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1.
Cardiovasc Res ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32065620

RESUMO

AIMS: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. CONCLUSION: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31912981

RESUMO

OBJECTIVES: This study aimed to present a case series of patient treated for stent underexpansion resistant to conventional treatment with intravascular lithotripsy (IVL). BACKGROUND: Stent underexpansion is a powerful predictor of long-term stent patency and correlates with unfavorable clinical outcomes. This case series demonstrates the utility of IVL in managing stent underexpansion resistant to conventional treatment. METHODS: We describe a case series of patients with stent underexpansion due to calcific coronary artery disease treated with IVL. Stent underexpansion was identified as an inability to adequately expand stents with conventional treatment. Only cases that failed to achieve adequate expansion with high-pressure noncompliant balloon inflation were included. RESULTS: Thirteen patients from six institutions have been included in this case series. The average age was 70.25 years with 76.9% of male patients. The average pre-IVL minimal stent area (MSA) was 2.71 mm2 , which improved to 6.44 mm2 post-IVL treatment, representing an average MSA gain of 238%. There were no procedural, peri-procedural, or 30-day major adverse cardiac and cerebrovascular event. CONCLUSION: This case series demonstrates that IVL is a feasible, safe alternative for the management of stent underexpansion due to calcific coronary disease.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31408105

RESUMO

AIMS: Cardiovascular thrombosis is responsible a quarter of deaths annually worldwide. Current imaging methods for cardiovascular thrombosis focus on anatomical identification of thrombus but cannot determine thrombus age or activity. Molecular imaging techniques hold promise for identification and quantification of thrombosis in vivo. Our objective was to assess a novel optical and positron-emitting probe targeting Factor XIIIa (ENC2015) as biomarker of active thrombus formation. METHODS AND RESULTS: Optical and positron-emitting ENC2015 probes were assessed ex vivo using blood drawn from human volunteers and passed through perfusion chambers containing denuded porcine aorta as a model of arterial injury. Specificity of ENC2015 was established with co-infusion of a factor XIIIa inhibitor. In vivo18F-ENC2015 biodistribution, kinetics, radiometabolism, and thrombus binding were characterized in rats. Both Cy5 and fluorine-18 labelled ENC2015 rapidly and specifically bound to thrombi. Thrombus uptake was inhibited by a factor XIIIa inhibitor. 18F-ENC2015 remained unmetabolized over 8 h when incubated in ex vivo human blood. In vivo, 42% of parent radiotracer remained in blood 60 min post-administration. Biodistribution studies demonstrated rapid clearance from tissues with elimination via the urinary system. In vivo,18F-ENC2015 uptake was markedly increased in the thrombosed carotid artery compared to the contralateral patent artery (mean standard uptake value ratio of 2.40 vs. 0.74, P < 0.0001). CONCLUSION : ENC2015 rapidly and selectively binds to acute thrombus in both an ex vivo human translational model and an in vivo rodent model of arterial thrombosis. This probe holds promise for the non-invasive identification of thrombus formation in cardiovascular disease.

5.
EuroIntervention ; 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31130523

RESUMO

AIMS: Coronary intravascular lithotripsy (IVL) is a novel approach to vascular calcium modification that restores vessel compliance allowing effective lesion expansion. In this study we report the capacity for coronary IVL to precipitate ventricular ectopics ("shocktopics") and asynchronous cardiac pacing. METHODS AND RESULTS: This was a retrospective review of all cases of coronary IVL (n=54) undertaken in the Royal Victoria Hospital, Belfast between 12th September 2018 and 1st March 2019. The indication for PCI was chronic stable angina in 46.1% (n=26), non-ST elevation acute coronary syndrome (NSTEACS) in 33.3% (n=18) and ST-elevation myocardial infarction (STEMI) in 18.5% (n=10) of patients. The incidence of coronary IVL provoked ventricular capture was 77.8% (n=42). Multivariable logistic regression analysis identified heart rate as the only independent predictor of an increased risk of IVL induced ventricular capture. Patients with a heart rate < 65 bpm prior to IVL were sixteen-fold more likely (OR 16.3 [2.4-110.8], p=0.004) likely to experience events compared to patients with a heart ≥ 65. "Shocktopic" beat morphology was largely uniform in each patient and appeared dependent on the target lesion location, in keeping with mechano-electric coupling through activation of local stretchactivated cardiomyocyte channels. No adverse clinical events occurred as a result of coronary IVL induced capture. CONCLUSIONS: Coronary IVL with the Shockwave Medical system is associated with a high incidence of "shocktopics" and asynchronous cardiac pacing that is largely dependent on the resting heart rate. There have been no clinical events associated with this phenomenon, but further systematic evaluation is warranted.

