Search
Showing 781–800 of 2058 publications.
-
Vernon, Stephen Thomas; Coffey, Sean; Bhindi, Ravinay; Soo Hoo, Soon Yeng; Nelson, Gregory I.C.; Ward, Michael R.; Hansen, Peter S.; Asrress, Kaleab N.; Chow, Clara Kayei; Celermajer, David S.; OSullivan, John F.; Figtree, Gemma A.Aims: Identification and management of the Standard Modifiable Cardiovascular Risk Factors (SMuRFs; hypercholesterolaemia, hypertension, diabetes and smoking) has substantially improved cardiovascular disease outcomes. However, cardiovascular disease remains the leading cause of death worldwide. Suspecting an evolving pattern of risk factor profiles in the ST elevation myocardial infarction (STEMI) population with the improvements in primary care, we hypothesized that the proportion of SMuRFless STEMI patients may have increased. Methods/results: We performed a single centre retrospective study of consecutive STEMI patients presenting from January 2006 to December 2014. Over the study period 132/695 (25%) STEMI patients had 0 SMuRFs, a proportion that did not significantly change with age, gender or family history. The proportion of STEMI patients who were SMuRFless in 2006 was 11%, which increased to 27% by 2014 (odds ratio 1.12 per year, 95% confidence interval: 1.041.22). The proportion of patients with hypercholesterolaemia decreased (odds ratio 0.92, 95% confidence interval 0.860.98), as did the proportion of current smokers (odds ratio 0.93, 95% confidence interval 0.860.99), with no significant change in the proportion of patients with diabetes and hypertension. SMuRF status was not associated with extent of coronary disease; in-hospital outcomes, or discharge prescribing patterns. Conclusion: The proportion of STEMI patients with STEMI poorly explained by SMuRFs is high, and is significantly increasing. This highlights the need for bold approaches to discover new mechanisms and markers for early identification of these patients, as well as to understand the outcomes and develop new targeted therapies. 2017, The European Society of Cardiology 2017.
-
Barraclough, Jennifer Y.; Garden, Frances L.; Toelle, Brett G.; O'Meagher, Shamus; Marks, Guy B.; Cowell, Christopher T.; Celermajer, David S.; Ayer, Julian Ganesh J.Background: Augmentation index (AIx) is a noninvasive measure of pulse wave reflection. AIx is associated with cardiovascular disease. Adult women have a higher AIx than men, but the factors determining this sex-related difference remain to be determined. Methods: To examine factors associated with AIx in adolescents, participants in the Childhood Asthma Prevention Study, followed from birth, were assessed at age 14 years, with AIx standardized to a heart rate of 75/min (AIx-75) and pulse wave velocity. Associations of AIx-75 and pulse wave velocity with height, change in height, and measures of puberty were assessed. Results: AIx-75 was higher in women compared to men [-24.5 (12.1) versus-32.3 (12.4)%; P < 0.001]. Lower AIx-75 was significantly related to greater change in height between 8 and 14 years, but not to achieved height. The sex difference in AIx was not independently related to puberty variables. Differences between sexes included early life weight gain, lipids, height, BMI-Z-score, change in height from 8 to 14 years, and age at peak height velocity. Change in AIx-75 from 8 to 14 years was highly associated with change in height (m) from 8 to 14 years (B = -88.8, 95% confidence interval-137.3 to-40.3, P = < 0.001). The difference between sexes established at 8 years was not amplified from 8 to 14 years. Conclusion: AIx is higher in girls than boys at 14 years and is closely associated with change in height between 8 and 14 years. Measures of puberty do not appear to independently influence the sex difference in AIx in adolescents. 2017 Wolters Kluwer Health, Inc.
