Journal of the American College of Cardiology
`© 2009 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`Vol. 54, No. 1, Suppl S, 2009
`ISSN 0735-1097/09/$36.00
`doi:10.1016/j.jacc.2009.04.012
`
`Updated Clinical Classification of Pulmonary Hypertension
`
`Gérald Simonneau, MD,* Ivan M. Robbins, MD,† Maurice Beghetti, MD,‡
`Richard N. Channick, MD,§ Marion Delcroix, MD, PHD,储 Christopher P. Denton, MD, PHD,¶
`C. Gregory Elliott, MD,# Sean P. Gaine, MD, PHD,** Mark T. Gladwin, MD,††
`Zhi-Cheng Jing, MD,‡‡ Michael J. Krowka, MD,§§ David Langleben, MD,储储
`Norifumi Nakanishi, MD, PHD,¶¶ Rogério Souza, MD##
`
`Clamart, France; Nashville, Tennessee; Geneva, Switzerland; La Jolla, California; Leuven, Belgium; London,
`United Kingdom; Salt Lake City, Utah; Dublin, Ireland; Pittsburgh, Pennsylvania; Shanghai, China;
`Rochester, Minnesota; Montréal, Québec, Canada; Osaka, Japan; and São Paulo, Brazil
`
`The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations
`
`of disease sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic ap-
`
`proaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH
`
`initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Sympo-
`
`sium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical
`
`classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial
`
`hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic
`
`PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1,
`
`and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate enti-
`
`ties in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary veno-
`
`occlusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to
`
`Group 1 (now called Group 1=). Thus, Group 1 of PAH is now more homogeneous.
`
`(J Am Coll Cardiol 2009;54:
`
`S43–54) © 2009 by the American College of Cardiology Foundation
`
`The classification of pulmonary hypertension (PH) has gone
`through a series of changes since the first classification was
`proposed in 1973 at an international conference on primary
`PH (PPH) endorsed by the World Health Organization
`(1,2). The initial classification designated only 2 categories,
`
`From the *Centre National de Référence des Maladies Vasculaires Pulmonaires,
`Université Paris-Sud Hôpital Antoine Béclère, Clamart, France; †Department of
`Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; ‡Pediatric
`Cardiology Unit, Hôpital des Enfants, University Hospital of Geneva, Geneva,
`Switzerland; §Division of Pulmonary and Critical Care Medicine, UCSD Medical
`Center, La Jolla, California; 储Center for Pulmonary Vascular Disease, Department of
`Pneumology, Gasthuisberg University Hospital, Leuven, Belgium; ¶Centre for
`Rheumatology, Royal Free Hospital, London, United Kingdom; #Department of
`Medicine, Intermountain Medical Center, University of Utah, Salt Lake City, Utah;
`**Department of Respiratory Medicine, Mater Misericordiae University Hospital,
`University College Dublin, Dublin, Ireland; ††Pulmonary, Allergy, and Critical Care
`Medicine, Hemostasis and Vascular Biology Research Institute, University of Pitts-
`burgh, Pittsburgh, Pennsylvania; ‡‡Department of Pulmonary Circulation, Shanghai
`Pulmonary Hospital, Tongji University, Shanghai, China; §§Department of Pulmo-
`nary and Critical Care Medicine, Division of Gastroenterology and Hepatology,
`Mayo Clinic, Rochester, Minnesota; 储 储Center for Pulmonary Vascular Disease, Sir
`Mortimer B. Davis Jewish General Hospital, Montréal, Québec, Canada; ¶¶Division
`of Cardiology and Pulmonary Circulation, Department of Internal Medicine National
`Cardiovascular Center, Osaka, Japan; and the ##Pulmonary Department, Heart
`Institute, University of São Paulo Medical School, São Paulo, Brazil. Please see the
`end of this article for each author’s conflict of interest information.
`Manuscript received February 6, 2009; accepted April 15, 2009.
`
`PPH or secondary PH, depending on the presence or
`absence of identifiable causes or risk factors. Twenty-five
`years later, the 2nd World Symposium on Pulmonary
`Arterial Hypertension (PAH) was held in Evian, France.
