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Background: Coronary Artery Disease (CAD) represents the leading cause of mortality and morbidity worldwide despite declines in the prevalence of environmental risk factors. This trend has drawn attention to the risk conferred by genetic variation. Twin and linkage studies demonstrate a profound hereditary risk for CAD, especially in young individuals. Rare genetic variants conferring high risk for extreme disease phenotypes can provide invaluable insight into novel mechanisms underlying CAD development. Methods: Whole exome sequencing was performed to characterize rare protein-altering variants in 52 early-onset CAD (EOCAD) patients encompassing the DECODE study. The enrichment of Mendelian dyslipidemias in EOCAD was assessed through interrogation of pathogenic mutations among known lipid genes. The identification of novel genetic CAD associations was conducted through case-only and case-control approaches across all protein-coding genes using rare variant burden and variance component tests. Lastly, beta coefficients for significant risk genes from the European population in the Early-onset Myocardial Infarction (EOMI) cohort (N=552) were used to construct calibrated, single-sample rare variant gene scores (RVGS) in DECODE Europeans (N=39) and a local European CAD-free cohort (N=77). Results: A 20-fold enrichment of Familial hypercholesterolemia mutation carriers was detected in EOCAD cases compared to CAD-free controls (P=0.005). Association analysis using EOMI Europeans revealed exome-wide and nominal significance for two known CAD/MI genes: CELSR2 (P=1.1x10-17) and APOA5 (P=0.001). DECODE association revealed exome-wide and nominal significance for genes involved in endothelial integrity and immune cell activity. RVGS based upon beta coefficients of significant CAD/MI risk genes were significantly increased in DECODE (z-score=1.84; p=0.03) and insignificantly decreased among CAD-free individuals (z-score=-1.61; p=0.053). Conclusion: Rare variants play a pivotal role in the development early CAD through Mendelian and polygenic mechanisms. Construction of RVGS that are calibrated against population and technical biases can facilitate discovery of single-sample and cohort-based associations beyond what is detectable using standard methods. / Thesis / Master of Science (MSc)

The functional capacity of patients with coronary artery disease is often limited by breathlessness. The intensity of breathlessness is primarily determined by respiratory muscle effort, which increases as the pressures generated by the inspiratory muscles approach maximum capacity. Exercise training can potentially decrease breathlessness by inducing adaptations that reduce the ventilatory demand and increase the maximum capacity of the respiratory muscles. This study examines the extent to which the physiological adaptations occurring with exercise training contribute to reductions in breathlessness in patients with coronary artery disease. The pre- and post-training results were compared in 21 patients participating in the McMaster University Cardiac Rehabilitation program. Respiratory parameters were measured at rest and during a progressive maximal exercise test. The intensity of breathlessness was measured by psychophysical techniques using the Borg scale. Following training, the capacity to generate maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and maximum inspiratory flow (Vimax) improved by 22%, 18% and 5%, respectively, with no significant change in vital capacity, forced expiratory volume in one second and maximum expiratory flow. Exercise capacity improved by 14%, with an 11% decrease in the maximum intensity of breathlessness experienced. Although maximum ventilation (Ve) did not change significantly, Ve per unit workload decreased by 10% and breathlessness per unit Ve decreased by 13%. At the highest similar workload between the 2 tests (850 kpm), breathlessness decreased by 34%, with a 19% reduction in Ve. Breathing frequency, mean inspiratory flow (Vt/Ti), inspiratory flow generated during exercise in relation to maximum inspiratory flow (Vi%max), and time of inspiration in relation to total duty cycle (Ti%Ttot) decreased significantly by 20%, 15%, 20% and 4%, respectively. The decreases in breathlessness were significantly related to the reduction in ventilation associated with training. A significant decrease in breathlessness remained after removing the variance accounted for by Ve, reflecting the improvements in respiratory muscle performance. The decreases in breathlessness were better correlated with improvements in the dynamic measure of Vimax than the static measure of MIP. The decreases in breathlessness were best correlated to the changes in Vi%max, which accounts for decreases in ventilatory demand and increases in respiratory muscle performance. Decreases in breathlessness primarily occurred in patients who achieved a training effect. Exercise training decreases breathlessness in patients with coronary artery disease largely through decreases in Ve, with improvements in respiratory muscle performance contributing to a lesser degree. / Thesis / Master of Science (MSc)

