Special Issue "Hereditary Hemorrhagic Telangiectasia: Recent Advances and Future Challenges"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Vascular Medicine".

Deadline for manuscript submissions: closed (15 September 2020).

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A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Hans-Jurgen Mager
E-Mail Website
Guest Editor
Department of Pulmonology, St. Antonius Ziekenhuis, Nieuwegein/Utrecht, The Netherlands
Interests: HHT; pulmonary hypertension; (other) pulmonary vascular diseases
Prof. Dr. Carmelo Bernabeu
E-Mail Website
Guest Editor
Biological Research Centre, Spanish National Research Council (CSIC) and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
Interests: HHT; vascular biology; angiogenesis; endothelial cells; animal model; genetics; TGF-β signaling; endoglin
Dr. Marco Post
E-Mail Website
Guest Editor
Department of Cardiology, St. Antonius Ziekenhuis, Nieuwegein/Utrecht and University Medical Center Utrecht, The Netherlands
Interests: HHT; pulmonary hypertension; congenital heart disease

Special Issue Information

Dear Colleagues,

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 a 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, but important steps in unravelling the mechanisms of disease haven been made.

This Special Issue aims to highlight not only the current knowledge regarding diagnosis and treatment of HHT, but also the newest insights in the molecular basis of HHT, because understanding the mechanisms of disease is essential for the development of new medicines or therapeutic strategies.

Dr. Hans-Jurgen Mager
Prof. Dr. Carmelo Bernabeu
Dr. Marco Post
Guest Editors

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Keywords

  • Hereditary Hemorrhagic Telangiectasia (HHT)
  • ALK1
  • ACVRL1
  • Endoglin (ENG)
  • arteriovenous malformations
  • embolization
  • VEGF

Published Papers (15 papers)

