Cardiac resynchronization therapy in adults with structural congenital heart disease and chronic heart failure.

AIMS: Evidence for CRT in adults with congenital heart disease (ACHD) and chronic heart failure is limited, with recommendations for its use extrapolated from the population with structurally normal hearts. This retrospective observational study investigates the efficacy of CRT in this heterogenous group, discussing factors predicting response to CRT. METHODS: Twenty-seven patients with structural ACHD who underwent CRT insertion or upgrade at a tertiary center in the United Kingdom were retrospectively studied. The primary outcome measure was clinical response to CRT, defined as improvement of NYHA class and/or improvement in systemic ventricular ejection fraction by one category. Secondary outcomes included change in QRS duration and adverse events. RESULTS: Thirty-seven percent of patients had a systemic right ventricle (sRV). RBBB was the commonest baseline QRS morphology (40.7%) despite this being an unfavorable characteristic for CRT. Overall, positive response to CRT was demonstrated in 18 patients (66.7%). NYHA class improved in 55.5% following CRT (p = .001) and 40.7% showed improvement in systemic ventricular ejection fraction (p = .118). There were no baseline characteristics that predicted response to CRT, and electrocardiographic measures such as QRS shortening post-CRT was not associated with positive response. Good response rates (60.0%) were demonstrated in those with sRV. CONCLUSION: CRT is efficacious in structural ACHD including in those who do not meet conventional criteria. Extrapolation of recommendations from adults with structurally normal hearts may be inappropriate. Future research should focus on improving patient selection for CRT, for example using techniques to better quantify mechanical dysynchrony and intra-procedural electrical activation mapping in these complex patients.

Pregnancy outcomes in women following the Ross procedure.

INTRODUCTION: The Ross procedure, where a pulmonary autograft (neoaorta) replaces the aortic valve, has excellent long-term outcomes in patients with congenital aortic valve disease. However, there are reports of neoaortic dilatation and dissection. An increasing number of women are wishing to become pregnant following the Ross procedure, but little is known about the occurrence and risks of neoaortic dilatation and complications in pregnancy. We investigated neoaorta function and outcomes in pregnancy following the Ross procedure. METHODS: This retrospective study investigated women post-Ross procedure at a tertiary ACHD unit between 1997 and 2021. Imaging evaluated neoaortic root dimensions and regurgitation pre-, and post- pregnancy, compared with matched non-pregnant controls. Primary endpoints were change in neoaortic dimensions, degree of regurgitation and adverse maternal outcomes. RESULTS: Nineteen pregnancies in 12 women were included. The mean change in neoaortic root diameter post-pregnancy was 1.8 mm (SD 3.4) (p = 0.017). There was no significant change in neoaortic dimensions in matched controls during follow-up. There were no cases of dissection, arrhythmia, acute coronary syndrome, or maternal mortality. Three deliveries were pre-term, including one emergency Caesarean section due to maternal cardiac decompensation, requiring aortic root replacement post-partum but there were no neonatal deaths. CONCLUSIONS: Pregnancy following the Ross procedure is associated with neoaortic dilatation, and pregnancy is generally well tolerated. Although adverse maternal outcomes are uncommon, there are still rare cases of cardiac complications in and around the time of pregnancy. These findings emphasise the need for accessible pre-pregnancy counselling, risk stratification and careful surveillance through pregnancy by specialist cardio-obstetric multi-disciplinary teams.

Factors and framing effects in support for net zero policies in the United Kingdom.

Achieving ambitious carbon reduction targets requires transformative change to society, with behaviour change playing an important role. Climate change mitigation ('net zero') policies are needed to accelerate and support such behaviour change. This study examined factors and framing effects in public support for net zero policies in the United Kingdom (UK), making use of a large probability sample (ntotal = 5,665) survey conducted in August 2021. It found that net zero policies are widely supported, with only taxes on red meat and dairy products being supported by less than half of the UK public. Climate worry and perceived fairness were the strongest and most consistent predictors of policy support for net zero policies. The results further suggest that support for net zero policies can be increased by emphasising the co-benefits of the policies, in particular where they are beneficial for health. However, the framing effects were very small. In contrast, public support for net zero policies is lower when potential lifestyle and financial costs are mentioned. This suggests that perceived fairness of the distribution of costs and lifestyle implications of policies are crucial for building and maintaining support for net zero.

