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Showing 301–320 of 2058 publications.
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Wee, Jason; Sukudom, Sara; Bhat, Saiuj; Marklund, Matti; Peiris, Niridu Jude; Hoyos, Camilla M.; Patel, Sanjay; Naismith, Sharon Linda; Dwivedi, Girish; Misra, Ashish K.Introduction: We conducted a systematic review and meta-analysis to review the relationship between midlife dyslipidemia and lifetime incident dementia. Methods: The databases Medline, Embase, Scopus, Web of Science, and Cochrane were searched from inception to February 20, 2022. Longitudinal studies examining the relationship between midlife lipid levels on dementia, dementia subtypes, and/or cognitive impairment were pooled using inverse-variance weighted random-effects meta-analysis. Results: Seventeen studies (1.2 million participants) were included. Midlife hypercholesterolemia was associated with increased incidence of mild cognitive impairment (effect size [ES] = 2.01; 95% confidence interval [CI] 1.19 to 2.84; I2 = 0.0%) and all-cause dementia (ES = 1.14; 95% CI: 1.07 to 1.21; I2 = 0.0%). Each 1 mmol/L increase in low-density lipoprotein was associated with an 8% increase (ES = 1.08, 95% CI: 1.03 to 1.14; I2 = 0.3%) in incidence of all-cause dementia. Discussion: Midlife dyslipidemia is associated with an increased risk of cognitive impairment in later life. 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.
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Zhao, Emma; Lowres, Nicole; Naismith, Sharon Linda; Tofler, Geoffrey H.; Bauman, Adrian Ernest; Gallagher, Robyn D.Background Cognitive impairment (CI) may contribute to difficulties in understanding and implementing secondary prevention behavior change after acute coronary syndrome (ACS), but the association is poorly understood. Objectives The aim of this study was to explore the prevalence of CI in patients 4 weeks post ACS and the association with health literacy and secondary prevention. Methods Patients with ACS who were free from visual deficits, auditory impairment, and dementia diagnoses were recruited and assessed 4 weeks post discharge for cognitive function (Montreal Cognitive Assessment and Hopkins Verbal Learning Test), health literacy (Newest Vital Sign), depression (Patient Health Questionnaire), physical activity (Fitbit Activity Tracker and Physical Activity Scale for the Elderly), and medication knowledge and adherence. Results Participants (n = 45) had an average age of 65 11 years, 82% were male, 64% were married/partnered, and 82% had high school education or higher. Overall CI was identified in 28.9% (n = 13/45) of the patients 4 weeks after discharge, which was composed of patients detected on both the Montreal Cognitive Assessment and Hopkins Verbal Learning Test (n = 3), patients detected on Montreal Cognitive Assessment alone (n = 6), and patients detected on Hopkins Verbal Learning Test alone (n = 4). Fewer patients with CI had adequate health literacy (61.4%) than patients with normal cognition (90.3%, P =.024). Significant correlations were found between Hopkins Verbal Learning Test scores and medication knowledge (0.4, P =.008) and adherence (0.33, P =.029). Conclusions In this exploratory study, 30% of patients with ACS demonstrated CI at 4 weeks post discharge. Two screening instruments were required to identify all cases. Cognitive impairment was significantly associated with health literacy and worth further investigation. Wolters Kluwer Health, Inc. All rights reserved.
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Offen, Sophie M.; Strange, G. A.; Playford, David A.; Celermajer, David S.; Stewart, S.Aims: We sought to analyse the distribution of TR severity and survival in a large cohort of adults with CIED leads. Methods: The distribution of TR severity was analysed in 18,797 adults (mean age 73.8+/-13.9, 63.3% men) with CIED leads undergoing echocardiography across 25 centres. Survival status and cause of death were linked and the relationship between TR severity and mortality during 2.6 (interquartile range 1.1-4.6) years follow-up examined. Data from 439,558 individuals (mean age 62.1 17.8 years, 51.5% men) without a CIED were subsequently incorporated in a pooled cohort analysis. Results: Overall, 8,824/18,797 individuals (47%) with a CIED had no/trivial TR; 5,490 (29.2%) mild TR; 3,068 (16.3%) moderate TR; and 1,415 (7.5%) severe TR. Moderate or greater TR was independently associated with age, female sex, atrial fibrillation and significant left heart disease (p<0.001 for all). 8,868 individuals (47.2%) died from any cause (43.2% from cardiovascular causes). Individuals with moderate or severe TR had a 1.6 to 2.5-fold increased risk of all-cause mortality in adjusted models, compared to those with no TR (p<0.001 for both). In the pooled cohort analysis, CIEDs were associated with a near 2-fold (95% CI 1.81-1.99; p<0.001) increased probability of moderate or greater TR, on adjusted basis. However, the mortality associated with moderate or greater TR did not differ significantly with respect to the presence or absence of a device lead. Conclusions: Moderate or greater TR is more prevalent in those with CIED's, even in adjusted models, and was independently associated with incremental risks for all-cause and cardiovascular mortality. 2022 Elsevier B.V.
