O presente trabalho objetivou explorar a eventual variação da expressão do mRNA e da proteína S100b no hipocampo, cerebelo e córtex cerebral de ratos neonatos em condições de anóxia, comparativamente à condições controle. Este estudo foi desenvolvido em ratos albinos, divididos em dois grupos: o grupo Experimental Anóxia (EA) e o grupo Experimental Controle (EC), que por sua vez foram subdivididos em tempos de 2, 4, 6, 12 e 24 horas no que se refere à coleta de amostras após a aplicação dos estímulos pré-estabelecidos para cada grupo. Dos períodos avaliados, nossos resultados indicaram que a anóxia proporcionou um pico na expressão gênica de S100b após duas horas e proteica após 4 horas nas áreas do hipocampo e cerebelo. O córtex cerebral do grupo EA quando comparado ao grupo EC, não apresentou nenhum aumento significante de S100b nos períodos avaliados. Os resultados obtidos contribuem de forma crucial para elucidação do papel da proteína S100b como biomarcadora na EHI, bem como no esclarecimento parcial da função deste gene com relação à fisiopatologia da doença. / The aim of the present study was to investigate the temporal variation in the expression of S100b mRNA and protein in the hippocampus, cerebellum, and cerebral cortex of newborn rats under conditions of anoxia compared with control rats. The study was performed using two groups albino rats: Experimental Anoxia (EA) and Experimental Control (EC). The animals in both EA and EC were distributed in the following subgroups relative to the time elapsed since the application of the stimuli predefined for each group: two, four, six, 12, and 24 hours. Anoxia induced a peak in the S100b gene expression after two hours and protein expression after 4 hours in the hippocampus and cerebellum. With respect to the cerebral cortex, S100b never exhibited a significant increase in the EA group compared with the EC group. The results of the present study represent a crucial contribution to the elucidation of the role protein S100b plays as a biomarker in HIE, as well as a contribution to the elucidation of the role the corresponding gene plays in the physiopathology of the disease.

No description available.

A encefalopatia hipóxico-isquêmica neonatal, ou simplesmente hipóxia-isquemia (HI) neonatal, é uma das principais causas de morbidade e mortalidade em neonatos humanos. De 20% a 50% dos recém-nascidos com HI severa morrem no período perinatal. Quando sobrevivem, 25% apresentam deficiências neuropsicológicas, como dificuldade de aprendizado, epilepsia e paralisia cerebral. Devido a isso, a eficácia de possíveis agentes neuroprotetores tem sido testada em modelos animais. Há razão para se pensar que a progesterona tem um forte potencial para o tratamento da HI neonatal, já que a sua utilização tem se mostrado benéfica em pesquisas relacionadas com lesão cerebral traumática, lesão cerebral isquêmica e outros modelos de lesão do sistema nervoso central (SNC) em adultos. Inúmeros estudos têm mostrado que o modelo animal de HI de Rice e Vannucci (1981) em animais neonatos, utilizado no presente trabalho, pode produzir lesões no sistema nervoso central relativamente previsíveis, e que estas lesões encefálicas parecem semelhantes às observadas clinicamente em humanos (SALMASO et al., 2014). Para a realização do modelo de HI foram utilizados ratos Wistar com idade de 7 dias (P7). Após a oclusão da carótida esquerda, os animais foram colocados em câmaras para exposição à atmosfera hipóxica com 8% O2/92% N2 por 90 minutos. Os animais foram divididos em cinco grupos experimentais: SHAM, HI, HI+PROG-PRÉ (PRÉ), HI+PROG-PÓS (PÓS), HI+PROG-PRÉ/PÓS (PP). Os termos PRÉ e PÓS referem-se à administração de progesterona (na dose de 5 mg/kg) antes ou após o procedimento de HI neonatal . Dependendo do grupo experimental, os animais foram tratados com progesterona imediatamente antes da isquemia e/ou 6 e 24 horas após o início da hipóxia. Foram analisados o peso corporal dos animais (imediatamente antes da isquemia e 6, 24 e 48 horas após o início da hipóxia), o volume de lesão cerebral, além da