Search
Showing 361–380 of 2058 publications.
-
Galougahi, Keyvan Karimi; Soukas, Peter A.; Kolski, Brian C.; Tayal, Raj; Parikh, Sahil A.; Armstrong, Ehrin J.; Petrossian, George A.; Kaki, Amir K.; Rosenfield, Kenneth A.; Gray, William A.; Ali, Ziad A.Intravascular lithotripsy (IVL) is a new technique for treatment of severely calcified lesions that uses acoustic shockwaves in a balloon-based system to induce fracture in calcific plaque, facilitating luminal gain and vessel expansion. In this review, we provide a concise summary of the available data and clinical experience of IVL in various peripheral vascular beds, including facilitating vascular access for large-bore devices. We discuss the physics and mode of action of IVL in modifying calcified plaques, include several illustrative examples of utility of IVL in peripheral interventions, and discuss the future directions for adoption of the technique in peripheral interventions. 2021
-
Weightman, William M.; Gibbs, Neville M.; Pavey, Warren A.; Larbalestier, Robert I.; Newman, Mark A.J.; Sheminant, Matthew R.; Matzelle, Shannon A.Background: There is some interest in long-term survival after various cardiac surgical strategies, including off-pump versus on-pump coronary artery surgery (CAG), mitral valve (MV) repair versus replacement, and aortic valve (AV) bioprosthetic versus mechanical replacement. Methods: We studied patients older than 49 years of age, recording risk factors and surgical details at the time of surgery. We classified procedures as: MV surgery with or without concurrent grafts or valves; AV surgery with or without concurrent CAG; or isolated CAG. Follow-up was through the state death register and state-wide hospital attendance records. Risk-adjusted survival was estimated using Cox proportional hazards. Observed survival was compared to the expected age- and sex- matched population survival. Results: During a median follow-up of 14.8 years 5,807 of 11,718 patients died. The difference between observed and expected survival varied between 3.4 years for AV surgery and 9.6 years for females undergoing MV surgery. The risk-adjusted mortality hazard rate after off-pump CAG was 0.93 (95% CI 0.81.0, p=0.84), MV repair 0.67 (95% CI 0.60.8, p<0.0001), MV bioprosthesis 0.82 (95% CI 0.81 (0.61.0, p=0.11) and bioprosthetic AV replacement 1.02 (95% CI 0.91.2, p=0.82). Conclusions: Compared to the general population, cardiac surgical patients have a shorter than expected life expectancy. We observed a survival benefit of mitral valve repair over replacement. We did not observe significant survival differences between off-pump and on-pump CAG, nor between bioprosthetic and mechanical replacement. 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
-
Li, Desmond K.; Smith, Lauren E.; Rookyard, Alexander W.; Lingam, Shivanjali J.; Koay, Yen Chin; McEwen, Holly P.; Twigg, Stephen Morris; Don, Anthony Simon; OSullivan, John F.; Cordwell, Stuart James; White, Melanie YvonneThe incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a high-fat diet (HFD) and pancreatic ?-cell dysfunction from streptozotocin (STZ) to produce hyperglycaemia, peripheral insulin resistance, hyperlipidaemia and elevated fat mass to mimic the clinical features of T2D. Ex vivo cardiac function was assessed using Langendorff perfusion with systolic and diastolic contractile depression observed in T2D hearts. Cohorts representing untreated, individual HFD- or STZ-treatments and the combined HFD + STZ approach were used to generate ventricular samples (n = 9 per cohort) for sequential and integrated analysis of the proteome, lipidome and metabolome by liquid chromatography-tandem mass spectrometry. This study found that in T2D hearts, HFD treatment primed the metabolome, while STZ treatment was the major driver for changes in the proteome. Both treatments equally impacted the lipidome. Our data suggest that increases in ?-oxidation and early TCA cycle intermediates promoted rerouting via 2-oxaloacetate to glutamate, ?-aminobutyric acid and glutathione. Furthermore, we suggest that the T2D heart activates networks to redistribute excess acetyl-CoA towards ketogenesis and incomplete ?-oxidation through the formation of short-chain acylcarnitine species. Multi-omics provided a global and comprehensive molecular view of the diabetic heart, which distributes substrates and products from excess ?-oxidation, reduces metabolic flexibility and impairs capacity to restore high energy reservoirs needed to respond to and prevent subsequent acute cardiovascular events. 2021 Elsevier Ltd
