Journal of the American College of Cardiology
`© 2013 by the American College of Cardiology Foundation
`
`Published by Elsevier Inc.
`
`Vol. 62, No. 25, Suppl D, 2013
`ISSN 0735-1097/$36.00
`029
`hrep://dx. doi.org/10.1016/4,jacc.201.
`
`
`
`Gerald Simonneau, MD," Michael A. Gatzoulis, MD, PHD,; Ian Adatia, MD,:
`David Celermajer, MD, PetD,: Chris Denton, MD, PHD,! Ardeschir Ghofrani, MD,®
`Miguel Angel Gomes Sanchez, MD,# R. Krishna Kumar, MD,Michael Landvzberg, MD,?}
` Ivan M. Robbins, MD
`Roberto F. Machado, MD,**
`Horst Olschewski, MD
`Rogiero Souza, MD, PHD4&
`
`Le Kremlin-Buétre 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 Sao 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 Word
`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 new 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 toe pediatric pulmonary hypertension in order te create
`a comprehensive, commonclassification for both aduits and children. Therefore, congenital or acquired ieft-heart
`inflaw/outflow obstructive lesions and congenital cardiomyapathies have been added te Group 2, and segmental
`pulmonary hypertension has been added to Group 5. Last, there were no changesfor Groups 2, 3, and 4.
`Gd Am Coll Cardio! 2013;62:D34-41) © 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 ofdisorders that cause PH were
`identified: pulmonary arterial hypertension (Group 1);
`pulmonary hypertension due to left heart disease (Group 2);
`
`has received grat support fromActelion, Pfizer, Bayer-Schering, GlaxoSmithKline,
`Frown the "Assistance publique-Hapitaux de Puris, Service de Pueumologic, Hépital
`Universitaire de Bicétre, Université Paris-Sud, Laborawire d’excellence en recherche
`aud Novartis. Dr. Gatzoulis has served ou advisery boards of Actelion UK and Global,
`Pfizer UK, and GlaxoSmithKline, and has received unrestricted educational grants
`sur le médicamentet innovation thérapeutique, and INSERM,Unité 999, Le Kremlin
`from Actelion and Pfizer UK. Dr. Adatia is a member of Critical Events Committee
`Bicétre, France; {Adult Congenital Heart Centre and Centre for Pulmonary Hyper-
`for the tadalafil study in pediatrics with Eli Lilly. Dr. Celermajer is a memberof the
`tension, Royal Brompton Hospital and the National Heart and Lung Institute,
`speakers’ bureau, serves on the advisory board of, and receives travel and research
`Imperial College, London, United Kingdom; {University of Alberta, Stollery Chil-
`
`support from Actelion. Dr. Dentonhas received payment for consultancy and speaker's
`dren’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta,
`fecs from Aciclion, Pfizer, GlaxoSmithKlinc, Digna, Sanofi Aventis, Bochringer
`Canada, §$Heart Research Institute, Royal Prince Alfred Hospital, University of
`
`Ingelheim, Roche, CST, Behring, and Genzyme; has rec
`grant funding from
`Sydney, Sydney, Australia;
`|[Centre for Rheumatology and Connective Tissue
`Encysive, Actelion, Novartis, and Genzyme; and has servedas clinical trial investigator
`Diseases, Division of Medicine, Royal Free Campus, UCL Medical School, London,
`aud steering committee member for Plizer, Actelion, Sanofi-Aventis, Medlimmune,
`United Kingdom; YUniversity of Giessen aud Marburg Lung Center, Geissen, Hesse,
`Digna, United Therapeutics, Novartis, and Celgene. Dr. Denton has
`received
`Germany; #Cardiology Service, Hospital Universitario 12 de Octubre, Madrid, Spain;
`consultancy and speaker fees from Actelion, Pfizer, GlaxoSmithKline, Digna, Sanofi-
`“Pediatric Cardiology, Amrita Inctivate of Medical Sciences, Cochin, Kerala, India;
`
`Aventis, Boehringer Ingelheim, Roche, CSL Behring, and Genzyme. Dr. Ghofrani
`+tChildrens’ Hospital, Boston, Massachusetts;
`niversity of Illinois, Chicago, Illi-
`has received support from Actelion, Bayer, GlaxoSmithKline, Merck, Novartis, and
`nois; §§Institute for Lung and Vascular Research, Medical University of Graz, Graz,
`Pfizer. Dr. Gomez Sanchez has received honoraria for consultations and speaking at
`Austria;
`|{Vanderbilt University Medical Center, Nashville, Tennessee; and the
`conferences from Actelion, Bayer, GlaxoSmithKline, Novartis, Pfizer, United Ther-
`q{Pulmonary Department, Heart Institute, University of Sao Paulo, Medical School,
`apeutics, and Ferrer Pharma. Dr. Landzherg has received research grants from
`S30 Paulo, Brazil. Dr. Simonneauhas served on advisory hoards of Eli Lilly, Actelion,
`Actelion, Myogen, and the NHI-RT; and is on the steering committee for Actelion.
