Whether a patient presents with deep vein thrombosis (DVT) or pulmonary embolism (PE) varies based on clinical factors. Patients with factor V Leiden (FVL) typically present with DVT while cancer patients present with PE. The biological mechanisms that determine DVT stability in the progression of DVT to PE are not known. Thus, little is known about the mechanism of thrombus stability, the factors involved, or the effect of anticoagulants on embolization and PE burden. In order to answer these questions, we first need to (i) develop a mouse model to evaluate DVT stability and its relationship with PE burden when treated with anticoagulants, (ii) determine if anticoagulants, by inhibiting thrombin, require FXIII to decrease thrombus stability, (iii) determine the effects of attenuating fibrinolysis, using epsilon aminocaproic acid (ε-ACA or EACA), supplemental FXIII and α2-AP, on clot stability and (iv) utilize our model to explain the FVL paradox. For our thrombus stability model, the femoral vein of C57BL/6, FXIII deficient (FXIII-/-), FVL heterozygous, or FVL homozygous female mice was subjected to ferric chloride (FeCl3) injury to initiate a non-occlusive thrombus. Treatment with saline, dalteparin, dabigatran, EACA or FXIII was administered 12 minutes after thrombus formation. Intravital videomicroscopy recorded the thrombus sizes and embolic events leaving the thrombus for 2 hours. Lungs were harvested, sectioned and stained for the presence of PE. Total and large embolic events were highest after dabigatran treatment compared to saline or dalteparin in wild-type (WT) mice. Variations in amounts of embolic events were not attributed to variations in thrombus size since thrombus size was similar between the groups. The number of emboli per lung slice was higher in dabigatran-treated mice. Large embolic events correlated positively with the number of emboli per lung slice independent of treatment. Dabigatran treatment in FXIII-/- mice did not alter embolization patterns suggesting that FXIII is required for dabigatran to decrease thrombus stability. EACA increases thrombus size significantly and therefore would not be a feasible alternative to IVC filters, as it will increase DVT size. FXIII marginally increased thrombus size. Treatment with FXIII decreases total and large embolic events in saline-, dalteparin- or dabigatran-treated mice, similar to EACA-treated mice. The number of emboli per lung slice was reduced after treatment with FXIII and EACA compared to non-treated mice. PE burden was not significantly different between FXIII anticoagulated mice or EACA-treated mice. The large embolic events correlate positively with PE burden. FVL heterozygous and homozygous mice had significantly reduced embolization and thrombus size grew significantly over time, this contrasted with WT mice, where thrombus size remained similar to the initial injury. PE burden was significantly reduced in the FVL mice compared to WT. Collectively, these data shows that we have successfully developed a mouse model of acute venous thrombus stability that can quantify emboli and PE burden. Consistent with clinical data, dabigatran, a DTI, was shown to acutely decrease thrombus stability and increase PE burden compared to LMWH or saline; an effect that was FXIII-dependent. Also, attenuating fibrinolysis with EACA, but not FXIII, increases thrombus size; but both increase DVT stability and decrease PE burden. Supplementing α2-AP did not alter thrombus stability. This suggests that administration of FXIII may be a better treatment option for DVT patients who are bleeding than EACA, since EACA may increase DVT size. Lastly, our model can explain the FVL paradox. Those with FVL have stable thrombus formation leading to an increased incidence of symptomatic DVT and a decreased risk of PE. / Thesis / Doctor of Philosophy (PhD)

According to the World Health Organization (WHO), Cardiovascular Disease (CVD) is the leading cause of death in the world. Biomechanics and fluid dynamics of blood flow play an important role in CVD mediation. Shear stress plays a major role in platelet-substrate interactions and thrombus formation and growth in blood flow, where under both pathological and physiological conditions platelet adhesion and accumulation occur. In this study, a three-dimensional dynamic model of platelet-rich thrombus growth in stenosed vessels using computational fluid dynamics (CFD) methods is introduced. Platelet adhesion, aggregation and activation kinetics are modeled by solving mass transport equations for blood components involved in thrombosis. The model was first verified under three different shear conditions and at two heparin levels. Three-dimensional simulations were then carried out to evaluate the performance of the model for severely damaged (stripped) aortas