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Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT and evaluated association of genotype with presence of any organ VM, and specifically with brain VM, liver VM and pulmonary AVM, by multivariate logistic regression analyses stratified by HHT mutation. Among all patients with HHT, neither polymorphism was significantly associated with presence of any organ VM; ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR = 1.48, P = 0.062). ACVRL1 c.314-35A>G was significantly associated with any VM among patients with HHT with ENG (OR = 2.66, P = 0.022), but not ACVRL1 (OR = 0.79, P = 0.52) mutations. ACVRL1 c.314-35A>G was also associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. There were no significant associations between ENG c.207G>A and any VM phenotype. These results suggest that common polymorphisms in HHT genes other than the mutated gene modulate phenotype severity of HHT disease, specifically presence of organ VM. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Transthoracic contrast echocardiography (TTCE) can detect pulmonary right-to-left shunting (RLS) and is used to screen for pulmonary arteriovenous malformations (PAVMs) in patients with hereditary hemorrhagic telangiectasia (HHT). We studied the prevalence and size of pulmonary RLS in HHT type 1, HHT type 2, and HHT-negative controls, and its positive predictive value (PPV) and negative predictive value (NPV) for PAVMs that can be treated by embolotherapy.Methods: In 343 consecutive persons referred for possible HHT as first-degree family members of index patients a TTCE and chest CT scan were performed. All persons were offered genetic analysis.Results: An HHT-causing mutation was confirmed in 92 (mean age 41 ± 15 y; 59% female) HHT1 relatives and in 97 (mean age 47 ± 14 y; 52% female) HHT2 relatives. TTCE showed a pulmonary RLS in 78 (85%) HHT1- and 34 (35%) HHT2-related mutation carriers, respectively (P < .0001). In HHT1 relatives, 29 of 53 (55%) PAVMs and in HHT2 relatives three of 17 (18%) PAVMS were treated, resulting in a PPV of TTCE for treatable PAVMs of 36.3% and 8.3%, respectively. The accompanying NPV was 100%. A minimal, moderate, or large shunt was present in 12 (13%), 24 (26%), and 42 (46%) HHT1-related, and in 20 (21%), 6 (6%), and 8 (8%) HHT2-related mutation carriers, respectively (P for trend < .0001). A large shunt predicted treatable PAVMs in 55.8% of HHT1 relatives and 37.5% of HHT2 relatives. TTCE was positive in four (6%) of 63 persons without HHT.Conclusions: A pulmonary shunt on TTCE is more prevalent and larger in HHT1- compared with HHT2-related mutation carriers. Shunt grading is helpful to predict treatable PAVMs, particularly in the HHT2 group. TTCE is also positive in a small fraction of persons without HHT. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurologic complications in patients with hereditary hemorrhagic telangiectasia (HHT). Therefore, screening is warranted. Transthoracic contrast echocardiography (TTCE) can effectively detect a pulmonary right-to-left shunt (RLS).Objectives: To determine prospectively the predictive value of TTCE grading to detect PAVMs on high-resolution CT (HRCT) scans of the chest and the indication for embolotherapy.Methods: Three hundred seventeen patients, referred for possible HHT, were screened for PAVMs. Patients who underwent both chest HRCT scanning and TTCE were included in the study (n = 281). For the purposes of this study we used a 3-point grading scale, and shunt grades 3 and 4 according to the classification model of Barzilai et al were combined. Embolotherapy was performed of all PAVMs judged large enough for treatment.Results: Echocardiographic criteria for a pulmonary RLS were present in 105 patients (41%) [mean (+/- SD) age, 43.7 +/- 15.7 years; female gender, 63%]. Chest HRCT scan findings were positive in 55 patients (52%) in this group. The positive predictive value of shunt grade for the presence of PAVMs on chest HRCT scans was 22.9% for grade 1 (n = 35), 34.8% for grade 2 (n = 23), and 83.0% for grade 3 (n = 47), respectively. None of the patients with PAVMs seen on chest HRCT scans and a TTCE grade 1 (n = 8) or 2 (n = 8) were candidates for embolotherapy. Of 39 patients with TTCE grade 3 and PAVMs seen on chest HRCT scans, 26 patients (67%) underwent embolotherapy.Conclusion: An increased echocardiographic shunt grade correlates with an increased probability of PAVMs seen on chest HRCT scans. Only patients with a TTCE grade 3 displayed PAVMs on chest HRCT scans that were large enough for embolotherapy. [ABSTRACT FROM AUTHOR]

Background: Pulmonary arteriovenous malformations (PAVMs) are direct connections between the pulmonary artery and vein, creating a right-to-left shunt (RLS). Embolization is indicated to prevent complications. Guidelines recommend follow-up chest CT scans to confirm persistent occlusion and embolization of all treatable PAVMs. Graded transthoracic contrast echocardiography (TTCE) after PAVM embolization may offer a reliable alternative in a subgroup of patients while preventing radiation exposure., Research Question: Can TTCE predict the need for additional embolotherapy in the postembolization population as accurately as it does in the treatment-naive population?., Study Design and Methods: Since 2018, follow-up after PAVM embolization at our study institution includes both TTCE and chest CT scan after 6 to 12 months and every 3 to 5 years thereafter. Patients who underwent at least 1 follow-up TTCE and chest CT scan were included. The indication for additional embolotherapy was discussed in a multidisciplinary team meeting. The primary outcome was the indication for additional embolotherapy in each RLS grade. Additionally, the association between the RLS grade and indication for additional embolotherapy was investigated., Results: A total of 339 patients with 412 embolization procedures were included; median time to follow-up TTCE was 7.5 months. An RLS was present in 399 postembolization TTCEs (97%): RLS grade 1 in 93 patients (23%), grade 2 in 149 patients (36%) and grade 3 in 157 patients (38%). In patients with RLS grades 0 and 1, no treatable PAVMs were found on CT scan. In patients with RLS grades 2 and 3, 22 (15%) and 72 (46%) underwent additional embolization., Interpretation: This study shows chest CT scan might be forgone in patients with RLS grades 0 and 1 after PAVM embolization., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024. Published by Elsevier Inc.)

