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Acute myocardial infarction is the commonest cause of death in firefighters, accounting for 45% of all deaths on duty. Compared with an average life expectancy of 77 years in the general population, the average age of cardiovascular death in firefighters is 50 years suggesting that occupational hazards are responsible for premature disease. The risk of acute myocardial infarction is increased 12- to 136-fold during rescue and firefighting duties, and is likely to reflect a combination of factors including strenuous physical exertion, mental stress, heat and pollutant exposure. Previous studies have established that the duties of a firefighter, in particular fire suppression, put inordinate strain on the cardiovascular system yet the exact mechanisms underlying the increased risk of myocardial infarction remain poorly defined. In a series of studies, I assessed the effect of occupation-specific risk factors on cardiovascular health in a combination of controlled and real-life studies in order to better define these mechanisms, hypothesising that exposure to high temperatures, strenuous physical exertion, psychological stress and air pollution either alone or in combination caused vascular dysfunction and thrombosis. In order to assess if firefighters had a greater cumulative risk of cardiovascular disease due to their occupation at baseline, I assessed the cardiovascular function of group of healthy, off-duty firefighters and compared this to a group of healthy age- and sex-matched off-duty police officers; an occupational group with similar responsibilities but a much lower risk of on-duty cardiovascular events. I was able to demonstrate that traditional cardiovascular risk factors, vascular endothelial function and thrombogenicity were similar in the two groups concluding that the excess of cardiovascular events and deaths in on-duty firefighters are due to the acute and transient effects of strenuous physical exertion, psychological stress, heat and exposure to air pollutants. Having established that off-duty firefighters had no apparent increased risk of cardiovascular events, I then went on to clarify the effects of combustion derived air pollution in the form of wood smoke on the cardiovascular system. The suppression of wildland or forest fires is globally the single most important duty of the fire service. Previous work within our institution has demonstrated the adverse effects of combustion derived air pollution, in the form of diesel exhaust, on the cardiovascular system. In a similar fashion, I assessed the effect of a wood smoke inhalation in a group of healthy off-duty firefighters by performing controlled exposures to wood smoke utilising a unique and well characterised facility. Interestingly, unlike diesel-exhaust, the exposure to wood smoke had no adverse effect on vascular endothelial function or thrombogenicity in this group concluding that cardiovascular events during wildland fire suppression may not be directly related to wood smoke inhalation but instead precipitated by other mechanisms such as strenuous physical exertion or dehydration. Latterly, I proceeded to evaluate the effects of strenuous physical exertion and heat exposure by comprehensively assessing a number of cardiovascular end points following controlled exposure to a fire simulation activity in a group of healthy, off-duty firefighters. I was able to demonstrate that exposure to extreme heat and physical exertion impaired vasomotor function and increased thrombus formation. Moreover, I demonstrated cardiac troponin concentrations increased suggesting that fire suppression activity may cause myocardial injury. These important findings suggest pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction. In the final phase of work, I endeavoured to assess the effects of real-life firefighter activities on the cardiovascular system. In an ambitious study, I attempted to undertake a comprehensive assessment of cardiovascular function in healthy firefighters following three periods of duty: fire suppression, alarm response and non-emergency activity. I was unable to complete enough studies to adequately power an analysis and draw any firm conclusions about the effect of these duties on cardiovascular health. Further work is required in a real-world setting to more clearly define the occupational risk factors underlying the increased risk of cardiovascular events associated with specific firefighter duties Understanding the biological mechanisms and environmental factors that predispose firefighters to cardiovascular events is essential if we are to develop effective methods for the prevention of acute myocardial infarction on-duty. This body of work has greatly improved the understanding of the mechanisms underlying the increased risk of cardiovascular events on duty and calls for the immediate evaluation of current practice in order to minimise risk to firefighters in the future. Examples of where improvements should be made include strategies to ensure adequate hydration and cooling following exposure to heat and physical exertion, change to working patterns to limit the duration of extreme exposures, and education, training and screening programmes to reduce the impact of traditional and occupational cardiovascular risk factors.

