. Familial (FPAH)
`1.3. Associated with (APAH):
`1.3.1. Collagen vascular disease
`1.3.2. Congenital systemic-to-pulmonary shunts**
`1.3.3. Portal hypertension
`1.3.4. HIV infection
`1.3.5. Drugs and toxins
`1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher
`disease, hereditary hemorrhagic telangiectasia,
`hemoglobinopathies, myeloproliferative disorders, splenectomy)
`1.4. Associated with significant venous or capillary involvement
`1.4.1. Pulmonary veno-occlusive disease (PVOD)
`1.4.2. Pulmonary capillary hemangiomatosis (PCH)
`1.5. Persistent pulmonary hypertension of the newborn
`2. Pulmonary hypertension with left heart disease
`2.1. Left-sided atrial or ventricular heart disease
`2.2. Left-sided valvular heart disease
`3. Pulmonary hypertension associated with lung diseases and/or hypoxemia
`3.1. Chronic obstructive pulmonary disease
`3.2. Interstitial lung disease
`3.3. Sleep-disordered breathing
`3.4. Alveolar hypoventilation disorders
`3.5. Chronic exposure to high altitude
`3.6. Developmental abnormalities
`4. Pulmonary hypertension due to chronic thrombotic and/or embolic
`disease
`4.1. Thromboembolic obstruction of proximal pulmonary arteries
`4.2. Thromboembolic obstruction of distal pulmonary arteries
`4.3. Non-thrombotic pulmonary embolism (tumor, parasites, foreign
`material)
`5. Miscellaneous
`Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of
`pulmonary vessels (adenopathy, tumor, fib