The Apelin-APJ system is transiently up-regulated in murine models of cardiac dysfunction. We have previously shown that Apelin-deficient mice subjected to aortic constriction suffer from severe fibrosis. In turn, we hypothesized that Apelin deficiency will also exaggerate the fibrosis phenotype post experimental myocardial infarction, associated with changes in fibroblast cell activity. Apelin-deficient and wildtype mice were randomly subjected to sham operation or left coronary artery ligation. Apelin deficiency worsened cardiac functionality, enhanced fibrosis-related gene expression and morphology, and enhanced vimentin intermediate filament expression, which may be involved in increasing fibroblast proliferation. MicroRNA target prediction softwares predict that apelin and vimentin 3 ’UTRs are potential targets of microRNA-378 regulation, and were confirmed with Luciferase reporter assays and western blot. Apelin up-regulation may be a useful strategy for attenuating unfavorable fibrosis through down-regulating vimentin-mediated adverse fibroblast activity. MicroRNA-378 regulation may be partly responsible for changes in apelin and vimentin expression.

Background: The goal of this study was to improve upon methodological limitations of previous studies to determine the existence and source of differences in the cardiac care of individuals with a history of depression or schizophrenia. The selected outcomes were three cardiac procedures: catheterization, percutaneous transluminal coronary angiography (PTCA), and coronary artery bypass graft (CABG); and three cardiac pharmaceuticals: beta-blockers, angiotensin converting enzyme (ACE) inhibitors and statins. Methods: This population-based retrospective cohort study consisted of 309, 790 individuals diagnosed with an AMI and admitted to an acute care hospital in Ontario between April 1, 1995 and March 31, 2009. The time-to-intervention for the depression and schizophrenia was estimated and compared to those without a mental disorder using Cox Proportional Hazards regression. Subgroup analyses were performed to evaluate the interaction between well-established confounders and the receipt of a cardiac intervention. Results: Persons with a history of depression were found to be more likely to receive a catheterization (HR=1.42, 95% CI=1.34-1.50) or PTCA (HR=1.48, 95% CI=1.40-1.57) if they had no previous CVD history, but were less likely to receive a catheterization (HR=0.71, 95% CI=0.51-0.99) or PTCA (HR=0.64, 95% CI=0.39-1.06) if they had a CVD history. In addition individuals with depression were less likely to receive a CABG, especially if they had a history of CVD (HR=0.38, 95% CI=0.24-0.60). Persons with a history of schizophrenia were found to be just as likely to receive a catheterization (HR=0.90, 95% CI=0.70-1.15) or a PTCA (HR=0.83, 95% CI=0.62-1.11). The likelihood of receiving a beta-blocker or statin was comparable or higher for persons with a history of depression (HR=1.07, 95% CI=1.03-1.11; 1.27, 95% ii i CI=1.22-1.32, respectively) and comparable for persons with a history of schizophrenia (HR=0.90, 95% CI=0.79-1.02; HR=0.97, 95% CI=0.83-1.14, respectively), with a small but significant prior drug use effect modification. Interpretation: Persons with depression or schizophrenia with no CVD history are just as likely to receive most recommended cardiac care interventions compared to those without a mental disorder. The source of the differences in care for individuals with a CVD history with depression and schizophrenia needs to be further explored. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-01-26 11:17:27.964

Cellular Cardiomyoplasty (cell therapy for myocardial regeneration) targets the basic pathophysiology of heart failure and represents a novel technique for augmenting the function of the failing heart. Previous studies have demonstrated massive mechanical losses in the first few minutes. Thus, efforts to reduce mechanical losses may prove more beneficial than those directed against biological losses alone. We believe that "Wash-out" into the disrupted blood vessels is responsible for these early losses. / In the first part of this study we hypothesized that by increasing the size of the injectate, the amount of immediate losses can be reduced achieving better retention. Using Alginate-poly-L-lysine-Alginate (APA) miscrocapsules of two different sizes (200mum&400mum) and comparing retention with bare microspheres (10mum) of similar size to MSCs, we demonstrated that immediate retention rate increased by four folds. The retention rate for group 1 (microspheres only) was 4.28+/-3.46% which was significantly lower than that for groups 2 (microspheres in 200mum microcapsules) at 16.45+/-12.66% and group 3 (microspheres in 400mum microcapsules) at 12.93+/-6.28% for Group (p<0.05). There was no difference between group 2 and 3. / In the second part, we investigated the potential of gradually increasing the cell load on functional improvement and engraftment using conventional intramuscular delivery. Five groups of rats received escalating doses of MSCs after surgically induced ischemia (gp1 no cells, gp2 0.5x 10 6, gp3 1.5x106, gp4 3x106,gp5 5x106 MSCs). At 7 weeks, we observed significant improvement in cardiac function in groups 3 to 5 compared to post-infarction baseline. This was not observed in groups 1 & 2. However, in groups 3 to 5, we observed no functional advantage for increasing the cell load beyond a minimal therapeutic dose. This is consistent with our hypothesis that small cells are washed out into the circulation. / We also showed the ability of Alginate-Poly-l-lysine-Alginate (APA) microcapsules to sustain the viability of encapsulated MSCs in-vitro. Finally, the ability of encapsulated MSCs to improve the function of the heart in-vivo was tested.