expressão das proteínas p-Akt e caspase-3 pela técnica de Western blotting. / Neonatal hypoxic-ischemic encephalopathy or simply neonatal hypoxia-ischemia (HI) is a main cause of morbidity and mortality in human neonates. Moreover, 25% of survivors show neuropsychological dysfunctions such as learning difficulties, epilepsy and cerebral palsy. Because of this, the effectiveness of potential neuroprotective agents has been tested in animal models. There is a reason to suppose that progesterone has a strong potential for the treatment of neonatal HI since its use has been shown to be beneficial in researches related to traumatic brain injury, ischemic brain injury and other central nervous system injury models (CNS) in adults. Several studies have shown that the newborn animal model of HI developed by Rice and Vannucci (1981), and used in the present study, can produce lesions in the central nervous system which are predictable and similar to those observed clinically in humans. In order to perform the HI model we used 7 days old (P7) Wistar rats. After occlusion of the left carotid, the animals were placed in hypoxic chambers and exposed to the hypoxic atmosphere (8% O2/92% N2 for 90 minutes). The animals were divided into five groups: SHAM, HI, HI+PROG-PRÉ (PRÉ), HI+PROG-PÓS (PÓS), HI+PROG-PRÉ/PÓS (PP).The PRÉ and PÓS terms refer to the administration of progesterone (5 mg/kg) before and/or after the HI procedure. Progesterone was administered immediately before ischemia, 6 and 24 hours after the beginning of hypoxia, depending on the experimental group. Body weight was evaluated immediately before ischemia and/or 6 and 24 hours after the start of hypoxia. The volume of brain damage, in addition to the expression of p-Akt and caspase-3 were also evaluated.

Micro-encapsulation of heart explant-derived stem cells (EDCs) within protective nanoporous gel (NPG) cocoons improves cardiac function and long-term retention of transplanted cells after ischemic injury by limiting detachment induced cell death and vascular clearance of intramyocardial injected cells. Although cocooned EDCs boost cardiac function, the fundamental mechanism is unclear. Here, we investigate the effects of altering cocoon stiffness and size on human EDC mediated repair of damaged myocardium using an immunodeficient mouse model of ischemic cardiomyopathy. First, we found that increasing cocoon stiffness by altering NPG content boosted cell viability and migration; effectively forcing cocooned cells to adopt a migratory, invasive phenotype. Although cocooning improved retention of transplanted cells, increasing cocoon stiffness had no additional effects on long-term engraftment despite markedly improving cardiac function and fibrosis after myocardial infarction. Given increased cocoon stiffness boosted the production and microRNA cargo within EDC nanovesicles, the observed benefits in post-ischemic function are likely dependent more on paracrine production of transplanted cells rather than simply increasing the number of cells retained. The effect of cocoon diameter on EDC phenotype and cell mediated repair of ischemic myocardium was evaluated using microfluidic-based cocooning enabling deterministic encapsulation within defined cocoon size and intracapsular cell number while maintaining a fixed cocoon stiffness. Increased cocoon size enhanced post-ischemic cardiac function by reducing clearance of transplanted cells and increased paracrine stimulation of endogenous repair. The latter being attributable to microfluidic cocooning closely following the expected Poisson distribution with smaller cocoons having a greater proportion of single cells while larger cocoons contained greater proportions of multicellular aggregates which enhanced cell-cell interactions to increase the amount and breadth of cytokines/nanoparticles delivered to injured myocardium. In conclusion, altering the biophysical properties of NPG surrounding cocooned cells provides a straightforward means of boosting the regenerative potential of heart EDCs for repair of injured myocardium.