with mild and severe stenosis degrees. For these cases, linear shear-dependent functions were developed for platelet-surface and platelet-platelet adhesion rates. It was confirmed that the platelet adhesion rate is not only a function of Reynolds number (or wall shear rate) but also the stenosis severity of the vessel. General correlations for adhesion rates of platelets as functions of stenosis and Reynolds number were obtained based on these cases. The model was applied to different experimental systems and shown to agree well with measured platelet deposition. Then, the Arbitrary Lagrangian Eulerian (ALE) formulation was used to model dynamic growth by including geometry change in the simulation procedure. The wall boundaries were discretely moved based on the amount of platelet deposition that occurs on the vessel wall. To emulate the dynamic behavior of platelet adhesion kinetics during thrombus growth, the validated model for platelet adhesion, which calculates platelet-surface adhesion rates as a function of stenosis severity and Reynolds number, was applied to the model. The model successfully predicts the nonlinear growth of thrombi in the stenosed area. These simulations provide a useful guide to understand the effect of growing thrombus on platelet deposition rate, platelet activation kinetics and occurrence of thromboembolism (TE) in highly stenosed arteries. / Ph. D. / Continuous platelet deposition in coronary arteries creates a narrow necking area at some susceptible regions such as bifurcations, stented arteries and ruptured vessel walls. These narrow regions, known as stenoses, are the number one cause of heart attacks. In this work, a predictive model of platelet deposition (i.e. thrombosis) is developed based on previous experimental and clinical data on human blood. Fluid shear stresses play a major role in platelet-substrate interactions and thrombus formation and growth in blood flow, where under both pathological and physiological conditions platelet adhesion and accumulation occur. In addition to simulating the blood flow patterns in arteries with computational fluid dynamics (CFD), the model is able to reliably predict the amount of platelets deposited in injured areas, the severity of the blockage in the blood flow, and the time for occlusion. The results of our model are much more accurate than previous models and are validated by comparing them to clinical data for thrombus formation in stenosed arteries. Thus, the project contributes towards better diagnosis and treatment of vascular disease with implications on the monitoring and management of cardiovascular diseases and providing useful guidelines to design improved devices such as left ventricular assist devices, mechanical heart valves, stents, etc.

No description available.

Thesis (MScMedSC (Medical Imaging and Clinical Oncology. Nuclear Medicine))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Single photon emission computed tomography (SPECT) with a superior contrast resolution has been shown to be more sensitive and specific with a lower nondiagnostic rate than planar imaging in many nuclear medicine studies but it is still not being routinely implemented in V/Q studies at many centres including Tygerberg Hospital. There are many studies on V/Q SPECT using Technegas as a ventilation agent but very limited studies available on 81m Kr gas. Aim: To clinically compare conventional planar and SPECT V/Q imaging using 81mKr gas in the diagnosis of pulmonary embolism, with CTPA as the gold standard. Patients and Methods: All patients referred with clinical suspicion of pulmonary embolism were assessed. The inclusion criteria were normal chest radiograph, normal renal function and no contrast allergy. Exclusion criteria were age below 18 years old, pregnancy, abnormal chest radiograph, abnormal serum creatinine/urea levels and unstable patients. A Well’s score was assigned to each enrolled patient. Perfusion scintigraphy was performed after intravenous injection 125 MBq of 99mTc MAA. Ventilation scintigraphy was performed with 81mKr gas. On a dual head camera, SPECT was done before planar acquisition, while perfusion was done before ventilation imaging in the same position. Planar V/Q images consisted of 6 standard views. All V/Q SPECT images were reconstructed using ordered-subset expectation-maximization (OSEM) algorithm and a post-reconstruction 3D Butterworth filters were applied. V/Q Planar and V/Q SPECT images were later evaluated and reviewed separately and reported based on recent EANM guidelines blinded to the CTPA results. All patients underwent multi-slice CTPA examinations on a 40-detector row scanner. The images were later assessed and reported blinded to the V/Q results. Statistical analysis was done using the Fisher exact test for comparison of