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Strange, G. A.; Stewart, S.; Playford, David A.; Strom, Jordan B.Background: Aortic stenosis (AS) is the most common valvular heart disease in high-income countries. Adjusted for clinical confounders, the risk associated with increasing AS severity across the spectrum of AS severity remains uncertain. Methods: The authors conducted an international, multicenter, parallel-cohort study of 217,599 Australian (mean age, 76.0 7.3 years; 49.3% women) and 30,865 US (mean age, 77.4 7.3 years; 52.2% women) patients aged ?65 years who underwent echocardiography. Patients with previous aortic valve replacement were excluded. The risk of increasing AS severity, quantified by peak aortic velocity (Vmax), was assessed through linkage to 97,576 and 14,481 all-cause deaths in Australia and the United States, respectively. Results: The distribution of AS severity (mean Vmax, 1.7 0.7 m/sec) was similar in both cohorts. Compared with those with Vmax of 1.0 to 1.49 m/sec, those with Vmax of 2.50 to 2.99 m/sec (US cohort) or Vmax of 3.0 to 3.49 m/sec (Australian cohort) had a 1.5-fold increase in mortality risk within 10 years, adjusting for age, sex, presence of left heart disease, and left ventricular ejection fraction. Overall, the adjusted risk for mortality plateaued (1.75- to 2.25-fold increased risk) above a Vmax of 3.5 m/sec. This pattern of mortality persisted despite adjustment for a comprehensive list of comorbidities and treatments within the US cohort. Conclusions: Within large, parallel patient cohorts managed in different health systems, similar patterns of mortality linked to increasingly severe AS were observed. These findings support ongoing clinical trials of aortic valve replacement in patients with nonsevere AS and suggest the need to develop and apply more proactive surveillance strategies in this high-risk population. 2022 American Society of Echocardiography
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McEwan, Phil C.; Ponikowski, Piotr P.; Shiri, Tinevimbo; Rosano, Giuseppe Massimo Claudio; Coats, Andrew J.S.; Dorigotti, Fabio; Ramez-De-Arellano, Antonio; Jankowska, Ewa AnitaObjective: To estimate clinical events and evaluate the financial implications of introducing ferric carboxymaltose (FCM) to treat iron deficiency (ID) at discharge in patients hospitalized for acute heart failure (AHF) with left ventricular ejection fraction (LVEF) <50% in the UK, Switzerland and Italy. Methods: A decision analytic cost-offset model was developed to evaluate the costs associated with introducing FCM for all eligible patients in three countries compared to a world without FCM, over a five-year time horizon. Data from AFFIRM-AHF clinical trial were used to model clinical outcomes, using an established cohort state-transition Markov model. Country-specific prevalence estimates were derived using data from real-world studies to extrapolate number of events and consequent cost totals to the population at risk on a national scale. Results: The cost-offset modeling demonstrated that FCM is projected to be a cost-saving intervention in all three country settings over a five-year time horizon. Savings were driven primarily by reduced hospitalizations and avoided cardiovascular deaths, with net cost savings of ?14,008,238, ?CHF25,456,455 and ?105,295,146 incurred to the UK, Switzerland and Italy, respectively. Limitations: Although AFFIRM-AHF was a multinational trial, efficacy data per country was not sufficiently large to enable country-specific analysis, therefore overall clinical parameters have been assumed to apply to all countries. Conclusions: This study provides further evidence of the potential cost savings achievable by treating ID with FCM at discharge in patients hospitalized for AHF with LVEF <50%. The value of FCM treatment within the healthcare systems of the UK, Switzerland and Italy was demonstrated even within a limited time frame of one year, with consistent cost savings indicated over a longer term. 