6.
Cardiovasc Revasc Med ; 20(12): 1048-1052, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30745059

RESUMO

BACKGROUND: Competitive flow from saphenous vein grafts (SVG) that remain patent following percutaneous coronary intervention (PCI) of the native vessel may compromise durability of the reconstructed vessel. SVG sacrifice has been advocated, but the safety and longer-term outcomes of this are unknown. METHODS: We retrospectively reviewed all post-bypass patients who following successful PCI of the native vessel underwent attempted saphenous vein graft (SVG) closure between January 2014 and July 2018 in two institutions. The co-primary end-points of interest were safety and target lesion failure (TLF), defined as a composite of cardiac death, target vessel recurrent myocardial infarction or clinically driven target lesion revascularisation (TLR). RESULTS: Of the 33 consecutive patients included, the reconstructed native vessel was a chronic total occlusion (CTO) in 93.9% of patients (n = 31) with a mean J-CTO score of 3.2 (±1.1) SVG closure was successful in 97.0% of patients (n = 32). Amplatzer Vascular Plugs (AVP; Abbott Vascular) were used in all patients with most grafts closed by a single plug (72.7%). The average procedure time was 20.1 min with evidence of a short learning curve. Over a mean follow up of 602 (±393) days from the date of SVG closure, the incidence of TLF was 9.1% (n = 3). There was an additional case of targe vessel failure (TVF) due to progression of native vessel disease not treated at the index procedure. SVG closure resulted in only 1 episode of "slow flow" that was transient and self-resolving. There were no other associated peri-procedural or in-hospital complications. CONCLUSION: Following native vessel PCI, SVG sacrifice may be considered to terminate the potentially deleterious effects of residual competitive flow. In selected cases, this approach achieves high success rate and favourable longer-term outcomes.

7.
Sci Total Environ ; 649: 99-110, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30172138

RESUMO

More than 1000 time-series of persistent organic pollutants (POPs) in Arctic biota from marine and freshwater ecosystems some extending back to the beginning of 1980s were analyzed using a robust statistical method. The Arctic area encompassed extended from Alaska, USA in the west to northern Scandinavian in the east, with data gaps for Arctic Russia and Arctic Finland. The aim was to investigate whether temporal trends for different animal groups and matrices were consistent across a larger geographical area. In general, legacy POPs showed decreasing concentrations over the last two to three decades, which were most pronounced for α-HCH and least pronounced for HCB and ß-HCH. Few time-series of legacy POPs showed increasing trends and only at sites suspected to be influenced by local source. The brominated flame retardant congener BDE-47 showed a typical trend of increasing concentration up to approximately the mid-2000s followed by a decreasing concentration. A similar trend was found for perfluorooctane sulfonic acid (PFOS). These trends are likely related to the relatively recent introduction of national and international controls of hexa- and hepta-BDE congeners and the voluntary phase-out of PFOS production in the USA in 2000. Hexabromocyclododecane (HBCDD) was the only compound in this study showing a consistent increasing trend. Only 12% of the long-term time-series were able to detect a 5% annual change with a statistical power of 80% at α < 0.05. The remaining 88% of time-series need additional years of data collection before fulfilling these statistical requirements. In the case of the organochlorine long-term time-series, 45% of these would require >20 years monitoring before this requirement would be fulfilled.


Assuntos
Charadriiformes/metabolismo , Exposição Ambiental , Peixes/metabolismo , Mamíferos/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Regiões Árticas , Monitoramento Ambiental , Água Doce , Mytilus edulis/metabolismo , Oceanos e Mares , Estações do Ano , Fatores de Tempo
8.
Cardiovasc Res ; 115(3): 669-677, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184110

RESUMO

AIMS: JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis. METHODS AND RESULTS: Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 µg/mL), bivalirudin (6 µg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively.JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 µg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both). CONCLUSION: Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications.

