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Showing 421–440 of 2058 publications.
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Thomson, Shannon; Waters, Karen Ann; Hennessy, Annemarie; Machaalani, RitaMaternal cigarette smoking (CS) and pre-eclampsia (PE) alter placental function and expression of important proteins which maintain homeostasis. Two interlinked pathways of interest are the unfolded protein response (UPR) and apoptosis. The UPR is upregulated in the PE placenta, but no data is available on the effects of CS and how it correlates with apoptotic expression. Samples of human placental tissue from normotensive non-smokers (n = 8), women with PE (n = 8), and CS (n = 8) were analysed using immunohistochemistry for 3 UPR markers (phosphorylated PKR-like endoplasmic reticulum (ER) kinase (pPERK), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6)), and an antibody microarray for 19 apoptotic and stress regulating markers. For the PE group compared to the normotensive group, staining for pPERK was increased in decidual tissue and villi, and for IRE1, the overall percentage of stained villi per field of view was increased. There were no differences in UPR expression comparing CS to controls. Of the apoptotic markers, only I?B? (Ser32/36), which is part of an inhibitory pathway, showed a significant decrease in the PE and CS groups compared to controls. These findings suggest UPR regulation is more evident in PE with a general increase in ER stress due to decreased inhibition of apoptosis as compared to CS for which UPR was not altered. 2021
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Lim, Michelle Su Anne; Strange, G. A.; Playford, David A.; Stewart, S.; Celermajer, David S.BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital heart disease in adults but is clinically heterogeneous. We aimed to describe the echocardiographic characteristics of BAV and compare patients with BAV with moderate-tosevere aortic stenosis (AS) with those with tricuspid aortic valve (TAV) stenosis. METHODS AND RESULTS: Using the National Echo Database of Australia, patients in whom BAV was identified were studied. Those with moderate-to-severe AS (mean gradient >20 mm Hg [BAV-AS]) were compared with those with TAV and moderatetosevere AS (TAV-AS). Of 264 159 adults whose aortic valve morphology was specified, 4783 (1.8%) had confirmed BAV (aged 49.617.4 years, 69% men). Of these, 42% had no AS, and 46% had no aortic regurgitation. Moderate-to-severe AS was detected in a greater proportion of patients with BAV with a recorded mean gradient (n=1112, 34%) compared with those with TAV (n=4377, 4%; P<0.001). Patients with BAV-AS were younger (aged 55.316.7 years versus 77.311.0 years; P<0.001), and where measured had larger ascending aortic diameters (378 mm versus 355 mm; P<0.001). Age and sex-adjusted mortality risk was significantly lower in patients with BAV-AS (hazard ratio, 0.53; 95% CI, 0.450.63; P<0.001). CONCLUSIONS: In this large study of patients across the spectrum of BAV disease, the largest proportion had no significant valvulopathy or aortopathy. Compared with those with TAV-AS, patients with BAV were more likely to have moderate-to-severe AS, have larger ascending aortas, and were over 2 decades younger at the time of AS diagnosis. Despite this, patients with BAV appear to have a more favorable prognosis when AS develops, compared with those with TAV-AS. REGISTRATION: URL: www.anzctr.org.au/; Unique identifier: ACTRN12617001387314. 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
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Orchard, Jessica Joan; Orchard, John William; Toresdahl, Brett G.; Asif, Irfan M.; Hughes, D. C.; La Gerche, AndrCrossed D.Sign; Semsarian, ChristopherObjective:To compare cardiovascular screening policies of Australian elite sporting organizations.Design:Online survey.Setting:Elite/professional sports in Australia.Participants:Chief medical officers (CMOs) of elite/professional sports in Australia, including rugby union and league, cricket, tennis, Australian football, and cycling.Assessment of Variables:Survey questions about each sport's cardiac screening policy: which screening components were included [eg, history and physical (H&P), resting 12-lead electrocardiogram (ECG)], whether screening was mandatory, whether the policy applied to elite junior and/or adult players, and which criteria were used to interpret ECGs.Main Outcome Measures:Which sports had a formal cardiac screening policy, which athletes the policy applied to, components of screening, ECG interpretation criteria used.Results:Chief medical officers for 22/31 (71%) sports responded, representing >5000 athletes. Of these, 19/22 (86%) perform regular screening (100% H&P; 89% included ECG) with international cyclists also having routine echocardiograms and stress testing. Thirty-Three percent of CMOs used the 2017 International Criteria for athlete ECG interpretation. Screening was mandatory with enforcement (26%), mandatory without enforcement (48%), and opt-out (26%). All screened adult elite athletes, and 68% screened junior elite athletes. Forty-Two percent indicated athletes were required to pay for screening tests, and 63% required athletes to pay for follow-up tests. Almost all (94%) sports with a sports physician as the CMO screened athletes.Conclusions:Most sports have a screening policy, with reasonable uniformity of components. All included H&P, and almost all included ECG. Only one sport included an echocardiogram and stress test as a standard (international players only). Promoting the latest ECG interpretation criteria may reduce false-positives and cost. Future work should explore cardiac emergency plans, screening infrastructure, cost, and long-Term follow-up. 2021 Lippincott Williams and Wilkins. All rights reserved.