Submitted by Rosina Valeria Lanzellotti Mattiussi Teixeira (rosina.teixeira@unisantos.br) on 2017-08-22T18:44:23Z No. of bitstreams: 1 Francisco Orlando Rafael Freitas.pdf: 3156371 bytes, checksum: 890fc3eea1e863771fa92f290802cb73 (MD5) / Made available in DSpace on 2017-08-22T18:44:23Z (GMT). No. of bitstreams: 1 Francisco Orlando Rafael Freitas.pdf: 3156371 bytes, checksum: 890fc3eea1e863771fa92f290802cb73 (MD5) Previous issue date: 2017-04-10 / The aim of this study was to evaluate the relationship between air pollution and adults ischemic heart disease admissions (IHD) in São Paulo city, stratified by gender, exploring lag structures for the period from 2000 to 2013. The is an ecological time series study. The data referring to O3, PM10, CO, SO2, NO2, minimum temperature and humidity were obtained from the Environmental Company of São Paulo State (CETESB). Hospital admissions were obtained from the Public Health System database (DATASUS). It was used the descriptive analysis and Generalized linear model of Poisson regression with third-degree polynomials, considering a distributed lag of up to seven days after exposure as well as controlling for long-term seasonality, weekdays. The significant level was 5%. For an interquartile range increase in PM10 (24.29¿g/m³) no significant effects were observed for the age group 30 to 44. But for the age group 45 to 60, there was an increase due to men admissions for 3.30% (95% CI: 1.64-4.96) and for females 2.88% (95% CI: 1.42-4.33) on the day of exposure. An interquartile range increase in SO2 (7.63 ¿g / m³), there was an increase of 6.99% (95% CI: 3.31-10.67) and 2.46% (95% CI: 0 , 51-4,42) on the day and the day after of exposure in the age group 30 to 44, and an increase of 3.91% (95% CI: 2.38-5.44) and 1.92% (95% CI: 1.10-2.73) in the age group 45 to 60. For NO2, an interquartile range (50.22 ¿g / m³) increases the total admissions in 6.17% (95% CI: 2.80-9.53) on the day of exposure, demonstrating acute effect. Ischemic heart diseases present an acute effect on people exposure to air pollutants, affecting both gender in the age groups. It is important the implementation of public policies aiming at levels of concentrations that do not affect the population health. / Este estudo tem por objetivo avaliar a relação entre poluição do ar e internações por doenças isquêmicas do coração (DIC), em adultos, na cidade de São Paulo, estratificada por sexo, explorando estruturas de defasagens, para o período de 2000 a 2013. O presente estudo é ecológico de séries temporais, no qual as análises foram estratificadas por faixa etária e sexo e incluíram internações por Doenças Isquêmicas do Coração (CID10: I50). Os dados referentes O3, PM10, CO, SO2, NO2, temperatura mínima e umidade foram obtidos da Companhia Ambiental do Estado de São Paulo (CETESB), já as internações hospitalares foram obtidas a partir do banco de dados do SUS (DATASUS). A relação entre poluentes do ar e fatores climáticos nas internações por doenças isquêmicas do coração foram analisadas por meio de um modelo de defasagem de distribuição polinomial tanto para a temperatura como para os poluentes do ar. Foi utilizado o modelo linear generalizado de regressão de Poisson com polinômio de terceiro grau e considerando uma defasagem distribuída de até sete dias após a exposição como também, controlando-se para sazonalidade de longa duração, dias da semana e feriados. A seguir, foi calculado o aumento no número de internações para a diferença interquartil dos poluentes significativos no modelo de regressão, bem como para os fatores meteorológicos. Verificou-se que o O3 não teve relação a todos os desfechos analisados. Para um aumento de interquartil de PM10 (24,29¿g/m³) não foi evidenciado efeito significativo pós-exposição entre 30 a 44 anos. Já para faixa etária de 45 a 60 anos, com aumento de um interquartil de PM10 houve elevação nas internações de homens por doença isquêmica do coração de 3,30% (IC95%: 1,64-4,96) e para o sexo feminino de 2,88% (IC95%: 1,42-4,33) no dia da exposição. Para as internações totais, com aumento de um interquartil (7,63 ¿g/m³) de SO2, houve elevação de 6,99% (IC95%: 3,31-10,67) e 2,46% (IC95%: 0,51-4,42) nas internações no dia da exposição e no dia seguinte referente a faixa etária de 30 a 44 anos e aumento de 3,91% (IC95%: 2,38-5,44) e 1,92% (IC95%: 1,10-2,73) para faixa etária de 45 a 60 anos. Referente ao NO2, uma variação interquartil (50,22 ¿g/m³) aumentou 6,17% (IC95%: 2,80-9,53) nas internações totais apenas no dia da exposição demonstrando efeito agudo. Com o aumento de um interquartil na concentração de CO igual a 1,28 ppm não foi evidenciado elevação das internações por DIC com relação a faixa etária e gênero/sexo. Diante do exposto, verifica-se que as Doenças Isquêmicas do coração apresentam efeito agudo a exposição aos poluentes do ar e aos fatores meteorológicos, afetando o sexo masculino e feminino nas faixas etárias estudadas, com isso evidencia-se a importância das políticas públicas voltadas para manutenção dos níveis de poluentes em concentrações que não afetem a saúde da população.

