INTRODUÇÃO: As doenças cardiovasculares representam uma importante causa de morte mundial. Geralmente, são a primeira causa, não só em países desenvolvidos, como também em desenvolvimento. Pacientes com Síndrome Coronária Aguda (SCA) sem supradesnivelamento do segmento ST (SST) apresentam ampla variação do risco para ocorrência de óbito ou eventos isquêmicos recorrentes. Determinar o risco da ocorrência desses eventos adversos é importante para a triagem inicial na seção de emergência, assim como para identificar os que se beneficiam de condutas mais agressivas, dispendiosas e de maior morbidade e mortalidade. OBJETIVO: Realizar um modelo simples de estratificação de risco, facilmente aplicável no Departamento de Emergência, em uma população brasileira não selecionada de ensaios clínicos com o uso de variáveis clínicas, eletrocardiográficas, bioquímicas e biomarcadores plasmáticos. CASUÍSTICA E MÉTODOS: É um estudo prospectivo de pacientes com SCA sem SST recrutados de 1 de julho de 2004 a 31 de outubro de 2006. Foram submetidos a seguimento de 14 e 30 dias para análise do desfecho de morte por todas as causas, infarto (re-infarto) e revascularização miocárdica urgente por isquemia recorrente e de 180 dias para o desfecho de morte por todas as causas. Excluíram-se os pacientes com bloqueios de ramo, ritmo de marcapasso, ritmo de fibrilação atrial e os com episódio isquêmico secundário a causas não cardíacas. Para o modelo de desenvolvimento, optou-se pelo desfecho de morte por todas as causas ou infarto (re-infarto) em até 30 dias. Dados da história clínica, exame físico, eletrocardiograma da admissão, hemograma, bioquímica e biomarcadores plasmáticos foram selecionados para uma análise exploratória. As variáveis que apresentassem nível de significância menor que 10% na análise exploratória ou que fossem consideradas de relevância clínica, foram submetidas a um modelo de regressão logística múltipla. RESULTADOS: A população de desenvolvimento foi de 1.027 pacientes, sendo 589 homens (57,4%) e média de idade de 61,55 anos (± 0,35). O desfecho combinado de morte ou infarto (re-infarto) em 30 dias ocorreu em 54 pacientes (5,3%). Em decorrência do fenômeno de multicolinearidade entre a depressão do segmento ST e a troponina I cardíaca, estas variáveis foram combinadas. Foram identificadas sete variáveis prognósticas: idade em anos; antecedentes pessoais de diabete melito ou acidente vascular cerebral; não uso de inibidor da enzima conversora da angiotensina; combinação de elevação da troponina I cardíaca e depressão do segmento ST; creatinina sérica. O C statistic para o modelo de desenvolvimento foi de 0,78 e para o Escore de Risco Dante Pazzanese foi de 0,74. CONCLUSÃO: Em pacientes com SCA sem SST, o Escore de Risco Dante Pazzanese mostrou-se de fácil execução, com alto valor preditivo para eventos cardiovasculares em 30 dias de evolução, orientando o prognóstico e o tratamento desses pacientes. Pode ser fonte de informações à equipe médica, ao paciente e a seus familiares, englobando importante informação prognóstica. / BACKGROUND: Cardiovascular diseases are usually the leading cause of death in both developed and developing countries. Patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) are at varying degrees of risk for death and recurrent ischemic events. It is important that the risk for these adverse events be determined for the initial screening at the emergency department, as well as for identifying patients who may benefit from treatment options that are more aggressive, expensive and associated with higher morbidity and mortality. OBJECTIVE: To develop a simple risk-stratification model, easily performed in the Emergency Department setting, based on a non-selected Brazilian sample of clinical trials using clinical, electrocardiographic, and biochemical variables, as well as plasma biomarkers. PATIENTS AND METHODS: This is a prospective study of patients with NSTE-ACS recruited from July 1 2004 to October 31 2006. Patients were followed up for 14 and 30 days to assess the endpoints of all-cause mortality, infarction (reinfarction), and urgent myocardial revascularization due to recurrent ischemia, and for 180 days to assess all-cause mortality. Patients with bundle branch blocks, pacemaker rhythm, or atrial fibrillation were excluded from the study, as were those with ischemic episodes of non-cardiac causes. For the model under development the endpoint chosen was all-cause mortality or infarction (reinfarction) up to 30 days. Data on clinical history, physical examination, admission electrocardiogram, blood cell count, biochemistry, and plasma biomarkers were selected for an exploratory analysis. Variables with a significance level of less than 10% on the exploratory analysis or considered clinically relevant were included in a multiple logistic regression model. RESULTS: The study population included 1027 patients, of which 589 were men (57.4%). Mean age was 61.55 (± 0.35). Fifty-four patients (5.3%) reached the endpoints of death and/or infarction (reinfarction) within 30 days. Due to the multicolinearity phenomenon between ST-segment depression and cardiac troponin I, these variables were combined. Seven prognostic variables were identified, namely, age in years, past history of diabetes mellitus or stroke, nonuse of angiotensin-converting enzyme inhibitors, increased cardiac troponin I levels combined with ST-segment depression; and serum creatinine. The C-statistic for the model was 0.78, and for the Dante Pazzanese Risk Score was 0.74. CONCLUSION: In non-ST-segment elevation ACS patients, the Dante Pazzanese Risk Score proved to be easy to perform, with a high predictive value for cardiovascular events at 30 days, guiding prognosis and treatment of these patients. It may be a source of information for the medical team, the patients and their families, including important prognostic data.

