Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1.

Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-ß/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.

BMP Receptor Inhibition Enhances Tissue Repair in Endoglin Heterozygous Mice.

Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a severe vascular disorder caused by mutations in the TGFß/BMP co-receptor endoglin. Endoglin haploinsufficiency results in vascular malformations and impaired neoangiogenesis. Furthermore, HHT1 patients display an impaired immune response. To date it is not fully understood how endoglin haploinsufficient immune cells contribute to HHT1 pathology. Therefore, we investigated the immune response during tissue repair in Eng+/- mice, a model for HHT1. Eng+/- mice exhibited prolonged infiltration of macrophages after experimentally induced myocardial infarction. Moreover, there was an increased number of inflammatory M1-like macrophages (Ly6Chigh/CD206-) at the expense of reparative M2-like macrophages (Ly6Clow/CD206+). Interestingly, HHT1 patients also showed an increased number of inflammatory macrophages. In vitro analysis revealed that TGFß-induced differentiation of Eng+/- monocytes into M2-like macrophages was blunted. Inhibiting BMP signaling by treating monocytes with LDN-193189 normalized their differentiation. Finally, LDN treatment improved heart function after MI and enhanced vascularization in both wild type and Eng+/- mice. The beneficial effect of LDN was also observed in the hind limb ischemia model. While blood flow recovery was hampered in vehicle-treated animals, LDN treatment improved tissue perfusion recovery in Eng+/- mice. In conclusion, BMPR kinase inhibition restored HHT1 macrophage imbalance in vitro and improved tissue repair after ischemic injury in Eng+/- mice.

Systematic screening in hereditary hemorrhagic telangiectasia: a review.

PURPOSE OF REVIEW: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterized by telangiectasia and arteriovenous malformations (AVMs). To date, five genetic types of HHT and one combined juvenile polyposis syndrome and HHT are known. Clinical and genetic screening of patients suspected with HHT is recommended to confirm the diagnosis and to prevent complications associated with HHT. The aim of this article is to give an overview of the evidence and to formulate a recommendation for clinicians concerning screening for HHT. RECENT FINDINGS: Complications of HHT such as stroke, brain abscess and intracranial hemorrhage are caused by pulmonary and cerebral AVMs (CAVMs) and can often be prevented by screening and treatment when possible. Screening and treatment of these AVMs will result in an increased life expectancy comparable with that of the general population as opposed to unscreened and untreated HHT patients. SUMMARY: Screening of HHT patients and their first-degree relatives is recommended to prevent severe complications including stroke, brain abscess and intracranial hemorrhage.

Pulmonary artery pseudoaneurysm after thoracic radiation therapy: A case report and review of the literature.

Pulmonary artery pseudoaneurysm (PAP) is a rare cause of hemoptysis. Potential causes include trauma, infection, or medical interventions. There is a risk of rupture, which is associated with a high mortality rate. We describe a 72-year-old patient, with a past medical history of a lung carcinoma for which she was treated with chemoradiotherapy 6 years prior, who presented with hemoptysis. She was hemodynamically stable and there were no other complaints. CT angiography of the thorax showed a PAP originating from a branch of the right pulmonary artery in the previously irradiated area. The patient was successfully treated by an embolization with plugs. Treatment of lung carcinoma with chemoradiotherapy can result in the development of a PAP. Clinicians should be aware of this complication, even years after the therapy. In literature, only a few cases of PAP in patients treated with (chemo)radiotherapy for lung cancer are described, with a maximum interval up to 7 years.

The evolution of survival of pulmonary arterial hypertension over 15 years.

The prognosis of pulmonary arterial hypertension (PAH) remains dismal. Over the years, multiple therapeutic advances have been introduced. This study evaluates the evolution of PAH survival over the past 15 years. We included 293 consecutive adult patients diagnosed with PAH between 2005 and 2019 (median age: 61.8 years, 70.3% female). Patients were divided into three cohorts based on the time of diagnosis: 2005-2009, 2010-2014, and 2015-2019 (2005-2009: n = 56; 2010-2014: n = 111; 2015-2019: n = 126). Transplant-free survival was measured from the date of right heart catheterization until patients reached the composite endpoint of lung transplant or death. Multivariable cox-pulmonary hypertension regression was used to study the effect of the time of diagnosis. The final cox model was fitted in both younger and older patients to evaluate the difference between these groups. During a median follow-up time of 4.1 (interquartile range: 2.2-7.3) years, 9 patients underwent lung transplantation and 151 patients died. The median overall transplant-free survival was 6.2 (5.5-8.0) years. Patients older than 56 years at baseline who were diagnosed in 2005-2009 showed better survival compared to patients diagnosed in 2010-2014 and 2015-2019 with an adjusted hazard ratio of, respectively, 2.12 (1.11-4.03) and 2.83 (1.41-5.69). Patients younger than 56 years showed neither an improved nor deteriorated survival over time. In conclusion, survival in patients with PAH did not improve over time, despite more available therapeutic options. This might be partly due to the changed demographic characteristics of the PAH patients and a still important diagnostic delay.