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Research

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Article
Safety of Catheter Embolization of Pulmonary Arteriovenous Malformations—Evaluation of Possible Cerebrovascular Embolism after Catheter Embolization of Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia/Osler Disease by Pre- and Post-Interventional DWI
J. Clin. Med. 2021, 10(4), 887; https://doi.org/10.3390/jcm10040887 - 22 Feb 2021
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Abstract
Background. This paper aimed to prospectively evaluate the safety of embolization therapy of pulmonary arteriovenous malformations (PAVMs) for the detection of cerebral infarctions by pre- and post-interventional MRI. Method One hundred and five patients (male/female = 44/61; mean age 48.6+/−15.8; range 5–86) with [...] Read more.
Background. This paper aimed to prospectively evaluate the safety of embolization therapy of pulmonary arteriovenous malformations (PAVMs) for the detection of cerebral infarctions by pre- and post-interventional MRI. Method One hundred and five patients (male/female = 44/61; mean age 48.6+/−15.8; range 5–86) with pre-diagnosed PAVMs on contrast-enhanced MRA underwent embolization therapy. The number of PAVMs treated in each patient ranged from 1–8 PAVMs. Depending on the size and localization of the feeding arteries, either Nester-Coils or Amplatzer vascular plugs were used for embolization therapy. cMRI was performed immediately before, and at the 4 h and 3-month post-embolization therapy. Detection of peri-interventional cerebral emboli was performed via T2w and DWI sequences using three different b-values, with calculation of ADC maps. Results Embolization did not show any post-/peri-interventional, newly developed ischemic lesions in the brain. Only one patient who underwent re-embolization and was previously treated with tungsten coils that corroded over time showed newly developed, small, diffuse emboli in the post-interventional DWI sequence. This patient already had several episodes of brain emboli before re-treatment due to the corroded coils, and during treatment, when passing the corroded coils, experienced additional small, clinically inconspicuous brain emboli. However, this complication was anticipated but accepted, since the vessel had to be occluded distally. Conclusion Catheter-based embolization of PAVMs is a safe method for treatment and does not result in clinically inconspicuous cerebral ischemia, which was not demonstrated previously. Full article
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Article
Comparison of Contrast Enhanced Magnetic Resonance Angiography to Computed Tomography in Detecting Pulmonary Arteriovenous Malformations
J. Clin. Med. 2020, 9(11), 3662; https://doi.org/10.3390/jcm9113662 - 14 Nov 2020
Viewed by 417
Abstract
Background: Computed tomography (CT) is considered the imaging modality of choice to diagnose pulmonary arteriovenous malformations PAVMs. The drawback of this technique is that it requires ionizing radiation. Magnetic resonance (MR) imaging does not have the limitation, but little is known about the [...] Read more.
Background: Computed tomography (CT) is considered the imaging modality of choice to diagnose pulmonary arteriovenous malformations PAVMs. The drawback of this technique is that it requires ionizing radiation. Magnetic resonance (MR) imaging does not have the limitation, but little is known about the performance of MR compared to CT for the detection of PAVMs. The aim of this study is to investigate the sensitivity of contrast-enhanced MR angiography (CE-MRA) in the detection of PAVMs with feeding artery diameters (FAD) > 2 mm. Methods: Patients with a grade 2 or 3 shunt on screening transthoracic contrast echocardiography (TTCE) were asked to participate. Included patients underwent chest CT and CE-MRA. CT was considered the reference standard. CT and CE-MRA scans were anonymized and assessed for the presence of PAVMs with FAD > 2 mm by one and two readers respectively. Data analysis was performed on per patient and per PAVM basis. Results: Fifty-three patients were included. 105 PAVMs were detected on CT, 45 with a FAD ≥ 2 mm. In per patient analysis, sensitivity and specificity of CE-MRA were 92% and 97% respectively for reader 1 and 92% and 62% for reader 2. Negative and positive predictive value (NPV/PPV) were 93% and 96% for R1 and 90% and 67% for R2. In per PAVM analysis, sensitivity, specificity, NPV and PPV were 96%, 99%, 100% and 86% for R1 and 93%, 96%, 100% and 56% for R2, respectively. Conclusions: CE-MRA has excellent sensitivity and NPV for detection of PAVMs with FAD ≥ 2 mm and can therefore be used to detect these PAVMs. We are hopeful that future advancements in CE-MRA technology will reduce false positive rates and allow for more broad use of CE-MRA in PAVM diagnosis and management. Full article
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Article