Comparison of left ventricular with right ventricular rapid pacing on tamponade during TAVI.

BACKGROUND: Small studies have suggested left ventricular (LV) rapid pacing has similar safety and efficacy to conventional right ventricular (RV) rapid pacing in transcatheter aortic valve implantation (TAVI). However, there are limited data on the comparative rates of tamponade. The study compared the rate of cardiac tamponade between LV and RV-pacing during TAVI. METHODS: Between 2008 and 2021, 1226 consecutive patients undergoing transfemoral or transaxillary TAVI were included. 470(38.3%) patients had TAVI deployment with RV-pacing and 756(61.7%) with LV-pacing. The primary outcome was the frequency and cause of cardiac tamponade. Secondary outcomes included efficacy, procedure duration and crossover rates. RESULTS: There was a trend to less tamponade with LV-pacing, which did not reach statistical significance [11(2.3%) vs 11(1.5%);P = 0.27]. There was no significant difference in the frequency of tamponade due to annular tear [4(0.9%) vs 9(1.2%);P = 0.59] or LV free-wall perforation [1(0.2%) vs 2(0.3%);P = 0.86]. The frequency of tamponade due to RV perforation was significantly lower in the LV-pacing group [0 vs 6(2.3%);P < 0.005)]. Two patients with tamponade due to RV perforation required emergency sternotomy of whom one died. Deployment success was similar (99% vs 99.6%;P=NS). Procedure duration was shorter with LV-pacing (70 vs 80 mins;P < 0.005). Crossover to RV-pacing was low (0.9%). There were no embolizations caused by loss-of-capture in either group. CONCLUSIONS: LV-pacing appears equally efficacious and is associated with a lower risk of tamponade due to RV perforation caused by the temporary pacing wire. LV-pacing was not associated with an increased risk of tamponade due to LV free-wall perforation.

The impact of the COVID-19 pandemic on application of European Society of Cardiology (ESC) guidelines for exercise in adults with CHD: a data-based questionnaire.

INTRODUCTION: Regular physical activity is safe and effective therapy for adults with CHD and is recommended by European Society of Cardiology guidelines. The COVID-19 pandemic poses enormous challenges to healthcare teams and patients when ensuring guideline compliance. We explored the implications of COVID-19 on physical activity levels in adult CHD patients. MATERIALS AND METHODS: A data-based questionnaire was distributed to adult CHD patients at a regional tertiary centre from October to November 2020. RESULTS: Prior to the COVID-19 pandemic, 96 (79.3%) of 125 respondents reported participating in regular physical activity, with 66 (52.8%) meeting target levels (moderate physical activity for at least 150 minutes per week). Commonest motivations for physical activity were general fitness (53.6%), weight loss (36.0%), and mental health benefits (30.4%). During the pandemic, the proportion that met target levels significantly decreased from 52.8% to 40.8% (p = 0.03). The commonest reason was fear of COVID-19 (28.0%), followed by loss of motivation (23.2%) and gym/fitness centre closure (15.2%). DISCUSSION: The COVID-19 pandemic has negatively impacted exercise levels of adult CHD patients. Most do not meet recommended physical activity levels, mainly attributable to fear of COVID-19. Even before the pandemic, only half of respondents met physical activity guidelines. Availability of online classes can positively impact exercise levels so could enhance guideline compliance. This insight into health perceptions and behaviours of adult CHD patients may help develop quality improvement initiatives to improve physical activity levels in this population.

Differential sulfation remodelling of heparan sulfate by extracellular 6-O-sulfatases regulates fibroblast growth factor-induced boundary formation by glial cells: implications for glial cell transplantation.