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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Galougahi, Keyvan Karimi; Zhang, Yunjia; Kienzle, Vivian J.; Liu, Chiachi; Quek, Lake Ee; Patel, Sanjay; Lau, Edmund M.T.; Cordina, Rachael Louise; Figtree, Gemma A.; Celermajer, David S.Efficacy of therapies that target the downstream nitric oxide (NO) pathway in pulmonary arterial hypertension (PAH) depends on the bioavailability of NO. Reduced NO level in PAH is secondary to uncoupling of endothelial nitric oxide synthase (eNOS). Stimulation of ?3 adrenergic receptors (?3 ARs) may lead to the recoupling of NOS and therefore be beneficial in PAH. We aimed to examine the efficacy of ?3 AR agonism as a novel pathway in experimental PAH. In hypoxia (5 weeks) and Sugen hypoxia (hypoxia for 5 weeks + SU5416 injection) models of PAH, we examined the effects of the selective ?3 AR agonist CL316243. We measured echocardiographic indices and invasive right ventricular (RV)pulmonary arterial (PA) hemodynamics and compared CL316243 with riociguat and sildenafil. We assessed treatment effects on RVPA remodeling, oxidative stress, and eNOS glutathionylation, an oxidative modification that uncouples eNOS. Compared with normoxic mice, RV systolic pressure was increased in the control hypoxic mice (p < 0.0001) and Sugen hypoxic mice (p < 0.0001). CL316243 reduced RV systolic pressure, to a similar degree to riociguat and sildenafil, in both hypoxia (p < 0.0001) and Sugen hypoxia models (p < 0.03). CL316243 reversed pulmonary vascular remodeling, decreased RV afterload, improved RVPA coupling efficiency and reduced RV stiffness, hypertrophy, and fibrosis. Although all treatments decreased oxidative stress, CL316243 significantly reduced eNOS glutathionylation. ?3 AR stimulation improved RV hemodynamics and led to beneficial RVPA remodeling in experimental models of PAH. ?3 AR agonists may be effective therapies in PAH. 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
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Nedoboy, Polina E.; Farnham, M. M. J.Hypoglycemia-associated autonomic failure (HAAF) is a serious, life-threatening complication of intensive insulin therapy, particularly in people with type 1 diabetes. The ketogenic diet is reported to beneficially affect glycemic control in people with type 1 diabetes, however its effects on the neurohormonal counterregulatory response to recurrent hypoglycemia and HAAF development are understudied. In this study we used Sprague Dawley rats to establish a HAAF model under non-diabetic and streptozotocin (STZ)-induced diabetic conditions and determined how nutritional ketosis affected the neurohormonal counterregulation and the activity of energy-sensing orexin (OX) neurons. We found that antecedent hypoglycemia diminished the sympathoexcitatory epinephrine response to subsequent hypoglycemia in chow-fed non-diabetic rats, but this did not occur in STZ-diabetic animals. In all cases a ketogenic diet preserved the epinephrine response. Contrary to expectations, STZ-diabetic keto-fed rats showed reduced OX activity in the recurrent hypoglycemia group, which did not occur in any other group. It is possible that the reduced activation of OX neurons is an adaptation aimed at energy conservation accompanied by diminished arousal and exploratory behaviour. Our data suggests that while a ketogenic diet has beneficial effects on glycemia, and epinephrine response, the reduced activation of OX neurons could be detrimental and warrants further investigation. 2022 by the authors.
