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Executive summary of the 12th HHT international scientific conference

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Abstract

Hereditary hemorrhagic telangiectasia is an autosomal dominant trait affecting approximately 1 in 5000 people. A pathogenic DNA sequence variant in the ENG, ACVRL1 or SMAD4 genes, can be found in the majority of patients. The 12th International Scientific HHT Conference was held on June 8–11, 2017 in Dubrovnik, Croatia to present and discuss the latest scientific achievements, and was attended by over 200 scientific and clinical researchers. In total 174 abstracts were accepted of which 58 were selected for oral presentations. This article covers the basic science and clinical talks, and discussions from three theme-based workshops. We focus on significant emergent themes and unanswered questions. Understanding these topics and answering these questions will help to define the future of HHT research and therapeutics, and ultimately bring us closer to a cure.

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References

  1. Zhang R, Han Z, Degos V, Shen F, Choi EJ, Sun Z, Kang S, Wong M, Zhu W, Zhan L, Arthur HM, Oh SP, Faughnan ME, Su H (2016) Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation. Angiogenesis 19:451–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ojeda-Fernandez L, Recio-Poveda L, Aristorena M, Lastres P, Blanco FJ, Sanz-Rodriguez F, Gallardo-Vara E, de Las Casas-Engel M, Corbi A, Arthur HM, Bernabeu C, Botella LM (2016) Mice lacking endoglin in macrophages show an impaired immune response. PLoS Genet 12:e1005935

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ruiz S, Zhao H, Chandakkar P, Chatterjee PK, Papoin J, Blanc L, Metz CN, Campagne F, Marambaud P (2016) A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. Sci Rep 5:37366

    Article  PubMed  PubMed Central  Google Scholar 

  4. Redgrave RE, Tual-Chalot S, Davison BJ, Singh E, Hall D, Amirrasouli MM, Gilchrist D, Medvinsky A, Arthur HM (2017) Cardiosphere-derived cells require endoglin for paracrine-mediated angiogenesis. Stem Cell Rep 8:1287–1298

    Article  CAS  Google Scholar 

  5. Baeyens N, Larrivee B, Ola R, Hayward-Piatkowskyi B, Dubrac A, Huang B, Ross TD, Coon BG, Min E, Tsarfati M, Tong H, Eichmann A, Schwartz MA (2016) Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol 214:807–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jin Y, Muhl L, Burmakin M, Wang Y, Duchez AC, Betsholtz C, Arthur HM, Jakobsson L (2017) Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling. Nat Cell Biol 19:639–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sugden WW, Meissner R, Aegerter-Wilmsen T, Tsaryk R, Leonard EV, Bussmann J, Hamm MJ, Herzog W, Jin Y, Jakobsson L, Denz C, Siekmann AF (2017) Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues. Nat Cell Biol 19:653–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Murphy PA, Kim TN, Huang L, Nielsen CM, Lawton MT, Adams RH, Schaffer CB, Wang RA (2014) Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proc Natl Acad Sci USA 111:18007–18012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Letteboer TG, Benzinou M, Merrick CB, Quigley DA, Zhau K, Kim IJ, To MD, Jablons DM, van Amstel JK, Westermann CJ, Giraud S, Dupuis-Girod S, Lesca G, Berg JH, Balmain A, Akhurst RJ (2015) Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14. Front Genet 6:67

    Article  PubMed  PubMed Central  Google Scholar 

  10. Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, Harradine KA, Arbelaez J, Luu MT, Roy R, Quigley D, Higgins MN, Zaid M, Aouizerat BE, van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Plauchu H, Hughes CC, Westermann CJ, Akhurst RJ (2012) Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun 3:616

    Article  PubMed  PubMed Central  Google Scholar 

  11. Saito T, Bokhove M, Croci R, Zamora-Caballero S, Han L, Letarte M, de Sanctis D, Jovine L (2017) Structural basis of the human endoglin-BMP9 interaction: insights into BMP signaling and HHT1. Cell Rep 19:1917–1928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xu C, Hasan SS, Schmidt I, Rocha SF, Pitulescu ME, Bussmann J, Meyen D, Raz E, Adams RH, Siekmann AF (2014) Arteries are formed by vein-derived endothelial tip cells. Nat Commun 5:5758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ruiz S, Chandakkar P, Zhao H, Papoin J, Chatterjee PK, Christen E, Metz CN, Blanc L, Campagne F, Marambaud P (2017) Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-offunction and improves HHT vascular pathology. Hum Mol Genet. https://doi.org/10.1093/hmg/ddx358