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Vaidya, Kaivan; Tucker, Bradley; Patel, Sanjay; Ng, Martin K.C.In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and mor-bidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these. 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Lau, Kieran; Waterhouse, Anna; Akhavan, Behnam; Gao, Lingzi; Kim, Ha-na; Tang, Fengying; Whitelock, John; Bilek, Marcela M.M.; Lord, Megan S.; Rnjak-Kovacina, JelenaBlood compatible materials are required for the development of therapeutic and diagnostic blood contacting devices as blood-material interactions are a key factor dictating device functionality. In this work, we explored biofunctionalization of silk biomaterials with a recombinantly expressed domain V of the human basement membrane proteoglycan perlecan (rDV) towards the development of blood compatible surfaces. Perlecan and rDV are of interest in vascular device development as they uniquely support endothelial cell, while inhibiting smooth muscle cell and platelet interactions. rDV was covalently immobilized on silk biomaterials using plasma immersion ion implantation (PIII), a new method of immobilizing proteins on silk biomaterials that does not rely on modification of specific amino acids in the silk protein chain, and compared to physisorbed and carbodiimide immobilized rDV. Untreated and treated silk biomaterials were examined for interactions with blood components with varying degrees of complexity, including isolated platelets, platelet rich plasma, blood plasma, and whole blood, both under agitated and flow conditions. rDV-biofunctionalized silk biomaterials were shown to be blood compatible in terms of platelet and whole blood interactions and the PIII treatment was shown to be an effective and efficient means of covalently immobilizing rDV in its bioactive form. These biomimetic silk biomaterials are a promising platform toward development of silk-based blood-contacting devices for therapeutic, diagnostic, and research applications. Statement of significance: Blood compatible materials are required for the development of therapeutic and diagnostic blood contacting devices as blood-material interactions are a key factor dictating device functionality. In this work, we explored biofunctionalization of silk biomaterials with a recombinantly expressed domain V (rDV) of the human basement membrane proteoglycan perlecan towards the development of blood compatible surfaces. Perlecan and rDV are of interest in vascular device development as they uniquely support endothelial cell, while inhibiting smooth muscle cell and platelet interactions. rDV was covalently immobilized on silk biomaterials using plasma immersion ion implantation (PIII), a new method of immobilizing proteins on silk biomaterials that does not rely on modification of specific amino acids in the silk protein chain. These biomimetic silk biomaterials are a promising platform toward development of silk-based blood-contacting devices for therapeutic, diagnostic, and research applications. 2021
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Bubb, Kristen J.; Harmer, Jason A.; Finemore, Meghan; Aitken, Sarah Joy; Ali, Zara S.; Billot, Laurent; Chow, Clara Kayei; Golledge, Jonathan; Mister, Rebecca L.; Gray, Michael P.; Grieve, Stuart M.; Hamburg, Naomi M.; Keech, Anthony C.; Patel, Sanjay; Puttaswamy, Vikram; Figtree, Gemma A.Introduction There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the ? 3 -adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating ? 3 -Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication. Methods and analysis The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ?40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care. Ethics and dissemination The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes. Trial registration number ACTRN12619000423112; Results. Authors 2021.