Yes / Background: Non-adherence to secondary prevention medicines (SPMs) among patients with coronary artery disease (CAD) remains a challenge in clinical practice. This study attempted to identify actual and potential modifiable barriers to adherence that can be addressed in cardiology clinical practice. Methods: This was a cross-sectional, postal survey-based study of the medicines-taking experience of patients with CAD treated at a secondary/tertiary care centre. All participants had been on SPM for ≥3 months. Results: In total, 696 eligible patients were sent the survey and 503 responded (72.3%). The median age was 70 years, and 403 (80.1%) were male; the median number of individual daily doses of all medicines was 6. The rate of non-adherence to at least one SPM was 43.5% (n=219), but 53.3% of reported non-adherence was to only one SPM. Statins contributed to 66.7% and aspirin to 61.7% of overall non-adherence identified by the Single Question (SQ) tool. In 30.8% of non-adherent patients (n=65), this was at least partly intentional. Barriers included forgetfulness (84.9%; n=186), worry that medicines will do more harm than good (33.8%; n=74), feeling hassled about medicines taking (18.7%; n=41), feeling worse when taking medicines (14.2%; n=31) and not being convinced of the benefit of medicines (9.1%; n=20). In a multivariate analysis, modifiable factors associated with overall non-adherence included being prescribed aspirin (OR: 2.22; 95% CI: 1.18 to 4.17), having specific concern about SPM (OR: 1.12; 95% CI: 1.07 to 1.18) and issues with repeat prescriptions (OR: 2.48; 95% CI: 1.26 to 4.90). Different factors were often associated with intentional versus unintentional non-adherence. Conclusions: Using appropriate self-report tools, patients share actual and potential modifiable barriers to adherence that can be addressed in clinical practice. Non-adherence behaviour was selective. Most non-adherence was driven by forgetfulness, concern about the harm caused by SPM and practical barriers. / The study was partially funded by the Leeds Teaching Hospitals Charitable Foundation.

Yes / Coronary artery bypass graft (CABG) using autologous saphenous vein continues to be a gold standard procedure to restore the supply of oxygen-rich blood to the heart muscles in coronary artery disease (CAD) patients with or without type 2 diabetes mellitus (T2DM). However, CAD patients with T2DM are at higher risk of graft failure. While failure rates have been reduced through improvements in procedure-related factors, much less is known about the molecular and cellular mechanisms by which T2DM initiates vein graft failure. This review gives novel insights into these cellular and molecular mechanisms and identifies potential therapeutic targets for development of new medicines to improve vein graft patency. One important cellular process that has been implicated in the pathogenesis of T2DM is protein O-GlcNAcylation, a dynamic, reversible post-translational modification of serine and threonine residues on target proteins that is controlled by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Protein O-GlcNAcylation impacts a range of cellular processes, including trafficking, metabolism, inflammation and cytoskeletal organisation. Altered O-GlcNAcylation homeostasis have, therefore, been linked to a range of human pathologies with a metabolic component, including T2DM. We propose that protein O-GlcNAcylation alters vascular smooth muscle and endothelial cell function through modification of specific protein targets which contribute to the vascular re-modelling responsible for saphenous vein graft failure in T2DM.

This dissertation investigated the psychometric properties and clinical applications of the Psychosocial Inventory for Cardiovascular Illness (PICI). The PICI is an inventory developed to measure the psychosocial risk factors for heart disease including anxiety, depression, stress, social isolation, and anger. The inventory was developed to measure the ways that each psychosocial risk factor contributes to the coronary artery disease process through the lifestyle behaviors and pathophysiological mechanisms with which they are associated. The primary purpose of the study was to examine predictive validity for the PICI. With support for predictive validity, the inventory may aid in early identification of individuals at