The hemocompatibility of crystalline Silicon Carbide (SiC), in its cubic form (i.e., 3C-SiC), has been evaluated and compared to Silicon (Si), the leading material in biosensing applications. Silicon carbide (SiC) is a hard, chemically robust material, very well suited for harsh environment applications, and has been suggested to have very good biocompatibility. Additionally, SiC in its amorphous form, has been used as a coating for medical implantable devices such as bone prosthetics and cardiovascular stents. However, assessment of single crystal 3C-SiC for cardiovascular applications has not been reported. In this research we have studied the interactions of single crystal 3C-SiC with platelets and human microvascular endothelial cell (HMVEC) to assess the degree of hemocompatibility of 3C-SiC. The more hemocompatible a material is, the less platelet adhesion would be expected. Using fluorescence microscopy higher platelet adhesion was statistically observed on Si than on SiC. In addition 3C-SiC surfaces showed less platelet reactivity, measured by the degree of platelet adhesion, aggregation and activation, with mostly circular morphology of adhered platelets while Si showed an elevated presence of non-activated (Circular) platelet clumps. Additionally, HMVEC proliferation assessment suggest that 3C-SiC performs comparably to high attachment culture wells with enhanced proliferation, without affecting cell morphology. These results suggest that 3C-SiC is a promising candidate for applications in the blood stream due to its low thrombogenic characteristics and good hemocompatibility.

Extracorporeal Membrane Oxygenation (ECMO) is a life-saving therapy usedfor support in critical heart and/or lung failure. Patient’s blood is pumped viaan artificial lung for oxygenation outside of the body. The circuit is composedof a blood pump, cannulae for drainage and reinfusion, a membrane lung,tubing and connectors. Its use is associated with thromboembolic complicationsand hemolytic damage. Detailed numerical studies of two blood pumps anda lighthouse tip drainage cannula were undertaken to characterize the flowstructures in different scenarios and their link to platelet activation. The pumpsimulations were modelled according to manufacturer’s proclaimed use but alsoin off-design conditions with flow rates used in adult and neonatal patients.Lagrangian Particle Tracking (LPT) was used to simulate the injection ofparticles similar in size to platelets to compute platelet activation state (PAS).The results indicated that low flow rates impacted PAS similarly to high flowrates due to increased residence time leading to prolonged exposure to shearstress despite the fact that shear per se was lower at low flow rate. Regardingthe cannula, the results showed that a flow pattern similar to a jet in crossflowdeveloped at the side holes. A parameter study was conducted to quantifydrainage characteristics in terms of flow rate distribution across the holes wheninput variables of flow rate, modelled fluid, and hematocrit were altered. Thefindings showed, across all the cases, that the most proximal hole row drainedthe largest fraction of fluid. The effects due to the non-Newtonian nature ofblood were confined to regions far from the cannula holes and the flow structuresshowed very limited dependence on the hematocrit. A scaling law was found tobridge the global drainage performance of fluid between water and blood. / <p>QC 210906</p>

Nos travaux montrent qu’au cours de la fibrillation atriale (FA), les microparticules (MP) reflètent et contribuent à un état d’hypercoagulabilité et pro-inflammatoire. Leurs concentrations similaires dans les deux oreillettes de patients en FA témoignent d’une absence de différence de statut pro-thrombotique entre ces deux cavités cardiaques. Au cours des procédures d’ablation de FA, les concentrations de MP évoluent parallèlement à l’augmentation de l’activation cellulaire et plaquettaire. Nous avons également montré dans l'altération tissulaire des oreillettes en FA, l'importance de la sénescence qui évolue avec la progression du trouble du rythme. Nous avons caractérisé un modèle cellulaire de sénescence réplicative de cellules endothéliales auriculaires de porc permettant d'identifier l'apparition d'un phénotype pro-thrombotique, pro-inflammatoire, pro-adhésif et de mieux comprendre la physiologie de la cellule endothéliale atriale sénescente et le rôle majeur du système rénine-angiotensine dans ces mécanismes. / Our data evidence that during atrial fibrillation (AF), microparticles (MP) contribute to an enhanced hypercoagulable and pro-inflammatory state. Similar concentrations of MP measured in left and right atria of AF patients highlight the absence of chamber-specific enhanced thrombogenic status. During AF ablation procedures, MP concentrations progress in parallel with cell and platelet activation. We also showed that AF progression is strongly related to human atrial senescence burden pointing toward a possible network that links in human atrium, senescence burden, endothelial dysfunction, thrombogenicity and atrial remodeling. We also developed a model of left atrium endothelial cell replicative senescence providing compelling evidences indicating that atrial endothelial senescence promotes thrombogenicity, inflammation and proteolysis. These data underline the major role of renin-angiotensin system in endothelial atrial cell senescence.