Therapies for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) include balloon pulmonary angioplasty (BPA) and PH-specific medical therapy. This study compares survival and its predictors before and after the introduction of BPA. BPA was independently associated with survival; however, there was no difference in overall survival between the two cohorts., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background/Objectives: The literature reports high complication rates in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who undergo balloon pulmonary angioplasty (BPA), especially in patients with poor pulmonary hemodynamics. Here, we describe the complications of BPA based on the new definitions. Methods: All patients with CTEPH who completed BPA treatment before 15 September 2023 were selected from the CTEPH database. Peri-procedural complications were collected and classified according to the 2023 consensus paper on BPA treatment. Complications were analyzed in subgroups of patients with pulmonary vascular resistance (PVR), ≤ or >6.6 WU, and mean pulmonary artery pressure (mPAP), ≤ or >45 mmHg, at first BPA. Results: In this analysis, 87 patients (63% women; mean age 61.1 ± 14.0 years; 62% on dual PH targeted medical therapy) underwent 426 (mean 4.9 ± 1.6 per patient) BPAs. Only non-severe complications occurred in 14% of BPA treatments and in 47% of the patients; 31% patients had a thoracic complication. The thoracic complications were mild (71%) or moderate (29%). Patients with a PVR > 6.6 WU ( n = 8) underwent more BPA treatments (6.6 ± 1.5 versus 4.6 ± 1.5, p = 0.002), had more complications (88% versus 41% of patients, p = 0.020), and had more thoracic complications (17% vs. 7% of BPAs, p = 0.013) than patients with PVR ≤ 6.6 WU. Patients with mPAP > 45 mmHg ( n = 13) also had more BPA treatments (6.5 ± 1.7 versus 4.6 ± 1.4, p < 0.001), more complications (77% versus 44% of patients, p = 0.027) and more thoracic complications (14% versus 8% of BPAs, p = 0.039) than patients with mPAP ≤ 45 mmHg. Conclusions: Complications occurred in 14% of BPAs and were mostly mild. Patients with severe pulmonary hemodynamics suffered more (thoracic) complications.

Aim: To investigate the association of resilience with self-care and quality of life in people with chronic obstructive pulmonary disease., Design: Cross-sectional study., Methods: Data were collected between February and May 2021. Self-care was measured with the self-care of chronic illness inventory, quality of life was measured with the clinical chronic obstructive pulmonary disease questionnaire and resilience was measured with the resilience evaluation scale. Possible confounders were included (sex, age, smoking, time since diagnosis of chronic obstructive pulmonary disease, educational level, social support and pulmonary function). Multiple regression analysis was performed among the determinants, confounders and both outcomes., Results: Participants scored fairly well on resilience (mean 22.5). Self-care scored reasonably well (mean maintenance 65.9, mean monitoring 70.9, mean management 59.9 and mean confidence 71.5). Quality of life scored mediocre (mean 2.6). The results of the linear multiple regression were resilience, which is associated with self-care confidence and quality of life when adjusted for possible confounders. This means people with chronic obstructive pulmonary disease with higher resilience have better self-care confidence and higher quality of life. The outcome contributes to strengthening nursing care and further developing nurses' knowledge. The results can contribute to increasing awareness for healthcare professionals that resilience can potentially increase self-care and quality of life., (© 2023 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Background: Pulmonary arteriovenous malformations (PAVMs) are direct connections between the pulmonary artery and the pulmonary vein, mostly associated with hereditary hemorrhagic telangiectasia (HHT). PAVMs can lead to severe neurologic complications such as stroke and brain abscess. The risk of complications decreases after embolization. Therefore, screening for PAVMs using transthoracic contrast echocardiography (TTCE) is recommended, including a rescreening interval of 5 years., Research Question: Is extension of the interval for rescreening patients without a pulmonary right-to-left shunt (RLS) of up to 10 years appropriate?, Study Design and Methods: Adult patients with HHT with 5- or 10-year follow-up TTCE, or both, were included. Patients who underwent PAVM embolization in the past or at baseline were excluded. The RLS grades and presence of a treatable PAVM were compared with baseline., Results: In total, 387 patients (median age, 45 years [interquartile range, 33-54 years]; 56% women) involving 5- and 10-year follow-up data in 363 and 166 patients, respectively, were included. None of the patients (n = 148) without a pulmonary RLS at baseline demonstrated a treatable PAVM after 5 and 10 years. Of the patients with a pulmonary RLS at baseline, 20 patients (9%) and three patients (3%) demonstrated a treatable PAVM at the 5- and 10-year follow-up, respectively. In most patients, the RLS grade remained stable over time., Interpretation: On the basis of the results of this retrospective study, we believe that the rescreening interval for patients with HHT without a pulmonary RLS at initial screening may be extended to 10 years. Those with a pulmonary RLS should be rescreened every 5 years because treatable PAVMs can evolve., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Haploinsufficiency for Endoglin (ENG) and activin A receptor type II-like I ( ACVRL1 /ALK1) lead to the formation of weak and abnormal vessels in hereditary hemorrhagic telangiectasia (HHT). These cause epistaxis (nosebleeds) and/or gastrointestinal blood loss. In vitro in cultured endothelial cells, tacrolimus has been shown to increase ENG and ALK1 expression. It is, therefore, a potential treatment option. We report here a proof-of-concept study in patients with HHT and severe epistaxis and/or gastrointestinal bleeding who were treated daily with orally-administered tacrolimus for twenty weeks. Twenty-five patients with HHT (11 females (44%)) and median age of 59 years were enrolled. Five patients (20%) stopped the trial prematurely-four due to (serious) adverse events ((S)AE). Twenty patients were included in further analyses. Hemoglobin levels increased during tacrolimus treatment from 6.1 (IQR 5.2-6.9) mmol/L at baseline (9.8 g/dL) to 6.7 (6.5-7.1) mmol/L (10.8 g/dL), p = 0.003. The number of blood transfusions over the twenty weeks decreased from a mean of 5.0 (±9.2) to 1.9 (±3.5), p = 0.04. In 64% of the patients, at least one AE occurred. Oral tacrolimus, thus, significantly increased hemoglobin levels and decreased blood transfusion needs, epistaxis and/or gastrointestinal bleeding in patients with HHT. However, side-effects were common. Further investigation of the potential therapeutic benefit is justified by the outcome of the study.

