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Showing 521–540 of 2058 publications.
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Ritchie, Rebecca H.; Galougahi, Keyvan Karimi; Figtree, Gemma A.[No abstract available]
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Nagata, Yoshiki; Yamagami, Takashi; Nutbeam, Don; Freedman, Ben Ben; Lowres, NicoleObjectives International guidelines recommend opportunistic screening for atrial fibrillation (AF); however, there is no current data to inform how often to repeat screening. We aimed to investigate the incremental annual yield and stroke risk of new AF cases in individuals screened annually over 4 years. Design A retrospective cohort study. Setting Hokuriku Health Service Association, Toyama prefecture, Japan. Participants Employees and their families receiving annual health examinations from Hokuriku Health Service Association. Intervention Each subject received an annual health examination (including 12-lead ECG) from 2014 to 2017. Only subjects with baseline ECGs in 2012 and/or 2013 were included. Main outcome measures Rates (cases/100 person-years) of new AF identified each year for 4 consecutive years of screening (stratified according to gender and age groups). Calculated stroke risk of new AF cases using modified CHA 2 DS 2 -VASc scores (without heart failure data) (CHA 2 DS 2 VASc = C: congestive heart failure [1 point]; H: hypertension [1 point]; A2: age 65-74 years [1 point] or age ?75 years [2 points]; D: diabetes mellitus [1 point]; S: prior stroke or transient ischemic attack [2 points]; VA: vascular disease [1 point]; and Sc: sex category [female] [1 point]) Results In 2014, 88 218 subjects had an ECG (46.812.5 years; 64% men): identifying 346 (0.39%) known AF and 69 (0.08%) new AF. The incidence rate of new AF increased with age from 0.01% (<50 years) to 0.98% (?75 years) and was higher in men (0.1%) than women (0.05%). Repeated annual screening over 4 years identified a consistent new AF yield 0.06%-0.10% per year (0.33%-0.55% ?65 years). Forty-two per cent of all new AF cases, and 76% of cases aged ?65 years, had a class-1 oral anticoagulation (OAC) recommendation (modified CHA 2 DS 2 -VASc score ?2 men, ?3 women). Conclusions Repeated annual ECG screening of the same population provides a consistent yield of new AF each year. The majority of new AF (?65 years) are eligible for anticoagulation for stroke prevention. Although AF prevalence and incidence are lower in Japan than Western countries, 2318 new cases would be identified in Toyama prefecture each year with annual screening, of whom ?927 would have a high stroke risk with a recommendation for OAC therapy. Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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Freedman, Ben Ben[No abstract available]
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Wong, Kam Cheong; Klimis, Harry; Lowres, Nicole; von Huben, Amy; Marschner, Simone L.; Chow, Clara KayeiWith increasing use of handheld ECG devices for atrial fibrillation (AF) screening, it is important to understand their accuracy in community and hospital settings and how it differs among settings and other factors. A systematic review of eligible studies from community or hospital settings reporting the diagnostic accuracy of handheld ECG devices (ie, devices producing a rhythm strip) in detecting AF in adults, compared with a gold standard 12-lead ECG or Holter monitor, was performed. Bivariate hierarchical random-effects meta-analysis and meta-regression were performed using R V.3.6.0. The search identified 858 articles, of which 14 were included. Six studies recruited from community (n=6064 ECGs) and eight studies from hospital (n=2116 ECGs) settings. The pooled sensitivity was 89% (95% CI 81% to 94%) in the community and 92% (95% CI 83% to 97%) in the hospital. The pooled specificity was 99% (95% CI 98% to 99%) in the community and 95% (95% CI 90% to 98%) in the hospital. Accuracy of ECG devices varied: sensitivity ranged from 54.5% to 100% and specificity ranged from 61.9% to 100%. Meta-regression showed that setting (p=0.032) and ECG device type (p=0.022) significantly contributed to variations in sensitivity and specificity. The pooled sensitivity and specificity of single-lead handheld ECG devices were high. Setting and handheld ECG device type were significant factors of variation in sensitivity and specificity. These findings suggest that the setting including user training and handheld ECG device type should be carefully reviewed. Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