-
Passman, Rod Stuart; Freedman, Ben Ben[No abstract available]
-
Wang, Haoqing Jerry; Zhou, Fang; Guo, Yuze; Ju, Lining ArnoldMechanobiology is an emerging field at the interface of biology and mechanics, investigating the roles of mechanical forces within biomolecules, organelles, cells, and tissues. As a highlight, the recent advances of micropipette-based aspiration assays and dynamic force spectroscopies such as biomembrane force probe (BFP) provide unprecedented mechanobiological insights with excellent live-cell compatibility. In their classic applications, these assays measure force-dependent ligandreceptor-binding kinetics, protein conformational changes, and cellular mechanical properties such as cortical tension and stiffness. In recent years, when combined with advanced microscopies in high spatial and temporal resolutions, these biomechanical nanotools enable characterization of receptor-mediated cell mechanosensing and subsequent organelle behaviors at single-cellular and molecular level. In this review, we summarize the latest developments of these assays for live-cell mechanobiology studies. We also provide perspectives on their future upgrades with multimodal integration and high-throughput capability. 2022, The Author(s).
-
Misra, Ashish K.; Rehan, Rajan; Lin, Alexander; Patel, Sanjay; Fisher, Edward A.Clonal expansion is a process that can drive pathogenesis in human diseases, with atherosclerosis being a prominent example. Despite advances in understanding the etiology of atherosclerosis, clonality studies of vascular cells remain in an early stage. Recently, several paradigm-shifting preclinical studies have identified clonal expansion of progenitor cells in the vasculature in response to atherosclerosis. This review provides an overview of cell clonality in atherosclerotic progression, focusing particularly on smooth muscle cells and macrophages. We discuss key findings from the latest research that give insight into the mechanisms by which clonal expansion of vascular cells contributes to disease pathology. The further probing of these mechanisms will provide innovative directions for future progress in the understanding and therapy of atherosclerosis and its associated cardiovascular diseases. 2021 Wolters Kluwer Health, Inc. All rights reserved.
-
Wang, Haoqing Jerry; Obeidy, Peyman; Wang, Zihao; Zhao, Yunduo Charles; Wang, Yao; Su, Qian Peter; Cox, Charles David; Ju, Lining ArnoldMechanical stimuli such as tension, compression, and shear stress play critical roles in the physiological functions of red blood cells (RBCs) and their homeostasis, ATP release, and rheological properties. Intracellular calcium (Ca2+) mobilization reflects RBC mechanosensing as they transverse the complex vasculature. Emerging studies have demonstrated the presence of mechanosensitive Ca2+ permeable ion channels and their function has been implicated in the regulation of RBC volume and deformability. However, how these mechanoreceptors trigger Ca2+ influx and subsequent cellular responses are still unclear. Here, we introduce a fluorescence-coupled micropipette aspiration assay to examine RBC mechanosensing at the single-cell level. To achieve a wide range of cell aspirations, we implemented and compared two negative pressure adjusting apparatuses: a homemade water manometer (?2.94 to 0mmH<inf>2</inf>O) and a pneumatic high-speed pressure clamp (?25 to 0mmHg). To visualize Ca2+ influx, RBCs were pre-loaded with an intensiometric probe Cal-520 AM, then imaged under a confocal microscope with concurrent bright-field and fluorescent imaging at acquisition rates of 10 frames per second. Remarkably, we observed the related changes in intracellular Ca2+ levels immediately after aspirating individual RBCs in a pressure-dependent manner. The RBC aspirated by the water manometer only displayed 1.1-fold increase in fluorescence intensity, whereas the RBC aspirated by the pneumatic clamp showed up to threefold increase. These results demonstrated the water manometer as a gentle tool for cell manipulation with minimal pre-activation, while the high-speed pneumatic clamp as a much stronger pressure actuator to examine cell mechanosensing directly. Together, this multimodal platform enables us to precisely control aspiration and membrane tension, and subsequently correlate this with intracellular calcium concentration dynamics in a robust and reproducible manner. 2022, The Author(s).