European Reference Network for Rare Vascular Diseases (VASCERN): When and how to use intravenous bevacizumab in Hereditary Haemorrhagic Telangiectasia (HHT)?

Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular multisystemic disease that leads to epistaxis, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT prevalence is estimated at 1/6000, i.e. around 85,000 European citizens, and is served by the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN). HHT treatments depend on clinical manifestations, and span multiple different medical, surgical and interventional disciplines. Separate to local treatments in the nose, in severe settings, intravenous bevacizumab has been proposed as treatment option, and the purpose of the current article is to assess the use of intravenous bevacizumab in patients with HHT in 2022 according to available data.

Vascular defects associated with hereditary hemorrhagic telangiectasia revealed in patient-derived isogenic iPSCs in 3D vessels on chip.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by weak blood vessels. HHT1 is caused by mutations in the ENDOGLIN (ENG) gene. Here, we generated induced pluripotent stem cells (hiPSCs) from a patient with rare mosaic HHT1 with tissues containing both mutant (ENGc.1678C>T) and normal cells, enabling derivation of isogenic diseased and healthy hiPSCs, respectively. We showed reduced ENG expression in HHT1 endothelial cells (HHT1-hiPSC-ECs), reflecting haploinsufficiency. HHT1c.1678C>T-hiPSC-ECs and the healthy isogenic control behaved similarly in two-dimensional (2D) culture, forming functionally indistinguishable vascular networks. However, when grown in 3D organ-on-chip devices under microfluidic flow, lumenized vessels formed in which defective vascular organization was evident: interaction between inner ECs and surrounding pericytes was decreased, and there was evidence for vascular leakage. Organs on chip thus revealed features of HHT in hiPSC-derived blood vessels that were not evident in conventional 2D assays.

The use of echo density to quantify pulmonary right-to-left shunt in transthoracic contrast echocardiography.

AIMS: Transthoracic contrast echocardiography (TTCE) is the recommended screening tool to detect pulmonary right-to-left shunt (RLS) caused by pulmonary arteriovenous malformations (PAVMs). We assessed a novel method to quantify the RLS using the change in echo density (ED) following contrast injection. METHODS AND RESULTS: An analysis of 437 consecutive patients [58% female, 47 years, interquartile range (IQR) 33-60] who underwent TTCE for the detection of a pulmonary RLS. Using ImageJ (National Institutes of Health), the change in ED was measured for each patient. This method was strongly correlated (Spearman's ρ = 0.89; P < 0.0001) with our standard method based on a four-point grading scale (no, mild, moderate, and severe RLS). In patients without a history of embolotherapy (n = 334), a PAVM was detected with chest computed tomography (CT) in 66 and embolotherapy was judged possible in 35 of these patients. The median increase in ED was higher in the latter: +20.1% (IQR 12.3-34.0) compared to non-treatable PAVM +0.2% (IQR -0.2 to 1.1). The specificity to detect treatable PAVMs increased from 87% to 90% when using the novel method without affecting the sensitivity (of 100%). Using the optimal cut-off value of +4.5% increase in ED, 8/74 (11%) needed chest CT-scans-individuals with a moderate or severe RLS-were no longer required without missing any treatable PAVM. CONCLUSIONS: The use of ED quantification for pulmonary RLS is promising; resulting in a substantial decrease in the number of chest CT scans needed. However, this method and the threshold should be validated in an independent study population.

Generation and genetic repair of 2 iPSC clones from a patient bearing a heterozygous c.1120del18 mutation in the ACVRL1 gene leading to Hereditary Hemorrhagic Telangiectasia (HHT) type 2.