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Tran, Derek L.; Maiorana, Andrew John; Davis, Glen Macartney; Celermajer, David S.; d'Udekem, Yves A.; Cordina, Rachael LouiseIn the current era, the majority of children born with congenital heart disease (CHD) will survive well into adulthood because of major advances in surgical techniques, as well as in critical and medical care. However, reoperation and palliative surgical interventions are increasingly common in the adults with CHD. Tools to risk stratify patients effectively and therapies to improve outcomes are required to optimize the management of adult patients with CHD during the preoperative and postoperative periods and beyond. Exercise testing is an invaluable tool to guide risk stratification. In addition, exercise training in patients with CHD may decrease postoperative complications by enhancing physiological reserve and also has an important role in physical rehabilitation. This review aims to provide individualized recommendations on exercise prescription in patients with CHD in the preoperative and postoperative settings. The response to exercise testing and prognostic implications is also discussed. 2021 The Society of Thoracic Surgeons
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Fusco-Allison, Gabrielle; Li, Desmond K.; Hunter, Benjamin; Jackson, Dan J.; Bannon, Paul Gerard; Lal, Sean P.; OSullivan, John F.There is an urgent need for models that faithfully replicate heart failure with preserved ejection fraction (HFpEF), now recognized as the most common form of heart failure in the world. In vitro approaches have several shortcomings, most notably the immature nature of stem cell-derived human cardiomyocytes [induced pluripotent stem cells (iPSC)] and the relatively short lifespan of primary cardiomyocytes. Three-dimensional organoids incorporating mature iPSCs with other cell types such as endothelial cells and fibroblasts are a significant advance, but lack the complexity of true myocardium. Animal models can replicate many features of human HFpEF, and rodent models are the most common, and recent attempts to incorporate haemodynamic, metabolic, and ageing contributions are encouraging. Differences relating to species, physiology, heart rate, and heart size are major limitations for rodent models. Porcine models mitigate many of these shortcomings and approximate human physiology more closely, but cost and time considerations limit their potential for widespread use. Ex vivo analysis of failing hearts from animal models offer intriguing possibilities regarding cardiac substrate utilisation, but are ultimately subject to the same constrains as the animal models from which the hearts are obtained. Ex vivo approaches using human myocardial biopsies can uncover new insights into pathobiology leveraging myocardial energetics, substrate turnover, molecular changes, and systolic/diastolic function. In collaboration with a skilled cardiothoracic surgeon, left ventricular endomyocardial biopsies can be obtained at the time of valvular surgery in HFpEF patients. Critically, these tissues maintain their disease phenotype, preserving inter-relationship of myocardial cells and extracellular matrix. This review highlights a novel approach, where ultra-thin myocardial tissue slices from human HFpEF hearts can be used to assess changes in myocardial structure and function. We discuss current approaches to modelling HFpEF, describe in detail the novel tissue slice model, expand on exciting opportunities this model provides, and outline ways to improve this model further. 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Khandkar, Chinmay; Patel, Sanjay; Arnott, Clare[No abstract available]
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Ruhoff, Alexander M.; Hong, Jun Ki; Gao, Lingzi; Singh, Jasneil; Tran, Clara T.H.; Mackie, Grace; Waterhouse, AnnaThrombosis on blood-contacting medical devices can cause patient fatalities through device failure and unstable thrombi causing embolism. The effect of material wettability on fibrin network formation, structure, and stability is poorly understood. Under static conditions, fibrin fiber network volume and density increase in clots formed on hydrophilic compared to hydrophobic polystyrene surfaces. This correlates with reduced plasma clotting time and increased factor XIIa (FXIIa) activity. These structural differences are consistent up to 50m away from the material surface and are FXIIa dependent. Fibrin forms fibers immediately at the material interface on hydrophilic surfaces but are incompletely formed in the first 5m above hydrophobic surfaces. Additionally, fibrin clots on hydrophobic surfaces have increased susceptibility to fibrinolysis compared to clots formed on hydrophilic surfaces. Under low-flow conditions, clots are still denser on hydrophilic surfaces, but only 5m above the surface, showing the combined effect of the surface wettability and coagulation factor dilution with low flow. Overall, wettability affects fibrin fiber formation at material interfaces, which leads to differences in bulk fibrin clot density and susceptibility to fibrinolysis. These findings have implications for thrombus formed in stagnant or low-flow regions of medical devices and the design of nonthrombogenic materials. 2021 Wiley-VCH GmbH