-
Ruan, Travis; Harney, Dylan James; Koay, Yen Chin; Loo, Lipin; Larance, Mark; Caron, LeslieSkeletal muscle weakness is linked to many adverse health outcomes. Current research to identify new drugs has often been inconclusive due to lack of adequate cellular models. We previously developed a scalable monolayer system to differentiate human embryonic stem cells (hESCs) into mature skeletal muscle cells (SkMCs) within 26 days without cell sorting or genetic manipulation. Here, building on our previous work, we show that differentiation and fusion of myotubes can be further enhanced using the anabolic factors testosterone (T) and follistatin (F) in combination with a cocktail of myokines (C). Importantly, combined TFC treatment significantly enhanced both the hESC-SkMC fusion index and the expression levels of various skeletal muscle markers, including the motor protein myosin heavy chain (MyHC). Transcriptomic and proteomic analysis revealed oxidative phosphorylation as the most up-regulated pathway, and a significantly higher level of ATP and increased mitochondrial mass were also observed in TFC-treated hESC-SkMCs, suggesting enhanced energy metabolism is coupled with improved muscle differentiation. This cellular model will be a powerful tool for studying in vitro myogenesis and for drug discovery pertaining to further enhancing muscle development or treating muscle diseases. 2022 by the authors. Licensee MDPI, Basel, Switzerland.
-
Chami, Jason; Nicholson, Calum; Strange, G. A.; Baker, David William; Cordina, Rachael Louise; Celermajer, David S.Background: Hospital discharge codes are relied upon for research, accounting/invoicing and health systems planning. Congenital heart disease (CHD), however, is uniquely difficult for non-cardiologists to code due to the rarity, variety and complexity of lesions. It is therefore important that the accuracy of hospital discharge codes is regularly checked to ensure that the prevalence and burden of CHD is being correctly estimated and recorded. Methods and results: We identified all inpatient admissions of adults with CHD to Royal Prince Alfred Hospital in Sydney, Australia from January 2018 to March 2021 (257 admissions, 106 unique patients). The associated discharge coding summaries were extracted and compared to the codes in the separately collected and audited Adult CHD database. Only a quarter of discharge coding summaries contained any diagnosis of CHD, and just one-tenth accurately recorded all appropriate CHD diagnoses. Patients with simple lesions were most likely to have a coded diagnosis of CHD, while those with moderate and complex lesions were much less likely. Moreover, patients admitted under a cardiovascular specialty were twice as likely to have a coded diagnosis of CHD, compared with those admitted under non-cardiovascular specialties (p ?= ?0.006). Overall, less than half of patients had any hospital-coded diagnosis of CHD in any admission over the three-year study period. Conclusions: Hospital discharge coding dramatically underreports CHD, especially for patients with moderate and severe CHD lesions and for admissions under non-cardiovascular specialties. This suggests that discharge coding-based estimates of the burden of CHD on hospitals and health systems may be substantially underestimated. 2022 The Authors
-