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Lan, Nick Si Rui; Ihdayhid, Abdul Rahman; Boardman, Glenn R.; Strange, G. A.; Playford, David A.; Dwivedi, Girish[No abstract available]
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Vermunicht, Paulien; Grecu, Mihaela; Deharo, Jean Claude; Buckley, Claire Mary; Pala, Elena; Mairesse, Georges H.; Farkowski, Micha? Miroslaw; Bergonti, Marco; Perfellner, Helmut; Hanson, Coral L.; Neubeck, Lis; Freedman, Ben Ben; Witt, Henning; Hills, Mellanie True; Lund, Jenny; Giskes, Katrina; Engler, Daniel; Schnabel, Renate B.; Heidbuchel, H. P.; Desteghe, LienBackground: There is no clear guidance on how to implement opportunistic atrial fibrillation (AF) screening in daily clinical practice. Objectives: This study evaluated the perception of general practitioners (GPs) about value and practicalities of implementing screening for AF, focusing on opportunistic single-time point screening with a single-lead electrocardiogram (ECG) device. Methods: A descriptive cross-sectional study was conducted with a survey developed to assess overall perception concerning AF screening, feasibility of opportunistic single-lead ECG screening and implementation requirements and barriers. Results: A total of 659 responses were collected (36.1% Eastern, 33.4% Western, 12.1% Southern, 10.0% Northern Europe, 8.3% United Kingdom & Ireland). The perceived need for standardized AF screening was rated as 82.7 on a scale from 0 to 100. The vast majority (88.0%) indicated no AF screening program is established in their region. Three out of four GPs (72.1%, lowest in Eastern and Southern Europe) were equipped with a 12-lead ECG, while a single-lead ECG was less common (10.8%, highest in United Kingdom & Ireland). Three in five GPs (59.3%) feel confident ruling out AF on a single-lead ECG strip. Assistance through more education (28.7%) and a tele-healthcare service offering advice on ambiguous tracings (25.2%) would be helpful. Preferred strategies to overcome barriers like insufficient (qualified) staff, included integrating AF screening with other healthcare programs (24.9%) and algorithms to identify patients most suitable for AF screening (24.3%). Conclusion: GPs perceive a strong need for a standardized AF screening approach. Additional resources may be required to have it widely adopted into clinical practice. 2023 Vermunicht, Grecu, Deharo, Buckley, Pal Mairesse, Farkowski, Bergonti, Perfellner, Hanson, Neubeck, Freedman, Witt, Hills, Lund, Giskes, Engler, Schnabel, Heidbuchel, Desteghe and for the AFFECT-EU investigators.
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Gallagher, Robyn D.; Chow, Clara Kayei; Parker, Helen M.; Neubeck, Lis; Celermajer, David S.; Redfern, Julie; Tofler, Geoffrey H.; Buckley, Thomas R.; Schumacher, Tracy L.; Hyun, Karice K.; Boroumand, Farzaneh; Figtree, Gemma A.Aims: Secondary prevention reduces coronary heart disease (CHD) progression. Traditional prevention programs including cardiac rehabilitation are under-accessed, which smartphone apps may overcome. To evaluate the effect of a game-based mobile app intervention (MyHeartMate) to improve cardiovascular risk factors and lifestyle behaviours. Methods and results: Single-blind randomized trial of CHD patients in Sydney, 2017-2021. Intervention group were provided the MyHeartMate app for 6 months. Co-designed features included an avatar of the patient's heart and tokens earned by risk factor work (tracking, challenges, and quizzes). The control group received usual care. Primary outcome was self-reported physical activity [metabolic equivalents (METs), Global Physical Activity Questionnaire] and secondary outcomes included lipid levels, blood pressure (BP), body mass index, and smoking. Pre-specified sample size was achieved (n = 390), age 61.2 11.5 years; 82.5% men and 9.2% current smokers. At 6 months, adjusted for baseline levels, the intervention group achieved more physical activity than control (median difference 329 MET mins/wk), which was not statistically significant (95% CI -37.4, 696; P = 0.064). No differences occurred between groups on secondary outcomes except for lower triglyceride levels in the intervention [mean difference -0.3 (95% CI -0.5, -0.1 mmoL/L, P = 0.004)]. Acceptability was high: 94.8% of intervention participants engaged by tracking exercise or BP and completing missions; 26.8% continued to engage for ?30 days. Participants (n = 14) reported the app supported tracking behaviours and risk factors, reinforcing and improving self-care confidence, and decreasing anxiety. Conclusion: A game-based app proved highly acceptable for patients with CHD but did not improve risk factors or lifestyle behaviours other than triglyceride levels. 2022 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