`The “Evian classification” attempted to create categories of
`PH that shared pathologic and clinical features as well as
`similar therapeutic options (3). This was a much broader,
`more encompassing classification, with 5 major categories; it
`allowed investigators to conduct clinical trials in a well-
`defined group of patients with a shared underlying patho-
`genesis. This has led to multiple clinical trials and the
`approval of 8 different medications worldwide for the
`treatment of PAH.
`The 3rd World Symposium on PAH was held in Venice,
`Italy, 5 years after the Evian conference. At this conference,
`the impact and usefulness of the “Evian classification” was
`reviewed, and modest changes were made. The most nota-
`ble change was to abandon the term PPH in favor of
`idiopathic pulmonary arterial hypertension (IPAH); familial
`PAH if there is a family history of PAH; or associated PAH
`if another cause, such as connective tissue disease or human
`immunodeficiency virus (HIV), is present. Although the
`term PPH had become well ingrained in the literature after
`Dresdale first used it in 1951 (4), it had become clear that
`
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`Simonneau et al.
`Classification and Epidemiology
`
`JACC Vol. 54, No. 1, Suppl S, 2009
`June 30, 2009:S43–54
`
`Abbreviations
`and Acronyms
`
`BMPR2 ⴝ bone
`
`morphogenetic protein
`
`receptor type 2
`
`CHD ⴝ congenital heart
`
`disease
`
`CTEPH ⴝ chronic
`
`thromboembolic pulmonary
`
`hypertension
`
`ESRD ⴝ end-stage renal
`
`disease
`
`HIV ⴝ human
`
`immunodeficiency virus
`
`IPAH ⴝ idiopathic
`
`pulmonary arterial
`
`hypertension
`
`OR ⴝ odds ratio
`
`PAH ⴝ pulmonary arterial
`
`hypertension
`
`PAP ⴝ pulmonary arterial
`
`pressure
`
`PCH ⴝ pulmonary capillary
`
`hemangiomatosis
`
`PH ⴝ pulmonary
`
`hypertension
`
`the pathologic changes and re-
`sponse to therapy were similar in
`several other conditions or dis-
`eases. The term “secondary PH”
`had been abandoned at the Evian
`meeting because it was confusing
`and did not help with diagnosis or
`in directing treatment (5) (Table
`1). The other prominent change
`made at the Venice meeting was to
`move pulmonary veno-occlusive
`disease (PVOD) and pulmonary
`capillary hemangiomatosis (PCH)
`from separate categories into a sin-
`gle subcategory of PAH. These 2
`entities have many similarities
`with each other, which will be
`discussed later in this article, as
`well as some similarities with
`PAH. The 2008 4th World Sym-
`posium on PH held in Dana
`Point, California, provided the op-
`portunity to slightly modify the
`previous clinical classifications.
`
`
`
`Venice Clinical Classificationof Pulmonary Hypertension (2003)
`
`Table 1
`
`Venice Clinical Classification
`of Pulmonary Hypertension (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 owing to chronic thrombotic and/or embolic disease
`
`4.1. Thromboembolic obstruction of proximal pulmonary arteries
`
`4.2. Thromboembolic obstruction of distal pulmonary arteries
`
`POPH ⴝ portopulmonary
`
`Dana Point Classification
`
`4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)
`
`PVR ⴝ pulmonary vascular
`
`resistance
`
`SCD ⴝ sickle cell disease
`
`TRV ⴝ tricuspid
`
`regurgitation jet velocity
`
`hypertension
`
`PPH ⴝ primary pulmonary
`
`hypertension
`
`PVOD ⴝ pulmonary veno-
`
`occlusive disease
`
`During the 4th World Sympo-
`sium on PH held in 2008 in
`Dana Point, California, the con-
`sensus of an international group
`of experts was to maintain the
`general philosophy and organiza-
`tion of the Evian-Venice classi-
`fications. However, in response
`to a questionnaire regarding the
`previous classification, a majority
`of experts (63%) felt that modi-
`fication of the Venice classification was required to accu-
`rately reflect information published over the past 5 years, as
`well as to clarify some areas that were unclear. The current
`Dana Point classification is listed in Table 2, with major
`changes highlighted.