-
Vanags, Laura Z.; Tan, Joanne Tsui Ming; Santos, Miguel; Michael, Praveesuda Lorwattanapongsa; Ali, Ziad A.; Bilek, Marcela M.M.; Wise, Steven G.; Bursill, C. A.We utilized a plasma activated coating (PAC) to covalently bind the active component of high density lipoproteins (HDL), apolipoprotein (apo) A-I, to stainless steel (SS) surfaces. ApoA-I suppresses restenosis and thrombosis and may therefore improve SS stent biocompatibility. PAC-coated SS significantly increased the covalent attachment of apoA-I, compared to SS alone. In static and dynamic flow thrombosis assays, PAC+apoA-I inhibited thrombosis and reduced platelet activation marker p-selectin. PAC+apoA-I reduced smooth muscle cell attachment and proliferation, and augmented EC attachment to PAC. We then coated PAC onto murine SS stents and found it did not peel or delaminate following crimping/expansion. ApoA-I was immobilized onto PAC-SS stents and was retained as a monolayer when exposed to pulsatile flow in vivo in a murine stent model. In conclusion, ApoA-I immobilized on PAC withstands pulsatile flow in vivo and retains its bioactivity, exhibiting anti-thrombotic and anti-restenotic properties, demonstrating the potential to improve stent biocompatibility. 2017 Elsevier Inc.
-
Abdo, Adrian I.; Rayner, Benjamin Saul; Van Reyk, David M.; Hawkins, Clare L.Low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl) produced by myeloperoxidase (MPO) is present in atherosclerotic lesions, where it is implicated in the propagation of inflammation and acceleration of lesion development by multiple pathways, including the induction of endothelial dysfunction. Thiocyanate (SCN-) ions are utilised by MPO to produce the oxidant hypothiocyanous acid (HOSCN), which reacts with LDL in a different manner to HOCl. Whilst the reactivity of HOCl-modified LDL has been previously studied, the role of HOSCN in the modification of LDL in vivo is poorly defined, although emerging evidence suggests that these particles have distinct biological properties. This is important because elevated plasma SCN- is linked with both the propagation and prevention of atherosclerosis. In this study, we demonstrate that both HOSCN- and HOCl-modified LDL inhibit endothelium-mediated vasorelaxation ex vivo in rat aortic ring segments. In vitro experiments with human coronary artery endothelial cells show that HOSCN-modified LDL decreases in the production of nitric oxide (NO) and induces the loss of endothelial nitric oxide synthase (eNOS) activity. This occurs to a similar extent to that seen with HOCl-modified LDL. In each case, these effects are related to eNOS uncoupling, rather than altered expression, phosphorylation or cellular localisation. Together, these data provide new insights into role of MPO and LDL modification in the induction of endothelial dysfunction, which has implications for both the therapeutic use of SCN- within the setting of atherosclerosis and for smokers, who have elevated plasma levels of SCN-, and are more at risk of developing cardiovascular disease. 2017 The Authors
-
Tu, Hans T.H.; Chen, Ziyuan; Swift, Corey; Churilov, Leonid; Guo, Ruibingt Bing; Liu, Xinfeng; JANNES, J.; Mok, Chung Tong Vincent; Freedman, Ben Ben; Davis, Stephen M.; Yan, BernardRationale: Paroxysmal atrial fibrillation is a common and preventable cause of devastating strokes. However, currently available monitoring methods, including Holter monitoring, cardiac telemetry and event loop recorders, have drawbacks that restrict their application in the general stroke population. AliveCor heart monitor, a novel device that embeds miniaturized electrocardiography (ECG) in a smartphone case coupled with an application to record and diagnose the ECG, has recently been shown to provide an accurate and sensitive single lead ECG diagnosis of atrial fibrillation. This device could be used by nurses to record a 30-s ECG instead of manual pulse taking and automatically provide a diagnosis of atrial fibrillation. Aims: To compare the proportion of patients with paroxysmal atrial fibrillation detected by AliveCor ECG monitoring with current standard practice. Sample size: 296 Patients. Design: Consecutive ischemic stroke and transient ischemic attack patients presenting to participating stroke units without known atrial fibrillation will undergo intermittent AliveCor ECG monitoring administered by nursing staff at the same frequency as the vital observations of pulse and blood pressure until discharge, in addition to the standard testing paradigm of each participating stroke unit to detect paroxysmal atrial fibrillation. Study outcome: Proportion of patients with paroxysmal atrial fibrillation detected by AliveCor ECG monitoring compared to 12-lead ECG, 24-h Holter monitoring and cardiac telemetry. Discussion: Use of AliveCor heart monitor as part of routine stroke unit nursing observation has the potential to be an inexpensive non-invasive method to increase paroxysmal atrial fibrillation detection, leading to improvement in stroke secondary prevention. 2017, 2017 World Stroke Organization.
