Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Ruíz, Santiago; Zhao, Haitian; Chandakkar, Pallavi; Papoin, Julien; Choi, Hyunwoo; Nomura-Kitabayashi, Aya; Patel, Radhika R.; Gillen, Matthew C.; Li, Diao; Chatterjee, Prodyot K.; He, Mingzhu; Al‐Abed, Yousef; Wang, Haichao; Metz, Christine N.; Oh, Seh–Hoon; Blanc, Lionel; Campagne, Fabien; Marambaud, Philippe

doi:10.1172/jci127425

Cited by 63 publications

(51 citation statements)

References 69 publications

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“…Therefore, other unknown mechanisms should be involved in gender differences. New insights in the underlying mechanisms may help to gain a better understanding of HHT pathophisiology and angiogenesis process, and could help to develop new treatments or drug repositioning [46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Gender differences in hereditary hemorrhagic telangiectasia severity

Mora-Luján

Iriarte

Alba

et al. 2020

Orphanet J Rare Dis

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Background: Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender. Methods: Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations-AVMs-embolization, liver transplantation or Young's surgery) or the presence of adverse outcomes (severe anemia, emergency department-ED-or hospital admissions and mortality). Results: One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality. Conclusions: HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.

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Section: Discussionmentioning

confidence: 99%

Gender differences in hereditary hemorrhagic telangiectasia severity

Mora-Luján

Iriarte

Alba

et al. 2020

Orphanet J Rare Dis

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“…Recent systematic reviews summarizing the published studies suggest that intranasal bevacizumab treatment does not have a significant effect on epistaxis in persons with HHT [ 7 , 8 ]. Other therapeutic options based on the role of PI3K and mTOR role in telangiectases formation have been recently suggested [ 33 , 34 ]. Severe epistaxis may cause gushing bleeds several times a day, resulting in iron deficiency anemia and transfusion dependency [ 1 ].…”

Section: Discussionmentioning

confidence: 99%

Topical Propranolol Improves Epistaxis Control in Hereditary Hemorrhagic Telangiectasia (HHT): A Randomized Double-Blind Placebo-Controlled Trial

Mei-Zahav

Gendler

Bruckheimer

et al. 2020

JCM

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Epistaxis is a common debilitating manifestation in hereditary hemorrhagic telangiectasia (HHT), due to mucocutaneous telangiectases. The epistaxis can be difficult to control despite available treatments. Dysregulated angiogenesis has been shown to be associated with telangiectases formation. Topical propranolol has demonstrated antiangiogenic properties. We performed a two-phase study, i.e., a double-blind placebo-controlled phase, followed by an open-label phase. The aim of the study was assessment of safety and efficacy of nasal propranolol gel in HHT-related epistaxis. Twenty participants with moderate-severe HHT-related epistaxis were randomized to eight weeks of propranolol gel 1.5%, or placebo 0.5 cc, applied to each nostril twice daily; and continued propranolol for eight weeks in an open-label study. For the propranolol group, the epistaxis severity score (ESS) improved significantly (−2.03 ± 1.7 as compared with −0.35 ± 0.68 for the placebo group, p = 0.009); hemoglobin levels improved significantly (10.5 ± 2.6 to 11.4 ± 2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (−1.99 ± 1.41, p = 0.005). The most common adverse event was nasal mucosa burning sensation. No cardiovascular events were reported. Our results suggest that topical propranolol gel is safe and effective in HHT-related epistaxis.

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“…Other treatments such as talidomide or estrogen/progesterone preparations have also shown improvement in hemoglobin levels or transfusion requirements in case reports or short series [21,22,40,41]. The hypothetical benefit in this scenario of future agents that block or activate pathways involved in HHT pathogenesis, such as sirolimus, tacrolimus, nintedanib, or a combination of them, needs further investigation [42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia: Risk Factors and Endoscopic Findings

Mora-Luján

Iriarte

Alba

et al. 2019

JCM

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Background: We aimed to describe risk factors for gastrointestinal (GI) bleeding and endoscopic findings in patients with hereditary hemorrhagic telangiectasia (HHT). Methods: This is a prospective study from a referral HHT unit. Endoscopic tests were performed when there was suspicion of GI bleeding, and patients were divided as follows: with, without, and with unsuspected GI involvement. Results: 67 (27.9%) patients with, 28 (11.7%) patients without, and 145 (60.4%) with unsuspected GI involvement were included. Age, tobacco use, endoglin (ENG) mutation, and hemoglobin were associated with GI involvement. Telangiectases were mostly in the stomach and duodenum, but 18.5% of patients with normal esophagogastroduodenoscopy (EGD) had GI involvement in video capsule endoscopy (VCE). Telangiectases ≤ 3 mm and ≤10 per location were most common. Among patients with GI disease, those with hemoglobin < 8 g/dL or transfusion requirements (65.7%) were older and had higher epistaxis severity score (ESS) and larger telangiectases (>3 mm). After a mean follow-up of 34.2 months, patients with GI involvement required more transfusions and more emergency department and hospital admissions, with no differences in mortality. Conclusions: Risk factors for GI involvement have been identified. Patients with GI involvement and severe anemia had larger telangiectases and higher ESS. VCE should be considered in patients with suspicion of GI bleeding, even if EGD is normal. Author Contributions: Conceptualization: J.M.M.-L. and A.R.-M.; data curation: J.M.M.-L., A.I., A.B., P.C. and A.R.-M.; formal analysis: J.M.M.-L., A.I., P.C. and A.R.-M.; investigation: J.M.Mmethodology: J.M.M.-L. and A.R.-M.; supervision: J.R., J.C. and A.R.-M.; validation: J.M.M.-L., A.I., E.A., M.Á.S.-C., A.B., P.C., F.C., J.R., J.C. and A.R.-M.; visualization: J.M.M.-L., E.A., F.C. and A.R.-M.; writing-original draft preparation: J.M.M.-L., A.I., E.A., M.Á.S.-C., A.B., P.C., F.C. and A.R.-M.; writing-review and editing: J.M.M.-L., J.R., J.C. and A.R.-M; funding acquisition: A.R.-M. All authors have read and agreed to the published version of the manuscript.

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Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Cited by 63 publications

References 69 publications

Gender differences in hereditary hemorrhagic telangiectasia severity

Gender differences in hereditary hemorrhagic telangiectasia severity

Topical Propranolol Improves Epistaxis Control in Hereditary Hemorrhagic Telangiectasia (HHT): A Randomized Double-Blind Placebo-Controlled Trial

Gastrointestinal Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia: Risk Factors and Endoscopic Findings

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