  14. Tse LV, Klinc KA, Madigan VJ, Castellanos Rivera RM, Wells LF, Havlik LP, Smith JK, Agbandje-McKenna M, Asokan A (2017) Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion. Proc Natl Acad Sci USA 114:E4812–E4821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shovlin CL, Jackson JE, Bamford KB, Jenkins IH, Benjamin AR, Ramadan H, Kulinskaya E (2008) Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 63:259–266

    Article  CAS  PubMed  Google Scholar 

  16. de Gussem EM, Edwards CP, Hosman AE, Westermann CJ, Snijder RJ, Faughnan ME, Mager JJ (2016) Life expextancy of parents with hereditary haemorrhagic telangiectasia. Orphanet J Rare Dis 11:46-016-0427-x

    Article  Google Scholar 

  17. Conrad MB, Ishaque BM, Surman AM, Kerlan RK Jr, Hope MD, Dickey MA, Hetts SW, Wilson MW (2015) Intraprocedural safety and technical success of the MVP micro vascular plug for embolization of pulmonary arteriovenous malformations. J Vasc Interv Radiol 26:1735–1739

    Article  PubMed  Google Scholar 

  18. Dupuis-Girod S, Chesnais AL, Ginon I, Dumortier J, Saurin JC, Finet G, Decullier E, Marion D, Plauchu H, Boillot O (2010) Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study. Liver Transpl 16:340–347

    PubMed  Google Scholar 

  19. Brinjikji W, Iyer VN, Wood CP, Lanzino G (2017) Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg 127(2):302–310. https://doi.org/10.3171/2016.7. JNS16847

  20. Krings T, Kim H, Power S, Nelson J, Faughnan ME, Young WL, Terbrugge KG, Brain Vascular Malformation Consortium HHT Investigator Group (2015) Neurovascular manifestations in hereditary hemorrhagic telangiectasia: imaging features and genotype-phenotype correlations. AJNR Am J Neuroradiol 36:863–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hosman AE, de Gussem EM, Balemans WAF, Gauthier A, Westermann CJJ, Snijder RJ, Post MC, Mager JJ (2017) Screening children for pulmonary arteriovenous malformations: Evaluation of 18 years of experience. Pediatr Pulmonol 52(9):1206–1211. https://doi.org/10.1002/ppul.23704

  22. Geirdal AO, Dheyauldeen S, Bachmann-Harildstad G, Heimdal K (2012) Quality of life in patients with hereditary hemorrhagic telangiectasia in Norway: a population based study. Am J Med Genet A 158A:1269–1278

    Article  PubMed  Google Scholar 

  23. Almis H, Bucak IH, Caliskan MN, Turgut M (2016) Evaluation of vitamin D levels in children with primary epistaxis. Int J Pediatr Otorhinolaryngol 89:97–101

    Article  PubMed  Google Scholar 

  24. Contis A, Gensous N, Viallard JF, Goizet C, Léauté-Labrèze C, Duffau P (2017) Efficacy and safety of propranolol for epistaxis in hereditary haemorrhagic telangiectasia: retrospective, then prospective study, in a total of 21 patients. Clin Otolaryngol 42(4):911–917. https://doi.org/10.1111/coa.12821

  25. Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, Roux A, Carette MF, Gilbert-Dussardier B, Hatron PY, Lacombe P, Lorcerie B, Riviere S, Corre R, Giraud S, Bailly S, Paintaud G, Ternant D, Valette PJ, Plauchu H, Faure F (2012) Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA 307:948–955

    Article  CAS  PubMed  Google Scholar 

  26. Dupuis-Girod S, Ambrun A, Decullier E, Fargeton AE, Roux A, Breant V, Colombet B, Riviere S, Cartier C, Lacombe P, Chinet T, Blivet S, Blondel JH, Gilbert-Dussardier B, Dufour X, Michel J, Harle JR, Dessi P, Faure F (2016) Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangectasia: a randomized clinical trial. JAMA 316:934–942

    Article  CAS  PubMed  Google Scholar 

  27. Finnamore H, Silva BM, Hickson BM, Whelan K, Shovlin CL (2017) 7-day weighed food diaries suggest patients with hereditary hemorrhagic telangiectasia may spontaneously modify their diet to avoid nosebleed precipitants. Orphanet J Rare Dis 12:60-017-0576-6