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Koo, Kevin; Inglis, Sally C.; Freedman, Ben Ben; Thijs, Vincent N.S.; Ferguson, CalebThis protocol for a Cochrane Review has been withdrawn as the author team is no longer available to complete this review. 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Ayer, Anita; Fazakerley, Daniel J.; Suarna, Cacang; Maghzal, Ghassan J.; Sheipouri, Diba; Lee, Kevin J.; Bradley, Michelle C.; Ferndez del R, Luc; Tumanov, Sergey; Kong, Stephanie M.Y.; van der Veen, Jelske N.; Yang, Andrian; Ho, Joshua W.K.; Clarke, Steven Gerard; James, David Ernest; Dawes, Ian W.W.; Vance, Dennis E.; Clarke, Catherine Freitag; Jacobs, RenL.; Stocker, RolandMitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans. To date, large-scale studies aimed at systematically interrogating endogenous systems that control CoQ biosynthesis and their potential utility to treat disease have not been carried out. Therefore, we developed a quantitative high-throughput method to determine CoQ concentrations in yeast cells. Applying this method to the Yeast Deletion Collection as a genome-wide screen, 30 genes not known previously to regulate cellular concentrations of CoQ were discovered. In combination with untargeted lipidomics and metabolomics, phosphatidylethanolamine N-methyltransferase (PEMT) deficiency was confirmed as a positive regulator of CoQ synthesis, the first identified to date. Mechanistically, PEMT deficiency alters mitochondrial concentrations of one-carbon metabolites, characterized by an increase in the S-adenosylmethionine to S-adenosylhomocysteine (SAM-to-SAH) ratio that reflects mitochondrial methylation capacity, drives CoQ synthesis, and is associated with a decrease in mitochondrial oxidative stress. The newly described regulatory pathway appears evolutionary conserved, as ablation of PEMT using antisense oligonucleotides increases mitochondrial CoQ in mouse-derived adipocytes that translates to improved glucose utilization by these cells, and protection of mice from high-fat diet-induced insulin resistance. Our studies reveal a previously unrecognized relationship between two spatially distinct lipid pathways with potential implications for the treatment of CoQ deficiencies, mitochondrial oxidative stress/dysfunction, and associated diseases. 2021 The Authors
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Nundlall, Nishant; Playford, David A.; Strange, G. A.; Davis, Timothy M.E.; Davis, Wendy AngelaThere is a paucity of epidemiologic data examining the relationship between pulmonary hypertension (PH) and diabetes. The aim of this study was to determine prevalence, incidence and associates of PH complicating type 2 diabetes. Data from 1430 participants (mean age 65.5 years, 51.5% males) in the Fremantle Diabetes Study Phase 2 (FDS2) were linked with the National Echocar-diographic Database of Australia (NEDA) to ascertain the prevalence and incidence of PH (estimated right ventricular systolic pressure (eRVSP) >30 mmHg as a new suggested threshold or the conventional >40 mmHg) over a 12-year period. PH prevalence in FDS2 was compared with that in NEDA overall and a geographically close sub-population. Multivariable analyses identified associates of prevalent/incident PH in the FDS2 cohort. Of 275 FDS2 patients (19.2%) with pre-entry echocar-diography, 90 had eRVSP >30 mmHg and 35 had eRVSP >40 mmHg (prevalences 32.7% (95% CI 27.338.7%) and 12.7% (9.117.4%), respectively), rates that are 3550% greater than national/local NEDA general population estimates. Moreover, 70 (5.0%) and 123 (9.2%) FDS2 participants were identified with incident PH at the respective eRVSP thresholds (incidence (95% CI) 7.6 (6.09.7) and 14.2 (11.817.0)/1000 person-years), paralleling data from recognised high-risk conditions such as systemic sclerosis. The baseline plasma N-terminal pro-brain natriuretic peptide concentration was the strongest independent associate of prevalent/incident PH. Approximately 1 in 8 people with type 2 diabetes have PH using the eRVSP >40 mmHg threshold. Its presence should be considered as part of regular clinical assessment of individuals with type 2 diabetes. 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Ravindran, Dhanya; Galougahi, Keyvan Karimi; Tan, Joanne Tsui Ming; Kavurma, Mary M.; Bursill, C. A.While the advent of drug-eluting stents has been clinically effective in substantially reducing the rates of major stent-related adverse events compared with bare metal stents, vascular biological problems such as neointimal hyperplasia, delayed re-endothelialization, late stent thrombosis are not eliminated and, increasingly, neoatherosclerosis is the underlying mechanism for very late stent failure. Further understanding regarding the mechanisms underlying the biological responses to stent deployment is therefore required so that new and improved therapies can be developed. This review will discuss the accumulating evidence that the chemokines, small inflammatory proteins, play a role in each key biological process of stent biocompatibility. It will address the chemokine system in its specialized roles in regulating the multiple facets of vascular biocompatibility including neointimal hyperplasia, endothelial progenitor cell (EPC) mobilization and re-endothelialization after vascular injury, platelet activation and thrombosis, as well as neoatherosclerosis. The evidence in this review suggests that chemokine-targeting strategies may be effective in controlling the pathobiological processes that lead to stent failure. Preclinical studies provide evidence that inhibition of specific chemokines and/or broad-spectrum inhibition of the CC-chemokine class prevents neointimal hyperplasia, reduces thrombosis and suppresses the development of neoatherosclerosis. In contrast, however, to these apparent deleterious effects of chemokines on stent biocompatibility, the CXC chemokine, CXCL12, is essential for the mobilization and recruitment of EPCs that make important contributions to re-endothelialization post-stent deployment. This suggests that future chemokine inhibition strategies would need to be correctly targeted so that all key stent biocompatibility areas could be addressed, without compromising important adaptive biological responses. 2021 Published on behalf of the European Society of Cardiology. All rights reserved.