categorical variables and the one-way ANOVA for continuous variables (p<0.05 was significant). Results: A total of 104 consecutive patients were referred with clinical suspicion of pulmonary embolism. Seventy-nine patients were excluded from this study mostly due to abnormal serum creatinine/urea levels. Only 25 patients were included in this study, with a mean age of 48 ± 19 years, and 64% being females. When compared to CTPA as gold standard, the prevalence of PE was 16% [5% – 37% at 95% CI], sensitivity 75% [21% – 99% at 95% CI], specificity 90% [68% – 98% at 95% CI], positive predictive value 60% [17% – 93% at 95% CI], negative predictive value 95% [73% – 100% at 95% CI] and diagnostic accuracy 88% [69% – 97%at 95% CI] for both V/Q Planar and SPECT. V/Q Planar showed a lower reader confidence i.e. could only clearly resolve 72% of cases compared to V/Q SPECT, which could precisely interpret all cases, showed more and better delineated mismatch vs match and segmental vs non-segmental defects. All patients who were scored as PE unlikely on Wells’ score (4) had PE ruled out on CTPA (p=0.04581) as well as 89% of patients on V/Q SPECT and V/Q Planar. Conclusion: Based on this study, V/Q Planar and V/Q SPECT have a similar diagnostic performance in patients with a normal or near normal chest X-rays. / AFRIKAANSE OPSOMMING: Enkelfoton emissie rekenaartomografie (EFERT) met beter kontrasresolusie is bewys om meer sensitief en spesifiek met ‘n laer nie-diagnostiese opbrengs as planare beelding in verskeie kerngeneeskunde ondersoeke te wees. In Tygerberg Hospitaal, soos in verskeie ander sentra, word dit egter steeds nie roetineweg vir ventilasie-perfusiestudies (V/Q) geïmplementeer nie. Daar is verskeie EFERT V/Q studies met Technegas as ventilasie agens, maar beperkte studies met 81m Kr gas beskikbaar. Doel: Om konvensionele planare en EFERT V/Q beelding vir die diagnose van pulmonale embolisme met mekaar te vergelyk, met rekenaartomografie pulmonale angiografie (RTPA) as goue standaard. Pasiënte en Metodes: Alle pasiënte wat met ‘n kliniese vermoede van pulmonale embolisme verwys is, is geevalueer. Die insluitingskriteria was ’n normale borskas Xstraal, normale nierfunksie en geen kontrasallergie nie. Uitsluitingskriteria was pasiënte jonger as 18 jaar, swanger pasiënte, abnormale borskas X-straal, abnormale serum kreatinien / ureumvlakke en onstabiele pasiënte. ’n Wells telling is vir elke pasiënt wat in die studie ingesluit is, bepaal. Perfusiebeelding is uitgevoer na die intraveneuse toediening van 125 MBq 99mTc MAA. Ventilasiestudies is gedoen met 81mKr gas. Die V/Q EFERT studies is voor die planare beelding met ’n dubbelkop gammakamera uitgevoer. Perfusiebeelding is voor die ventilasie in dieselfde posisie verkry. V/Q planare beelding het bestaan uit 6 standaard beelde. Alle V/Q EFERT is met “ordered-subset expectationmaximization” (OSEM) algoritmes verwerk, en post-rekonstruksie 3D Butterworth filters is toegepas. V/Q planare en V/Q EFERT beelding is later afsonderlik en sonder RTPA inligting volgens onlangse EANM riglyne evalueer en gerapporteer. ‘n Veelsnit RTPA met ‘n 40 snit skandeerder is op alle pasiënte uitgevoer. Die beelde is later beoordeel en gerapporteer sonder inagneming van die V/Q beeldingsresultate Statistiese verwerking is gedoen met die Fisher presisietoets vir vergelyking van kategoriese veranderlikes en die eenrigting ANOVA vir kontinue veranderlikes (p<0.05 is statisties betekenisvol). Resultate: ‘n Totaal van 104 opeenvolgende pasiënte met ‘n kliniese vermoede van pulmonale embolisme is verwys. Nege-en-sewentig pasiënte is uitgesluit, in die meeste gevalle as gevolg van abnormale serum kreatinienvlakke. Slegs 25 pasiënte is ingesluit, met ’n gemiddelde ouderdom van 48 ± 19 jaar, en 64% vroue. In vergelyking met RTPA as goudstandaard, was die prevalensie van PE 16% [5% – 37% met 95% VI], sensitiwiteit 75% [21% – 99% met 95% VI], spesifisiteit 90% [68% – 98% met 95% VI], positiewe voorspellingswaarde 60% [17% – 93% met 95% VI], negatiewe voorspellingswaarde 95% [73% – 100% met 95% VI] en diagnostiese akkuraatheid van 88% [69% – 97% met 95% VI] vir beide planare en EFERT V/Q beelde. V/Q planare beelde het ‘n laer lesersvertroue getoon, nl. dat slegs 72% van gevalle opgelos kon word relatief tot V/Q EFERT beelde, wat in alle gevalle presies geïnterpreteer kon word, met meer en beter omskrewe nie-ooreenstemmende teenoor ooreenstemmende en segmentele teenoor nie-segmentele defekte. In alle pasiënte met ‘n Wells puntetelling van 4 is PE met die RTPA uitgeskakel (p=0.04581), terwyl dit in 89% van pasiënte met V/Q EFERT en planare beelde uitgeskakel is. Gevolgtrekking: Gebaseer op hierdie studie het V/Q planare en EFERT beelding ‘n ooreenstemmende diagnostiese prestasie in pasiënte met ’n normale of naby normale borskas X-straal.

