Rozprawy doktorskie na temat „Fast Diagnosis of Heart Diseases”

Heart disease is a major cause of death in western countries. In order to diagnose and monitor heart disease, 3D echocardiography is an important tool, as it provides a fast, relatively low-cost, portable and harmless way of imaging the moving heart. Segmentation of cardiac walls is an indispensable method of obtaining quantitative measures of heart function. However segmentation of ultrasound images has its challenges: image quality is often relatively low and current segmentation methods are often not fast. It is desirable to make the segmentation technique as fast as possible, making quantitative heart function measures available at the time of recording. In this thesis, we test two state-of-the-art fast segmentation techniques to address this issue; furthermore, we develop a novel technique for finding the best segmentation propagation strategy between points of time in a cardiac image sequence. The first fast method is Graph Cuts (GC), an energy minimisation technique that represents the image as a graph. We test this method on static 3D echocardiography to segment the myocardium, varying the importance of the regulariser function. We look at edge measures, position constraints and tissue characterisation and find that GC is relatively fast and accurate. The second fast method is Random Forests (RFos), a discriminative classifier using binary decision trees, used in machine learning. To our knowledge, we are the first to test this method for myocardial segmentation on 2D and 3D static echocardiography. We investigate the number of trees, image features used, some internal parameters, and compare with intensity thresholding. We conclude that RFos are very fast and more accurate than GC segmentation. The static RFo method is subsequently applied to all time frames. We describe a novel optical flow based propagation technique that improves the static results by propagating the results from well-performing time frames to less-performing frames. We describe a learning algorithm that learns for each frame which propagation strategy is best. Furthermore, we look at the influence of the number of images and of the training set available per tree, and we compare against other methods that use motion information. Finally, we perform the same propagation learning method on the static GC results, concluding that the propagation method improves the static results in this case as well. We compare the dynamic GC results with the dynamic RFo results and find that RFos are more accurate and faster than GC.

Information technology has virtually altered every aspect of human life in the present era. The application of informatics in the health sector is rapidly gaining prominence and the benefits of this innovative paradigm are being realized across the globe. This evolution produced large number of patients’ data that can be employed by computer technologies and machine learning techniques, and turned into useful information and knowledge. This data can be used to develop expert systems to help in diagnosing some life-threating diseases such as heart diseases, with less cost, processing time and improved diagnosis accuracy. Even though, modern medicine is generating huge amount of data every day, little has been done to use this available data to solve challenges faced in the successful diagnosis of heart diseases. Highlighting the need for more research into the usage of robust data mining techniques to help health care professionals in the diagnosis of heart diseases and other debilitating disease conditions. Based on the foregoing, this thesis aims to develop a health informatics system for the classification of heart diseases using data mining techniques focusing on Radial Basis functions and emerging Neural Networks approach. The presented research involves three development stages; firstly, the development of a preliminary classification system for Coronary Artery Disease (CAD) using Radial Basis Function (RBF) neural networks. The research then deploys the deep learning approach to detect three different types of heart diseases i.e. Sleep Apnea, Arrhythmias and CAD by designing two novel classification systems; the first adopt a novel deep neural network method (with Rectified Linear unit activation) design as the second approach in this thesis and the other implements a novel multilayer kernel machine to mimic the behaviour of deep learning as the third approach. Additionally, this thesis uses a dataset obtained from patients, and employs normalization and feature extraction means to explore it in a unique way that facilitates its usage for training and validating different classification methods. This unique dataset is useful to researchers and practitioners working in heart disease treatment and diagnosis. The findings from the study reveal that the proposed models have high classification performance that is comparable, or perhaps exceed in some cases, the existing automated and manual methods of heart disease diagnosis. Besides, the proposed deep-learning models provide better performance when applied on large data sets (e.g., in the case of Sleep Apnea), with reasonable performance with smaller data sets. The proposed system for clinical diagnoses of heart diseases, contributes to the accurate detection of such disease, and could serve as an important tool in the area of clinic support system. The outcome of this study in form of implementation tool can be used by cardiologists to help them make more consistent diagnosis of heart diseases.

[Truncated abstract. Formulae and special characters in this field can only be approximated. See PDF version for accurate reproduction.] Magnetic resonance imaging (MRI) has been developed over the past two and a half decades to enable non-invasive assessment of soft tissues in the human body. MRI provides images of the tissues in the body with intensities weighted by nuclear magnetic relaxation properties of the tissue. Recent advances have utilised MRI as a quantitative tool with the nuclear magnetic relaxation rates in tissues being accurately quantified. One clinical application of quantitative MRI has been in the quantification of body iron stores in the management of iron overload diseases. MR images also contain information about the spatial variations of relaxation rates, which could be clinically useful. In the quantification of liver iron concentrations, proton transverse relaxation rate (R2) maps have been used not only to quantify iron concentrations but also to visualise the spatial variations. The work in this thesis addresses the use of spatial information from proton transverse relaxation rate maps in clinical practice. The quantitative spatial information contained in these maps is analysed in two clinically important settings, namely the non-invasive assessment of liver fibrosis and the assessment of magnetic susceptibility artefacts in cardiac proton transverse relaxometry. Spatial distributions of liver R2 maps were quantified using texture measures based on grey-tone spatial dependence (GTSD) matrices. Some of these measures gave a statistically significant distinction between patients with minimal or no fibrosis and those with fibrosis or cirrhosis. Distinction of fibrosis using this technique was enhanced in subjects with iron overload diseases, suggesting that iron is required as a contrast agent for sufficient sensitivity of image texture to fibrosis. In subjects with low tissue iron concentrations, tissue hydration was observed to also have an influence on R2. In patients with end stage liver disease, a model combining tissue iron concentration and tissue hydration gave a better prediction of R2 than iron concentration alone. A model combining several of the texture measures was developed using logistic regression and was found to improve distinction of high-grade fibrosis from low-grade fibrosis. For the distinction of F0 and F1 fibrosis stages (as assessed by the METAVIR system) from F2 and above the area under the receiver-operating characteristic (ROC) curve was 0.75. As this model was developed using a cohort of subjects with varying pathologies, the performance of the model is expected to improve if only iron-loaded subjects are considered.