`
`Group 1: PAH
`
`Pulmonary arterial hypertension has been the focus of the
`classification of PH since the first classification in 1973. The
`nomenclature of the subgroups and associated conditions
`has evolved since that time, and additional modifications
`were made in the Dana Point classification.
`1.1./1.2. Idiopathic and heritable PAH. Pulmonary arte-
`rial hypertension may occur in different clinical conditions
`depending on associated diseases. Idiopathic PAH corre-
`sponds to sporadic disease in which there is neither a family
`history of PAH nor an identified risk factor. When PAH
`
`5. Miscellaneous
`
`Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary
`
`vessels (adenopathy, tumor, fibrosing mediastinitis)
`
`occurs in a familial context, germline mutations in the bone
`morphogenetic protein receptor type 2 (BMPR2) gene, a
`member of the transforming growth factor ␤ signaling
`family, can be detected in approximately 70% of cases (6,7).
`More rarely, mutations in activin receptor-like kinase type
`1, or endoglin, also members of the transforming growth
`factor ␤ signaling family, have been identified in patients
`with PAH, predominantly with coexistent hereditary hem-
`orrhagic telangiectasia. Recently, it has been suggested that
`patients with PAH associated with BMPR2 mutations may
`represent a subgroup of patients with more severe disease
`who are less likely to demonstrate vasoreactivity than those
`with IPAH without BMPR2 mutations (8 –10).
`Because BMPR2 mutations have also been detected in
`11% to 40% of apparently idiopathic cases with no family
`history (11,12), the distinction between idiopathic and
`familial BMPR2 mutations is artificial. All patients with
`BMPR2 mutations have heritable disease, whether the
`patient is the first identified case, possibly with a de novo
`mutation, or other family members were previously diag-
`nosed with PAH. In addition, in 30% or fewer families with
`PAH, no BMPR2 mutation has been identified. Thus, it
`was decided to abandon the term “familial PAH” in the new
`classification and to replace it with the term “heritable
`PAH.” Heritable forms of PAH include IPAH with germ-
`line mutations (mainly BMPR2 but also activin receptor-
`
`044
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`

`JACC Vol. 54, No. 1, Suppl S, 2009
`June 30, 2009:S43–54
`
`
`
`Updated Clinical Classification ofPulmonary Hypertension (Dana Point, 2008)
`
`Table 2
`
`Updated Clinical Classification of
`Pulmonary Hypertension (Dana Point, 2008)
`
`1. Pulmonary arterial hypertension (PAH)
`
`1.1. Idiopathic PAH
`
`1.2. Heritable
`
`1.2.1. BMPR2
`
`1.2.2. ALK1, endoglin (with or without hereditary hemorrhagic
`
`telangiectasia)
`
`1.2.3. Unknown
`
`1.3. Drug- and toxin-induced
`
`1.4. Associated with
`
`1.4.1. Connective tissue diseases
`
`1.4.2. HIV infection
`
`1.4.3. Portal hypertension
`
`1.4.4. Congenital heart diseases
`
`1.4.5. Schistosomiasis
`
`1.4.6. Chronic hemolytic anemia
`
`1.5 Persistent pulmonary hypertension of the newborn
`
`1=. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary
`
`hemangiomatosis (PCH)
`
`2. Pulmonary hypertension owing to left heart disease
`
`2.1. Systolic dysfunction
`
`2.2. Diastolic dysfunction
`
`2.3. Valvular disease
`
`3. Pulmonary hypertension owing to lung diseases and/or hypoxia
`
`3.1. Chronic obstructive pulmonary disease
`
`3.2. Interstitial lung disease
`
`3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern
`
`3.4. Sleep-disordered breathing
`
`3.5. Alveolar hypoventilation disorders
`
`3.6. Chronic exposure to high altitude
`
`3.7. Developmental abnormalities
`
`4. Chronic thromboembolic pulmonary hypertension (CTEPH)
`
`5. Pulmonary hypertension with unclear multifactorial mechanisms
`
`5.1. Hematologic disorders: myeloproliferative disorders, splenectomy
`
`5.2. Systemic disorders: sarcoidosis, pulmonary Langerhans cell
`
`histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis
`
`5.3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid
`
`disorders
`
`5.4. Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure
`
`on dialysis
`
`Main modifications to the previous Venice classification are in bold.