9.
BJGP Open ; 1(4): bjgpopen17X101217, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30564691

RESUMO

Background: General practice in the UK is 'in crisis'. With 20% of GP workload relating to musculoskeletal (MSK) problems, an orthopaedic Integrated Clinical Assessment and Treatment Service (ICATS) could help support assessment of these patients in primary care, alleviating pressure on GPs. However, practitioners in ICATS must be trained appropriately to ensure its effectiveness. Aim: This evaluation aimed to identify the training levels of doctors in one Northern Ireland orthopaedic ICATS system, what their future training needs are, and suggestions for how this service could be improved to better support general practice. Design & setting: A questionnaire study in an orthopaedic ICATS, Northern Ireland. Method: All seven doctors working within the Southern Trust orthopaedic ICATS were asked to complete a questionnaire detailing their training and experience in MSK medicine. Their views on how the service could be improved were elicited. Results: Six of seven questionnaires were returned. All responders were Members of the Royal College of General Practitioners (MRCGP), while five of six held a Diploma in Sports and Exercise Medicine (Dip SEM). Half of responders suggested that MSK ultrasound could be beneficial within ICATS. However, it was viewed that extensive training would be required before paediatric MSK patients could be included. Conclusion: High levels of training and experience were reported by responders, suggesting ICATS provides a high-level MSK service. Furthermore, it was noted that inclusion of MSK ultrasound and paediatric patients into this service could be beneficial but not without undertaking further training. With appropriate funding and support the ICATS service has the potential to expand the clinical services it offers to general practice, helping to reduce work pressures in primary care at this time of crisis for UK general practice.

10.
PeerJ ; 6: e5187, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018857

RESUMO

At present, amphipod crustaceans comprise 9,980 species, 1,664 genera, 444 subfamilies, and 221 families. Of these, 1,940 species (almost 20%) have been discovered within the last decade, including 18 fossil records for amphipods, which mostly occurred in Miocene amber and are probably all freshwater species. There have been more authors describing species since the 1950s and fewer species described per author since the 1860s, implying greater taxonomic effort and that it might be harder to find new amphipod species, respectively. There was no evidence of any change in papers per author or publication life-times of taxonomists over time that might have biased apparent effort. Using a nonhomogeneous renewal process model, we predicted that by the year 2100, 5,600 to 6,600 new amphipod species will be discovered. This indicates that about two-thirds of amphipods remain to be discovered which is twice the proportion than for species overall. Amphipods thus rank amongst the least well described taxa. To increase the prospect of discovering new amphipod species, studying undersampled areas and benthic microhabitats are recommended.

11.
Earths Future ; 6(3): 396-409, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29938210

RESUMO

The impacts of land use have been shown to have considerable influence on regional climate. With the recent international commitment to limit global warming to well below 2°C, emission reductions need to be ambitious and could involve major land-use change (LUC). Land-based mitigation efforts to curb emissions growth include increasing terrestrial carbon sequestration through reforestation, or the adoption of bioenergy crops. These activities influence local climate through biogeophysical feedbacks, however, it is uncertain how important they are for a 1.5° climate target. This was the motivation for HAPPI-Land: the half a degree additional warming, prognosis, and projected impacts-land-use scenario experiment. Using four Earth system models, we present the first multimodel results from HAPPI-Land and demonstrate the critical role of land use for understanding the characteristics of regional climate extremes in low-emission scenarios. In particular, our results show that changes in temperature extremes due to LUC are comparable in magnitude to changes arising from half a degree of global warming. We also demonstrate that LUC contributes to more than 20% of the change in temperature extremes for large land areas concentrated over the Northern Hemisphere. However, we also identify sources of uncertainty that influence the multimodel consensus of our results including how LUC is implemented and the corresponding biogeophysical feedbacks that perturb climate. Therefore, our results highlight the urgent need to resolve the challenges in implementing LUC across models to quantify the impacts and consider how LUC contributes to regional changes in extremes associated with sustainable development pathways.