-
Fay, Matthew R.; Fitzmaurice, David Andrew; Freedman, Ben BenBackground: Individuals with atrial fibrillation (AF) face a fivefold increased risk of ischaemic stroke compared with those without the condition. Recent studies suggest that individuals with asymptomatic AF also face an increased risk of ischaemic stroke, but their condition is often not recognized and diagnosed until an ischaemic stroke event has occurred. Identification of individuals with undiagnosed AF at increased risk for stroke is critical in promoting optimal intervention with anticoagulants. Objectives: In this narrative review, we consider the benefits and limitations of various proposed screening strategies, whether single or multiple time-points, in addition to devices for implementation in the primary care setting. Outcomes: Opportunistic screening via pulse palpation with subsequent referral for 12-lead electrocardiogram testing has been shown to cost-effectively identify individuals with asymptomatic AF. Some handheld devices suitable for use in primary care settings are now available and may facilitate screening of large cohorts of individuals considered to be at increased risk of AF, such as those aged ?65 years or those diagnosed with or undergoing monitoring for hypertension. Conclusions: It was determined that improved detection and diagnosis of AF, combined with appropriate anticoagulation strategies, will be crucial for improving stroke prevention and reducing its associated social and economic costs. 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
-
Abbott, Stephen B.G.; Saper, Clifford B.Key points: Glutamatergic neurons in the median preoptic area were stimulated using genetically targeted Channelrhodopsin 2 in transgenic mice. Stimulation of glutamatergic median preoptic area neurons produced a profound hypothermia due to cutaneous vasodilatation. Stimulation also produced drinking behaviour that was inhibited as water was ingested, suggesting pre-systemic feedback gating of drinking. Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap. Abstract: The median preoptic nucleus (MnPO) serves an important role in the integration of water/electrolyte homeostasis and thermoregulation, but we have a limited understanding these functions at a cellular level. Using CreLox genetic targeting of Channelrhodospin 2 in VGluT2 transgenic mice, we examined the effect of glutamatergic MnPO neuron stimulation in freely behaving mice while monitoring drinking behaviour and core temperature. Stimulation produced a strong hypothermic response in 62% (13/21) of mice (core temperature: ?4.60.5C, P=0.001 vs. controls) caused by cutaneous vasodilatation. Stimulating glutamatergic MnPO neurons also produced robust drinking behaviour in 82% (18/22) of mice. Mice that drank during stimulation consumed 912163?l (n=8) during a 20min trial in the dark phase, but markedly less during the light phase (42183?l, P=0.0025). Also, drinking during stimulation was inhibited as water was ingested, suggesting pre-systemic feedback gating of drinking. Both hypothermia and drinking during stimulation occurred in 50% of mice tested. Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap. Thus, activation of separate but overlapping populations of glutamatergic MnPO neurons produces effects on drinking and autonomic thermoregulatory mechanisms, providing a structural basis for their frequently being coordinated (e.g. during hyperthermia). 2017 The Authors. The Journal of Physiology 2017 The Physiological Society
-
Callaghan, Fraser Maurice; Grieve, Stuart M.Purpose: 4D-flow MRI obtains a time-dependent 3D velocity field; however, its use for the calculation of higher-order parameters is limited by noise. We present an algorithm for denoising 4D-flow data. Theory and Methods: By integrating a velocity field and eliminating streamlines in noisy flow, depicted by high curvature, a denoised dataset may be extracted. This method, defined as the velocity field improvement (VFIT) algorithm, was validated in an analytical dataset and using in vivo data in comparison with a computation fluid dynamics (CFD) simulation. As a proof of principal, wall shear stress (WSS) measurements in the