Fibroblasts from a patient carrying a heterozygous 18bp deletion in exon 8 of the ACVRL1 gene (c.1120del18) were reprogrammed using episomal vectors. The in-frame deletion in ACVRL1 causes the loss of 6 amino acids of the protein, which is associated with Hereditary Hemorrhagic Telangiectasia (HHT) type 2 (Letteboer et al., 2005). CRISPR-Cas9 editing was used to genetically correct the mutation in the induced pluripotent stem cells (iPSCs). The top5-predicted off-target sites were not altered. Patient and isogenic iPSCs showed high pluripotent marker expression, in vitro differentiation capacity into all three germ layers and displayed a normal karyotype. The obtained isogenic pairs will enable proper in vitro disease modelling of HHT (Roman and Hinck, 2017).

European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT).

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an "AVM" bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening:1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion.2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients.3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider.4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly.We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.

Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events. RESULTS: Sixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1-3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1-3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males (p = 0.009), and in patients with ENG pathogenic variants (p = 0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years). CONCLUSIONS: With potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.

Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations (AVMs) ranging from telangiectases to larger AVMs. Mutations in two genes cause HHT; ENG (HHT1) and ACVRL1 (HHT2). Although the hallmark for clinical diagnosis is the presence of telangiectases, there are few publications reporting the relative distribution and frequency of these features between HHT1 and HHT2. Here, the results of such analysis of telangiectases in 268 patients with HHT1 and 130 patients with HHT2 are described. Localization of the telangiectases is reported, and patients were clustered by age to estimate the site prevalence for different age categories. We show that telangiectases of the nasal mucosa are present at a higher prevalence and start to appear earlier in life than those of the oral mucosa or dermal sites in patients with either HHT1 or HHT2. Oral and nasal mucosal telangiectases are present earlier in life in patients with HHT1 compared to patients with HHT2, whereas dermal lesions are more frequent and appear earlier in life in patients with HHT2. In patients with either HHT1 or HHT2, the number of sites affected increases with age. In patients with HHT1, more women than men had skin telangiectases, particularly on the face. These results confirm that the frequency of AVMs differ between patients with HHT1 and HHT2, and that these differences can be detected on physical examination.

European Reference Network For Rare Vascular Diseases (VASCERN) Outcome Measures For Hereditary Haemorrhagic Telangiectasia (HHT).

Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia that leads to nosebleeds, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT is estimated to affect 85,000 European citizens, but most health care providers have limited prior HHT exposure or training.Outcome Measures were developed and implemented by the HHT Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN), in order to maximise the number of patients receiving good care. The measures specifically target areas where optimal management reduces morbidity and mortality in HHT patients, and were designed to be robust to emerging new evidence. Thresholds are the percentage of patients in particular settings who have been recommended screening, or provided with written advice. The 5 Outcome Measures cover (1) pulmonary AVM screening; (2) written nosebleed advice, (3) assessment of iron deficiency; (4) antibiotic prophylaxis prior to dental and surgical procedures for patients with pulmonary AVMs, and (5) written advice on pregnancy. They are not a blueprint for detailed HHT management, but are suitable for all clinicians to be aware of and implement.In summary, these 5 Outcome Measures provide metrics to identify healthcare providers of good care, and encourage care improvement by all healthcare providers.

Distribution of talc suspension during treatment of malignant pleural effusion with talc pleurodesis.

Talc pleurodesis is an effective technique for the management of symptomatic malignant pleural effusions. It is assumed that a good dispersion of talc suspension contributes to the final success of this treatment. For this purpose, guidelines often advise to rotate the patient after intra-pleural instillation of the sclerosant. This prospective, randomized study analyses the dispersion of talc suspension and the overall success rate in patients with malignant effusions. After instillation of 99mTc-sestamibi-labeled talc suspension ten subjects were rotated for 1 h, while the ten other patients remained in a stable supine body position. Scintigraphic imaging was done in two directions immediately after instillation and after 1 h with a clamped drain. The overall success of the treatment was assessed 1 month after the pleurodesis. The dispersion of talc was limited and unequal in 75% of the subjects. In two patients with apparently good distribution on anterior views, the lateral views of the scintigraphy showed only limited distribution. Rotation of the patients did not influence the dispersion of sludge after 1 min or 1 h. Pleurodesis was successful in 85% of the patients after 1-month follow-up. Standard rotation protocols for patients with malignant pleural effusion do not affect the overall dispersion of talc suspension and should be abolished because of the discomfort caused to the patients.

Rerouting anomalous hepatic venous connection to the left atrium.

Total hepatic venous drainage into the left atrium is an extremely uncommon abnormality. We present a patient in whom the hepatic veins drained into the left atrium in the absence of other intracardiac or extracardiac anomalies. Surgical correction of the anomalous hepatic venous connection was performed by suturing the hepatic veins to the right atrium.