12.
Environ Sci Pollut Res Int ; 25(23): 22499-22528, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29956262

RESUMO

Polychlorinated biphenyls (PCBs) can be used as chemical sentinels for the assessment of anthropogenic influences on Arctic environmental change. We present an overview of studies on PCBs in the Arctic and combine these with the findings from ArcRisk-a major European Union-funded project aimed at examining the effects of climate change on the transport of contaminants to and their behaviour of in the Arctic-to provide a case study on the behaviour and impact of PCBs over time in the Arctic. PCBs in the Arctic have shown declining trends in the environment over the last few decades. Atmospheric long-range transport from secondary and primary sources is the major input of PCBs to the Arctic region. Modelling of the atmospheric PCB composition and behaviour showed some increases in environmental concentrations in a warmer Arctic, but the general decline in PCB levels is still the most prominent feature. 'Within-Arctic' processing of PCBs will be affected by climate change-related processes such as changing wet deposition. These in turn will influence biological exposure and uptake of PCBs. The pan-Arctic rivers draining large Arctic/sub-Arctic catchments provide a significant source of PCBs to the Arctic Ocean, although changes in hydrology/sediment transport combined with a changing marine environment remain areas of uncertainty with regard to PCB fate. Indirect effects of climate change on human exposure, such as a changing diet will influence and possibly reduce PCB exposure for indigenous peoples. Body burdens of PCBs have declined since the 1980s and are predicted to decline further.


Assuntos
Poluentes Atmosféricos/análise , Bifenilos Policlorados/análise , Poluentes do Solo/análise , Poluentes Químicos da Água/análise , Poluição do Ar/estatística & dados numéricos , Animais , Regiões Árticas , Mudança Climática , Monitoramento Ambiental/métodos , Humanos , Gelo , Modelos Teóricos , Oceanos e Mares , Rios/química , Estações do Ano
13.
Sci Data ; 5: 180057, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29633985

RESUMO

Large data sets used to study the impact of anthropogenic climate change on the 2013/14 floods in the UK are provided. The data consist of perturbed initial conditions simulations using the Weather@Home regional climate modelling framework. Two different base conditions, Actual, including atmospheric conditions (anthropogenic greenhouse gases and human induced aerosols) as at present and Natural, with these forcings all removed are available. The data set is made up of 13 different ensembles (2 actual and 11 natural) with each having more than 7500 members. The data is available as NetCDF V3 files representing monthly data within the period of interest (1st Dec 2013 to 15th February 2014) for both a specified European region at a 50 km horizontal resolution and globally at N96 resolution. The data is stored within the UK Natural and Environmental Research Council Centre for Environmental Data Analysis repository.

14.
Environ Sci Pollut Res Int ; 25(33): 33001-33013, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28762048

RESUMO

A first review on occurrence and distribution of pharmaceuticals and personal care products (PPCPs) is presented. The literature survey conducted here was initiated by the current Assessment of the Arctic Monitoring and Assessment Programme (AMAP). This first review on the occurrence and environmental profile of PPCPs in the Arctic identified the presence of 110 related substances in the Arctic environment based on the reports from scientific publications, national and regional assessments and surveys, as well as academic research studies (i.e., PhD theses). PPCP residues were reported in virtually all environmental compartments from coastal seawater to high trophic level biota. For Arctic environments, domestic and municipal wastes as well as sewage are identified as primary release sources. However, the absence of modern waste water treatment plants (WWTPs), even in larger settlements in the Arctic, is resulting in relatively high release rates for selected PPCPs into the receiving Arctic (mainly) aquatic environment. Pharmaceuticals are designed with specific biochemical functions as a part of an integrated therapeutically procedure. This biochemical effect may cause unwanted environmental toxicological effects on non-target organisms when the compound is released into the environment. In the Arctic environments, pharmaceutical residues are released into low to very low ambient temperatures mainly into aqueous environments. Low biodegradability and, thus, prolonged residence time must be expected for the majority of the pharmaceuticals entering the aquatic system. The environmental toxicological consequence of the continuous PPCP release is, thus, expected to be different in the Arctic compared to the temperate regions of the globe. Exposure risks for Arctic human populations due to consumption of contaminated local fish and invertebrates or through exposure to resistant microbial communities cannot be excluded. However, the scientific results reported and summarized here, published in 23 relevant papers and reports (see Table S1 and following references), must still be considered as indication only. Comprehensive environmental studies on the fate, environmental toxicology, and distribution profiles of pharmaceuticals applied in high volumes and released into the Nordic environment under cold Northern climate conditions should be given high priority by national and international authorities.