`Pfizer, Rayer-Schering, GlaxoSmithKline, and Novartis; has received payment for
`lectures by Ei Lilly, Pliver, Bayer-Schering, and GlaxoSimithKbue; aud bis institution
`Dr. Machado has received institutional grant support Qwithout salary support) from
`Simmoneau 2013
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`JACC Vol. 62, No. 25, Suppl D, 2013
`December 24, 2013:034-44
`
`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 somespecific items related
`to pediatric pulmonary hypertension in order to have
`a comprehensive classification common for adults and
`children (Table 1).
`
`Group i: Pulmenary 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.
`
`Hortable Pulmonary Hypertension
`
`In 80% offamilies with multiple cases of pulmonaryarterial
`hypertension (PAH), mutations of the bone morphogenic
`protein receptor type 2 (BMPR2), a member ofthe 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
`receptor kinase-1 (ALK,)
`(7),
`endoglin (ENG)
`(8),
`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 norelationships relevant to the contents of this paper to disclose.
`Manuscript received October 15, 2013; accepted October 22, 2013.
`Simmoneau 2013
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`Simonneau et al.
`Classification of Pulmonary Hypertension
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`D35
`
`new gene mutations have been
`identified:
`a mutation in cav-
`eolin-1 (CAV1) which encodes
`a membrane protein of caveolae,
`abundantin 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
`TGFsignaling mayprovide new
`insights into the pathogenesis of
`PAH.
`
`Brug and Toxin-induced
`Pulmonary Hypertension
`
`
`
`GHB = 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 newbom
`
`PYR = pulmonary vascular
`resistance
`
`SCD = sickle cell disease
`
`Sci-PAH = schistesomiasis-
`associated PAH
`
`FQF = tumor growth factor
`
`TKI = tyrosine kinase
`inhibitor
`
`A number of drugs and toxins
`have been identified as risk fac-
`tors for the development ofPAH
`and were includedin 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 mechanismsof action
`as those in the definite orlikely category but which have not
`yet been studied. Last, an unlikely associationis defined as
`one in which a drug has beenstudied in epidemiologic studies
`and an association with PAHhas 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. Thefirst 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 nationalregistry from 1999 to 2011.
`Of these cases, 70 patients had confirmed pre-capillary
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`D36
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`Simonneau etai.
`Classification of Pulmonary Hypertension
`
`
`
`Undated Classiication of Pulmonary Mypertension*
`
`1. Pulmonary arterial hypertension
`1.1 Idiopathic PAH
`1.2 Heritable PAH
`1.2.4 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
`1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
`1”. 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
`S Chronic thromboembolic pulmonary hypertension (CTEPH)
`a. Pulmonary hypertension with unclear multifactorial mechanisms
`5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative
`disorders, splenectomy
`5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis,
`lymphangioleiomyomatosis
`§.3 Metabolic disorders:glycogen storage disease Gaucherdisease,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 = bone morphogenic protein receptor type Il; CAV1 = caveolin-1; ENG = endoglin;
`HIV = human inimunodeficiency virus; PAH = 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 pulmonaryarteries, chronic thromboembolism,
`portal hypertension, and congestive heart
`failure. The
`prognosis of CMLhas been transformed bytyrosine 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 maybe a potential complication of
`dasatinib use (15).