Resumo: A insuficiência cardíaca, já denominada de epidemia do século XXI é, de entre as doenças cardiovasculares, a única cuja incidência e prevalência continuam a crescer, apesar dos imensos progressos feitos na área da terapêutica nas últimas duas décadas. Caracteriza-se por elevada mortalidade – superior à do conjunto das neoplasias malignas -, grande morbilidade, consumo de recursos e custos exuberantes. É um dos problemas mais graves de Saúde Pública dos Países industrializados, cujo manejo deverá constituir uma prioridade para os Serviços Nacionais de Saúde. Todavia, o reconhecimento universal da gravidade desta situação tem originado poucas soluções concretas para conter a epidemia, cujo protagonismo não cessa de aumentar. É possível hoje prevenir, tratar de forma a retardar a evolução da doença ou até revertê-la, desde que diagnosticada atempadamente. Qualquer atitude nestas áreas pressupõe um diagnóstico correcto, precoce e completo da situação, sem o qual não haverá um tratamento adequado. O diagnóstico tem preocupado bem menos os investigadores e os clínicos que a terapêutica. É, contudo, comprovadamente difícil a todos os níveis dos Cuidados de Saúde e constitui certamente a primeira barreira ao controlo da situação. OBJECTIVOS: À luz do conhecimento actual e da nossa própria experiência, propusemo-nos analisar os problemas do diagnóstico da insuficiência cardíaca e a forma como eles se repercutem no manejo da doença e na saúde das populações. Foram objectivos desta dissertação avaliar como a evolução dos modelos de insuficiência cardíaca e de disfunção ventricular influenciaram a definição e os critérios de diagnóstico da doença ao longo do tempo; as consequências geradas pela falta de consenso quanto à definição e aos critérios de diagnóstico nas diferentes fases de evolução desta entidade; discutir o papel da clínica e dos exames complementares no diagnóstico da síndrome e nas estratégias de rastreio da disfunção cardíaca; apontar alguns caminhos e possíveis metodologias para o manejo da doença de forma a que possamos, no futuro, diagnosticar melhor para melhor prevenir, tratar e conter a epidemia. METODOLOGIA: A metodologia utilizada neste trabalho decorre directamente da actividade assistencial diária e da investigação clínica gerada no interesse pelos problemas com que nos deparámos, ao longo dos anos, na área da insuficiência cardíaca. A par com o estudo epidemiológico da insuficiência cardíaca em Portugal, desenvolvemos um protocolo original para a avaliação da qualidade do diagnóstico no ambulatório e do papel da clínica e dos diferentes exames complementares no diagnóstico da síndrome. Avaliámos os problemas do diagnóstico da insuficiência cardíaca em meio hospitalar através de um inquérito endereçado aos Directores de Serviço, pelo Grupo de Estudo de Insuficiência Cardíaca da Sociedade Portuguesa de Cardiologia. Analisámos a qualidade do diagnóstico da insuficiência cardíaca codificado à data da alta hospitalar. Após a criação de uma área específica, vocacionada para o internamento de doentes com insuficiência cardíaca, avaliámos o seu impacto no diagnóstico e tratamento da síndrome. Também testámos o desempenho dos peptídeos natriuréticos no diagnóstico dos diferentes tipos de insuficiência cardíaca sintomática, em meio hospitalar. Os resultados parciais da investigação clínica foram sendo comunicados à comunidade científica e publicados em revistas da especialidade. Discutimos, nesta dissertação, os artigos publicados e em publicação, à luz do estado actual da arte na área do diagnóstico. Reflectimos sobre as consequências das dificuldades no diagnóstico da insuficiência cardíaca e apontamos possíveis caminhos para implementar o rastreio. RESULTADOS: Em 1982, muito no início da nossa actividade clínica, cientes da complexidade da insuficiência cardíaca e do desafio que a sua abordagem constituía para os clínicos,empenhávamo-nos no desenvolvimento de uma classificação fisiopatológica original da insuficiência cardíaca, que foi tema para a Tese de Doutoramento da Professora Doutora Fátima Ceia em 1989. sistemático da doença, melhorar os cuidados prestados aos doentes e diminuir os custos envolvidos no manejo da síndrome. No artigo 1 – Insuficiência cardíaca: novos conceitos fisiopatológicos e implicações terapêuticas – publicado em 1984, descrevemos, à luz do conhecimento da época, a insuficiência cardíaca como uma doença sistémica, resultado da interacção entre os múltiplos mecanismos de compensação da disfunção cardíaca. Desenvolvemos “uma classificação fisiopatológica com implicações terapêuticas” original, onde delineámos os diferentes tipos de insuficiência cardíaca, as suas principais características clínicas, hemodinâmicas, funcionais e anatómicas e propuzemos terapêutica individualizada de acordo com a definição e o diagnóstico dos diferentes tipos de insuficiência cardíaca. Em 1994, no artigo 2 – A insuficiência cardíaca e o clínico no fim do século vinte – salientamos a forma como os diferentes mecanismos de compensação interagem, influenciam a evolução da doença no tempo, produzem síndromes diferentes e fundamentam a actuação terapêutica. Discutimos a evolução da definição da doença de acordo com o melhor conhecimento da sua fisiopatologia e etiopatogenia. Sublinhamos a necessidade de desenvolver estratégias para a prevenção da doença, o diagnóstico precoce e o tratamento atempado. Ainda no primeiro capítulo: Insuficiência cardíaca: da fisiopatologia à clínica – um modelo em constante evolução – revisitámos os sucessivos modelos fisiopatológicos da insuficiência cardíaca: cardio-renal, hemodinâmico, neuro-hormonal e imuno-inflamatório e a sua influência na definição da síndrome e nos critérios de diagnóstico. Analisámos a evolução do conceito de disfunção cardíaca que, à dicotomia da síndrome em insuficiência cardíaca por disfunção sistólica e com função sistólica normal, contrapõe a teoria do contínuo na evolução da doença. Esta última, mais recente, defende que estas duas formas de apresentação não são mais do que fenótipos diferentes, extremos, de uma mesma doença que origina vários cenários, desde a insuficiência cardíaca com fracção de ejecção normal à disfunção sistólica ventricular grave No capítulo II - O diagnóstico da insuficiência cardíaca: problemas e consequências previsíveis - analisamos as consequências da falta de critérios de diagnóstico consensuais para a insuficiência cardíaca em todo o seu espectro, ao longo do tempo. As dificuldades de diagnóstico reflectem-se nos resultados resultados dos estudos epidemiológicos. Vivemos essa dificuldade quando necessitámos de definir critérios de diagnóstico exequíveis no ambulatório, abrangendo todos os tipos de insuficiência cardíaca e de acordo com as Recomendações, para o programa EPICA –EPidemiologia da Insuficiência Cardíaca e Aprendizagem – desenhado para os Cuidados Primários de Saúde. No artigo 3 – Epidemiologia da insuficiência cardíaca e Aprendizagem – desenhado para os Cuidados Primários de Saúde. No artigo 3 – Epidemiologia da insuficiência cardíaca – discutimos as consequências dos grandes estudos epidemiológicos terem adoptado ao longo dos anos definições e critérios de diagnóstico muito variáveis,conduzindo a valores de prevalência e incidência da doença por vezes também muito diferentes. O problema agudiza-se quando se fala em insuficiência cardíaca com fracção de ejecção normal ou com disfunção diastólica, ou ainda em rastreio da disfunção cardíaca assintomática, situações para as quais tem sido extraordinariamente difícil consensualizar critérios de diagnóstico e estratégias. É notória a ausência de grandes estudos de terapêutica no contexto da insuficiência cardíaca com fracção de ejecção normal ou com disfunção diastólica que, à falta de Recomendações terapêuticas baseadas na evidência, continuamos a tratar de acordo com a fisiopatologia. Assim, discrepâncias provavelmente mais relacionadas com os critérios de diagnóstico utilizados do que com diferenças reais entre as populações, dificultam o nosso entendimento quanto ao real peso da insuficiência cardíaca e da disfunção ventricular assintomática. Também comprometerão certamente a correcta alocação de recursos para necessidades que, na realidade, conhecemos mal. O artigo 4 – Prévalence de l’ insuffisance cardiaque au Portugal – apresenta o desenho dos estudos EPICA e EPICA-RAM. O EPICA foi dos primeiros estudos a avaliar a prevalência da insuficiência cardíaca sintomática global, na comunidade, de acordo com os critérios da Sociedade Europeia de Cardiologia. Definimos critérios ecocardiográficos de disfunção cardíaca para todos os tipos de insuficiência cardíaca, nomeadamente para as situações com fracção de ejecção normal, numa época em que ainda não havia na literatura Recomendações consensuais. No artigo 5 – Prevalence of chronic heart failure in Southwestern Europe: the EPICA study - relatamos a prevalência da insuficiência cardíaca em Portugal con-supra-diagnosticada em 8,3%. A codificação hospitalar falhou uma percentagem significativa de doentes com insuficiência cardíaca, minimizando assim o peso da síndrome, com eventual repercussão na alocação dos recursos necessários ao seu manejo no hospital e para a indispensável interface com os Cuidados Primários de Saúde. No artigo 8 – Tratamento da insuficiência cardíaca em hospitais portugueses: resultados de um inquérito – todos os inquiridos relataram dificuldades no diagnóstico atempado da insuficiência cardíaca. Os Directores dos Serviços de Cardiologia reclamam mais recursos humanos vocacionados e estruturas hospitalares especializadas no diagnóstico e tratamento da síndrome, enquanto que os Directores dos Serviços de Medicina necessitam de facilidades de acesso aos métodos complementares de diagnóstico como a ecocardiografia e de maior apoio do Cardiologista. As dificuldades no diagnóstico da insuficiência cardíaca,a todos os níveis de cuidados, acarretam assim consequências epidemiológicas, sócio-económicas e financeiras nefastas para o doente individual, a planificação do Sistema Nacional de Saúde e para a Saúde Pública No capítulo III relembramos a importância do diagnóstico completo da insuficiência cardíaca que, para além do diagnóstico sindromático e anatomo-funcional, deverá incluir o diagnóstico etiológico, e das comorbilidades. Muitos destes aspectos podem comprometer a interpretação dos exames complementares de diagnóstico e, não raramente, as indicações dos fármacos que influenciam a sobrevida dos doentes, a estratégia terapêutica e o prognóstico da síndrome Conscientes das dificuldades no diagnóstico da insuficiência cardíaca nos Cuidados Primários de Saúde e do papel preponderante dos especialistas em Medicina Familiar na contenção da epidemia, propusemo-nos, como objectivos secundários do estudo EPICA (artigo 5), investigar a acuidade diagnóstica dos instrumentos à disposição daqueles colegas, na prática clínica diária: a clínica e os exames complementares de diagnóstico de primeira linha. O artigo 10 – The diagnosis of heart failure in primary care: value of symptoms and signs - documenta o valor limitado dos sinais, sintomas e dados da história pregressa, quando usados isoladamente, no diagnóstico da síndrome. Todos têm baixa sensibilidade para o diagnóstico. Têm maior valor preditor os associados às situações congestivas, mais graves: a dispneia paroxística nocturna (LR 35,5), a ortopneia (LR 39,1), a dificuldade respiratória para a marcha em plano horizontal (LR 25,8), o ingurgitamento jugular > 6 cm com hepatomegalia e edema dos membros inferiores (LR 130,3), que estão raramente presentes na população de insuficientes cardíacos do ambulatório (sensibilidade <10%). O galope ventricular (LR 30,0), a taquicardia >110ppm (LR 26,7) e os fervores crepitantes (LR 23,3) também estão associados ao diagnóstico, mas são também pouco frequentes na população estudada (sensibilidade < 36%). São ainda preditores do diagnóstico o tratamento prévio com digitálico (LR 24,9) e/ou com diurético (LR 10,6), uma história prévia de edema pulmonar agudo (LR 54,2) ou de doença das artérias coronárias (LR 7,1). No artigo 11- Aetiology, comorbidity and drug therapy of chronic heart failure in the real world: the EPICA substudy - confirmámos que a hipertensão arterial é, de entre os factores de risco e/ou etiológicos, a causa mais frequente de insuficiência cardíaca no ambulatório, em Portugal (80%). Trinta e nove por cento dos doentes do estudo EPICA têm história de doença coronária e 15% de fibrilhação auricular. Quantificámos a comorbilidade e analisámos a sua potencial influência no facto da prescrição terapêutica estar aquém das Recomendações internacionais em Portugal, como aliás em toda a Europa. No artigo 12 - The value of electrocardiogram and X-ray for confirming or refuting a suspected diagnosis of heart failure in the community – demonstrámos que os dados do ECG e do RX do tórax não permitem predizer o diagnóstico de insuficiência cardíaca na comunidade; 25% dos doentes com insuficiência cardíaca objectiva tinham ECG ou RX do tórax normais. No artigo 13 - Evaluation of the performance and concordance of clinical questionnaires for heart failure in primary care - comparámos sete questionários e sistemas de pontuação habitualmente utilizados nos grandes estudos, para o diagnóstico da insuficiência cardíaca. Mostraram ter, na sua maioria, uma concordância razoável ou boa entre si. Foram muito específicos (>90%) mas pouco sensíveis. Aumentaram a probabilidade do diagnóstico de 4,3% pré-teste para 25 a 30% pós-teste. Revelaram-se um melhor instrumento para a exclusão da causa cardíaca dos sintomas do que para o diagnóstico da síndrome O artigo 14 - Epidemiologia da insuficiência cardíaca em Portugal continental: novos dados do estudo EPICA – compara as características dos doentes com suspeita clínica, não comprovada, de insuficiência cardíaca (falsos positivos), com os casos de insuficiência cardíaca. Os primeiros são mais idosos, mais mulheres, com mais excesso de peso, menos história de doença das artérias coronárias. Confirma ainda que a clínica, o ECG e o Rx tórax não permitem diferenciar os doentes com insuficiência cardíaca por disfunção sistólica ventricular daqueles que têm fracção de ejecção normal. Perante o desafio do diagnóstico da insuficiência cardíaca com fracção de ejecção normal, as dificuldades de acesso à ecocardiografia na comunidade e os custos acrescidos do exame, pretendemos averiguar no artigo 15 - The diagnostic challenge of heart failure with preserved systolic function in primary care setting: an EPICA-RAM sub-study - o desempenho do BNP no rastreio dos doentes com a suspeita clínica do diagnóstico, a enviar para ecocardiografia. Testámos o desempenho do teste como preditor do diagnóstico clínico da insuficiência cardíaca com função sistólica preservada, bem como dos indicadores ecocardiográficos de disfunção diastólica utilizados no estudo: dilatação da aurícula esquerda e hipertrofia ventricular esquerda. O teste apenas foi bom preditor da dilatação da aurícula esquerda, mas não do diagnóstico clínico deste tipo de insuficiência cardíaca, nem da presença de hipertrofia ventricular esquerda diagnosticada por ecocardiografia (área abaixo da curva ROC: 0,89, 0,56 e 0,54 respectivamente). Concluímos que, isoladamente, não será um bom método de rastreio da doença na comunidade, nem poderá substituir o ecocardiograma no doente com a suspeita clínica do diagnóstico, pelo menos nas fases precoces, pouco sintomáticas da doença. Estudámos e comparámos o desempenho dos peptídeos natriuréticos do tipo B - BNP e NT-proBNP - no diagnóstico da insuficiência cardíaca sintomática, por disfunção sistólica e com fracção de ejecção preservada, no internamento hospitalar. Avaliámos doentes e voluntários normais, de forma a estabelecermos os cut-off do nosso laboratório. Relatámos os resultados deste trabalho no artigo 16 – Valor comparativo do BNP e do NT-proBNP no diagnóstico da insuficiência cardía-ca. Ambos os testes tiveram um excelente desempenho no diagnóstico da insuficiência cardíaca sintomática, em meio hospitalar, mas nenhum foi capaz de diferenciar a insuficiência cardíaca com disfunção sistólica ventricular da que tem fracção de ejecção normal Revimos, à luz do conhecimento actual, o desempenho dos diferentes exames complementares, nomeadamente dos peptídeos natriuréticos e da ecocardiografia, no diagnóstico da insuficiência cardíaca sintomática global, por disfunção sistólica ventricular e com fracção de ejecção normal e discutimos os critérios mais recentemente propostos e as últimas Recomendações internacionais Discutimos as estratégias propostas para o rastreio da disfunção ventricular assintomática que é, na comunidade, pelo menos tão frequente quanto a sintomática. Existe evidência de que tratar precocemente a disfunção ventricular sistólica assintomática se traduz em benefícios reais no prognóstico e, tal como no caso da disfunção sistólica sintomática, é custo-eficiente. Autilização do método padrão para o rastreio da disfunção cardíaca na população obrigaria à realização de ecocardiograma a todos os indivíduos, o que é técnica e economicamente incomportável. Vários estudos têm vindo a testar diversas estratégias alternativas, na procura de uma metodologia que seja, também ela, custo-eficiente. Os autores são unânimes no aspecto em que nenhum exame, quando avaliado isoladamente, foi útil para o rastreio da disfunção cardíaca. Contudo apontam para o ECG e/ou os peptídeos natriuréticos, integrados ou não em esquemas de pontuação clínica, como testes úteis para o pré-rastreio para ecocardiografia. Permitem diminuir os pedidos de ecocardiograma e os custos do rastreio, que se torna tão custo-efectivo quanto o do cancro da mama ou do colo do útero. Alguns autores preconizam ainda a avaliação qualitativa da disfunção cardíaca por ecocardiograma portátil, no contexto de ECG anómalo ou de peptídeo natriurético elevado, antes da referenciação para o ecocardiograma completo. Apontam esta estratégia como sendo a mais custo-eficiente para o rastreio da disfunção cardíaca. Finalmente, tecemos alguns comentários finais quanto a perspectivas de futuro para o manejo da insuficiência cardíaca. É premente estabelecer uma definição precisa e universal da síndrome e critérios de diagnóstico consensuais, claros, objectivos, simples e reprodutíveis para todo o espectro da insuficiência cardíaca, para que possamos num futuro próximo avaliar de forma correcta a extensão do problema, organizar cuidados médicos eficientes e acessíveis a todos e melhorar o prognóstico dos doentes, numa política imprescindível e inevitável de contenção dos custos. Perante os problemas de diagnóstico da síndrome no ambulatório, consideramos ser necessário implementar programas de formação continuada e facilitar o diálogo e a colaboração entre Cuidados Primários de Saúde e Unidades especializadas no manejo da doença, à imagem do que fizemos pontualmente aquando do programa EPICA e do que está a ser desenvolvido em vários países europeus e nos Estados Unidos da América, sob a forma de redes alargada de prestação de cuidados, para a insuficiência cardíaca. As clínicas de insuficiência cardíaca, a laborar sobretudo em meio hospitalar, já deram provas quanto à maior conformidade do diagnóstico (e tratamento) de acordo com as Recomendações, assim como na melhoria da qualidade de vida e sobrevida dos doentes. No artigo 17 - Implementar as Recomendações na prática clínica: benefícios de uma Unidade de Insuficiência Cardíaca Aguda - relatamos a nossa experiência quanto à melhoria da qualidade dos cuidados prestados, nas áreas do diagnóstico e tratamento, numa unidade funcional dedicada ao internamento dos doentes com insuficiência cardíaca aguda. Defendemos que estas áreas específicas de internamento se devem articular com outras,nomeadamente hospitais de dia de insuficiência cardíaca, podendo ou devendo até ser diferentes na sua estrutura e recursos, de acordo com as necessidades das populações no seio das quais são implementadas. Cabe-lhes um papel determinante na interacção com os Cuidados Primários de Saúde, na formação médica continuada e de outros profissionais de saúde e na recepção e orientação dos doentes referenciados para a especialidade.São ainda necessários esforços redobrados para a identificação e controlo dos factores de risco e para o estabelecimento de estratégias de rastreio da disfunção ventricular na comunidade. Tal é passível de ser feito e é custo-eficiente, mas exige a colaboração de técnicos de saúde, investigadores e poder político para avaliar das necessidades reais, implementar e controlar a qualidade destas estratégias, sem as quais não conseguiremos conter a epidemia. SUMMARY: Despite there has been substantial progress in the treatment of heart failure over the last several decades, it is the only cardiovascular disorder that continues to increase in both prevalence and incidence. Characterised by very poor survival and quality of life heart failure is responsible for among the highest healthcare costs for single conditions in developed countries. Heart failure is therefore becoming an increasing concern to healthcare worldwide and must be a priority to National Health Services. It is already called the epidemic of the 21 st century. A correct diagnosis is the cornerstone leading to effective management of the syndrome. An early, accurate and complete diagnosis has become crucial with the identification of therapies that can delay or reverse disease progression and improve both morbidity and mortality. Diagnostic methods may need to encompass screening strategies, as well as symptomatic case identification. Until now, investigation has been over focused on pharmacological treatment; relatively little work has been done on assessing diagnostic tools. This is actually a difficult condition to diagnose at all levels of care, and misdiagnosis must be the first barrier to the control of the epidemic. AIMS Considering current and up-dated knowledge and ourown experience we analyse the problems in diagnosing heart failure and cardiac dysfunction and how they affect patient’s clinical outcome and public health care. It was our aim to analyse how increasing knowledge about cardiac dysfunction influenced the concept of heart failure, its definition and diagnostic criteria; the problems resulting from the use of non consensual definitions and diagnostic criteria; the role of clinical data and diagnostic tests on the diagnosis of the syndrome and on the screening for cardiac dysfunction in the community; to discuss best strategies to enhance diagnostic management of heart failure in all its spectrum, in order to halt the epidemic in the near future. METHODS: The investigation on which the present dissertation is based was developed progressively, along the years, during our every-day clinical practice. Various original clinical investigations and review papers, related to challenges in heart failure management and especially to diagnosis, were presented in scientific meetings and/or published gradually as partial results were obtained. The EPICA Programme (epidemiology of heart failure and awareness), a large-scale epidemiological study on heart failure in Portugal, addressed as secondary endpoints, problems of heart failure misdiagnosis in primary care and the value of clinics and different diagnostic tests to confirme or refute the diagnosis of the syndrome suspected on clinical grounds. But problems on the diagnosis of heart failure are not confined to primary care. Therefore, under the auspices of the Working Group of Heart Failure of the Portuguese Society of Cardiology, a survey on the management of heart failure at hospital was addressed to the heads of Portuguese Cardiology and Internal Medicine Wards. Compliance with Guidelines on diagnosis and treatment of heart failure, perceived difficulties and requests to a better management of the syndrome were ascertained. We have then explored the validity of a coded diagnosis of heart failure at death/discharge from the Department of Medicine of S. Francisco Xavier Hospital, and the rate of misdiagnosis. Gains on compliance with Guidelines on the diagnosis and treatment of heart failure, before and after the implementation of an acute heart failure unit in this Department were assessed. We also compared the performance of type-B natriuretic peptides – BNP and NT-proBNP – on systolic and diastolic heart failure diagnosis, in order to implement the more adequate test. In this thesis we discuss our published papers against the state of the art on heart failure diagnosis, and actual consequences of misdiagnosing. We revisit the accuracy of the different diagnostic testes to a definite diagnosis of the disease. Finally we analyse the different ways of screening for cardiac TESE3 AF 6/9/08 12:25 PM Page 309 310 Summary dysfunction and the more cost-efficient strategies to enhance heart failure diagnosis and management. RESULTS Since 1982, at the very beginning of our clinical activity, already aware of the complexity of the management of heart failure, we were involved in the development of an original pathophysiological heart failure classification, theme of Professor Fátima Ceia Doctoral Thesis discussed in 1989. Paper 1 - Heart Failure. New pathophysiological approach to therapy – published in 1984, described heart failure as a systemic disease resulting from the interaction of the different compensatory mechanisms. We proposed a new dynamic, pathophysiological and aetiological approach to the diagnosis of heart failure syndromes, based on clinics and conventional non-invasive assessment with drug management implications. In 1994, in paper 2 – Heart failure and the physician - towards the XXI century – we discussed the way how the compensatory mechanisms interact, produce the different heart failure syndromes and affect the evolution of the disease. Changing definitions according to the knowledge of the pathophysiology of heart failure at that time were revisited. The need for a universally accepted definition leading to early and accurate diagnosis and treatment of the syndrome was pointed-out. We called for strategies to prevent heart failure. In an up-dated review titled: Heart failure: from pathophysiology to clinics – a model in constant evolution – we revisit the changing pathophysiological models of heart failure – cardio-renal, haemodynamic, neuro-hormonal and imuno-inflamatory models - and their influence on the definition of the syndrome. Traditional dicotomization of heart failure in systolic and diastolic dysfunction is discussed. Rather than being considered as separate diseases with a distinct pathophysiology, systolic and diastolic heart failure may be merely different clinical presentations within a phenotypic spectrum of one and the same disease. Implications for the definition and diagnosis of heart failure are self evident. In chapter II – The diagnosis of heart failure: problems and foreseeable consequences - we analyse epidemiological, clinical and financial consequences of non consensual definition and diagnostic criteria of heart failure for individual patients, Healthcare Systems and Public Health. Problems resulting from the absence of a universally accepted definition of heart failure are clearly illustrated by current epidemiological data and were revisited in paper 3 – Epidemiology of heart failure. In various epidemiological studies measured prevalence and incidence of the syndrome diverge significantly. This worrying variation is certainly more due to different definitions and used diagnostic criteria than true differences between populations. We faced these difficulties when we had to design the EPICA programme, a large population-based study where we had to define simple, effective and easy to obtain diagnostic criteria of heart failure, for the whole spectrum of the disease, in primary care setting. The problem grew when we focused on heart failure with normal ejection function where diagnostic criteria were far from consensual. Therefore large trials on heart failure with normal ejection fraction and consensual evidence-based Guidelines on diagnosis and treatment of diastolic heart failure are still missing. Paper 4 – Prevalence of heart failure in Portugal - presents the design of the EPICA Programme. The EPICA study was one of the first large epidemiological studies addressing the prevalence of global heart failure, in the community, according to the European Guidelines for the diagnosis of the syndrome. We had to define simple, precise echocardiographic criteria to confirm a suspected diagnosis of heart failure on clinical grounds, in all its spectrum. At that time, Guidelines for heart failure with normal ejection fraction where far from consensual and non applicable to the ambulatory. In paper 5 - Prevalence of heart failure in Southwestern Europe: the EPICA study - we reported the prevalence of heart failure in mainland Portugal. From 5434 attendants of primary care centres, representative of the Portuguese population above 25 years, 551 had heart failure, leading to a prevalence of global heart failure of 4.35%, increasing sharply with age in both genders; 1.36% had systolic dysfunction and 1.7% normal ejection fraction. TESE3 AF 6/9/08 12:25 PM Page 310 Summary 311 In paper 6 – Epidemiology of heart failure in primary care in Madeira: the EPICA-RAM study - we report an overall prevalence of heart failure of 4.69%, with systolic dysfunction in 0.76% and with a normal ejection fraction in 2.74% of the cases. Discrepancies in the prevalence of the different types of heart failure between mainland and Madeira are probably related to different Public Health Care organization. Both studies showed that only half of the patients with a suspected diagnosis of heart failure on clinical grounds had the diagnosis confirmed by objective evidence of cardiac dysfunction. It’s therefore probable that unnecessary drugs were prescribed to patients who didn’t need them while others, who would benefit, were not correctly treated for heart failure. Paper 7 – Diagnosis of heart failure in primary care – is a review of the state of the art of the diagnosis of heart failure in primary care setting. It focused on main challenges faced by primary care physicians, namely difficulties on the access to imaging and strategies to screen for cardiac dysfunction. General practitioners awareness and training on the diagnosis and treatment of the syndrome are crucial to halt the epidemic. But problems on the diagnosis of heart failure are not exclusive of primary care. Heart failure is the first cause of hospitalization of patients above 65 years in medical wards, and accounts for more than 70% of the costs with the syndrome. In paper 9 – Validity of a diagnosis of heart failure: implications of misdiagnosing – we reported a prevalence of heart failure in patients hospitalized in our Medicine Department, during a six month period, of 17%. The diagnosis was actually sub-coded at death /discharge. The accuracy of the death / discharge coded diagnosis was 72.2%; the syndrome was under-diagnosed in 21.1% of the cases and over-diagnosed in 8.3%. The discharge codes failed a significant percentage of heart failure cases, biased the actual burden of the syndrome and compromise the allocation of resources to manage in-hospital heart failure and to develop specialised programmes of interaction with primary care. In paper 8 – Treatment of heart failure in Portuguese hospitals: results of a questionnaire – everybody reported difficulties in the management of heart failure. Heads of Cardiology Wards needed more specialised physicians and nurses as well as specific heart failure units for the management of the syndrome, and Heads of Internal Medicine Wards demand more facilities, easier access to echocardiography, and support from heart failure specialised cardiologists. Difficulties in the diagnosis of heart failure at all levels of care, have huge epidemiological, clinical and economic consequences for the individual patient, National Health Services and Public Health. In chapter III, we revisit the relevance of a complete diagnosis of heart failure. An appraisal based on symptoms alone is clearly an incomplete and inaccurate representation of the severity of cardiovascular disease. Determination of cardiac status requires evaluation of composite etiologic, anatomic, and physiologic diagnoses. Functional class and comorbidities must complement the diagnosis, leading to the more appropriate and individualized treatment. Aware of the uncertainty of the diagnosis of heart failure in primary care setting and of the role of General Practitioners in the management of the syndrome, we have evaluated in pre-specified substudies of the EPICA programme, the accuracy of clinics and tests available to the diagnosis of heart failure in the community. Paper 10 – The diagnosis of heart failure in primary care: value of symptoms and signs – confirmed that symptoms and signs and clinical history have limited value in diagnosing heart failure when used alone. The signs and symptoms that best predicted a diagnosis of heart failure were those associated with more severe disease. Among current symptoms, the history of paroxysmal nocturnal dyspnoea (LR 35.5), orthopnea (LR 39.1) and dyspnoea when walking on the flat (LR 25.8) were associated with a diagnosis of heart failure. However, these symptoms were not frequent within this population (sensitivity < 36%). Jugular pressure > 6 cm with hepatic enlargement, and oedema of the lower limbs (LR 130.3), a ventricular gallop (LR 30.0), a heart rate above 110 bpm (LR 26.7), and rales (LR 23.3), were all associated with a diagnosis of heart failure but TESE3 AF 6/9/08 12:25 PM Page 311 312 Summary were infrequent findings (sensitivity < 10%). Prior use of digoxin (LR 24.9) and/or diuretics (LR 10.6), an history of coronary artery disease (LR 7.1) or of pulmonary oedema (LR 54.2) were also associated with a greater likelihood of having heart failure. In paper 11 – Aetiology, comorbidity and drug therapy of chronic heart failure in the real world: the EPICA substudy – aetiological features and therapy relevant comorbidities were analysed. Hypertension was the more frequent risk factor/aetiology of heart failure in the community in Portugal (about 80%). Thirty nine percent had an history of coronary artery disease, and 15% had atrial fibrillation. In paper 12 – The value of electrocardiogram and X-ray for confirming or refuting a suspected diagnosis of heart failure in the community – we reported that ECG and X-ray features are not sufficient to allow heart failure to be reliably predicted in the community. Twenty five percent of patients with heart failure had a normal ECG or chest X-ray. In paper 13 – Evaluation of the performance and concordance of clinical questionnaires for heart failure in the primary care – we compared the accuracy of seven clinical questionnaires and scores for the diagnosis of heart failure in the community, and their concordance. Concordance was good between most of the questionnaires. Their low sensibility impairs their usefulness as diagnostic instruments, but their high specificity (>90%) makes them useful for the identification of patients with symptoms and signs from non-cardiac cause. In paper 14 – Epidemiology of heart failure in mainland Portugal: new data from the EPICA study -characteristics of patients with a definite diagnosis of heart failure and of those in whom the diagnosis of heart failure suspected on clinical grounds was excluded (false positive) were compared. The laters were older, more frequently women, had excessive weight, and a history of coronary artery disease was less frequent. Clinics, ECG and chest X-ray could not distinguish patients with heart failure due to systolic dysfunction from those with normal ejection fraction. Considering the limited and costly access to echocardiography in the community we address in paper 15 - the diagnostic challenge of heart failure with preserved systolic function in primary care: an EPICA-RAM substudy. The performance of BNP as a predictor of a diagnosis of heart failure with preserved systolic function according to ESC Guidelines, left ventricular hypertrophy and dilated left atria by echocardiography was tested. BNP was a good predictor of a dilated left atria, but not of the diagnosis of heart failure with preserved systolic function or of left ventricular hypertrophy (AUC: 0.89, 0.56, and 0.54 respectively). We conclude that BNP measurement alone was not a suitable screening test for heart failure with normal ejection fraction in the community, at least in patients with no or mild symptoms.In paper 16 – Comparative value of BNP and NTproBNP on the diagnosis of heart failure – we first established normal values and cut-offs for our laboratory.Then we assess the diagnostic accuracy of both peptides for the in-hospital diagnosis of heart failure due to systolic dysfunction and with normal ejection fraction. BNP and NT-proBNP had an excellent and similar accuracy to the diagnosis of both types of symptomatic heart failure, but none could distinguish patients with systolic heart failure from those with normal ejection fraction. We revisited the role of the various tests on the diagnosis of heart failure with systolic dysfunction, and with normal ejection fraction and discussed the more recent International Guidelines. There is a great piece of evidence that early treatment of asymptomatic left ventricular systolic dysfunction is cost-effective. Therefore, several screening strategies were investigated. ECG and type B natriuretic peptides measurements, alone or as part of clinical scores, allowed cost-effective community-based screening for left ventricular systolic dysfunction, especially in high-risk subjects. A programme including hand-held echocardiography, following NT-proBNP or ECG pre-screening prior to traditional echocardiogram was the most cost-effective.Screening strategies for left ventricular dysfunction proved no more costly than existing screening programmes such as those for cervical or breast cancer. Conversely, as far as we know, there is no proven strategy to efficiently screen for diastolic dysfunction in the community.Finally we discuss perspectives for heart failure TESE3 AF 6/9/08 12:25 PM Page 312 Summary 313 management in the near future. Simple, reliable and consensual diagnostic procedures are crucial to evaluate the actual burden of the disease, to comply with Guidelines and to reduce healthcare utilisation and costs. As the management of the syndrome in primary care has been hampered by perceived difficulties in diagnosis, improving diagnostic skills is essential and remains a continuous challenge for primary care clinicians. Moreover, patients may require more investigations and treatments that may not be available or very familiar to General Practitioners. Shared care is therefore necessary. Disease management programmes when available and accessible, are the preferred choice to address this issue. This multidisciplinary model of care delivered in specialized heart failure clinics, heart failure day hospitals and many other heart failure care stru-ctures, have shown success in improving quality of life, and reducing morbi-mortality and costs. In paper 17 - Translating Guidelines into clinical practice: benefits of an acute heart failure unit - we report a better compliance with Guidelines on diagnosis and treatment of heart failure after the implementation of a specialized heart failure unit in our Internal Medicine Department. We defend the implementation of heart failure programme management networks to provide optimal care for both patients and health care providers. They may consist of different structures to better address the needs of the referred patient, the referral physician and the regional health care system, and should have a crucial role in transition between primary and secondary care. Managing heart failure requires resources across the entire spectrum of care. Strategies to prevent heart failure include both primary and secondary prevention, and should encompass risk factors control and screening strategies for cardiac dysfunction in the community. Screening for high risk patients and, at least, for patients with asymptomatic systolic dysfunction is cost effective. Therefore, to improve heart failure outcomes and halt the epidemic, this will require shared efforts from investigators, clinicians and politicians. Health care strategy with adequate funding are imperative for successfull heart failure management. RÉSUMÉ: L’insuffisance cardiaque, déjà appelée d’épidémie du XXIeme siècle, est un problème de Santé Publique partout en Europe. Malgré les immenses progrès faits dans le domaine du traitement, dans les deux dernières décennies, l’insuffisance cardiaque est parmi les maladies cardiovasculaires la seule dont l’incidence et prévalence ne cessent d’augmenter. Ses principales caractéristiques sont une mortalité très élevée -supérieure à celle de l’ensemble des cancers - et un impact économique considérable sur les Systèmes de Santé. La prise en charge des insuffisants cardiaques doit ainsi être envisagée comme une priorité absolue. Toutefois, et bien que la sévérité de la situation soit universellement reconnue, Gouvernements et Systèmes de Santé n’ont pris que très peu de mesures concrètes, visant à freiner l’épidémie qui ne cesse de croître. Nous pouvons aujourd’hui prévenir et, sinon guérir l’insuffisance cardiaque, du moins la traiter de façon à freiner la progression de la maladie, ainsi nous soyons capables de faire le diagnostique à temps. Toute attitude térapêutique présume un diagnostique précoce et complet de la situation, sans lequel nulle attitude correcte ne pourra être prise. OBJECTIFS: Nous nous proposons analyser les problèmes du diagnostique de l’insuffisance cardiaque, à la lumière des connaissances actuelles et de notre propre expérience. Parmi les objectifs de ce travail, nous avons évalué la façon d’ont l’évolution des concepts d’insuffisance et de dysfonction cardiaque a influencé la définition et les critères de diagnostique, au cours des temps, et les conséquences du manque de consensus quant à la définition et aux critères de diagnostique pour les différentes phases d’évolution de la maladie. Nous avons discuté le rôle des symptômes, signaux et examens complémentaires dans le diagnostique de l'insuffisance cardiaque et dans les stratégies de screening de la dysfonction cardíaque. Finalement nous avons discuté quelques chemins et possibles stratégies à envisager pour la prise en charge de ces malades pour que, dans un future proche, nous soyons capables de mieux les traiter, mais aussi de mieux prévenir la maladie de façon à freiner l’épidémie. MÉTHODOLOGIE: La méthodologie utilisée pour ce travail dérive directement de l’expérience acquise dans la prise en charge des malades, et de l’investigation gérée par les difficultés perçues quant au diagnostique de l’insuffisance cardiaque, au long des années. Quand de l’élaboration de l’étude EPICA née de la nécessité d’obtenir des données épidémiologiques nationales en ce qui concerne l’insuffisance cardiaque au Portugal, nous avons conçu, selon un dessin original, un protocole d’investigation qui nous a permis d’évaluer la qualité du diagnostique de l’insuffisance cardiaque réalisé par les médecins de famille ainsi que le rôle des symptômes, des signaux, des données de l´histoire clinique, de l’électrocardiogramme e de la radiographie du thorax, dans le diagnostique de l’ insuffisance dans l’ambulatoire. Nous avons aussi investigué la qualité du diagnostique établi pendant l’hospitalisation. Nous avons déterminé la réelle prévalence de l’insuffisance cardíaque hospitalisée dans notre service au long de six mois et celle qui a été codifiée au moment de la sortie de l´hôpital. Nous avons encore comparé la qualité do diagnostique avant et après l’ouverture d’une unité d’insuffisance cardiaque et la performance des différents peptides natriurétiques dans le diagnostique du syndrome. Sous la forme de réponse à un questionnaire, qui leur a été adressé par le Groupe de Travail d’insuffisance cardiaque de la Société Portugaise de Cardiologie, sur la prise en charge de l’insuffisance cardiaque, les Directeurs des Services de Cardiologie et Médicine Interne de tout le Pays se sont prononcés sur à leurs difficultés, en ce qui concerne le diagnostique et le traitement de l’insuffisance cardiaque. Les résultats des investigations partielles ont été communiqués à la communauté scientifique et publiés dans les journaux de la spécialité, au long de ces dernières années. Cette dissertation est constituée par les papiers publiés et en publication auxquels nous avons additionné une révision de l’état actuel de l’art du diagnostique de l’insuffisance cardiaque, ainsi q’une réflexion sur les 317 TESE3 AF 6/9/08 12:25 PM Page 317 318 Résumé conséquences des difficultés éprouvées au diagnostique de la maladie et sur la manière d’améliorer la prise en charge de l’insuffisance cardiaque.RÉSULTATS: En 1982, l’hors de notre début d’activité, nous avons eu très tôt la perception de la complexité de l’insuffisance cardiaque et du défi que constituait, pour les cliniciens, la prise en charge de ces malades. Nous avons participé au développement d’une classification physiopathologique originale qui a servi de base pour le doctorat de la Professeur Fátima Ceia en 1989. L’article 1 – Insuffisance cardiaque : nouveaux concepts physiopathologiques et leurs applications thérapeutiques – publié en 1984, nous décrivons déjà l’insuffisance cardiaque comme une maladie systémique, résultat de l’interaction des différents mécanismes de compensation de la dysfonction cardiaque. Nous proposons « une classification physiopathologique avec application thérapeutique » originale, où nous définissons les différents types d’insuffisance cardiaque et leurs caractéristiques cliniques, hémodynamiques, fonctionnelles et anatomiques et proposons un traitement individualisé d’accord avec la définition et le diagnostique de chacun de ces différents types d’insuffisance cardiaque. En 1994, l’article 2 – L’insuffisance cardiaque et le clinicien à la fin du XXème siècle – fait une description détaillée de comment les différents mécanismes de compensation interagissent, influencent l’évolution de la maladie, produisent les différents syndromes et justifient le choix du type de traitement. Nous discutons l’évolution de la définition de la maladie d’accord avec l’évolution de l’investigation et une meilleure connaissance de la physiopathologie de la dysfonction cardiaque. Nous soulignons la nécessité du diagnostique et du traitement précoces et quant urgent il est de développer des stratégies capables de prévenir la maladie. Les investigateurs défendent aussi l’existence d’un continu entre l’insuffisance cardiaque à fraction d’éjection normale e celle qui s’accompagne de dysfonction systolique ventriculaire. Ce concept défend l’existence de plusieurs syndromes d’insuffisance cardiaque qui ne représenteront que des phénotypes différents d’une même maladie. Des nouvelles Recommandations pour le diagnostique et exclusion de l’insuffisance cardiaque à fraction d’éjection normale / dysfonction diastolique surgissent. Nous revisitons ces nouveaux concepts dans le chapitre: L’insuffisance cardiaque: de la physiopathologie à la clinique - un modèle en constante évolution. Au chapitre II – Le diagnostique de l’insuffisance cardiaque: problèmes et conséquences prévisibles - nous analysons les conséquences du manque de critères de diagnostique consensuels pour l’insuffisance cardiaque au long de tout son spectre. Les difficultés avec le diagnostique se répercutent sur les résultats des grandes études épidémiologiques. Nous avons senti cette difficulté quand, lors de l’élaboration du programme EPICA – ÉPidémiologie de l’Insuffisance Cardiaque et Apprentissage - nous avons voulu définir les critères pour le diagnostique de l’insuffisance cardiaque de tous les types, applicables à l’ambulatoire et d’accord avec les Recommandations Internationales. L’article 3 - Épidémiologie de l’insuffisance cardiaque – analyse les conséquences des différentes définitions et critères de diagnostique utilisés dans les grandes études épidémiologiques qui, au long des années, ont publié des prévalences et incidences très variables de l’insuffisance cardiaque. Ce problème s’aggrave encore quand il s’agit de l’épidémiologie de l’insuffisance cardiaque à fraction d’éjection normale ou dysfonction diastolique, ou des stratégies pour le screening de la dysfonction cardiaque asymptomatique, situations à définitions et critères encore moins consensuels. L’inexistence de Recommandations appuyées sur l’évidence, pour le traitement de l’insufisance cardiaque à fraction d’éjection normale ou à dysfonction diastolique, est une autre des conséquences de ces difficultés. C’est ainsi que des différences de méthodologie, de définitions et de critères de diagnostique, plutôt que des différences réelles entre les populations, difficultent notre connaissance quant à la réelle surcharge que l’insuffisance cardiaque et la dysfonction cardiaque imposent au Système National de Santé. Il est ainsi difficile de prévoir les recours nécessaires, à attribuer à une situation qui est mal connue. L’ article 4 – Prévalence de l’insuffisance cardiaque au Portugal – présente le dessin des études EPICA et EPICA-RAM. EPICA a été l’une des premières études TESE3 AF 6/9/08 12:25 PM Page 318 Résumé 319 à évaluer la prévalence de l’insuffisance cardiaque symptomatique globale, de l’ambulatoire, suivant les Recommandations de la Société Européenne de Cardiologie pour le diagnostique de l’insuffisance cardiaque. Nous y définissons des critères echocardiographiques précis pour tous les types d’insuffisance cardiaque, notamment celle à fraction d’éjection normale, alors qu’à l’époque il n’y avait pas encore de Recommandations consensuelles pour le diagnostic de cette situation. L’article 5 – Prevalence of chronic heart failure in Southwestern Europe : the EPICA study - relate la prévalence de l’insuffisance cardiaque au Portugal continental en 1998. Dans une population de 5434 individus âgés de plus 25 ans, représentative de la population portugaise nous avons identifié 551 cas d’insuffisance cardiaque, correspondant à une prévalence de 4,3%, qui augmente avec l´âge, chez les deux genres ; chez 1,3% la dysfonction ventriculaire est systolique, alors que 1,75% ont une fraction d’éjection normale. L’article 6 – Epidemiology of chronic heart failure in Primary Care in the Autonomic Region of Madeira: the EPICA-RAM study – a suivi le même protocole d’investigation et relate une prévalence de l’insuffisance cardiaque globale de 4,69%, 0,76 % à dysfonction ventriculaire systolique et 2,74% à fraction d’éjection normale. Ces deux études confirment que quand le diagnostique est suspecté par la clinique il ne se confirme objectivement qu’en la moitié des cas, ce qui fait supposer que beaucoup de malades seront sous médication inappropriée pour l’insuffisance cardiaque alors que d’autres, qui auraient tout intérêt à la faire, en seront probablement privés. L’article 7 – Diagnosis of chronic heart failure in Primary Care - revoit l’état de l’art quant au diagnostique de l’insuffisance cardiaque dans la communauté et discute les principaux défis auxquels les médecins de famille sont soumis, notamment les difficultés d’accès aux examens complémentaires de diagnostique et le screening de la dysfonction cardiaque asymptomatique dans la population en général. Mais les problèmes de diagnostique de l’insuffisance cardiaque, se posent transversalement à tous les niveaux, à l’hôpital comme chez le médecin de famille. Bien que l’insuffisance cardiaque soit la première cause d’hospitalisation après les 65 ans, responsable pour la plupart des coûts consommés par le syndrome, le diagnostique y est sous-estimé. L’article 9 – Validity of a diagnosis of heart failure : implications of misdiagnosing – démontre que l’insuffisance cardiaque a été la première cause d’hospitalisation dans notre service, pendant une période de six mois, ayant une prévalence de 17% et a été largement sous codifiée. La sous codification du diagnostique ne fait que diminuer le vrai poids du syndrome, menant à l’allocation incorrecte de recours pour la prise en charge de l’insuffisance cardiaque à l´hôpital et pour l’établissement de programmes capables de faire l’indispensable interface avec l’ambulatoire. En réponse au questionnaire sur la prise en charge de l’insuffisance cardiaque, que nous résumons dans l’article 8 – Traitement de l’insuffisance cardiaque dans les hôpitaux portugais : résultats d’un questionnaire - les Directeurs des Services de Médicine Interne ont relaté leurs difficultés d’accès à l’échocardiographie en temps utile et réclamé plus de collaboration du cardiologue; les Directeurs des Services de Cardiologie demandent plus de spécialistes et de structures vocationnées pour le diagnostique et traitement de l’insuffisance cardiaque. Les difficultés posées par le diagnostique de l’insuffisance cardiaque à tous les niveaux de soins, entraînent des conséquences épidémiologiques, socioéconomiques et financières néfastes pour le patient, la planification du Système National de Santé et la Santé Publique. Au chapitre III nous rappelons l’importance du diagnostique complet de l’insuffisance cardiaque. Au diagnostique anatomique, fonctionnel et du syndrome, il faut absolument joindre l’étiologie, la classe fonctionnelle e les comorbidités qui conditionnent souvent l’interprétation des testes de diagnostique, le traitement et le pronostique. Conscients des difficultés éprouvées para les médecins de famille, pour diagnostiquer correctement et en temps utile l’insuffisance cardiaque dans l’ambulatoire, et du rôle de ces Spécialistes en ce qui concerne la contention de l’épidémie, nous nous sommes proposés, comme objectifs secondaires de l’étude EPICA,d’investiguer la performance des instruments de diagnostique disponibles et à portée de ces cliniciens. L’article 10 – The diagnosis of heart failure in primary TESE3 AF 6/9/08 12:25 PM Page 319 320 Résumé care: value of symptoms and signs – documente les limitations des symptômes, signaux et des données cliniques, quand utilisés de forme isolée, pour le diagnostique de l’insuffisance cardiaque. Ils sont tous peu sensibles et ceux qui ont la plus grande valeur prédictive sont ceux qui s’associent aux formes congestives, plus graves, de la maladie: la dyspnée paroxysmale nocturne (LR 35,5), l’orthopnée (LR 39,1), la difficulté respiratoire pendant la marche en plan horizontal (LR 25,8), l’ ingurgitation jugulaire > 6 cm accompagnée d’ hépatomégalie e d’oedème des membres inférieurs (LR 130,3), le galop ventriculaire (LR 30,0), la tachycardie >110ppm (LR 26,7) et les crépitations pulmonaires (LR 23,3) sont ainsi associés au diagnostique, mais sont très peu fréquents chez les insuffisants cardiaques tout venant de l’ambulatoire. Un traitement antérieur avec du diurétique (LR 10,6) ou de la digoxine (LR 24,9), ou encore un épisode antérieur d’oédeme pulmonaire aigu (LR 54,2), sont d’autres prédicteurs du diagnostique. L’article 11 – Aetiology, comorbidity and drug therapy of chronic heart failure in the real world: the EPICA substudy – confirme que l´hypertension artérielle est, d’entre tous les facteurs de risque, la principale étiologie de l’insuffisance cardiaque dans l’ambulatoire au Portugal (80%). Trente neuf pourcent des malades inclus dans l’étude EPICA avaient une histoire de maladie coronarienne et 15% de fibrillation auriculaire. Nous avons encore analysé la comorbidité et son influence sur la prescription, en sachant que la prescription des médicaments recommandés pour l’insuffisance cardiaque est, au Portugal comme d’une forme générale en Europe, bien inférieur au désirable. L’article 12 - The value X- ray for confirming or refuting a suspected diagnosis of heart failure in the community – démontre que les données de l’électrocardiogramme e de la radiographie du thorax, par sois même, ne prédisent pas correctement le diagnostique de l’insuffisance cardiaque dans l’ambulatoire; 25% des insuffisants cardiaques inclus dans EPICA avaient un électrocardiogramme où une radiographie du thorax normal. Al’article 13 - Evaluation of the performance and concordance of clinical questionnaires for heart failure in primary care – nous avons comparé sept questionnaires ou scores cliniques habituellement utilisés pour le diagnostique de l’insuffisance cardiaque dans les grandes études épidémiologiques et de médicaments. Ils ont démontré avoir une concordance à peine raisonnable à bonne entre eux, et être très spécifiques (>90%) pour le diagnostique mais peu sensibles. Ils augmentent la probabilité du diagnostique de 4,3% prétest vers 25 à 30% post-test et se révèlent ainsi des instruments plus utiles dans l’exclusion d’une cause cardiaque pour les symptômes que pour le diagnostique de l’insuffisance cardiaque. L’article 14 – Épidémiologie de l’insuffisance cardiaque au Portugal continental : nouvelles données de l’étude EPICA – compare les caractéristiques des malades qui, ayant une clinique compatible avec le syndrome, ont été inclus dans EPICA mais n’avaient pas de dysfonction cardiaque objective (faux positifs), avec ceux qui ont eu leur diagnostique objectivement confirmé. Les premiers étaient plus âgés, il y avait plus de femmes, plus de poids excessif, moins de maladie coronarienne. L’investigation confirme encore que les données de l’électrocardiogramme e de la radiographie du torax ne distinguent pas les insuffisants cardiaques qui ont une dysfonction systolique ventriculaire de ceux qui ont une fraction d’éjection normale. Face au défi du diagnostique de l’insuffisance cardiaque à fraction d’éjection normale, aux difficultés d’accès à l’échocardiographie dans l’ambulatoire, au prix de l’examen et aux critères encore peu consensuels pour le diagnostique de cette situation, nous avons analysé et publié à l’article 15 – The diagnostic challenge of heart failure with preserved systolic function in primary care setting: an EPICA-RAM substudy - la valeur des peptides natriurétiques du type B, NTproBNP, comme test de triage des malades qui, parmi ceux qui présentent une clinique compatible avec le syndrome, devront confirmer objectivement le diagnostique par échocardiographie. Ainsi, nous avons évalué la performance du test comme prédicteur : du diagnostique d’insuffisance cardiaque à fraction d’éjection normale, selon les Recommandations internationales, d’hypertrophie ventriculaire gauche et de dilatation de l’auricule gauche. Le NT-proBNP n’à été bon prédicteur que de ce dernier paramètre, ce qui nous fait conclure que le test ne permet pas de trier les malades de façon à diminuer les nécessités d’échocardiographie face à une hypothèse clinique d’insuffisance cardiaque, du moins en ce qui concerne les cas peu évolués, fréquemment asymptomatiques, de TESE3 AF 6/9/08 12:25 PM Page 320 Résumé 321 l’ambulatoire. Nous avons aussi comparé la performance des peptides natriurétiques du type B - BNP et NT-proBNP – quant au diagnostique de l’insuffisance cardiaque symptomatique à dysfonction ventriculaire systolique et à fraction d’éjection normale, traitée à l’hôpital. Les résultats de cette investigation sont révélés dans l’article 16 – Comparative value of BNP and NT-proBNP for the diagnosis of heart failure. Les deux tests ont démontré une performance excelente et comparable dans le diagnostique du syndrome, mais aucun n’a été capable de distinguer les deux types d’insuffisance cardiaque. Nous avons revu et discuté l’état de l’art quant au rôle des différents examens complémentaires, notamment des peptides natriurétiques et de l’échocardiographie, dans le diagnostique des différents types d’insuffisance et de dysfonction cardiaque, ainsi que les toutes dernières Recommandations internationales. Nous avons analysé les stratégies proposées pour le screening de la dysfonction ventriculaire asymptomatique, qui est au moins aussi fréquente dans l’ambulatoire que l’insuffisance cardiaque symptomatique. Par ailleurs, l’évidence montre que le traitement précoce de la dysfonction ventriculaire asymptomatique, est efficace et diminue les coûts. Le gold standard pour le screening de la dysfonction ventriculaire imposerait la réalisation d’un échocardiogramme à toute la population, ce qui est incomportable. Plusieurs stratégies ont été investiguées, ces dernières années, à la recherche de celle qui sera la plus efficace tout en épargnant le plus possible. Tous affirment que aucun examen isolé ne pourra être suffisant pour ce screening. Par contre, l’électrocardiogramme et/ou les peptides natriurétiques, incorporés ou non en scores cliniques, sont souvent évoqués comme testes efficaces pour le pré-screening des patients à envoyer à l’échocardiographie. Son utilisation diminue le nombre ’échocardiogrammes nécessaires et la dépense, tout en étant au moins aussi efficace que le screening du cancer du sein ou du colle de l’utérus, exige un investissement qui n’est en rien supérieur. Quelques auteurs ont démontré que l'exécution d’un échocardiogramme qualitatif, fait avec un échocardiographe portable, après l’ECG ou la détermination du BNP/ NT-proBNP et avant l’échocardiogramme complet, améliore encore la stratégie pour le screening de la dysfonction cardiaque. Finalement nous terminons avec quelques commentaires concernant les perspectives futures pour la prise en charge de l’insuffisanc e cardiaque. Il est absolument urgent et primordial d’établir d’une définition précise et universelle, ainsi que de critères de diagnostique objectifs, simples et reproductibles, applicables à tout le spectre de l’insuffisance cardiaque, de façon à ce que, dans un futur proche, nous soyons capables de connaître le véritable poids de l’insuffisance cardiaque, d’organiser une prise en charge le plus efficace possible tout en respectant l’inévitable contention des dépenses publiques. Les problèmes de diagnostique de l’ambulatoire exigent que les médecins de famille disposent de programmes de formation continus et que le dialogue avec l’hôpital et les spécialistes soit facilité, tel que nous l’avons fait, de forme programmée, systématiquement,pendant le programme EPICA. Les cliniques d’insuffisance cardiaque et les programmes structurés de prise en charge de l’insuffisance cardiaque ont démontré leur efficacité. Ils permettent une meilleure implémentation des Recommandations de diagnóstique et traitement, améliorent la qualité de vie et la survie des insuffisants cardiaques qui y sont suivis. Dans l’article 17 - Translating Guidelines into clinical practice : benefits of an acute heart failure unit - nous rendons compte de notre expérience en ce qui concerne les gains obtenus quant au diagnostic et traitement des insuffisants cardiaques hospitalisés dans notre service avant et après l’ouverture d’une unité d’insuffisance cardiaque et qui nous a permi d’amelliorer la qualité des soins prêtés à ces malades. Nous défendons que ces unités spécialement vocationnées pour la prise en charge de l’insuffisance cardiaque doivent se multiplier, s’intégrer en programmes plus vastes d’organisation de soins à prêter aux insuffisants cardiaques, qui incluent notamment l´hôpital de jour et adopter des structures variables d’accord avec les nécessités des populations qu’elles servent. Ces programmes de prise en charge de l’insuffisance cardiaque pourront assumer un rôle déterminant dans la formation scientifique des médecins, spécialement des médecins de famille, dans l’interface entre les soins primaires et l’hôpital et dans la référentiation des insuffisants cardiaques. Tous les efforts pour identifier et corriger précocement les facteurs de risque cardiovasculaire et développer TESE3 AF 6/9/08 12:25 PM Page 321 Résumé des stratégies pour le screening de la dysfonction cardiaque doivent être multipliés comme stratégies de prévention. Tout cela est possible, efficace à un pris semblable à celui d’autres programmes déjà en cours, mais exige la collaboration de tous, population, professionnels de santé, investigateurs et pouvoir politique qui viabilise l’évaluation des nécessités, le montage de ces programmes multidisciplinaires, et en contrôle la qualité, de façon à ce que très vite nous puissions contrôler cette épidémie.