`
`ALK1 ⫽ activin receptor-like kinase type 1; BMPR2 ⫽ bone morphogenetic protein receptor type
`
`2; HIV ⫽ human immunodeficiency virus.
`
`like kinase 1 or endoglin) and familial cases with or without
`identified germline mutations (13,14). The new category of
`“heritable PAH” does not mandate genetic testing in
`patients with IPAH or in familial cases of PAH. Genetic
`testing, when called for, should be performed as a part of a
`comprehensive program that includes genetic counseling
`and discussion of the risks, benefits, and limitations of such
`testing (15).
`1.3. Drug- and toxin-induced PAH. A number of risk
`factors for the development of PAH have been identified
`and were included in the previous Evian and Venice
`classifications (3,5). Risk factors for PAH include “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 phe-
`notype (age, gender).” Risk factors were categorized as
`definite, very likely, possible, or unlikely, based on the
`“strength of their association with PH and their probable
`causal role.” In the current classification, the categorization
`
`Simonneau et al.
`Classification and Epidemiology
`
`S45
`
`of risk factors and the likelihood of developing PAH have
`been modified. Updated risk factors and associated condi-
`tions for PAH are presented in Table 3. A “definite”
`association is defined as an epidemic, such as occurred with
`appetite suppressants in the 1960s, or large, multicenter
`epidemiologic studies demonstrating an association between
`a drug and PAH. A “likely” association is defined as a
`single-center, case-control study demonstrating an associa-
`tion or a multiple-case series. “Possible” is defined as drugs
`with similar mechanisms of action as those in the “definite”
`or “likely” categories but which have not yet been studied
`(e.g., drugs used to treat attention-deficit disorder). Lastly,
`an “unlikely” association is defined as one in which a drug
`has been studied in epidemiologic studies and an association
`with PAH has not been demonstrated.
`Aminorex, fenfluramine derivatives, and toxic rapeseed
`oil represent the only identified “definite” risk factors for
`PAH (3,5). A recent retrospective analysis of more than 100
`cases of PAH associated with fenfluramine exposure showed
`that this category shares clinical, functional, hemodynamic,
`and genetic features with IPAH, suggesting that fenflura-
`mine exposure represents a potential trigger for PAH
`without influencing its clinical course (16).
`The most recent surveillance study of PH, Surveillance of
`Pulmonary Hypertension in America (SOPHIA), enrolled
`1,335 subjects at tertiary PH centers in the U.S. between
`1998 and 2001 (17). This study confirmed the association of
`fenfluramine and dexfenfluramine intake with the develop-
`ment of PAH. The average monthly number of IPAH cases
`did not change during the study, which was, however,
`conducted after fenfluramine and its derivates had been
`withdrawn from the U.S. market. A novel finding was that
`St. John’s Wort (odds ratio [OR]: 3.6, vs. thromboembolic
`PH) and over-the-counter antiobesity agents containing
`phenylpropanolamine (OR: 5.2, vs. thromboembolic PH)
`also increased the risk of developing IPAH.
`The SOPHIA study examined intake of a variety of
`nonselective monoamine reuptake inhibitors, selective sero-
`tonin reuptake inhibitors, antidepressants, and anxiolytics,
`and found no increased risk for developing PAH (17).
`However, a recent case-control study of selective serotonin
`
`
`
`Updated Risk Factors forand Associated Conditions of PAH
`
`Table 3
`
`Updated Risk Factors for
`and Associated Conditions of PAH
`
`Definite
`
`Aminorex
`
`Fenfluramine
`
`Dexfenfluramine
`
`Toxic rapeseed oil
`
`Likely
`
`Amphetamines
`
`L-tryptophan
`
`Methamphetamines
`
`Possible
`
`Cocaine
`
`Phenylpropanolamine
`
`St. John’s Wort
`
`Chemotherapeutic agents
`
`SSRI
`
`Unlikely
`
`Oral contraceptives
`
`Estrogen
`
`Cigarette smoking
`
`PAH ⫽ pulmonary arterial hypertension; SSRI ⫽ selective serotonin reuptake inhibitor.
`
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`Simonneau et al.
`Classification and Epidemiology
`
`JACC Vol. 54, No. 1, Suppl S, 2009
`June 30, 2009:S43–54
`
`reuptake inhibitor use in pregnant women after 20 weeks of
`gestation showed an increased risk (OR: 6.1) in the off-
`spring of developing persistent PH of the newborn, a form
`of PAH (18). Based on this study, selective serotonin
`reuptake inhibitors may play a role in the development of
`PH, at least in association with pregnancy, and therefore
`they have been reclassified in the “possible” category.
`Amphetamine use represents a “likely” risk factor for
`PAH, although they are rarely taken as a single agent and
`are frequently used in combination with fenfluramine. A
`recent comprehensive retrospective study suggested a strong
`relationship with the use of methamphetamine (inhaled,
`smoked, oral, or intravenous) and the occurrence of IPAH
`(19). Based primarily on the results of this study, metham-
`phetamine use is now considered a “very likely” risk factor
`for the development of PAH. Additional changes in drug-
`and toxin-induced PAH will be discussed later. With the
`exception of hereditary hemorrhagic telangiectasia associ-
`ated with PAH, the first 3 subcategories of Group 1,
`idiopathic, heritable, and drug- and toxin-induced PAH,
`are all associated with the development of isolated pulmo-
`nary arterial diseases.
`1.4.1. PAH associated with connective tissue diseases.
`PAH associated with connective tissue diseases represents
`an important clinical subgroup. The prevalence of PAH has
`been well established only for systemic sclerosis. Two recent
`prospective studies using echocardiography as a screening
`method and right heart catheterization for confirmation
`found a prevalence of PAH of between 7% and 12% (20,21).
`Several
`long-term studies suggest that the outcome of
`patients with PAH associated with systemic sclerosis is
`markedly worse than that of patients with IPAH, despite
`the use of modern therapies.
`Importantly, PAH does not represent the only cause of
`PH in systemic sclerosis. Pulmonary hypertension owing to
`lung fibrosis is also frequent (22), and diastolic left heart
`dysfunction is not uncommon (23). There is also primary
`cardiac involvement in the disease process (24). These
`observations emphasize the importance of a complete eval-
`uation when PH is suspected in patients with systemic
`sclerosis and the need for right heart catheterization to
`confirm the diagnosis of PH and to accurately classify its
`etiology to determine appropriate treatment.
`In systemic lupus erythematosis (25,26) and mixed con-
`nective tissue disease (27,28),
`the prevalence of PAH
`remains unknown but likely occurs less frequently than in
`systemic sclerosis. In the absence of fibrotic lung disease,
`PAH has been reported infrequently in other connective
`tissue diseases such as Sjögren syndrome (29), polymyositis
`(30), or rheumatoid arthritis (31).
`1.4.2. HIV infection. Pulmonary arterial hypertension is a
`rare but well-established complication of HIV infection
`(32,33). Epidemiologic data in the early 1990s, a time when
`therapy with highly active antiretroviral therapy was not yet
`available, indicated a prevalence of 0.5% (95% confidence
`interval: 0.10% to 0.50%) (34). The prevalence of HIV-
`
`associated PAH was evaluated more recently and showed a
`stable prevalence of 0.46% (95% confidence interval: 0.32%
`to 0.64%) (35). Human immunodeficiency virus-associated
`PAH has clinical, hemodynamic, and histologic character-
`istics similar to those seen in IPAH. The mechanism for the
`development of PH remains unclear. Because neither the
`virus nor viral DNA has been found in pulmonary endo-
`thelial cells, an indirect action of virus through secondary
`messengers such as cytokines, growth factors, endothelin, or
`viral proteins is strongly suspected.
`Uncontrolled studies suggest that patients with severe
`HIV-associated PAH could benefit from bosentan or long-
`term infusion of epoprostenol (36,37). Interestingly, in a
`substantial number of cases, normalization of pulmonary
`vascular hemodynamics can be obtained with therapy indi-
`cated for PAH; this is very rarely seen in IPAH (38).
`1.4.3. Portopulmonary hypertension. The development
`of PAH in association with elevated pressure in the portal
`circulation is known as portopulmonary hypertension
`(POPH) (39,40). Portal hypertension, rather than the
`presence of underlying liver disease, is the main determining
`risk factor for the development of POPH. Prospective
`hemodynamic studies have shown that 2% to 6% of patients
`with portal hypertension have PH (41,42). Right heart
`catheterization is absolutely mandatory for the definitive
`diagnosis of POPH because several factors may increase
`pulmonary arterial pressure (PAP) in the setting of ad-
`vanced liver disease (e.g., high flow associated with the
`hyperdynamic circulatory state and increased pulmonary
`capillary wedge pressure owing to fluid overload and/or
`diastolic dysfunction). Pulmonary vascular resistance (PVR)
`is usually normal in these cases. Pathologic changes in the
`small arteries appear identical to those seen in IPAH. A
`recent multicenter case-control study identified 2 risk fac-
`tors for the development of POPH: female sex and auto-
`immune hepatitis (43). Interestingly, hepatitis C infection
`was associated with a decreased risk. A recent, large cohort
`study of POPH showed that long-term prognosis was
`related to the presence and severity of cirrhosis and to
`cardiac function (44).
`1.4.4. Congenital heart diseases. A significant proportion
`of patients with congenital heart disease (CHD), in partic-
`ular those with relevant systemic-to-pulmonary shunts, will
`develop PAH if left untreated. Persistent exposure of the
`pulmonary vasculature to increased blood flow, as well as
`increased pressure, may result in pulmonary obstructive
`arteriopathy, which leads to increased PVR that will result
`in shunt reversal. Eisenmenger syndrome is defined as
`CHD with an initial large systemic-to-pulmonary shunt
`that induces progressive pulmonary vascular disease and
`PAH, with resultant reversal of the shunt and central
`cyanosis (45,46). Eisenmenger syndrome represents the
`most advanced form of PAH associated with CHD. The
`histopathologic and pathobiologic changes seen in patients
`with PAH associated with congenital
`systemic-to-
`pulmonary shunts (e.g., endothelial dysfunction of
`the
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`JACC Vol. 54, No. 1, Suppl S, 2009
`June 30, 2009:S43–54
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`Simonneau et al.
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`Anatomic-Pathophysiologic Classificationof Congenital Systemic-to-PulmonaryShunts Associated With Pulmonary ArterialHypertension (Modified From Venice 2003)
`
`pulmonary shunts (Table 4) to provide a more detailed
`description of each condition. This anatomic and patho-
`physiologic classification may be too complex to be used in
`clinical practice; however, 4 quite distinct phenotypes can be
`recognized (Table 5).
`1.4.5. Schistosomiasis. Another important modification of
`the new classification is the inclusion of PH associated with
`schistosomiasis in Group 1.
`In the previous classification, this form of PH was
`subcategorized in Group 4 as PH owing to chronic throm-
`botic and/or embolic disease. Embolic obstruction of pul-
`monary arteries by schistosoma eggs was thought to be the
`primary mechanism responsible for the development of PH
`(51). However, more recent publications indicate that PH
`associated with schistosomiasis can have a similar clinical
`presentation to IPAH (52), with similar histologic findings,
`including the development of plexiform lesions (53). The
`mechanism of PAH in patients with schistosomiasis is
`probably multifactorial. It may include POPH, a frequent
`complication of this disease (54), and local vascular inflam-
`mation as a result of impacted schistosoma eggs, whereas
`mechanical obstruction by schistosoma eggs seems to play a
`minor role. PAH associated with schistosomiasis represents
`a frequent form of PAH, especially in countries in which the
`infection is endemic. It is estimated that more than 200
`million people are infected with any of the 3 species of
`schistosoma and that 4% to 8% of patients will develop
`hepatosplenic disease. Data from a recent study based on
`invasive hemodynamics showed that the prevalence of PAH
`in patients with hepatosplenic disease was 4.6%; also im-
`portant was the prevalence of post-capillary hypertension
`(3.0%), reinforcing the need for invasive hemodynamics for
`the proper diagnosis of PAH in schistosomiasis (55).
`1.4.6. Chronic hemolytic anemia. The chronic hemolytic
`anemias represent a new subcategory of PAH; these were
`previously categorized under “other” as conditions associ-
`ated with the development of PAH. Since the Venice
`classification, there has been increasing evidence that PAH
`is a complication of chronic hereditary and acquired hemo-
`lytic anemias, including sickle cell disease (SCD) (56,57),
`thalassemia (58), hereditary spherocytosis (59), stomatocy-
`tosis (60), and microangiopathic hemolytic anemia (61).
`Pulmonary hypertension has been described most fre-
`quently in patients with SCD with histologic lesions similar
`
`Table 4
`
`Anatomic-Pathophysiologic Classification
`of Congenital Systemic-to-Pulmonary
`Shunts Associated With Pulmonary Arterial
`Hypertension (Modified From Venice 2003)
`
`1. Type
`
`1.1. Simple pre-tricuspid shunts
`
`1.1.1. Atrial septal defect (ASD)
`
`1.1.1.1. Ostium secundum
`
`1.1.1.2. Sinus venosus
`
`1.1.1.3. Ostium primum
`
`1.1.2. Total or partial unobstructed anomalous pulmonary venous return
`
`1.2. Simple post-tricuspid shunts
`
`1.2.1. Ventricular septal defect (VSD)
`
`1.2.2. Patent ductus arteriosus
`
`1.3. Combined shunts (describe combination and define predominant defect)
`
`1.4. Complex congenital heart disease
`
`1.4.1. Complete atrioventricular septal defect
`
`1.4.2. Truncus arteriosus
`
`1.4.3. Single ventricle physiology with unobstructed pulmonary blood flow
`
`1.4.4. Transposition of the great arteries with VSD (without pulmonary stenosis)
`
`and/or patent ductus arteriosus
`
`1.4.5. Other
`
`2. Dimension (specify for each defect if ⬎1 congenital heart defect)
`
`2.1. Hemodynamic (specify Qp/Qs)*
`
`2.1.1. Restrictive (pressure gradient across the defect)
`
`2.1.2. Nonrestrictive
`
`2.2. Anatomic
`
`2.2.1. Small to moderate (ASD ⱕ2.0 cm and VSD ⱕ1.0 cm)
`
`2.2.2. Large (ASD ⬎2.0 cm and VSD ⬎1.0 cm)
`
`3. Direction of shunt
`
`3.1 Predominantly systemic-to-pulmonary
`
`3.2 Predominantly pulmonary-to-systemic
`
`3.3 Bidirectional
`
`4. Associated cardiac and extracardiac abnormalities
`
`5. Repair status
`
`5.1. Unoperated
`
`5.2. Palliated (specify type of operation[s], age at surgery)
`
`5.3. Repaired (specify type of operation[s], age at surgery)
`
`*Ratio of pulmonary (Qp) to systemic (Qs) blood flow.
`
`pulmonary vasculature) are similar to those observed in
`idiopathic or other associated forms of PAH.
