Background: Symptomatic heart failure is a chronic and disabling condition that affects over 350 000 Canadians and is characterized by inevitable progression. Historically, research on the ways to increase survival has focused on biomedical factors. However, the continued poor prognosis of heart failure has prompted the search for other ways to improve the lives of these patients. Research in other chronic conditions demonstrates that social circumstances, described collectively as individual social interactions (e.g. social support, social participation) and community social factors (e.g. social capital, social norms), can influence health outcomes. Purpose: The purpose of this research was to describe and assess the impact of selected social circumstances potentially related to heart failure outcomes. Methods: Two literature reviews and one empirical study were performed. Conceptual models were proposed to describe the hypothesized pathways between selected social circumstances and heart failure outcomes. The first review was a systematic review of quantitative studies evaluating the relationship between social support and both rehospitalization and death. The review included a critical analysis of the methods employed by previous studies. The second review integrated the qualitative and quantitative literature describing the relationship between individual social interactions (including support, roles and participation) and the quality of life of patients or experience of living with heart failure. A narrative summary was provided and an integration of findings from both qualitative and quantitative study designs was performed. In the empirical study, patients‘ demographic and clinical information was examined simultaneously with selected community factors in a multilevel analysis. Outcomes of interest included rehospitalization or death of heart failure patients. Results: The systematic review shows that previous quantitative research has linked social support to reduced rehospitalization, but there is little evidence to link it with prolonged survival. The critique of the methods describes an inadequate conceptualization and inconsistent measurement of social support. A conceptual model showing how social support can influence rehospitalization is proposed. The integrative review presents qualitative research that identified the following social interactions as important components of the heart failure experience: social support, social participation and role fulfillment. However, no quantitative relationship between social support and quality of life was found. The potential reasons for the discrepant findings between the qualitative and quantitative studies include: the focus on social support as the only component of social interactions assessed in the quantitative literature; and the inconsistent measurement of social support. A conceptual model is presented to describe the multiple components of social interactions and the theoretical basis for their effects. The multilevel analysis demonstrates that individual factors exerted the strongest effect on heart failure outcomes in most models. Community characteristics had little influence on rehospitalization or death. Study design and analysis issues are proposed to explain these findings. Conclusion: The literature reviews and the empirical study provide a contribution to the population health literature, offering a broad approach to assessing the determinants of disease progression in heart failure patients. This thesis research advances the discussion about which social circumstances may influence heart failure outcomes and their pathways. The use of the proposed conceptual models in future research will help clarify the role of social circumstances in the prognosis of heart failure.

Cardiotoxicity associated with many cancer drugs is a critical issue facing physicians these days and a huge hurdle that must be overcome for a side effects-free cancer therapy. Survival of cardiac myocytes is compromised upon the exposure to certain chemotherapeutic drugs. Unfortunately, the mechanisms implicated in cardiac toxicity and the pathways governing myocyte survival are poorly understood. The following thesis addresses the mechanisms underlying the cardiotoxicity of two anticancer drugs, doxorubicin (DOX) and Imatinib mesylate (Gleevec). Transcription factor GATA-4, has recently emerged as an indispensable factor in the adult heart adaptive response and cardiomyocyte survival. Therefore, the specific aim of this project was to determine the role of GATA-4, its upstream regulators, as well as partners in survival. A combination of cell and molecular techniques done on in vivo, and ex vivo models were utilized to tackle these issues. In this study, we confirmed the cardiotoxicity of the anticancer drug, Imatinib mesylate and found to be age dependent. GATA-4, already known to be implicated in DOX-induced toxicity, was confirmed as an Imatinib target. At the molecular level, we identified IGF-1 and AKT as upstream regulators of GATA-4. Moreover, we confirmed ZFP260 (PEX-1), a key regulator of the cardiac hypertrophic response, as a GATA-4 collaborator in common prosurvival pathways. Collectively, these results provide new insights on the mechanisms underlying drug-induced cardiotoxicity and raise the exciting possibility that cancer drugs are negatively affecting the same prosurvival pathway(s), in which GATA-4 is a critical component. Therapeutic interventions aimed at enhancing GATA-4 activity may be interesting to consider in the context of treatments with anticancer drugs.