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Pijning, Aster E.; Blyth, Mitchell T.; Coote, Michelle L.; Passam, Freda H.; Chiu, Joyce; Hogg, Philip J.The ?IIb?3 integrin receptor coordinates platelet adhesion, activation, and mechanosensing in thrombosis and hemostasis. Using differential cysteine alkylation and mass spectrometry, we have identified a disulfide bond in the ?IIb subunit linking cysteines 490 and 545 that is missing in ?1 in 3 integrin molecules on the resting and activated human platelet surface. This alternate covalent form of ?IIb?3 is predetermined as it is also produced by human megakaryoblasts and baby hamster kidney fibroblasts transfected with recombinant integrin. From coimmunoprecipitation experiments, the alternate form selectively partitions into focal adhesions on the activated platelet surface. Its function was evaluated in baby hamster kidney fibroblast cells expressing a mutant integrin with an ablated C490-C545 disulfide bond. The disulfide mutant integrin has functional outside-in signaling but extended residency time in focal adhesions due to a reduced rate of clathrin-mediated integrin internalization and recycling, which is associated with enhanced affinity of the ?IIb subunit for clathrin adaptor protein 2. Molecular dynamics simulations indicate that the alternate covalent form of ?IIb requires higher forces to transition from bent to open conformational states that is in accordance with reduced affinity for fibrinogen and activation by manganese ions. These findings indicate that the ?IIb?3 integrin receptor is produced in various covalent forms that have different cell surface distribution and function. The C490, C545 cysteine pair is conserved across all 18 integrin ? subunits, and the disulfide bond in the ?V and ?2 subunits in cultured cells is similarly missing, suggesting that the alternate integrin form and function are also conserved. 2021 American Society of Hematology
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Lowres, Nicole; Freedman, Ben Ben[No abstract available]
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Freedman, Ben Ben; Lowres, Nicole[No abstract available]
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Woldendorp, Kei; Doyle, Mathew P.; Black, Deborah Ann; Ng, Martin K.C.; Keech, Anthony C.; Grieve, Stuart M.; Bannon, Paul GerardBackground: Recent high-resolution computed tomography studies after transcatheter aortic valve insertion (TAVI) have reported a high prevalence of subclinical valve thrombosis (SCVT), potentially contributing to increased risk of late stroke. We aimed to investigate SCVT in patients after TAVI, with a focus on prevalence, predisposing factors, management, and potential sequelae. Methods: A comprehensive literature review of patients with SCVT after TAVI was carried out on all published studies in 3 major electronic databases from their inception until October 2019. Studies with sufficient data were included in a meta-analysis comparing the risk of stroke between patients with SCVT and those with normal valve function, as well as the protective effects of antiplatelet and anticoagulation on preventing SCVT. Results: From 3456 patients examined in a comprehensive review, 398 patients (11.5%) demonstrated evidence of SCVT during follow-up. Dual antiplatelet therapy was given in 45.5% of cases, single antiplatelet therapy in 19.8%, and oral anticoagulation in 28.5%. A meta-analysis demonstrated that rates of stroke were more than 3 times greater in patients with SCVT compared with those without (logistic odds, 1.10; 95% confidence interval, 0.63-1.57, P < .0001). Oral anticoagulation was superior to dual antiplatelet therapy or single antiplatelet therapy, preventing the formation of SCVT (logistic odds, 1.05, 95% confidence interval, 1.71 to 0.39, P < .0001). Conclusions: Subclinical valve thrombosis is seen in 11.5% of patients after TAVI and is associated with increased risk of stroke. When oral anticoagulation is used postprocedurally, it is more effective than either dual or single-antiplatelet therapy in preventing subclinical valve thrombosis. These findings suggest that further studies are needed to define the optimal antithrombotic regimen to mitigate thrombotic and embolic sequelae after TAVI. 2020
