Explore the vast range of titles available.

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.

Radiation therapy is a staple approach for cancer treatment, whereas radioresistance of cancer cells remains a substantial clinical problem. In response to ionizing radiation (IR) induced DNA damage, cancer cells can sustain/activate pro-survival signaling pathways, leading to apoptotic resistance and induction of cell cycle checkpoint/DNA repair. Previous studies show that Rac1 GTPase is overexpressed/hyperactivated in breast cancer cells and is associated with poor prognosis. Studies from our laboratory reveal that Rac1 activity is necessary for G2/M checkpoint activation and cell survival in response to IR exposure of breast and pancreatic cancer cells. In this study, we investigated the effect of Rac1 on the survival of breast cancer cells treated with hyper-fractionated radiation (HFR), which is used clinically for cancer treatment. Results in this report indicate that Rac1 protein expression is increased in the breast cancer cells that survived HFR compared with parental cells. Furthermore, this increase of Rac1 is associated with enhanced activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) signaling pathways and increased levels of anti-apoptotic protein Bcl-xL and Mcl-1, which are downstream targets of ERK1/2 and NF-κB signaling pathways. Using Rac1-specific inhibitor and dominant-negative mutant N17Rac1, here we demonstrate that Rac1 inhibition decreases the phosphorylation of ERK1/2 and inhibitory κBα (IκBα), as well as the levels of Bcl-xL and Mcl-1 protein in the HFR-selected breast cancer cells. Moreover, inhibition of Rac1 using either small molecule inhibitor or dominant-negative N17Rac1 abrogates clonogenic survival of HFR-selected breast cancer cells and decreases the level of intact poly(ADP-ribose) polymerase, which is indicative of apoptosis induction. Collectively, results in this report suggest that Rac1 signaling is essential for the survival of breast cancer cells subjected to HFR and implicate Rac1 in radioresistance of breast cancer cells. These studies also provide the basis to explore Rac1 as a therapeutic target for radioresistant breast cancer cells.

Right ventricular (RV) ejection fraction (EF) by cardiac magnetic resonance (CMR) correlates to outcome in precapillary pulmonary hypertension (pPH) patients, but is insensitive to early changes. Strain might provide incremental information. In this study, we compare right atrial (RA) and RV strain in pPH patients to healthy controls, and evaluate the prognostic value of strain in pPH. In this cross-sectional study, 45 pPH patients and 20 healthy controls underwent CMR, and feature-tracking derived RA and RV strain were evaluated. pPH patients had impaired RA reservoir and conduit strain, and RV longitudinal strain (LS), compared to healthy controls. In pPH patients with preserved RVEF (≥ 50%, n = 18), RA reservoir (35% ± 9 vs. 41% ± 6, p = 0.02) and conduit strain (16% ± 8 vs. 23% ± 5, p = 0.004), and RV–LS (−25% ± 4 vs. −31% ± 4, p < 0.001) remained impaired, compared to healthy controls. The association of strain with the primary endpoint (combination of all-cause death, lung transplantation, and heart failure hospitalization) was evaluated using a multivariable Cox regression model. RV–LS (HR 1.18, 95%–CI 1.04–1.34, p = 0.01) and RA strain (reservoir: HR 0.87, 95%–CI 0.80–0.94, p = 0.001; conduit: HR 0.85, 95%–CI 0.75–0.97, p = 0.02, booster: HR 0.81, 95%-CI 0.71–0.92, p = 0.001) were independent predictors of outcome, beyond clinical and imaging features. In conclusion, pPH patients have impaired RA strain and RV–LS, even when RVEF is preserved. In addition, RA strain and RV–LS were independent predictors of adverse prognosis. These results emphasize the incremental value of RA and RV strain analyses, to detect alterations in RV function, even before RVEF declines.

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.

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.

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.