The incidence of heart failure (HF) continues to grow despite advances to current therapies which are effective insofar as slowing disease progression. Cardiac stem cell (CSC) therapy is an emerging treatment for the reversal of HF. We sought to examine the effect of genetically engineering CSCs to over-express stromal cell-derived factor 1α (SDF1α) on myocardial repair. SDF1α over-expressing CSCs exhibited a broader paracrine signature resulting in increased stimulation of capillary network formation and chemotaxis under in vitro conditions. Using a murine model of myocardial ischemia, we demonstrated over-expression of SDF1α increased myocardial SDF1α content, reduced scar burden and increased activation of PI3K/AKT signaling as compared to non-transduced CSC and vehicle controls. These effects improved cardiac function without increasing cell engraftment suggesting that the mechanisms driving these benefits are largely paracrine mediated. Taken together this data suggests that transplantation of CSCs genetically programmed to over-express SDF1α provides superior cardiac repair by boosting the content of cardio-protective cytokines during the critical healing phase after myocardial infarction.

Purpose: To develop a lightweight, safe, and controllable electrical heating vest for heart failure and/or hypertension patients. Methods: a. A literature review related to the topic was conducted. b. A model of a simplified human body thermoregulation system was developed and simulated. It was used to predict the power requirement of the battery to increase core body temperature up to 1 Celsius degree (°C). c. A prototype with a smart controller was developed d. In-vitro tests of the prototype were conducted to assess performance and safety. e. The prototype was tested on 10 healthy human volunteers and the results were analyzed. Results: a. An average core body temperature increase of 0.3 °C (P<0.05) was observed in healthy human volunteer tests within 30 minutes. b. The vest induced decreases in systolic blood pressure of 5.5 mmHg and diastolic blood pressure of 4.8 mmHg on average. Conclusions: A carbon-fiber vest can increase body core temperature by 0.3°C lowering systolic and diastolic blood pressure, which can be potentially used for helping heart failure and/or hypertension patients.

Blood-derived circulatory angiogenic cells (CACs) and resident cardiac stem cells (CSCs) have both been shown to improve cardiac function after myocardial infarction (MI) but the superiority of either cell type has long been an area of speculation with no definitive head-to-head trial. In this study, we compared the paracrine profile of human CACs and CSCs, alone or in combination. We characterized the therapeutic ability of these cells to salvage myocardial function in an immunodeficient mouse model of MI by transplanting these cells as both single and dual cell therapies seven days after experimental anterior wall MI. CACs and CSCs demonstrated unique paracrine repertoires with equivalent effects on angiogenesis, stem cell migration and myocardial repair. Combination therapy with both cell types synergistically improves post infarct myocardial function greater than either therapy alone. This synergy is likely mediated by the complementary paracrine signatures that promote revascularization and the growth of new myocardium.