Thesis (MScEng (Mechanical and Mechatronic Engineering))--University of Stellenbosch, 2010.
ENGLISH ABSTRACT: The research presented in this thesis serves to provide a tool to autonomously screen for cardiovascular disease in the rural areas of Africa. Vital information thus obtained from patients can be communicated to advanced medical centres by Telemedicine. Cardiovascular disease is then detected in its initial stages, which is essential to its effective treatment. The system developed in this study uses recorded heart sounds and electrocardiogram signals to distinguish between normal and abnormal heart conditions. This system improves on standard diagnostic tools in that it does not require cumbersome and expensive imaging equipment or a highly trained operator. Heart sound- and electrocardiogram signals from 62 volunteers were recorded with the prototype Precordialcardiogram device as part of a clinical study to aid in the development of the autonomous auscultation software and to screen patients for cardiovascular disease. These volunteers consisted of 28 patients of Tygerberg Hospital with cardiovascular disease and, for control purposes, 34 persons with normal heart conditions. The autonomous auscultation system developed during this study, interprets data obtained with the Precordialcardiogram device to autonomously acquire a normal or abnormal diagnosis. The system employs wavelet soft thresholding to denoise the recorded signals, followed by the segmentation of heart sound by identifying peaks in the electrocardiogram. Novel frequency spectral information was extracted as features from the heart sounds, by means of ensemble empirical mode decomposition and auto regressive modelling. These features proved to be particularly significant and played a major role in the screening capability of the system. New time domain based features were identified, established on the specific characteristics of the various cardiovascular diseases encountered during the study. These features were extracted via the energy ratios between different parts of ventricular systole and diastole of each recorded cardiac cycle. The respective features were classified to characterise typical heart diseases as well as healthy hearts with an ensemble artificial neural network. Herein the decisions of all the members were combined to obtain a final diagnosis. The performance of the autonomous auscultation system used in concert with the Precordialcardiogram device prototype, as determined through the leave-one-out crossvalidation method, had a sensitivity rating of 82% and a specificity rating of 88%. These results demonstrate the potential benefit of the Precordialcardiogram device and the developed autonomous auscultation software in a Telemedicine environment.
AFRIKAANSE OPSOMMING: Hierdie tesis beskryf die navorsing van 'n outonome toetsing en sifting stelsel vir kardiovaskulêre siektes in landelike dele van Afrika, vanwaar mediese inligting per telefoon versend kan word. Die apparaat maak vroeë opsporing van kardiovaskulêre siektes moontlik, wat essensieel is vir effektiewe behandeling daarvan en ook die koste-effek van hierdie siektes verminder. In die huidige ontwikkelde stelsel word normale sowel as abnormale hart-toestande getipeer met opnames van hartklanke sowel as elektrokardiogram-seine. Voordele wat hierdie stelsel bo standaard diagnostiese metodes het, sluit die hanteerbare formaat van die hele apparaat sowel as die nie-noodsaaklikheid van duur beeldskeppende apparaat, of hoogs opgeleide personeel. Hartklank- en elektrokardiogramseine van 62 vrywilligers is met die prototipe "Precordialcardiogram" apparaat opgeneem om by te dra tot die ontwikkeling van die rekenaar sagteware vir die outonome auscultatsie stelsel en om die pasiëntsiftingsvermoë daarvan te toets. Die vrywilligers het 28 pasiënte van Tygerberg hospitaal met abnormale harttoestande ingesluit, sowel as ‘n kontrolegroep van 34 persone met normale harttoestande. Die outonome auskultasie-stelsel wat tot stand gekom het deur hierdie ondersoek maak gebruik van “wavelet” sagte drempeling om geraas uit die opgeneemde seine te verwyder. Daarna word die hartklanke gesegmenteer deur die pieke van die elektrokardiogram te identifiseer. Deur middel van "ensemble empirical mode decomposition" en outoregressiewe modellering, is nuwe inligting aangaande die frekwensie spektra van hartklanke, aanwysend van spesifieke harttoestande, verkry. Die beduidendheid van hierdie eienskappe is bewys en het 'n belangrike rol in die siftingsvermoë van die stelsel gespeel. Hierbenewens is nuwe tyd-gebaseerde eienskappe van die onderskeie kardiovaskulêre siektes wat tydens die ondersoek bestudeer is, geïdentifiseer. Hierdie eienskappe is geëien deur die energie-verhoudings tussen verskillende dele van die ventrikulêre sistolie en diastolie van elke opgeneemde hartsiklus te ontleed. 'n "Ensemble artificial neural network" is gebruik om die geïdentifiseerde eienskappe van hartsiektes sowel as normale harttoestande, te klassifiseer. Hierin is besluite van al die lede van die netwerk gekombineer, ten einde ‘n finale diagnose te maak. Die klassifiseerder se geldigheid is kruis-bevestig deur middel van die laat-een-uit kruisbevestigings-metode. Deur middel van die kruis-bevestigingsmetode is die bedryfsvermoëns van die outonome auskultasie-stelsel, toegerus met die "Precordialcardiogram" apparaat, repektiewelik op 82% vir sensitiwiteit en 88% vir spesifisiteit vasgestel. Hierdie resultate demonstreer die benuttingspotensiaal van die apparaat in 'n Telemedisyne omgewing.