Assuntos
Cosméticos/análise , Preparações Farmacêuticas/análise , Poluentes Químicos da Água/análise , Animais , Regiões Árticas , Biodegradação Ambiental , Ecossistema , Ecotoxicologia , Meio Ambiente , Monitoramento Ambiental/métodos , Cadeia Alimentar , Água Doce/química , Humanos , Água do Mar/química , Esgotos/química , Águas Residuárias
15.
Antioxid Redox Signal ; 28(9): 819-836, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-28540736

RESUMO

SIGNIFICANCE: Air pollution is a major global health concern with particulate matter (PM) being especially associated with increases in cardiovascular morbidity and mortality. Diesel exhaust emissions are a particularly rich source of the smallest sizes of PM ("fine" and "ultrafine") in urban environments, and it is these particles that are believed to be the most detrimental to cardiovascular health. Recent Advances: Controlled exposure studies to diesel exhaust in animals and man demonstrate alterations in blood pressure, heart rate, vascular tone, endothelial function, myocardial perfusion, thrombosis, atherogenesis, and plaque stability. Oxidative stress has emerged as a highly plausible pathobiological mechanism by which inhalation of diesel exhaust PM leads to multiple facets of cardiovascular dysfunction. CRITICAL ISSUES: Diesel exhaust inhalation promotes oxidative stress in several biological compartments that can be directly associated with adverse cardiovascular effects. FUTURE DIRECTIONS: Further studies with more sensitive and specific in vivo human markers of oxidative stress are required to determine if targeting oxidative stress pathways involved in the actions of diesel exhaust PM could be of therapeutic value. Antioxid. Redox Signal. 28, 819-836.


Assuntos
Anormalidades Cardiovasculares/fisiopatologia , Sistema Cardiovascular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Emissões de Veículos/toxicidade , Pressão Sanguínea , Anormalidades Cardiovasculares/induzido quimicamente , Humanos , Material Particulado
16.
Arterioscler Thromb Vasc Biol ; 38(2): 448-456, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29269513

RESUMO

OBJECTIVE: BMS-986120 is a novel first-in-class oral PAR4 (protease-activated receptor 4) antagonist with potent and selective antiplatelet effects. We sought to determine for the first time, the effect of BMS-986120 on human ex vivo thrombus formation. APPROACH AND RESULTS: Forty healthy volunteers completed a phase 1 parallel-group PROBE trial (Prospective Randomized Open-Label Blinded End Point). Ex vivo platelet activation, platelet aggregation, and thrombus formation were measured at 0, 2, and 24 hours after (1) oral BMS-986120 (60 mg) or (2) oral aspirin (600 mg) followed at 18 hours with oral aspirin (600 mg) and oral clopidogrel (600 mg). BMS-986120 demonstrated highly selective and reversible inhibition of PAR4 agonist peptide (100 µM)-stimulated P-selectin expression, platelet-monocyte aggregates, and platelet aggregation (P<0.001 for all). Compared with pretreatment, total thrombus area (µm2/mm) at high shear was reduced by 29.2% (95% confidence interval, 18.3%-38.7%; P<0.001) at 2 hours and by 21.4% (9.3%-32.0%; P=0.002) at 24 hours. Reductions in thrombus formation were driven by a decrease in platelet-rich thrombus deposition: 34.8% (19.3%-47.3%; P<0.001) at 2 hours and 23.3% (5.1%-38.0%; P=0.016) at 24 hours. In contrast to aspirin alone, or in combination with clopidogrel, BMS-986120 had no effect on thrombus formation at low shear (P=nonsignificant). BMS-986120 administration was not associated with an increase in coagulation times or serious adverse events. CONCLUSIONS: BMS-986120 is a highly selective and reversible oral PAR4 antagonist that substantially reduces platelet-rich thrombus formation under conditions of high shear stress. Our results suggest PAR4 antagonism has major potential as a therapeutic antiplatelet strategy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439190.


