Journal of the American College of Cardiology
`Ó 2013 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`Vol. 62, No. 25, Suppl D, 2013
`ISSN 0735-1097/$36.00
`http://dx.doi.org/10.1016/j.jacc.2013.10.029
`
`Updated Clinical Classification of Pulmonary Hypertension
`
`Gerald Simonneau, MD,* Michael A. Gatzoulis, MD, PHD,y Ian Adatia, MD,z
`David Celermajer, MD, PHD,x Chris Denton, MD, PHD,k Ardeschir Ghofrani, MD,{
`Miguel Angel Gomez Sanchez, MD,# R. Krishna Kumar, MD,** Michael Landzberg, MD,yy
`Roberto F. Machado, MD,zz Horst Olschewski, MD,xx Ivan M. Robbins, MD,kk
`Rogiero Souza, MD, PHD{{
`Le Kremlin-Bicêtre and Paris, France; London, United Kingdom; Edmonton, Alberta, Canada;
`Sydney, Australia; Marburg, Germany; Madrid, Spain; Kerala, India; Boston, Massachusetts;
`Chicago, Illinois; Graz, Austria; Nashville, Tennessee; and São Paulo, Brazil
`
`In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which
`share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World
`Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous
`clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial
`hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the
`newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH
`subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with
`chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In
`addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create
`a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart
`inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental
`pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4.
`(J Am Coll Cardiol 2013;62:D34–41) ª 2013 by the American College of Cardiology Foundation
`
`Pulmonary hypertension (PH) was previously classified into
`2 categories: 1) primary pulmonary hypertension; or 2)
`secondary pulmonary hypertension according to the presence
`of identified causes or risk factors (1).
`Since the second World Symposium on pulmonary
`hypertension held in Evian,
`in 1998 (2), a clinical
`
`to individualize
`classification was established in order
`different categories of PH sharing similar pathological
`findings, similar hemodynamic characteristics and, similar
`management. Five groups of disorders that cause PH were
`identified: pulmonary arterial hypertension (Group 1);
`pulmonary hypertension due to left heart disease (Group 2);
`
`From the *Assistance publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital
`Universitaire de Bicêtre, Université Paris-Sud, Laboratoire d’excellence en recherche
`sur le médicament et innovation thérapeutique, and INSERM, Unité 999, Le Kremlin
`Bicêtre, France; yAdult Congenital Heart Centre and Centre for Pulmonary Hyper-
`tension, Royal Brompton Hospital and the National Heart and Lung Institute,
`Imperial College, London, United Kingdom; zUniversity of Alberta, Stollery Chil-
`dren’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta,
`Canada; xHeart Research Institute, Royal Prince Alfred Hospital, University of
`Sydney, Sydney, Australia; kCentre for Rheumatology and Connective Tissue
`Diseases, Division of Medicine, Royal Free Campus, UCL Medical School, London,
`United Kingdom; {University of Giessen and Marburg Lung Center, Geissen, Hesse,
`Germany; #Cardiology Service, Hospital Universitario 12 de Octubre, Madrid, Spain;
`**Pediatric Cardiology, Amrita Institute of Medical Sciences, Cochin, Kerala, India;
`yyChildrens’ Hospital, Boston, Massachusetts; zzUniversity of Illinois, Chicago, Illi-
`nois; xxInstitute for Lung and Vascular Research, Medical University of Graz, Graz,
`Austria; kkVanderbilt University Medical Center, Nashville, Tennessee; and the
`{{Pulmonary Department, Heart Institute, University of São Paulo, Medical School,
`São Paulo, Brazil. Dr. Simonneau has served on advisory boards of Eli Lilly, Actelion,
`Pfizer, Bayer-Schering, GlaxoSmithKline, and Novartis; has received payment for
`lectures by Eli Lilly, Pfizer, Bayer-Schering, and GlaxoSmithKline; and his institution
`