Background: Sarcoidosis is a systemic disease of unknown aetiology with significant morbidity and mortality. The PULSAR study prospectively performed cardiac analysis including systematic pulmonary hypertension screening in sarcoidosis patients newly referred to a tertiary sarcoidosis center. In this manuscript we studied the four-year mortality of this population., Methods and Main Findings: Between august 2015 and October 2017, 399 patients (58% male, mean age 49.4 years, 90.5% Caucasian) were included and followed for a mean period of 4.3±0.7 years. In total, 10 patients had died at the time of analysis. 1-, 2-, 3- and 4-year survival rate was 100% (n=399), 99.0% (n=399), 98.2% (n=399) and 94.6% (n=276). Most patients died of respiratory failure, other causes were heterogeneous including cardiac, neurological and non-sarcoidosis origin. A low CPI score or modified Walsh score was associated with higher mortality, similar for high PH probability on echocardiography and elevated right ventricular systolic pressure., Conclusion: This study highlights that elevated RVSP and presence of PH on echocardiography and progression of fibrotic disease with subsequent decline in pulmonary function test are important factors for mortality in sarcoidosis patients., (Copyright © 2022. Published by Elsevier Ltd.)

Background and Objective: Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and its aetiology is unclear. Different pathophysiological mechanisms in sarcoidosis-associated pulmonary hypertension (SAPH) are known. Clinical phenotyping can aid clinicians in choosing the optimal treatment strategy. This study aimed to describe clinical phenotypes of SAPH and their characteristics., Methods: A retrospective cohort study was performed on all SAPH patients at a tertiary referral centre. All patients were extensively analysed and discussed case by case in a multidisciplinary expert team to determine the most likely pathophysiological mechanism of PH. Patients were then classified into conceptual clinical phenotypes., Results: Forty (40) patients with SAPH were identified between 2010 and 2019. Three (3) patients were classified as the postcapillary phenotype. Of the remaining 37 patients with precapillary PH, six were classified as 'compression of pulmonary vasculature', 29 as 'parenchymal', one as 'suspected vasculopathy', and one as 'chronic pulmonary emboli' phenotypes. Of the patients with compression of pulmonary vasculature, four showed compression by fibrotic disease and two by active sarcoidosis-based disease. Within the parenchymal phenotype, 20 patients (69%) showed pulmonary vascular resistance >3.0 Wood Units (WU) and had significantly lower diffusing capacity of the lung for carbon monoxide compared with the nine patients (31%) with pulmonary vascular resistance ≤3.0 WU., Conclusion: SAPH had multiple pathophysiological mechanisms and clinical phenotypes in this retrospective study. Further studies are necessary to examine how these phenotypes can affect appropriate treatment and prognosis., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The inhibiting effects of itraconazole, an antifungal drug on vascular endothelial growth factor (VEGF) have recently been discovered. By inhibiting VEGF, itraconazole has shown potential in clinical trials as anti-cancer treatment. In hereditary hemorrhagic telangiectasia (HHT) patients, VEGF levels are elevated and inhibition of VEGF can decrease bleeding. Itraconazole could potentially serve as anti-angiogenic therapy for HHT-related bleeding. We report a proof of concept study with HHT patients and severe epistaxis. Patients were treated with daily 200 mg orally administered itraconazole for sixteen weeks. Twenty-one HHT patients, 8 females (38%), 13 males (62%), median age of 59 years (interquartile range (IQR) 55-69) were enrolled. Of these patients, 13 (62%) were diagnosed with HHT type 1, seven (33%) with HHT type 2 and in one patient (5%), no pathognomonic HHT mutation was found. Four patients (19%) prematurely terminated the study (3 due to mild or moderate side-effects) resulting in 17 patients included in the analyses. The median epistaxis severity score significantly decreased during treatment from 6.0 (IQR 5.1-7.2) to 3.8 (IQR 3.1-5.2) (p = 0.006). The monthly epistaxis frequency decreased from 56 to 38 epistaxis episodes (p = 0.004) and the monthly duration from 407 to 278 minutes (p = 0.005). Hemoglobin levels did not significantly change. The quality of life showed a small but significant improvement. In conclusion, oral itraconazole significantly improved epistaxis in HHT patients. The potential benefit of itraconazole in HHT should be further investigated.