descending aorta were compared with those defined by CFD. Results: The VFIT algorithm achieved a >100% noise reduction of a corrupted analytical dataset. In addition, 4D-flow data were cleaned to show improved spatial resolution and near wall velocity representation. WSS measures compared well with CFD data and bulk flow dynamics were retained (<2% difference in flow measurements). Conclusion: This study presents a method for denoising 4D-flow datasets with improved spatial resolution. Bulk flow dynamics are accurately conserved while velocity and velocity gradient fields are improved; this is important in the calculation of higher-order parameters such as WSS, which are shown to be more comparable to CFD measures. Magn Reson Med 78:19591968, 2017. 2016 International Society for Magnetic Resonance in Medicine. 2016 International Society for Magnetic Resonance in Medicine
-
Stanton, Kelly M.; Ganigara, Madhusudan; Corte, Peter; Celermajer, David S.; McGuire, Mark A.; Torzillo, Paul John; Corte, Tamera Jo; Puranik, RajeshBackground Autopsy reports suggest that cardiac sarcoidosis occurs in 20 to 25% of patients with pulmonary sarcoidosis, yet the clinical ante-mortem diagnosis is made in only 5% of cases. Current diagnostic algorithms are complex and lack sensitivity. Cardiac Magnetic Resonance imaging (CMR) provides an opportunity to detect myocardial involvement in sarcoidosis. The aim of this study is to determine the prevalence and clinical significance of late gadolinium enhancement (LGE) on CMR in patients with sarcoidosis. Methods Consecutive patients with biopsy-proven sarcoidosis undergoing CMR were retrospectively evaluated for cardiac sarcoidosis. Medical records were correlated with CMR. Results Forty-six patients were evaluated. Late gadolinium enhancement was present in 22%, indicating myocardial involvement, and 70% had corresponding hyper-intense T2 signal indicating active inflammation. Late gadolinium enhancement was 18% +/? 9.7% of overall left ventricular (LV) mass and most commonly located in the basal to mid septum. There was no association between LGE and cardiovascular symptoms or pulmonary stage. Eighty per cent of patients with LGE did not fulfill conventional diagnostic criteria for cardiac sarcoidosis. However, LGE was associated with clinically significant arrhythmia (p < 0.01) and a lower LVEF (p = 0.04). Conclusions Using CMR, we identified a higher prevalence of cardiac sarcoidosis than previously reported clinical studies, a prevalence which is more consistent with autopsy data. The presence of LGE was highly correlated with clinically significant arrhythmias and lower LVEF. 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
-
Xu, Bei; Shanmugalingam, Renuka; Chau, Katrina; Pears, Suzanne; Hennessy, Annemarie; Makris, AngelaEarly administration of low dose acetyl salicylic acid (Aspirin) in high risk women reduces the risk of early onset preeclampsia. This study aims to investigate the effect of aspirin on trophoblast integration and the its effect on angiogenic and invasive pathways in an in-vitro model of preeclampsia. Red fluorescent-labeled human uterine myometrial microvascular endothelial cells (UtMVECs) were seeded on matrigel to form endothelial networks. Green fluorescent-labeled trophoblastic HTR-8/SVneo cells were co-cultured with the endothelial networks with/without TNF-a (0.5 ng/mL) and/or aspirin (0.1 mM) for 24 h. Fluorescent images were captured and quantified by Image J to examine the effects of TNF-a and aspirin on the trophoblast-endothelial integration. Conditioned media were collected to measure free VEGF, PlGF and sFlt-1 by ELISA and PGF1a by Enzyme immunoassay (EIA). Cells were retrieved to examine mRNA expression of angiogenic factors (VEGF, PlGF and sFlt-1), invasion markers (MMP-2 and TIMP-1), endothelial cell activation markers (E-selectin and VCAM), eNOS and cyclooxygenase (COX)-2 by quantitative PCR. Aspirin reversed the inhibitory effect of TNF-a on trophoblast cell integration into endothelial cellular networks. TNF-a increased PGF1a production (128 11%, p < 0.05), whilst aspirin reversed the TNF-a effect on PGF1a production (19 4%, p < 0.01). TNF-a decreased the mRNA expression of PlGF, eNOS, MMP-2 and TIMP-1, and stimulated COX2, E-selectin and VCAM mRNA expression. Aspirin did not reverse the TNF-a effect on these molecules. Aspirin improves trophoblast cell integration into endothelial cellular networks by inhibiting the effect of TNF-a via PGI<inf>2</inf> with no significant effect on antiangiogenic, invasive or endothelial activation markers. 2017