increased risk for coronary artery disease (CAD) so that behavioral, psychosocial, and medical interventions can be implemented. Both healthy and cardiac samples were used in the inventory development and validation process. The PICI was administered in conjunction with similar inventories and physiological markers of CAD were collected including percent of coronary artery blockage and history of heart attacks. Item analysis and factor analysis were used to yield a 20-item PICI comprised of three subscales to include Negative Affect, Social Isolation, and Anger. It was hypothesized that the PICI subscales would predict group membership; whether or not a participant carried a diagnosis of CAD, and would be have a strong relationship to the physiological markers of CAD that were measured. Analysis revealed that the PICI was unable to predict diagnostic status and did not have a strong relationship with the physiological markers of CAD. Results suggest that the PICI has acceptable reliability and construct validity as demonstrated in the current sample, yet further investigation must be conducted to gain support for the instrument’s predictive abilities. / text

Introdução:O diabetes mellitus tipo 2 (DM2) está associado ao aumento da mortalidade por doença arterial coronária (DAC). O DM2 afeta o metabolismo de lípides, levando à dislipidemia, caracterizada por hipertrigliceridemia e baixa concentração plasmática de HDL-colesterol. Transferências de lípides entre HDL e outras lipoproteínas são passos cruciais no metabolismo e função da HDL. Objetivo: Investigar se o desenvolvimento de DAC em pacientes com DM2 está associado com alterações na transferência de lípides para HDL. Métodos: Foram estudados 79 pacientes com DM2 portadores de DAC obstrutiva (DM2-DAC) e 76 pacientes com DM2 e artérias coronárias angiograficamente normais (DM2). Foram avaliados o perfil lipídico, apolipoproteínas, composição lipídica da HDL, dosagem de CETP e LCAT. No ensaio de transferência, as amostras de plasma foram incubadas por 1h a 37º com uma nanoemulsão artificial marcada com 3H-éster de colesterol e 14Cfosfolípides ou 3H -triglicérides e 14C-colesterol não esterificado. A quantificação da transferência de lípides da nanoemulsão doadora para a HDL foi feita após a precipitação da fração não HDL. O tamanho da HDL foi medido por laser light scattering. Resultados: Os pacientes DM2-DAC apresentaram maior concentração de colesterol total (DM2-DAC=218±48; DM2=193±36; p < 0,001), LDL-C (147±44 vs 124±33; p < 0,001) e apoB (103,1±20,4 vs 96,0 ± 19,5; p = 0,03) que o grupo sem DAC. Os grupos não mostraram diferença com relação à concentração plasmática de triglicérides (DM2-DAC=171 ± 73; DM2=154 ± 70; p=0,1) e HDL-C (41±9 vs 38±8; p=0,07). A transferência de éster de colesterol (4,0 ± 0,6 vs 4,3 ± 0,7; p=0,005) e de colesterol não esterificado (7,6 ± 1,2 vs 8,2±1,5; p=0,006) foi menor no grupo com DAC, porém esse grupo teve maior concentração de colesterol não esterificado no plasma (36,3 ± 8,0 vs 33,6±6,5 ;p=0,02). A concentração de CETP foi menor no grupo DM2DAC (2,1±1,0 vs 2,5 ±1,1; p=0,02 ). O diâmetro das partículas de HDL não diferiu entre os grupos (8,9 ± 1,2 vs 9,0±0,6; p=0,4), nem a composição lipídica da HDL (éster de colesterol: 52,2 ± 10,8 vs 50,6 ± 10,7; p=0,38; colesterol não esterificado: 9,0 ± 2,8 vs 8,4 ± 2,7; p=0,19; triglicérides: 13,4 ± 3,9 vs 12,4 ± 3,9; p=0,11e fosfolípides:77,2 ± 16,7 vs 78,8 ± 20,5; p=0,60). A atividade da enzima LCAT não diferiu entre os grupos (1,34 ± 0,12 vs 1,33 ± 0,10; p=0,9). As transferências de todos os lípides apresentaram correlação entre si. Na análise multivariada, a presença de DAC influenciou a transferência de éster de colesterol, quando ajustado para HDL-C, apoA1, CETP massa e LDL-C (r2=0,5, p=0,03) e a transferência de colesterol não esterificado, quando ajustado para apoA1, apoB, LCAT, glicemia, idade e sexo (r2 = 0,7, p = 0,003). Conclusão: Na amostra estudada, pacientes diabéticos portadores de DAC apresentam menor transferência de colesterol para HDL comparados com os pacientes diabéticos sem DAC obstrutiva / Aim: Type 2 diabetes mellitus (DM2) is associated with morbidity and mortality secondary to coronary artery disease (CAD). DM2 affects lipid metabolism, and diabetic dyslipidemia is characterized by increased levels of tryglicerides and reduced levels of HDL-cholesterol. Lipid transfer between HDL and the other lipoproteins is a crucial step in HDL function and metabolism. Objective: The purpose of this study was investigate whether the susceptibility of patients with type 2 diabetes mellitus to develop CAD is related with alterations in lipid transfers to HDL. Methods: 79 patients with DM2 and obstructive CAD (DM2- CAD) and 76 with DM2 (DM2 group) and angiographic normal coronary arteries