Hereditary Hemorrhagic Telangiectasia (HHT) and Survival: The Importance of Systematic Screening and Treatment in HHT Centers of Excellence
J. Clin. Med. 2020, 9(11), 3581; https://doi.org/10.3390/jcm9113581 - 06 Nov 2020
Viewed by 397
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 [...] Read more.
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 difference 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. Full article
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Article
Topical Propranolol Improves Epistaxis Control in Hereditary Hemorrhagic Telangiectasia (HHT): A Randomized Double-Blind Placebo-Controlled Trial
J. Clin. Med. 2020, 9(10), 3130; https://doi.org/10.3390/jcm9103130 - 28 Sep 2020
Cited by 1 | Viewed by 701
Abstract
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 [...] Read more.
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. Full article
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Article
Differential Expression of Circulating Plasma miRNA-370 and miRNA-10a from Patients with Hereditary Hemorrhagic Telangiectasia
J. Clin. Med. 2020, 9(9), 2855; https://doi.org/10.3390/jcm9092855 - 03 Sep 2020
Cited by 1 | Viewed by 579
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder that presents with telangiectases and arteriovenous malformations. HHT is a genetically heterogeneous disorder, involving mutations in endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2) genes [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disorder that presents with telangiectases and arteriovenous malformations. HHT is a genetically heterogeneous disorder, involving mutations in endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ACVRL1/ALK1; HHT2) genes that account for over 85% of all HHT patients. The current diagnosis of HHT patients remains at the clinical level, but many suspected patients do not have a clear HHT diagnosis or do not show pathogenic mutations in HHT genes. This situation has prompted the search for biomarkers to help in the early diagnosis of the disease. We have analyzed the plasma levels in HHT patients of selected micro-RNAs (miRNAs), small single-stranded RNAs that regulate gene expression at the transcriptional level by interacting with specific RNA targets. A total of 16 HHT1 and 17 HHT2 plasma samples from clinically confirmed patients and 16 controls were analyzed in this study. Total RNA was purified from plasma, and three selected miRNAs (miRNA-10a, miRNA-214, and miRNA-370), related to the pathobiology of cardiovascular diseases and potentially targeting ENG or ALK1, were measured by quantitative polymerase chain reaction. Compared with controls, levels of miRNA-370, whose putative target is ENG, were significantly downregulated in HHT1, but not in HHT2, whereas the levels of miRNA-10a, whose putative target is ALK1, were significantly upregulated in HHT2, but not in HHT1. In addition, the levels of miRNA-214, potentially targeting ENG and ALK1, did not change in either HHT1 or HHT2 patients versus control samples. While further studies are warranted, these results suggest that dysregulated plasma levels of miRNA-370 or miRNA-10a could help to identify undiagnosed HHT1 or HHT2 patients, respectively. Full article
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Article
Genotype–Phenotype Correlations in Children with HHT
J. Clin. Med. 2020, 9(9), 2714; https://doi.org/10.3390/jcm9092714 - 22 Aug 2020
Cited by 1 | Viewed by 774
Abstract
Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT), a rare autosomal dominant disease mostly caused by mutations in three known genes (ENG, ACVRL1, and SMAD4), is characterized by the development of vascular malformations (VMs). Patients with HHT may present with mucocutaneous telangiectasia, as well as organ arteriovenous malformations (AVMs) of the central nervous system, lungs, and liver. Genotype–phenotype correlations have been well described in adults with HHT. We aimed to investigate genotype–phenotype correlations among pediatric HHT patients. Demographic, clinical, and genetic data were collected and analyzed in 205 children enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. A chi-square test was used to determine the association between phenotypic presentations and genotype. Among 205 patients (age range: 0–18 years; mean: 11 years), ENG mutation was associated with the presence of pulmonary AVMs (p < 0.001) and brain VM (p < 0.001). The presence of a combined phenotype—defined as both pulmonary AVMs and brain VMs—was also associated with ENG mutation. Gastrointestinal bleeding was rare (4.4%), but was associated with SMAD4 genotype (p < 0.001). We conclude that genotype–phenotype correlations among pediatric HHT patients are similar to those described among adults. Specifically, pediatric patients with ENG mutation have a greater prevalence of pulmonary AVMs, brain VMs, and a combined phenotype. Full article
Article