Stroke is the 5th leading cause of death and the leading cause of disability in the United States, but there are only two available therapies, tissue plasminogen activator and endovascular thrombectomy. As both therapies focus on removal of the clot, the subsequent pathologic processes, i.e. inflammation, cerebrovascular breakdown, ATP depletion, etc. are left untreated, contributing to worsened patient outcome. Many clinical trials have unsuccessfully attempted to address these mechanisms. The blood-brain barrier (BBB), a system of non-fenestrated endothelial cells, extracellular matrix, and astrocytic endfeet, is significantly impacted after ischemic stroke in its role of preventing the free movement of proteins from the blood into the brain. In fact, BBB dysfunction is viewed as one of the major facilitators of damage following ischemic stroke, leading to increased infarct volumes and worsened patient outcomes. Interestingly, a family of endothelial integrins, the b1 integrins, have been shown to regulate tight junction proteins preventing the free movement of molecules. When expression of the tight junctions are decreased, this results in increased BBB permeability. To test this concept, our laboratory has previously shown the knockout of the particular β1 integrin, α5β1, is neuroprotective following ischemic stroke through BBB stabilization. To determine if therapeutically targeting integrin a5b1 was feasible, we first determined if brain integrin a5b1 expression increases after experimental mouse ischemic stroke model, specifically tandem/transient common carotid artery/middle cerebral artery occlusion. We found that integrin a5b1 does increase acutely, by post-stroke day (PSD)2, and continued in an exponential fashion through PSD4. Next, we determined if integrin a5b1 was therapeutically accessible by systemic treatment (i.e. intraperitoneal or intravenous) by being located on the inside (luminal surface) of vasculature. We found that location of integrin a5b1 was dependent on the area relative to the stroke injury. The core, or area of direct impact, demonstrated expression of integrin a5b1 on the outside vasculature (abluminal surface), while per-infarct expression was localized to the lumen. Lastly, to determine the activity of integrin a5b1 following ischemic stroke, we showed that the potential ligands (binding partners), plasma fibronectin, fibrinogen, and amyloid-b, do not bind integrin a5b1 after ischemic stroke. Next, we determined the therapeutic potential of targeting integrin a5b1 with the small peptide, ATN-161. ATN-161 has undergone clinical trials in solid tumors, with limited side effects reported. First, we determined that intraperitoneal (IP) injection of ATN-161 was safe after ischemic stroke, showing no changes in heart rate, pulse distention (blood pressure), or body temperature. Next, we found that IP administration of ATN-161 after experimental ischemic stroke reduced infarct volumes, edema, and functional deficit. Furthermore, these results were due to reduction of BBB permeability and anti-inflammatory effects. Interestingly, ATN-161 reduced cytokine production, prevented leukocyte infiltration, and leukocyte recruitment. Collectively, these results suggest that targeting integrin a5b1 with ATN-161 is 1) feasible, 2) safe and 3) effective, suggesting that ATN-161 may be a novel therapeutic treatment for ischemic stroke.