Thesis (PhD (Biomedical Sciences))--University of Stellenbosch, 2010.
Bibliography
ENGLISH ABSTRACT: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder worldwide. The disease is characterized by extreme variability in the amount of hypertrophy that develops in different patients in response to sarcomeric protein-encoding gene mutations. The underlying defect in HCM is altered contractility of the sarcomere, primarily due to a defective sarcomere. Although numerous disease-causing genes have been identified for HCM, the factors that modify the amount of hypertrophy that develops in a given person are still unknown, it can be hypothesized that molecules that affect contractility can act as modifiers of the hypertrophic signal, and therefore influence the development of hypertrophy. Cardiac contractility is regulated by dynamic phosphorylation of proteins within the sarcomere by kinases such as cAMP-activated protein kinase A (PKA). Because speed and energy efficiency of cardiac muscle contraction has to be regulated in order to match the body’s needs, PKA is anchored close to its targets by A-kinase anchoring proteins (AKAPs) to enable spatio-temporal control of phosphorylation. Cardiac myosin binding protein-C (cMyBPC) and cardiac troponin I (cTNI) are HCM-causing sarcomeric proteins which regulate contractility in response to PKA phosphorylation. In a previous study, our laboratory identified a phosphodiesterase 4D-interacting protein as ligand of the N-terminal of cMyBPC via a yeast-two-hybrid (Y2H) cardiac library screen. This protein is also known in the literature as myomegalin (MMGL) isoform 4. Because phosphodiesterases and PKA are sometimes anchored by the same anchoring protein (AKAP), we hypothesized that MMGL isoform 4 acts as an AKAP by anchoring PKA to the phosphorylatable N-terminal of cMyBPC, and tested this by direct protein-protein interaction analyses in a yeast-based system. The MMGL cDNA was cloned into a bait vector, which was directly assessed for interaction with two distinct PKA regulatory-subunit preys. We further investigated the function of MMGL itself by using the Y2H bait to screen a cardiac cDNA library for novel MMGL interactors. All the prey clones identified via these Y2H analyses were subsequently sequenced to determine their identity. Based on their identities and subcellular localization, all putative Y2H MMGL-prey interactions were further assessed by additional, separate biochemical techniques viz. in vivo co-immunoprecipitation and in vivo 3D co-localization. The interactions between MMGL and its known PKA-phosphorylatable sarcomeric ligands were also investigated under conditions of β-adrenergic stress, by quantitatively measuring levels of co-localization before and upon addition of the β-adrenergic agonist isoproterenol. Furthermore, in order to evaluate the role of MMGL in cMyBPC phosphorylation, we assessed the expression of the different phosphorylation isoforms of cMyBPC, with and without β-adrenergic stimulation, in the context of siRNA-mediated MMGL knockdown. We further hypothesized that MMGL and PKA may serve as modifiers of the hypertrophic phenotype. This was tested by conducting a single nucleotide polymorphism (SNP) genotyping study of the genes encoding MMGL and the regulatory subunits of PKA viz. PDE4DIP, PRKAR1A and PRKAR2A, respectively, and comparing genotypic data with clinical phenotypic traits in a family-based association study. A panel of 353 individuals, including genetically and clinically affected as well as unaffected HCM individuals, was identified. All these individuals were screened for the presence or absence of all three South African HCM founder mutations, and blood was collected and DNA extracted. Genotypes at multiple SNPs in each gene were determined by subjecting the DNA samples to TaqMan® allelic discrimination technology. Statistical analysis using quantitative transmission disequilibrium testing (QTDT) was done in order to establish whether the difference in genotype in these three genes might have an effect on HCM phenotype. Our results showed that MMGL interacted with both PKA regulatory subunits as well as with other cardiac proteins that are PKA targets, including the sarcomeric protein cTNI. It was confirmed that two regulatory subunits of PKA (PRKAR1A and PRKAR2A), cardiac ankyrin repeat protein (CARP), copper metabolism gene MURR1 domain 4 (COMMD4), α-enolase (ENO1), β-enolase (ENO3) and cTNI are novel interactors of MMGL. In order to classify a protein as an AKAP, interaction with one of PKA’s regulatory subunits are prerequisite; MMGL showed interaction with both, confirming our hypothesis of MMGL being an AKAP, moreover, classifying it as a novel dual-specific sarcomeric AKAP. The identities of the AKAPs involved in the phosphorylation of cMyBPC and cTNI had been unknown; our results indicate that MMGL is the AKAP involved in the phosphorylation of both these PKA targets. We also showed that quantitatively more interaction occurs between MMGL and its sarcomeric ligands cMyBPC and cTNI under β-adrenergic stress. This implicates that under elevated cAMP levels, PKA is dynamically recruited by MMGL to the PKA targets cMyBPC and cTNI, presumably to mediate cardiac stress responses and leading to increased cardiac contractility. Furthermore, siRNA-mediated knockdown of MMGL lead to a reduction of cMyBPC levels under conditions of β-adrenergic stress, indicating that MMGL-assisted phosphorylation is requisite for protection of cMyBPC against proteolytic cleavage. The SNP modifier study indicated that one variant in PDE4DIP (rs1664005) showed strong association with numerous clinical hypertrophy traits, including maximal interventricular septum thickness, as well as a number of other composite score traits. Two variants in PRKAR1A (rs11651687 and rs3785906) also showed strong association with some of these clinical hypertrophy traits. These results therefore suggest that variants in these two genes may act as modifiers of the HCM phenotype. In conclusion, this study ascribes a novel function to MMGL isoform 4: it meets all criteria for classification as an AKAP and appears to be involved in the phosphorylation of cMyBPC as well as cTNI; hence MMGL is likely to be an important component in the regulation of cardiac contractility, and by extension, in the development of hypertrophy. This has further implications for understanding the patho-aetiology of mutations in cMyBPC and cTNI, and raises the question of whether MMGL might itself be considered a candidate HCM-causing factor.
AFRIKAANSE OPSOMMING: Hipertrofiese kardiomiopatie (HKM) is die mees algemeenste oorerflike hartspier siekte wêreldwyd. Die siekte word gekenmerk deur die uiterste variasie in die hoeveelheid hipertrofie wat in verskillende pasiënte ontwikkel as gevolg van sarkomeriese proteïen-koderende mutasies. Die onderliggende gebrek in HKM is geaffekteerde kontraktiliteit van die sarkomeer, hoofsaaklik as gevolg van ‘n gebrekkige sarkomeer. Alhoewel daar verskeie siekte-veroorsakende gene vir HKM geïdentifiseer is, bly die faktore wat die hoeveelheid hipertrofie in ‘n gegewe persoon modifiseer, onbekend. Daar kan dus gehipotiseer word dat molekules wat kontraktiliteit beïnvloed as modifiseerders van die hipertrofiese sein kan optree, en dus die ontwikkeling van hipertrofie beïnvloed. Hartspier kontraktiliteit word gereguleer deur die dinamiese fosforilasie van proteïene binne die sarkomeer deur kinases soos bv. cAMP-geaktiveerde proteïen kinase A (PKA). Die spoed en energie doeltreffendheid van hartspier kontraksie moet gereguleer word om by die liggaam se behoeftes aan te pas; dus word PKA naby sy teikens deur A-kinase anker proteïene (AKAPs) geanker om sodoende die beheer van fosforilasie beide in die korrekte area sowel as tydsduur te reguleer. Kardiale miosien-bindingsproteïen C (cMyBPC), asook kardiale troponien I (cTNI), is beide HKM-veroorsakende sarkomeriese proteïene wat kontraktiliteit beheer deur middel van fosforilasie deur PKA. In ‘n vorige studie in ons laboratorium is ‘n fosfodiesterase 4D-interaksie proteïen as bindingsgenoot van die N-terminaal van cMyBPC geïdentifiseer deur middel van ‘n gis-twee-hibried (G2H) kardiale biblioteek sifting. In die literatuur staan dié proteïen ook bekend as miomegalin (MMGL) isovorm 4. Fosfodiesterases en PKA word soms deur dieselfde anker proteïen (AKAP) geanker, dus het ons hipotiseer dat MMGL isovorm 4 ook as AKAP kan optree deur PKA aan die fosforileerbare N-terminaal van cMyBPC te anker. Die hipotese is getoets deur middel van direkte proteïen-proteïen interaksie analises in ‘n gis-gebaseerde sisteem. Die MMGL cDNA was in ‘n jag-plasmied gekloneer, wat toe direk ge-evalueer is vir interaksie met twee verskillende PKA regulatoriese-subeenheid prooi-plasmiede. Die funksie van MMGL self is verder ondersoek deur die G2H jag-plasmied te gebruik om ‘n kardiale cDNA biblioteek te sif, sodoende om nuwe MMGL bindingsgenote te identifiseer. Alle prooi klone wat deur dié G2H analises geïdentifiseer is, was daarna onderworpe aan DNA-volgorde bepaling om hul identiteit vas te stel. Afhangende van hul identiteite en subsellulêre lokalisering, is alle moontlike G2H MMGL-prooi interaksies verder ge-evalueer deur bykomende, afsonderlike biochemiese tegnieke viz. in vivo ko-immunopresipitasie asook in vivo 3D ko-lokalisering. Die interaksie tussen MMGL en sy bekende PKA-gefosforileerde sarkomeriese bindingsgenote was ook ondersoek onder kondisies van β-adrenergiese stres, deur kwantitatief die vlakke van ko-lokalisering te meet voor en na byvoeging van die β-adrenergiese agonis isoproterenol. Om verder die rol van MMGL in cMyBPC fosforilasie te ondersoek, het ons die uitdrukking van die verskillende fosforilasie isovorms van cMyBPC, met en sonder β-adrenergiese stimulasie, in die konteks van siRNA-bemiddelde MMGL uitklop, bepaal. Ons het verder hipotiseer dat MMGL en PKA as modifiseerders van die hipertrofiese fenotipe mag dien. Dit is getoets deur ‘n enkel nukleotied polimorfisme (SNP) genotiperings studie van die gene wat kodeer vir MMGL en die regulatoriese subeenhede van PKA, viz. PDE4DIP, PRKAR1A en PRKAR2A, en daarna dié genotipiese data met kliniese fenotipiese data te vergelyk in ‘n familie-gebaseerde assosiasie studie. ‘n Paneel van 353 individue wat genetiese en klinies geaffekteerde, sowel as ongeaffekteerde HKM individue insluit, was geidentifiseerd. Alle individue was ondersoek vir die aanwesigheid of afwesigheid van al drie Suid-Afrikaanse HKM stigter mutasies; bloedmonsters is gekollekteer en DNA uitgetrek. Die genotipes van veelvoudige SNPs in elke geen was bepaal deur die DNA monsters aan TaqMan® alleliese diskriminasie tegnologie met behulp van die ABI TaqMan® Validated SNP Genotyping Assays sisteem te analiseer. Statistiese analises deur middel van kwantitatiewe transmissie disekwilibrium toetse (QTDT) was gedoen om te bepaal of die verskil in genotipe in hierdie drie gene ‘n effek op HKM fenotipe het. Ons resultate het gewys dat MMGL interaksie toon met beide PKA regulatoriese subeenhede, sowel as met ander kardiale proteïene wat ook PKA teikens is, insluitende die sarkomeriese proteïen cTNI. Dit is bevestig dat die twee regulatoriese subeenhede van PKA (PRKAR1A en PRKAR2A), kardiale ankyrin herhaal proteïen (CARP), koper metabolisme geen MURR1 domein 4 (COMMD4), α-enolase (ENO1), β-enolase (ENO3) en cTNI almal nuwe bindingsgenote van MMGL is. ‘n Proteïen moet interaksie met een van die regulatoriese subeenhede van PKA toon om as AKAP geklassifiseer te word; MMGL het interaksie met beide getoon, wat ons hipotese bevestig dat MMGL ‘n AKAP is, asook dat MMGL as ‘n nuwe dubbel-spesifieke sarkomeriese AKAP geklassifiseer kan word. Die identiteite van die AKAPs wat betrokke is in die fosforilasie van cMyBPC en cTNI was onbekend tot nou; ons resultate wys dat MMGL die AKAP is wat betrokke is in die fosforilasie van beide hierdie PKA teikens. Ons wys ook dat daar kwantitatief meer interaksie plaasvind tussen MMGL en sy sarkomeriese bindingsgenote cMyBPC en cTNI onder kondisies van β-adrenergiese stres. Dit impliseer dat PKA dinamies verwerf word deur MMGL, onder verhoogde vlakke van cAMP, tot by die PKA teikens cMyBPC en cTNI, moontlik om kardiale stres-response te bemiddel en dus te lei na verhoogde spierkontraksie. Verder het siRNA-bemiddelde uitklop van MMGL gelei na ‘n vermindering van cMyBPC vlakke onder kondisies van β-adrenergiese stres. Dit dui aan dat fosforilasie deur middel van MMGL-bystand ‘n voorvereiste is vir beskerming van cMyBPC teen proteolise. Die SNP modifiseerder studie het gewys dat een variant in PDE4DIP (rs1664005) sterk assosiasie toon met verskeie kliniese hipertrofie kenmerke, insluitende maksimale interventrikulêre septum diktheid, sowel as ander van die saamgestelde telling kenmerke. Twee variante in PRKAR1A (rs11651687 en rs3785906) het ook sterk assosiasie getoon met verskeie van die kliniese hipertropfie kenmerke. Hierdie resultate dui dus daarop dat variante in hierdie twee gene as modifiseerders van die HKM fenotipe mag optree. In samevatting skryf hierdie studie ‘n nuwe funksie aan MMGL isovorm 4 toe: dit voldoen aan alle vereistes om as AKAP geklassifiseer te word en dit blyk of dit betrokke is in die fosforilasie van cMyBPC en cTNI; dus is MMGL waarskynlik ‘n belangrike komponent in die regulasie van hartspier sametrekking, en dus met uitbreiding, in die ontwikkeling van hipertrofie. Dit hou verdere implikasies in om die siekte-oorsaak van mutasies in cMyBPC en cTNI te verstaan, en stel die vraag of MMGL self as ‘n kandidaat HKM-veroorsakende geen kan beskou word.
Medical Research Council
University of Stellenbosch
Prof Paul van Helden