were studied. Lipid profile, apolipoproteins, HDL lipid composition, CETP and LCAT activity were evaluated. In the lipid transfer assay, fasting plasma samples were incubated for 1h at 37°C with a donor artificial nanoemulsion labeled with 3H -cholesteryl-esters and 14C-phospholipids or 3H-triglycerides and 14C-unesterified cholesterol. Radioactive lipids transferred from the donor nanoemulsion to HDL were quantified in the supernatant after chemical precipitation of non-HDL fractions and nanoemulsion. HDL size was measured by laser light scattering. Results: In DM2-CAD, total cholesterol (DM2- DAC=218 ± 48; DM2=193±36; p < 0,001), LDL-C (147 ± 44 vs 124±33; p < 0,001) and apoB (103,1±20,4 vs 96,0±19,5; p=0,03) were higher than in DM2 group. The groups showed no differences with respect to plasma triglycerides levels (DM2-DAC=171± 73; DM2=154 ± 70; p=0,1) nor HDL-C (41 ± 9 vs 38±8; p=0,07). DM2-CAD showed diminished transfer to HDL of esterified cholesterol (4,0±0,6 vs 4,3 ± 0,7; p = 0,005) and unesterified cholesterol (7,6 ± 1,2 vs 8,2 ± 1,5; p=0,006). However, the DM2-CAD group showed higher levels of plasmatic unesterified cholesterol (36,3±8,0 vs 33,6±6,5 ;p=0,02). CETP mass was lower in the DM2- CAD group (2,1 ± 1,0 vs 2,5 ± 1,1; p=0,02 ). HDL particle diameter was not different between groups (8,9±1,2 vs 9,0 ± 0,6; p=0,4) neither its lipid composition (esterified cholesterol: 52,2 ± 10,8 vs 50,6 ± 10,7; p=0,38; unesterified cholesterol: 9,0 ± 2,8 vs 8,4 ± 2,7; p=0,19; triglycerides: 13,4 ± 3,9 vs 12,4 ± 3,9; p=0,11; phospholipids: 77,2 ± 16,7 vs 78,8 ± 20,5; p=0,60). LCAT activity was not different in the two groups (1,34±0,12 vs 1,33±0,10; p=0,9). In multivariate analysis, DAC influenced cholesteryl ester transfer, when adjusted to HDL-C, apoA1, CETP mass and LDL-C (r2=0,5, p=0,03), and unesterified cholesterol transfer, when adjusted to apoA1, apoB, LCAT, glycemia, age and sex (r2=0,7, p=0,003). Conclusion: In these sample, DM2-CAD patients show diminished cholesterol transfer to HDL particles when compared to diabetic patients without obstructive CAD

Introdução: apesar das recomendações de todas as diretrizes sobre a doença arterial coronária e das evidências científicas de que o tratamento medicamentoso otimizado acrescido de intervenção sobre os fatores de risco e a melhoria do estilo de vida reduzem eventos cardiovasculares fatais não-fatais, essa terapêutica de prevenção secundária continua a ser subutilizada na prática clínica. Objetivos: Primário: demonstrar que a utilização de um programa de otimização da prática clínica em pacientes com doença arterial coronária estável aumenta a prescrição de medicamentos comprovadamente eficazes na prevenção secundária desta doença. Secundários: a) documentar a prática clínica vigente em termos de terapia medicamentosa e de medidas para a mudança do estilo de vida b) identificar as ferramentas utilizadas na estratégia para a otimização da prática clínica quanto à eficácia e aderência à medicação prescrita. Métodos: trata-se de um estudo de corte transversal para documentar a prática clínica vigente, seguido de componente longitudinal em que a utilização das ferramentas para a otimização da prática clínica foi avaliada por meio de novo corte transversal, com nova coleta de dados. Foram identificados retrospectivamente através dos prontuários, 710 pacientes consecutivos portadores de doença arterial coronária (Fase 1). Após a aplicação das ferramentas, foram incluídos 705 pacientes consecutivos atendidos no serviço com a coleta dos mesmos dados, para a análise comparativa. Além disso, foram selecionados do primeiro grupo, de forma aleatória, 318 prontuários de seis a doze meses após a primeira avaliação, para a coleta dos mesmos dados, que foram comparados com as informações iniciais destes mesmos pacientes. (Fase 3). Resultados: comparação entre Fase 1 e Fase 2: as características demográficas eram comparáveis entre os dois grupos. Quanto aos fatores de risco, houve melhora com diferença significativa para o tabagismo (p=0,019), dislipidemia (p<0,001) hipertensão arterial e atividade física regular (p<0,001). Quanto aos exames laboratoriais, não houve diferença estatisticamente significativa entre as duas populações. Comparando a prescrição dos fármacos recomendados, houve diferença significativa para IECA (67,2% versus 56,8%, p<0,001); ARA II (25,4% versus 32,9%, p=0,002) e betabloqueador (88,7% versus 91,9%, p=0,047). Comparação entre Fase 1 e Fase 3: os dados demográficos foram semelhantes, assim como as características clínicas, com exceção da doença arterial periférica obstrutiva: 31 pacientes (9,7%) e 42 (13,3%), p=0,007. Em relação aos fatores de risco, consideramos apenas os modificáveis tabagismo e atividade física. Para o tabagismo, considerando três