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Carroll, Luke; Gardiner, Kelly; Ignasiak, Marta Teresa; Holmehave, Jeppe; Shimodaira, Shingo; Breitenbach, Thomas; Iwaoka, Michio; Ogilby, Peter R.; Pattison, David I.; Davies, Michael J.Selenium compounds have been identified as potential oxidant scavengers for biological applications due to the nucleophilicity of Se, and the ease of oxidation of the selenium centre. Previous studies have reported apparent second order rate constants for a number of oxidants (e.g. HOCl, ONOOH) with some selenium species, but these data are limited. Here we provide apparent second order rate constants for reaction of selenols (RSeH), selenides (RSeR?) and diselenides (RSeSeR) with biologically-relevant oxidants (HOCl, H<inf>2</inf>O<inf>2</inf>, other peroxides) as well as overall consumption data for the excited state species singlet oxygen (1O<inf>2</inf>). Selenols show very high reactivity with HOCl and 1O<inf>2</inf>, with rate constants > 108 M?1 s?1, whilst selenides and diselenides typically react with rate constants one- (selenides) or two- (diselenides) orders of magnitude slower. Rate constants for reaction of diselenides with H<inf>2</inf>O<inf>2</inf> and other hydroperoxides are much slower, with k for H<inf>2</inf>O<inf>2</inf> being <1 M?1 s?1, and for amino acid and peptide hydroperoxides ~102 M?1 s?1. The rate constants determined for HOCl and 1O<inf>2</inf> with these selenium species are greater than, or similar to, rate constants for amino acid side chains on proteins, including the corresponding sulfur-centered species (Cys and Met), suggesting that selenium containing compounds may be effective oxidant scavengers. Some of these reactions may be catalytic in nature due to ready recycling of the oxidized selenium species. These data may aid the development of highly efficacious, and catalytic, oxidant scavengers. 2020 Elsevier Inc.
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Lowres, Nicole; Hillis, Graham Scott; Gladman, Marc A.; Kol, Mark R.; Rogers, James F.; Chow, Vincent; Touma, Ferris; Barnes, Cara; Auston, Joanne; Freedman, Ben BenBackground: Atrial fibrillation (AF) secondary to non-cardiac surgery and medical illness is common and, although often transient, is associated with an increased risk of stroke and mortality. This pilot study tested the feasibility of self-monitoring to detect recurrent AF in this setting and the frequency with which it occurred. Methods: Patients with new secondary AF after non-cardiac surgery or medical illness that reverted to sinus rhythm before discharge were recruited in three tertiary hospitals in Australia. Participants performed self-monitoring for AF recurrence using a Handheld single-lead ECG device 34 times/day for 4-weeks. Results: From 16,454 admissions, 224 (1.4%) secondary AF cases were identified. Of these, 94 were eligible, and 29 agreed to participate in self-monitoring (66% male; median age 67 years). Self-monitoring was feasible and acceptable to participants in this setting. Self-monitoring identified AF recurrence in 10 participants (34%; 95% CI, 18% ?54%), with recurrence occurring ? 9 days following discharge in 9/10 participants. Only 4 participants (40%) reported associated palpitations with recurrence. Six participants (60%) with recurrence had a CHA<inf>2</inf>DS<inf>2</inf>-VA score ? 2, suggesting a potential indication for oral anticoagulation. Conclusions: Approximately 1 in 3 patients with transient secondary AF will have recurrent AF within nine days of discharge. These recurrent episodes are often asymptomatic but can be detected promptly using patient self-monitoring, which was feasible and acceptable. Future research is warranted to further investigate the incidence of secondary AF, the rate of recurrence after discharge and its prognosis, and whether use of oral anticoagulation can reduce stroke in this setting. 2020 The Authors