`has received grant support from Actelion, Pfizer, Bayer-Schering, GlaxoSmithKline,
`and Novartis. Dr. Gatzoulis has served on advisory boards of Actelion UK and Global,
`Pfizer UK, and GlaxoSmithKline; and has received unrestricted educational grants
`from Actelion and Pfizer UK. Dr. Adatia is a member of Critical Events Committee
`for the tadalafil study in pediatrics with Eli Lilly. Dr. Celermajer is a member of the
`speakers’ bureau, serves on the advisory board of, and receives travel and research
`support from Actelion. Dr. Denton has received payment for consultancy and speaker’s
`fees from Actelion, Pfizer, GlaxoSmithKline, Digna, Sanofi Aventis, Boehringer
`Ingelheim, Roche, CSL Behring, and Genzyme; has received grant funding from
`Encysive, Actelion, Novartis, and Genzyme; and has served as clinical trial investigator
`and steering committee member for Pfizer, Actelion, Sanofi-Aventis, MedImmune,
`Digna, United Therapeutics, Novartis, and Celgene. Dr. Denton has received
`consultancy and speaker fees from Actelion, Pfizer, GlaxoSmithKline, Digna, Sanofi-
`Aventis, Boehringer Ingelheim, Roche, CSL Behring, and Genzyme. Dr. Ghofrani
`has received support from Actelion, Bayer, GlaxoSmithKline, Merck, Novartis, and
`Pfizer. Dr. Gomez Sanchez has received honoraria for consultations and speaking at
`conferences from Actelion, Bayer, GlaxoSmithKline, Novartis, Pfizer, United Ther-
`apeutics, and Ferrer Pharma. Dr. Landzberg has received research grants from
`Actelion, Myogen, and the NHLBI; and is on the steering committee for Actelion.
`Dr. Machado has received institutional grant support (without salary support) from
`
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`
`

`

`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D34–41
`
`Simonneau et al.
`Classification of Pulmonary Hypertension
`
`D35
`
`pulmonary hypertension due to chronic lung disease and/or
`hypoxia (Group 3); chronic thromboembolic pulmonary
`hypertension (Group 4); and pulmonary hypertension due to
`unclear multifactorial mechanisms (Group 5). During the
`successive world meetings, a series of changes were carried
`out, reflecting some progresses in the understanding of the
`disease. However, the general architecture and the philosophy
`of the clinical classification were unchanged. The current
`clinical classification of pulmonary hypertension (3) is now
`well accepted and, widely used in the daily practice of
`pulmonary hypertension experts. It has been adopted by the
`Guidelines Committee of the Societies of Cardiology and,
`Pneumology (4,5). Moreover, this classification is currently
`used by the U.S. Food and Drug Administration and the
`European Agency for Drug Evaluation for the labelling of
`new drugs approved for pulmonary hypertension.
`During the Fifth World Symposium held in 2013 in
`Nice, France, the consensus was to maintain the general
`disposition of previous
`clinical
`classification. Some
`modifications and updates, especially for Group 1, were
`proposed according to new data published in the last
`years. It was also decided in agreement with the Task
`Force on Pediatric PH to add some specific items related
`to pediatric pulmonary hypertension in order to have
`a comprehensive classification common for adults and
`children (Table 1).
`
`Group 1: Pulmonary Arterial Hypertension (PAH)
`
`Since the second World Symposium in 1998, the nomen-
`clature of the different subcategories of Group 1 have
`markedly evolved and, additional modification were made in
`the Nice classification.
`
`Heritable Pulmonary Hypertension
`
`In 80% of families with multiple cases of pulmonary arterial
`hypertension (PAH), mutations of the bone morphogenic
`protein receptor type 2 (BMPR2), a member of the tumor
`growth factor (TGF)-beta super family, can be identified
`(6). In addition, 5% of patients have rare mutations in other
`genes belonging to the TGFb super family: activin-like
`(7),
`endoglin (ENG)
`(8),
`receptor kinase-1 (ALK1)
`and mothers against decapentaplegic 9 (Smad 9)
`(9).