Ischemic stroke is the leading cause of disability world-wide and affects over 800,000 people per year in the United States. The majority of these strokes are ischemic due to a blockage of blood flow to the brain. Damage to the brain occurs at the onset of stroke, neuronal cell death is irreversible and therefore, quick treatment to remove blockage is critical factor in the recovery from stroke. Mechanical thrombectomy as a treatment for ischemic stroke provides an ideal opportunity to collect blood distal and proximal to the cerebral thrombus to examine neurochemical changes occurring during stroke. The purpose of this dissertation was to explore the trajectory of neurochemical changes that occur in response to ischemic stroke during the first 72 hours and the physiological response from stroke patients to improve stroke outcomes. The specific aims were to: 1) to determine whether venous blood gases predict infarct volume and/or mortality in acute ischemic stroke in young male rats; 2) determine whether venous blood gases predict infarct and edema volume, and/or mortality in acute ischemic stroke in aged male and female rats; 3) compare the presence and relative concentrations of acid/base and electrolytes in static blood distal to thrombus and in peripheral blood drawn from adults who received thrombectomy for ischemic stroke and identify associations to postreperfusion functional outcomes. Specific Aim One was addressed by evaluation of young (three-month old) Sprague-Dawley rats that underwent permanent or transient middle cerebral artery occlusion (MCAO). Pre- and post-MCAO venous samples from permanent and transient models provided pH, carbon dioxide, oxygen, bicarbonate, glucose, hematocrit, hematocrit, and electrolyte values of ionized calcium, potassium and sodium. The analyses indicated that mean differences in the blood gas and electrolytes between pre- to post-MCAO and pH and iCa2+ were predictors of infarct volume in the permanent MCAO model. The second aim was addressed by evaluation of aged (18 month old) male and female rats pre-MCAO, post-MCAO, and at 72 hours of permanent MCAO venous blood gas samples (pH, carbon dioxide, oxygen, bicarbonate, glucose, hematocrit, hematocrit, and electrolyte concentrations of ionized calcium, potassium and sodium). Changes in pH (from pre-MCAO to post-MACO and post-MCAO to 72 hours) and changes in Na+ and iCa2+ (from post-MCAO to 72 hours) were predictors of infarct volume and edema volume, respectively in both sexes. Cox regression revealed there was a 3.25 times increased risk for mortality based on changes (cut-off range within -2.00 to - 7.00) in bicarbonate levels (pre- to post-MCAO). The third aim was addressed by evaluation of acid/base balance (pH, carbon dioxide, oxygen, bicarbonate, ionized calcium, potassium and sodium) of ischemic stroke patients who underwent mechanical thrombectomy. Our results suggests sex differences matter in ischemic stroke populations. Significant differences occur within proximal blood between the sexes. Additionally, females had approximately 2.5 hour increased time between stroke symptom onset to thrombectomy completion time (described as infarct time). Changes in bicarbonate and base deficit were predictors of infarct time, but only in our female population.

Les maladies cardiovasculaires sont une des principales causes de morbidité et de mortalité au monde. La plus courante est l’infarctus du myocarde définit pathologiquement par la mortalité cellulaire dû à une ischémie prolongée d’une partie du ventricule gauche. L'ischémie est caractérisée par un apport sanguin insuffisant causé par une obstruction d’une artère coronaire. La restauration, en clinique, du flux sanguin, appelée reperfusion, est considérée comme la méthode la plus efficace contre les dommages ischémiques. Paradoxalement, cette restauration du flux sanguin est associée à une exacerbation de la lésion tissulaire, entraînant alors des lésions d'ischémie-reperfusion (I/R). Dans le but de limiter ces lésions, le conditionnement ischémique myocardique est une avancée majeure dans le domaine de la cardioprotection. Ce protocole confère ses effets cardioprotecteurs via le recrutement de divers mécanismes endogènes suivant l’activation de deux voies intracellulaires : la voie RISK (Reperfusion Injury Salvage Kinase) et/ou la voie SAFE (Survivor Activator Factor Enhancer). Ces voies impliquent l'activation de différentes cascades de signalisation et de protéines kinases. En particulier, concernant la voie SAFE, le transducteur de signal et l'activateur de transcription-3 STAT3, a