    Article  Google Scholar 

  28. Silva BM, Hosman AE, Devlin HL, Shovlin CL (2013) Lifestyle and dietary influences on nosebleed severity in hereditary hemorrhagic telangiectasia. Laryngoscope 123:1092–1099

    Article  PubMed  Google Scholar 

  29. Vorselaars VM, Velthuis S, Snijder RJ, Mager JJ, Post MC (2016) Thoracic aorta dilation in patients with hereditary hemorrhagic telangiectasia due to SMAD4 gene mutation. Am J Med Genet A 170:811–812

    Article  PubMed  Google Scholar 

  30. Zhang L, Magli A, Catanese J, Xu Z, Kyba M, Perlingeiro RC (2011) Modulation of TGF-beta signaling by endoglin in murine hemangioblast development and primitive hematopoiesis. Blood 118:88–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lastres P, Bellon T, Cabanas C, Sanchez-Madrid F, Acevedo A, Gougos A, Letarte M, Bernabeu C (1992) Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-containing surface antigen. Eur J Immunol 22:393–397

    Article  CAS  PubMed  Google Scholar 

  32. Shovlin CL (2014) Pulmonary arteriovenous malformations. Am J Respir Crit Care Med 190:1217–1228

    Article  PubMed  PubMed Central  Google Scholar 

  33. Boother EJ, Brownlow S, Tighe HC, Bamford KB, Jackson JE, Shovlin CL (2017) Cerebral abscess associated with odontogenic bacteremias, hypoxemia, and iron loading in immunocompetent patients with right-to-left shunting through pulmonary arteriovenous malformations. Clin Infect Dis 65(4):595–603. https://doi.org/10.1093/cid/cix373

  34. Limeres Posse J, Alvarez Fernandez M, Fernandez Feijoo J, Medina Henriquez J, Lockhart PB, Chu VH, Diz Dios P (2016) Intravenous amoxicillin/clavulanate for the prevention of bacteraemia following dental procedures: a randomized clinical trial. J Antimicrob Chemother 71:2022–2030

    Article  CAS  PubMed  Google Scholar 

  35. Bruhn KW, Spellberg B (2015) Transferrin-mediated iron sequestration as a novel therapy for bacterial and fungal infections. Curr Opin Microbiol 27:57–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Botella LM, Sanz-Rodriguez F, Komi Y, Fernandez-L A, Varela E, Garrido-Martin EM, Narla G, Friedman SL, Kojima S (2009) TGF-beta regulates the expression of transcription factor KLF6 and its splice variants and promotes co-operative transactivation of common target genes through a Smad3-Sp1-KLF6 interaction. Biochem J 419:485–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, Oh SH, Walter G, Raizada MK, Sorg BS, Oh SP (2009) Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest 119:3487–3496

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Shovlin CL (2015) Circulatory contributors to the phenotype in hereditary hemorrhagic telangiectasia. Front Genet 6:101

    Article  PubMed  PubMed Central  Google Scholar 

  39. Mollet IG, Patel D, Govani FS, Giess A, Paschalaki K, Periyasamy M, Lidington EC, Mason JC, Jones MD, Game L, Ali S, Shovlin CL (2016) Low dose iron treatments induce a DNA damage response in human endothelial cells within minutes. PLoS ONE 11:e0147990

    Article  PubMed  PubMed Central  Google Scholar 

  40. Shovlin CL, Gilson C, Busbridge M, Patel D, Shi C, Dina R, Abdulla FN, Awan I (2016) Can iron treatments aggravate epistaxis in some patients with hereditary hemorrhagic telangiectasia? Laryngoscope 126:2468–2474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shovlin CL, Patel T, Jackson JE (2016) Embolisation of PAVMs reported to improve nosebleeds by a subgroup of patients with hereditary haemorrhagic telangiectasia. ERJ Open Res 2:00035-2016 (eCollection 2016 Apr)

    Article  PubMed  PubMed Central  Google Scholar 

  42. Peter MR, Jerkic M, Sotov V, Douda DN, Ardelean DS, Ghamami N, Lakschevitz F, Khan MA, Robertson SJ, Glogauer M, Philpott DJ, Palaniyar N, Letarte M (2014) Impaired resolution of inflammation in the Endoglin heterozygous mouse model of chronic colitis. Mediators Inflamm 2014:767185