Previously, it has been shown that rat Schwann cells (SCs), but not olfactory ensheathing cells (OECs), form a boundary with astrocytes, due to a SC-specific secreted factor. Here, we identify highly sulfated heparan sulfates (HSs) and fibroblast growth factors (FGFs) 1 and 9 as possible determinants of boundary formation induced by rat SCs. Disaccharide analysis of HS in SC-conditioned and rat OEC-conditioned media showed that SCs secrete more highly sulfated HS than OECs. The dependence of the boundary-forming activity on high levels of sulfation was confirmed using a panel of semisynthetic modified heparins with variable levels of sulfation. Furthermore, extracellular HS 6-O-endosulfatase enzymes, Sulf 1 and Sulf 2, were expressed at a significantly lower level by SCs compared with OECs, and siRNA reduction of Sulfs in OECs was, in itself, sufficient to induce boundary formation. This demonstrates a key role for remodelling (reduction) of HS 6-O-sulfation by OECs, compared with SCs, to suppress boundary formation. Furthermore, specific anti-FGF1 and anti-FGF9 antibodies disrupted SC-astrocyte boundary formation, supporting a role for an HS sulfation-dependent FGF signaling mechanism via FGF receptors on astrocytes. We propose a model in which FGF1 and FGF9 signaling is differentially modulated by patterns of glial cell HS sulfation, dependent on Sulf 1 and Sulf 2 expression, to control FGF receptor 3-IIIb-mediated astrocytic responses. Moreover, these data suggest manipulation of HS sulfation after CNS injury as a potential novel approach for therapeutic intervention in CNS repair.

Structure and epitope distribution of heparan sulfate is disrupted in experimental lung hypoplasia: a glycobiological epigenetic cause for malformation?

BACKGROUND: Heparan sulfate (HS) is present on the surface of virtually all mammalian cells and is a major component of the extracellular matrix (ECM), where it plays a pivotal role in cell-cell and cell-matrix cross-talk through its large interactome. Disruption of HS biosynthesis in mice results in neonatal death as a consequence of malformed lungs, indicating that HS is crucial for airway morphogenesis. Neonatal mortality (~50%) in newborns with congenital diaphragmatic hernia (CDH) is principally associated with lung hypoplasia and pulmonary hypertension. Given the importance of HS for lung morphogenesis, we investigated developmental changes in HS structure in normal and hypoplastic lungs using the nitrofen rat model of CDH and semi-synthetic bacteriophage ('phage) display antibodies, which identify distinct HS structures. RESULTS: The pulmonary pattern of elaborated HS structures is developmentally regulated. For example, the HS4E4V epitope is highly expressed in sub-epithelial mesenchyme of E15.5 - E17.5 lungs and at a lower level in more distal mesenchyme. However, by E19.5, this epitope is expressed similarly throughout the lung mesenchyme.We also reveal abnormalities in HS fine structure and spatiotemporal distribution of HS epitopes in hypoplastic CDH lungs. These changes involve structures recognised by key growth factors, FGF2 and FGF9. For example, the EV3C3V epitope, which was abnormally distributed in the mesenchyme of hypoplastic lungs, is recognised by FGF2. CONCLUSIONS: The observed spatiotemporal changes in HS structure during normal lung development will likely reflect altered activities of many HS-binding proteins regulating lung morphogenesis. Abnormalities in HS structure and distribution in hypoplastic lungs can be expected to perturb HS:protein interactions, ECM microenvironments and crucial epithelial-mesenchyme communication, which may contribute to lung dysmorphogenesis. Indeed, a number of epitopes correlate with structures recognised by FGFs, suggesting a functional consequence of the observed changes in HS in these lungs. These results identify a novel, significant molecular defect in hypoplastic lungs and reveals HS as a potential contributor to hypoplastic lung development in CDH. Finally, these results afford the prospect that HS-mimetic therapeutics could repair defective signalling in hypoplastic lungs, improve lung growth, and reduce CDH mortality.

Heparan sulfate in lung morphogenesis: The elephant in the room.