-
Bhaskar, Sonu M.M.; Cordato, Dennis John; Cappelen-Smith, Cecilia; Cheung, Andrew K.; Ledingham, David R.M.; Celermajer, David S.; Levi, Christopher RoyceDiagnosis, treatment, and secondary management of cryptogenic stroke patients pose a formidable challenge. The scenario is further complicated in patients with native and prosthetic valvular heart disease. We present a case study of a 36-year-old man who received intravenous thrombolysis (IV-tPA) and endovascular thrombectomy (EVT) for presumed cryptogenic complete middle cerebral artery infarction who made a surprisingly excellent clinical recovery despite poor baseline and postintervention neuroimaging. Retrospective gram stain of his clot confirmed a diagnosis of infective endocarditis. This raises an important issue regarding need for more routine histopathological analysis of clot retrieved after EVT in cryptogenic stroke patients particularly those with valvular heart disease. 2017 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
-
Evin, Morgane A.; Magne, Julien; Grieve, Stuart M.; Rieu, Ris; Pibarot, PhilipeBACKGROUND: Reference values of hemodynamic parameters for the assessment of prosthetic heart valves are necessary, and ideally need to be provided by entities independent of the valve manufacturers. Thus, the study aim was to provide, in vitro, normal reference values of the effective orifice area (EOA) for different models and sizes of mitral prosthetic valve, and to assess the determinants of EOA and mean transvalvular pressure gradient (mTPG). METHODS: Four models of mechanical prostheses were tested (one mono-leaflet, three bi-leaflet) and four models of bioprostheses (two bovine pericardial, two porcine) on a double-activation pulsed duplicator that was specifically designed and optimized for assessing the hemodynamic performance of mitral prosthetic valves. The hemodynamic conditions were standardized and included for bioprostheses: two mitral flow volumes, three mean aortic pressures, two heart rates, and three E/A ratios. The EOAs were measured with Doppler echocardiography, using the same method (continuity equation) as was used in the clinical setting. Overestimation in term of EOA was defined according to guidelines as >0.25 cm2. RESULTS: EOA reference values were recorded. For mono-leaflet prostheses (Medtronic Hall 7700, size 25 to 31 mm) 2.29 and 3.49; for bi-leaflet prostheses (St. Jude Medical Master and Master HP, sizes 25 to 33 mm and On-X valve, sizes 27-29 mm) 1.34 and 4.74 cm2; for porcine bioprostheses (Medtronic Mosaic CINCH, sizes 25 to 31 mm and St. Jude Epic 100, sizes 25 to 33 mm) 1.35 and 3.56 cm2; for bovine pericardial bioprosthetic valves (Edwards Perimount 6900P and Magna Ease 7300, sizes 25 to 33 mm) 1.67 and 2.36 cm2. There were some discrepancies between the normal reference EOAs measured compared to those provided by the prosthesis manufacturers, or in published reports. The bioprosthetic EOAs were shown to be smaller than the manufacturers' values in 32% of valves (by an average of 0.57 0.28 cm2) versus in 7% of valves when compared to values reported elsewhere (by an average of 0.43 0.17 cm2). The relationship between EOA and internal orifice area (IOA) varied according to the type of prosthesis. The EOA was close to the IOA in mechanical valves (regression slopes 0.87-0.99) but was much smaller than the IOA in bioprosthetic valves (slopes 0.25-0.30). The EOA was influenced by prosthesis diameter, prosthesis stent diameter and height, while the mTPG was influenced by EOA and heart rate. CONCLUSIONS: The present study has provided normal reference values of EOAs for several frequently used mitral prostheses. This information may be helpful for identifying and quantifying prosthetic valve dysfunction and prosthesis-patient mismatch.
