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Coronary heart disease (CHD) remains the single leading cause of natural death worldwide. Despite significant advances in the diagnosis and treatment, CHD accounts for 1 out of every 6 deaths in the United States. Myocardial infarct (MI) as a result of CHD causes irreversible damage to the heart through the loss of viable myocardial tissue. Patients surviving the initial MI are at risk of developing heart failure due to lost contractile function and adverse cardiac remodeling. Improvement in the survival rates for MI have led to an increase in the incidence of heart failure, affecting approximately 5 million people in the United States. Although treatment of heart failure has improved, the mortality rates of heart failure remain high with 1 in 5 dying within the first year of diagnosis and 50% dying within 5 years. The cost of caring for heart failure patients ranks number one in Medicare. Oxidative stress plays an important role in the etiology and pathophysiology of CHD and heart failure. The transcription factor Nrf2 is a master regulator of cellular antioxidant defense mechanisms, controlling the expression of numerous antioxidant and detoxification genes through the Antioxidant Response Element (ARE) in the promoter regions. The cytoprotective effects of Nrf2 have been demonstrated in a variety of organs and disease states; however, the role of Nrf2 in the heart and heart disease has not been defined. The work presented here defines roles of Nrf2 in limiting cardiac injury and the progression to heart failure (Chapter II), protecting cardiac myocytes from oxidative stress through the preservation of mitochondria (Chapter III), and mediating the infarct reducing effects of statins, one of the most prescribed pharmacological agent (Chapter IV). In order to investigate a role of Nrf2 in the pathology of ischemic injury in the heart, a mouse model of ischemia and myocardial infarct by occlusion of the left anterior descending coronary artery was used. Nrf2 knockout mice subjected to ischemia/reperfusion injury experienced a larger infarct size than wild-type mice. Furthermore, mice lacking Nrf2 experienced a higher mortality rate and an accelerated progression to heart failure, indicated by severely compromised contractile function and reduced cardiac output, within 10 days following an MI. Morphological examination revealed maladaptive remodeling, including myocyte hypertrophy, heart enlargement, and dilated left ventricle, in Nrf2 KO mice that was absent in WT mice. Analysis of cardiac function by echocardiogram revealed increased left ventricular mass, increased systolic volume, decreased fraction shortening, reduced ejection fraction, and decreased cardiac output in Nrf2 KO mice. Nrf2 KO mice also demonstrated expression of biomarkers of heart failure, such as expression of fetal gene program, with elevated levels of β-MHC, ANF, and BNP mRNA in the myocardium. Interestingly, a lack of immune cell infiltrate and myofibroblasts as well as a deficiency in collagen deposition were observed in the infarcted region of hearts from Nrf2 KO mice. These data indicate that Nrf2 plays an important role in protecting the myocardium from ischemic injury and the progression to heart failure. Lack of Nrf2 response results in deficiency of wound healing and instead initiation of maladaptive remodeling, leading to heart failure. Mitochondria are key sources of reactive oxygen species (ROS) generation, as well as important targets for ROS-induced cell injury. Cardiac myocytes have the highest content of mitochondria among all cell types and can be particularly susceptible to mitochondrial dysfunction due to the high metabolic demand associated with the contractile function of the heart. With cardiomyocytes (CMCs) isolated from neonatal rats and kept under tissue culture conditions, mitochondria exist in elaborated networks. Such networks were replaced by predominately individual punctate mitochondria 24 hours after exposure to a sublethal dose of H₂O₂. Mitochondrial morphology was altered with membrane swelling and disorganization of inner cristae with areas of condensation. Disrupted mitochondrial morphology was associated with a loss of membrane potential and decreased expression of mitochondrial proteins involved in the electron transport chain, such as cytochrome b and cytochrome c. Nrf2 overexpression prevented H₂O₂ from inducing morphological changes in mitochondria and the reduction of cytochrome b and cytochrome c expresssion. Although Nrf2 is known as a transcription factor regulating antioxidant and detoxification genes, Nrf2 overexpression did not significantly reduce the level of protein oxidation as measured by carbonyl formation. Instead, we found that Nrf2 localizes to the outer mitochondrial membrane, suggesting a direct role of Nrf2 in mitochondrial protection. As further evidence of a direct role in mitochondrial protection, a cell-free system of mitochondria isolated from the myocardium of Nrf2 knockout mice were more sensitive to permeability transition, an indicator of mitochondrial dysfunction. Combined, these data suggest that Nrf2 protects mitochondria from oxidant injury likely through direct interaction with mitochondria. In the clinic, statins are now commonly administered for patients experiencing MI or CHD. Statins have become mainstays in the treatment of hypercholesterolemia and atherosclerosis as inhibitors of the rate limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. In addition, statins have been shown to elicit pleiotropic effects, including plaque stabilization, maintenance of endothelial function, anti-inflammatory actions, and antioxidant capabilities, independent of effects on cholesterol synthesis. Recently, these pleiotropic effects have been implicated in providing acute protection against ischemia and reperfusion injury, which has led to the use of high dose statins clinically before revascularization of an ischemic event. I have found that administration of atorvastatin in mice induced Nrf2 protein levels in the heart, brain, lung, and liver. While atorvastatin reduced infarct size following an MI in wild-type mice, this protective effect was lost in mice lacking Nrf2. Failure of atorvastatin to protect against MI in Nrf2 knockout mice indicates that Nrf2 plays a critical role in mediating the protective effects of acute statin treatment. Nrf2 induction by statins is a novel discovery. In order to understand the mechanism of such statin effect, I used an in vitro cell system, in which a variety of statins, atorvastatin, simvastatin, lovastatin, and pravastatin, were found to elevate Nrf2 protein levels. Elevation of Nrf2 by statins was independent of increased protein stability or transcriptional regulation. Instead, statins increased Nrf2 mRNA association with ribosomal complexes and induced Nrf2 protein through a translational mechanism. Recruitment of Nrf2 mRNA to ribosomes and induction of Nrf2 protein was dependent on activation of PI3 kinase. These studies provide evidence that Nrf2 plays a critical role in protecting cardiac myocytes and the heart from oxidative stress and MI. In the absence of Nrf2, mice experienced worse cardiac injury following MI and quickly advanced to heart failure. Mechanistically, this work has identified a novel role of Nrf2 in preserving mitochondrial morphology and integrity during oxidative stress through a direct interaction with the outer mitochondrial membrane. Finally, a newly defined role of Nrf2 induction by statins in mediating protection against MI by acute statin therapy indicates that modulation of Nrf2 may represent a viable pharmacological target for cardiac protection in humans.