Nos dias atuais, grande parte das intervenções cirúrgicas inclui o implante de materiais. Os grandes obstáculos na implantação de próteses em organismos humanos são a coagulação sanguínea em contato com o material devido ao alto grau de ativação plaquetária e a compatibilidade dos tecidos biológicos ao material implantado. Agregando melhorias de propriedades mecânicas a superfícies biocompatíveis, materiais poliméricos apresentam grandes tendências a serem excelentes candidatos a biomateriais para tais aplicações. O objetivo deste trabalho foi realizar modificações superficiais em polímeros através do método de implantação por feixe iônico a fim de se investigar mudanças induzidas em suas propriedades superficiais e estudar possíveis mudanças em sua biocompatibilidade, em específico, sua hemocompatibilidade. Amostras de policarbonato foram irradiadas com feixes de íons de argônio com energia 23 keV e cinco diferentes doses. As superfícies das amostras foram analisadas com medidas de ângulo de contato, microscopia de força atômica, espectroscopia de massa de íons secundários, espectroscopia de fotoelétrons, espectroscopia de retroespalhamento Rutherford, deteção de recuo elástico, espectroscopia de raios-X induzidos por partículas e testes de adesão plaquetária. Os resultados das diferentes técnicas apontaram de forma consistente a uma série de alterações químicas e físicas induzidas nas superfícies das amostras, dentre elas: a perda significativa de hidrogênio nas amostras irradiadas, aumento do grau de reticulação entre as cadeias poliméricas que levou ao aumento de elétron deslocalizados e mudança de coloração, remoção de aditivos, migração à superfície de átomos de argônio implantados e alteração de hidrofilicidade. Ao confrontar todos os resultados obtidos com os resultados dos testes de adesão plaquetária, constatou-se que os efeitos observados aumentam o caráter trombogênico da superfície do policarbonato e que a remoção de aditivos com grupos sulfato e sulfonato após irradiação com argônio teve grande influência em tal aumento. / In the current days, a big part of the surgical interventions includes the implant of materials. The great obstacles for prosthesis implantation in living organisms are the blood clotting when in contact to the material due to a high level of platelet activation and the biological tissues compatibility to the implanted material. By joining improvements on mechanical properties to biocompatible surfaces, polymer materials present high tendencies to be excellent biomaterials candidates for such applications. The objective of this work was to perform surface modification in polymers through the ion beam implantation method in order to investigate changes induced in their surface properties and study possible biocompatibility changes. Samples of polycarbonate were irradiated with argon ion beam with 23 keV energy and different doses. The surfaces of the samples were analyzed by contact angle measurements, atomic force microscopy, secondary ion mass spectroscopy, x-ray photoelectron spectroscopy, Rutherford backscattering spectroscopy, elastic recoil detection, particle induced x-ray spectroscopy and platelet adhesion tests. The results from the different techniques pointed consistently to a series of chemical and physical changes induced on the samples\' surfaces, such as: significant loss of hydrogen for the irradiated samples, increase of cross-linking between polymer chains which led to the increase of delocalized electrons and color change, removal of additives, migration of argon atoms to the surface and hydrophilicity changes. By comparing all the obtained results to the platelet adhesion tests results, it was found that the observed effects increase the thrombogenic characteristic of the polycarbonate surface and that the removal of additives with sulfate and sulfonate groups after the argon irradiation had great influence on such increase.