`Simmoneau 2013
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`JACC Vol. 62, No. 25, Suppl D, 2043
`December 24, 2013:D34-41
`
`PAH *
`
`Undated ClaseWication for Brag and Toxininduced
`
`Definite Possible
`
`Aminorex
`Cocaine
`
`Fenfluramine
`Dexfenfluramine
`
`Phenylpropanolamine
`St. John’s wort
`
`Toxic rapeseed oil
`Chemotherapeutic agents
`Benfluorex
`Interferon « and 6
`
`SSRIs;
`Amphetamineltike drugs
`Likely Unlikely
`
`Amphetamines
`Oral contraceptives
`LTryptophan
`Estrogen
`Methamphetamines
`Cigarette smoking
`Dasatinib
`
`*Nice 2013. {Selective serotonin reuptake inhibitor (SSRis) have been demonstrated as a risk
`factor for the development of persistent pulmonary hypertension in the newbom (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.
`
`Montaniet 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 PAHof 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)-« 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 PHregistry 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-« for hepatitis C and showed
`a significant increase in pulmonaryvascularresistance (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, 2013:034-44
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`Simonneau et al.
`Classification of Pulmonary Hypertension
`
`D37
`
`improvement. Regarding a potential mechanism, several
`experimental studies have found that IFN-o and INF-B
`induced the release of endothelin-1 by pulmonary vascular
`cells (20).
`this retrospective analysis of the French
`In summary,
`registry together with experimental data suggested that [FN
`therapy maybe a trigger for PAH. However, most of the
`patients exposed to IFN also had someotherrisk 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 -f are
`considered possible risks factors of PH.
`life-
`a
`is
`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 inlate
`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 PAHin adults
`is unclear.
`Although presently there is no demonstrated association
`with PAH,several drugs with mechanismsof 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 toreportall side effects of drugs to local
`pharmaceutical agencies and pharmaceutical companies.
`
`patients with a mean pulmonary artery pressure (PAP)
`between 21 and 24 mm Hgare at high risk for the devel-
`opment of overt PH within 3 years and should be closely
`followed (34).
`
`PAM Associated With HAY iifeethon
`
`The prevalence of PAHassociated 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 ofspecific PAHdrugs, 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 PAHtherapies 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 parametersafter
`several years of treatment (38).
`
`PAH Acsoctated 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 independentofthe severity ofthe 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).
`
`PAM Associated With
`
`Cengenitial Haart Disease in Adulis
`
`PAM Associated With Connective Tissue Diseases
`
`Increasing numbers of children with congenital heart di-
`sease (CHD) nowsurvive to adulthood. This reflects im-
`provement in CHD management in recent decades, and
`The prevalence of PAH is well established only in sclero-
`both the number and complexity of adults with CHD
`continue to increase. It is estimated that 10% of adults with
`derma, and rate of occurrence is estimated between 7% and
`CHD may also have PAH (44). The presence of PAH in
`12% (29,30). The prognosis for patients with PAH associ-
`CHD has an adverse impact on quality of life and outcome
`ated with scleroderma remains poor and worse compared to
`other PAH subgroups. The 1-year mortality rate in patients
`(45,46).
`A well-recognized clinical phenotype of patients with
`with idiopathic PAH is approximately 15% (31) versus 30%
`volume and pressure overload (i.c., with large ventricular or
`in PAH-associated with scleroderma (32). Recent data
`arterial shunts) are at much higher risk of developing early
`suggest
`that
`in scleroderma, early diagnosis and early
`PAHthan patients with volume overload only (ie., with
`intervention may improve long-term outcome (33). Inter-
`atrial shunts). Nevertheless, there are some exceptions, and
`estingly, it has been recently demonstrated that scleroderma
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`Classification of Pulmonary Hypertension
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`JACC Vol. 62, No. 25, Suppl D, 2043
`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 amongadults 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
`CHDshas evolved sensibly from 2008. It remains clinical
`and simple, thus widely applicable. Importantly, it is now
`aligned with the Nice Pediatric classification, as PAHin
`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 whodo not belong to Group 1 (PAH)are included in
`different groups of the general clinical classification (..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 CHDare 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/PVRineverysingle patient. Here we make
`specific reference to patients with the Fontan circulation
`(atrio- or cavopulmonaryconnectionsas palliation for “single
`
`Discase*
`
`Undated Ciwiea! Classification of Pulmonary Arterial
`Hyperionsion Asscciaiod With Congenital Heart
`
`
`
`Criteria for Clasing Cardias Shuts in PAM Patients
`Asanniaiot With Congenital Heart Defects *
`PVR, Wood units Correctable;
`
`PVRi, Wood units/m7
`<4
`<2.3
`Yes
`>8
`>4.6
`No
`48
`2.3-46
`Individual patient evaluation
`in tertiary centers
`*Criteria: the long-term impact of defect closure in the presence of pulmonary arterial hypertension
`(PAH) with increased PVRis largely unknown. There are a lack of data in this controversial area,
`and caution must be exercised. {Correctable with surgery or intravascular nonsurgical procedure.