Made available in DSpace on 2017-07-21T14:35:56Z (GMT). No. of bitstreams: 1 Anderson Jose de Melo Silva.pdf: 2395463 bytes, checksum: ffa3d1c0f5669babc3c89ef037bd4833 (MD5) Previous issue date: 2017-10-06 / The Acute Coronary Syndrome (ACS) defines a range of clinical changes that are compatible with myocardial ischemia, resulting in the death of myocardial cells due functional deficit of blood flow, characterizing the acute myocardial infarction (AMI). The AMI is evidenced through clinical data that are reinforced by electrocardiogram (ECG), imaging and even the biochemical markers (biomarkers) evaluation, such as serum creatine phosphokinase (CK), its isoenzyme MB fraction (CK-MB), troponin and new biomarkers not yet included in routine laboratory tests, such as myeloperoxidase (MPO). In addition to new laboratory markers, science allows the development of new technologies for clinical assessment of patients, providing new information and less risk, such as non-invasive evaluation of intracranial pressure (ICP). This study is justified by the need to predict earlier the complications in patients with suspected AMI, as well as evaluate them as to the diagnosis and prognosis of the event in question. Thus, we sought to study patients with suspected ACS/AMI about the cardiovascular risk and possible PIC change through traditional biomarkers, most current markers ( "gold standard") and new biomarkers and new ICP monitoring technology. Therefore, from a population of 20 patients, randomly selected according to gender and age, separated into two groups: CK-MB≥25 IU (n = 6) and CK-MB<25 IU (n = 14), which were submitted to measurement of PIC and PAS, as well as biochemical and hematological measurements, and specific cardiac biomarkers. As a result, there was correlation of clinical significance between the values of creatine kinase MB fraction (CK-MB) and glycated hemoglobin (HGBA1C). From these data, it started to study two cases that were selected two patients. It was observed that even with changes of CK-MB, troponin and myeloperoxidase (compared to laboratory practice reference values for traditional markers and "gold standard" and MPO value considered normal in the literature), it was found not manifestations that have allowed to observe reduction of cerebral compliance, where the waves P2 are larger than P1, and therefore, there were no PIC changes identified for patients under the conditions studied. Thus, it was concluded that, even without demonstration of PIC change in this work, it is not possible to exclude the value of its inclusion in the clinical evaluation, considering that biases, like the sample universe and the time of collection of PIC or the use of medication at the admission time on hospital, may have contributed to the non-registration of changes in ICP, even in cases where patients had an unfavorable evolution of the clinical picture. / A Síndrome Coronariana Aguda (SCA) define uma gama de alterações clinicas que são compatíveis com um quadro de isquemia miocárdica, acarretando na morte de células do tecido miocárdico devido ao déficit funcional do fluxo sanguíneo, caracterizando o Infarto Agudo do Miocárdio (IAM). O IAM pode se revelar através de dados clínicos que são reforçados pelo eletrocardiograma (ECG), exames de imagem e ainda a pesquisa de marcadores bioquímicos (biomarcadores), tais como Creatinafosfoquinase (CK), sua isoenzima fração MB (CK-MB), troponina e novos biomarcadores ainda não inclusos na rotina laboratorial, tais como mieloperoxidase (MPO). Além de novos marcadores laboratoriais a ciência permite o desenvolvimento de novas tecnologias para avaliação clínica dos pacientes, proporcionando novas informações e menor risco, tais como a avaliação não invasiva da pressão intracraniana (PIC). O presente trabalho justifica-se pela necessidade de se prever intercorrências com maior antecedência em pacientes com suspeita de IAM, assim como em avaliá-los quanto ao diagnóstico e prognóstico do evento em questão. Desta forma, buscou-se estudar pacientes com suspeita de SCA/IAM quanto ao risco cardiovascular e possível alteração de PIC por meio biomarcadores tradicionais, marcadores mais atuais ("padrão ouro") e novos biomarcadores e nova tecnologia de acompanhamento da PIC. Para tanto, de uma população de 20 pacientes, escolhidos aleatoriamente quanto ao gênero e idade, separou-se em dois grupos: CK-MB≥25 UI (n=6) e CK-MB˂ 25 UI (n=14), os quais foram submetidos à aferição de PIC e PAS, além de dosagens bioquímicas e hematológicas, bem como biomarcadores cardíacos. Como resultado, observou-se correlação de significância clinica entre os valores de creatinofosfoquinase fração MB (CK-MB) e hemoglobina glicada (HgbA1C). A partir destes dados, passou-se ao estudo de dois casos clínicos em que foram selecionados dois pacientes. Foi observado que, mesmo com alterações de CK-MB, troponinas e Mieloperoxidase (comparando-se a valores de referencia da prática laboratorial para os marcadores tradicionais e "padrão ouro" e valor de MPO considerado normal em literatura especializada), constatou-se não haver manifestações que permitissem observar redução da complacência cerebral, quando as ondas P2 se dão maiores que ondas P1 e, portanto, não foram identificadas alterações de PIC para os pacientes nas condições estudadas. Com isso, concluiu-se que, mesmo não havendo demonstração de alteração de PIC neste trabalho, não se pode excluir o valor de sua inclusão na avaliação clínica, dado que vieses como universo amostral, bem como o momento da coleta da PIC e ou uso de medicação no momento da admissão hospitalar, podem ter contribuído para o não-registro de alterações da PIC, mesmo em casos que os pacientes tiveram uma evolução desfavorável do quadro clínico.

Introdução: O teste de caminhada de seis minutos (TC6M) é um teste muito utilizado para avaliar as condições de saúde de idosos e saudáveis, bem como pacientes com doenças pulmonares e cardiovasculares. Porém, poucos são os relatos na literatura científica habitual sobre a utilização do teste de caminhada de seis minutos para avaliar a morbidade e mortalidade de pacientes após infarto agudo do miocárdio (IAM). Objetivo: O objetivo deste estudo foi verificar se o TC6M tem valor preditivo para morbidade e/ou mortalidade cardiovascular após IAM. Queremos verificar o ponto de corte da distância no TC6M para síndrome coronariana aguda, insuficiência cardíaca, re-hospitalização ou óbito por causa cardiovascular. Método: Trata-se de um estudo observacional, no qual se utilizou análise de prontuários, contato telefônico, correio e SIM (Sistema de Informação de Mortalidade da Secretaria de Saúde) de pacientes com diagnóstico de IAM não complicado que realizaram o TC6M antes da alta hospitalar. Desfechos observados: síndrome coronariana aguda, insuficiência cardíaca, acidente vascular cerebral, re-hospitalização e óbito por causa cardiovascular. A coleta de dados se deu no Instituto Dante Pazzanese de Cardiologia, por meio de análise de prontuário e foram incluídos no estudo, os pacientes com diagnóstico de IAM não complicado que realizaram o teste de caminhada de seis minutos antes da alta hospitalar. Para análise estatística foram utilizados: correlação de Pearson ou Spearman, teste t de Student ou Mann-Whitney e ANOVA ou teste de Kruskall Wallis para analisar os efeitos das características físicas e clínicas dos pacientes analisados na distância percorrida no TC6M. Estas características e a distância percorrida foram avaliadas nos desfechos, ao longo de tempo, observando a curva de viii sobrevivência de Kaplan-Meier ou a sobrevivência em média de Cox, a significância dos efeitos foi testada por teste de log-rank ou pelo modelo de riscos proporcionais de Cox, respectivamente. Também foi ajustado um modelo de sobrevivência de Cox final para avaliar o efeito de todas as co-variáveis juntamente presentes no desfecho. Na análise múltipla foi utilizado o método de seleção de variáveis forward para selecionar as variáveis mais associadas à sobrevida. O tamanho dos efeitos, quando significativos, foi medido pela odds ratio (OR). Resultados: Foram incluídos 234 pacientes, 173(73,9 por cento ) do sexo masculino, 57,18 (10,35) anos, 103(44 por cento ) IAM anterior, 182 (77,8 por cento ) Killip I, 190 (81,2 por cento ) com terapia de reperfusão e fração de ejeção do ventrículo esquerdo de 49,99 (10,14) por cento . Foram observados 89 (38,03 por cento ) pacientes com pelo menos um desfecho adverso, sendo 18 (8,1 por cento ) óbitos por causa cardiovascular num período de seguimento médio de 1.355,47 (777,53) dias. A distância do TC6M não se associou à ocorrência dos desfechos adversos, porém à ocorrência de óbito, resultando dois modelos: a) metragem do primeiro quartil (370,5 m) (OR = 2,737; p = 0,046), índice de percepção de esforço (IPE) de Borg (OR = 1,380; p = 