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Bernier, Michel; Mitchell, Sarah Jayne; Wahl, Devin; Diaz, Antonio; Singh, Abhishek K.; Seo, Wonhyo; Wang, Mingy; Ali, Ahmed; Kaiser, Tamzin A.; Price, Nathan L.; Aon, Miguel Antonio; Kim, Eun-young; Petr, Michael Angelo; Cai, Huan; Warren, Alessa; Di Germanio, Clara; Francesco, Andrea Di; Fishbein, Kenneth W.; Guiterrez, Vince; Harney, Dylan James; Koay, Yen Chin; MacH, John; Enamorado, Ignacio Navas; Pulpitel, Tamara Jayne; Wang, Yushi; Zhang, Jing; Zhang, Li; Spencer, Richard G.S.; Becker, Kevin G.; Egan, Josephine M.; Lakatta, Edward G.; OSullivan, John F.; Larance, Mark; LeCouteur, David G.; Cogger, Victoria Carroll; Gao, Bin; Ferndez-Hernando, Carlos; Cuervo, Ana Maria; de Cabo, Rafael C.In this study, Bernier et al. report on the off-label use of disulfiram to combat diet-induced obesity in mice through normalization of body weight and improvement of various physiological outcomes related to body composition and insulin responsiveness.; Obesity is a top public health concern, and a molecule that safely treats obesity is urgently needed. Disulfiram (known commercially as Antabuse), an FDA-approved treatment for chronic alcohol addiction, exhibits anti-inflammatory properties and helps protect against certain types of cancer. Here, we show that in mice disulfiram treatment prevented body weight gain and abrogated the adverse impact of an obesogenic diet on insulin responsiveness while mitigating liver steatosis and pancreatic islet hypertrophy. Additionally, disulfiram treatment reversed established diet-induced obesity and metabolic dysfunctions in middle-aged mice. Reductions in feeding efficiency and increases in energy expenditure were associated with body weight regulation in response to long-term disulfiram treatment. Loss of fat tissue and an increase in liver fenestrations were also observed in rats on disulfiram. Given the potent anti-obesogenic effects in rodents, repurposing disulfiram in the clinic could represent a new strategy to treat obesity and its metabolic comorbidities. 2020; 2020
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Barraclough, Jennifer Y.; Joglekar, Mugdha V.; Januszewski, Andrzej S.; Martez, Gonzalo J.; Celermajer, David S.; Keech, Anthony C.; Hardikar, Anandwardhan A.; Patel, SanjayBackground: Circulating microRNAs (miRNAs) may play a pathogenic role in acute coronary syndromes (ACS). It is not yet known if miRNAs dysregulated in ACS are modulated by colchicine. We profiled miRNAs in plasma samples simultaneously collected from the aorta, coronary sinus, and right atrium in patients with ACS. Methods: A total of 396 of 754 miRNAs were detected by TaqMan real-time polymerase chain reaction from EDTA-plasma in a discovery cohort of 15 patients (n = 3 controls, n = 6 ACS standard therapy, n = 6 ACS standard therapy plus colchicine). Fifty-one significantly different miRNAs were then measured in a verification cohort of 92 patients (n = 13 controls, n = 40 ACS standard therapy, n = 39 ACS standard therapy plus colchicine). Samples were simultaneously obtained from the coronary sinus, aortic root, and right atrium. Results: Circulating levels of 30 of 51 measured miRNAs were higher in ACS standard therapy patients compared to controls. In patients with ACS, levels of 12 miRNAs (miR-17, -106b-3p, -191, -106a, -146a, -130a, -223, -484, -889, -425-3p, -629, -142-5p) were lower with colchicine treatment. Levels of 7 of these 12 miRNA were higher in ACS standard therapy patients compared to controls and returned to levels seen in control individuals after colchicine treatment. Three miRNAs suppressed by colchicine (miR-146a, miR-17, miR-130a) were identified as regulators of inflammatory pathways. MicroRNAs were comparable across sampling sites with select differences in the transcoronary gradient of 4 miRNA. Conclusion: The levels of specific miRNAs elevated in ACS returned to levels similar to control individuals following colchicine. These miRNAs may mediate ACS (via inflammatory pathways) or increase post-ACS risk, and could be potentially used as biomarkers of treatment efficacy. The Author(s) 2020.