Nos dias atuais, grande parte das intervenções cirúrgicas inclui o implante de materiais. Os grandes obstáculos na implantação de próteses em organismos humanos são a coagulação sanguínea em contato com o material devido ao alto grau de ativação plaquetária e a compatibilidade dos tecidos biológicos ao material implantado. Agregando melhorias de propriedades mecânicas a superfícies biocompatíveis, materiais poliméricos apresentam grandes tendências a serem excelentes candidatos a biomateriais para tais aplicações. O objetivo deste trabalho foi realizar modificações superficiais em polímeros através do método de implantação por feixe iônico a fim de se investigar mudanças induzidas em suas propriedades superficiais e estudar possíveis mudanças em sua biocompatibilidade, em específico, sua hemocompatibilidade. Amostras de policarbonato foram irradiadas com feixes de íons de argônio com energia 23 keV e cinco diferentes doses. As superfícies das amostras foram analisadas com medidas de ângulo de contato, microscopia de força atômica, espectroscopia de massa de íons secundários, espectroscopia de fotoelétrons, espectroscopia de retroespalhamento Rutherford, deteção de recuo elástico, espectroscopia de raios-X induzidos por partículas e testes de adesão plaquetária. Os resultados das diferentes técnicas apontaram de forma consistente a uma série de alterações químicas e físicas induzidas nas superfícies das amostras, dentre elas: a perda significativa de hidrogênio nas amostras irradiadas, aumento do grau de reticulação entre as cadeias poliméricas que levou ao aumento de elétron deslocalizados e mudança de coloração, remoção de aditivos, migração à superfície de átomos de argônio implantados e alteração de hidrofilicidade. Ao confrontar todos os resultados obtidos com os resultados dos testes de adesão plaquetária, constatou-se que os efeitos observados aumentam o caráter trombogênico da superfície do policarbonato e que a remoção de aditivos com grupos sulfato e sulfonato após irradiação com argônio teve grande influência em tal aumento. / In the current days, a big part of the surgical interventions includes the implant of materials. The great obstacles for prosthesis implantation in living organisms are the blood clotting when in contact to the material due to a high level of platelet activation and the biological tissues compatibility to the implanted material. By joining improvements on mechanical properties to biocompatible surfaces, polymer materials present high tendencies to be excellent biomaterials candidates for such applications. The objective of this work was to perform surface modification in polymers through the ion beam implantation method in order to investigate changes induced in their surface properties and study possible biocompatibility changes. Samples of polycarbonate were irradiated with argon ion beam with 23 keV energy and different doses. The surfaces of the samples were analyzed by contact angle measurements, atomic force microscopy, secondary ion mass spectroscopy, x-ray photoelectron spectroscopy, Rutherford backscattering spectroscopy, elastic recoil detection, particle induced x-ray spectroscopy and platelet adhesion tests. The results from the different techniques pointed consistently to a series of chemical and physical changes induced on the samples\' surfaces, such as: significant loss of hydrogen for the irradiated samples, increase of cross-linking between polymer chains which led to the increase of delocalized electrons and color change, removal of additives, migration of argon atoms to the surface and hydrophilicity changes. By comparing all the obtained results to the platelet adhesion tests results, it was found that the observed effects increase the thrombogenic characteristic of the polycarbonate surface and that the removal of additives with sulfate and sulfonate groups after the argon irradiation had great influence on such increase.

Biomaterials-associated thrombosis is dependent critically upon electrochemical response of fibrinogen on material surface. The relationship between the response and anti-thrombogenicity of biomaterials is not well-established. Titanium oxide appears to have good anti-thrombogenicity and little is known about its underlying essential chemistry. We correlate their anti-thrombogenicity directly to electrochemical behaviors in fibrinogen containing buffer solution. High degree of inherent n-type doping was noted to contribute the impedance preventing charge transfer from fibrinogen into film (namely its activation) and consequently reduced degree of anti-thrombogenicity. The impedance was the result of high donor carrier density as well as negative flat band potential.