Stanton, Kelly M.; Liu, Hongjuan; Kienzle, Vivian J.; Bursill, C. A.; Bao, Shisan; Celermajer, David S.Background: Exercise is associated with a less atherogenic lipid profile; however, there is limited research on the effect of exercise on atherosclerotic plaque composition and markers of plaque stability. Methods: A total of 110 apolipoprotein (apo)E?/? mice were placed on a chow diet and randomly assigned to control or exercise for a period of 10 weeks, commencing either at 12 weeks of age (the early-stage atherosclerosis, EA group) or at 40 weeks of age (the late-stage atherosclerosis, LA group). At the end of the exercise period, blood was assayed for lipids. Histologic analysis of the aortic sinus was undertaken to assess plaque size and composition that includes macrophage content, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and 2). Results: A total of 103 mice (38 EA, 65 LA) completed the protocol. In the EA group, exercise reduced plasma total cholesterol (TC) (?16%), free cholesterol (?13%), triglyceride (TG) (?35%), and phospholipid (?27%) levels, when compared to sedentary control mice (p < 0.01). In the EA group, exercise also significantly reduced plaque stenosis (?25%, p < 0.01), and there were higher levels of elastin (3-fold increase, p < 0.0001) and collagen (11-fold increase, p < 0.0001) in plaques, compared to control mice. There was an increase in plaque MMP-2 content in the exercise group (13% increase, p < 0.05) but no significant difference in macrophage or MCP-1 content. In the LA group, exercise reduced plaque stenosis (?18%, p < 0.05), but there was no significant difference in plaque composition. There was no difference in macrophage, MCP-1, or MMP-2 content in the LA groups. TIMP-1 was lower with exercise in both the EA and LA groups (?59%, p < 0.01 and ?51%, p < 0.01 respectively); however, there was no difference in TIMP-2 levels. Conclusion: A 10-week exercise period reduces atherosclerotic plaque stenosis when commenced at both early- and late-stage atherosclerosis. Intervening earlier with exercise had a greater beneficial effect on lipids and plaque composition than when starting exercise at a later disease stage. 2022 Stanton, Liu, Kienzle, Bursill, Bao and Celermajer.
-
Stanton, Kelly M.; Kienzle, Vivian J.; Dinnes, Dana L.M.; Kotchetkov, Irina; Jessup, Wendy; Kritharides, Leonard; Celermajer, David S.; Rye, Kerry AnneBACKGROUND: Exercise is associated with a reduced risk of cardiovascular disease. Increased high-density lipoprotein cholesterol (HDL-C) levels are thought to contribute to these benefits, but much of the research in this area has been limited by lack of well-controlled subject selection and exercise interventions. We sought to study the effect of moderate and high-intensity exercise on HDL function, lipid/lipoprotein profile, and other cardiometabolic parameters in a homogeneous population where exercise, daily routine, sleep patterns, and living conditions were carefully controlled. METHODS AND RESULTS: Male Army recruits (n=115, age 220.3 years) completed a 12-week moderate-intensity exercise program. A subset of 51 subsequently completed a 15-week high-intensity exercise program. Fitness increased and body fat decreased after moderate-and high-intensity exercise (P<0.001). Moderate-intensity exercise increased HDL-C and apoli-poprotein A-I levels (6.6%, 11.6% respectively), and decreased low-density lipoprotein cholesterol and apolipoprotein B levels (7.2%, 4.9% respectively) (all P<0.01). HDL-C and apolipoprotein A-I levels further increased by 8.2% (P<0.001) and 6.3% (P<0.05) after high-intensity exercise. Moderate-intensity exercise increased ABCA-1 (ATP-binding cassette transporter A1) mediated cholesterol efflux by 13.5% (P<0.001), which was sustained after high-intensity exercise. In a selected subset the ability of HDLs to inhibit ICAM-1 (intercellular adhesion molecule-1) expression decreased after the high (P<0.001) but not the moderate-intensity exercise program. CONCLUSIONS: When controlling for exercise patterns, diet, and sleep, moderate-intensity exercise improved HDL function, lipid/lipoprotein profile, fitness, and body composition. A sequential moderate followed by high-intensity exercise program showed sustained or incremental benefits in these parameters. Improved HDL function may be part of the mechanism by which exercise reduces cardiovascular disease risk. 2022 The Authors.