Background: The initial systolic blood pressure (SBP) in patients with acute heart failure (AHF) can be used as a guide when choosing specific pharmacologic treatments by helping identify the underlying type of HF (e.g., HF with preserved ejection fraction). Clinical experience and research data from our medical center suggests that AHF with elevated SBP may be presenting less frequently than in the past. This may call into question the utility of initial SBP as a clinical guide. The goal of this Master’s Thesis is to test the hypothesis that the frequency of AHF patients with a SBP>160mmhg has declined over time. Methods: This observational study compares data from 4 cohorts of adult patients admitted with AHF in central MA. Data were obtained from a contemporary (2011-2013) study of patients with AHF as well as from the 1995, 2000, 2006 Worcester Heart Failure Study (WHFS) cohorts. The Framingham criteria the diagnostic criterion for AHF. The main outcome was the proportion of patients with AHF with a SBP > 160 mmHg who presented in each of the 4 study cohorts and was examined by multivariate logistic regression. Results: 2,366 patients comprised the study population. The average age was 77 years, 55% were female, 94% white, and 75% had prior HF. In 1995 33.6% of AHF patients had a SBP >160 mmHg compared to 19.5% in 2011-2013 (p160 mmHg in 2006 (0.64, (0.42-0.96)) and 2011-13 (0.46, (0.28-0.74)). Conclusion: The proportion of patients with AHF and an initial SBP >160 mmHg has significantly declined over time. This may warrant a reexamination of the utility of SBP to inform diagnosis and treatment in patients with AHF.