Aim: To determine whether there are differences between idiopathic and hereditary haemorrhagic telangiectasia (HHT) associated pulmonary arteriovenous malformations (PAVMs) (HHT-PAVM) regarding clinical and radiographic characteristics, and the results of embolotherapy., Materials and Methods: A retrospective analysis was undertaken of all adult and adolescent patients who were diagnosed with a PAVM on chest computed tomography (CT) from January 2006 until August 2019., Results: In total, 41 patients with idiopathic PAVMs and 194 patients with genetically confirmed HHT and PAVMs were included. Idiopathic PAVMs were more frequently observed in female patients, were more solitary, and predominantly located in the lower lobes. The diameter of the feeding artery and type of PAVM (simple versus complex) were similar. Embolotherapy results were comparable between both groups with similar re-embolisation rates., Conclusions: PAVMs of idiopathic origin are predominantly found in women, more frequently located in the lower lobes, and solitary compared to HHT-PAVMs; however, the outcome of treatment is the same, suggesting that treatment and follow-up should be similar in both groups., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.

Description: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications., Methods: The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved., Recommendations: The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Hereditary haemorrhagic telangiectasia (HHT) is supposedly rare in Africa, with only three pathogenic variants documented to date. We describe the clinical and genetic features of HHT patients in central South Africa, who fulfilled the Curaçao criteria. Sixteen patients (median age 38.5 years, range 12-65 years), from six families were included. Fifteen patients were of African descent and one was of Afrikaner descent. The mean epistaxis severity score was 3.18, and the median haemoglobin was 9.5 g/dL (range 3.5-13.5 g/dL). On transthoracic contrast echocardiography 69% had a shunt grade ≥ 1, but only 20% had pulmonary arteriovenous malformations (AVMs) on computed tomography of the chest. Hepatic AVMs were found in 13% of patients, while 13% had brain vascular malformations. Four patients were HIV positive, of whom two had worsening epistaxis while they had opportunistic infections and poor HIV control. We identified six pathogenic variants (four in ENG and two in ACVRL1) in the six probands, three of which had been described previously. Three variants have apparently not been reported previously: ENG c.[1336&#95;1337dup];[ =] p.[(Asp446fs)];[( =)], ENG c.[ 690?&#95;816+?del] p.[(?)], and ACVRL1 c.[268&#95;274delins57];[ =] p.[(Cys90fs)];[( =)]. We confirmed the diagnosis of HHT in sixteen patients and identified pathogenic variants in ENG or ACVRL1 in all six probands in central South Africa, where HHT has been underreported. We describe three pathogenic variants: two of ENG and one of ACVRL1. We will be able to implement pre-symptomatic screening of patients in our area, and improve their management.

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.

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.

Pulmonary hypertension (PH) is a well-known complication of sarcoidosis, defined by a mean pulmonary artery pressure of ≥25 mm Hg. Since both PH and sarcoidosis are rare diseases, data on sarcoidosis-associated PH (SAPH) is retrieved mostly from small retrospective studies. Estimated prevalence of SAPH ranges from 3% in patients referred to a tertiary center up to 79% in patients awaiting lung transplant. Most patients with SAPH show advanced parenchymal disease as the underlying mechanism. However, some patients have disproportional elevated pulmonary artery pressure, and PH can occur in sarcoidosis patients without parenchymal disease. Other mechanisms such as vascular disease, pulmonary embolisms, postcapillary PH, extrinsic compression, and other sarcoidosis-related comorbidities might contribute to SAPH. The diagnosis of PH in sarcoidosis is challenging since symptoms and signs overlap. Suspicion can be raised based on symptoms or tests, such as pulmonary function tests, laboratory findings, electrocardiography, or chest CT. PH screening mainly relies on transthoracic echocardiography. Right heart catheterization should be considered on a case-by-case basis in patients with clinical suspicion of PH, taking into account clinical consequences. Treatment options are considered on patient level in a PH expert center, and might include oxygen therapy, immunosuppressive, or PH-specific therapy. However, qualitative evidence is scarce. Furthermore, in a subset of patients, interventional therapy or eventually lung transplant can be considered. SAPH is associated with high morbidity. Mortality is higher in sarcoidosis patients with PH compared with those without PH, and increases in patients with more advanced stages of sarcoidosis and/or PH., Competing Interests: None declared., (Thieme. All rights reserved.)

Abnormal vasculature is a key feature of hereditary hemorrhagic telangiectasia (HHT) and can also present in the nail fold capillary beds. However, the exact prevalence and the clinical diagnostic value in HHT are still largely unknown. The nail fold can be easily and noninvasively inspected with a capillary microscope. We therefore retrospectively assessed the prevalence and diagnostic value of abnormal nail fold capillaries in all patients who were screened between January 2000 and July 2017 for the presence of HHT and underwent capillary microscopy in St Antonius Hospital, The Netherlands. Capillary microscopy results and clinical characteristics were extracted from medical files and the prevalence of abnormal nail fold capillaries was calculated and the diagnostic value of the Curaçao criteria with and without capillary microscopy results was assessed. Of the 1761 individuals screened, 923 (52%) were diagnosed with a clinical and/or genetic HHT diagnosis. In these patients, capillary microscopy was normal in 23% ( n = 218), enlarged loops were seen in 11% ( n = 99), and giant loops in 66% ( n = 606). The sensitivity and specificity of the Curaçao criteria for the diagnosis of HHT without capillary microscopy results were 96% and 90%, respectively. The addition of the presence of giant loops to the Curaçao criteria led to a small increase in sensitivity to 97% without affecting the specificity. In conclusion, the prevalence of nail fold abnormalities in patients with HHT is high. Capillary microscopy can be a useful, easy, and noninvasive diagnostic tool in HHT.