0,020) e saturação periférica de oxigênio (SpO2) < 90 por cento (OR = 2,326; p = 0,103); b) metragem do teste de log rank (232 m) (p = 0,036; OR = 3,459), índice de Borg (OR = 1,351; p = 0,044) e SpO2 < 90 por cento (OR = 2,936; p = 0,030). A metragem e a SpO2 também se associaram à pior sobrevida ao longo do tempo: modelo 1) IPE Borg (OR = 1,334; p = 0,041, SpO2 < 90 por cento (OR = 2,675; p = 0,067) e a distância de 370,5m (OR = 2,882; p = 0,042) e modelo 2: SpO2 < 90 por cento (OR = 4,193; p=0,004) e distância de 232m (OR = 5,014; p=0,005). Numa análise do comportamento da FC, SpO2 e PS e PD ao longo do tempo no TC6M entre os grupos óbito e não óbito foram observadas diferenças significantes apenas da FC (p < 0,0001) e SpO2 (p < 0,0001). Conclusão: Na amostra estudada, a distância e a SpO2 < 90 por cento no TC6M se associaram ao óbito e à pior sobrevida em pacientes após IAM não complicado. / Background: The six-minute walk test (6MWT) is a test used to assess the prognosis of patients with heart failure, chronic obstructive pulmonary disease and health status of the elderly. However, there are few reports in the scientific literature about the use of this test as a tool to assess the prognosis after acute myocardial infarction (AMI) patients. The aim of this study is to assess the prognostic value of the 6MWT in AMI patients. We also intend to point out whether there is a minimum distance in the 6MWT that defines a group of patients with worse prognosis, i.e, in the occurrence of death, re-infarction, or heart failure re-hospitalization from cardiovascular causes. Methods: This is an observational study for which we used analysis of medical records, telephone contact, mail and SIM (Mortality Information System of the Department of Health) of uncomplicated AMI patients who underwent 6MWT before hospital discharge. Observed outcomes: acute coronary syndrome, heart failure, stroke,re-hospitalization and cardiovascular death. Data collection has taken place at the Institute Dante Pazzanese of Cardiology, with analysis of medical records and has be included patients with uncomplicated AMI who underwent 6MWT before discharge. Statistical analysis: we used Pearson or Spearman correlation, Student\'s t test or Mann-Whitney test and ANOVA or Kruskal Wallis test to analyze the effects of physical and clinical characteristics in 6MWT distance. Such characteristics and the 6MWT distance were evaluated in outcomes over time, observing the Kaplan-Meier survival curve or the average survival by Cox, the significance of the effects was tested by log-rank test or the Cox proportional hazards model, respectively. It was also set a Cox survival x model to assess the effects of all covariates together present in the outcomes. We used selection of forward variables for multivariate analysis to select the variables most associated with survival. The size of the effects was measured by odds ratio (OR). Results: We included 234 patients, 173(73,9 per cent ) males, 57.18 (10.35) years old, 103(44 per cent ) anterior AMI, 182 (77.8 per cent ) Killip I, 190 (81.2 per cent ) with reperfusion therapy and left ventricular ejection fraction = 49.99 (10.14) per cent . We observed 89 (84.03 per cent ) patients with cardiovascular outcomes and 18 (8.1 per cent ) deaths for 1,355.47 (777.53) days of follow up. There was no association between the 6MWT distance and the combined endpoints. We observed association with 6MWT distance and death, resulting two models: a) distance of first quartile (370.5 m) (OR = 2.737, p = 0.046), Borg scale of perceived exertion (SPE) (OR = 1.380, p = 0.020) and oxygen saturation (SpO2) <90 per cent (OR = 2.326, p = 0,103); b) distance of the log rank test (232 m) (OR = 3.459, p = 0.036), Borg SPE (OR = 1.351, p = 0.044) and SpO2 <90 per cent (OR = 2.936, p = 0.030). The distance and the SpO2 were also associated with poor survival over time: model 1) Borg SPE (OR = 1.334, p = 0.041, SpO2 <90 per cent (OR = 2.675, p = 0.067) and 6MWT distance = 370.5 m (OR = 2.882, p = 0.042) and model 2: SpO2 <90 per cent (OR = 4.193, p = 0.004) and 6MWT distance = 232m (OR = 5.014, p = 0.005). In comparison with death group and survival group, there was a significant difference in HR (p <0.0001) and SpO2 (p <0.0001) overtime. Conclusion: The distance and SpO2 < 90 per cent in 6MWT were associated with death and worse survival conditions in patients after uncomplicated AMI.

