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Pulmonary Veno-Occlusive Disease

2017; Lippincott Williams & Wilkins; Volume: 136; Issue: 21 Linguagem: Inglês

10.1161/circulationaha.117.031158

1524-4539

Dave P. Miller, Harrison W. Farber,

Vascular Anomalies and Treatments

HomeCirculationVol. 136, No. 21Pulmonary Veno-Occlusive Disease Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPulmonary Veno-Occlusive DiseaseWelcome to the PAHty (Bostonian for Party) Dave P. Miller, MS and Harrison W. Farber, MD Dave P. MillerDave P. Miller Verily Life Sciences, Mountain View, CA (D.P.M.) and Harrison W. FarberHarrison W. Farber Pulmonary Center, Boston University School of Medicine, MA (H.W.F.). Originally published21 Nov 2017https://doi.org/10.1161/CIRCULATIONAHA.117.031158Circulation. 2017;136:2034–2036Article, see p 2022When caring for our patients with pulmonary arterial hypertension (PAH), how many times have we wondered, could this patient really have pulmonary veno-occlusive disease/pulmonary capillary hemangiomiatosis (PVOD/PCH)? This question typically arises if there is a suggestive computed tomography scan, a low diffusing capacity of the lungs for carbon monoxide, substantial hypoxemia, or, certainly, a poor response to PAH-specific medications or development of pulmonary edema (PVOD/PCH versus unsuspected diastolic dysfunction). In fact, we recently were referred such a patient: the computed tomography scan showed septal thickening and lymphadenopathy, the diffusing capacity of the lungs for carbon monoxide was low, hypoxia requiring 8 to 10 L of supplemental oxygen was present, and marked clinical deterioration occurred after being started on PAH therapy with ambrisentan and tadalafil. Ultimately, the patient underwent lung biopsy to prove what we were certain was PVOD/PCH. To our surprise, histologically, there was no venous involvement, and she was diagnosed with idiopathic PAH (IPAH). However, based on the study by Hadinnapola and colleagues in this issue of Circulation,1 which found significant overlap in clinical, radiological, and in 1 case even histological findings, could she still have had EIF2AK4 mutations and thus PVOD/PCH genetically?In contrast to IPAH, which involves small pulmonary arteries, vascular remodeling in PVOD/PCH affects predominantly septal veins and venules, as well as capillaries.2 PVOD and PCH, previously thought to be separate conditions, are now felt to represent variable expression of the same disease.2,3 Initial clinical presentation is similar to that of IPAH, but patients with PVOD/PCH are at high risk of developing pulmonary edema and worsening hypoxia after treatment with pulmonary vasodilators. Identification of these patients using clinical measures can be difficult, and diagnosis is often only confirmed postmortem because of the anesthetic and surgical risks of lung biopsy in a patient with severe pulmonary hypertension.It is interesting to note that the current study suggests potentially even greater overlap between PVOD/PCH and IPAH than previously recognized. In this study,1 the authors examined EIF2AK4 mutations and phenotypic characteristics in a cohort of 864 patients with IPAH or heritable PAH and an additional 16 patients with diagnosed PVOD/PCH. They observed biallelic EIF2AK4 mutations in 14 patients (biallelic, meaning mutations in both EIF2AK4 genes with either a homozygous mutation or compound heterozygous mutation). However, 75%. However, a direct comparison with these earlier studies is impossible, particularly because the primary survival analysis mixed prevalent and newly diagnosed patients without accounting for left truncation. This could lead to an overestimation of survival time for the prevalent patients because the time at risk for an event began only after enrollment, and including the time between diagnosis and enrollment leads to immortal time bias.Some uncertainty exists regarding response to therapy in the patients classified as IPAH who were found to have biallelic EIF2AK4 mutations. Was it what would be expected in a patient with PVOD/PCH or was it more like that expected in a patient with IPAH? In other words, is the response to therapy driven by the phenotype or genotype? The authors note that patients with a clinical diagnosis of IPAH and biallelic EIF2AK4 mutations treated with PAH-specific therapies did not improve their functional class at either 1 or 3 years after diagnosis as did the other PAH groups (Table X in the online-only Data Supplement for the article by Morrell et al.1) However, significant data were missing during later follow-up. Had these patients been transplanted or lost or had they died? In future studies, use of a composite end point of survival, free from transplant or major clinical worsening, may clarify this point. If the short-term response is at least similar to that of patients with IPAH, early referral for transplant may not be as crucial, and a trial of medical therapies might be considered.What Should the Clinician Do With This Information?Ultimately, that is the most important question if we are to use this information to help the patient with PAH and improve care. Further underlying the complexity of this issue is the 1 patient in the study in whom tissue was available. The clinical phenotype suggested IPAH, the genetic analysis suggested PVOD/PCH, and the histology was more consistent with IPAH, in that the pathology was predominantly precapillary. To make this situation even more difficult, overlaps occurred in the radiological characteristics of the patients examined. No pattern was sensitive or specific for PVOD/PCH. Thus, the genotype-phenotype relationships of these patients may be much more complex and less clear than expected. Yet the outcome among the patients with biallelic EIF2AK4 mutations was generally poorer. As such, should a clinician treat the phenotype or genotype? Based on these data and our current clinical understanding of this entity, we cannot yet be certain. However, this study is thought-provoking and has opened a new door in potential research and clinical studies that will hopefully lead to clarity on these questions.Oh, and our patient: she has had an exceptional hemodynamic and clinical response to intravenous epoprostenol. We assume she had IPAH after all (at least phenotypically).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Harrison W. Farber, MD, The Pulmonary Center, Boston University School of Medicine, 72 East Concord St, R-304, Boston, MA 02118. E-mail [email protected]References1. Hadinnaopla C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmuller P, Preston SD, Southwood M, Hernandez-Sanchez J, Martin J, Treacy C, Yates K, Bogaard H, Church C, Coghlan G, Condliffe R, Corris PA, Gibbs S, Girerd B, Holden S, Humbert M, Kiely DG, Lawrie A, Machado R, Ross RM, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Sutharalingham J, Toshner M, Trembath R, Vonk Noordegraaf A, Wilkins MR, Wort SJ, Wharton J, Graf S. Phenotypic characterization of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension.Circulation.2017; 136:2022–2033. doi: 10.1161/CIRCULATIONAHA.117.028351.LinkGoogle Scholar2. Chaisson NF, Dodson MW, Elliott CG. Pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease.Clin Chest Med. 2016; 37:523–534. doi: 10.1016/j.ccm.2016.04.014.CrossrefMedlineGoogle Scholar3. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD. Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry.Chest. 2010; 137:376–387. doi: 10.1378/chest.09-1140.CrossrefMedlineGoogle Scholar4. Montani D, Girerd B, Jaïs X, Levy M, Amar D, Savale L, Dorfmüller P, Seferian A, Lau EM, Eyries M, Le Pavec J, Parent F, Bonnet D, Soubrier F, Fadel E, Sitbon O, Simonneau G, Humbert M. Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study.Lancet Respir Med. 2017; 5:125–134. doi: 10.1016/S2213-2600(16)30438-6.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hernandez-Gonzalez I, Tenorio J, Palomino-Doza J, Martinez Meñaca A, Morales Ruiz R, Lago-Docampo M, Valverde Gomez M, Gomez Roman J, Enguita Valls A, Perez-Olivares C, Valverde D, Gil Carbonell J, Garrido-Lestache Rodríguez-Monte E, del Cerro M, Lapunzina P, Escribano-Subias P and West J (2020) Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4, PLOS ONE, 10.1371/journal.pone.0232216, 15:4, (e0232216) Hadinnapola C, Gräf S and Morrell N (2018) Response by Hadinnapola et al to Letter Regarding Article, "Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension", Circulation, 137:22, (2413-2414), Online publication date: 29-May-2018. November 21, 2017Vol 136, Issue 21 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.031158PMID: 29158214 Originally publishedNovember 21, 2017 Keywordsheritable pulmonary arterial hypertensionpulmonary veno-occlusive diseaseEditorialsidiopathic pulmonary arterial hypertensionPDF download Advertisement SubjectsGeneticsMortality/SurvivalPulmonary Hypertension