Background: The initial systolic blood pressure (SBP) in patients with acute heart failure (AHF) can be used as a guide when choosing specific pharmacologic treatments by helping identify the underlying type of HF (e.g., HF with preserved ejection fraction). Clinical experience and research data from our medical center suggests that AHF with elevated SBP may be presenting less frequently than in the past. This may call into question the utility of initial SBP as a clinical guide. The goal of this Master’s Thesis is to test the hypothesis that the frequency of AHF patients with a SBP>160mmhg has declined over time. Methods: This observational study compares data from 4 cohorts of adult patients admitted with AHF in central MA. Data were obtained from a contemporary (2011-2013) study of patients with AHF as well as from the 1995, 2000, 2006 Worcester Heart Failure Study (WHFS) cohorts. The Framingham criteria the diagnostic criterion for AHF. The main outcome was the proportion of patients with AHF with a SBP > 160 mmHg who presented in each of the 4 study cohorts and was examined by multivariate logistic regression. Results: 2,366 patients comprised the study population. The average age was 77 years, 55% were female, 94% white, and 75% had prior HF. In 1995 33.6% of AHF patients had a SBP >160 mmHg compared to 19.5% in 2011-2013 (p160 mmHg in 2006 (0.64, (0.42-0.96)) and 2011-13 (0.46, (0.28-0.74)). Conclusion: The proportion of patients with AHF and an initial SBP >160 mmHg has significantly declined over time. This may warrant a reexamination of the utility of SBP to inform diagnosis and treatment in patients with AHF.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Os cuidados de enfermagem para crianÃas com cardiopatia congÃnita devem ser estabelecidos e executados tÃo logo se suspeite do diagnÃstico de defeito cardÃaco congÃnito, voltados sempre para a detecÃÃo precoce de sinais de descompensaÃÃo e manutenÃÃo de condiÃÃes Ãtimas para a cirurgia. Objetivou-se caracterizar o quadro de diagnÃsticos de enfermagem apresentados por crianÃas com cardiopatias congÃnitas. Estudo de natureza observacional, longitudinal desenvolvido nos meses de julho a novembro de 2004. A amostra foi composta por 45 crianÃas internadas em um hospital da rede pÃblica do municÃpio de Fortaleza-CearÃ. Para a coleta, foram utilizados entrevista e exame clÃnico de enfermagem. As crianÃas foram acompanhadas durante quinze dias de internamento desde a data de sua admissÃo. No perÃodo efetivaram-se seis avaliaÃÃes diagnÃsticas com intervalo de 48 horas. O processo de elaboraÃÃo e inferÃncia dos diagnÃsticos e problemas colaborativos seguiu as etapas de coleta, interpretaÃÃo / agrupamento das informaÃÃes e nomeaÃÃo de categorias. Foram encontrados 22 diagnÃsticos de enfermagem, 34 fatores relacionados e 13 problemas colaborativos diferentes nas 270 avaliaÃÃes realizadas. Observou-se associaÃÃo estatisticamente significante entre os diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade, Crescimento e desenvolvimento retardados e PerfusÃo tissular ineficaz. Estes diagnÃsticos apresentaram associaÃÃo com os fatores relacionados: DesequilÃbrio da ventilaÃÃo-perfusÃo, HiperventilaÃÃo, ReduÃÃo mecÃnica do fluxo sangÃÃneo, SecreÃÃes brÃnquicas e SecreÃÃes retidas. Os diagnÃsticos IntolerÃncia à atividade e Crescimento e desenvolvimento retardados mostraram associaÃÃo com o sexo feminino. Nos diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade, Crescimento e desenvolvimento retardados e DÃbito cardÃaco diminuÃdo, identificaram-se diferenÃas de mÃdia de sobrevida entre crianÃas atà 4 meses e acima de 4 meses. Os diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade e Risco para infecÃÃo ocorreram precocemente no perÃodo de internamento. Entre os diagnÃsticos, seis evidenciaram maiores oscilaÃÃes em suas trajetÃrias de ocorrÃncia no tempo: PadrÃo respiratÃrio ineficaz, IntolerÃncia à atividade, DesobstruÃÃo ineficaz das vias aÃreas, Hipertermia, PadrÃo de sono perturbado e Risco para intolerÃncia à atividade. Foram construÃdos cinco modelos paramÃtricos no domÃnio tempo, com vistas a predizer a ocorrÃncia desses diagnÃsticos de enfermagem. O ajustamento das equaÃÃes para os diagnÃsticos PadrÃo de sono perturbado e Hipertermia denotou grande dispersÃo entre os dados e a linha de tendÃncia, indicando que, alÃm do tempo, outras variÃveis determinam a proporÃÃo de crianÃas que manifestarÃo esses diagnÃsticos. Considera-se a importÃncia de se realizar pesquisas de caracterizaÃÃo do quadro de diagnÃsticos para determinaÃÃo das necessidades de assistÃncia de enfermagem à crianÃa cardiopata. O conhecimento da evoluÃÃo temporal das respostas do indivÃduo pode direcionar os cuidados de enfermagem para as reais necessidades do cliente, facilitando, assim, a escolha de intervenÃÃes mais adequadas

Heterotaxy refers to the abnormal arrangement of internal organs in relation to each other. Model organism studies have shown that functions of more than eighty genes are required for normal asymmetric left-right organ development. CRELD1 has been shown to be necessary for proper heart development and mutations in CRELD1 are known to increase risk of cardiac atrioventricular septal defects (AVSD). AVSD is the most common form of heart defect associated with heterotaxy, and we have previously shown that some individuals with heterotaxy-related AVSD have mutations in CRELD1. Therefore, we propose to examine the CRELD1 gene in a large sample of patients with heterotaxy syndrome. Our goal was to determine if mutations in CRELD1 are associated with other manifestations of heterotaxy or if they only coincide with AVSD. To achieve this aim, a sample size of 126 patients with heterotaxy collected by Dr. Belmont, Baylor college of Medicine, Texas, with approximately 66% of the heterotaxy population with different types of heart defects, were used for this study. Ten exons, promoter regions, and regulatory elements in the introns of CRELD1 gene were sequenced and analyzed. In this study three different heterozygous missense mutations in CRELD1 were identified in three unrelated individuals. These three individuals were diagnosed with different forms of heart defects in addition to AVSD. All three mutations were identified in highly conserved regions of CRELD1 possibly altering the CRELD1 properties. This demonstrates that mutations in CRELD1 may increase the susceptibility of AVSD in heterotaxy population. This information can help us to find factors effecting disease susceptibility in heterotaxy patients since the heart defects are a complex trait with incomplete penetrance.

Thesis (MScEng)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: This thesis investigates the feasibility of the laser Doppler vibrometer (LDV) for use in the autonomous auscultation of the human heart. As a non-contact measurement device, the LDV could become a very versatile biomedical sensor. LDV, stethoscope, piezoelectric accelerometer (PA) and electrocardiogram (ECG) signals were simultaneously recorded from 20 volunteers at Tygerberg Hospital. Of the 20 volunteers, 17 were confirmed to have cardiovascular disease. 3 patients with normal heart sounds were recorded for control data. The recorded data was successfully denoised using soft threshold wavelet denoising and ensemble empirical mode decomposition. The LDV was compared to the PA in common biomedical applications and found to be equally accurate. The heart sound cycles for each participant were segmented using a combination of ECG data and a simplicity curve. Frequency domain features were extracted from each heart cycle and input into a k-nearest neighbours classifier. It was concluded that the LDV can form part of an autonomous, non-contact auscultation system.
AFRIKAANSE OPSOMMING: Hierdie tesis ondersoek die haalbaarheid daarvan om die laser Doppler vibrasiemeter (LDV) vir die outonome beluistering van die menslike hart te gebruik. As 'n kontaklose meettoestel kan die LDV werklik 'n veelsydige biomediese sensor word. Twintig vrywilligers by die Tygerberg Hospitaal se LDV-, stetoskoop-, piësoelektriese versnellingsmeter (PV)- en elektrokardiogram (EKG) seine is gelyktydig opgeneem. Uit die 20 vrywilligers was daar 17 bevestigde gevalle van kardiovaskulêre siektes. Die data van drie pasiënte met normale hartklanke is as kontroledata opgeneem. Geraas is suksesvol uit die opgeneemde data verwyder deur 'n kombinasie van sagtedrempelgolf en saamgestelde empiriese modus ontladingstegnieke. Die LDV was vergelyk met die PV vir algemene biomediese gebruike en daar was gevind dat dit vergelykbare akkuraatheid het. Die hartklanksiklusse van elke deelnemer is gesegmenteer deur EKG data en 'n eenvoudskromme te kombineer. Frekwensiegebiedskenmerke is uit elke hartsiklus onttrek en in 'n k-naastebuurpunt klassifiseerder ingevoer. Daar is tot die gevolgtrekking gekom dat die LDV deel van 'n outonome, kontaklose beluisteringstelsel kan uitmaak.

Thesis (MScEng (Mechanical and Mechatronic Engineering))--University of Stellenbosch, 2007.
This thesis is concerned with the testing of an “auscultation jacket” as a means of recording heart sounds and electrocardiography (ECG) data from patients. A classification system based on Neural Networks, that is able to discriminate between normal and abnormal heart sounds and murmurs, has also been developed . The classification system uses the recorded data as training and testing data. This classification system is proposed to serve as an aid to physicians in diagnosing patients with cardiac abnormalities. Seventeen normal participants and 14 participants that suffer from valve-related heart disease have been recorded with the jacket. The “auscultation jacket” shows great promise as a wearable health monitoring aid for application in rural areas and in the telemedicine industry. The Neural Network classification system is able to differentiate between normal and abnormal heart sounds with a sensitivity of 85.7% and a specificity of 94.1%.

Thesis (Ph.D.)--Electrical and Computer Engineering, Georgia Institute of Technology, 2008.
Committee Chair: Skrinjar, Oskar; Committee Member: Oshinski, John; Committee Member: Tannenbaum, Allen; Committee Member: Vela, Patricio; Committee Member: Yezzi, Anthony

In developing countries, acute respiratory infections (ARIs) are responsible for two million deaths per year. Most victims are children who are less than 5 years old. Pneumonia kills 5000 children per day. The statistics for cardiovascular diseases (CVDs) are even more alarming. According to a 2009 report from the World Health Organization (WHO), CVDs kill 17 million people per year. In many resource-poor parts of the world such as India and China, many people are unable to access cardiologists, pulmonologists, and other specialists. Hence, low skilled health professionals are responsible for screening people for ARIs and CVDs in these areas. For example, in the rural areas of the Philippines, there is only one doctor for every 10,000 people. By contrast, the United States has one doctor for every 500 Americans. Due to advances in technology, it is now possible to use a smartphone for audio recording, signal processing, and machine learning. In my thesis, I have developed an Android application named Smart Auscultation. Auscultation is a process in which physicians listen to heart and lung sounds to diagnose disorders. Cardiologists spend years mastering this skill. The Smart Auscultation application is capable of recording and classifying heart sounds, and can be used by public or clinical health workers. This application can detect abnormal heart sounds with up to 92-98% accuracy. In addition, the application can record, but not yet classify, lung sounds. This application will be able to help save thousands of lives by allowing anyone to identify abnormal heart and lung sounds.