été identifié comme un acteur clé dans le postconditionnement ischémique (PostCI). Il est suggéré que les effets cardioprotecteurs attribués à STAT3 soient liés à ses effets en tant que facteur de transcription et en tant que régulateur de l’activité mitochondriale, mais tout n’est pas encore connu. En revanche, il est admis que STAT3 est activé par la phosphorylation ciblant les résidus tyrosine 705 et sérine 727. Dans nos travaux actuels, nous avions initialement pour objectif d’étudier les rôles cardioprotecteurs mitochondriaux de STAT3 après une I/R et un PostCI. Cependant, nous n'avons pas été en mesure de détecter STAT3 dans les mitochondries de cardiomyocytes adultes de souris, dans des conditions basales et de stress, en utilisant différentes approches. Fait intéressant, nous avons montré une localisation exclusive de STAT3 dans les myocytes cardiaques adultes, le long des tubules T, et nous avons mis en évidence les inconvénients des techniques précédemment utilisées.Outre les rôles putatifs de STAT3 dans les mitochondries, nous avons ciblé ses effets dans la signalisation et la génomique au cours de l'I/R et du PostCI. Nous avons tout d’abord cherché à déterminer, pendant l’I/R et le PostCI, la cinétique temporelle d’activation de STAT3 et des autres kinases de la voie RISK, notamment Akt et les MAPK ERK1 / 2, JNK et p38. En outre, nous avions pour objectif d’étudier les liens entre les voies SAFE et RISK en déchiffrant les liens entre STAT3 et les kinases RISK au cours du PostCI. Nous avons montré qu’après une ischémie et un temps court de reperfusion, STAT3 et ERK1/2 sont activés, et que l’utilisation d’un PostCI active d’autant plus STAT3 en induisant exclusivement la phosphorylation de sa tyrosine. Nous avons également montré que l’interconnexion entre les voies SAFE et RISK, dans le protocole PostCI utilisé, se fait par STAT3 et ERK1/2. À partir de ces résultats, nous nous sommes dirigés vers la génomique grâce à laquelle nous avons étudié l'activité de STAT3 au cours de l'IPoC. À cet égard, nous avons montré que STAT3 est impliqué dans la régulation de la réponse inflammatoire au cours de la PostCI. Dans l’ensemble, cette étude présente une approche globale des fonctions mitochondriales, de signalisation et génomiques de STAT3 dans le contexte de la protection cardiaque / Cardiovascular diseases are leading causes of morbidity and mortality worldwide. Among the mostly prevailing cardiovascular diseases is myocardial infarction, which is pathologically defined as myocardial death due to a prolonged ischemia. Ischemia is an insufficient supply of blood caused by a blockade in the coronary arteries. The early restoration of blood flow is considered the most effective method against the ischemic lesions. Paradoxically, this blood flow restoration is associated with an exacerbation of the tissue injury, leading to the ischemia-reperfusion (I/R) injury. To avoid this injury, the myocardial ischemic conditioning protocol has rejuvenated the field of cardioprotection. This protocol confers its cardioprotective effects via recruiting various endogenous mechanisms following the activation of two intracellular pathways: the reperfusion injury salvage kinase (RISK) or survivor activator factor enhancer (SAFE) pathways. These pathways involve the activation of different signaling cascades and protein kinases. Zooming in through the SAFE pathway, the signal transducer and activator of transcription-3, STAT3, has been identified as a prominent key player in ischemic postconditioning (IPoC). The cardioprotective effects attributed to STAT3 are suggested to be linked to its roles as a transcription factor and as a regulator of the mitochondrial activity, but these are not well studied and elaborated. STAT3 is activated by phosphorylation, which targets the tyrosine 705 and serine 727 residues. In our current work, we initially aimed to investigate the mitochondrial cardioprotective roles of STAT3 following I/R and IPoC. However, we were not able to detect STAT3 in the mitochondria of adult mouse cardiomyocytes under variousbasal and stress conditions using different approaches. Interestingly, we showed an exclusive STAT3 pattern in adult cardiac myocytes, along the T-tubules, and highlighted drawbacks of previously used techniques. Aside from the mitochondrial roles of STAT3, we targeted its signaling and genomic roles during I/R and IPoC. We first aimed to determine, during I/R and IPoC, the temporal kinetics of activation of STAT3 and the other kinases of the RISK pathway including Akt and the MAPKs ERK1/2, JNK and p38. In