Purpose. The Occlutech Figulla occluder has been proven safe and effective at midterm follow-up after percutaneous atrial septal defect (ASD) closure. We describe the safety and efficacy at long-term follow-up in adults. Methods. All consecutive adult patients that underwent ASD closure between 2008 and 2015 were included. All complications were registered. Residual left-to-right shunt (LRS) was diagnosed using color-Doppler transthoracic echocardiography (TTE). Right-to-left shunting was diagnosed using contrast TTE. Successful closure was defined as no LRS at follow-up. Results. In total, 166 patients (mean age 56.7 ± 16.1 years; 62% female) underwent percutaneous ASD closure using the Occlutech Flex I (70%) or Flex II (30%) device (diameter 24 mm; range 10–40 mm) under general anaesthesia and transoesophageal echocardiographic guidance. Long-term follow-up data were available for 144 patients (87%) with a mean follow-up of 5.9 ± 2.6 years, a total of 814 patient-years. During hospitalization, device embolization occurred in three patients (1.8%) with successful extraction in all. During the long-term follow-up, 15 patients (9.8%) suffered new-onset atrial fibrillation and stroke occurred in 2.1%. There was no residual LRS at 12-month follow-up. No device embolization occurred during the long-term follow-up. Conclusion. Percutaneous ASD closure using the Occlutech device appears to be safe at long-term follow-up with a high successful closure rate at one year.

Background The relative new subspecialty ‘cardio-oncology’ was established to meet the growing demand for an interdisciplinary approach to the management of cancer therapy–related cardiovascular adverse events. In recent years, specialised cardio-oncology services have been implemented worldwide, which all strive to improve the cardiovascular health of cancer patients. However, limited data are currently available on the outcomes and experiences of these specialised services, and optimal strategies for cardio-oncological care have not been established. Aim The ONCOR registry has been created for prospective data collection and evaluation of cardio-oncological care in daily practice. Methods Dutch hospitals using a standardised cardio-oncology care pathway are included in this national, multicentre, observational cohort study. All patients visiting these cardio-oncology services are eligible for study inclusion. Data collection at baseline consists of the (planned) cancer treatment and the cardiovascular risk profile, which are used to estimate the cardiotoxic risk. Information regarding invasive and noninvasive tests is collected during the time patients receive cardio-oncological care. Outcome data consist of the incidence of cardiovascular complications and major adverse cardiac events, and the impact of these events on the oncological treatment. Discussion Outcomes of the ONCOR registry may aid in gaining more insight into the incidence of cancer therapy–related cardiovascular complications. The registry facilitates research on mechanisms of cardiovascular complications and on diagnostic, prognostic and therapeutic strategies. In addition, it provides a platform for future (interventional) studies. Centres with cardio-oncology services that are interested in contributing to the ONCOR registry are hereby invited to participate.

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 Assessing haemodynamic congestion based on filling pressures instead of clinical congestion can be a way to further improve quality of life (QoL) and clinical outcome by intervening before symptoms or weight gain occur in heart failure (HF) patients. The clinical efficacy of remote monitoring of pulmonary artery (PA) pressures (CardioMEMS; Abbott Inc., Atlanta, GA, USA) has been demonstrated in the USA. Currently, the PA sensor is not reimbursed in the European Union as its benefit when applied in addition to standard HF care is unknown in Western European countries, including the Netherlands. Aims To demonstrate the efficacy and cost-effectiveness of haemodynamic PA monitoring in addition to contemporary standard HF care in a high-quality Western European health care system. Methods The current study is a prospective, multi-centre, randomised clinical trial in 340 patients with chronic HF (New York Heart Association functional class III) randomised to HF care including remote monitoring with the CardioMEMS PA sensor or standard HF care alone. Eligible patients have at least one hospitalisation for HF in 12 months before enrolment and will be randomised in a 1:1 ratio. Minimum follow-up will be 1 year. The primary endpoint is the change in QoL as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Secondary endpoints are the number of HF hospital admissions and changes in health status assessed by EQ-5D-5L questionnaire including health care utilisation and formal cost-effectiveness analysis. Conclusion The MONITOR HF trial will evaluate the efficacy and cost-effectiveness of haemodynamic monitoring by CardioMEMS in addition to standard HF care in patients with chronic HF. Clinical Trial Registration number NTR7672.