O infarto do miocárdio (IM), uma das principais causas de morte nas sociedades industrializadas, é sempre acompanhado por uma notável alteração da modulação autonômica, caracterizada por hiperatividade simpática e diminuição do tono parassimpático ao coração. O bloqueio da atuação do simpático cardíaco tem sido amplamente utilizado como estratégia terapêutica eficaz para redução da morbi-mortalidade em pacientes com IM. Entretanto, há evidências de que o restabelecimento da função parassimpática ao coração pode ser igualmente benéfica, uma vez que a diminuição do parassimpático cardíaco é um fator de risco independente de morte súbita. Assim, o objetivo do presente estudo foi avaliar a influência da inibição da acetilconinesterase plasmática (AChE), por meio da administração endovenosa do brometo de piridostigmina (PIR), sobre o eletrocardiograma (ECG), hemodinâmica e modulação autonômica apos o IM agudo em ratos. Ratos foram anestesiados com uretana e mantidos a uma temperatura de 36-37 ºC. Tiveram eletrodos subcutâneos para registro do ECG implantados, e a artéria e veia femoral cateterizadas para medida direta de PA e administração de drogas, respectivamente. Experimentos preliminares foram realizados para determinação de uma dose de PIR que não causasse grande repercussão hemodinâmica. A atividade da acetilcolinesterase plasmática, bem como o tono autonômico cardíaco também foram avaliados em ratos normais. Em outro protocolo, ratos anestesiados, sob registro contínuo do ECG e PA, tiveram o ramo descendente anterior da artéria coronária esquerda ligado para provocar um extenso IM e, após 10 min, foram tratados com PIR (0,25 mg/kg, i.v) ou salina (solução fisiológica 0,9%), e os registros foram acompanhados por 4 h. Ratos controles tiveram o tórax aberto, mas a artéria coronária foi mantida intacta. Ao final, os ratos tiveram o coração retirado para avaliação da extensão da isquemia miocárdica e para o estudo da conexina 43. A administração endovenosa de PIR foi efetiva em reduzir a atividade da AChE e provocou uma discreta redução da FC (438±8 para 387±10 bpm), sem alteração da PA. Ratos tratados com PIR tiveram menor tono simpático e maior tono vagal cardíaco que os ratos que receberam salina. O tratamento com PIR diminuiu a incidência de arritmias nos animais com IM e aumentou a porcentagem de ratos que sobreviveram até a 4ª hora após o infarto (72 vs 58% nos não tratados). A PIR também preveniu o aumento do intervalo QTc, observado após o IM em ratos não tratados (=-2±4, vs 33±13 ms). A quantidade de conexina 43 foi marcadamente reduzida pelo IM em ratos não tratados (0,7±0,1 vs 2,2±0,4 ua), redução esta que não ocorreu nos ratos com IM tratados com PIR (1,3±0,3 ua). Por fim, foi realizado um ensaio, in vitro, em cardiomiócitos da linhagem H9c2 em cultura, e foi observado que a PIR preveniu a degradação da Cx43 induzida por meio isquêmico durante 4 horas. Portanto, a administração aguda de PIR provocou uma bradicardia pouco intensa, sem repercussões hemodinâmicas importantes, aumentou o tono vagal cardíaco, preveniu o prolongamento do intervalo QTc, diminuiu a incidência de arritmias, e preveniu a degradação da Cx43 nos corações dos ratos infartados. / Myocardial infarction (MI), a leading cause of death in industrialized societies, is always accompanied by a remarkable change in cardiovascular autonomic modulation, characterized by sympathetic overactivity and decreased vagal tone to the heart. The blockade of the cardiac sympathetic activity has been widely used as an effective therapeutic strategy to reduce morbidity and mortality in patients with MI. However, there is evidence that improvement of parasympathetic function can also be beneficial since reduction of cardiac vagal function is an independent risk factor for sudden death. The aim of this study was to evaluate the influence of inhibition of plasma acetilconinesterase (AChE), by intravenous administration of pyridostigmine bromide (PYR) on the electrocardiogram (ECG), hemodynamics and cardiovascular autonomic modulation shortly after MI in rats. Rats were anesthetized with urethane and maintained on a heating pad. Subcutaneous electrodes to record the ECG were installed and catheters were inserted into femoral artery and vein for measurement of blood pressure and drug administration, respectively. Preliminary experiments were performed to determine a dose of PYR that would not cause major