categorias (nunca, ex-fumante e atual), não houve diferença significativa entre as duas fases. Para a atividade física, a proporção de pacientes sem informação para esta variável era elevada, 83,9% na primeira fase e 72,8% na terceira fase, dificultando a análise estatística. Quanto às medidas de exame físico, houve redução significativa do peso, p=0,044, pressão arterial sistólica e diastólica, p<0,001. Os exames laboratoriais não mostraram diferenças significativas entre as duas fases. Em relação à prescrição de medicamentos recomendados, houve diferença para IECA (64,8% versus 61,6%, p=0,011) e ARA II (27,0% versus 31,3%, p=0,035). Conclusão: com base nos resultados obtidos, o presente estudo permite concluir: não houve mudança significativa na utilização de medicamentos comprovadamente eficazes na prevenção secundária da DAC entre o período pré- e pós-intervenção; houve melhora significativa em relação ao tabagismo e atividade física na Fase 2; melhora substancial nos níveis de pressão arterial, tanto sistólica como diastólica na comparação tanto entre a Fase 1 e 2 como entre a Fase 1 e 3; a inclusão de enfermeiro treinado para gerenciar o processo é fundamental para a eficácia do programa; programas abrangentes de melhoria de qualidade assistencial em hospitais terciários e acadêmicos, provavelmente devem ser continuados por período de seguimento superior a um ano. / Background: despite guidelines recommendations on coronary artery disease treatment and scientific evidence confirming that optimal medical therapy added to risk factors and lifestyle management, reduce both fatal and non-fatal cardiovascular events, these secondary prevention strategies have been underutilized in clinical practice. Objectives: Primary: to demonstrate the utilization of a clinical improvement program in stable coronary artery disease patients would increase the evidence-proved treatment prescription in secondary prevention. Secondaries: a) to describe the ongoing clinical practice on medical therapy and lifestyle change counseling b) to identify tools to be utilized in the strategy to improve clinical practice, assessing efficacy and adherence to prescribed treatment. Methods: cross-sectional study to describe the ongoing clinical practice, followed by a longitudinal component in which the tools utilization to improve clinical practice was assessed by means of additional crosssectional data collection. 710 consecutive coronary artery disease patients were included after chart review following eligibility criteria (Phase 1). After tools implementation, within 6-month period, 705 patients were included (Phase 2) for comparative analysis. Randomly, 318 patients from Phase 1 were selected, 6-12 months after the first evaluation (Phase 3). Results: Phase 1 to Phase 2 comparison: demography was comparable. Concerning to risk factors, there were improvement on smoking (p=0,019), dyslipidemia (p<0,001), hypertension and physical activity (p<0,001). There were no statistical significant differences on laboratory results. By comparing the proven pharmacological treatment prescription, there was significant difference on ACEI (67,2% versus 56,8%, p<0,001); ARB II (25,4% versus 32,9%, p=0,002) and beta-blocker (88,7% versus 91,9%, p=0,047). Phase 1 to Phase 3 comparison: demography was comparable, as well as clinical characteristics, except peripheral artery disease: 31 patients (9,7%) and 42 (13,3%), p=0,007. Regarding risk factors, smoking and physical activity were considered. There was no significant difference on smoking rates taking into account three categories (never, ex-smoker and smoker). The proportion of patients without available data for physical activity was high, 83,9% (Phase 1) and 72,8% (Phase 3), making the data analysis not appropriated. Anthropometric measurement showed significant on weight reduction, p=0,044, both systolic and diastolic blood pressure, p<0,001. Laboratory results did not show significant differences. There was statistical significant difference on ACEI (64,8% versus 61,6%, p=0,011) and ARB II (27,0% versus 31,3%, p=0,035). Conclusion: based upon study results the following might be concluded: there was no significant change on the evidence-based pharmacological treatment utilization on secondary prevention coronary artery disease patients between pre and post-intervention Phases; there was significant improvement concerning smoking and physical activity in Phase 2; substantial improvement on blood pressure levels, both systolic and diastolic in both comparisons (Phase 1 to 2 and Phase 1 to 3); the inclusion of a case-manager for the process management is crucial for program efficacy; comprehensive programs for clinical practice improvement in tertiary academic hospitals should be pursued for longer follow-up period.