`Approximately 20% of families have no detectable mutations
`in currently known disease-associated genes. Recently two
`
`Actelion and United Therapeutics; and has served on advisory boards of Gilead and
`United Therapeutics. Dr. Olschewski has received consultancy and lecture fees from
`Actelion, Bayer, Lilly, Gilead, GlaxoSmithKline, Pfizer, and Unither; and consultancy
`fees from NebuTec. Dr. Robbins has received honoraria from United Therapeutics,
`Gilead, and Actelion for attending advisory board meetings; has received honoraria
`from Actelion, Gilead, United Therapeutics, and Bayer; and he has been the primary
`investigator on industry-sponsored studies from Actelion, Gilead, United Therapeu-
`tics, GeNO, Novartis, and Aires in which payment was made to Vanderbilt University.
`Dr. Souza has received consultancy/lecture fees from Bayer. All other authors report
`that they have no relationships relevant to the contents of this paper to disclose.
`Manuscript received October 15, 2013; accepted October 22, 2013.
`
`new gene mutations have been
`identified: a mutation in cav-
`eolin-1 (CAV1) which encodes
`a membrane protein of caveolae,
`abundant in the endothelial cells
`of the lung (10), and KCNK3, a
`gene encoding potassium channel
`super family K member-3 (11).
`The identification of these new
`genes not intimately related to
`TGFb signaling may provide new
`insights into the pathogenesis of
`PAH.
`
`Drug- and Toxin-Induced
`Pulmonary Hypertension
`
`Abbreviations
`and Acronyms
`
`CHD = congenital heart
`disease
`
`HAART = highly active
`antiretroviral therapy
`
`HIV = human
`immunodeficiency virus
`
`IFN = interferon
`
`PAH = pulmonary arterial
`hypertension
`
`PAP = pulmonary arterial
`pressure
`
`PH = pulmonary
`hypertension
`
`POPH = portopulmonary
`hypertension
`
`PPHN = persistent
`pulmonary hypertension of
`the newborn
`
`PVR = pulmonary vascular
`resistance
`
`SCD = sickle cell disease
`
`Sch-PAH = schistosomiasis-
`associated PAH
`
`TGF = tumor growth factor
`
`TKI = tyrosine kinase
`inhibitor
`
`A number of drugs and toxins
`have been identified as risk fac-
`tors for the development of PAH
`and were included in the previous
`classification (3). Risk factors
`were categorized according to
`the strength of evidence, as defi-
`nite, likely, possible, or unlikely
`(Table 2).
`A definite association is de-
`fined as an epidemic or large
`multicenter epidemiologic studies
`demonstrating an association between a drug and PAH. A
`likely association is defined as a single case-control study
`demonstrating an association or a multiple-case series.
`Possible is defined as drugs with similar mechanisms of action
`as those in the definite or likely category but which have not
`yet been studied. Last, 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.
`Over the last 5 years, new drugs have been identified or
`suspected as potential risk factors for PAH.
`Since 1976, Benfluorex (MEDIATOR, Laboratories
`Servier, Neuilly-Sur-Seine, France) has been approved in
`Europe as a hypolipidemic and hypoglycemic drug. This
`drug is in fact a fenfluramine derivative, and its main
`metabolite is norfenfluramine, similar to Isomeride. Ben-
`fluorex, due to its pharmacological properties, was with-
`drawn from the market in all European countries after 1998
`(date of the worldwide withdrawal of fenfluramine deriva-
`tives), except in France where the drug was marketed until
`2009 and was frequently used between 1998 and 2009 as
`a replacement for Isomeride. The first case series reporting
`benfluorex-associated PAH was published in 2009. In
`addition to 5 cases of severe PAH, 1 case of valvular disease
`was also reported (12). Recently, Savale et al. (13) reported
`85 cases of PAH associated with benfluorex exposure,
`identified in the French national registry from 1999 to 2011.
`Of these cases, 70 patients had confirmed pre-capillary
`
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`
`

`

`D36
`
`Simonneau et al.