Syfte: Syftet med studien var att undersöka hur vanligt det är med stress och depression efter genomgången hjärtinfarkt. Vidare planeras att undersöka samband mellan stress och depression samt också eventuella skillnader mellan könen för hur stress och depression upplevs efter genomgången hjärtinfarkt. Metod: Patienter som varit inlagda för hjärtinfarkt vid Akademiska sjukhuset i Uppsala inkluderas i studien. Patienterna skall ha genomgått hjärtinfarkt och/eller PCI och/eller CABG. De tre enkäterna Vardagslivets stress, Känsloläge samt MADRS användes. Frekvenser och korrelationer beräknades med IBM SPSS Statistics version 19. Tillstånd för studien söktes hos klinikchef. Resultat: Antalet patienter i studien är 18. Förekomsten av självskattad depression efter hjärtinfarkt uppmättes till 6%. Självskattad stress varierade mellan patienterna, dock skattade 33%, höga nivåer av stress. Skillnader i hur kvinnor och män upplever stress och depression efter genomgången hjärtinfarkt kunde inte bestämmas i denna studie. Ett signifikant svagt samband mellan stress och depression visades dock (r = 0,52, p= 0,029). Slutsats: Patienter med nyligen genomgången hjärtinfarkt kan uppleva depression i efterförloppet. Att behandla depressionen kan ge ökad livskvalitet. / Objective: The aim of this study was to investigate the frequency of depression and stress after a myocardial infarction. Other aims were to study the relationship between stress and depression and also differences between the sexes in their experience of stress and depression after a myocardial infarction. Method: Patients being hospitalized at Akademiska sjukhuset in Uppsala, Sweden were included in the study. Patients with a myocardial infarction and/or coronary angioplasty and/or coronary bypass surgery were included. Three questionnaires The Everyday Life Stress Scale, The Depressive Mood Scale and MADRS where used. Frequencies and correlations were calculated using IBM SPSS Statistics version 19. Permission for the study was sought from the clinic manager. Result: 18 participants were included in the study. The frequency of self estimated depression after a myocardial infarction was 6%. The frequency of self estimated stress varied throughout the population but 33% estimated their stress as high. Differences in stress and depression between women and men could not be determined in this study. A weak significant correlation between stress and depression was however shown (r = 0,52, p= 0,029). Conclusion: Patients who have gone through a myocardial infarction can experience depression afterwards. Treating depression can improve quality of life.