-
Hong, Jun Ki; Mathur, Kavya; Ruhoff, Alexander M.; Akhavan, Behnam; Waterhouse, Anna; Neto, ChiaraTethered-liquid perfluorocarbon (TLP) coatings show promise for blood-contacting medical device applications to reduce blood adhesion and delay thrombosis. However, their fabrication and longevity under external fluid flow is not well characterized. A vapor phase silanization reaction leading to the formation of tethered-perfluorocarbon (TP) layers containing large bumpy aggregates, 300 200nm thick, on top of an underlying 35 15nm thick uniform coating is reported. The vapor phase method compares favorably to the well-established liquid phase deposition to reproducibly create slippery coatings on silicon and polystyrene with very low water sliding angles (2 1), without the need to control humidity conditions. The TP layer retains perfluorinated lubricants up to 20000 s1, using a cone-and-plate rheometer, with the higher viscosity lubricant perfluoroperhydrophenanthrene being more resistant to depletion than perfluorodecalin. TLP infused with either of the lubricants effectively reduces adhesion of fibrin from human whole blood relative to TP and control hydrophilic and hydrophobic surfaces. The combination of highly fluorinated TP coatings grafted from the vapor phase to create nanoscale structured surfaces infused with higher viscosity lubricant may be the most suitable combination for clinical applications of liquid-infused surfaces to reduce thrombosis in blood-contacting medical devices under flow. 2022 Wiley-VCH GmbH.
-
Zhao, Yunduo Charles; Wang, Haoqing Jerry; Wang, Yao; Lou, Jizhong; Ju, Lining ArnoldThe von Willebrand factor (VWF), by interacting with the circulatory system and platelets, harnesses hemodynamic forces to form hemostatic plugs or occlusive thrombi. The autoinhibitory modules (AIMs) flanking the VWF-A1 domain were found to contribute to its biomechanical activation. However, how AIM sequences regulate the VWF-A1 binding behavior is controversial and incompletely understood as their structures are currently unsolvable by crystallography. To address this, we first performed molecular dynamics simulations to predict the N-terminal AIM (N-AIM; residues Q1238-E1260) structure. Excitingly, we found that N-AIM could cooperate with C-AIM to form a joint Rotini-like structure, thereby partially autoinhibiting the VWF-A1-GPIb? interaction. Furthermore, we used biomembrane force probe (BFP) assays to experimentally demonstrate that the VWF-A1 containing long N-AIM sequence (1238-A1) exhibited catch-bond behavior as the force first decelerated (catch) and then accelerated (slip) the dissociation. Conversely, VWF-A1 with short N-AIM (1261-A1) displayed bi-variable behaviors with either catch (1261H-A1) or slip bonds (1261L-A1). Notably, such bi-variable transition happened at low temperatures or high pH levels, whereas Q1238-E1260 stabilized the 1238-A1 catch bond regardless of the environmental factors. The physiological study was complemented by platelet perfusion assays using microfluidics. Taken together, these studies provide new mechanobiology on how N-AIM serves as a mechano-regulator of VWF activity, which inspires future VWF-A1 dependent antithrombotic approaches. 2022 The Author(s).