hemodynamic consequences. Plasma AChE activity, and cardiac autonomic tone were also evaluated in normal rats. Then, anesthetized rats under continuous recording of ECG and BP, had the anterior descending branch of the left coronary artery ligated to elicit extensive MI and, after 10 min, were treated with PYR (0.25 mg/kg, iv) or saline (0.9% NaCl) and monitored for the next 4 h. Control rats had the chest open, but coronary artery was kept intact. At the end, the rats had the heart removed to determine the size of myocardial isquemia and to study connexin 43. Intravenous administration of PYR was effective in reducing AChE activity of and caused a mild reduction in HR (438±8 to 387±10 bpm) with no change in BP. Also, rats treated with PYR had lower sympathetic and higher cardiac vagal tone as compared to untreated rats. The treatment with PYR decreased the incidence of arrhythmias after MI and increased the percentage of rats that survived until the 4th hour after infarction (72 vs 58 % in untreated). PYR also prevented the increase in QTc interval observed after MI in untreated rats (=-2±4 vs 33±13 ms). The amount of connexin 43 was markedly reduced by MI in untreated rats (2.24±0.46 vs 0.72±0.14 au), nevertheless, this reduction was not observed in infarcted rats that received PYR (1.31±0.29 au). Finally, an in vitro assay was performed on the line H9c2 cardiomyocytes in culture, and it was observed that PYR prevented the degradation of Cx43 induced by ischemic medium for 4 hours. Therefore, the acute administration of PYR caused mild bradycardia without hemodynamic repercussions, increased vagal tone, prevented the prolongation of the QTc interval and decreased the incidence of arrhythmias and prevented the degradation of Cx43 in infarcted rat hearts.

Ding Baoguo. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. 225-247). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

by Xiao Gang. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 91-99). / Abstract also in Chinese. / ACKNOWLEDGEMENTS --- p.i / SUMMARY --- p.1 / Chapter 1 --- LITERATURE REVIEW / Chapter 1.1 --- MAGNESIUM --- p.3 / Chapter 1.1.1 --- GENERAL FUNCTION OF MAGNESIUM --- p.3 / Chapter 1.1.2 --- ABSORPTION AND METABOLISM OF MAGNESIUM --- p.6 / Chapter 1.1.3 --- CLINICAL ASPECTS --- p.8 / Chapter 1.1.4 --- METHODS OF DETERMINATION OF MAGNESIUM --- p.11 / Chapter 1.2 --- ZINC --- p.13 / Chapter 1.2.1 --- GENERAL FUNCTION OF ZINC --- p.13 / Chapter 1.2.2 --- ABSORPTION AND METABOLISM OF ZINC --- p.14 / Chapter 1.2.3 --- CLINICAL ASPECTS --- p.16 / Chapter 1.2.4 --- ASSESSMENT OF THE BODY ZINC STATUS --- p.19 / Chapter 1.2.5 --- METHODS OF DETERMINATION OF ZINC --- p.20 / Chapter 1.3 --- COPPER --- p.21 / Chapter 1.3.1 --- GENERAL FUNCTION OF COPPER --- p.21 / Chapter 1.3.2 --- ABSORPTION AND METABOLISM OF COPPER --- p.21 / Chapter 1.3.3 --- CLINICAL ASPECT --- p.25 / Chapter 1.3.4 --- LABORATORY ASSESSMENT OF COPPER STATUS --- p.28 / Chapter 1.3.5 --- METHODS FOR THE DETERMINATION OF COPPER --- p.29 / Chapter 1.4 --- SELENIUM --- p.31 / Chapter 1.4.1 --- GENERAL FUNCTION OF SELENIUM --- p.31 / Chapter 1.4.2 --- ABSORPTION AND METABOLISM OF SELENIUM --- p.31 / Chapter 1.4.3 --- CLINICAL ASPECTS --- p.34 / Chapter 1.4.4 --- ASSESSMENT --- p.36 / Chapter 1.4.5 --- METHODS OF DETERMINATION OF SELENIUM --- p.37 / Chapter 1.5 --- INTRODUCTION TO ATOMIC ABSORPTION SPECTROPHOTOMETRY --- p.38 / Chapter 1.5.1 --- PRINCIPLE OF AAS --- p.38 / Chapter 1.5.2 --- INSTRUMENTATION --- p.39 / Chapter 2 --- INTRODUCTION --- p.43 / Chapter 2.1 --- TRACE ELEMENT DEFICIENCY IN HOSPITAL PATIENT --- p.43 / Chapter 2.2 --- MICRONUTRIENT DEFICIENCY AMONG PATIENTS WITH ACUTE MYOCARDIAL INFARCTION --- p.44 / Chapter 2.2.1 --- MAGNESIUM DEFICIENCY --- p.44 / Chapter 2.2.2 --- CHANGE OF ZINC AND COPPER IN AMI --- p.47 / Chapter 2.2.3 --- SELENIUM DEFICIENCY --- p.50 / Chapter 2.3 --- OBJECTIVES OF THIS PROJECT --- p.52 / Chapter 3 --- MATERIALS AND METHODS / Chapter 3.1 --- PATIENTS SELECTION --- p.53 / Chapter 3.1.1 --- CONTROL GROUP --- p.53 / Chapter 3.1.2 --- AMI GROUP --- p.53 / Chapter 3.1.3 --- DIGOXIN TREATMENT GROUP --- p.54 / Chapter 3.2 --- ANALYTIC METHODS --- p.55 / Chapter 3.2.1 --- DETERMINATION OF SERUM Magnesium --- p.55 / Chapter 3.2.2 --- DETERMINATION OF SERUM ZINC --- p.57 / Chapter 3.2.3 --- DETERMINATION OF SERUM COPPER --- p.60 / Chapter 3.2.4 --- DETERMINATION OF SERUM SELENIUM --- p.63 / Chapter 4 --- RESULTS --- p.68 / Chapter 4.1 --- RESULTS OF EVALUATION OF ANALYTICAL --- p.68 / Chapter 4.1.1 --- RESULTS OF METHODS EVALUATION OF SERUM ZINC ASSAY --- p.68 / Chapter 4.1.2 --- RESULTS OF METHODS EVALUATION OF SERUM COPPER ASSAY --- p.71 / Chapter 4.1.3 --- RESULTS OF METHODS EVALUATION OF SERUM SELENIUM ASSAY --- p.73 / Chapter 4.2 --- RESULTS OF PATIENTS STUDY --- p.76 / Chapter 4.2.1 --- CONTROL GROUP --- p.76 / Chapter 4.2.2 --- PATIENTS WITH ACUTE MYOCARDIAL INFARCTION I DEMOGRAPHIC DATA --- p.77 / Chapter 4.2.3 --- DIGOXIN GROUP --- p.83 / Chapter 5 --- DISCUSSION --- p.85 / Chapter 5.1 --- AMI PATIENTS AND TRACE ELEMENT STATUS --- p.85 / Chapter 5.2 --- MAGNESIUM AND ZINC STATUS IN PATIENTS RECEIVING DIGOXIN TREATMENT --- p.88 / REFERENCE --- p.91 / LIST OF TABLES --- p.99 / LIST OF TABLES --- p.102 / TABLES & FIGURES

"Recent evidence suggests that delivering human mesenchymal stem cells (hMSCs) to the infarcted heart reduces infarct size and improves ventricular performance. However, cell delivery systems have critical limitations such as inefficient cell retention and poor survival, and lack targeted localization. Our laboratories have recently developed a method to produce discrete fibrin microthreads that can be attached to a needle and delivered to a precise location within the heart wall. We hypothesize that fibrin microthreads will support hMSC proliferation, survival and retention of multipotency, and may therefore facilitate targeted hMSC delivery to injured tissues such as infarcted myocardium. To test this hypothesis, we bundled 100 μm diameter microthreads to provide grooves to encourage initial cell attachment. We seeded hMSCs onto the microthread bundles by applying 50,000 cells in 100 μL of media. The number of cells adhered to the microthreads was determined up to 5 days in culture. Cell density on the fibrin microthreads increased over time in culture, achieving an average density of 730 ± 101 cells/mm2. A LIVE/DEAD assay confirmed that the cells were viable and Ki-67 staining verified the increase in cell number over time was due to proliferation. Additionally, functional differentiation assays proved that the hMSCs cultured on microthreads retained their ability to differentiate into adipocytes and osteocytes. The results of this study demonstrate that delivering 1 to 4 cell seeded microthread bundles to the infarcted rat myocardium has the potential to produce a positive improvement in mechanical function and these microthreads support hMSC proliferation and survival. Additionally these findings suggest that cell-seeded microthreads may serve a platform technology to improve localized delivery of viable cells to infarcted myocardium to promote functional tissue regeneration. "

"The stiffness of scaffolds used in surgical ventricular restoration may play an important role in the degree to which they facilitate regeneration of functional cardiac tissue. The stiffness of the scaffold influences the phenotype of cells which are present in it as well as their ability to deform the scaffold. The goal of this study was to evaluate in vitro methods to characterize and alter the stiffness of new scaffold materials. Membrane inflation testing, an in vitro mechanical testing method, was evaluated in this study because of its ease of use and the similar mode of loading which it shares with scaffolds implanted in vivo. The structural stiffness of two scaffold materials, urinary bladder matrix and Dacron, were determined in vivo and using membrane inflation testing. Despite higher tensions and lower area stretch ratios for scaffolds tested using membrane testing, similar changes in structural stiffness between the two materials were found for both methods (5.6 ± 3.3 fold in vivo, 5.0 ± 1.0 in vitro). This finding demonstrated that membrane inflation testing is a useful in vitro method for measuring changes in structural stiffness between scaffold materials with a level of sensitivity similar to that which is measured in vivo. Membrane inflation testing was used to assess the effectiveness of altering scaffold stiffness through exposure to various cell culture conditions. Incubation of a biological membrane in cell culture media resulted in a drastic decrease in the elastic modulus from its initial value (3.55 ± 0.52 MPa) after 2 weeks (1.79 ± 0.30 MPa), 4 weeks (1.04 ± 0.09 MPa), and 10 weeks (0.014 ± 0.01 MPa). When fibroblasts