The intensive care unit treats the most critically ill patients in the hospital, and as such the clinical staff in the intensive care unit have to deal with complex, time-sensitive and life-critical situations. Commonly, patients present with multiple organ dysfunctions, require breathing and cardiovascular support, which make diagnosis and treatment even more challenging. As a result, clinical staff are faced with processing large quantities of often confusing information, and have to rely on experience and trial and error. This occurs despite the wealth of cardiovascular metrics that are available to the clinician. Computer models of the cardiovascular system can help enormously in an intensive care setting, as they can take the monitored data, and aggregate it in such a way as to present a clear and understandable picture of the cardiovascular system. With additional help that such systems can provide, diagnosis can be more accurate and arrived at faster, alone with better optimised treatment that can start sooner, all of which results in decreased mortality, length of stay and cost. This thesis presents a model of the cardiovascular system, which mimics a specific patient’s cardiovascular state, based on only metrics that are commonly measured in an intensive care setting. This intentional limitation gives rise to additional complexities and challenges in identifying the model, but do not stand in the way of achieving a model that can represent and track all the important cardiovascular dynamics of a specific patient. One important complication that comes from limiting the data set is need for an estimation for the ventricular time-varying elastance waveform. This waveform is central to the dynamics of the cardiovascular model and is far too invasive to measure in an intensive care setting. This thesis thus goes on to present a method in which the value-normalised ventricular time-varying elastance is estimated from only metrics which are commonly available in an intensive care setting. Both the left and the right ventricular time-varying elastance are estimated with good accuracy, capturing both the shape and timing through the progress of pulmonary embolism and septic shock. For pulmonary embolism, with the algorithm built from septic shock data, a time-varying elastance waveform with median error of 1.26% and 2.52% results for the left and right ventricles respectively. For septic shock, with the algorithm built from pulmonary embolism data, a time-varying elastance waveform with median error of 2.54% and 2.90% results for the left and right ventricles respectively. These results give confidence that the method will generalise to a wider set of cardiovascular dysfunctions. Furthermore, once the ventricular time-varying elastance is known, or estimated to a adequate degree of accuracy, the time-varying elastance can be used in its own right to access valuable information about the state of the cardiovascular system. Due to the centrality and energetic nature of the time-varying elastance waveform, much of the state of the cardiovascular system can be found within the waveform itself. In this manner this thesis presents three important metrics which can help a clinician distinguish between, and track the progress of, the cardiovascular dysfunctions of pulmonary embolism and septic shock, from estimations based of the monitored pressure waveforms. With these three metrics, a clinician can increase or decrease their probabilistic measure of pulmonary embolism and septic shock.

No description available.