-
Gao, Lan; Moodie, Marj L.; Freedman, Ben Ben; Lam, Christina; Tu, Hans T.H.; Swift, Corey; Ma, Szeho; Mok, Chung Tong Vincent; Sui, Yi; Sharpe, David M.; Ghia, Darshan K.; JANNES, J.; Davis, Stephen M.; Liu, Xinfeng; Yan, BernardBACKGROUND: The effectiveness of a nurse-led in-hospital monitoring protocol with mobile ECG (iECG) was investigated for detecting atrial fibrillation in patients post-ischemic stroke or post-transient ischemic attack. The study aimed to assess the cost-effectiveness of using iECG during the initial hospital stay compared with standard 24-hour Holter monitoring. METHODS AND RESULTS: A Markov microsimulation model was constructed to simulate the lifetime health outcomes and costs. The rate of atrial fibrillation detection in iECG and Holter monitoring during the in-hospital phase and characteristics of modeled population (ie, age, sex, CHA2DS2-VASc) were informed by patient-level data. Costs related to recurrent stroke, stroke management, medications (new oral anticoagulants), and rehabilitation were included. The cost-effectiveness analysis outcome was calculated as an incremental cost per quality-adjusted life-year gained. As results, monitoring patients with iECG post-stroke during the index hospitalization was associated with marginally higher costs (A$31 196) and greater benefits (6.70 quality-adjusted life-years) compared with 24-hour Holter surveillance (A$31 095 and 6.66 quality-adjusted life-years) over a 20-year time horizon, with an incremental cost-effectiveness ratio of $3013/ quality-adjusted life-years. Monitoring patients with iECG also contributed to lower recurrence of stroke and stroke-related deaths (140 recurrent strokes and 20 deaths avoided per 10 000 patients). The probabilistic sensitivity analyses suggested iECG is highly likely to be a cost-effective intervention (100% probability). CONCLUSIONS: A nurse-led iECG monitoring protocol during the acute hospital stay was found to improve the rate of atrial fibrillation detection and contributed to slightly increased costs and improved health outcomes. Using iECG to monitor patients post-stroke during initial hospitalization is recommended to complement routine care. 2022 The Authors.
-
Ozdemir, Denizhan; Galougahi, Keyvan Karimi; Petrossian, Gregory; Ezratty, Charlotte; Dominguez-Sulca, Dylan; Chowdhury, Elma; Scheiner, Jonathan; Thomas, Susan V.; Shlofmitz, Richard Alan; Ali, Ziad A.Purpose of Review: To provide a review of recent literature on the treatment of moderate-to-severe calcification in coronary and peripheral vasculature with intravascular lithotripsy (Shockwave Medical, Santa Clara, CA). Recent Findings: Moderate-to-severe calcific plaques constitute a significant proportion of lesions treated with transcatheter interventions in the coronary and peripheral vascular beds and portend lower procedural success rates, increased periprocedural major adverse events, and unfavorable long-term clinical outcomes compared to non-calcific plaques. Intravascular lithotripsy (IVL) is a new technique that uses acoustic shock waves in a balloon-based system to induce fracture in the calcium deposits to facilitate luminal gain and stent expansion. Summary: IVL demonstrated high procedural success and low complication rates in the management of moderate-to-severe calcification in coronary and peripheral vascular beds and led to large luminal gain by modification of calcific plaque as assessed by optical coherence tomography. Further studies will determine the role of IVL in an integrated, protocolized approach to the treatment of severely calcified plaques in the coronary and peripheral vascular beds. 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
-
Shi, Han; El Kazzi, Mary; Liu, Yuyang; Gao, Antony; Schroder, Angie L.; Vuong, Sally; Young, Pamela A.; Rayner, Benjamin Saul; van Vreden, Caryn; King, Nicholas J.C.; Witting, Paul KennethAim: Imaging mass cytometry (IMC) affords simultaneous immune-labelling/imaging of multiple antigens in the same tissue. Methods utilizing multiplex data beyond co-registration are lacking. This study developed and applied an innovative spatial analysis workflow for multiplex imaging data to IMC data determined from cardiac tissues and revealed the mechanism(s) of neutrophil-mediated post-myocardial-infarction damage. Methods: IMC produced multiplex images with various redox/inflammatory markers. The cardiac peri-infarct zone (PIZ) was determined to be up to 240m from the infarct border based on the presence of neutrophils. The tissue region beyond the infarct was defined as the remote area (RA). ImageJ was used to quantify the immunoreactivity. Functional assessments included infarct size, cell necro/apoptosis, total thiol assay and echocardiogram. Results: Expression of damage markers decreased in order from the infarct area to PIZ and then RA, reflecting the neutrophil density in the regions. Concentrically spaced shoreline contour analysis around the cardiac infarct extending into the PIZ showed that immunoreactivity for damage markers decreased linearly with increasing distance from the infarct, concomitant with a decreasing neutrophil-myeloperoxidase (MPO) gradient from the infarct to the PIZ. Stratifying by concentric bands around individual MPO+-signal identified that the immunoreactivity of haem-oxygenase-1 (HO-1) and phosphorylated-p38 mitogen-activated protein kinase (pP38) peaked near neutrophils. Furthermore, spatial dependence between neutrophils and markers of cardiac cellular damage was confirmed by nearest-neighbour distance analysis. Post-infarction tissue exhibited declined functional parameters that were associated with neutrophil migration from the infarct to PIZ. Conclusion: This image-based quantitative protocol revealed the spatial association and provided potential molecular pathways responsible for neutrophil-mediated damage post-infarction. 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.