Cardiac hypertrophy and heart failure (HF) remains one of the major health problems in the UK and worldwide. However, advances in their management are limited because the underlying pathological mechanisms are not completely understood. Therefore, it is important to understand novel signalling pathways leading to HF. Myocardial hypertrophy is a crucial pathophysiological process that can lead to the development of HF. Signalling initiated by members of G-protein-coupled receptors (GPCRs) proteins plays an important role in mediating cardiac hypertrophy. One member of this family, the G-protein coupled receptor 99 (GPR99), may have a crucial role in the heart because it acts as a receptor for alpha-ketoglutarate, a metabolite that is elevated in heart failure patients. GPR99 is expressed in the heart, but its precise function during cardiac pathophysiological processes is unknown. The aim of this PhD study is to investigate the role of GPR99 during cardiac hypertrophy. In this study I used in vivo and in vitro approaches to investigate whether GPR99 is directly involved in mediating cardiac hypertrophy. Mice with genetic deletion of GPR99 (GPR99-/-) exhibited a significant increase in hypertrophy following two weeks of transverse aortic constriction (TAC) as indicated by heart weight/tibia length ratio (HW/TL). In addition, GPR99-/- mice displayed increased cardiomyocytes cross-sectional area (CSA) after TAC compared to wild-type (WT) littermates. Hypertrophic markers such as brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) were also elevated in GPR99-/- mice following TAC compared to WT mice. Although interstitial fibrosis was indistinguishable in both genotypes after TAC, a precursor of fibrosis, collagen, type III, alpha1 (COL3A1) was elevated in GPR99-/- mice compared to WT mice after TAC. The baseline cardiac function as indicated by ejection fraction (EF) and fractional shortening (FS) were reduced in GPR99-/- mice compared to WT littermates following TAC. Furthermore, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septum wall thickness (IVS) and posterior wall thickness at diastole (PW) indicated profound wall thickening and enlargement of the left ventricular (LV) chamber in GPR99-/- mice compared to WT littermates after TAC. In an attempt to examine the mechanism through which GPR99 signals during hypertrophy, I performed molecular analyses based on the data from yeast two hybrid screening showing that GPR99 interacted with COP9 signalosome element 5 (CSN5). Using immunoprecipitation assay, I found that GPR99 formed a ternary complex with CSN5 and non-receptor tyrosine kinase 2 (TYK2). TYK2 is known as a regulator of pro-hypertrophic molecules including signal transducer and activation of transcription 1 (STAT1) and STAT3. I found that the activation of these molecules was increased in GPR99-/- mice following TAC and correspondingly, adenovirus-mediated overexpression of GPR99 in neonatal rat cardiomyocytes (NRCM) blunted TYK2 phosphorylation. In conclusion, my study has identified GPR99 as a novel regulator of pathological hypertrophy via the regulation of the STAT pathway. Identification of molecules that can specifically activate or inhibit this receptor may be very useful in the development of a new therapeutic approach for cardiac hypertrophy in the future.

A redução do consumo de alimentos é freqüente durante a descompensação da insuficiência cardíaca, quando há um aumento do gasto energético basal. Os triglicérides de cadeia média, utilizados como suplementação energética, aumentam a densidade calórica dos alimentos, contribuindo para o metabolismo energético dos pacientes com insuficiência cardíaca. O objetivo foi avaliar o efeito da suplementação de triglicérides de cadeia média sobre o quoeficiente respiratório, na insuficiência cardíaca congestiva e na baixa ingestão alimentar. Foi realizado um estudo randomizado aberto com 45 pacientes de 18 a 70 anos com insuficiência cardíaca congestiva descompensada, fração de ejeção < 0,45, sem drogas vasoativas, dieta oral, IMC < 25kg/m2 para adultos e < 27 kg/m2 para idosos. Foram alocados aleatoriamente para grupo com suplementação de TCM e grupo controle. Os grupos realizaram duas medidas de VCO2 e VO2, por calorimetria indireta. O QR foi avaliado pela análise de variância com medidas repetidas. Foi considerado significante P < 0,05. 