Die akute Lungenarterienembolie stellt eine häufige Erkrankung dar, welche mit einer hohen Letalität einhergeht. Die Risikostratifizierung und Therapieplanung beruht derzeit primär auf klinischen Parametern, Biomarkerbestimmungen und den Ergebnissen der Echokardiographie. Fr¨¹here Untersuchungen zeigten einen möglichen Nutzen von Heart-type Fatty-Acid Binding Protein (H-FABP) als Prognosemarker. Hierbei wurden allerdings unselektierte Patientenkollektive verwendet. Der Nutzen von H-FABP in der Risikostratifizierung normotensiver Patienten mit einer akuten Lungenarterienembolie ist bislang nicht untersucht. H-FABP ist ein Enzym des Myokards, welches eine tragende Bedeutung im Fettstoffwechsel der Myozyten spielt. Es wird bei einer Schädigung des Herzmuskels ins Blutplasma freigesetzt und ist dort innerhalb kurzer Zeit als Marker einer Myokardischämie nachweisbar. Insgesamt wurde in dieser Studie die prognostische Aussagekraft von H-FABP bei 126 normotensiven Patienten mit einer akuten Lungenarterienembolie im Hinblick auf 30-Tages-Komplikationen sowie ihr Langzeit¨¹berleben untersucht. Innerhalb von 30 Tagen kam es bei 9 (7%) Patienten zu Komplikationen. In dieser Subpopulation zeigten sich signifikant (p<0,001) erhöhte H-FABP-Spiegel (median 11,2 ng/ml; IQR 8,0-36,8) im Vergleich zu der Patientengruppe, in der keine Komplikationen auftraten (median 3,4 ng/ml; IQR 82,1-4,9). 29 Patienten zeigten bei Aufnahme einen H-FABP-Wert oberhalb des mittels ROC-Analyse ermittelten cut-offs von 6 ng/ml. Hiervon entwickelten 8 (28%) Patienten Komplikationen. Von 97 Patienten mit einem normwertigen H-FABP-Wert kam es in einem Fall zu Komplikationen (negativer prädiktiver Wert 0,99; p<0,001). Damit lag bei einem erhöhten H-FABP-Spiegel ein 36,6-fach erhöhtes Komplikationsrisiko vor. Die etablierten Marker Troponin T und NT-proBNP waren hingegen nicht mit dem vermehrten Auftreten von Komplikationen assoziiert. Die Kombination von H-FABP mit einer Tachykardie erscheint ein äußerst n¨¹tzlicher und praktikabler Prognosemarker f¨¹r Komplikationen zu sein (OR 33,4; p<0,001). H-FABP zeigte sich außerdem als ein signifikanter Parameter f¨¹r ein verk¨¹rztes Langzeit¨¹berleben (HR 4,5; p<0,001). Die Ergebnisse dieser Studie deuten darauf hin, dass H-FABP ein n¨¹tzlicher Biomarker in der Risikostratifizierung hämodynamisch stabiler Patienten mit einer akuten Lungenarterienembolie ist.

O diagnóstico da tromboembolia pulmonar aguda (EPA) e a avaliação da gravidade desta condição é desafiador. Enquanto as concentrações de troponina I cardíaca (TI) já estão bem estabelecidas quanto ao risco de estratificação, não há estudos prévios que tenham examinado se há alguma relação linear entre as concentrações de TI cardíaca e a gravidade da EPA. Além disso, as metaloproteinases (MMPs) da matriz extracelular estão envolvidas na fisiopatologia da EPA. Entretanto, é desconhecido se o aumento da atividade gelatinolítica das MMPs após a EPA reflete a gravidade desta condição. Nós examinamos se as concentrações circulantes destes biomarcadores aumentam em proporção à gravidade da EPA experimental induzida em cães anestesiados. A EPA foi induzida com coágulos de sangue autólogo (salina, 1, 3 ou 5 mL/Kg) injetados no átrio direito. As avaliações hemodinâmicas foram realizadas no momento basal e 120 minutos após a EPA. Da mesma forma, foram realizadas as quantificações de troponina I no soro e a zimografia das MMPs 2 e 9 no plasma. Nossos resultados sugerem não haver aumento significativo da atividade gelatinolítica da pró-MMP-2 no plasma após a EPA, enquanto que a atividade da pró-MMP-9 aumenta em 80% apenas no grupo que recebeu 5 mL/Kg de coágulos. A TI cardíaca no soro e a atividade da pró-MMP-9 no plasma tiveram uma correlação positiva com o índice de resistência vascular pulmonar (p=0,007 e rs=0,833 para a TI, e p=0,034 e rs=0,684 para a pró-MMP-9) e com a pressão média na artéria pulmonar (p=0,005 e rs=0,610 para a TI, e p=0,022 e rs=0,720 para a pró-MMP-9). Concluímos que a TI cardíaca e a pró-MMP-9 circulantes aumentam em proporção à gravidade da EPA, embora o aumento da pró-MMP-9 não seja muito evidente em graus menos severos da EPA. Estes achados podem ser relevantes para a clínica da EPA. / Making the diagnosis of acute pulmonary thromboembolism (APT) and assessing its severity is very challenging. While cardiac troponin I (CTI) levels are promising in risk stratification, no previous study has examined whether there is a linear relation between CTI levels and the severity of APT. Moreover, matrix metalloproteinases (MMPs) are involved in the pathophysiology of APT. However, it is unknown whether the increases in MMP levels after APT reflect the severity of this condition. We examined whether the circulating levels of these biomarkers increase in proportion to the severity of experimental APT induced in anesthetized dogs. APT was induced with autologous blood clots (saline, 1, 3, or 5 mL/kg) injected into the right atrium. Hemodynamic evaluations were carried out for 120 min. Gelatin zymography of MMP-2 and MMP-9 from plasma samples were performed and serum CTI levels were determined at baseline and 120 min after APT. Our results sugest that while no significant increases in pro-MMP-2 levels were found after APT, pro-MMP-9 levels increased by 80% only after 5 mL/kg of clot embolization. Serum CTI and plasma pro-MMP-9 levels correlated positively with pulmonary vascular resistance (p=0.007 and rs=0.833 for troponin I, and p=0.034 and rs=0.684 for pro-MMP-9) and with pulmonary artery pressure (p=0.005 and rs=0.610 for troponin I, and p=0.022 and rs=0.720 for pro-MMP-9). We conclude that circulating CTI and pro-MMP-9 increase in proportion to the severity of APT, although the increases in plasma pro-MMP-9 are less clear with less severe APT. These findings may be relevant for clinical APT.