-
Stewart, S.; Chan, Yih Kai; Playford, David A.; Strange, G. A.Objective We addressed the paucity of data describing the characteristics and consequences of incident aortic stenosis (AS). Methods Adults undergoing echocardiography with a native aortic valve (AV) and no AS were studied. Subsequent age-specific and sex-specific incidence of AS were derived from echocardiograms conducted a median of 2.8 years apart. Progressive AV dysfunction and individually linked mortality were examined per AS category. Results 49 449 men (53.9%, 60.915.8 years) and 42 229 women (61.616.9 years) with no initial evidence of AS were identified. Subsequently, 6293 (6.9%) developed AScomprising 5170 (5.6%), 636 (0.7%), 339 (0.4%) and 148 (0.2%) cases of mild, moderate, severe low-gradient and severe high-gradient AS, respectively. Age-adjusted incidence rates of all grades of AS were 17.5 cases per 1000 men/annum and 18.7 cases per 1000 women/annum: rising from ~5 to ~40 cases per 1000/annum in those aged <30 years vs >80 years. Median peak AV velocity increased by +0.57 (+0.36 to +0.80) m/s in mild AS compared with +2.75 (+2.40 to +3.19) m/s in severe high-gradient AS cases between first and last echocardiograms. During subsequent median 7.7 years follow-up, 24 577 of 91 678 cases (26.8%) died. Compared with no AS, the adjusted risk of all-cause mortality was 1.42-fold higher in mild AS, 1.92-fold higher in moderate AS, 1.95-fold higher in severe low-gradient AS and 2.27-fold higher in severe, high-gradient AS cases (all p<0.001). Conclusions New onset AS is a common finding among older patients followed up with echocardiography. Any grade of AS is associated with higher mortality, reinforcing the need for proactive vigilance. Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
-
Engler, Daniel; Hanson, Coral L.; Desteghe, Lien; Boriani, Giuseppe; Diederichsen, Sen Za; Freedman, Ben Ben; Pala, Elena; Potpara, Tatjana S.; Witt, Henning; Heidbuchel, H. P.; Neubeck, Lis; Schnabel, Renate B.Objectives Atrial fibrillation (AF) screening may increase early detection and reduce complications of AF. European, Australian and World Heart Federation guidelines recommend opportunistic screening, despite a current lack of clear evidence supporting a net benefit for systematic screening. Where screening is implemented, the most appropriate approaches are unknown. We explored the views of European stakeholders about opportunities and challenges of implementing four AF screening scenarios. Design Telephone-based semi-structured interviews with results reported using Consolidated criteria for Reporting Qualitative research guidelines. Data were thematically analysed using the framework approach. Setting AF screening stakeholders in 11 European countries. Participants Healthcare professionals and regulators (n=24) potentially involved in AF screening implementation. Intervention Four AF screening scenarios: single time point opportunistic, opportunistic prolonged, systematic single time point/prolonged and patient-led screening. Primary outcome measures Stakeholder views about the challenges and feasibility of implementing the screening scenarios in the respective national/regional healthcare system. Results Three themes developed. (1) Current screening approaches: there are no national AF screening programmes, with most AF detected in symptomatic patients. Patient-led screening exists via personal devices, creating screening inequity. (2) Feasibility of screening: single time point opportunistic screening in primary care using single-lead ECG devices was considered the most feasible. Software algorithms may aid identification of suitable patients and telehealth services have potential to support diagnosis. (3) Implementation requirements: sufficient evidence of benefit is required. National screening processes are required due to different payment mechanisms and health service regulations. Concerns about data security, and inclusivity for those without primary care access or personal devices must be addressed. Conclusions There is an overall awareness of AF screening. Opportunistic screening appears the most feasible across Europe. Challenges are health inequalities, identification of best target groups for screening, streamlined processes, the need for evidence of benefit and a tailored approach adapted to national realities. 2022 BMJ Publishing Group. All rights reserved.