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Snir, Afik D.; Ng, Martin K.C.; Strange, G. A.; Playford, David A.; Stewart, S.; Celermajer, David S.Background: There are currently no established prognostic models for low-gradient severe aortic stenosis (AS), including those with low-flow, low-gradient (LFLG) or normal-flow, low-gradient (NFLG) severe AS. The cardiac damage staging classification has been validated as a clinically useful prognostic tool for high-gradient severe AS but not yet for these other common subtypes of severe AS, LFLG and NFLG. Methods: The authors analyzed data from the National Echo Database of Australia, a large national, multicenter registry with individual data linkage to mortality. Of 192,060 adults (mean age, 62.8 17.8 years) with comprehensive ultrasound profiling of the native aortic valve studied between 2000 and 2019, 12,013 (6.3%) had severe AS. On the basis of standard echocardiographic parameters, 5,601 patients with high-gradient, 611 with classical and 959 with paradoxical LFLG, and 911 with NFLG severe AS were identified. Mean follow-up was 88 45 months. All-cause and cardiovascular-related mortality were assessed for each group on an adjusted basis (age and sex) and analyzed by cardiac damage stage. Results: Patients with LFLG AS had greater associated cardiac damage at diagnosis (stages 3 and 4 in 34% of those with classical LFLG, 22.5% of those with paradoxical LFLG, 15.5% of those with NFLG, and 14% of those with high-gradient AS; P < .001). For all four major subtypes of severe AS, there was a progressive increase in 1- and 5-year mortality with increasing cardiac damage score. For example, for paradoxical LFLG severe AS, compared with stage 0 patients, adjusted 1-year all-cause mortality was 22% higher in stage 1 patients, 55% higher in stage 2 patients (P = .095), and 155% higher in stage 3 and 4 patients (P < .001). Among patients with classical LFLG severe AS, compared with stage 1 patients, adjusted 1-year all-cause mortality was 55% higher in stage 2 patients (P = .018) and 100% higher in stage 3 and 4 patients (P < .001). Conclusions: Regardless of severe AS subtype, increasing severity denoted by the cardiac damage staging classification is strongly associated with increasing mortality risk. 2021 American Society of Echocardiography
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Chen, Weiyu; Tumanov, Sergey; Fazarkeley, Daniel; Cantley, James; James, David Ernest; Dunn, Louise L.; Shaik, Taqi; Suarna, Cacang; Stocker, RolandBackground & aims: Plasma concentrations of bilirubin, a product of heme catabolism formed by biliverdin reductase A (BVRA), inversely associate with the risk of metabolic diseases including hepatic steatosis and diabetes mellitus in humans. Bilirubin has antioxidant and anti-inflammatory activities and may also regulate insulin signaling and peroxisome proliferator-activated receptor alpha (PPAR?) activity. However, a causal link between bilirubin and metabolic diseases remains to be established. Here, we used the global Bvra gene knockout (Bvra/) mouse as a model of deficiency in bilirubin to assess its role in metabolic diseases. Approach & results: We fed mice fat-rich diets to induce hepatic steatosis and insulin resistance. Bile pigments were measured by LC-MS/MS, and hepatic lipids by LC-MS/MS (non-targeted lipidomics), HPLC-UV and Oil-Red-O staining. Oxidative stress was evaluated measuring F<inf>2</inf>-isoprostanes by GC-MS. Glucose metabolism and insulin sensitivity were verified by glucose and insulin tolerance tests, ex vivo and in vivo glucose uptake, and Western blotting for insulin signaling. Compared with wild type littermates, Bvra/ mice contained negligible bilirubin in plasma and liver, and they had comparable glucose metabolism and insulin sensitivity. However, Bvra/ mice exhibited an inflamed and fatty liver phenotype, accompanied by hepatic accumulation of oxidized triacylglycerols and F<inf>2</inf>-isoprostanes, in association with depletion of ?-tocopherol. ?-Tocopherol supplementation reversed the hepatic phenotype and observed biochemical changes in Bvra/ mice. Conclusions: Our data suggests that BVRA deficiency renders mice susceptible to oxidative stress-induced hepatic steatosis in the absence of insulin resistance. 2021 The Authors
