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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.

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.

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.

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.

Several disease related factors of pulmonary hypertension (PH) can negatively impact the nutritional status, leading to an increased risk of malnutrition. However, there are no studies on the best method for nutritional screening in PH patients. Therefore, the aim of this study was to determine the diagnostic accuracy of two screening tools: the Malnutrition Universal Screening Tool (MUST) and the Mini Nutritional Assessment Short‐Form (MNA‐SF). This cross‐sectional single center study included PH outpatients. Cut‐off values MUST ≥ 1 and MNA‐SF ≤ 11 were used for state of (risk of) malnutrition. The diagnostic criteria of the Global Leadership Initiative on Malnutrition (GLIM) were used as reference for diagnosing malnutrition. Diagnostic accuracy was determined by sensitivity, specificity, predictive positive value, negative predictive value, Cohen's Kappa‐ value (K) and area under the curve. Out of the 103 PH patients (age 67 years (SD 11.5), 66% female), 27% were malnourished according to the GLIM criteria. Both MUST and MNA‐SF had an insufficient sensitivity (60.7% [CI: 41%–97%] vs. 64.3% [CI: 44%–81%]). The MUST had a specificity of 100% [CI: 95%–100%], PPV 100% [CI:94%–100%] and NPV 87.2% [CI:79%–93%]. The specificity of the MNA‐SF was 81.3% [CI:70%–89%], PPV 56.3% [CI: 39%–73%] and NPV 85.9% [CI: 77%–93%]. The MUST had a higher K‐value 0.692 and AUC (0.804) compared to the K‐value 0.437 and AUC (0.728) of the MNA‐SF. This study indicated that both MUST and MNA‐SF are inaccurate to detect (risk of) malnutrition in PH outpatients. Future studies are needed to strive for a more sensitive screening tool.

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-β/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.

In patients with chronic thromboembolic pulmonary hypertension (CTEPH) who undergo balloon pulmonary angioplasty (BPA), pretreatment with PH‐targeted medical therapy may be beneficial to improve clinical parameters and pulmonary hemodynamics. This study aims to describe clinical results of PH‐targeted therapy prior to BPA. All consecutive patients with CTEPH who underwent BPA treatment were selected from our CTEPH database. Medical treatment strategy, clinical parameters, and pulmonary hemodynamics at time of diagnosis and at the first BPA were analyzed. In total 92 CTEPH patients who started BPA treatment (64.1% women; 60.4 ± 14.1 years of age; 62.0% NYHA FC III/IV) were included. Most patients received dual oral PH‐targeted medical therapy (68.5%) prior to BPA. Between diagnosis and first BPA (median time 13.9 [7.5–30.7] months) significant improvements were observed in patients treated with PH‐targeted medical therapy for both clinical (6MWD: +28.2 m [5.1–51.3], log NTproBNP: −0.4 pg/ml [−0.8 to −0.1]) as well as pulmonary hemodynamic parameters (mPAP: −6.5 mmHg [−8.5 to −4.5], CO: +0.6 L/min [0.2–1.0] and PVR: −2.8 WU [−3.5 to −2.1]). The overall complication rate per BPA (out of a total of 441 procedures) was 15.0% for patients on monotherapy and 14.9% for those on dual/triple PH‐targeted medical therapy. No severe complications occurred. In conclusion, pretreatment with PH‐targeted medical therapy prior to BPA results in an improvement in clinical‐ and pulmonary hemodynamic parameters.

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 Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. Methods To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. Results Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30–84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban ( n  = 15), Rivaroxaban ( n  = 14), and Dabigatran ( n  = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. Conclusions Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomal dominant disorder characterized by an aberrant vascular development. The resulting vascular lesions range from smaller mucocutaneous telangiectases to large visceral arteriovenous malformations, especially in the skin, lung, gastrointestinal tract and the brain. Mutations in the genes encoding endoglin (ENG, chromosome 9q34) and activin A receptor type-like kinase 1 (ALK-1, also named ACVRL1, chromosome 12q13) are associated with HHT1 and HHT2, respectively. We report here on the genetic and molecular heterogeneity found in the HHT population in the Netherlands. Probands of 104 apparently unrelated families were studied and we performed sequence analysis on both the ENG gene and ALK-1 gene. In most of the probands, we found a mutation in one of the two genes: 53% in the ENG gene and 40% in the ALK-1 gene. In 7% of the families no ENG or ALK1 mutation was found. The mutations detected were deletions, insertions, nonsense, missense and splice site mutations. The majority were novel mutations.