-
Tran, Derek L.; Kamaladasa, Yasith; Muz, Phillip A.; Kotchetkova, Irina; D'Souza, Mario I.; Celermajer, David S.; Maiorana, Andrew John; Cordina, Rachael LouiseBackground: Exercise training is important for people with congenital heart disease (CHD). However, accurate exercise intensity prescription remains challenging. We sought to evaluate the validity of using the percentage of peak HR (%HR<inf>peak</inf>) and HR reserve (%HRR) methods to estimate exercise intensity in people with CHD. Methods: Cardiopulmonary exercise tests from 2009 to 2017 were reviewed. Light, moderate, and vigorous exercise intensity were characterized using guideline-based percentage of peak oxygen uptake (VO<inf>2</inf>) ranges, and corresponding HRs were averaged at each intensity. The estimated average HR for each exercise intensity category was calculated using the %HRR and %HR<inf>peak</inf> methods. Differences between the average HR at each intensity (reference HR) and the estimated HRs were determined. Results: 265 subjects were included (mean age, 29 10 years, 48% females). The %HRR and age-predicted maximal HR (%HR<inf>max</inf>) methods were the most accurate, but were still only within the guideline-defined HR ranges less than 65% of the time. Age-predicted %HR<inf>max</inf> was the most accurate in the light and moderate-intensity categories, within the defined intensity range 59% and 63% of the time respectively. For vigorous-intensity exercise, %HR<inf>peak</inf> was the most accurate, with the average HR within the defined intensity range 84% of the time. %HR<inf>peak</inf> tended to underestimate exercise intensity, while %HRR overestimated it. Conclusions: Using common HR methods for estimating exercise intensity may not be valid in many people with CHD. The %HRR and age-predicted %HR<inf>max</inf> methods were the most accurate but were out of range for around one-third of the cohort. 2022 The Authors
-
Zhao, Yunduo Charles; Li, Zhenhai; Ju, Lining Arnoldvon Willebrand factor (VWF) senses and responds to the hemodynamic forces to interact with the circulatory system and platelets in hemostasis and thrombosis. The dark side of this mechanobiology is implicated in atherothrombosis, stroke, and, more recently, the COVID-19 thrombotic symptoms. The force-responsive element controlling VWF activation predominantly resides in the N terminal auto-inhibitory module (N-AIM) flanking its A1 domain. Nevertheless, the detailed mechano-chemistry of soluble VWF N-AIM is poorly understood at the sub-molecular level as it is assumed to be unstructured loops. Using the free molecular dynamics (MD) simulations, we first predicted a hairpin-like structure of the soluble A1 N-AIM derived polypeptide (Lp; sequences Q1238-E1260). Then we combined molecular docking and steered molecular dynamics (SMD) simulations to examine how Lp regulates the A1-GPIb? interaction under tensile forces. Our simulation results indicate that Lp suppresses the catch bond in a sandwich complex of A1-Lp-GPIb? yet contributes an additional catch-bond residue D1249. To experimentally benchmark the binding kinetics for A1-GPIb? in the absence or presence of Lp, we conducted the force spectroscopybiomembrane force probe (BFP) assays. We found similar suppression on the A1-GPIb? catch bond with soluble Lp in presence. Clinically, as more and more therapeutic candidates targeting the A1-GPIb? axis have entered clinical trials to treat patients with TTP and acute coronary syndrome, our work represents an endeavor further towards an effective anti-thrombotic approach without severe bleeding side effects as most existing drugs suffer. 2022 The Royal Society of Chemistry.