-
Chen, Yunfeng; Ju, Lining Arnold; Rushdi, Muaz Nik; Ge, Chenghao; Zhu, ChengMechanosensing describes the ability of a cell to sense mechanical cues of its microenvironment, including not only all components of force, stress, and strain but also substrate rigidity, topology, and adhesiveness. This ability is crucial for the cell to respond to the surrounding mechanical cues and adapt to the changing environment. Examples of responses and adaptation include (de)activation, proliferation/apoptosis, and (de)differentiation. Receptor-mediated cell mechanosensing is a multistep process that is initiated by binding of cell surface receptors to their ligands on the extracellular matrix or the surface of adjacent cells. Mechanical cues are presented by the ligand and received by the receptor at the binding interface; but their transmission over space and time and their conversion into biochemical signals may involve other domains and additional molecules. In this review, a four-step model is described for the receptor-mediated cell mechanosensing process. Platelet glycoprotein Ib, T-cell receptor, and integrins are used as examples to illustrate the key concepts and players in this process.
-
Yeo, Giselle C.; Baldock, Clair; Wise, Steven G.; Weiss, Anthony StevenTropoelastin, as the monomer unit of elastin, assembles into elastic fibers that impart strength and resilience to elastic tissues. Tropoelastin is also widely used to manufacture versatile materials with specific mechanical and biological properties. The assembly of tropoelastin into elastic fibers or biomaterials is crucially influenced by key submolecular regions and specific residues within these domains. In this work, we identify the functional contributions of two rarely occurring negatively charged residues, glutamate 345 in domain 19 and glutamate 414 in domain 21, in jointly maintaining the native conformation of the tropoelastin hinge, bridge and foot regions. Alanine substitution of E345 and/or E414 variably alters the positioning and interactive accessibility of these regions, as illustrated by nanostructural studies and detected by antibody and cell probes. These structural changes are associated with a lower propensity for monomer coacervation, cross-linking into morphologically and functionally atypical hydrogels, and markedly impaired and abnormal elastic fiber formation. Our work indicates the crucial significance of both E345 and E414 residues in modulating specific local structure and higher-order assembly of human tropoelastin. 2016 American Chemical Society.
