<p> Meta-analysis is a statistical method to summarize the overall evidence of effects on intervention by systematically combining outcomes from available studies in the literature which are homogeneous in research methodology and research interest. The objective of this project is to evaluate the treatment effects of preoperative aspirin on bleeding and other cardiovascular outcomes from 11 randomized control trials (RCT) and 19 observational (non-RCT) studies. Both Bayesian meta-analysis and classical (frequentist) meta-analysis were applied to continuous and binary outcomes, and the results were compared.</p> <p> The robustness of the Bayesian approach is assessed by examining the performances of different likelihood functions and priors. We also discuss strategies on dealing with zero-event studies for binary outcomes, and the implementation of multiple imputation (MI) technique to missing data for continuous outcomes.</p> <p> Most results of primary analysis agree between the Bayesian and classical approaches. We suggest that the final conclusion of a meta-analysis should be based on the comparison of the results from both Bayesian and classical approaches.</p> / Thesis / Master of Science (MSc)

<p> Calcium (Ca2+) is an important signaling molecule and hence its movement across cell membranes must be tightly regulated. The intracellular Ca2+ concentration ([Ca2+]i) in smooth muscle and endothelium controls the coronary tone. After stimulation, decreasing the [Ca2+]i back to resting levels is achieved mainly by the sodium calcium exchanger (NCX), the plasma membrane calcium pump (PMCA) or the sarcoendoplasmic reticulum calcium pump (SERCA). The present study will focus on NCX and its interactions with SERCA in the smooth muscle and endothelium of pig coronary artery.</p> <p> Aim 1 of my thesis is determination of activity levels of NCX in smooth muscle cells (SMC) and endothelial cells (EC). The NCX activity in cultured cells was approximately 5 times greater in EC than in SMC. The NCX inhibitors KB-R7943 and SEA 0400 blocked the NCX mediated Ca2+ entry, as did collapsing the Na+ gradient with monensin. NCX1 is the isoform largely responsible for NCX activity in SMC and EC. NCX activity was also assayed as the Ca2+ efflux in cultured cells and as Ca2+ uptake in plasma membrane vesicles isolated from freshly isolated smooth muscle.</p> <p> Aim 2 is to assess the existence of a functional NCX mediated Ca2+ entry linked to SERCA in SMC. In the absence of thapsigargin, BAPTA loading SMC increased the NCX mediated uptake. Thapsigargin did not affect the Ca2+ uptake in BAPTA loaded cells but it inhibited the Ca2+ uptake in cells that were not loaded with BAPTA. These data are consistent with a model in which SER acts as a sink for the NCX mediated Ca2+ entry. However, with BAPTA chelation and the resulting lower intracellular Ca2+, the need for SER to act as a sink is eliminated, and NCX is driven in full force. EC did not demonstrate a NCX-SERCA linkage.</p> <p> Arterial SMC and EC differ in their structure and function. The function of SMC is the generation of tone which is achieved by the Ca2+ dependent contractile filaments. Since these filaments are distributed throughout the cell, Ca2+ must be transported to and removed from deep within the cell. As a result, the SER may play a large role in Ca2+ regulation in the SMC. Furthermore, SMC also contain higher levels of high affinity Ca2+ pumps (SERCA and PMCA) and thus Ca2+ is more tightly regulated. Endothelial cells release nitric oxide in response to an increase in [Ca2+]i, which relaxes the smooth muscle. The endothelial nitric oxide sythase produces nitric oxide and is located adjacent to the PM in EC. The SER that removes Ca2+ from deep within the cell cytosol may play a small role in Ca2+ dependent modulation of the endothelial nitric oxide synthase activity. Based on the Western blot data, EC contain a greater amount of the high capacity NCX, thus the larger quantities of Ca2+ can be removed from the cell and the vicinity of endothelial nitric oxide synthase.</p> / Thesis / Master of Science (MSc)

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)