addition, we aimed to decipher the interlink between the SAFE and RISK pathways through deciphering the interlink between STAT3 and the RISK kinases following IPoC. We showed that a short reperfusion time activates STAT3 and ERK1/2 following ischemia, and that the application of IPoC further activates STAT3 through inducing its tyrosine phosphorylation. We also showed that the interlink between SAFE and RISK pathways, in the IPoC protocol we used, is through STAT3 and ERK1/2. From this signaling level, we moved toward the genomic level whereby we investigated the genomic activity of STAT3 during IPoC. In this regard, we have shown that STAT3 is involved in the regulation of the inflammatory response during IPoC. Overall, this study presents a global approach of STAT3’s mitochondrial, signaling and genomic functions in the context of cardiac protection

<p>The cardiac wall has complex three-dimensional fiber structures and mechanical properties that enable the heart to efficiently pump the blood through the body. By studying the myocardial strains induced during diastole, information about the pumping performance of the heart and what mechanisms that are responsible for this effective blood filling, can be achieved. Two different computation methods for myocardial strain, both based on data acquired from marker technique, were compared using a theoretical cylinder model. The non-homogeneous polynomial fitting method yielded higher accuracy than a homogeneous tetrahedron method, and was further used to investigate cardiac and fiber strains at different wall depths and myocardial regions in normal and ischemic ovine hearts. Large spatial and regional variations were found, as well as alterations, conveyed by ischemic conditions, of fiber mechanisms responsible for the circumferential expansion and wall thinning during diastole.</p>

Background and aims. In patients consulting for chest pain, it is of great importance to evaluate the possibility of ischemic heart disease (IHD). The aims in this thesis were to investigate the accuracy of the general practitioners’ clinical assessments and the applicability of exercise testing and myocardial perfusion scintigraphy (MPS) in patients consulting for chest pain in primary care. Statins are known to prevent IHD. A further aim was therefore to investigate if a relation could be detected on a population basis between the use of statins and the morbidity of acute myocardial infarction (AMI). Methods. All patients from 20 to 79 years, consulting for a new episode of chest pain in three primary health care centres, were included during almost two years from 1998 to 2000. The patients were managed according to the clinical evaluation. The presence of IHD was excluded either by clinical examination only, or if stable IHD was in question, by exercise testing and if the exercise test was inconclusive by an additional MPS. If unstable IHD or myocardial infarction was suspected, referral for emergency hospital examination was made. Correlations between statin sales and the morbidity of AMI in Sweden’s municipalities were analysed in an ecological, register based study. Adjustment was made for sales of antidiabetics, socio-economic deprivation indexes and geographic coordinates. Results. Consultations for chest pain represented 1.5% of all consultations in the ages 20 to 79 and were made by 554 patients. In 281 patients IHD was excluded by clinical examination only. In 208 patients stable IHD and in 65 unstable IHD was in question. Four patients (1.4%) evaluated as not having IHD, were diagnosed with angina pectoris or AMI within three months. Exercise testing was performed in 191 patients and revealed no IHD in 134 and IHD in 14 patients. In 43 patients the exercise test results were equivocal. Thirty-nine of these patients underwent MPS, which showed no IHD in 20 and IHD in 19 of the patients. In a follow up almost six years later, neither mortality rate nor prevalence of IHD differed significantly between the 384 study patients evaluated not to have IHD and the population controls. Statin sales and AMI-incidence or mortality showed no strong associations from 1998 to 2002. Conclusions. ·Primary care is an appropriate level of care for ruling out IHD as the cause of chest pain, with sufficient safety and for diagnostics of stable IHD. ·Exercise testing and myocardial perfusion scintigraphy are useful procedures when investigating chest pain patients in primary care. ·The results indicate that preventive measures other than increased statin treatment should be considered to further decrease AMI-morbidity.