O objetivo deste estudo foi avaliar a dose efetiva de radiação nos exames de CCTA através dos métodos Prospectivo e Retrospectivo do ECG. A coleta de dados foi realizada na Clínica Sabedotti, em Ponta Grossa – PR, em um equipamento General Electric modelo VCT XT, de 64 linhas de detecção. A dose efetiva foi mensurada para 30 casos, selecionados aleatoriamente do Picture Archival and Communication System – PACS, Arquivamento e Comunicação de Imagens, a partir do Produto Dose Comprimento (DLP) reportado pelo equipamento para cada exame e pelo fator de conversão (EDLP) definido pela Comissão Europeia para região cardíaca (EDLP = 0,014). Os resultados apontaram diferenças expressivas quanto à dose de radiação entregue ao paciente de acordo com o método de aquisição empregado, Retrospectivo ou Prospectivo do ECG.
The aim of this study was to evaluate the effective dose received by patients undergoing CCTA in both acquisition methods in the period June 1st to October 30th, 2013. Data collection was performed at the Clínica Sabedotti in Ponta Grossa/PR, with General Electric Equipment VCT XT, 64 detections lines. The effective dose was measured from the thirty cases randomly selected of Picture Archival and Communication System – PACS, reported by Dose Lenght Product (DLP) equipment for each examination and the conversion factor (EDLP) set by the European Commission for cardiac region (EDLP = 0.014). The results showed significant differences in radiation dose delivered to the patient according to the employee acquisition method, Retrospective or Prospective of ECG.

Para avaliar a hipótese da presença de inflamação em artérias pulmonares periféricas de pacientes com hipertensão pulmonar (HP) decorrente de cardiopatias congênitas, foram quantificadas células inflamatórias através de marcação imunohistoquímica em biópsias de 26 pacientes e comparadas com 11 controles sem cardiopatia. Detectou-se quantidades semelhantes de células inflamatórias nos dois grupos, mas com predomínio de linfócitos T no grupo controle e de macrófagos jovens no grupo HP. Esses achados podem estar relacionados com a redução do estímulo dependente de macrófagos para diferenciação e maturação de linfócitos T nos cardiopatas e/ou a deficiência imunológica primária nesses pacientes
To evaluate the hypothesis of increased inflammation in peripheral pulmonary arteries from patients with pulmonary hypertension secondary to congenital cardiac shunts, we quantified the inflammatory cells with the aid of immunohystochemistry in 26 biopsies (HP group), comparing them to 11 patients with no cardiac disease. Similar quantities of inflammatory cells were observed in the two groups, with a predominance of T-lymphocytes in the controls and of young macrophages in the HP group. These findings could be related to a reduction of macrophagic stimulus to the differentiation and maturation of T-lymphocytes and/or to a primary immunological deficiency in patients with congenital cardiac shunts

Lu, Yan.
"October 2010."
Thesis (M.Phil.)--Chinese University of Hong Kong, 2011.
Includes bibliographical references (leaves 65-68).
Abstracts in English and Chinese.
Abstract --- p.i
Acknowledgement --- p.iv
Chapter 1. --- Introduction --- p.1
Chapter 1.1 --- Electrocardiogram --- p.1
Chapter 1.1.1 --- ECG Measurement --- p.2
Chapter 1.1.2 --- Cardiac Conduction Pathway and ECG Morphology --- p.4
Chapter 1.1.3 --- A Basic Clinical Approach to ECG Analysis --- p.6
Chapter 1.2 --- Cardiovascular Disease --- p.7
Chapter 1.3 --- Motivation --- p.9
Chapter 1.4 --- Related Work --- p.10
Chapter 1.5 --- Overview of Proposed Approach --- p.11
Chapter 1.6 --- Thesis Outline --- p.13
Chapter 2. --- ECG Signal Preprocessing --- p.14
Chapter 2.1 --- ECG Model and Its Generalization --- p.14
Chapter 2.1.1 --- ECG Dynamic Model --- p.14
Chapter 2.1.2 --- Generalization of ECG Model --- p.15
Chapter 2.2 --- Empirical Mode Decomposition --- p.17
Chapter 2.3 --- Baseline Wander Removal --- p.20
Chapter 2.3.1 --- Sources of Baseline Wander --- p.20
Chapter 2.3.2 --- Baseline Wander Removal by EMD --- p.20
Chapter 2.3.3 --- Experiments on Baseline Wander Removal --- p.21
Chapter 2.4 --- ECG Denoising --- p.24
Chapter 2.4.1 --- Introduction --- p.24
Chapter 2.4.2 --- Instantaneous Frequency --- p.26
Chapter 2.4.3 --- Problem of Direct ECG Denoising by EMD : --- p.28
Chapter 2.4.4 --- Model-based Pre-filtering --- p.30
Chapter 2.4.5 --- EMD Denoising Using Significance Test --- p.33
Chapter 2.4.6 --- EMD Denoising using Instantaneous Frequency --- p.35
Chapter 2.4.7 --- Experiments --- p.39
Chapter 2.5 --- Chapter Summary --- p.44
Chapter 3. --- ECG Classification --- p.45
Chapter 3.1 --- Database --- p.45
Chapter 3.2 --- Feature Extraction --- p.46
Chapter 3.2.1 --- Feature Selection --- p.46
Chapter 3.2.2 --- Feature Dimension Reduction by GDA --- p.48
Chapter 3.3 --- Classification by Support Vector Machine --- p.50
Chapter 3.4 --- Experiments --- p.53
Chapter 3.4.1 --- Performance of Feature Reduction --- p.54
Chapter 3.4.2 --- Performance of Classification --- p.57
Chapter 3.4.3 --- Performance Comparison with Other Works --- p.60
Chapter 3.5 --- Chapter Summary --- p.61
Chapter 4. --- Conclusions --- p.63
Reference --- p.65

儘管心力衰竭的診斷和治療已取得了長足進步，但是心力衰竭依然是目前主要的致殘和致死病因。而且，隨著人口的老齡化，心力衰竭的發病率不斷上升。然而心力衰竭的快速診斷、心功能評價以及患者的危險分層依然面臨眾多挑戰。Acoustic cardiography 是一項經濟簡單的新技術。憑藉獨有的雙功能感測器，這項技術可以同時評估收縮間期（systolic time intervals）以及舒張期心音（diastolic heart sounds）。這項技術提供的主要參數包括：第三心音分數（S3 score；第三心音存在的可能性），電機械時間（EMAT, electromechanical activation time；從心電圖Q 波到心音圖第一心音的時間）及電機械時間比例（%EMAT；電機械時間占整個心動週期的比例），收縮障礙指數（SDI, systolic dysfunctionindex）。本論文主要涵蓋Acoustic cardiography 在心力衰竭患者中如下三個方面 的應用：
一、心力衰竭的診斷和不同亞型的識別
本研究入組了 94 名高血壓但無心力衰竭患者、109 名射血分數正常的心力衰竭患者以及89 名射血分數減低的心力衰竭患者，我們發現%EMAT 可以鑒別射血分數正常的心力衰竭和高血壓患者。另一方面，SDI 是鑒別分射血分數正常和射血分數減低患者的最好指標。
二、心力衰竭患者心功能障礙嚴重程度評估
此研究共招募 94 名高血壓患者和127 名射血分數減低的心力衰竭患者。結果顯示：SDI 可以鑒別射血分數減低的心力衰竭和高血壓患者。亞組分析顯示：SDI 可以區分射血分數嚴重減低和中度減低的心力衰竭患者；S3 score 可以識別伴舒張功能嚴重障礙的心力衰竭患者。
三、心力衰竭患者的危險分層
共計 474 名心力衰竭患者被納入此研究，平均隨訪時間484±316 天，169名患者死亡，其中125 名死於心臟病。SDI 和S3 score 都是全因死亡率的獨立預測因數；Kaplan Meier 分析顯示：SDI ≥ 5 或S3 score ≥ 4.12 的心力衰竭患者的生存率顯著降低。
通過以上三個方面的研究，我們發現這項新技術有助於（1）心力衰竭的診斷和不同亞型的識別；（2）評估心力衰竭患者的心功能障礙嚴重程度，進而發現其中的高危人群；（3）心力衰竭患者的危險分層。因此，這項新技術有望在心力衰竭患者的管理中扮演早期診斷、評估以及危險分層的重要角色。
Despite recent advances in its management, heart failure remains a major cause of disability and death and its prevalence is still increasing as the population ages. However, rapid and accurate bedside diagnosis, evaluation as well as risk stratification of heart failure still remain challenging.
Acoustic cardiography (AUDICOR, Inovise Medical, Inc., Portland, OR, USA) is a novel and user friendly equipment which can be used in a wide variety of clinical conditions. With proprietary dual-functional sensors, this technology permits simultaneous acquisition of detailed information regarding systolic time intervals and diastolic heart sounds and provides a computerized interpretation of the findings. Major acoustic cardiographic parameters include S3 score (probability that the third heart sound exists), electromechanical activation time (EMAT, interval from Q wave to the first heart sound; %EMAT is the proportion of cardiac cycle that EMAT occupies), and systolic dysfunction index (SDI= exp [S3 score/10] x QRS interval x QR interval x %EMAT).This thesis will cover 3 aspects of clinical application of acoustic cardiography in heart failure patients.
I. Identification of heart failure and its phenotypes
We performed one study involving 94 patients with hypertension without heart failure, 109 patients with heart failure with normal ejection fraction (HFNEF, EF > 50%) and 89 patients with heart failure and reduced ejection fraction (HFREF, EF < 50%). We found that %EMAT significantly differentiated HFNEF from hypertension. Whereas SDI out-performed the other acoustic cardiographic parameters in differentiating HFREF from HFNEF.
II. Assessment of HFREF patients at high risk by evaluating the severity of left ventricular (LV) systolic and diastolic dysfunction
Ninety-four hypertensive patients without heart failure and 127 HFREF patients (EF < 50%) were consecutively recruited for the study. SDI significantly differentiated HFREF from hypertension. In subgroup analysis, SDI discriminated HFREF patients with severely impaired EF (EF ≤ 35%) from those with moderately impaired EF (35% < EF <50%). S3 score > 4.67 identified HFREF patients with restrictive LV filling pattern.
III. Risk stratification in patients with heart failure
A total of 474 patients hospitalized for heart failure were enrolled into our study. During a mean follow-up time of 484±316 days, 169 (35.7%) patients died and 125 (26.4%) of them died of cardiac causes. After controlling for other potential confounders, we found that S3 score ≥ 4.12, and SDI ≥ 5 were both independent predictors for all-cause mortality. Kaplan-Meier analysis showed that heart failure patients with SDI ≥ 5 or S3 score ≥ 4.12 had a significantly lower survival rate than those with lower SDI or S3 score.
In summary, this bedside technology offers a wide variety of clinical applications in (1) identification of heart failure and its phenotypes; (2) assessmet of HFREF patients at high risk by evaluating the severity of LV systolic and diastolic dysfunction; (3) risk stratification in patients with heart failure. Thus, acoustic cardiography is likely to be helpful in the management of heart failure patients, acting as an early detection, evaluation and risk-stratification tool.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Wang, Shang.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2012.
Includes bibliographical references (leaves 123-135).
Abstract also in Chinese.
DECLARATION OF ORIGINALITY --- p.i
ACKNOWLEDGEMENTS --- p.ii
PUBLICATIONS RELATED TO THIS THESIS --- p.iv
Full publications --- p.iv
Conference presentations --- p.v
TABLE OF CONTENTS --- p.vi
LIST OF TABLES --- p.xi
LIST OF FIGURES --- p.xiii
LIST OF ABBREVIATIONS --- p.xv
ABSTRACT --- p.xviii
論文摘要 --- p.xx
Chapter PART I --- LITERATURE REVIEW --- p.1
Chapter Chapter 1 --- Introduction to Acoustic Cardiography --- p.2
Chapter 1.1 --- History of auscultation, phonocardiography --- p.2
Chapter 1.2 --- STIs --- p.3
Chapter 1.2.1 --- Conventional STIs --- p.3
Chapter 1.1.2 --- Echocardiographic STI --- p.5
Chapter 1.3 --- Acoustic cardiography --- p.7
Chapter 1.3.1 --- ECG parameters of acoustic cardiography --- p.11
Chapter 1.3.2 --- Systolic parameters of acoustic cardiography --- p.12
Chapter 1.3.3 --- Diastolic Parameters of acoustic cardiography --- p.13
Chapter 1.4 --- Comparison between acoustic cardiography and traditional phonocardiography --- p.19
Chapter Chapter 2 --- Clinical Application of Acoustic Cardiography --- p.27
Chapter 2.1 --- Mechanism of generation of S3 and S4 --- p.27
Chapter 2.2 --- Prevalence of S3 and S4 --- p.28
Chapter 2.3 --- Clinical auscultation of S3 and S4 problems --- p.29
Chapter 2.4 --- Rapid identification of heart failure or LV dysfunction --- p.32
Chapter 2.4.1 --- S3 and S4 --- p.32
Chapter 2.4.2 --- EMAT --- p.33
Chapter 2.4.3 --- SDI --- p.34
Chapter 2.4.5 --- Other derived acoustic cardiographic parameters --- p.34
Chapter 2.5 --- Predicting elevated LV filling pressure --- p.35
Chapter 2.6 --- Improving diagnostic utility of BNP in detection of heart failure or LV dysfunction --- p.36
Chapter 2.7 --- Hemodynamic correlations of acoustic cardiographic parameters --- p.37
Chapter 2.8 --- Prognostic value of acoustic cardiography --- p.38
Chapter 2.9 --- Cardiac resynchronization therapy --- p.39
Chapter 2.10 --- Detection of ischemia --- p.40
Conclusions --- p.42
Chapter PART II --- STUDIES ON APPLICATION OF ACOUSTIC CARDIOGRAPHY --- p.48
Chapter Chapter 3 --- Acoustic Cardiography Helps to Identify Heart Failure and Its Phenotypes --- p.49
Introduction --- p.49
Methods --- p.50
Participants and study design --- p.50
Echocardiography --- p.51
Acoustic cardiography --- p.52
Assessment of reproducibility --- p.55
Statistical analysis --- p.55
Results --- p.56
Characteristics of study subjects --- p.56
Acoustic cardiographic and echocardiographic characteristics --- p.59
Diagnostic characteristics of acoustic cardiography --- p.64
Analysis of covariance results --- p.68
Inter-operator reproducibility --- p.68
Discussion --- p.68
Chapter Chapter 4 --- Rapid Bedside Identification of High-Risk Population in Heart Failure with Reduced Ejection Fraction by Acoustic Cardiography --- p.72
Introduction --- p.72
Methods --- p.73
Study population --- p.73
Echocardiography --- p.73
Acoustic cardiography --- p.74
Assessment of reproducibility --- p.74
Statistical analysis --- p.74
Results --- p.75
Baseline characteristics of study subjects --- p.75
Acoustic cardiographic and echocardiographic characteristics --- p.78
Diagnostic test characteristics of acoustic cardiography --- p.84
Analysis of covariance results --- p.89
Inter-operator reproducibility --- p.89
Discussion --- p.89
Chapter Chapter 5 --- Prognostic value of Acoustic Cardiography in Risk Stratification of Patients With Heart Failure --- p.93
Introduction --- p.93
Methods --- p.94
Study population --- p.94
Acoustic cardiography --- p.94
Echocardiography --- p.94
Endpoint --- p.95
Assessment of reproducibility --- p.95
Statistical analysis --- p.95
Results --- p.96
Study population --- p.96
All-cause mortality --- p.100
Cardiac death --- p.100
Subgroup analysis in 232 patients undergoing echocardiography --- p.107
Inter-operator reproducibility --- p.107
Discussion --- p.114
Strengths and potential limitations --- p.115
Chapter PART III --- CONCLUSIONS --- p.117
Chapter Chapter 6 --- Summary of the Present Studies --- p.118
Chapter I. --- Identification of heart failure and its phenotypes --- p.118
Chapter II. --- Assessment of HFREF patients at high risk by evaluating the severity of LV systolic and diastolic dysfunction --- p.119
Chapter III. --- Risk stratification in patients with heart failure --- p.119
Chapter Chapter 7 --- Future Research Directions --- p.121
References --- p.123