75% dos pacientes foram identificados em eutrofia pelo IMC, porém destes, 67% foram diagnosticados com desnutrição calórica e 65% com desnutrição protéico calórica quando analisados e classificados os indicadores de dobras cutâneas. A proporção de lipídeos aumentou de 9,5% para 57% das recomendações com 236,7 ± 95,0 kcal/d do triglicérides de cadeia média (P <0,001). A ingestão de calorias aumentou de 1966,3 ± 643,3 kcal /d para 2202,7 ± 708,4 kcal /d no grupo intervenção e manteve 1960,7 ± 702,6 kcal /d no grupo controle. Não houve variação significativa quoeficiente respiratório (grupo triglicérides de cadeia média +0,4%; grupo controle: +2,5%, P = 0,458). Quatro pacientes apresentaram efeitos adversos ao suplemento, no entanto, sem necessidade de suspensão. O triglicéride de cadeia média não reduziu o quoeficiente respiratório, no entanto melhorou a proporção de carboidratos e lipídios, contribuindo para a melhora do aproveitamento energético. / Food intake reduction is frequent during decompensation of heart failure, when basal energy expenditure increases. In addition, medium chain triglycerides are used as energy supplementation increases caloric density of food, contributing to energy metabolism of patients with heart failure. The objective was to evaluate the effect of supplementation of medium chain triglycerides on the respiratory coefficient in congestive heart failure and low food intake. We conducted a randomized open label study with 45 patients from 18 to 70 years old with decompensated congestive heart failure, ejection fraction < 0,45, without intravenous inotropic drugs, oral diet and body mass index < 25 kg/m2 for adults and <27 kg/m2 for the elderly Patients were randomly allocated to supplementation with medium chain triglycerides or control group. They were submitted to two measurements of VCO2 and VO2 by indirect calorimetry. Analysis of variance with repeated measures analyzes respiratory coefficient change and two-sided. P< 0,05 was significant. 75% of patients were identified in eutrophic by body mass index, but these, 67% were diagnosed with calorie malnutrition and 65% with protein calorie malnutrition when analyzed and classified by skinfolds measures. Adequate proportion of carbohydrates and lipids increased from 9,5% to 57% of patients with 236,7 ± 95,0 kcal/d of medium chain triglycerides (P<0,001). Caloric intake increased from 1966,3 ± 643,3 kcal/d to 2202,7 ± 708,4 kcal/d in the medium chain triglycerides group and remained 1960,7 ± 702,6 kcal/d in control group. There was not a significant respiratory coefficient variation (medium chain triglycerides group +0,4%; control group: +2,5%; P=0,458). Four patients presented adverse effects with medium chain triglycerides; however, without requirement of withdrawal. Medium chain triglycerides did not reduce respiratory coefficient, however they improved carbohydrates and lipids proportion, contributing to improvement of energy utilization.

INTRODUÇÃO: As doenças cardiovasculares estão entre as principais causas de óbito no Brasil e no mundo. Dentre as doenças cardiovasculares, a insuficiência cardíaca (IC) participa de maneira importante para morbi-mortalidade por ser via final de todas as entidades que acometem o coração. A internação hospitalar constitui momento crucial no tratamento e sobrevida dos pacientes com IC. Neste momento, em que o estado da doença atinge seu período mais crítico, é de grande importância o conhecimento dos pacientes com maior risco, que necessitam de cuidados mais intensos. No entanto, a apuração dos custos hospitalares é tarefa difícil, principalmente nas situações de alta complexidade, onde a utilização de recursos nos diversos setores do hospital, materiais e medicamentos, é muito heterogênea. Assim, a busca de variáveis clínicas capazes de ajudar a identificar os pacientes com maior risco, morbidade hospitalar (e conseqüente maior tempo de internação), e o custo destas internações foram o escopo deste estudo. OBJETIVO: primariamente, identificar variáveis clínicas capazes de predizer prognóstico de sobrevida e custos de internação numa população de pacientes internados por IC. Secundariamente, determinar custo mediano destas internações, correlacionando os as variáveis clínicas, de etiologia da cardiopatia de base, e com o perfil hemodinâmico na admissão hospitalar. Visamos ainda projetar os dados da Instituição no modelo de regressão por árvore de decisão proposto pelo estudo ADHERE. MÉTODOS: Realizamos um estudo retrospectivo na qual foram analisados dados consecutivos referentes a internações de pacientes que chegaram ao Pronto Socorro do InCor e permaneceram no Hospital por mais de 24 horas, sendo internados nos anos de 2006 e 2007. Foram avaliados dados clínicos na chegada ao pronto atendimento e evolutivos durante a internação. Foi realizada avaliação de custo da doença durante internação hospitalar através de modelo misto de análises de custos diretos contabilizados por absorção total e rateio dos setores de apoio. Análises