Antithrombotic Therapy in Hereditary Hemorrhagic Telangiectasia: Real-World Data from the Gemelli Hospital HHT Registry
J. Clin. Med. 2020, 9(6), 1699; https://doi.org/10.3390/jcm9061699 - 02 Jun 2020
Cited by 1 | Viewed by 752
Abstract
Although Hereditary Hemorrhagic Telangiectasia (HHT) is characterized by an overwhelming bleeding propensity, patients with this disease may also present medical conditions that require antithrombotic therapy (AT). However, precise information on indications, dosage, duration, effectiveness, and safety of AT in HHT patients is lacking. [...] Read more.
Although Hereditary Hemorrhagic Telangiectasia (HHT) is characterized by an overwhelming bleeding propensity, patients with this disease may also present medical conditions that require antithrombotic therapy (AT). However, precise information on indications, dosage, duration, effectiveness, and safety of AT in HHT patients is lacking. We performed a retrospective analysis of the HHT Registry of our University Hospital and found 26 patients who received AT for a total of 30 courses (19 courses of anticoagulant therapy and 11 courses of antiplatelet therapy). Indications to treatments included: atrial fibrillation, venous thrombosis and pulmonary embolism, heart valve replacement, retinal artery occlusion, secondary prevention after either stroke or myocardial infarction, and thromboprophylaxis for surgery. The total time of exposure to antiplatelet therapy was 385 months and to anticoagulant therapy 169 months. AT was generally well tolerated, with no fatal bleedings and no significant changes in hemoglobin levels. However, we found three major bleedings, with an incidence rate of 6.5 per 100 patients per year. When only patients treated with anticoagulants were considered, the incidence rate of major bleedings increased to 21.6 per 100 patients per year. Our study indicates that major bleeding may occur in HHT patients receiving AT, with a substantially increased rate in those treated with anticoagulants. Further studies are needed to fully estimate the tolerability of antithrombotic drugs in HHT. Full article
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Article
Trauma Can Induce Telangiectases in Hereditary Hemorrhagic Telangiectasia
J. Clin. Med. 2020, 9(5), 1507; https://doi.org/10.3390/jcm9051507 - 17 May 2020
Cited by 1 | Viewed by 813
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease of the fibrovascular tissue resulting in visceral vascular malformations and (muco-) cutaneous telangiectases with recurrent bleedings. The mechanism behind the disease is not fully understood; however, observations from HHT mouse models suggest that mechanical [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease of the fibrovascular tissue resulting in visceral vascular malformations and (muco-) cutaneous telangiectases with recurrent bleedings. The mechanism behind the disease is not fully understood; however, observations from HHT mouse models suggest that mechanical trauma may induce the formation of abnormal vessels. To assess the influence of environmental trauma (mechanical or light induced) on the number of telangiectases in patients with HHT, the number of telangiectases on the hands, face, and lips were counted on 103 HHT patients possessing at least three out of four Curaçao criteria. They were then surveyed for information concerning their dominant hand, exposure to sunlight, and types of regular manual work. Patients developed more telangiectases on their dominant hand and lower lip (Wilcoxon rank sum test: p < 0.001). Mechanical stress induced by manual work led to an increased number of telangiectases on patients’ hands (Mann–Whitney U test: p < 0.001). There was also a positive correlation between sun exposure and the number of telangiectases on the lips (Mann–Whitney U test: 0.027). This study shows that mechanical and UV-induced trauma strongly influence the formation of telangiectases in HHT patients. This result has potential implications in preventive measures and on therapeutic approaches for HHT. Full article
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Article
Efficacy and Safety of a 0.1% Tacrolimus Nasal Ointment as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial
J. Clin. Med. 2020, 9(5), 1262; https://doi.org/10.3390/jcm9051262 - 26 Apr 2020
Cited by 2 | Viewed by 1221
Abstract
Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks [...] Read more.
Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time. Full article
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Article
Gastrointestinal Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia: Risk Factors and Endoscopic Findings
J. Clin. Med. 2020, 9(1), 82; https://doi.org/10.3390/jcm9010082 - 28 Dec 2019
Cited by 8 | Viewed by 950
Abstract
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, [...] Read more.
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. Full article