Pulmonary hypertension (PH) is a well-recognised complication of sarcoidosis. Non-invasive diagnosis is challenging due to limited accuracy of echocardiography in interstitial lung disease. This study evaluates the value of echocardiographic PH probability for diagnosing PH in pulmonary sarcoidosis. All consecutive patients between August 2015 and November 2018 were prospectively screened for PH, and classified as low, intermediate or high PH probability. Patients with intermediate or high PH probability were referred for right heart catheterisation. PH was defined as a mean pulmonary artery pressure of ≥ 25 mm Hg. Additional data on pulmonary function and chest-CT was collected. Of all 479 patients, PH was present in 17 and absent in 19 patients. Six patients refused right heart catheterisation. PH was present in 33% and 75% of patients with intermediate and high PH probability respectively (n = 36). TRV max was measurable in 46% of all patients. Measurability did not correlate with FVC% predicted or presence of significant fibrosis. In intermediate and high PH probability, TRV max < 2.9 m/s successfully ruled out PH whereas a TRV max > 3.4 confirmed PH in all patients. If TRV max was absent or in between 2.9 and 3.4, secondary echocardiographic signs were not able to improve the diagnostic accuracy. PH is unlikely in patients with a TRV max < 2.9 m/s on echocardiography, whereas PH is highly suspected in a TRV max > 3.4 m/s. Discrimination is challenging if the TRV max is between 2.9-3.4 m/s or absent. Additional secondary signs do not improve discrimination. Decision making for further investigations should be made by an expert team.

Objective: The current experience with combination therapy in chronic thromboembolic pulmonary hypertension (CTEPH) is limited. We present the first survival results up to 5 years for dual combination therapy versus monotherapy in CTEPH., Methods: All consecutive, non-operated CTEPH or residual PH after pulmonary endarterectomy patients treated with PH-specific medical therapy between January 2002 and November 2019 were included. We report and compare survival between monotherapy and (upfront or sequential) dual combination therapy until five years after medication initiation., Results: In total, 183 patients (mean age 65 ± 14 years, 60% female, 66% WHO FC III/IV, 86% non-operated) were included, of which 83 patients received monotherapy and 100 patients received dual combination therapy. At baseline, patients receiving combination therapy had a higher NT-proBNP (p = 0.02) mean pulmonary artery pressure (p = 0.0001) and pulmonary vascular resistance (p = 0.02), while cardiac index was lower (p = 0.03). Total follow-up duration was 3.3 ± 1.8 years, during which 31 (17%) patients died. Estimated 1-, 3- and 5-year survival for monotherapy were 99%, 92% and 79%, respectively. For combination therapy percentages were 98%, 89% and 70%, respectively. Survival did not significantly differ between both groups (p = 0.22)., Conclusion: Survival up to 5 years for patients treated with combination therapy, regardless of the combination strategy, was similar as patients with monotherapy, despite worse clinical and haemodynamic baseline characteristics., (© 2020 The Authors.)

Background: Macitentan treatment for chronic thromboembolic pulmonary hypertension (CTEPH) in the routine clinical setting is increasing. However, 'real world' macitentan experience is scarce and is needed to differentiate from controlled clinical trial settings., Objective: We describe our outcomes and clinical 'real world' experience of macitentan mono- and combination therapy with riociguat or sildenafil in CTEPH., Methods: We included all consecutive CTEPH patients, either non-operated or with residual PH after pulmonary endarterectomy (PEA), treated with macitentan in the St. Antonius hospital in Nieuwegein, the Netherlands, between 01-2014 and 11-2019. We describe clinical outcomes and adverse events (AEs) until 2 years after macitentan initiation., Results: In total 73 CTEPH patients on macitentan were included, of which 18 patients were clinically inoperable (n = 7 declined PEA, n = 11 nonacceptable risk-benefit) and 55 had technically inoperable CTEPH (n = 48)/residual PH (n = 7). Clinically inoperable patients (mean age 72.4 ± 10.2 years, 61% female, 28% macitentan monotherapy, observation period 2.0 (1.9-2.0) years) had a survival of 100% and clinical worsening (CW)-free survival of 88% at 2-year follow-up respectively, with a significant increased 6-min walking distance (6MWD). Technically inoperable/residual PH patients (mean age 62.1 ± 14.1 years, 60% female, 27% macitentan monotherapy, observation period 2.0 (1.0-2.0) years) had a 2-year survival and CW-free survival of 86% and 68% respectively, with significant improved 6MWD and NT-proBNP. Nonsevere AEs were reported in 30% of all patients., Conclusion: Macitentan mono- and combination therapy in non-operated CTEPH and residual PH is safe and improves clinical outcomes till 2-year follow-up., Competing Interests: Declaration of competing interest M. van Thor, J. Mager and M. Post report grants from Actelion Pharmaceuticals. L ten Klooster has nothing to disclose. R. Snijder reports grants from Pfizer and Actelion Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Balloon pulmonary angioplasty (BPA) is an emerging treatment in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease (CTED). We describe the first safety and efficacy results of BPA in the Netherlands., Methods: We selected all consecutive patients with inoperable CTEPH and CTED accepted for BPA treatment who had a six-month follow-up in the St. Antonius Hospital in Nieuwegein and the Amsterdam University Medical Center (UMC) in Amsterdam. Functional class (FC), N‑terminal pro-brain natriuretic peptide (NT-proBNP), 6‑minute walking test distance (6MWD) and right-sided heart catheterisation were performed at baseline and six months after last BPA. Complications for each BPA procedure were noted., Results: A hundred and seventy-two BPA procedures were performed in 38 patients (61% female, mean age 65 ± 15 years). Significant improvements six months after BPA treatment were observed for functional class (63% FC I/II to 90% FC I/II, p = 0.014), mean pulmonary artery pressure (-8.9 mm Hg, p = 0.0001), pulmonary vascular resistance (-2.8 Woods Units (WU), p = 0.0001), right atrial pressure (-2.0 mm Hg, p = 0.006), stroke volume index (+5.7 ml/m 2 , p = 0.009) and 6MWD (+48m, p = 0.007). Non-severe complications occurred in 20 (12%) procedures., Conclusions: BPA performed in a CTEPH expert centre is an effective and safe treatment in patients with inoperable CTEPH.