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Vigder, Niv; Suarna, Cacang; Corcilius, Leo; Nadel, James; Chen, Weiyu; Payne, Richard J.; Tumanov, Sergey; Stocker, RolandConversion of the redox probe hydroethidine (HE) to 2-chloroethidium (2-Cl-E+) by myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) provides comparable specificity and superior sensitivity to measurement of 3-chlorotyrosine (3-Cl-Tyr), the gold standard biomarker for MPO chlorinating activity in biological systems. However, a limitation of the former method is the complex mixture of products formed by the reaction of HE with reagent HOCl, coupled with the difficult purification of 2-Cl-E+ from this mixture for analytical purposes. This limitation prompted us to test whether 2-Cl-E+ could be formed by reaction of HE with the strong and widely used chlorinating agent, N-chlorosuccinimide (NCS). Unexpectedly, such reaction yielded 2-chlorohydroethidine (2-Cl-HE) as the major product in addition to 2-Cl-E+, as assessed by high performance liquid chromatography (HPLC), mass spectrometry (MS), and nuclear magnetic resonance (NMR). 2-Cl-HE was also observed to be the major chlorination product formed from HE with both reagent and enzymatically generated HOCl, just as it was formed ex vivo in different healthy and diseased mouse and human tissues upon incubation with glucose/glucose oxidase to generate a flux of hydrogen peroxide (H<inf>2</inf>O<inf>2</inf>). Quantification of 2-Cl-HE plus 2-Cl-E+ improved the sensitivity of the HE-based method compared with measurement of only 2-Cl-E+. Moreover, 2-chlorodimidium (2-Cl-D+) was developed as a practical internal standard instead of the previously used internal standard, deuterated 2-Cl-E+ (d<inf>5</inf>-2-Cl-E+). Overall, the present study describes an improved method for the detection of MPO/chlorinating activity in biological systems of health and disease. 2022
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Tsai, Kevin Hung Yueh; Shi, Huaikai; Parungao, Roxanne J.; Naficy, Sina; Ding, Xiaotong; Ding, Xiaofeng; Hew, Jonathan J.; Wang, Xiaosuo; Chrzanowski, Wojciech; Lavery, Gareth G.; Li, Zhe; Issler-Fisher, Andrea C.; Chen, Jun; Tan, Qian; Maitz, Peter K.M.; Cooper, Mark S.; Wang, YiweiBackground: Excessive scarring and fibrosis are the most severe and common complications of burn injury. Prolonged exposure to high levels of glucocorticoids detrimentally impacts on skin, leading to skin thinning and impaired wound healing. Skin can generate active glucocorticoids locally through expression and activity of the 11?-hydroxysteroid dehydrogenase type 1 enzyme (11?-HSD1). We hypothesised that burn injury would induce 11?-HSD1 expression and local glucocorticoid metabolism, which would have important impacts on wound healing, fibrosis and scarring. We additionally proposed that pharmacological manipulation of this system could improve aspects of post-burn scarring. Methods: Skin 11?-HSD1 expression in burns patients and mice was examined. The impacts of 11?-HSD1 mediating glucocorticoid metabolism on burn wound healing, scar formation and scar elasticity and quality were additionally examined using a murine 11?-HSD1 genetic knockout model. Slow-release scaffolds containing therapeutic agents, including active and inactive glucocorticoids, were developed and pre-clinically tested in mice with burn injury. Results: We demonstrate that 11?-HSD1 expression levels increased substantially in both human and mouse skin after burn injury. 11?-HSD1 knockout mice experienced faster wound healing than wild type mice but the healed wounds manifested significantly more collagen deposition, tensile strength and stiffness, features characteristic of excessive scarring. Application of slow-release prednisone, an inactive glucocorticoid, slowed the initial rate of wound closure but significantly reduced post-burn scarring via reductions in inflammation, myofibroblast generation, collagen production and scar stiffness. Conclusions: Skin 11?-HSD1 expression is a key regulator of wound healing and scarring after burn injury. Application of an inactive glucocorticoid capable of activation by local 11?-HSD1 in skin slows the initial rate of wound closure but significantlyimproves scar characteristics post burn injury. 2023 The Author(s). Published by Oxford University Press.
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Liu, Ken; Chen, Jinbiao; Zhao, Yang; Boland, Jade A.; Ting, Kaka; Lockwood, Glen P.; McKenzie, Catriona A.; Kench, J. G.; Vadas, Mathew Alexander; Gamble, Jennifer R.; McCAUGHAN, G. W.Introduction: Liver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model. Methods: We first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy. Results: Human data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups. Discussion: CD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one. 2023 Liu, Chen, Zhao, Boland, Ting, Lockwood, McKenzie, Kench, Vadas, Gamble and McCaughan.
