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Artigo em Inglês | MEDLINE | ID: mdl-31422134


OBJECTIVES: The goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque. BACKGROUND: High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. METHODS: In a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. RESULTS: In total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33). CONCLUSIONS: Dual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303).

Nano Today ; 26: 8-12, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31217806


Environmental nanoparticles and manufactured nanoparticles (MNMs) can share many of the same physicochemical properties and, therefore, could have similar toxicological profiles. Inhalation of nanoparticles in air pollution has effects throughout the body; however, the potential for inhaled MNMs to affect multiple organs requires further investigation. The biological mechanisms that link nanoparticles deposition in the lung to their systemic actions remain to be established; however, the passage of nanoparticles into the blood ("translocation") represents a compelling explanation. This article highlights experimental work in animals and man showing that inhaled gold nanoparticles pass into the blood and accumulate at sites of vascular disease. The article discusses the properties of nanoparticles that could influence translocation and highlights some avenues for future research. The processes described have clear relevance, both for MNMs and sources of nanoparticles in air pollution. The authors emphasise the need for risk assessment of potential nanoparticle exposure routes that consider the multiple organ systems.

ACS Nano ; 11(5): 4542-4552, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28443337


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.

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
Circulation ; 135(14): 1284-1295, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28373523


BACKGROUND: Rates of myocardial infarction in firefighters are increased during fire suppression duties, and are likely to reflect a combination of factors including extreme physical exertion and heat exposure. We assessed the effects of simulated fire suppression on measures of cardiovascular health in healthy firefighters. METHODS: In an open-label randomized crossover study, 19 healthy firefighters (age, 41±7 years; 16 males) performed a standardized training exercise in a fire simulation facility or light duties for 20 minutes. After each exposure, ex vivo thrombus formation, fibrinolysis, platelet activation, and forearm blood flow in response to intra-arterial infusions of endothelial-dependent and -independent vasodilators were measured. RESULTS: After fire simulation training, core temperature increased (1.0±0.1°C) and weight reduced (0.46±0.14 kg, P<0.001 for both). In comparison with control, exposure to fire simulation increased thrombus formation under low-shear (73±14%) and high-shear (66±14%) conditions (P<0.001 for both) and increased platelet-monocyte binding (7±10%, P=0.03). There was a dose-dependent increase in forearm blood flow with all vasodilators (P<0.001), which was attenuated by fire simulation in response to acetylcholine (P=0.01) and sodium nitroprusside (P=0.004). This was associated with a rise in fibrinolytic capacity, asymptomatic myocardial ischemia, and an increase in plasma cardiac troponin I concentrations (1.4 [0.8-2.5] versus 3.0 [1.7-6.4] ng/L, P=0.010). CONCLUSIONS: Exposure to extreme heat and physical exertion during fire suppression activates platelets, increases thrombus formation, impairs vascular function, and promotes myocardial ischemia and injury in healthy firefighters. Our findings provide pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction in firefighters. CLINICAL TRIAL REGISTRATION: URL: Unique identifier: NCT01812317.

Doenças Cardiovasculares/etiologia , Endotélio Vascular/fisiopatologia , Bombeiros , Trombose/fisiopatologia , Estudos Cross-Over , Feminino , Fogo , Humanos , Masculino
Part Fibre Toxicol ; 11: 62, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25487196


BACKGROUND: Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. METHODS: In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m³ particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4-6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. RESULTS: Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P < 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P > 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P < 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P > 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P > 0.05 for all). CONCLUSIONS: Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration.

Endotélio Vascular/efeitos dos fármacos , Lesão por Inalação de Fumaça/fisiopatologia , Trombose/etiologia , Doenças Vasculares/etiologia , Sistema Vasomotor/efeitos dos fármacos , Adulto , Ciclismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Bombeiros , Humanos , Masculino , Ativação Plaquetária/efeitos dos fármacos , Risco , Escócia/epidemiologia , Fumaça/efeitos adversos , Lesão por Inalação de Fumaça/sangue , Lesão por Inalação de Fumaça/imunologia , Lesão por Inalação de Fumaça/metabolismo , Trombose/epidemiologia , Doenças Vasculares/epidemiologia , Rigidez Vascular/efeitos dos fármacos , Sistema Vasomotor/imunologia , Sistema Vasomotor/metabolismo , Sistema Vasomotor/fisiopatologia , Madeira , Adulto Jovem
Thromb Haemost ; 108(1): 176-82, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22627761


Platelets are the principal component of the innate haemostatic system that protect from traumatic bleeding. We investigated whether lyophilised human platelets (LHPs) could enhance clot formation within platelet-free and whole blood environments using an ex vivo model of deep arterial injury. Lyophilised human platelets were produced from stored human platelets and characterised using conventional, fluorescent and electron microscopic techniques. LHPs were resuspended in platelet-free plasma (PFP) obtained from citrated whole human blood to form final concentrations of 0, 20 and 200 x 109 LHPs/L. LHPs with recalcified PFP or whole blood were perfused through the chamber at low (212 s⁻¹) and high (1,690 s⁻¹) shear rates with porcine aortic tunica media as thrombogenic substrate. LHPs shared morphological characteristics with native human platelets and were incorporated into clot generated from PFP or whole blood. Histomorphometrically measured mean thrombus area increased in a dose-dependent manner following the addition of LHPs to PFP under conditions of high shear [704 µm² ± 186 µm² (mean ± SEM), 1,511 µm² ± 320 µm² and 2,378 µm² ± 315 µm², for LHPs at 0, 20 and 200 x 109 /l, respectively (p= 0.012)]. Lyophilised human platelets retain haemostatic properties when reconstituted in both PFP and whole blood, and enhance thrombus formation in a model of deep arterial injury. These data suggest that LHPs have the potential to serve as a therapeutic intervention during haemorrhage under circumstances of trauma, and platelet depletion or dysfunction.

Artérias/lesões , Coagulação Sanguínea , Plaquetas , Hemorragia/prevenção & controle , Técnicas Hemostáticas , Agregação Plaquetária , Adolescente , Adulto , Animais , Liofilização , Humanos , Modelos Animais , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Suínos , Adulto Jovem