The Apelin-APJ system is transiently up-regulated in murine models of cardiac dysfunction. We have previously shown that Apelin-deficient mice subjected to aortic constriction suffer from severe fibrosis. In turn, we hypothesized that Apelin deficiency will also exaggerate the fibrosis phenotype post experimental myocardial infarction, associated with changes in fibroblast cell activity. Apelin-deficient and wildtype mice were randomly subjected to sham operation or left coronary artery ligation. Apelin deficiency worsened cardiac functionality, enhanced fibrosis-related gene expression and morphology, and enhanced vimentin intermediate filament expression, which may be involved in increasing fibroblast proliferation. MicroRNA target prediction softwares predict that apelin and vimentin 3 ’UTRs are potential targets of microRNA-378 regulation, and were confirmed with Luciferase reporter assays and western blot. Apelin up-regulation may be a useful strategy for attenuating unfavorable fibrosis through down-regulating vimentin-mediated adverse fibroblast activity. MicroRNA-378 regulation may be partly responsible for changes in apelin and vimentin expression.

No description available.

This study examined the relationship between social support and self-care agency in post myocardial infarction (MI) patients. Hypothesis I stated that total social support and it's three subscales are positively related to total self-care agency and it's six subscales. Hypothesis II stated that the three subscales of social support will predict total selfcare agency in post MI patients. A convenience sample of 28 post myocardial infarction patients from a large midwestern metropolitan hospital participated in the study. The Norbeck Social Support Questionnaire (NSSQ) was used to measure the social support variable. The Denyes Self-Care Agency Instrument (DSCAI) was utilized to measure the self-care agency variable. The study supported a positive and significant relationship between social support and self-care agency. The study further supported significant relationships between the subscales of social support and four of the subscales of self-care agency. Affect (a subscale of social support), contributed to 27% of the variance in selfcare agency. The results demonstrated congruent findings with previous studies, reflecting a positive and significant relationship between social support and self-care agency. The study findings have implications for improving nursing practice for myocardial infarction patients and for further nursing research among this population. / School of Nursing

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.

Myocardial infarction activates the renin-angiotensin system, consequently upregulating aldosterone production that may stimulate pathological cardiac fibrosis via mineralocorticoid receptor (MR) activation. Results presented in this thesis were derived from an in vitro experimental model using cultures of human cardiac fibroblasts to study the effect of aldosterone on elastin production. They first confirmed that treatment with 1-50 nM of aldosterone leads to a significant increase in collagen type I production via MR activation. Most importantly, we discovered that treatment with 1-50 nM of aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition. Strikingly, pretreatment with MR antagonist spironolactone did not eliminate aldosterone-induced increases in elastin production. Interestingly, while cultures treated with elevated aldosterone concentrations (100 nM and 1 µM) showed a further increase (~3.5-fold) in collagen and (~3-fold) in elastin mRNA levels, they demonstrated subsequent increases only in the net deposition of collagen but not elastin. In fact, cultures treated with elevated aldosterone concentrations displayed a striking decrease in the net deposition of insoluble elastin, which could be reversed with spironolactone or with MMP inhibitors doxycycline or GM6001. Most importantly, we discovered that the pro-elastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor (IGF-IR) and that the IGF-IR kinase inhibitor AG1024 or an anti-IGF-IR neutralizing antibody inhibits both IGF-I- and aldosterone-induced elastogenesis (Bunda et al., Am J Pathol. 171:809-819, 2007). Furthermore, we showed that the PI3 kinase signaling pathway propagates the elastogenic signal following IGF-IR activation and that activation of c-Src is an important prerequisite for aldosterone-dependent facilitation of the IGF-IR/PI3 kinase signaling. Results of explorative microarray analysis of 1 hour aldosterone-treated cultures revealed that aldosterone treatment upregulated expression of a heterotrimeric G protein, Gα13, that activates the PI3 kinase signaling pathway. We additionally demonstrated that aldosterone treatment transiently increases the interaction between Gα13 and c-Src and that siRNA-dependent elimination of Gα13 inhibited the pro-elastogenic effect of aldosterone. In summary, aldosterone, which stimulates collagen production in cardiac fibroblasts through the MR-dependent pathway, also increases elastogenesis via a parallel MR-independent pathway involving the activation of Gα13, c-Src, and IGF-IR/PI3 kinase signaling.

No description available.

