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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”

2018; Lippincott Williams & Wilkins; Volume: 137; Issue: 22 Linguagem: Inglês

10.1161/circulationaha.118.033970

1524-4539

Charaka Hadinnapola, Stefan Gräf, Nicholas W. Morrell,

Pulmonary Hypertension Research and Treatments

HomeCirculationVol. 137, No. 22Response 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" Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse 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" Charaka Hadinnapola, MB, BChir, Stefan Gräf, PhD and Nicholas W. Morrell, MD, FMedSci Charaka HadinnapolaCharaka Hadinnapola Department of Medicine, University of Cambridge, United Kingdom. , Stefan GräfStefan Gräf Department of Medicine, University of Cambridge, United Kingdom. and Nicholas W. MorrellNicholas W. Morrell Department of Medicine, University of Cambridge, United Kingdom. Originally published29 May 2018https://doi.org/10.1161/CIRCULATIONAHA.118.033970Circulation. 2018;137:2413–2414In Response:We thank Hernandez-Gonzalez et al for their response to our recent article.1 In this study, we demonstrated that the clinical, radiological, and histological features in patients with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH) (including those carrying biallelic EIF2AK4 mutations) can show significant overlap with those of idiopathic pulmonary arterial hypertension (PAH). In our study, none of the patients found to have a molecular diagnosis (biallelic EIF2AK4 mutations) consistent with PVOD/PCH, but classified by expert clinicians as idiopathic PAH, developed pulmonary edema in response to pulmonary artery vasodilator therapies. This may account for the apparent increased survival reported in our study compared with Montani et al,2 who ascertained cases of clinically obvious cases of PVOD/PCH. Indeed, Navas Tejedor et al3 also show a better prognosis in Romani patients carrying a founder mutation in EIF2AK4, who were tolerant of pulmonary artery vasodilator therapies.As eloquently described by Miller and Faber4 in the editorial accompanying our article, the key question is how this affects clinical practice. We would assert that clinical genetic testing is of value in the early identification of PVOD/PCH. We showed that the diagnostic yield of biallelic EIF2AK4 mutations was 53% in patients <50 years of age with a diffusion coefficient for carbon monoxide <50% of predicted. Although the presence of biallelic EIF2AK4 mutations is not of prognostic significance in cohorts of patients with PVOD/PCH, it might well be in patients diagnosed with idiopathic PAH. In our article, we show a worse prognosis in patients with an apparent clinical diagnosis of idiopathic PAH even though they were "tolerant" of pulmonary artery vasodilator therapies. Therefore, early identification of these patients may facilitate early transplantation assessment and careful monitoring when pulmonary artery vasodilatory therapies are initiated.Specific information on consanguinity was not collected as part of our study. However, of the 7 patients with homozygous rare and predicted deleterious EIF2AK4 mutations, 5 (71%) were of South Asian descent, perhaps pointing toward a shared kinship.Because this disease is ultrarare, further study of distinct subgroups requires international collaboration to obtain sufficient numbers. Only with such large prospective studies can we validate and build on these preliminary but intriguing observations. Pulmonary venopathy is an important aspect of pulmonary hypertension associated with connective tissue disease and left-sided heart disease. Thus, these questions may have much wider clinical relevance.DisclosuresNone.Footnoteshttp://circ.ahajournals.orgReferences1. Hadinnapola C, Bleda M, Haimel M, Screaton N, Swift A, Dorfmüller 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, MacKenzie Ross R, Moledina S, Montani D, Newnham M, Peacock A, Pepke-Zaba J, Rayner-Matthews P, Shamardina O, Soubrier F, Southgate L, Suntharalingam J, Toshner M, Trembath R, Vonk Noordegraaf A, Wilkins MR, Wort SJ, Wharton J, Gräf S, Morrell NW; NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH. 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. 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 Scholar3. Navas Tejedor P, Palomino Doza J, Tenorio Castano JA, Enguita Valls AB, Rodriguez Reguero JJ, Martinez Menaca A, Hernandez Gonzalez I, Bueno Zamora H, Lapunzina Badia PD, Escribano Subias P. Variable expressivity of a founder mutation in the EIF2AK4 gene in hereditary pulmonary veno-occlusive disease and its impact on survival.Rev Esp Cardiol. 2018; 71:86–94.CrossrefMedlineGoogle Scholar4. Miller DP, Farber HW. Pulmonary veno-occlusive disease: welcome to the PAHty (Bostonian for party).Circulation. 2017; 136:2034–2036. doi: 10.1161/CIRCULATIONAHA.117.031158.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Nagai A (2019) Current Clinical Management and Basic Research in Pediatric Pulmonary Hypertension小児循環器領域における肺高血圧症:臨床と基礎のフロントライン, Pediatric Cardiology and Cardiac Surgery, 10.9794/jspccs.35.136, 35:3, (136-152), Online publication date: 1-Sep-2019. Liang K, Chang S, Chen Y, Lin W, Tsai W and Wang K (2022) Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2022.911649, 9 May 29, 2018Vol 137, Issue 22 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.033970PMID: 29844075 Originally publishedMay 29, 2018 PDF download Advertisement SubjectsGeneticsPulmonary Hypertension