estatísticas incluíram modelos de: regressão de proporcional de Cox para variáveis de morbidade-permanência hospitalar, regressão logística para variáveis de mortalidade hospitalar, e regressão através de árvores de decisão para definição de variáveis prioritárias. RESULTADOS: Foram avaliadas 577 internações de pacientes diferentes, sendo 60% do sexo masculino, e idade mediana de 69 anos (57-77). As principais variáveis clínicas preditoras de tempo de internação para nossa população foram: perfil hemodinâmico C, necessidade de dobutamina, ventilação mecânica, ou antibióticos. As principais variáveis clínicas preditoras de mortalidade foram: fração de ejeção, pressão arterial sistólica, clearence estimado de creatinina, ocorrência de infecção hospitalar, e a necessidade de dobutamina, noradrenalina, ou cateteres centrais. Todas estas variáveis compuseram os modelos de regressão. O custo mediano das internações foi de R$ 4.450 (1.353 - 13.432), sendo o fator independente na análise multivariada, o tempo de internação hospitalar, que teve mediana de 5 dias (2-13). A mortalidade hospitalar geral foi de 132 pacientes (23%). CONCLUSÃO: As variáveis clínicas preditoras de tempo de internação para nossa população foram: perfil hemodinâmico, necessidade de dobutamina, ventilação mecânica, ou antibióticos. As variáveis clínicas preditoras de mortalidade foram a fração de ejeção, a pressão arterial sistólica, o clearence estimado de creatinina, a ocorrência de infecção hospitalar, e a necessidade de dobutamina, noradrenalina, ou cateteres centrais. Estas variáveis foram diferentes daquelas apontadas por outros estudos. A etiologia chagásica se correlacionou à maior incidência de choque cardiogênico, caracterizando assim maiores taxas de mortalidade, tempo de permanência, e custos frente às outras etiologias. A presença de choque cardiogênico na entrada se correlacionou a altas taxas de mortalidade, internações mais prolongadas, e maiores de custos de internação. O modelo descrito pelo estudo ADHERE pôde ser aplicado em nossa população, porém, propusemos outro modelo de árvore de decisão composto pelas variáveis: presença de choque cardiogênico uréia sérica, e pressão arterial sistólica, que apresentou maior acurácia em relação ao desfecho mortalidade hospitalar. O custo das internações variou muito de acordo com a evolução clínica dos pacientes, e conseqüentemente, seu tempo de internação hospitalar. No caso de pacientes atendidos pelo SUS, menos de um terço das internações tiveram custos inferiores ao valor médio das AIHs pagas por internações de pacientes com IC. / BACKGROUND: Heart diseases are the main mortality cause in Brazil and the rest of the world. Among those diseases, heart failure (HF) is utmost importance because it is the final pathway for overall heart diseases. Acute decompensate HF is a crucial situation while treating this disease because of its severity. At this critical time, stratification of risk is imperative in order to determine care. Hospital costs determination, however, is difficult in high complexity situations that use resources in a heterogeneity manner. The look for the clinical variables that could identify patients at higher risk for morbidity (and length of stay), mortality, and costs were the main aims of this study. OBJECTIVES: primarily to identify clinical variable able to predict survive and costs in a population of patients admitted by HF. Secondarily, determine median costs for the admissions, correlating these values to clinical variables, etiologies of HF, and hemodynamic profile at entrance. We aimed also to run our data in the tree regression model previously proposed by the ADHERE registry. METHODS: we reviewed consecutively 577 admissions records of different patients admitted by acute decompensated heart failure that stayed for more than 24 hours at the hospital during 2006 and 2007. Clinical data at the admissions and in-hospital follow-up data were analyzed. Costs analysis was performed through a mix model of microcosting (for direct resources) and average costing (for indirect resources). Statistical analysis included regression models as follows: Cox proportional for length of stay variables, logistic for hospital mortality, and classification and regression tree for defining priority variables. RESULTS: among the 577 patients, 60% were men; median age was 69 years (57- 77). The main predictor variables for length of stay were as follows: C hemodynamic profile, need for dobutamine, mechanic ventilation, or antibiotics. The main predictor variables for mortality were as follows: ejection fraction, systolic blood pressure, estimated creatinine clearance, occurrence of hospital