`Classification of Pulmonary Hypertension
`
`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D34–41
`
`Table 1
`
`Updated Classification of Pulmonary Hypertension*
`
`Table 2
`
`Updated Classification for Drug- and Toxin-Induced
`PAH*
`
`1. Pulmonary arterial hypertension
`1.1 Idiopathic PAH
`1.2 Heritable PAH
`1.2.1 BMPR2
`1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3
`1.2.3 Unknown
`1.3 Drug and toxin induced
`1.4 Associated with:
`1.4.1 Connective tissue disease
`1.4.2 HIV infection
`1.4.3 Portal hypertension
`1.4.4 Congenital heart diseases
`1.4.5 Schistosomiasis
`10 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
`100. Persistent pulmonary hypertension of the newborn (PPHN)
`2. Pulmonary hypertension due to left heart disease
`2.1 Left ventricular systolic dysfunction
`2.2 Left ventricular diastolic dysfunction
`2.3 Valvular disease
`2.4 Congenital/acquired left heart inflow/outflow tract obstruction and
`congenital cardiomyopathies
`3. Pulmonary hypertension due 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 lung diseases
`4. Chronic thromboembolic pulmonary hypertension (CTEPH)
`5. Pulmonary hypertension with unclear multifactorial mechanisms
`5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative
`disorders, splenectomy
`5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,
`lymphangioleiomyomatosis
`5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
`5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure,
`segmental PH
`
`*5th WSPH Nice 2013. Main modifications to the previous Dana Point classification are in bold.
`BMPR ¼ bone morphogenic protein receptor type II; CAV1 ¼ caveolin-1; ENG ¼ endoglin;
`HIV ¼ human immunodeficiency virus; PAH ¼ pulmonary arterial hypertension.
`
`pulmonary hypertension (PH) with a median ingestion
`duration of 30 months and a median delay between start of
`exposure and diagnosis of 108 months. One-quarter of
`patients in these series showed coexisting PH and mild to
`moderate valvular heart diseases (14).
`Chronic myeloproliferative (CML) disorders are a rare cause
`of PH, involving various potential mechanisms (Group 5)
`including high cardiac output, splenectomy, direct obstruc-
`tion of pulmonary arteries, chronic thromboembolism,
`portal hypertension, and congestive heart
`failure. The
`prognosis of CML has been transformed by tyrosine kinase
`inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib.
`Although, TKIs are usually well tolerated, these agents are
`associated nevertheless with certain systemic side effects
`(edema, musculoskeletal pain, diarrhea, rash, pancytopenia,
`elevation of
`liver enzymes). It is also well established
`that
`imatinib may induce cardiac toxicity. Pulmonary
`complications and specifically pleural effusions have been
`reported more frequently with dasatinib. In addition, case
`reports suggested that PH may be a potential complication of
`dasatinib use (15).
`
`Definite
`Aminorex
`Fenfluramine
`Dexfenfluramine
`Toxic rapeseed oil
`
`Benfluorex
`SSRIsy
`
`Likely
`
`Amphetamines
`L-Tryptophan
`Methamphetamines
`
`Possible
`
`Cocaine
`Phenylpropanolamine
`St. John’s wort
`Chemotherapeutic agents
`Interferon a and b
`Amphetamine-like drugs
`
`Unlikely
`
`Oral contraceptives
`Estrogen
`Cigarette smoking
`
`Dasatinib
`*Nice 2013. ySelective serotonin reuptake inhibitor (SSRIs) have been demonstrated as a risk
`factor for the development of persistent pulmonary hypertension in the newborn (PPHN) in preg-
`nant women exposed to SSRIs (especially after 20 weeks of gestation). PPHN does not strictly
`belong to Group 1 (pulmonary arterial hypertension [PAH]) but to a separated Group 1. Main
`modification to the previous Danapoint classification are in bold.
`
`Montani et al. (16) recently published incidental cases of
`dasatinib-associated PAH reported in the French registry.
`Between November 2006 and September 2010, 9 cases
`treated with dasatinib at the time of PH diagnosis were
`identified. At diagnosis, patients had moderate to severe pre-
`capillary PH confirmed by heart right catheterization. No
`other PH cases were reported with other TKIs at the time
`of PH diagnosis. Interestingly, clinical,
`functional, and
`hemodynamic improvements were observed within 4 months
`of dasatinib discontinuation in all but 1 patient. However,
`after a median follow-up of 9 months, most patients did not
`demonstrate complete recovery, and 2 patients died. Today,
`more than 13 cases have been observed in France among
`2,900 patients treated with dasatinib for CML during the
`same period, giving the lowest estimate incidence of
`dasatinib-associated PAH of 0.45%. Finally, notifications of
`almost 100 cases of PH have been submitted for European
`pharmaceutical vigilance. Dasatinib is considered a likely risk
`factor for PH (Table 2).
`Few cases of PAH associated with the use of interferon
`(IFN)-a or -b (17,18) have been published so far. Recently,
`all cases of PAH patients with a history of IFN therapy
`notified in the French PH registry were analyzed (19). Fifty-
`three patients with PAH and a history of IFN use were
`identified between 1998 and 2012. Forty-eight patients were
`treated with IFN-a for chronic hepatitis C, most of them
`had an associated risk factor for PH such as human
`immunodeficiency virus
`(HIV)
`infection and/or portal
`hypertension. Five other cases were treated with IFNb for
`multiple sclerosis; those patients did not have any associated
`risks factor for PAH. The mean delay between initiation of
`IFN therapy and PAH diagnosis was approximately 3 years.
`Sixteen additional patients with previously documented
`PAH were treated with IFN-a for hepatitis C and showed
`a significant increase in pulmonary vascular resistance (PVR)
`within a few months of therapy initiation; in half of them,
`withdrawal of IFN resulted in a marked hemodynamic
`
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`

`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D34–41
`
`Simonneau et al.
`Classification of Pulmonary Hypertension
`
`D37
`
`improvement. Regarding a potential mechanism, several
`experimental studies have found that IFN-a and INF-b
`induced the release of endothelin-1 by pulmonary vascular
`cells (20).
`In summary, this retrospective analysis of the French
`registry together with experimental data suggested that IFN
`therapy may be a trigger for PAH. However, most of the
`patients exposed to IFN also had some other risk factors for
`PAH, and a prospective case control study is mandatory to
`definitively establish a link between IFN exposure and
`development of PAH. At this time, IFN-a and -b are
`considered possible risks factors of PH.
`is a life-
`Persistent PH of
`the newborn (PPHN)
`threatening condition that occurs in up to 2 per 1,000
`live-born infants. During the past 15 years, many studies
`have specifically assessed the associations between use of
`serotonin reuptake inhibitors (SSRIs) during pregnancy and
`the risk of PPHN with discordant results from no associa-
`tion to 6-fold increased risk (21–26).
`A recent study involving nearly 30,000 women who had
`used SSRIs during pregnancy found that every use in late
`pregnancy increased the risk of PPHN by more than
`2-fold. Based on this large study, SSRIs can be considered
`a definite risk factor for PPHN (27). Whether exposure to
`SSRIs is associated with an increased risk of PAH in adults
`is unclear.
`Although presently there is no demonstrated association
`with PAH, several drugs with mechanisms of actions similar
`to amphetamines, used to treat a variety of conditions
`including obesity (fentermine/topiramate [Qsiva]), attention
`deficit disorder (methylphenidate) (28), Parkinson’s disease
`(ropinirole), and narcolepsy (mazindol), need to be moni-
`tored closely for an increase in cases of PAH.
`In summary, several new drugs have recently been iden-
`tified as definite, likely, or possible risk factors for PAH. In
`order to improve detection of potential drugs that induce
`PAH, it is important to outline the critical importance of
`obtaining a detailed history of current and prior exposure in
`every PAH patient. The proliferation of national and
`international registries should provide the unique opportu-
`nity to collect these data prospectively. In addition, one must
`emphasize the need to report all side effects of drugs to local
`pharmaceutical agencies and pharmaceutical companies.
`
`PAH Associated With Connective Tissue Diseases
`
`The prevalence of PAH is well established only in sclero-
`derma, and rate of occurrence is estimated between 7% and
`12% (29,30). The prognosis for patients with PAH associ-
`ated with scleroderma remains poor and worse compared to
`other PAH subgroups. The 1-year mortality rate in patients
`with idiopathic PAH is approximately 15% (31) versus 30%
`in PAH-associated with scleroderma (32). Recent data
`suggest
`that
`in scleroderma, early diagnosis and early
`intervention may improve long-term outcome (33). Inter-
`estingly, it has been recently demonstrated that scleroderma
`
`patients with a mean pulmonary artery pressure (PAP)
`between 21 and 24 mm Hg are at high risk for the devel-
`opment of overt PH within 3 years and should be closely
`followed (34).
`
`PAH Associated With HIV Infection
`
`The prevalence of PAH associated with HIV infection has
`remained stable within the last decade, estimated to be 0.5%
`(35). Before the era of highly active antiretroviral therapy
`(HAART) and the development of specific PAH drugs, the
`prognosis
`for HIV-PAH was extremely poor, with a
`mortality rate of 50% in 1 year (36). The advent of HAART
`and the wide use of PAH therapies in HIV patients have
`dramatically improved their prognosis, and the current
`survival rate at 5 years in the French cohort is more than
`70% (37). Interestingly, approximately 20% of these cases
`experience a normalization of hemodynamic parameters after
`several years of treatment (38).
`
`PAH Associated With Portal Hypertension
`
`Hemodynamic studies have shown that PAH is confirmed
`in 2% to 6% of patients with portal hypertension, so called
`portopulmonary hypertension (POPH) (39,40). The risk of
`developing POPH is independent of the severity of the liver
`disease (41). Long-term prognosis is related to the severity
`of cirrhosis and to cardiac function (41). There is wide
`discrepancy in the published survival estimates of patients
`with POPH. In, the U.S. REVEAL registry (42) patients
`with POPH had a poor prognosis, even worse that those
`with idiopathic PAH with a 3-year survival rate of 40%
`versus 64%, respectively. In the French registry, the 3-year
`survival rate of POPH was 68%, slightly better than that
`of idiopathic PAH (43). These discordant results are likely
`explained by important differences with respect
`to the
`severity of liver disease. In the U.S. REVEAL registry,
`most of
`these patients were referred from liver trans-
`plantation centers, whereas in the French cohort, most
`patients had mild cirrhosis (39–43).
`
`PAH Associated With
`Congenital Heart Disease in Adults
`
`Increasing numbers of children with congenital heart di-
`sease (CHD) now survive to adulthood. This reflects im-
`provement in CHD management in recent decades, and
`both the number and complexity of adults with CHD
`continue to increase. It is estimated that 10% of adults with
`CHD may also have PAH (44). The presence of PAH in
`CHD has an adverse impact on quality of life and outcome
`(45,46).
`A well-recognized clinical phenotype of patients with
`volume and pressure overload (i.e., with large ventricular or
`arterial shunts) are at much higher risk of developing early
`PAH than patients with volume overload only (i.e., with
`atrial shunts). Nevertheless, there are some exceptions, and
`
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`

`D38
`
`Simonneau et al.
`Classification of Pulmonary Hypertension
`
`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D34–41
`
`we speculate that a permissive genotype might place some
`patients with CHD at higher risk of developing PAH.
`Given the prevalence of PAH among adults with CHD, we
`suggest that every patient with CHD merits an appropriate
`assessment in a tertiary setting to determine whether PAH is
`present. While it is anticipated that the number of patients
`with Eisenmenger syndrome, the extreme end of the PAH/
`CHD spectrum, complicated also by chronic cyanosis, will
`decrease in the coming years and there will be an increasing
`number of patients with complex and/or repaired CHD
`surviving to adulthood with concomitant PH (47). The
`present clinical subclassification of PAH associated with
`CHDs has evolved sensibly from 2008. It remains clinical
`and simple, thus widely applicable. Importantly, it is now
`aligned with the Nice Pediatric classification, as PAH in
`association with CHD is a lifelong disease (Table 3). We
`have proposed criteria for shunt closure in patients with net
`left to right shunting who may represent a management
`dilemma (Table 4). Other types of PH in association with
`CHD who do not belong to Group 1 (PAH) are included in
`different groups of the general clinical classification (i.e.,
`congenital or acquired left heart inflow/outflow obstructive
`lesions and congenital cardiomyopathies
`in Group 2).
`Segmental PH (PH in one or more lobes of one or both
`lungs) is included in Group 5. In addition, some patients
`with PH associated with CHD are difficult to classify, such
`as patients with transposition of great arteries and those
`with PH following atrial redirection surgery or following
`neonatal arterial switch operation. This reinforces the need
`to delineate the underlying cardiac anatomy/physiology and
`severity of PAH/PVR in every single patient. Here we make
`specific reference to patients with the Fontan circulation
`(atrio- or cavopulmonary connections as palliation for “single
`
`Table 3
`
`Updated Clinical Classification of Pulmonary Arterial
`Hypertension Associated With Congenital Heart
`Disease*
`
`1. Eisenmenger syndrome
`Includes all large intra- and extra-cardiac defects which begin as systemic-to-
`pulmonary shunts and progress with time to severe elevation of pulmonary
`vascular resistance (PVR) and to reversal (pulmonary-to-systemic) or
`bidirectional shunting; cyanosis, secondary erythrocytosis and multiple organ
`involvement are usually present.
`2. Left-to-right shunts
` Correctabley
` Noncorrectable
`Include moderate to large defects; PVR is mildly to moderately increased
`systemic-to-pulmonary shunting is still prevalent, whereas cyanosis is not
`a feature.
`3. Pulmonary arterial hypertension (PAH) with coincidental congenital heart disease
`Marked elevation in PVR in the presence of small cardiac defects, which
`themselves do not account for the development of elevated PVR; the clinical
`picture is very similar to idiopathic PAH. To close the defects in contraindicated.
`4. Post-operative PAH
`Congenital heart disease is repaired but PAH either persists immediately after
`surgery or recurs/develops months or years after surgery in the absence of
`significant postoperative hemodynamic lesions. The clinical phenotype is often
`aggressive.
`
`*Nice 2013.
`
`Table 4
`
`PVRi, Wood units/m2
`<4
`>8
`4-8
`
`Criteria for Closing Cardiac Shunts in PAH Patients
`Associated With Congenital Heart Defects*
`Correctabley
`Yes
`No
`Individual patient evaluation
`in tertiary centers
`
`PVR, Wood units
`<2.3
`>4.6
`2.3–4.6
`
`*Criteria: the long-term impact of defect closure in the presence of pulmonary arterial hypertension
`(PAH) with increased PVR is largely unknown. There are a lack of data in this controversial area,
`and caution must be exercised. yCorrectable with surgery or intravascular nonsurgical procedure.
`PVR ¼ pulmonary vascular resistance; PVRi ¼ pulmonary vascular resistance index.
`
`ventricle” type hearts), who do not fulfill standard criteria for
`PH but may have an increased PVR. There are very limited
`surgical alternatives for this group of patients with complex
`anatomy/physiology. There has been some recent evidence
`of potential clinical response to specific PAH therapies in
`Fontan patients, which needs further exploration before
`therapeutic recommendations can been made (48,49).
`
`PAH Associated With Schistosomiasis
`
`Schistosomiasis-associated PAH (Sch-PAH) was included
`in Group 1 in 2008. Previously it was in Group 4 (chronic
`thromboembolism disease). Today, Sch-PAH is potentially
`the most prevalent cause of PAH worldwide. Schistosomi-
`asis affects over 200 million people, of whom 10% develop
`hepatosplenic
`schistomiasis
`(50). PAH occurs
`almost
`exclusively in this population, and 5% of patients with
`hepatosplenic schistosomiasis may develop PAH (51). The
`hemodynamic profile of Sch-PAH is similar to that of
`POPH (52). Its mortality rate may reach up to 15% at 3
`years (52). Recent uncontrolled data indicate that PAH
`therapies may benefit patients with Sch-PAH (53).