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Ventricular Arrhythmia in the Fontan Circulation: Prevalence, Risk Factors and Clinical ImplicationsTan, Charis Q.Y.; Zannino, Diana; Clendenning, Carley; Offen, Sophie M.; Gentles, Thomas L.; Ayer, Julian Ganesh J.; Tanous, David J.; Wijesekera, Vishva A.; Grigg, Leeanne Elizabeth; Celermajer, David S.; McGuire, Mark A.; d'Udekem, Yves A.; Cordina, Rachael LouiseObjective: Sudden cardiac death (SCD) and malignant ventricular arrhythmia (VA) are increasingly recognized as important issues for people living with a Fontan circulation, but data are lacking. We sought to characterize the cohort who had sudden cardiac death, most likely related to VA and/or documented VA in the Australia and New Zealand Fontan Registry including risk factors and clinical outcomes. Methods: A retrospective cohort study was performed. Inclusion criteria were documented non-sustained ventricular tachycardia, sustained ventricular tachycardia, ventricular fibrillation, resuscitated cardiac arrest or SCD > 30 days post-Fontan completion. Results: Of 1611 patients, 20 (1.2%) had VA; 14 (1.0%) had VA without SCD and 6 (<1%) had SCD (6% of all deaths recorded in Registry; 5 of those had documented VA at the time of arrest and 1 was presumed to be VA-associated). The median age at first VA was 20.5 (1432) years, 10 (50%) were females, and the median age at Fontan operation was 8 (417) years. On univariable analysis, hypoplastic left heart syndrome (p = 0.03) and older age Fontan operation (p < 0.001) were associated with VA. Earlier Fontan era (p < 0.003), atriopulmonary Fontan (p < 0.001), pre-Fontan atrioventricular valve repair (p = 0.013) pre-or post-Fontan atrial arrhythmia (p = 0.010) were associated with SCD. Patients with VA had a 3 times higher risk of death or heart transplant (HR 3.27(1.19, 8.98), p = 0.02). Conclusions: A proportion of people living with a Fontan circulation have malignant VA. Routine VA screening in this cohort is essential. More data are needed to aid risk stratification. 2023, Tech Science Press. All rights reserved.
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Hume, Robert D.; Kanagalingam, Shaan; Deshmukh, Tejas; Chen, Siqi; Mithieux, Suzanne M.; Rashid, Fairooj N.; Roohani, Iman; Lu, Juntang; Doan, Tram; Graham, Justine Dinny; Clayton, Zoe E.; Slaughter, Eugene; Kizana, Eddy; Stempien-Otero, April S.; Brown, Paula; Thomas, Liza; Weiss, Anthony Steven; Chong, James J.H.Background: Myocardial infarction (MI) is among the leading causes of death worldwide. Following MI, necrotic cardiomyocytes are replaced by a stiff collagen-rich scar. Compared to collagen, the extracellular matrix protein elastin has high elasticity and may have more favorable properties within the cardiac scar. We sought to improve post-MI healing by introducing tropoelastin, the soluble subunit of elastin, to alter scar mechanics early after MI. METHODS AND RESULTS: We developed an ultrasound-guided direct intramyocardial injection method to administer tropoelastin directly into the left ventricular anterior wall of rats subjected to induced MI. Experimental groups included shams and infarcted rats injected with either PBS vehicle control or tropoelastin. Compared to vehicle treated controls, echocardiography assessments showed tropoelastin significantly improved left ventricular ejection fraction (64.74.4% versus 46.03.1% control) and reduced left ventricular dyssynchrony (11.43.5 ms versus 31.15.8 ms control) 28 days post-MI. Additionally, tropoelastin reduced post-MI scar size (8.91.5% versus 20.92.7% control) and increased scar elastin (225.8% versus 6.21.5% control) as determined by histological assessments. RNA sequencing (RNAseq) analyses of rat infarcts showed that tropoelastin injection increased genes associated with elastic fiber formation 7 days post-MI and reduced genes associated with immune response 11 days post-MI. To show translational relevance, we performed immunohistochemical analyses on human ischemic heart disease cardiac samples and showed an increase in tropoelastin within fibrotic areas. Using RNA-seq we also demonstrated the tropoelastin gene ELN is upregulated in human ischemic heart disease and during human cardiac fibroblast-myofibroblast differentiation. Furthermore, we showed by immunocytochemistry that human cardiac fibroblast synthesize increased elastin in direct response to tropoelastin treatment. Conclusions: We demonstrate for the first time that purified human tropoelastin can significantly repair the infarcted heart in a rodent model of MI and that human cardiac fibroblast synthesize elastin. Since human cardiac fibroblasts are primarily responsible for post-MI scar synthesis, our findings suggest exciting future clinical translation options designed to therapeutically manipulate this synthesis. 2023 Authors. All rights reserved.