Background: Pulmonary hypertension (PH) is a known complication of pulmonary sarcoidosis and is associated with higher morbidity and mortality. Currently, there are no approved PH-targeted therapies for sarcoidosis-associated pulmonary hypertension (SAPH). Macitentan is frequently used as treatment for pulmonary arterial hypertension, but no results are known in the SAPH population., Objective: We investigated the safety and effect of macitentan as treatment for SAPH., Methods: We retrospectively reviewed our patient database for all SAPH patients receiving macitentan as treatment, with a minimum follow-up of twelve months for monitoring safety. Safety outcomes included reported side-effects, hospitalisations and mortality. Furthermore, six-minutes walking distance, New York Heart Association functional class and NT-proBNP levels were collected., Results: Six cases (three men) with a median age of 64 years (range 52-74 years) were identified. During macitentan treatment, one patient experienced side effects and aborted therapy after five days of treatment and died 16 months later. Three patients were hospitalised during treatment for congestive heart failure. Four patients showed improvement of their functional class and three patients in exercise capacity after 12 months of therapy., Conclusion: Macitentan was well tolerated in five out of six cases with severe pulmonary sarcoidosis and PH. Functional capacity improved in four cases. Prospective controlled trials are warranted before therapeutic recommendations can be made. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 74-78) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Objective: Research comparing bosentan and macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH., Methods: All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation., Results: In total, 112 patients receiving bosentan or macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for macitentan. Two-year survival rate was 91% for bosentan and 80% for macitentan (HR mortality macitentan 1.85 [0.56-6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW macitentan 2.16 [0.962-4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up., Conclusion: CTEPH patients receiving bosentan or macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.

Background: To improve clinical outcome, patients with inoperable and residual chronic thromboembolic pulmonary hypertension (CTEPH) can be treated with riociguat. The aim of this study is to explore long-term outcomes and to compare our 'real world' data with previous research., Methods: We included all consecutive patients with technical inoperable and residual CTEPH, in whom riociguat therapy was initiated from January 2014 onwards, with patients followed till January 2019. Survival, clinical worsening (CW), functional class (FC), N-terminal pro brain natriuretic peptide (NT-proBNP) and 6-minute walking distance (6MWD) were described yearly after riociguat initiation., Results: Thirty-six patients (50% female, mean age 64.9 ± 12.1 years, 54% WHO FC III/IV and 6MWD 337 ± 138 m could be included, with a mean follow-up of 2.3 ± 1.2 years. Survival and CW-free survival three years after initiation of riociguat were 94% and 78%, respectively. The 6MWD per 10 m at baseline was a significant predictor (HR 0.90 [0.83-0.97], p  = 0.009) for CW. At three years follow-up the WHO FC and 6MWD improved and NT-proBNP decreased compared to baseline., Conclusion: Our study confirms that riociguat is an effective treatment in patients with technical inoperable and residual CTEPH at long-term follow-up. Although our results are consistent with previous studies, more 'real world' research is necessary to confirm long-term results.

Background: Hereditary Hemorrhagic Telangiectasia type 2 (HHT2) is an inherited genetic disorder characterized by vascular malformations and hemorrhage. HHT2 results from ACVRL1 haploinsufficiency, the remaining wild-type allele being unable to contribute sufficient protein to sustain endothelial cell function. Blood vessels function normally but are prone to respond to angiogenic stimuli, leading to the development of telangiectasic lesions that can bleed. How ACVRL1 haploinsufficiency leads to pathological angiogenesis is unknown., Methods: We took advantage of Acvrl1 +/- mutant mice that exhibit HHT2 vascular lesions and focused on the neonatal retina and the airway system after Mycoplasma pulmonis infection, as physiological and pathological models of angiogenesis, respectively. We elucidated underlying disease mechanisms in vitro by generating Acvrl1 +/- mouse embryonic stem cell lines that underwent sprouting angiogenesis and performed genetic complementation experiments. Finally, HHT2 plasma samples and skin biopsies were analyzed to determine whether the mechanisms evident in mice are conserved in humans., Results: Acvrl1 +/- retinas at postnatal day 7 showed excessive angiogenesis and numerous endothelial "tip cells" at the vascular front that displayed migratory defects. Vascular endothelial growth factor receptor 1 (VEGFR1; Flt-1) levels were reduced in Acvrl1 +/- mice and HHT2 patients, suggesting similar mechanisms in humans. In sprouting angiogenesis, VEGFR1 is expressed in stalk cells to inhibit VEGFR2 (Flk-1, KDR) signaling and thus limit tip cell formation. Soluble VEGFR1 (sVEGFR1) is also secreted, creating a VEGF gradient that promotes orientated sprout migration. Acvrl1 +/- embryonic stem cell lines recapitulated the vascular anomalies in Acvrl1 +/- (HHT2) mice. Genetic insertion of either the membrane or soluble form of VEGFR1 into the ROSA26 locus of Acvrl1 +/- embryonic stem cell lines prevented the vascular anomalies, suggesting that high VEGFR2 activity in Acvrl1 +/- endothelial cells induces HHT2 vascular anomalies. To confirm our hypothesis, Acvrl1 +/- mice were infected by Mycoplasma pulmonis to induce sustained airway inflammation. Infected Acvrl1 +/- tracheas showed excessive angiogenesis with the formation of multiple telangiectases, vascular defects that were prevented by VEGFR2 blocking antibodies., Conclusions: Our findings demonstrate a key role of VEGFR1 in HHT2 pathogenesis and provide mechanisms explaining why HHT2 blood vessels respond abnormally to angiogenic signals. This supports the case for using anti-VEGF therapy in HHT2.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disease characterised by multisystemic vascular dysplasia. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT. Both diseases can be the result of genetic mutations in ACVLR1 and ENG encoding for proteins involved in the transforming growth factor-beta (TGF-β) superfamily, a signalling pathway that is essential for angiogenesis. Changes within this pathway can lead to both the proliferative vasculopathy of HPAH and arteriovenous malformations seen in HHT. Clinical signs of the disease combination may not be specific but early diagnosis is important for appropriate treatment. This review describes the molecular mechanism and management of HPAH and HHT.