Com a transição epidemiológica no Brasil, as doenças crônicas passaram a ser responsáveis pelo maior número de óbitos entre homens e mulheres. Entre os componentes que definem o estado de saúde humana, alguns do contexto geográfico, como clima local e fatores socioeconômicos, parecem influenciar na mortalidade por doenças do aparelho circulatório, tais como no acidente cerebral vascular (AVC) e na embolia pulmonar (EP). O objetivo principal deste trabalho foi verificar a influência do contexto geográfico (variáveis meteorológicas, índice climático e fatores socioeconômicos) na mortalidade por doenças do aparelho circulatório (AVC e EP) no município de São Paulo, no período de 2002 a 2011. Para analisar a associação da mortalidade com as variáveis meteorológicas foi utilizado um modelo linear generalizado empregando-se o método de Poisson e os modelos de lags distribuídos. Espacialmente a associação da mortalidade com as variáveis socioeconômicas foram testadas utilizando-se os modelos de regressão espacial OLS e GWR. Como resultado encontramos que tanto o frio quanto o calor são fatores de risco para todos os tipos de AVC e EP, com risco maior dependendo do tipo em homens e mulheres. Espacialmente os valores mais elevados do risco relativo (RR) da mortalidade por AVC estavam concentrados nas regiões periféricas do municipio de São Paulo, o que coincidiu com as áreas de menor renda per capita e vegetação e maior porcentagem de população preta. Já com relação à distribuição espacial dos altos valores de RR por EP esses estavam presentes principalmente na região central do município. Concluindo, a nossa pesquisa gerou grande quantidade de resultados que mostram que tanto as variáveis ambientais como socioeconômicas têm influência na mortalidade por algumas doenças do aparelho circulatório. Tendo em vista que o atendimento de urgência para os casos de AVC e EP pode evitar óbitos e sequelas graves, a melhor compreensão da importância do contexto geográfico pode permitir o desenvolvimento de sistemas de alertas junto aos serviços de atendimento de urgência e o direcionamento de campanhas para a prevenção dos fatores de risco evitáveis. / With the epidemiological transition in Brazil, chronic diseases are now responsible for more deaths among men and women. Among the components that define the state of human health, some geographical context, as local climate and socioeconomic factors appear to influence the mortality from circulatory diseases, such as in stroke and pulmonary embolism (PE). The main objective of this study was to investigate the influence of the geographical context (meteorological variables, climate index and socioeconomic factors) in mortality from cardiovascular diseases (stroke and PE) in São Paulo, between 2002 to 2011. In order to analyze the association of mortality with the meteorological variables we used a generalized linear model using the Poisson distribution and distributed lag non linear models. Spatially the association of mortality with socioeconomic variables were tested using the spatial regression models OLS and GWR. As a result we found that both the cold and the heat are risk factors for all types of stroke and PE with a higher risk depending on the type of men and women. Spatially the highest values of relative risk (RR) for stroke mortality were concentrated in the outskirts of the city of São Paulo, which coincided with areas of lower per capita income and vegetation and higher percentage of black population. In relation to spatial distribution of high values of RR PE by these were present mainly in the inner area. In conclusion, our research has generated a lot of results that show that both environmental and socioeconomic variables influence on mortality from some diseases of the circulatory system. In view of the urgent care for stroke and PE cases can avoid serious sequelae and deaths, a better understanding of the importance of geographic context may allow the development of warning systems at the urgent care services and targeting campaigns for the prevention of avoidable risk factors.

Thesis (B.S.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1980. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Includes bibliographical references. / by Martin Raymond Prince. / B.S.