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Love, Dominic T.; Guo, Chaorui; Nikelshparg, Evelina I.; Brazhe, Nadezda A.; Sosnovtseva, Olga V.; Hawkins, Clare L.A host of chronic inflammatory diseases are accelerated by the formation of the powerful oxidant hypochlorous acid (HOCl) by myeloperoxidase (MPO). In the presence of thiocyanate (SCN-), the production of HOCl by MPO is decreased in favour of the formation of a milder oxidant, hypothiocyanous acid (HOSCN). The role of HOSCN in disease has not been fully elucidated, though there is increasing interest in using SCN- therapeutically in different disease settings. Unlike HOCl, HOSCN can be detoxified by thioredoxin reductase, and reacts selectively with thiols to result in reversible modifications, which could potentially reduce the extent of MPO-induced damage during chronic inflammation. In this study, we show that exposure of macrophages, a key inflammatory cell type, to HOSCN results in the reversible modification of multiple mitochondrial proteins, leading to increased mitochondrial membrane permeability, decreased oxidative phosphorylation and reduced formation of ATP. The increased permeability and reduction in ATP could be reversed by pre-treatment of the macrophages with cyclosporine A, implicating a role for the mitochondrial permeability transition pore. HOSCN also drives cells to utilise fatty acids as an energetic substrate after the inhibition of oxidative phosphorylation. Raman imaging studies highlighted the ability of HOSCN to perturb the electron transport chain of mitochondria and redistribute these organelles within the cell. Taken together, these data provide new insight into the pathways by which HOSCN can induce cytotoxicity and cellular damage, which may have relevance for the development of inflammatory disease, and therapeutic strategies to reduce HOCl-induced damage by supplementation with SCN-. 2020 The Authors
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Vanichkitrungruang, Siriluck; Chuang, Christine Y.; Hawkins, Clare L.; Davies, Michael J.Endothelial cell dysfunction is an early event in cardiovascular disease and atherosclerosis. The origin of this dysfunction is unresolved, but accumulating evidence implicates damaging oxidants, including hypochlorous acid (HOCl), a major oxidant produced by myeloperoxidase (MPO), during chronic inflammation. MPO is released extracellularly by activated leukocytes and binds to extracellular molecules including fibronectin, a major matrix glycoprotein involved in endothelial cell binding. We hypothesized that MPO binding might influence the modifications induced on fibronectin, when compared to reagent HOCl, with this including alterations to the extent of damage to protein side-chains, modified structural integrity, changes to functional domains, and impact on nae human coronary artery endothelial cell (HCAEC) adhesion and metabolic activity. The effect of increasing concentrations of the alternative MPO substrate thiocyanate (SCN?), which might decrease HOCl formation were also examined. Exposure of fibronectin to MPO/H<inf>2</inf>O<inf>2</inf>/Cl? is shown to result in damage to the functionally important cell-binding and heparin-binding fragments, gross structural changes to the protein, and altered HCAEC adhesion and activity. Differences were observed between stoichiometric, and above-stoichiometric MPO concentrations consistent with an effect of MPO binding to fibronectin. In contrast, MPO/H<inf>2</inf>O<inf>2</inf>/SCN? induced much less marked changes and limited protein damage. Addition of increasing SCN? concentrations to the MPO/H<inf>2</inf>O<inf>2</inf>/Cl? system provided protection, with 20 ?M of this anion rescuing damage to functionally-important domains, decreasing chemical modification, and maintaining normal HCAEC behavior. Modulating MPO binding to fibronectin, or enhancing SCN? levels at sites of inflammation may therefore limit MPO-mediated damage, and be of therapeutic value. 2020 The Author(s)
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Hong, Jun Ki; Gao, Lingzi; Singh, Jasneil; Goh, Tiffany; Ruhoff, Alexander M.; Neto, Chiara; Waterhouse, AnnaAlthough blood-contacting medical devices are used widely, blood clot formation (thrombosis) leads to device failure and potentially catastrophic adverse thrombotic events for patients, such as stroke or pulomonary embolism. Systemic anti-thrombotic drugs aimed at reducing these complications do not always prevent device thrombosis and can cause increased bleeding risks. Therefore, our understanding of material thrombosis mechanisms needs to be improved in order to develop next generation blood-contacting medical devices and materials. Medical device development requires material thrombogenicity evaluation according to the International Standards 10993-4 Biological evaluation of medical devices-Selection of tests for interactions with blood, which highlights that one of the key aspects for testing is a clinically relevant flow system. In this review, we first provide an overview of the current knowledge regarding material thrombosis and important physical and biological aspects of blood flow in relation to thrombus formation. We then examine commonly used in vitro flow systems to evaluate material and medical device thrombosis, focusing on their capabilities, advantages and disadvantages. Finally, we explore recent advances in technology that will aid in improving the design and fabrication of flow systems, mechanistic analysis and computational modelling. The Royal Society of Chemistry.