Health-related quality of life (HRQL) measures taken before and after coronary artery bypass grafting (CABG) aid in determining meaningful patient-perceived outcomes associated with alternative clinical interventions. This study compared performance of the Medical Outcomes Study Short Form-36 (MOS SF-36) subscales for Physical Functioning (PF), Role Physical (RP), Mental Health (MH), and Role Emotional (RE) against two other questionnaires, i.e. the Veteran's Specific Activity Questionnaire (VSAQ: self-efficacy for vigorous physical activity) and the Beck Depression Inventory (BDI-II: mental-emotional functioning). Seventy-one patients (59-M; 12-F; age, Mean + SD = 63 ± 8.6 years) were administered these three questionnaires just before and 3 months following CABG surgery. Score distributions were evaluated for the pre- and post-surgery measurements, as were change scores after CABG. All measures except the MOS SF-36 subscales for RP and RE showed statistically significant change after CABG (p<0.01). Only the subscales of RP and RE demonstrated substantial ceiling (21.0% and 56.3%) and floor effects (49.3% and 16.9%). Evaluation of individual change scores after CABG indicated that 59% and 62% of the patients, respectively, had clinically meaningful increases in the two measures of physical capability, i.e. PF and VSAQ. In contrast, 60% and 72% of patients, respectively, showed no clinically meaningful changes in the two measures of emotional functioning, i.e. RE and BDI-II scores. Chi-square analyses revealed that use of scales with similar definitional constructs resulted in significantly different surgical outcomes for the following: PF vs VSAQ (p<0.001), RP vs VSAQ (p<0.02); and MH vs BDI-II (p<0.0001). These findings illustrate the limitations in performance of the MOS SF-36 for assessing changes of importance in HRQL after CABG. The VSAQ and BDI-II, two simple measures of physical and emotional functioning that are fundamentally similar to those contained in the MOS SF-36, appear to be sensitive markers for detecting changes in these important outcomes after CABG surgery. / Master of Science

A patient monitoring system for cardiopulmonary bypass surgery has been developed. This monitoring system uses a SWAN 286-10 computer (fully IBM PC/AT compatible) and a DT280l-A Input/Output board to monitor seven surgical parameters. This system monitors six temperatures, the hemoglobin content, the arterial oxygen saturation, the venous oxygen saturation, the oxygen consumption, and the blood flow rate through the cardiopulmonary bypass circuit. Additionally, there are three individual timers available. Details and the evaluation of the hardware and software design of this monitoring system are presented. Also, recommendations for clinical use are discussed. / Master of Science / incomplete_metadata

Yes / Background/purpose Coronary heart disease is the leading cause of morbidity in patients with type 2 diabetes mellitus (T2DM), frequently resulting in a requirement for coronary revascularization using the internal mammary artery (IMA) or saphenous vein (SV). Patency rates of SV grafts are inferior to IMA and further impaired by T2DM whilst IMA patencies appear similar in both populations. Smooth muscle cells (SMC) play a pivotal role in graft integration; we therefore examined the phenotype and proliferative function of IMA- and SV-SMC isolated from non-diabetic (ND) patients or those diagnosed with T2DM. Methods/materials SMC were cultured from fragments of SV or IMA. Morphology was analyzed under light microscopy (spread cell area measurements) and confocal microscopy (F-actin staining). Proliferation was analyzed by cell counting. Levels of RhoA mRNA, protein and activity were measured by real-time RT-PCR, western blotting and G-LISA respectively. Results IMA-SMC from T2DM and ND patients were indistinguishable in both morphology and function. By comparison, SV-SMC from T2DM patients exhibited significantly larger spread cell areas (1.5-fold increase, P < 0.05), truncated F-actin fibers and reduced proliferation (33% reduction, P < 0.05). Furthermore, lower expression and activity of RhoA were observed in SV-SMC of T2DM patients (37% reduction in expression, P < 0.05 and 43% reduction in activity, P < 0.01). Conclusions IMA-SMC appear impervious to phenotypic modulation by T2DM. In contrast, SV-SMC from T2DM patients exhibit phenotypic and functional changes accompanied by reduced RhoA activity. These aberrancies may be epigenetic in nature, compromising SMC plasticity and SV graft adaptation in T2DM patients.

No / We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.

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.

The American Heart Association (2006) has identified cardiovascular disease as the leading cause of death in the United States for every year except 1918 since 1900. Cardiac surgery is an increasingly common method of treating this problem (Contrada, Goyal, Cather, Rafalson, Idler et al. , 2004). Researchers have found that depression is associated with serious complications related to cardiac surgery (Connemey, Shapiro, McLaughlin, Bagiella, & Sloan, 2001 ). Many researchers have identified factors associated with depression in these patients. The purpose of this thesis was to identify and synthesize these current research findings. Studies included were published from 1997-2006 and focused on male and female patients 18 years of age and older, primarily undergoing Coronary Artery Bypass Grafting (CABG). The synthesis of these findings includes both the factors associated with developing depression and the complications associated with depression. Common factors associated with its development included female gender, lower socioeconomic status, pessimism, and poorer cognitive and physical functioning. Complications associated with depression included decreased physical functioning, healing, and cognitive functioning, as well as increased hospital stays, readmissions, cardiac events, and mortality. The associated factors may help to identify patients at high risk for developing depression, while the complications emphasize its importance. Limitations were acknowledged and recommendations for nursing research, education, and practice are included.