`PVR = pulmonary vascular resistance; PVRi = pulmonary vascular resistance index.
`
`ventricle” type hearts), who do not fulfill standardcriteria for
`PH but mayhave an increased PVR. Thereare 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 Hemelytic Anemia
`
`N
`
`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.
`. Leftto-+ight shunts
`e Correctable;
`@ 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; theclinical
`picture is very similar to idiopathic PAH. To close the defects in contraindicated.
`as. 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.
`
`Simmoneau 2013
`
`Chronic hemolytic anemia such as sickle cell disease, thal-
`assemia, spherocytosis, and stomatocytosis are associated
`with an increased risk of PH. The cause of PHis 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 onlyin 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.
`IND129819
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`HIGHLY CONFIDENTIAL
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`LIQ00018070
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`
`
`
`
`
`
`Brazilian
`French
`Cohort (57)
`Cohort (56)
`(n = 8)
`{n = 24)
`Characteristic
`_
`160+6
`RAP, mm Hg
`33.1 4+ 8.9
`304+6
`mPAP, mm Hg
`16.0 + 5.7
`1647
`PCWP, mm Hg
`5.00 + 1.36*
`87419
`CO, /min-Cl, I/min/m?*
`179 + 120
`138 + 58
`PVR, dyn-s-em®
`*Cardiac index use instead of cardiac output in the Brazilian cohort.
`Cl = cardiac index; CO = cardiac output; mPAP = mean pulmonary artery pressure;
`PCWP = pulmonary capillary wedge pressure; PH = pulmonary hypertension; PVR = pulmonary
`vascular resistance; RAP = right atrial pressure; SCD = sickle cell disease.
`
`U.S.
`Cohort (62)
`(n = 56)
`10+5
`3649
`1645
`8+3
`229 + 149
`
`vascular injuries are quite common in patients with SCD;
`however, not a single case with plexiform lesions could be
`found (61).
`Three recent hemodynamic studies provided baseline
`hemodynamic data in patients with SCD and PH (56-62).
`Findings were similar among the 3 cohorts, with a high
`cardiac output between 8 and 9 l/min and moderate eleva-
`tion in mean PAP (from 30 to 60 mm Hg) (Table 5). SCD
`patients with a pre-capillary PH had a modest elevation in
`PVR that was 3 or 4 times less than PVR observed in other
`PAH subgroups (Table 6). Among the 11 patients of the
`French SCD cohort with a confirmed pre-capillary PH
`(mean pulmonaryartery pressure [mPAP] >25 mm Hgand
`pulmonary capillary wedge pressure <15 mm Hg), no
`patient fulfilled the hemodynamiccriteria for PAH, detined
`as PVR >250 dyn-s:cm™? (56).
`Specific therapies approved for the treatment of PAH
`include prostacyclin derivatives, endothelin receptor antago-
`nists, and phosphodiesterase-5 inhibitors. However, none of
`these agents is currently approved for the treatment of
`PH associated with SCD due to the lack ofdata in this specific
`population. Recently, the effect of bosentan was assessed in
`a
`randomized double-blind placebo-controlled trial of
`patients with sickle cell disease and PH (63). Overall,
`bosentan appeared to be well tolerated, although the small
`sample size precluded an analysis of its efficacy. Another
`randomized, double-blind, placebo-controlled study designed
`to evaluate the safety andefficacy ofsildenafil was prematurely
`halted after interim analysis showed that sildenafil-treated
`patients werelikely to have more acutesickle cell pain crises
`(35%)