-
Murphy, Adrianna; Banerjee, Amitava; Breithardt, Gun?ter E.; Camm, Alan John; Commerford, Patrick Joseph; Freedman, Ben Ben; Gonzez-Hermosillo, Jes Antonio; Halperin, Jonathan Lee; Lau, Chu Pak; Perel, Pablo A.; Xavier, Denis; Wood, David A.; Jouven, Xavier P.; Morillo, Carlos A.Background The World Heart Federation has undertaken an initiative to develop a series of Roadmaps to promote development of national policies and health systems approaches, and to identify potential roadblocks on the road to effective prevention, detection, and management of cardiovascular disease in low-and middle-income countries (LMICs) and develop strategies for overcoming these. This Roadmap focuses on atrial fibrillation (AF). AF is the most common, clinically significant arrhythmia and, among other clinical outcomes, is associated with increased risk of stroke. Methods Development of this Roadmap included a review of published guidelines and research papers, and consultation with an expert committee comprising experts in clinical management of AF and health systems research in LMICs. The Roadmap identifies 1) key interventions for detection, diagnosis, and management of AF; 2) gaps in implementation of these interventions (knowledge-practice gaps); 3) health system roadblocks to implementation of AF interventions in LMICs; and 4) potential strategies for overcoming these. Results More research is needed on determinants and primary prevention of AF. Knowledge-practice gaps for detection, diagnosis, and management of AF are present worldwide, but may be more prominent in LMICs. Potential barriers to implementation of AF interventions include long distances to health facilities, shortage of health care professionals with training in AF, including interpretation of ECG, unaffordability of oral anticoagulants for patient households, reluctance on the part of physicians to initiate oral anticoagulant (OAC) therapy, and lack of awareness of the importance of persistent adherence to OAC therapy. Potential solutions include training of nonphysician health workers and pharmacists in pulse-taking, use of telemedicine technologies to transmit electrocardiogram results, engagement of nonphysician health workers in OAC therapy adherence support, and country-specific support and education programs for noncardiologist health care professionals. Conclusions AF affects millions of people worldwide and, left untreated, increases the risk and severity of stroke and heart failure. Although guidelines for the detection, diagnosis, and management of AF exist, there are gaps in implementation of these guidelines globally, and in particular in LMICs. This Roadmap identifies some potential solutions that may improve AF outcomes in LMICs but require further evaluation in these settings. 2017 World Heart Federation (Geneva)
-
Cartland, Si; Harith, Hanis H.; Genner, Scott W.; Dang, Lei; Cogger, Victoria Carroll; Vellozzi, Melissa A.; Di Bartolo, Belinda Ann; Thomas, Shane R.; Adams, Leon Anton; Kavurma, Mary M.Non-alcoholic fatty liver disease (NAFLD) incorporates steatosis, non-alcoholic steato-hepatitis (NASH) and liver cirrhosis, associating with diabetes and cardiovascular disease (CVD). TNF-related apoptosis-inducing ligand (TRAIL) is protective of CVD. We aimed to determine whether TRAIL protects against insulin resistance, NAFLD and vascular injury. Twelve-week high fat diet (HFD)-fed Trail -/- mice had increased plasma cholesterol, insulin and glucose compared to wildtype. Insulin tolerance was impaired with TRAIL-deletion, with reduced p-Akt, GLUT4 expression and glucose uptake in skeletal muscle. Hepatic triglyceride content, inflammation and fibrosis were increased with TRAIL-deletion, with elevated expression of genes regulating lipogenesis and gluconeogenesis. Moreover, Trail -/- mice exhibited reduced aortic vasorelaxation, impaired insulin signaling, and >20-fold increased mRNA expression for IL-1?, IL-6, and TNF-?. In vitro, palmitate treatment of hepatocytes increased lipid accumulation, inflammation and fibrosis, with TRAIL mRNA significantly reduced. TRAIL administration inhibited palmitate-induced hepatocyte lipid uptake. Finally, patients with NASH had significantly reduced plasma TRAIL compared to control, simple steatosis or obese individuals. These findings suggest that TRAIL protects against insulin resistance, NAFLD and vascular inflammation. Increasing TRAIL levels may be an attractive therapeutic strategy, to reduce features of diabetes, as well as liver and vascular injury, so commonly observed in individuals with NAFLD. 2017 The Author(s).