Background and aims: Heart failure (HF) is a common health problem worldwide. Despite its importance, the epidemiology of HF is incompletely understood. Frequent references to an ‘epidemic of HF’ are at odds with recent reports of a decline in mortality from heart failure. In addition, reports based on admissions to hospital with a diagnosis of HF show that an earlier upward trend levelled off in the late 1990s in most developed countries. However, HF is a heterogeneous condition with multiple underlying causes. A decline in the severity of acute myocardial infarction (AMI), one of the major underlying causes of HF, and improvement in the treatment of patients with AMI as well as of hypertension are factors that might produce contradictory effects on the epidemiology of HF. Recent claims of a major contribution of improved survival after AMI to the reported epidemic of HF in the United States of America need to be examined in other populations. This thesis aims to define more precisely the epidemiological features of heart failure in Australia, and how these have evolved over the last decade. It examines secular trends in mortality, hospital admissions, incidence and survival related to HF. Methods: Trends in mortality from HF and admission to hospital with a diagnosis of HF are examined using computerized records of all deaths occurring in Australia for calendar years 1997-2003 and National Hospital Morbidity Data for financial years 1996-1997 to 2003-2004, obtained from the Australian Institute of Health and Welfare. A death or admission to hospital was defined as involving HF if at least one of the causes of death or one of the diagnoses of each separation was coded to any of the relevant rubrics within the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) or 10th Revision, Australian Modification (ICD-10-AM). The analyses are based on age- and sex-specific death and hospital separation rates for HF either as underlying cause (or principal diagnosis) or mentioned anywhere on the death certificate (or recorded in any diagnostic position in the hospital electronic file) for each calendar or financial year. The investigation of trends in incidence and outcome of early-onset HF (HF complicating an index AMI within 28 days) and late-onset HF after AMI (HF developing 28 days after an index AMI) was based on the World Health Organization MONItoring trends and determinants of CArdiovascular disease (MONICA) register in Western Australia. The study included all residents aged 25-64 years of Perth, the capital city of Western Australia, who were admitted to hospital between 1988 and 1993 with non-fatal definite AMI and who had no history of AMI or HF in the hospital record. Trends in incidence and outcome of early- and late-onset HF were investigated using appropriate statistical methods. Results: From a total of 907,242 deaths occurring in Australia between 1997 and 2003, heart failure was coded as the underlying cause of death (UCD) for 29,341 (3.2%) and was mentioned anywhere on the death certificate in 135,268 (14.9%). Over this period, in both sexes, there were decreases in the absolute numbers of deaths and in the age-specific and age-standardized mortality rates for HF either as UCD or mentioned anywhere on the death certificate. HF was mentioned in 24.6% and 17.8% of deaths attributed to ischaemic heart disease and circulatory disease respectively, and these proportions remained unchanged over the period of study. In addition, HF as UCD accounted for 8.3% of deaths due to circulatory disease and this did not change from 1997 to 2003. From a total of 48,562,285 separations from hospital between 1996-7 and 2003-4, HF was coded as the principal diagnosis for 344,081 (0.8%) and was mentioned anywhere on the hospital record in 1,212,109 (2.5%). While the number of separations with HF remained stable, the age- and sex-standardized separation rate for HF recorded as principal diagnosis decreased from 2.0 per 1000 population in 1996-1997 to 1.7 per 1000 population in 2003- 2004. The corresponding values for HF recorded in any diagnostic position were 7.8 and 5.0 per 1000 population. From all patients (N = 4006) who met the criteria for first-ever, non fatal ‘definite’ AMI in the Perth MONICA Register, 897 (22.4%) had early-onset HF complicating the index event. After adjustment for age and sex, the odds of developing HF declined by 13% (odds ratio for the period 1989-1993 relative to 1984-1988 = 0.87, 95% confidence interval (95%CI): 0.75 to 1.01). After adjustment for age and history of diabetes and hypertension, the hazard of death in patients with early-onset HF (i.e. case fatality) declined by 26% (HR for the period 1989-1993 relative to 1984-1988 = 0.74, 95%CI: 0.57 to 0.96). Of 3109 patients who did not develop early-onset HF, 406 (13.1%) had at least one subsequent hospital admission with a diagnosis of HF (defined as late-onset HF). Following adjustment for age and sex, the hazard ratio for late-onset HF for the period 1989-1993 relative to 1984-1988 was 0.85 (95% confidence interval (95%CI): 0.69-1.04). History of diabetes and hypertension, current smoking, length of initial admission for AMI, recurrent acute coronary syndrome and coronary artery revascularization procedures were predictors of late-onset HF. After a median follow-up of 3.2 years and adjustment for age (≥70 years) and history of diabetes, the hazard of death in patients with late-onset HF did not change over the period of study (HR for year = 1.02, 95%CI: 0.98 to 1.06). Conclusion: For reasons discussed in the body of the thesis, the observed decline in mortality from HF measured as either number of deaths or rate probably reflects a real change in the epidemiology of HF. In addition, there was no increase in the number of hospital admissions involving HF and standardized rates of hospital separations fell in Australia between 1996 and 2004. These results do not support a major increase in the caseload of HF over recent years. In addition, a decline in the risk of early- and late-onset HF after AMI as well as all the evidence on decline in incidence and severity of coronary artery disease and hypertension argue against an increase in inflow from these two important risk factors of HF. However, taking all of the influences on the epidemiology of HF together, it is likely that because of the increasing number of older people, the number of new cases of HF will rise over the next few years, even if the incidence rate falls.