Heart disease is the leading cause of death globally. Early diagnosis is the key to successful treatment. By providing noninvasive, non-ionizing, and real-time imaging, echocardiography plays a critical role in identifying heart disease. Compared to other imaging modalities, ultrasound has unparalleled temporal resolution. High frame-rate imaging has enabled the development of new metrics to characterize myocardial mechanics. Strain imaging measures the heart's deformation throughout the cardiac cycle, providing a quantitative assessment of cardiac health. The intention of this dissertation is to bring Myocardial Elastography (ME) closer to clinical realization. ME is a high frame-rate strain imaging technique for transthoracic and intracardiac echocardiography. This work consists of four Aims. There is a fundamental trade-off between spatial and temporal resolution in strain imaging. In Aim 1, the optimal transmit sequence that generates the most accurate and precise strain estimate was determined. Two common approaches to coherent compounding (full and partial aperture) were compared in simulation and in transthoracic imaging of healthy human subjects (n=5). The optimized subaperture compounding sequence (25-element subperture, 90° angular aperture, 10 virtual sources, 300 Hz frame rate) was compared to the optimized steered compounding sequence (60° angular aperture, 15° tilt, 10 virtual sources, 300 Hz frame rate) and was found to measure strain in healthy human subjects with equivalent precision. The optimal compounding configuration was then evaluated against two other high-frame rate transmit strategies, ECG-gated focused imaging, and wide-beam imaging, in simulation and in healthy subjects (n=7). Achieving the highest level of strain precision, ECG-gated focused imaging was determined to be the preferred imaging approach in patients capable of sustaining a breath hold, with compounding preferred in those unable to do so. Rapid diagnosis is essential to successful treatment of myocardial infarction. In Aim 2, ME's ability to track infarct formation and recovery, and localize infarct using regional strain measurments, was investigated in a large animal survival model (n=11). Infarcts were generated via ligation of the left anterior descending, imaging regularly for up to 28 days. A radial strain-based metric, percentage of healthy myocardium by strain (PHM_ε), was developed as a marker for healthy myocardial tissue. PHM_ε was strongly linearly correlated with actual infarct size as determined by gross pathology (R2 = 0.80). ME was capable of diagnosing individual myocardial segments as non-infarcted or infarcted with high sensitivity (82%), specificity (92%), and precision (85%) (ROC AUC = 0.90), and tracked infarct recovery from collateral reperfusion through time. Noninvasive strain imaging at rest can improve pre-test probability accuracy, and reduce unnecessary stress testing. In Aim 3, ME's potential to provide early diagnosis of coronary artery disease was investigated in an ongoing study. Patients undergoing myocardial perfusion imaging were recruited (n=126). Perfusion scores were used as the reference standard. Morphological transformations were integrated into the processing pipeline to reduce variability in the strain measurements. PHM_ε was reintroduced and used to differentiate between patients with and without coronary artery disease. ME was capable of distinguishing between normal patients and those with significant ischemia or infarct (subjects with perfusion defects at rest) with statistical significance (p < 0.05), although a greater sample size is needed to confirm the results. One of the most common treatments for arrhythmia, catheter ablation, can fail if the lesion line intended to terminate the abnormal rhythm is non-contiguous. In Aim 4, the gap resolution and clinical feasibility of Intracardiac Myocardial Elastography (IME) strain imaging, an ablation monitoring technique, was investigated. Lesion size estimation and gap resolution was evaluated in an open chest canine model (n=3), wherein lesion lines consisting of three lesions and two gaps were generated in each canine left ventricle via epicardial ablation. All gaps were resolvable. Average lesion and gap areas were measured with high agreement (33 ± 14 mm2 and 30 ± 15 mm2, respectively) when compared against gross pathology (34 ± 19 mm2 and 26 ± 11 mm2, respectively). Gaps as small as 11 mm2 (3.6 mm on epicardial surface) were identifiable. Patients undergoing ablation to treat typical cavotricuspid isthmus atrial flutter (n=5) were imaged throughout the procedure. In all patients, strain decreased in the cavotricuspid isthmus after ablation (mean paired difference of -17 ± 11 %, p < 0.05). Together, these Aims intend to translate a promising imaging method from research to clinical reality.

by Leung Sze-wing.
Thesis (M.Phil.)--Chinese University of Hong Kong, 1999.
Includes bibliographical references (leaves 79-84).
Abstracts in English and Chinese.
ACKNOWLEDGEMENT --- p.II
ABSTRACT --- p.III
摘要 --- p.V
CONTENTS --- p.VI
Chapter CHAPTER 1 --- INTRODUCTION --- p.1
Chapter 1.1 --- Objectives --- p.1
Chapter 1.2 --- Prevalence of Heart Diseases --- p.1
Chapter 1.3 --- Importance of ECG Monitoring --- p.2
Chapter 1.4 --- Wireless Electrode --- p.2
Chapter 1.5 --- Analogue-to-Digital Converters --- p.3
Chapter 1.6 --- Organization of Thesis --- p.4
Chapter CHAPTER 2 --- LITERATURE REVIEW --- p.5
Chapter 2.1 --- Telemetry --- p.5
Chapter 2.1.1 --- "Definitions of ""Telemetry “" --- p.5
Chapter 2.1.2 --- Advantages of Telemetry --- p.6
Chapter 2.1.3 --- History of Telemetry --- p.7
Chapter 2.1.4 --- Special Considerations on Telemetry System --- p.10
Chapter 2.2 --- Sigma-Delta Converter --- p.12
Chapter 2.2.1 --- Conventional Digitizing Circuitry --- p.12
Chapter 2.2.2 --- "Single, Dual-Slope A/D Converters" --- p.13
Single-Slope A/D Converter --- p.13
Dual-Slope Converter --- p.75
Chapter 2.2.3 --- Successive Approximation (SAR) --- p.17
Chapter 2.2.4 --- Flash Converters --- p.18
Chapter 2.2.5 --- Sigma-Delta Converter --- p.18
Chapter 2.3 --- Conclusion --- p.20
Chapter CHAPTER 3 --- WIRELESS ELECTRODE --- p.21
Chapter 3.1 --- """Single Electrode"" Measurement" --- p.21
Chapter 3.2 --- VSE (Virtual Single Electrode) --- p.21
Concentric Electrode --- p.21
Chapter 3.3 --- WE (Wireless Electrode) --- p.24
Chapter 3.4 --- Discussion --- p.29
Chapter CHAPTER 4 --- SIGMA-DELTA CONVERTER FOR ECG SIGNALS --- p.30
Chapter 4.1 --- Motivations --- p.30
Chapter 4.2 --- Baseband Application --- p.31
Chapter 4.2.1 --- Simulation Results --- p.31
Chapter 4.2.2 --- Experimental Results --- p.48
Chapter 4.3 --- Wireless Application --- p.58
Chapter 4.3.1 --- General Description --- p.58
Chapter 4.3.2 --- Simulation Results --- p.59
Chapter 4.3.3 --- Scenario 1 (Analogue Decoding) --- p.70
Chapter 4.3.4 --- Scenario II (Digital Decoding) --- p.73
Chapter 4.4 --- Discussion and Conclusion --- p.76
Chapter CHAPTER 5 --- CONCLUSION AND FUTURE WORK --- p.77
Chapter 5.1 --- General Conclus ion --- p.77
Chapter 5.2 --- Future Work --- p.78
BIBLIOGRAPHY --- p.79
LIST OF ABBREVIATIONS --- p.85

1. An explicit mathematical description of PEP in terms of DBP was proposed, which in the first time quantitatively clarified the ventricular and arterial effects on PEP timing.
2. A nonlinear pressure-volume relationship which reflected the natural arterial wall properties was introduced into the asymmetric T-tube arterial model, which effectively and quantitatively described the effect of pulsatile BP on arterial parameters, e.g., compliance, PTT etc.
3. A mathematical relationship between PAT and BP was firstly proposed as a result of the heart-arterial interaction, which simulated a significantly strong and negative relationship between PAT and SBP and between PAT and MBP but a much weaker negative relationship between PAT and DBP during exercise. The hypothesis was supported by the experiment data. To our knowledge, it is the first study describing the quantitative relation of PAT and BP by both model-based study and experimental data.
4. A novel wearable measurable CO parameter, PTRR, was proposed and it successfully showed a significantly high and positive correlation with CO during exercise both in model simulation and in the experiments.
5. Linear prediction models using PAT to estimate MBP and using PTRR to estimate CO were proposed and evaluated in two exercise experiments conducted on 84 subjects with different ages and cardiovascular diseases. Results showed the proposed method could achieve the accuracy required for medical diagnosis.
6. Taken the findings in 3, 4 and 5 together, this study in the first time provided both the theoretical basis and experimental verifications of developing a wearable and direct measurement technique of CPO in dynamic exercise using multiple physiological signals measured on body surface.
Cardiac power output (CPO) is defmed as the product of mean arterial blood pressure (MBP) and cardiac output (CO), and CPO measured during peak dynamic exercise (i.e. peak CPO) has been shown as a powerful predictor of death for heart failure patients. However, so far there has been no existing device which directly measures CPO, and CPO is acquired from simultaneous measurement of MBP and CO. Further, simultaneous MBP and CO measurement during dynamic exercise is a challenge for current BP and CO methods. Therefore, there is an urgent need to develop new devices which are fully wearable and unobtrusive for monitoring of CPO during dynamic exercise. Since the core problem in most wearable devices is how to estimate the target cardiovascular parameter, e.g. CPO in this study, through physiological signals measured from body surface, this thesis focus on developing a direct measurement technique of CPO in dynamic exercise using multiple physiological signals measured on body surface, specifically, electrocardiogram (ECG) and photoplehtysmogram (PPG).
Finally, based on the theoretical and experimental verifications, linear prediction models were proposed to estimate MBP from PAT and estimate CO from PTRR. The results showed that PAT can estimate MBP with a standard deviation of 7.42 mmHg, indicating PAT model has the potential to achieve the accuracy required by AMMI standard (mean error within +/- 5 mmHg and SD less than 8 mmHg). The results also showed that PTRR can estimate CO with a percent error of 22.57%, showing an accuracy which was considered as clinically acceptable (percent error less than 30%).
Heart failure is the end stage of many cardiovascular diseases, such as hypertension, coronary heart disease, diabetes mellitus, etc. Around 5.8 million people in the United States have heart failure and about 670,000 people are diagnosed with it each year. In 2010, heart failure will cost the United States $30.2 billion, and the cost of healthcare services is a major component of this total. With the resultant burden on health care resources it is imperative that heart failure patients with different risk stages are identified, ideally with objective indicators of cardiac dysfunction, in order that appropriate and effective treatment can be instituted.
In order to verify the theoretical findings, two experiments were carried out. One was incremental supine bicycle exercise conducted on 19 young healthy subjects and the other was incremental to maximum supine bicycle exercise conducted on 65 subjects, including heart failure patients, cardiovascular patients and healthy elderly. PAT showed significantly high and negative correlation with SBP and MBP, but lower correlation with DBP. PTRR showed significantly high and positive correlation with CO.
In this thesis, a model based study is conducted to address the above problem. Firstly, we deduced the mathematical expression of PEP as a function of DBP by introducing the arbitrary heart rate into the exponential mathematical description of a pressure-source model. Secondly, an asymmetric T-tube model was modified by introducing a nonlinear pressure-volume relationship where PTT was expressed as a dependent variant of BP. Thirdly, we proposed the mathematical equation between PAT and BP by coupling the modified ventricular and arterial models. Then, the relationships between PAT with systolic blood pressure (SBP), MBP and DBP were simulated under changing heart contractility, preload, heart rate, peripheral resistance, arterial stiffness and a mimic exercise condition. The simulation results indicated significantly high and negative correlations between PAT and SBP and between PAT and MBP whereas the correlation between DBP and PAT was low.
Next, we developed a novel CO index, namely pulse time reflection ratio (PTRR), expressed in terms of MBP and mean aortic reflection coefficient (Gamma(0)), from the modified asymmetric T-tube model. PTRR was further expressed in terms of PAT and inflection point area (IPA), a surrogate of Gamma(0) from the shape feature of PPG. The simulation results suggested significantly and positive relationship between PTRR and CO and between IPA and Gamma(0) during dynamic exercise.
Recently, a wearable measurable parameter, pulse arrival time or PAT, has been developed for BP measurement. PAT is the time delay from the R peak of ECG to the systolic foot of PPG. PAT consists of two timing components, the pre-ejection period (PEP) of the heart and pulse transit time (PTT). PTT is related to BP by an arterial elastic model and thus can be used to estimate beat-to-beat BP. However, PTT is difficult to be measured through a wearable device, and thus PAT is usually used as a surrogate of PTT for BP estimation, under the assumption of a constant PEP. However, PEP is not a constant but changing with physiological conditions, which may alter the PAT-BP relationship. Thus, it is important to clarify the PAT-BP relationship and address the feasibility of MBP estimation using PAT during dynamic exercise.
To summarize, the original contributions of this thesis are:
Wang, Ling.
Adviser: Y.T. Zhang.
Source: Dissertation Abstracts International, Volume: 73-03, Section: B, page: .
Thesis (Ph.D.)--Chinese University of Hong Kong, 2010.
Includes bibliographical references.
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.

Cardiac diseases and conduction disorders are associated with stroke, heart failure and sudden cardiac death and are a major health concern worldwide. In the US alone, more than 14 million people suffer from heart rhythm disorders. Current mapping and characterization techniques in the clinic involve invasive procedures, which are time-consuming, costly, and may involve ionizing radiation. In this dissertation, we introduce Electromechanical Wave Imaging (EWI) as a non-invasive, ultrasound-based treatment planning tool for pre-procedure characterization and assessment of arrhythmia in the clinic. In particular, standard EWI processing methods for mapping the electromechanical wave (EW), i.e. the onset of the mechanical activity following the depolarization of the heart, are described and detailed. Next, validation of EWI is performed with 3D electromechanical mapping and the EW propagation is shown to follow the electrical activation in all four chambers of the heart. Demonstration of the value of EWI for the characterization of cardiac arrhythmia is accomplished in vivo in a large animal model. First, EWI is shown capable of localizing the earliest region of activation in the ventricles during pacing from a standard pacemaker lead, as well as during pacing from a novel biological pacemaker. Repeatability is also demonstrated between consecutive cardiac cycle during normal sinus rhythm and during pacing. Then, in the atria, we demonstrate that EWI is capable of accurately identifying focal sources while pacing from several locations in both the left and right atria. In addition to being capable of localizing the focal source, EWI is also shown capable of differentiating between endocardial and epicardial focal sources. Finally, it is shown that EWI can correctly identify regions of infarction and monitor formation of infarcts over several days, after ligation of the left anterior descending coronary artery of canine hearts. Novel processing techniques aimed at extracting quantitative parameters from EWI estimates are then developed and implemented. Details of the implementation of processing methods for estimating the velocity of the EW propagation are presented, and a study of the EW velocity values in a canine heart before and after infarct formation is conducted. Electromechanical cycle length mapping (ECLM), which is aimed at extracting local rates of electromechanical activation in the heart, is then introduced and its implementation detailed. ECLM is subsequently validated in a paced canine heart in vivo. Finally, initial clinical feasibility is demonstrated. First, in the study of treatment of chaotic arrhythmia such as in the case of atrial fibrillation patients undergoing direct current cardioversion, ECLM is shown to be able to confirm acute treatment success. Then, the clinical value of EWI in the electrophysiology lab as a treatment planning tool for the characterization of focal arrhythmia is shown in ventricular tachycardia and Wolff-Parkinson-White patients. EWI is currently only a step away from real-world clinical application. As a non-invasive, ultrasound-based imaging modality, EWI is capable of providing relevant insights into the origins of an arrhythmia and has the potential to position itself in the clinic as a uniquely valuable pre-procedure planning tool for the non-invasive characterization of focal arrhythmias.

Wang Mei.
"July 2002."
Thesis (Ph.D.)--Chinese University of Hong Kong, 2002.
Includes bibliographical references (p. 208-233).
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.