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Coffi Dit Gleize, Kanako; Tran, Clara T.H.; Waterhouse, Anna; Bilek, Marcela M.M.; Wickham, Shelley F.J.Activated microplates are widely used in biological assays and cell culture to immobilize biomolecules, either through passive physical adsorption or covalent cross-linking. Covalent attachment gives greater stability in complex biological mixtures. However, current multistep chemical activation methods add complexity and cost, require specific functional groups, and can introduce cytotoxic chemicals that affect downstream cellular applications. Here, we show a method for one-step linker-free activation of microplates by energetic ions from plasma for covalent immobilization of DNA and protein. Two types of energetic ion plasma treatment were shown to be effective: plasma immersion ion implantation (PIII) and plasma-activated coating (PAC). This is the first time that PIII and PAC have been reported in microwell plates with nonflat geometry. We confirm that the plasma treatment generates radical-activated surfaces at the bottom of wells despite potential shadowing from the walls. Comprehensive surface characterization studies were used to compare the PIII and PAC microplate surface composition, wettability, radical density, optical properties, stability, and biomolecule immobilization density. PAC plates were found to have more nitrogen and lower radical density and were more hydrophobic and more stable over 3 months than PIII plates. Optimal conditions were obtained for high-density DNA (PAC, 0 or 21% nitrogen, pH 3-4) and streptavidin (PAC, 21% nitrogen, pH 5-7) binding while retaining optical properties required for typical high-throughput biochemical microplate assays, such as low autofluorescence and high transparency. DNA hybridization and protein activity of immobilized molecules were confirmed. We show that PAC activation allows for high-density covalent immobilization of functional DNA and protein in a single step on both 96- and 384-well plates without specific linker chemistry. These microplates could be used in the future to bind other user-selected ligands in a wide range of applications, for example, for solid phase polymerase chain reaction and stem cell culture and differentiation. 2022 American Chemical Society.
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Giskes, Katrina; Lowres, Nicole; Orchard, Jessica Joan; Li, Jialin; McKenzie, Kirsty; Hespe, Charlotte Mary; Freedman, Ben BenObjective: To assess whether atrial fibrillation (AF) self-screening stations in general practice waiting rooms improve AF screening, diagnosis, and stroke risk management. Design, setting: Intervention study (planned duration: twelve weeks) in six New South Wales general practices (two in rural locations, four in greater metropolitan Sydney), undertaken during 28 August 2020 5 August 2021. Participants: People aged 65 years or more who had not previously been diagnosed with AF, and had appointments for face-to-face GP consultations. People with valvular AF were excluded. Intervention: AF self-screening station and software, integrated with practice electronic medical record programs, that identified and invited participation by eligible patients, and exported single-lead electrocardiograms and automated evaluations to patients medical records. Main outcome measures: Screening rate; incidence of newly diagnosed AF during intervention and pre-intervention periods; prescribing of guideline-recommended anticoagulant medications. Results: Across the six participating practices, 2835 of 7849 eligible patients (36.1%) had face-to-face GP appointments during the intervention period, of whom 1127 completed AF self-screening (39.8%; range by practice: 1274%). AF was diagnosed in 49 screened patients (4.3%), 44 of whom (90%) had CHA<inf>2</inf>DS<inf>2</inf>-VA scores of 2 or more (high stroke risk). The incidence of newly diagnosed AF during the pre-intervention period was 11 cases per 1000 eligible patients; during the intervention period, it was 22 per 1000 eligible patients (screen-detected: 17 per 1000 eligible patients; otherwise detected: 4.6 per 1000 eligible patients). Prescribing of oral anticoagulation therapy for people newly diagnosed with AF and high stroke risk was similar during the pre-intervention (20 of 24, 83%) and intervention periods (46 of 54, 85%). Conclusions: AF self-screening in general practice waiting rooms is a feasible approach to increasing AF screening and diagnosis rates by reducing time barriers to screening by GPs. AF self-screening could reduce the number of AF-related strokes. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12620000233921 (prospective). 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.
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Tse, Benita C.Y.; Ferguson, Angela L.; Koay, Yen Chin; Grau, Georges Emile Raymond; Don, Anthony Simon; Byrne, Scott NapierThe ability of ultraviolet radiation to suppress the immune system is thought to be central to both its beneficial (protection from autoimmunity) and detrimental (carcinogenic) effects. Previous work revealed a key role for lipids particularly platelet-activating factor and sphingosine-1-phosphate in mediating UV-induced immune suppression. We therefore hypothesized that there may be other UV-induced lipids that have immune regulatory roles. To assess this, mice were exposed to an immune suppressive dose of solar-simulated UV (8 J/cm2). Lipidomic analysis identified 6 lipids (2 acylcarnitines, 2 neutral lipids, and 2 phospholipids) with significantly increased levels in the skin-draining lymph nodes of UV-irradiated mice. Imaging mass spectrometry of the lipids in combination with imaging mass cytometry identification of lymph node cell subsets indicated a preferential location of UV-induced lipids to T cell areas. In vitro co-culture of skin-draining lymph node lipids with lymphocytes showed that lipids derived from UV-exposed mice have no effect on T cell activation but significantly inhibited T cell proliferation, indicating that the lipids play an immune regulatory role. These studies are important first steps in identifying novel lipids that contribute to UV-mediated immune suppression. 2023 Tse, Ferguson, Koay, Grau, Don and Byrne.
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King, Gregory; Buratto, Edward; Cordina, Rachael Louise; Iyengar, Ajay J.; Grigg, Leeanne Elizabeth; Kelly, Andrew J.; Bullock, Andrew M.; Ayer, Julian Ganesh J.; Alphonso, Nelson D.; d'Udekem, Yves A.; Konstantinov, Igor E.Objective: The effect of ventricular dominance and previous atrioventricular valve (AVV) surgery on patient outcomes after Fontan operation remains unclear. We sought to determine the effect of ventricular dominance and previous AVV surgery on transplantation-free survival and long-term AVV competency in patients with atrioventricular septal defect (AVSD) and Fontan circulation. Methods: We conducted a retrospective study of 1703 patients in the Australia and New Zealand Fontan Registry, who survived Fontan operation between 1987 and 2021. Results: Of 174 patients with AVSD, 60% (105/174) had right ventricular (RV) dominance and 40% (69/174) had left ventricular (LV) dominance. The cumulative incidence of moderate or greater AVV regurgitation at 25 years after Fontan operation in patients with LV dominance was 56% (95% CI, 35%-72%), compared with 54% (95% CI, 40%-67%) in patients with RV dominance (P = .6). Nonetheless, transplantation-free survival at 25 years in patients with LV dominance was 94% (95% CI, 86%-100%), compared with 67% (95% CI, 52%-87%) in patients with RV dominance (hazard ratio, 5.9; 95% CI, 1.4-25.4; P < .01). Of note, transplantation-free survival was not different in patients who underwent AVV surgery before or at Fontan completion compared with those who did not (15 years: 81% [95% CI, 62%-100%] vs 88% [95% CI, 81%-95%]; P = .3). Conclusions: In patients with AVSD and Fontan circulation the rate of moderate or greater common AVV regurgitation is similar in those with LV and RV dominance. RV dominance, rather than previous AVV surgery, is a risk factor for death or transplantation. 2022
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Offen, Sophie M.; Puranik, Rajesh; Baker, David William; Cordina, Rachael Louise; Chard, Richard B.; Celermajer, David S.Background: The prevalence and determinants of tricuspid regurgitation (TR) in patients with repaired Tetralogy of Fallot (rTOF) remain incompletely understood. Objectives: To explore the prevalence of and factors associated with TR in patients with rTOF, specifically, the relationship of right ventricular (RV) dilatation with TR severity. Methods: Patients (?17 yrs) with rTOF referred to our service (20002019) were identified. Those with severe pulmonary stenosis, significant shunt, or previous tricuspid valve surgery were excluded. Using standard cardiac MRI protocols, RV, right atrial (RA) and tricuspid valve (TV) parameters were measured and compared. Results: 68 consecutively eligible patients with rTOF were included in the study (27 9 yrs., 35% female). Despite substantial RV volume overload (mean RVEDVi 153 mL/m2), the majority of the cohort (78%) had no or only mild TR. RA volumes, tenting height/area and annular diameter were normal (4.9 2.0 mm, 1.1 1.0 cm2 and 32.4 6.2 mm, respectively). There was no significant correlation of TR fraction with RVEDVi (r = 0.13; p = 0.30), RVEF (r = 0.09; p = 0.44) or tricuspid annular diameter (r = 0.07; p = 0.62). Only RAVi showed a weak but significant correlation with TR fraction (0.29; p = 0.03). In a pooled cohort analysis, including both rTOF patients and adults with a dilated RV from pre-tricuspid shunt lesions, only rTOF was independently associated with higher TR fraction (p = 0.017). Conclusion: Despite substantial RV dilatation in a cohort with rTOF, there was surprisingly little TR. We found poor correlation between RVEDVi, RA volumes, tricuspid annular dilatation and the presence of significant TR. These findings question commonly held notions regarding the pathophysiology of functional TR in these patients. 2022 Elsevier B.V.