Aim: Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary arteriovenous malformations (PAVMs) in hereditary haemorrhagic telangiectasia. Shunt quantification is used to find treatable PAVMs. So far, there has been no study investigating the reproducibility of this diagnostic test. Therefore, this study aimed to describe inter-observer and inter-injection variability of TTCE., Methods: We conducted a prospective single centre study. We included all consecutive persons screened for presence of PAVMs in association with hereditary haemorrhagic telangiectasia in 2015. The videos of two contrast injections per patient were divided and reviewed by two cardiologists blinded for patient data. Pulmonary right-to-left shunts were graded using a three-grade scale. Inter-observer and inter-injection agreement was calculated with κ statistics for the presence and grade of pulmonary right-to-left shunts., Results: We included 107 persons (accounting for 214 injections) (49.5% male, mean age 45.0 ± 16.6 years). A pulmonary right-to-left shunt was present in 136 (63.6%) and 131 (61.2%) injections for observer 1 and 2, respectively. Inter-injection agreement for the presence of pulmonary right-to-left shunts was 0.96 (95% confidence interval (CI) 0.9-1.0) and 0.98 (95% CI 0.94-1.00) for observer 1 and 2, respectively. Inter-injection agreement for pulmonary right-to-left shunt grade was 0.96 (95% CI 0.93-0.99) and 0.95 (95% CI 0.92-0.98) respectively. There was disagreement in right-to-left shunt grade between the contrast injections in 11 patients (10.3%). Inter-observer variability for presence and grade of the pulmonary right-to-left shunt was 0.95 (95% CI 0.91-0.99) and 0.97 (95% CI 0.95-0.99) respectively., Conclusion: TTCE has an excellent inter-injection and inter-observer agreement for both the presence and grade of pulmonary right-to-left shunts.

Background: Mutations in the genes ENG, ACVRL1 and SMAD4 that are part of the transforming growth factor-beta signalling pathway cause hereditary haemorrhagic telangiectasia (HHT). Mutations in non-HHT genes within this same pathway have been found to associate with aortic dilation. Therefore, we investigated the presence of aortic dilation in a large cohort of HHT patients as compared to non-HHT controls., Methods: Chest computed tomography of consecutive HHT patients (ENG, ACVRL1 and SMAD4 mutation carriers) and non-HHT controls were reviewed. Aortic root dilation was defined as a z-score>1.96. Ascending and descending aorta dimensions were corrected for age, gender and body surface area., Results: In total 178 subjects (57.3% female, mean age 43.9±14.9years) were included (32 SMAD4, 47 ENG, 50 ACVRL1 mutation carriers and 49 non-HHT controls). Aortopathy was present in a total of 42 subjects (24% of total). Aortic root dilatation was found in 31% of SMAD4, 2% of ENG, 6% of ACVRL1 mutation carriers, and 4% in non-HHT controls (p<0.001). The aortic root diameter was 36.3±5.2mm in SMAD4 versus 32.7±3.9mm in the non-SMAD4 group (p=0.001). SMAD4 was an independent predictor for increased aortic root (β-coefficient 3.5, p<0.001) and ascending aorta diameter (β-coefficient 1.6, p=0.04)., Conclusions: SMAD4 gene mutation in HHT patients is independently associated with a higher risk of aortic root and ascending aortic dilation as compared to other HHT patients and non-HHT controls., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease with multi-systemic vascular dysplasia. Early diagnosis through screening is important to prevent serious complications. How best to screen children of affected parents for pulmonary arteriovenous malformations (PAVMs) is often subject to debate. Transthoracic contrast echocardiogram (TTCE) is considered optimal in screening for PAVMs in adults. Guidelines for the screening of children are not specific, reflecting the lack of scientific evidence on the best method to use., Objective: Aims of this study are (i) to evaluate our current screening method, consisting of history, physical examination, pulse oximetry, and chest radiography and (ii) to assess whether postponing more invasive screening for PAVMs until adulthood is safe., Methods: This is a prospective observational cohort study using a patient database., Results: Over a period of 18 years (mean follow-up 9.21 years, SD 4.72 years), 436 children from HHT families were screened consecutively. A total of 175/436 (40%) children had a diagnosis of HHT. PAVMs were detected in 39/175 (22%) children, 33/39 requiring treatment by embolotherapy. None of the screened children suffered any PAVM-associated complications with this screening method., Conclusion: This study shows that a conservative screening method during childhood is sufficient to detect large PAVMs and protect children with HHT for PAVM-related complications. Postponing TTCE and subsequent chest CT scanning until adulthood to detect any smaller PAVMs does not appear to be associated with major risk., (© 2017 Wiley Periodicals, Inc.)

Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurological complications in hereditary haemorrhagic telangiectasia (HHT). Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary right-to-left shunts (RLS). Although growth of PAVMs is shown in two small studies, no studies on follow-up with TTCE exist.All HHT patients underwent a second TTCE 5 years after initial screening. Patients with a history of PAVM embolisation were excluded. Pulmonary RLS grade on TTCE after 5 years was compared to the grade at screening.200 patients (53.5% female, mean±sd age at screening 44.7±14.1 years) were included. Increase in RLS grade occurred in 36 (18%) patients, of whom six (17%) underwent embolisation. The change in grade between screening and follow-up was not more than one grade. Of patients with nontreatable pulmonary RLS at screening (n=113), 14 (12.4%) underwent embolisation. In patients without pulmonary RLS at initial screening (n=87), no treatable PAVMs developed during follow-up.Within 5 years, no treatable PAVMs developed in HHT patients without pulmonary RLS at initial screening. Increase in pulmonary RLS grade occurred in 18% of patients, and never increased by more than one grade. Of patients with nontreatable pulmonary RLS at initial screening, 12% underwent embolisation., (Copyright ©ERS 2016.)

Background: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disease associated with epistaxis, arteriovenous malformations and telangiectasias. Disease complications may result in premature death., Method: We investigated life-expectancies of parents of HHT patients compared with their non-HHT partners using self- or telephone-administered questionnaires sent to their children. Patients were extracted from the databases of 2 participating HHT Centres: the Toronto HHT Database (Toronto, Canada) and the St. Antonius Hospital HHT Database (Nieuwegein, The Netherlands)., Results: Two hundred twenty five/407 (55%) of respondents were included creating HHT- (n = 225) and control groups (n = 225) of equal size. Two hundred thirteen/225 (95%) of the HHT group had not been screened for organ involvement of the disease prior to death. The life expectancy in parents with HHT was slightly lower compared to parents without (median age at death 73.3 years in patients versus 76.6 years in controls, p0.018). Parents with ACVRL 1 mutations had normal life expectancies, whereas parents with Endoglin mutations died 7.1 years earlier than controls (p = 0.024). Women with Endoglin mutations lived a median of 9.3 years shorter than those without (p = 0.04). Seven/123 (5%) of deaths were HHT related with a median age at death of 61.5 years (IQ range 54.4-67.7 years)., Conclusion: Our study showed that the life expectancy of largely unscreened HHT patients was lower than people without HHT. Female patients with Endoglin mutations were most strikingly at risk of premature death from complications. These results emphasize the importance of referring patients with HHT for screening of organ involvement and timely intervention to prevent complications.

Objective: To determine the role of Gja5 that encodes for the gap junction protein connexin40 in the generation of arteriovenous malformations in the hereditary hemorrhagic telangiectasia type 2 (HHT2) mouse model., Approach and Results: We identified GJA5 as a target gene of the bone morphogenetic protein-9/activin receptor-like kinase 1 signaling pathway in human aortic endothelial cells and importantly found that connexin40 levels were particularly low in a small group of patients with HHT2. We next took advantage of the Acvrl1(+/-) mutant mice that develop lesions similar to those in patients with HHT2 and generated Acvrl1(+/-); Gja5(EGFP/+) mice. Gja5 haploinsufficiency led to vasodilation of the arteries and rarefaction of the capillary bed in Acvrl1(+/-) mice. At the molecular level, we found that reduced Gja5 in Acvrl1(+/-) mice stimulated the production of reactive oxygen species, an important mediator of vessel remodeling. To normalize the altered hemodynamic forces in Acvrl1(+/-); Gja5(EGFP/+) mice, capillaries formed transient arteriovenous shunts that could develop into large malformations when exposed to environmental insults., Conclusions: We identified GJA5 as a potential modifier gene for HHT2. Our findings demonstrate that Acvrl1 haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events-heterozygosity, loss of heterozygosity, and angiogenic stimulation-are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development., (© 2016 American Heart Association, Inc.)

Background: Patients with a hereditary vascular disorder called Rendu-Osler-Weber syndrome (Hereditary Haemorrhagic Telangiectasia, HHT) haemorrhage easily due to weak-walled vessels. Haemorrhage in lungs or brain can be fatal but patients suffer most from chronic and prolonged nosebleeds (epistaxis), the frequency and intensity of which increases with age. Several years ago, it was discovered serendipitously that the drug Thalidomide had beneficial effects on the disease symptoms in several of a small group of HHT patients: epistaxis and the incidence of anaemia were reduced and patients required fewer blood transfusions. In addition, they reported a better quality of life. However, Thalidomide has significant negative side effects, including neuropathy and fatigue., Methods: We followed up all HHT patients in the Netherlands who had been taking Thalidomide at the time the original study was completed to find out (i) how many had continued taking Thalidomide and for how long (ii) the nature and severity of any side-effects and (iii) whether side-effects had influenced their decision to continue taking Thalidomide., Results: Only a minority of patients had continued taking the drug despite its beneficial effects on their symptoms and that the side effects were the primary reason to stop., Conclusion: Despite symptom reduction, alternative treatments are still necessary for epistaxis in HHT patients and a large-scale clinical trial is not justified although incidental use in the most severely affected patients can be considered.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain, liver and lungs. Pulmonary hypertension (PH) is increasingly recognised as a severe complication of HHT. PH may be categorised into two distinct types in patients with HHT. Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations. Less frequently, the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension. Differentiation between both forms of PH by right heart catheterisation is essential, since both entities are associated with severe morbidity and mortality with different treatment options. Therefore all HHT patients should be referred to an HHT centre.