-
Polonchuk, Liudmila; Chabria, Mamta; Badi, Laura; Hoflack, Jean Christophe; Figtree, Gemma A.; Davies, Michael J.; Gentile, CarmineThree-dimensional in vitro cell systems are a promising alternative to animals to study cardiac biology and disease. We have generated three-dimensional in vitro models of the human heart ("cardiac spheroids", CSs) by co-culturing human primary or iPSC-derived cardiomyocytes, endothelial cells and fibroblasts at ratios approximating those present in vivo. The cellular organisation, extracellular matrix and microvascular network mimic human heart tissue. These spheroids have been employed to investigate the dose-limiting cardiotoxicity of the common anti-cancer drug doxorubicin. Viability/cytotoxicity assays indicate dose-dependent cytotoxic effects, which are inhibited by the nitric oxide synthase (NOS) inhibitor L-NIO, and genetic inhibition of endothelial NOS, implicating peroxynitrous acid as a key damaging agent. These data indicate that CSs mimic important features of human heart morphology, biochemistry and pharmacology in vitro, offering a promising alternative to animals and standard cell cultures with regard to mechanistic insights and prediction of toxic effects in human heart tissue. 2017 The Author(s).
-
Celermajer, David S.; Nasir-Ahmad, Subha[No abstract available]
-
Carroll, Luke; Pattison, David I.; Davies, Justin Bryan; Anderson, Robert F.; Lez-Alarc, Camilo; Davies, Michael J.Free radicals are produced during physiological processes including metabolism and the immune response, as well as on exposure to multiple external stimuli. Many radicals react rapidly with proteins resulting in side-chain modification, backbone fragmentation, aggregation, and changes in structure and function. Due to its low oxidation potential, the indole ring of tryptophan (Trp) is a major target, with this resulting in the formation of indolyl radicals (Trp). These undergo multiple reactions including ring opening and dimerization which can result in protein aggregation. The factors that govern Trp dimerization, the rate constants for these reactions and the exact nature of the products are not fully elucidated. In this study, second-order rate constants were determined for Trp dimerization in Trp-containing peptides to be 26 108 M?1 s?1 by pulse radiolysis. Peptide charge and molecular mass correlated negatively with these rate constants. Exposure of Trp-containing peptides to steady-state radiolysis in the presence of NaN<inf>3</inf> resulted in consumption of the parent peptide, and detection by LC-MS of up to 4 different isomeric Trp-Trp cross-links. Similar species were detected with other oxidants, including CO<inf>3</inf> - (from the HCO<inf>3</inf> - -dependent peroxidase activity of bovine superoxide dismutase) and peroxynitrous acid (ONOOH) in the presence or absence of HCO<inf>3</inf> -. Trp-Trp species were also isolated and detected after alkaline hydrolysis of the oxidized peptides and proteins. These studies demonstrate that Trp formed on peptides and proteins undergo rapid recombination reactions to form Trp-Trp cross-linked species. These products may serve as markers of radical-mediated protein damage, and represent an additional pathway to protein aggregation in cellular dysfunction and disease. 2017 Elsevier Inc.
-
Chau, Katrina; Hennessy, Annemarie; Makris, AngelaPlacental growth factor (PlGF) is an increasingly important molecule in the prediction, diagnosis and treatment of pre-eclampsia. It has pro-angiogenic effects on the feto-placental circulation and supports trophoblast growth. Mechanisms by which PlGF expression is regulated continue to be investigated. Low circulating PlGF precedes the manifestation of clinical disease in pre-eclamptic pregnancies and intrauterine growth restriction. This suggests that low PlGF is a marker of abnormal placentation, but it remains uncertain whether this is a cause or consequence. Prediction of pre-eclampsia using PlGF is promising and may assist in the targeting of resources to women at highest risk of adverse pregnancy outcomes. Promisingly, experimental animal models of pre-eclampsia have been successfully treated with supplemental PlGF. Treatment of pre-eclampsia with PlGF is a potential therapeutic option requiring further exploration. This review focuses specifically on the role of PlGF in normal and pathological placental development and in the clinical management of pre-eclampsia.