Heparan sulfate (HS) is a structurally complex polysaccharide located on the cell surface and in the extracellular matrix, where it participates in numerous biological processes through interactions with a vast number of regulatory proteins such as growth factors and morphogens. HS is crucial for lung development; disruption of HS synthesis in flies and mice results in a major aberration of airway branching, and in mice, it results in neonatal death as a consequence of malformed lungs and respiratory distress. Epithelial-mesenchymal interactions governing lung morphogenesis are directed by various diffusible proteins, many of which bind to, and are regulated by HS, including fibroblast growth factors, sonic hedgehog, and bone morphogenetic proteins. The majority of research into the molecular mechanisms underlying defective lung morphogenesis and pulmonary pathologies, such as bronchopulmonary dysplasia and pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH), has focused on abnormal protein expression. The potential contribution of HS to abnormalities of lung development has yet to be explored to any significant extent, which is somewhat surprising given the abnormal lung phenotype exhibited by mutant mice synthesizing abnormal HS. This review summarizes our current understanding of the role of HS and HS-binding proteins in lung morphogenesis and will present in vitro and in vivo evidence for the fundamental importance of HS in airway development. Finally, we will discuss the future possibility of HS-based therapeutics for ameliorating insufficient lung growth associated with lung diseases such as CDH.

Heparan sulfate phage display antibodies identify distinct epitopes with complex binding characteristics: insights into protein binding specificities.

Heparan sulfate (HS) binds and modulates the transport and activity of a large repertoire of regulatory proteins. The HS phage display antibodies are powerful tools for the analysis of native HS structure in situ; however, their epitopes are not well defined. Analysis of the binding specificities of a set of HS antibodies by competitive binding assays with well defined chemically modified heparins demonstrates that O-sulfates are essential for binding; however, increasing sulfation does not necessarily correlate with increased antibody reactivity. IC50 values for competition with double modified heparins were not predictable from IC50 values with corresponding singly modified heparins. Binding assays and immunohistochemistry revealed that individual antibodies recognize distinct epitopes and that these are not single linear sequences but families of structurally similar motifs in which subtle variations in sulfation and conformation modify the affinity of interaction. Modeling of the antibodies demonstrates that they possess highly basic CDR3 and surrounding surfaces, presenting a number of possible orientations for HS binding. Unexpectedly, there are significant differences between the existence of epitopes in tissue sections and observed in vitro in dot blotted tissue extracts, demonstrating that in vitro specificity does not necessarily correlate with specificity in situ/vivo. The epitopes are therefore more complex than previously considered. Overall, these data have significance for structure-activity relationships of HS, because the model of one antibody recognizing multiple HS structures and the influence of other in situ HS-binding proteins on epitope availability are likely to reflect the selectivity of many HS-protein interactions in vivo.

Ergonomics and cytotechnologists: reported musculoskeletal discomfort.

Analysis of this survey of 244 responding cytotechnologists shows that a high percentage still suffer from musculoskeletal disorders commonly associated with poor ergonomic design in the workplace, despite the variety of ergonomically designed microscopes that have been introduced into the market. Although Kalavar and Hunting surveyed a small group of cytotechnologists in the Washington, DC, area in 1996, no broad-based study has focused specifically on these professionals. The landmark study of microscope ergonomics, published by Soderberg in 1980, documented widespread musculoskeletal complaints in the electronics industry. This article identifies and discusses the types of musculoskeletal discomforts experienced by cytotechnologists. We propose that both practicing and student cytotechnologists receive training in ergonomic principles and appropriate interventions, such as improved work practices, proper ergonomic aids, well-designed workstations, and ergonomically designed equipment. More than 85% of respondents reported some musculoskeletal discomfort. Among the symptoms presented are headache, neck pain and stiffness, pain of the lower and upper back, and upper-extremity discomfort. Neurological symptoms, such as numbness, tingling, and/or pain in the hand and fingers, are often associated with repetitive motion. More than one-third reported numbness, tingling, and/or pain in the left-hand fingers, usually used for the fine-focus control knob. Almost one-half of respondents reported such symptoms for the right hand and fingers, normally used to manipulate the mechanical stage controls. Only 9% of the respondents were left-handed. Most (91%) were right handed. Although just over one-third (34.4%) of respondents worked for an employer with an ergonomics program, ergonomic assessments had been performed for only about one-half (17.6%) of these. In addition, approximately 10% of respondents indicated that ergonomics assessments had been performed on their workstations, even though the employer did not have an ergonomics program. Because of the high prevalence of reported symptoms, we recommend that all cytologists be trained in basic ergonomic principles and the proper use of ergonomic aids. These interventions should reduce the prevalence of musculoskeletal discomfort in medical microscopists.