Assuntos
Benzofuranos/administração & dosagem , Plaquetas/efeitos dos fármacos , Fibrinolíticos/administração & dosagem , Imidazóis/administração & dosagem , Morfolinas/administração & dosagem , Inibidores da Agregação de Plaquetas/administração & dosagem , Agregação Plaquetária/efeitos dos fármacos , Receptores de Trombina/antagonistas & inibidores , Tiazóis/administração & dosagem , Trombose/prevenção & controle , Administração Oral , Adulto , Aspirina/administração & dosagem , Benzofuranos/efeitos adversos , Benzofuranos/farmacocinética , Plaquetas/metabolismo , Clopidogrel/administração & dosagem , Feminino , Fibrinolíticos/efeitos adversos , Fibrinolíticos/farmacocinética , Voluntários Saudáveis , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Masculino , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Estudos Prospectivos , Receptores de Trombina/sangue , Escócia , Transdução de Sinais/efeitos dos fármacos , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Trombose/sangue , Trombose/diagnóstico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
Circ Cardiovasc Interv ; 10(6)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28625964

RESUMO

BACKGROUND: Development of the CrossBoss and Stingray devices for antegrade dissection and reentry (ADR) of chronic total occlusions has improved historically suboptimal outcomes. However, the outcomes, safety, and failure modes of the technique have to be studied in a larger patient cohort. This preplanned substudy of the RECHARGE registry (Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom) aims to evaluate the value and use of ADR and determine its future position in contemporary chronic total occlusion intervention. METHODS AND RESULTS: Patients were selected if an ADR strategy was applied. Outcomes, safety, and failure modes of the technique were assessed. The ADR technique was used in 23% (n=292/1253) of the RECHARGE registry and was mainly applied for complex lesions (Japanese chronic total occlusion score=2.7±1.1). ADR was the primary strategy in 30% (n=88/292), of which 67% were successful. Bail-out ADR strategies were successful in 63% (n=133/210). The Controlled ADR (ie, combined CrossBoss-Stingray) subtype was applied most frequently (32%; n=93/292) and successfully (81%; n=75/93). Overall per-lesion success rate was 78% (n=229/292), after use of additional bail-out strategies. The inability to reach the distal target zone (n=48/100) or to reenter (n=43/100) most commonly led to failure. ADR-associated major events occurred in 3.4% (n=10/292). CONCLUSIONS: Although mostly applied as a bail-out strategy for complex lesions, the frequency, outcomes, and low complication rate of the ADR technique and its subtypes confirm the benefit and value of the technique in hybrid chronic total occlusion percutaneous coronary intervention, especially when antegrade wiring or retrograde approaches are not feasible. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02075372.


Assuntos
Oclusão Coronária/terapia , Intervenção Coronária Percutânea/métodos , Idoso , Algoritmos , Doença Crônica , Tomada de Decisão Clínica , Angiografia Coronária , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/fisiopatologia , Técnicas de Apoio para a Decisão , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
20.
ACS Nano ; 11(5): 4542-4552, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28443337

RESUMO

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2-200 nm primary diameter), with translocation markedly greater for particles <10 nm diameter. Gold nanoparticles preferentially accumulated in inflammation-rich vascular lesions of fat-fed apolipoproteinE-deficient mice. Furthermore, following inhalation, gold particles could be detected in surgical specimens of carotid artery disease from patients at risk of stroke. Translocation of inhaled nanoparticles into the systemic circulation and accumulation at sites of vascular inflammation provides a direct mechanism that can explain the link between environmental nanoparticles and cardiovascular disease and has major implications for risk management in the use of engineered nanomaterials.


Assuntos
Nanopartículas Metálicas/administração & dosagem , Doenças Vasculares/metabolismo , Administração por Inalação , Adulto , Animais , Ouro , Voluntários Saudáveis , Humanos , Pulmão/patologia , Masculino , Camundongos , Nanopartículas , Nanoestruturas/análise , Tamanho da Partícula , Doenças Vasculares/terapia
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