were cultured on the scaffolds for 10 weeks an increase in elastic modulus (0.134 ± 0.05 MPa) over scaffolds incubated in culture media for the same amount of time was observed. The increase in elastic modulus due to the presence of fibroblasts was accompanied by an increase in the percentage of collagen in the samples (54.1 ± 5.1 % without fibroblasts, 83.2 ± 5.1 % with fibroblasts). Contrary to expectation, addition of ascorbic acid to the media to increase production of collagen by the fibroblasts resulted in a decrease in elastic modulus (0.030 ± 0.01 MPa) compared to scaffolds cultured with fibroblasts in standard media and a decrease in the amount of enzymatically degraded collagen (40.8 ± 4.7 % without ascorbic acid, 21.1 ± 3.3 % with ascorbic acid). Regeneration of cardiac tissue after a myocardial infarction is a complicated process which is influenced by a myriad of different factors. Future studies investigating the exact role which substrate stiffness has on regeneration will be essential to the development of improved cardiac scaffolds. Characterization of the stiffness of these scaffolds by membrane inflation and manipulation through exposure to cell culture conditions are powerful approaches to facilitate future studies."

Myocardial infarction results in tissue necrosis, leading to cell loss and ultimately to cardiac failure. Implantation of immature progenitor cells into the scar area may compensate for the cell loss and provides a new therapeutic avenue for infarct treatment. Premature myoblasts derived from skeletal muscle are one of the best candidates for this therapeutic purpose, because biopsies used for autologous cell therapy can be accessed easily, the isolated myoblasts can proliferate well in vitro, and the skeletal and cardiac muscles are structurally and functionally similar. In this study we investigated the survival and differentiation of the implanted skeletal myoblasts in the non-cryoinjured myocardium and the myocardial scar, using a syngeneic Lewis rat model. A therapeutic dose of 4x106 skeletal myoblasts/animal was implanted into the non-cryoinjured and scar tissue, and the fate of the implant was monitored at 12, 28 and 56 days after implantation by immunohistochemistry. We detected fast myosin heavy chain (fMHC) expression at each time point but significantly fewer positive cells in the scar than in the non-injured tissue. This was consistent with the staining patterns of slow myosin heavy chain (sMHC) and myogenin that overlapped with fMHC positive areas. Although the implanted myoblasts differentiated into skeletal muscle cells, they did not transdifferentiate into cardiac muscle, demonstrated by the absence of cardiac troponin I expression. During this analysis we developed a model, which could be useful to test new strategies for myoblast implantation (dosage, genetic modification, new injection technique etc.) designed to promote better engraftment of cultured myoblasts in the myocardial scar.

Cardiovascular disease (CVD) is a complex combination of multiple conditions. The majority of deaths within CVD include heart attacks and strokes caused by atherosclerotic disease. The pathophysiological process for atherosclerotic disease occurs within the endothelial lining of the vessels of the body. This prolonged process occurs when cholesterol deposits form irregularity in luminal flow resulting in decreased blood flow and ischaemia. This unstable cholesterol plaque can rupture resulting in clot formation and artery occlusion. Within this thesis I aim to show background to the relevant pathophysiology of ischaemic heart disease (IHD) with the main emphasis on acute myocardial infarction (AMI), the history of its therapy to current therapy. I will discuss the theorised role of stem cell therapy within animal models and previous clinical trials within regenerative medicine and AMI. I will describe and discuss the method and the results of the REGENERATE-AMI trial (Clintrial.gov: NCT00765453), which will include the safety and efficiency of the therapy, and the possible cytokine mechanism by which this therapy may exert it effect. Additionally I will describe the potential for assessing myocardial oedema using 3-slice T2-STIR short axis stack imaging post AMI compared to the conventional 10-slice T2-STIR technique to assess its feasibility and clinical similarity to assess its use as a tool in translational research.