`
`Chronic Hemolytic Anemia
`
`Chronic hemolytic anemia such as sickle cell disease, thal-
`assemia, spherocytosis, and stomatocytosis are associated
`with an increased risk of PH. The cause of PH is unclear
`and often multifactorial, including chronic thromboembo-
`lism, splenectomy, high cardiac output, left-heart disease,
`and hyperviscosity; the role of an inactivation of nitric oxide
`by free plasma hemoglobin due to chronic hemolysis is
`controversial (54,55).
`The prevalence and characteristic of PH in chronic
`hemolytic anemia has been extensively studied only in sickle
`cell disease (SCD). In SCD, PH confirmed by right-heart
`catheterization and defined as a mean PAP 25 mm Hg
`occurs in 6.2% (56) to 10% of patient (57). Post-capillary
`PH due to left-heart disease represents the most frequent
`cause, with a prevalence of 3.3% (56) to 6.3% (57). The
`prevalence of pre-capillary PH is lower but not rare: 2.9%
`(56) to 3.7% (57). The classification of pre-capillary PH
`associated with SCD has evolved during the successive
`world meetings, revealing uncertainties in potential causes.
`
`038
`
`

`

`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:D34–41
`
`Simonneau et al.
`Classification of Pulmonary Hypertension
`
`D39
`
`Table 5
`
`Hemodynamic Characteristics in Patients With
`PH Associated With SCD in 3 Different Cohorts:
`France, Brazil, and United States
`
`Characteristic
`RAP, mm Hg
`mPAP, mm Hg
`PCWP, mm Hg
`CO, l/min–CI, l/min/m2*
`5
`PVR, dyn$s$cm
`
`French
`Cohort (56)
`(n ¼ 24)
`10  6
`30  6
`16  7
`8.7  1.9
`138  58
`
`Brazilian
`Cohort (57)
`(n ¼ 8)
`d
`33.1  8.9
`16.0  5.7
`5.00  1.36*
`179  120
`
`U.S.
`Cohort (62)
`(n ¼ 56)
`10  5
`36  9
`16  5
`8  3
`229  149
`
`*Cardiac index use instead of cardiac output in the Brazilian cohort.
`CI ¼ cardiac index; CO ¼ cardiac output; mPAP ¼ mean pulmonary artery pressure;
`PCWP ¼ pulmonary capillary wedge pressure; PH ¼ pulmonary hypertension; PVR ¼ pulmonary
`vascular resistance; RAP ¼ right atrial pressure; SCD ¼ sickle cell disease.
`
`In the Evian classification (2), it was placed in Group 4
`(chronic thromboembolism). In the Venice and Dana Point
`classifications (3), it was shifted to Group 1 (PAH). Pre-
`capillary PHs belonging to Group 1 share some character-
`istics: 1) histological findings of major proliferation of the
`wall of pulmonary arteries including plexiform lesions;
`2) severe hemodynamic impairment, with PVR >3 Woods
`5); and 3) well-documented response
`units (240 dyn$s$cm
`to PAH-specific therapies.
`into the
`In SCD, autopsy studies providing insight
`characteristics of pulmonary vascular lesions are limited.
`The best-documented study (58) reported 20 cases and
`obtained photomicrographs of the lesions; among them,
`12 patients were considered having plexiform lesions. In
`fact, 8 of these 12 cases had histological evidence of hepatic
`cirrhosis, which is a major confounding factor. Moreover,
`the picture of the pulmonary vascular changes considered
`plexiform lesions were not typical and may correspond to
`recanalyzed thrombi (P. Dorfmüller, personal communica-
`tion, February 2013). Another autopsy study of 21 cases
`(59) reported 66.6% of microthrombotic and/or thrombo-
`embolic lesions, whereas mild moderate or severe pulmonary
`vasculopathy was observed in only one-third of
`this
`population. A larger autopsy study of 306 cases of SCD
`patients with a clinical suspicion of PH found thrombo-
`embolic lesions in 24% but no cases of pulmonary vascul-
`opathy lesions (60). A recent review of autopsy cases in
`a single tertiary center in Brazil found that pulmonary
`
`vascular injuries are quite common in patients with SCD;
`however, not a single case with plexiform lesio