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Gallagher, Celine; Orchard, Jessica Joan; Nyfort-Hansen, Karin S.; Sanders, Prashanthan; Neubeck, Lis; Hendriks, Jeroen M.L.Background Atrial fibrillation (AF) is a growing epidemic. Current models of care delivery are inadequate in meeting the needs of the population with AF. Furthermore, quality of life is known to be poor in patients with AF and is associated with adverse patient outcomes. Objective The aim of this study was to determine if nurse-led education and cardiovascular risk factor modification, undertaken using the principles of motivational interviewing, facilitated by an electronic decision support tool to ensure the appropriate use of oral anticoagulation (OAC), could improve health-related quality of life (HRQoL), guideline adherence to OAC, and cardiovascular risk factor profiles in individuals with AF. Methods This was a multicenter, prospective, randomized controlled feasibility study of 72 individuals with AF. The intervention involved 1 face-to-face nurse-delivered education and risk factor management session with 4 follow-up telephone calls over a 3-month period to monitor progress. The primary outcome measure was HRQoL as assessed by the Short Form-12 survey. Results A total of 72 participants were randomized, with 36 individuals in each arm completing follow-up. Mean age was 65 11 years and 44% were women. At 3 months follow-up, no significant differences between groups were observed for the physical or mental component summary scores of the Short Form-12, nor any of the subscales. Appropriate use of OAC did not differ between groups at final follow-up. Conclusions A brief nurse-delivered educational intervention did not significantly impact on HRQoL or risk factor status in individuals with AF. Further research should focus on interventions of greater intensity to improve outcomes in this population. Trial Registration: ACTRN12615000928516. Wolters Kluwer Health, Inc. All rights reserved.
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Wali, Jibran A.; Koay, Yen Chin; Chami, Jason; Wood, Courtney; Corcilius, Leo; Payne, Richard J.; Rodionov, Roman Nikolaevich; Birkenfeld, Andreas L.; Samocha-Bonet, Dorit; Simpson, Stephen James; OSullivan, John F.Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture. 2020 the American Physiological Society
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Sung, Joseph Jao Yiu; Stewart, Cameron L.; Freedman, Ben Ben[No abstract available]
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Indja, Ben Elias; Woldendorp, Kei; Vallely, Michael P.; Grieve, Stuart M.Background: New-onset atrial fibrillation (NOAF) is a well-recognised, although variably reported complication following surgical aortic valve replacement (SAVR). Rates of NOAF following transcatheter aortic valve implantation (TAVI) seem to be notably less than SAVR, even though this population is typically older and of higher risk. The aim of this study was to determine the prevalence of NOAF in both these populations and associated postoperative outcomes. Methods: We conducted a systematic review and meta-analysis of studies reporting rates of NOAF post SAVR or TAVI, along with early postoperative outcomes. Twenty-five (25) studies with a total of 13,010 patients were included in the final analysis. Results: The prevalence of NOAF post SAVR was 0.4 (95% CI 0.360.44) and post TAVI 0.15 (95% CI 0.110.18). NOAF was associated with an increased risk of postoperative cerebrovascular accident (CVA) for SAVR and TAVI (RR 1.44 95% CI 1.012.06 and RR 2.24 95% CI 1.463.45 respectively). NOAF was associated with increased mortality in the TAVI group (RR 3.02 95% CI 1.555.9) but not the SAVR group (RR 1.00, 95% CI 0.541.84). Hospital length of stay was increased for both TAVI and SAVR patients with NOAF (MD 2.54 days, 95% CI 2.03.00) and (MD 1.64 days, 95% CI 0.043.24 respectively). Conclusions: The prevalence of NOAF is significantly less following TAVI, as compared to SAVR. While NOAF is associated with increased risk of postoperative stroke for both groups, for TAVI alone NOAF confers increased risk of early mortality. 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
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Saxena, Ashish; Ng, Eddie Yin Kwee; Manchanda, Chirag; Canchi, TejasIn this study, a cardiac thermal pulse evaluation-based carotid artery stenosis detection method is proposed. It is postulated that the presence of stenosis in the carotid artery results in a thermal lag in skin temperature at the neck skin surface that can be quantified to the degree of stenosis. A finite volume method-based transient bioheat transfer study was performed on a carotid artery-jugular vein 3-Dimensional (3D) geometry model encapsulated by the neck tissue. As the transient physiological blood flow in the carotid artery thermally interacts with the blood perfusion in the neck tissue, a thermal fluctuation or cardiac thermal pulse is resulted in the top-neck skin localized surface temperature contours. Two tissue blood perfusion models, constant (temperature-independent) and varying (temperature-dependent), were used to comparatively study the cardiac thermal pulse characterized by their signal noise. For 0% stenosis case, compared to the constant perfusion model, the average instantaneous noise for the varying perfusion model was found to be significantly lower (0.02 0.01 versus 0.05 0.01, p < 0.01). Furthermore, varying degrees of stenosis (25%, 50%, and 75%) were introduced in the carotid artery to study their effect on the cardiac thermal pulse. It was observed that there is a successive shift in the phase of the cardiac thermal pulse with an increase in the degree of stenosis in the carotid artery. This study demonstrates the potential of a cardiac thermal pulse evaluation-based indirect screening tool for carotid artery stenosis. 2020 Elsevier Ltd
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Cartland, Si; Tamer, Nicole; Patil, Manisha S.; Di Bartolo, Belinda Ann; Kavurma, Mary M.Systemic hypertension, characterized by elevated blood pressure ?140/90mmHg, is a major modifiable risk factor for cardiovascular disease. Hypertension also associates with non-alcoholic fatty liver disease (NAFLD), which is becoming common due to a modern diet and lifestyle. The aim of the present study was to examine whether a high-fat "Western" diet had effects on hypertension and associated NAFLD. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were placed on a normal chow or high-fat diet for 8weeks; blood pressure was measured fortnightly and body weight recorded weekly. As expected, SHR had elevated blood pressure compared to WKY. Diet did not influence blood pressure. Compared to SHR, WKY rats gained more weight, associating with increased white adipose tissue weight. Normotensive rats also had higher plasma cholesterol and triglycerides in response to a Western diet, with no changes in plasma glucose levels. Neither strain developed atherosclerosis. Interestingly, high-fat diet-fed SHR had increased liver weight, associating with a significant level of hepatic lipid accumulation not observed in WKY. Further, they exhibited hepatocellular ballooning and increased hepatic inflammation, indicative of steatohepatitis. These findings suggest that a high-fat Western diet promotes features of NAFLD in SHR, but not WKY rats. Importantly, the high-fat diet had no effect on blood pressure. 2020 Company of the International Journal of Experimental Pathology (CIJEP)
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El Kazzi, Mary; Rayner, Benjamin Saul; Chami, Belal; Dennis, Joanne Marie; Thomas, Shane R.; Witting, Paul KennethSignificance: Acute myocardial infarction (AMI) is a leading cause of death worldwide. Post-AMI survival rates have increased with the introduction of angioplasty as a primary coronary intervention. However, reperfusion after angioplasty represents a clinical paradox, restoring blood flow to the ischemic myocardium while simultaneously inducing ion and metabolic imbalances that stimulate immune cell recruitment and activation, mitochondrial dysfunction and damaging oxidant production. Recent Advances: Preclinical data indicate that these metabolic imbalances contribute to subsequent heart failure through sustaining local recruitment of inflammatory leukocytes and oxidative stress, cardiomyocyte death, and coronary microvascular disturbances, which enhance adverse cardiac remodeling. Both left ventricular dysfunction and heart failure are strongly linked to inflammation and immune cell recruitment to the damaged myocardium. Critical Issues: Overall, therapeutic anti-inflammatory and antioxidant agents identified in preclinical trials have failed in clinical trials. Future Directions: The versatile neutrophil-derived heme enzyme, myeloperoxidase (MPO), is gaining attention as an important oxidative mediator of reperfusion injury, vascular dysfunction, adverse ventricular remodeling, and atrial fibrillation. Accordingly, there is interest in therapeutically targeting neutrophils and MPO activity in the setting of heart failure. Herein, we discuss the role of post-AMI inflammation linked to myocardial damage and heart failure, describe previous trials targeting inflammation and oxidative stress post-AMI, highlight the potential adverse impact of neutrophil and MPO, and detail therapeutic options available to target MPO clinically in AMI patients. Copyright 2020, Mary Ann Liebert, Inc., publishers 2020.
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El Kazzi, Mary; Shi, Han; Vuong, Sally; Wang, Xiaosuo; Chami, Belal; Liu, Yuyang; Rayner, Benjamin Saul; Witting, Paul KennethReperfusion therapy increases survival post-acute myocardial infarction (AMI) while also stimulating secondary oxidant production and immune cell infiltration. Neutrophils accumulate within infarcted myocardium within 24 h post-AMI and release myeloperoxidase (MPO) that catalyses hypochlorous acid (HOCl) production while increasing oxidative stress and inflammation, thereby enhancing ventricular remodelling. Nitroxides inhibit MPO-mediated HOCl production, potentially ameliorating neutrophil-mediated damage. Aim: Assess the cardioprotective ability of nitroxide 4-methoxyTEMPO (4MetT) within the setting of AMI. Methods: Male Wistar rats were separated into 3 groups: SHAM, AMI/R, and AMI/R + 4MetT (15 mg/kg at surgery via oral gavage) and subjected to left descending coronary artery ligation for 30 min to generate an AMI, followed by reperfusion. One cohort of rats were sacrificed at 24 h post-reperfusion and another 28 days post-surgery (with 4MetT (15 mg/kg) administration twice daily). Results: 3-chlorotyrosine, a HOCl-specific damage marker, decreased within the heart of animals in the AMI/R + 4-MetT group 24 h post-AMI, indicating the drug inhibited MPO activity; however, there was no evident difference in either infarct size or myocardial scar size between the groups. Concurrently, MPO, Nf?B, TNF?, and the oxidation marker malondialdehyde increased within the hearts, with 4-MetT only demonstrating a trend in decreasing MPO and TNF levels. Notably, 4MetT provided a significant improvement in cardiac function 28 days post-AMI, as assessed by echocardiography, indicating potential for 4-MetT as a treatment option, although the precise mechanism of action of the compound remains unclear. 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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Liu, Yuyang; Burton, Thomas Joseph; Rayner, Benjamin Saul; San Gabriel, Patrick T.; Shi, Han; El Kazzi, Mary; Wang, Xiaosuo; Dennis, Joanne Marie; Ahmad, Gulfam A.U.; Schroder, Angie L.; Gao, Antony; Witting, Paul Kenneth; Chami, BelalUlcerative colitis is a condition characterised by the infiltration of leukocytes into the gastrointestinal wall. Leukocyte-MPO catalyses hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN) formation from chloride (Cl?) and thiocyanous (SCN?) anions, respectively. While HOCl indiscriminately oxidises biomolecules, HOSCN primarily targets low-molecular weight protein thiols. Oxidative damage mediated by HOSCN may be reversible, potentially decreasing MPO-associated host tissue destruction. This study investigated the effect of SCN? supplementation in a model of acute colitis. Female mice were supplemented dextran sodium sulphate (DSS, 3% w/v) in the presence of 10 mM Cl? or SCN? in drinking water ad libitum, or with salts (NaCl and NaSCN only) or water only (controls). Behavioural studies showed mice tolerated NaSCN and NaCl-treated water with water-seeking frequency. Ion-exchange chromatography showed increased fecal and plasma SCN? levels in thiocyanate supplemented mice; plasma SCN? reached similar fold-increase for smokers. Overall there was no difference in weight loss and clinical score, mucin levels, crypt integrity and extent of cellular infiltration between DSS/SCN? and DSS/Cl? groups. Neutrophil recruitment remained unchanged in DSS-treated mice, as assessed by fecal calprotectin levels. Total thiol and tyrosine phosphatase activity remained unchanged between DSS/Cl? and DSS/SCN? groups, however, colonic tissue showed a trend in decreased 3-chlorotyrosine (1.5-fold reduction, p < 0.051) and marked increase in colonic GCLC, the rate-limiting enzyme in glutathione synthesis. These data suggest that SCN? administration can modulate MPO activity towards a HOSCN-specific pathway, however, this does not alter the development of colitis within a DSS murine model. 2020