    Article  PubMed  PubMed Central  Google Scholar 

  43. Mahmoud M, Allinson KR, Zhai Z, Oakenfull R, Ghandi P, Adams RH, Fruttiger M, Arthur HM (2010) Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res 106:1425–1433

    Article  CAS  PubMed  Google Scholar 

  44. Tual-Chalot S, Mahmoud M, Allinson KR, Redgrave RE, Zhai Z, Oh SP, Fruttiger M, Arthur HM (2014) Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression. PLoS ONE 9:e98646

    Article  PubMed  PubMed Central  Google Scholar 

  45. Allinson KR, Lee HS, Fruttiger M, McCarty JH, Arthur HM (2012) Endothelial expression of TGFbeta type II receptor is required to maintain vascular integrity during postnatal development of the central nervous system. PLoS ONE 7:e39336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lebrin F, Goumans MJ, Jonker L, Carvalho RL, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, ten Dijke P (2004) Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 23:4018–4028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kawasaki K, Freimuth J, Meyer DS, Lee MM, Tochimoto-Okamoto A, Benzinou M, Clermont FF, Wu G, Roy R, Letteboer TG, Ploos van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Westermann CJ, Coffey RJ Jr, Akhurst RJ (2014) Genetic variants of Adam17 differentially regulate TGFbeta signaling to modify vascular pathology in mice and humans. Proc Natl Acad Sci USA 111:7723–7728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ricard N, Ciais D, Levet S, Subileau M, Mallet C, Zimmers TA, Lee SJ, Bidart M, Feige JJ, Bailly S (2012) BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 119:6162–6171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Corti P, Young S, Chen CY, Patrick MJ, Rochon ER, Pekkan K, Roman BL (2011) Interaction between alk1 and blood flow in the development of arteriovenous malformations. Development 138:1573–1582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ola R, Dubrac A, Han J, Zhang F, Fang JS, Larrivee B, Lee M, Urarte AA, Kraehling JR, Genet G, Hirschi KK, Sessa WC, Canals FV, Graupera M, Yan M, Young LH, Oh PS, Eichmann A (2016) PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun 7:13650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu (2016) EASL clinical practice guidelines: vascular diseases of the liver. J Hepatol 64:179–202

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA

    Jillian W. Andrejecsk & Christopher C. W. Hughes

  2. Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands

    Anna E. Hosman & Johannes J. Mager

  3. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Ramiro de Maeztu 9, 28040, Madrid, Spain

    Luisa M. Botella

  4. Vascular Science, National Heart and Lung Institute, Imperial College London, London, UK

    Claire L. Shovlin

  5. Institute of Genetic Medicine, Centre for Life, Newcastle University, Newcastle, NE1 3BZ, UK

    Helen M. Arthur

  6. Hospices Civils de Lyon, Genetic Unit and HHT Reference Center, Bron, School of Medical and University Lyon 1, Lyon, France

    Sophie Dupuis-Girod

  7. Gastroenterology and Endoscopy Department, Reference Center for Hereditary Hemorrhagic Telangiectasia, Maggiore Hospital, ASST Crema, Crema, Italy

    Elisabetta Buscarini

  8. Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands

    Franck Lebrin

  9. CNRS UMR 7587, INSERM U979, Institut Langevin, ESPCI, Paris, France

    Franck Lebrin

  10. Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands

    Christine L. Mummery

  11. Department of Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands

    Marco C. Post

Authors
  1. Jillian W. Andrejecsk
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  2. Anna E. Hosman
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  3. Luisa M. Botella
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  4. Claire L. Shovlin
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  5. Helen M. Arthur
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  6. Sophie Dupuis-Girod
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  7. Elisabetta Buscarini
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  8. Christopher C. W. Hughes
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  9. Franck Lebrin
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  10. Christine L. Mummery
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  11. Marco C. Post
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  12. Johannes J. Mager
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Corresponding author

Correspondence to Franck Lebrin.

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Co-first authors: Jillian W. Andrejecsk and Anna E. Hosman.

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Andrejecsk, J.W., Hosman, A.E., Botella, L.M. et al. Executive summary of the 12th HHT international scientific conference. Angiogenesis 21, 169–181 (2018). https://doi.org/10.1007/s10456-017-9585-2

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  • DOI: https://doi.org/10.1007/s10456-017-9585-2

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