`It has been reported that a large proportion of patients
`with CHD develop some degree of PAH (47– 49). The
`prevalence of PAH associated with congenital systemic-to-
`pulmonary shunts in Europe and North America has been
`estimated to range between 1.6 and 12.5 cases per million
`adults, with 25% to 50% of this population affected by
`Eisenmenger syndrome (50). Following the Dana Point
`meeting,
`it was decided to update the pathologic and
`pathophysiologic classification of CHD with systemic-to-
`
`Clinical Classification of Congenital Systemic-to-Pulmonary Shunts Associated to PAH
`
`Table 5
`
`Clinical Classification of Congenital Systemic-to-Pulmonary Shunts Associated to PAH
`
`A. Eisenmenger syndrome
`
`Includes all systemic-to-pulmonary shunts resulting from large defects and leading to a severe increase in PVR and
`
`a reversed (pulmonary-to-systemic) or bidirectional shunt; cyanosis, erythrocytosis, and multiple organ involvement
`
`are present
`
`B. PAH associated with systemic-to-pulmonary
`
`Includes moderate to large defects; PVR is mildly to moderately increased, systemic-to-pulmonary shunt is still prevalent,
`
`shunts
`
`and no cyanosis is present at rest
`
`C. PAH with small defects
`
`Small defects (usually ventricular septal defects ⬍1 cm and atrial septal defects ⬍2 cm of effective diameter assessed
`
`by echocardiography); clinical picture is very similar to idiopathic PAH
`
`D. PAH after corrective cardiac surgery
`
`Congenital heart disease has been corrected, but PAH is still present immediately after surgery or recurs several months
`
`or years after surgery in the absence of significant postoperative residual lesions
`
`PAH ⫽ pulmonary arterial hypertension; PVR ⫽ pulmonary vascular resistance.
`
`047
`
`

`

`S48
`
`Simonneau et al.
`Classification and Epidemiology
`
`JACC Vol. 54, No. 1, Suppl S, 2009
`June 30, 2009:S43–54
`
`to those found in IPAH, including plexiform lesions in 1
`case series (62). However, the prevalence of PAH in SCD
`is not clearly established. The largest study of patients with
`SCD, which defined PH echocardiographically by the
`presence of tricuspid regurgitation jet velocity (TRV) ⱖ2.5
`m/s, found that 32% of patients had PH (57). However,
`using a TRV ⬎2.5 m/s on echocardiography to define PH
`can lead to a substantial number of false positive cases of PH
`not confirmed by right heart catheterization (35,63). When
`a TRV ⬎3.0 m/s was used, corresponding to an estimated
`systolic PAP of ⬎41 mm Hg, only 9% of the cohort met the
`criteria for PH. Right heart catheterization was carried out
`in only 18 of 63 patients with TRV ⬎2.5 m/s. In this
`subpopulation, PH defined by a mean PAP ⬎25 mm Hg
`was confirmed in 17 patients; however, pulmonary wedge
`pressure was elevated in some patients. A substantial pro-
`portion of patients with SCD have pulmonary venous
`hypertension: 46% in 1 study of 26 patients with SCD and
`PH (64). In addition, some patients present with a hyperki-
`netic state with moderate elevation in mean PAP and
`normal PVR. Thus, although it appears that some patients
`with SCD do develop PAH, the prevalence of PAH in
`SCD is undoubtedly much lower than 32%. Prospective
`epidemiologic studies using echocardiographic screening
`and direct hemodynamic confirmation with right heart
`catheterization in all patients with suspected PH are ongo-
`ing and will evaluate the precise prevalence of PAH in
`SCD. The mechanism of PAH in SCD remains uncertain.
`A probable hypothesis is that chronic hemolysis results in
`high rates of nitric oxide consumption and produces a state
`of resistance to nitric oxide bioactivity (65). Consequently,
`smooth muscle guanosine monophosphate, a potent vaso-
`dilator/antiproliferative mediator, is not activated (66).
`
`Group 1=: PVOD and/or PCH
`
`The conditions of PVOD and PCH are uncommon, but
`they are increasingly recognized as causes of PH (67). In the
`Evian classification,
`these 2 entities were placed in 2
`different groups, both distinct from PAH: PVOD was
`included in the pulmonary venous hypertension category,
`and PCH was included in the heterogeneous group of
`disorders believed to directly affect the pulmonary vascula-
`ture. Pathologic studies indicate, however, that PVOD and
`PCH are often quite similar in terms of changes in the
`pulmonary parenchyma (i.e., pulmonary hemosiderosis, in-
`terstitial edema, and lymphatic dilation) and the develop-
`ment of pulmonary arterial
`intimal fibrosis and medial
`hypertrophy. Similarities in pathologic features and clinica