**About the Editors**

**Hans-Jurgen Mager** MD, Ph.D., is a pulmonologist, working in the St. Antonius Hospital, in Nieuwegein, which is the national HHT center of excellence in the Netherlands. He has more than 20 years experience in HHT care and research. He is chair of the Global Research and Medical Advisory Board of Cure HHT and a member of the HHT working group of VASCERN, the European Reference Network for rare vascular diseases. In addition, he is secretary of the Dutch association of pulmonologists (NVALT).

**Carmelo Bernabeu** Ph.D., serves as a section editor of the *Journal of Clinical Medicine* (Vascular Medicine). He is a Research Professor at the Biological Research Centre Margarita Salas, Spanish Research Council (CSIC) Madrid, Spain, member of the Centre for Biomedical Network Research on Rare Diseases (CIBERER) of Spain, and Chair Emeritus and current member of the Global Research Medical Advisory Board, Cure HHT Foundation International, US. After receiving his PhD from Autonomous University of Madrid in Spain, he worked, first as a postdoctoral scholar at the Molecular Biology Institute, University of California (UCLA) in Los Angeles, and then as a Research Fellow at the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Dr. Bernabeu is currently an active researcher with specific interests in the field of vascular biology, namely focused on the rare disease known as hereditary hemorrhagic telangiectasia (HHT) and the two major proteins involved, endoglin and ALK1, their roles as transforming growth factor-beta receptors in endothelial cells, and their involvement in angiogenesis, vascular remodeling, hypertension, cancer and preeclampsia. He has supervised 14 PhD students and is an author of more than 200 peer-reviewed articles (total citations > 15,500; h index = 67) and several international patents.

**Marco Post** MD, Ph.D., is a Professor in Pulmonary Vascular Disease at the University of Utrecht, the Netherlands. He works as a cardiologist and member of the HHT team in the St. Antonius Hospital, the HHT Center of Excellence in the Netherlands. He is a member of the Global Research Medical Advisory Board of the Cure HHT Foundation International and the HHT working group of the VASCERN, the European Reference Network for Rare Vascular Diseases. He is the author of more than 180 peer-reviewed articles.

## **Preface to "Hereditary Hemorrhagic Telangiectasia: Recent Advances and Future Challenges"**

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal heritable disease, leading to vascular malformations, ranging from mucocutaneous telangiectases to large arteriovenous malformations, which can occur in different organs. HHT is associated with a decreased quality of life and severe complications. If untreated, the disease leads to decreased life expectancy. Recent years have brought advances in diagnosis and treatment, but not a cure for HHT. The exact molecular etiology is still unknown and there is an urgen<sup>t</sup> need for more systematic research. Because understanding the mechanisms of disease is essential for the development of new medicines or therapeutic strategies, this book aims to highlight not only the current knowledge regarding the diagnosis and treatment of HHT, but also the newest insights into the molecular basis of HHT. Among the different contributions, we would like to emphasize: (i) the key role of a systematic screening and treatment of patients at HHT Centers (de Gussem et al. 2020), (ii) the knowledge about genetics, genotype-phenotype correlations, second-hits and circulating biomarkers of HHT (Bernabeu et al. 2020; Cannavicci et al. 2020; Geisthoff et al. 2020; Kilian et al. 2020; Ruiz-Llorente et al. 2020); (iii) advances in imaging and treatment of arteriovenous malformations of the lung, liver and gastrointestinal tract using contrast-enhanced magnetic resonance angiography, computed tomography, endoscopy and embolotherapy (Daniel et al. 2020; Harwin et al. 2020; Mora-Lujan et al. 2020; Majumdar et al. 2020; Van den Heuvel et al. 2020; Schneider et al. 2021), and (iv) pharmacological strategies for HHT-related nose and gastrointestinal bleeding, using well known and repurposed drugs, including bevacizumab, propranolol, tacrolimus, and antithrombotic drugs (Albinana et al. 2020; Dupuis-Girod et al. 2020; Gaetani et al. 2020; Mei-Zahav et al. 2020; ˜ Mora-Lujan et al. 2020).

> **Hans-Jurgen Mager, Carmelo Bernabeu, Marco Post** *Editors*

#### **Hereditary Hemorrhagic Telangiectasia (HHT) and Survival: The Importance of Systematic Screening and Treatment in HHT Centers of Excellence**

**Els M. de Gussem 1,**†**, Steven Kroon 2,**†**, Anna E. Hosman 2, Johannes C. Kelder 3, Martijn C. Post 4,5, Repke J. Snijder 2 and Johannes J. Mager 2,\***


Received: 21 October 2020; Accepted: 3 November 2020; Published: 6 November 2020

**Abstract:** Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease, is characterized by telangiectases and arteriovenous malformations (AVMs). Untreated AVMs, especially in the lungs—pulmonary AVMs (PAVMs)—can result in morbidity with a decreased life expectancy. We have investigated whether HHT patients, systematically screened for HHT-related organ involvement and treated if needed, have a similar survival as persons without HHT. We included all individuals screened for HHT between 2004 and 2016 with a genetically or clinically confirmed diagnosis (HHT group) or excluded diagnosis (non-HHT control group). The social security number was used to confirm status as dead or alive in December 2019. We included 717 HHT patients and 471 controls. There was no di fference in survival between the HHT and the non-HHT control group. The HHT group had a life expectancy of 75.9 years (95% confidence interval (CI) 73.3–78.6), comparable to the control group (79.3 years, 95% CI 74.8–84.0, Mantel–Cox test: *p* = 0.29). In conclusion, the life expectancy of HHT patients systematically screened for HHT-related organ involvement and treated if needed in an HHT center of excellence was similar compared to their controls, justifying systematic screening and treatment in HHT patients.

**Keywords:** telangiectasia; hereditary hemorrhagic; vascular malformations; survival; life expectancy