In the present study clinical performance of new highly cardiospecific biochemical markers of myocardial injury was investigated and these markers were compared with conventional enzymes. The multimarker risk assessment score index, including biochemical markers of myocardial injury, inflammation and haemostasis, was developed for the prognosis of patients after ACS. The prognostic value of BNP concentration changes in predicting LV remodeling and dysfunction after MI was evaluated along with other biochemical markers of myocardial injury.

Myocardial fibrosis is a common pathological finding in patients with cardiovascular disease and is believed to be a major contributing factor in the development of end stage organ failure. Early events that promote the development of myocardial fibrosis are not well understood. Rapid cellular infiltration into the cardiac tissue is evident in fibrosis but the infiltrating populations and their functions have yet to be completely elucidated. The aim of this thesis was to characterize the phenotype and function of this cellular population in a model of hypertension mediated myocardial fibrosis. Furthermore, we intended to explore therapies that target this population and ameliorate fibrosis. We characterized a novel population of infiltrating cells as circulating fibroblast progenitor cells, termed fibrocytes. We determined that this population does not appear to specifically migrate in response to previously established chemotactic signals (CCL2 or CXCL12). We found that fibrocytes respond to fibrogenic stimuli (AngII and CTGF) by increasing the expression of collagen and CTGF, an early molecular mediator of fibrosis, while also promoting fibrocyte differentiation. Using an anti-hypertension treatment, we found that hypertension as a physiologic stimulus likely promotes cellular infiltration and corresponding fibrosis. We also established that treatment with activated protein C (aPC) conferred protection against the development of myocardial fibrosis, potentially by inhibiting fibrocyte recruitment and/or activation. Lastly, to assess fibrocyte involvement in the progression of human myocardial fibrosis we assessed fibrocytes in levels in the circulation of patients with ischemic heart disease compared to healthy controls. We found that patients with ischemic heart disease had an increase of circulating cells that have the potential to become fibrocytes compared to healthy controls and therefore likely contribute to myocardial fibrosis. From this data, we propose that fibrocytes are a key effector cell that directly promotes pathologic fibrosis within the injured myocardium. Understanding their migration and function is therefore essential to the development of future therapies targeting this cell type to inhibit their role in fibrosis.

The purpose of this study was to determine if del Nido cardioplegia provides superior protection for aged and young adult hearts. We used our isolated working heart model of cardioplegic arrest and reperfusion to compare functional recovery in both senescent and young adult rat hearts, with delivery of del Nido or our standard cardioplegia. In the aged hearts, use of del Nido cardioplegia prevented spontaneous contractions during arrest, reduced troponin release, and provided superior functional recovery during working heart. In contrast, in the young adult hearts, although stroke work was higher in the del Nido group, there were no significant differences in spontaneous activity, troponin release, and cardiac output between del Nido and standard cardioplegia, suggesting that del Nido cardioplegia did not provide superior functional recovery in the young adult heart. Del Nido cardioplegia has the potential to provide superior myocardial protection for elderly patients undergoing cardiac surgery.

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.