Review

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Review
The Role of Liver Imaging in Hereditary Hemorrhagic Telangiectasia
J. Clin. Med. 2020, 9(11), 3750; https://doi.org/10.3390/jcm9113750 - 21 Nov 2020
Viewed by 586
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by spontaneous epistaxis, telangiectasia, and visceral vascular malformations. Hepatic vascular malformations are common, though a minority are symptomatic. Symptoms are dependent on the severity and exact type of shunting caused by the [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by spontaneous epistaxis, telangiectasia, and visceral vascular malformations. Hepatic vascular malformations are common, though a minority are symptomatic. Symptoms are dependent on the severity and exact type of shunting caused by the hepatic malformation: Arteriosystemic shunting leads to manifestations of high output cardiac failure, and arterioportal shunting leads to portal hypertension. Radiologic imaging, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), is an important tool for assessing liver involvement. Doppler ultrasonography is the first-line screening modality for HHT-related liver disease, and it has a standardized scale. Imaging can determine whether shunting is principally to the hepatic vein or the portal vein, which can be a key determinant of patients’ symptoms. Liver-related complications can be detected, including manifestations of portal hypertension, focal liver masses as well as ischemic cholangiopathy. Ultrasound and MRI also have the ability to quantify blood flow through the liver, which in the future may be used to determine prognosis and direct antiangiogenic therapy. Full article
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Review
Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia
J. Clin. Med. 2020, 9(11), 3571; https://doi.org/10.3390/jcm9113571 - 05 Nov 2020
Cited by 4 | Viewed by 615
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for [...] Read more.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved. Full article
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Review
Non-Coding RNAs and Hereditary Hemorrhagic Telangiectasia
J. Clin. Med. 2020, 9(10), 3333; https://doi.org/10.3390/jcm9103333 - 17 Oct 2020
Cited by 1 | Viewed by 575
Abstract
Non-coding RNAs (ncRNAs) are functional ribonucleic acid (RNA) species that include microRNAs (miRs), a class of short non-coding RNAs (∼21–25 nucleotides), and long non-coding RNAs (lncRNAs) consisting of more than 200 nucleotides. They regulate gene expression post-transcriptionally and are involved in a wide [...] Read more.
Non-coding RNAs (ncRNAs) are functional ribonucleic acid (RNA) species that include microRNAs (miRs), a class of short non-coding RNAs (∼21–25 nucleotides), and long non-coding RNAs (lncRNAs) consisting of more than 200 nucleotides. They regulate gene expression post-transcriptionally and are involved in a wide range of pathophysiological processes. Hereditary hemorrhagic telangiectasia (HHT) is a rare disorder inherited in an autosomal dominant fashion characterized by vascular dysplasia. Patients can develop life-threatening vascular malformations and experience severe hemorrhaging. Effective pharmacological therapies are limited. The study of ncRNAs in HHT is an emerging field with great promise. This review will explore the current literature on the involvement of ncRNAs in HHT as diagnostic and pathogenic factors. Full article
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Review
Approach to Pulmonary Arteriovenous Malformations: A Comprehensive Update
J. Clin. Med. 2020, 9(6), 1927; https://doi.org/10.3390/jcm9061927 - 19 Jun 2020
Cited by 7 | Viewed by 1142
Abstract
Pulmonary arteriovenous malformations (PAVMs) are abnormal direct vascular communications between pulmonary arteries and veins which create high-flow right-to-left shunts. They are most frequently congenital, usually in the setting of hereditary hemorrhagic telangiectasia (HHT). PAVMs may be asymptomatic or present with a wide variety [...] Read more.
Pulmonary arteriovenous malformations (PAVMs) are abnormal direct vascular communications between pulmonary arteries and veins which create high-flow right-to-left shunts. They are most frequently congenital, usually in the setting of hereditary hemorrhagic telangiectasia (HHT). PAVMs may be asymptomatic or present with a wide variety of clinical manifestations such as dyspnea, hypoxemia, or chest pain. Even when asymptomatic, presence of PAVMs increases patients’ risk of serious, potentially preventable complications including stroke or brain abscess. Transcatheter embolotherapy is considered the gold standard for treatment of PAVMs. Though previous guidelines have been published regarding the management of PAVMs, several aspects of PAVM screening and management remain debated among the experts, suggesting the need for thorough reexamination of the current literature. The authors of this review present an updated approach to the diagnostic workup and management of PAVMs, with an emphasis on areas of controversy, based on the latest literature and our institutional experience. Full article
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Review
Review of Pharmacological Strategies with Repurposed Drugs for Hereditary Hemorrhagic Telangiectasia Related Bleeding
J. Clin. Med. 2020, 9(6), 1766; https://doi.org/10.3390/jcm9061766 - 06 Jun 2020
Cited by 4 | Viewed by 1609
Abstract
The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 [...] Read more.
The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria: epistaxis, telangiectases, arteriovenous malformations in internal organs, and family history. Genetically speaking, more than 90% of HHT patients show mutations in ENG or ACVRL1/ALK1 genes, both belonging to the TGF-β/BMP9 signaling pathway. Despite clear knowledge of the symptoms and genes of the disease, we still lack a definite cure for HHT, having just palliative measures and pharmacological trials. Among the former, two strategies are: intervention at “ground zero” to minimize by iron and blood transfusions in order to counteract anemia. Among the later, along the last 15 years, three different strategies have been tested: (1) To favor coagulation with antifibrinolytic agents (tranexamic acid); (2) to increase transcription of ENG and ALK1 with specific estrogen-receptor modulators (bazedoxifene or raloxifene), antioxidants (N-acetylcysteine, resveratrol), or immunosuppressants (tacrolimus); and (3) to impair the abnormal angiogenic process with antibodies (bevacizumab) or blocking drugs like etamsylate, and propranolol. This manuscript reviews the main strategies and sums up the clinical trials developed with drugs alleviating HHT. Full article
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