infections, and need for dobutamine, norepinephrine, or central catheters. All these variables composed the regression models. Median admission cost was R$ 4.450 (1.353 13.432). Length of stay was an independent factor for predicting costs, with median of 5 days (2-13). Inhospital mortality rate was 23% (132 patients). CONCLUSION: The main predictor variables for length of stay were as follows: hemodynamic profile, need for dobutamine, mechanic ventilation, or antibiotics. The main predictor variables for mortality were as follows: ejection fraction, systolic blood pressure, estimated creatinine clearance, occurrence of hospital infections, and need for dobutamine, norepinephrine, or central catheters. These variables differ from other studies that evaluated similar outcomes. Chagas heart disease etiology was correlated to higher rates of cardiogenic shock, mortality rates, length of stay, and costs. The model used in the ADHERE registry could be used in our population; however, we proposed another variables integrating the regression and classification tree (systolic blood pressure, blood urea nitrogen, and hemodynamic profile C). This model presented greater accuracy for hospital mortality in our population. The cost of admissions ranged according to clinical evolution of the patients, and as consequence of length of stay. Less than a third of the admissions reimbursed by the government had their costs below the mean estimated value for reimbursement

There are an estimated 5 million family caregivers supporting persons suffering from advanced heart failure (AHF) which constitutes the final stage of cardiovascular disease and is the primary cause of death for 1 in 8 Americans. AHF caregivers are instrumental in monitoring symptoms, promoting adherence, communicating with healthcare providers and making treatment choices for their care recipients (CRs) at the end of life. What little is known about the AHF caregiver experience comes from surveys, instruments and structured interviews and tends to exclude caregivers of CRs with advanced disease. The purpose of this interpretive phenomenology was to elicit the meaning of caring for a spouse with AHF and is the first of its kind in the US. Seven older spouses caring for persons with NYHA class III-IV HF recruited by the Advance Practice RN of a large regional hospital participated in 3 reflective interviews over the course of 2 months. Grounded in the Philosophy of Ethics by Paul Ricoeur and using a method based on his Theory of Interpretation, their reflections revealed the essence of the caregiver experience as "being fearfully vigilant, at the mercy of the disease while worrying about that which remains unspoken". Separate inquiries invited participants to explore the meaning of symptom interpretation which was likened to "a walk in the fog on the rocky shore by a treacherous river"; and communication which illuminated caregivers' ethical intention in caring for themselves and their loved ones. The fourth and final research question explored caregivers' meaning making in the experience, symptom interpretation and communication over time which uncovered several missed opportunities for advance care planning. Findings support and add to recent models in palliative care, shared care and advance care planning in AHF. This study gives healthcare providers insight into the challenges to respect, self esteem and autonomy encountered by aging couples in the context of AHF. Participants identified personal learning needs related to being a caregiver, symptom interpretation, and managing clinical and emotional manifestations of AHF. Naming specific barriers in communication with their CRs as well as with healthcare providers they called for relationship counseling for the CG-CR dyad, and to be respected as part of the team by healthcare providers. Participants gave moving examples of how current models of care failed to meet their needs, with urgent implications for coordinated care by an interdisciplinary team of healthcare providers. This study identified the need for more phenomenological inquiry to understand (1) implications of CR's cognitive fluctuations on decision making for preferences of care, (2) CRs' personality changes attributed to an awareness of death being near, (3) the need to retain a purpose in living both as individuals and as a couple, and (4) how CRs reconcile daily choices in illness management and adherence with preferences for care at the end of life.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第22835号 / 社医博第111号 / 新制||社医||11(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 佐藤 俊哉, 教授 川上 浩司, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM