Binary transgenic (BT) mice with doxycycline (DOX)-suppressible cardiac-specific over-expression of endothelin 1 (ET 1) exhibit progressive heart failure, QRS prolongation, and death following DOX withdrawal. However, the molecular basis and reversibility of the electrophysiological abnormalities in this model were not known. Here we assess the mechanisms underlying ET 1 mediated electrical remodelling, and its role in heart failure. Prior attempts to prevent this model of ET-1 induced cardiomyopathy with ET receptor antagonism were not beneficial. We now propose to evaluate the effectiveness of blocking the synthesis of ET-1 with CGS 26303, a dual inhibitor of endothelin converting enzyme (ECE) and neutral endopeptidase. BT vs. littermate control mice were withdrawn from DOX and serially studied with ultrasound biomicroscopy, octapolar catheters, multi-electrode epicardial mapping, histopathology, Western blot, immunohistochemistry and qRT-PCR. Prolonged ventricular activation and depressed rate of ventricular activation were detected as early as 4 wks after transgene activation, when structure and function of the heart remained unaffected. By 8 wks of ET-1 over-expression, biventricular systolic and diastolic dysfunction, myocardial fibrosis, cardiomyocyte hypertrophy, prolonged ventricular activation and repolarization, depressed rate of ventricular activation, and abnormal atrioventricular nodal function were observed. Within 4 wks of ET-1 induction, reduction were observed in connexin-43 mRNA, protein, and phosphorylation, Nav1.5 mRNA and protein, Na+ conductance, K+ channel interacting protein-2 mRNA and Kv4.2 mRNA. Chromatin immunoprecipitation revealed that nuclear factor κB preferentially binds to Cx43 and Nav1.5 promoters. Importantly, the associated electrophysiological abnormalities at this time point were reversible upon suppression of ET 1 over-expression and completely prevented the development of structural and functional remodelling. Treatment with CGS-26303 (5 mg/kg/day) failed to improve survival, or hemodynamic and contractile decline. ET-1-mediated ventricular conduction delays correlates with gap junction and ion channel remodelling, and precedes heart failure. The sequence and reversibility of this phenotype suggest that a primary abnormality in electrical remodelling may contribute to the pathogenesis of heart failure. CGS 26303 failed to prevent this cardiomyopathic phenotype. These data suggest that chronically high levels of bigET-1, as seen in heart failure, may induce increased ECE activity and/or non-ECE ET-1 synthesis, thus circumventing the efficacy of ECE blockade in this model.

Binary transgenic (BT) mice with doxycycline (DOX)-suppressible cardiac-specific over-expression of endothelin 1 (ET 1) exhibit progressive heart failure, QRS prolongation, and death following DOX withdrawal. However, the molecular basis and reversibility of the electrophysiological abnormalities in this model were not known. Here we assess the mechanisms underlying ET 1 mediated electrical remodelling, and its role in heart failure. Prior attempts to prevent this model of ET-1 induced cardiomyopathy with ET receptor antagonism were not beneficial. We now propose to evaluate the effectiveness of blocking the synthesis of ET-1 with CGS 26303, a dual inhibitor of endothelin converting enzyme (ECE) and neutral endopeptidase. BT vs. littermate control mice were withdrawn from DOX and serially studied with ultrasound biomicroscopy, octapolar catheters, multi-electrode epicardial mapping, histopathology, Western blot, immunohistochemistry and qRT-PCR. Prolonged ventricular activation and depressed rate of ventricular activation were detected as early as 4 wks after transgene activation, when structure and function of the heart remained unaffected. By 8 wks of ET-1 over-expression, biventricular systolic and diastolic dysfunction, myocardial fibrosis, cardiomyocyte hypertrophy, prolonged ventricular activation and repolarization, depressed rate of ventricular activation, and abnormal atrioventricular nodal function were observed. Within 4 wks of ET-1 induction, reduction were observed in connexin-43 mRNA, protein, and phosphorylation, Nav1.5 mRNA and protein, Na+ conductance, K+ channel interacting protein-2 mRNA and Kv4.2 mRNA. Chromatin immunoprecipitation revealed that nuclear factor κB preferentially binds to Cx43 and Nav1.5 promoters. Importantly, the associated electrophysiological abnormalities at this time point were reversible upon suppression of ET 1 over-expression and completely prevented the development of structural and functional remodelling. Treatment with CGS-26303 (5 mg/kg/day) failed to improve survival, or hemodynamic and contractile decline. ET-1-mediated ventricular conduction delays correlates with gap junction and ion channel remodelling, and precedes heart failure. The sequence and reversibility of this phenotype suggest that a primary abnormality in electrical remodelling may contribute to the pathogenesis of heart failure. CGS 26303 failed to prevent this cardiomyopathic phenotype. These data suggest that chronically high levels of bigET-1, as seen in heart failure, may induce increased ECE activity and/or non-ECE ET-1 synthesis, thus circumventing the efficacy of ECE blockade in this model.

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.

Introduction and Purpose: In chronic heart failure (CHF), exercise rehabilitation results in a reduced risk of mortality, decreased disease severity, and increased functional ability. Resistance training is an important component of cardiac rehabilitation; however, an optimal training velocity that produces physiological and functional benefits at minimal perceived exertion and cardiovascular stress has yet to be identified. CHF patients need to be very efficient and perform the exercise that will give them the greatest benefits because of their poor exercise tolerance and increased risk of cardiovascular complications during exercise. In older populations, high velocity resistance training results in greater improvements in functional ability than low velocity resistance training. The use of high velocity resistance training in patients with CHF has yet to be examined; however it may enhance higher velocity activities of daily living while using a lower training load. The lower load associated with high velocity training may be less strenuous and result in lower cardiovascular stress, whilst maintaining a relatively similar power output compared to traditional low-velocity training. The purpose of this study was to compare the acute cardiovascular responses and perceived exertion of high and low velocity resistance exercises. Methods and Measures: 6 male and 1 female patients with systolic heart failure (CHF NYHA Class I-III) were recruited to perform two separate, randomly assigned exercise sessions. These sessions consisted of 5 exercises (hack squat, chest press, knee flexion, lat pull down and knee extension); one with a low velocity of contraction (3 second concentric phase: 3 second eccentric phase at 50% of the slow velocity 1-RM) and one with a high velocity (1 second concentric phase: 3 second eccentric phase at 50% of the high velocity 1-RM). During both sessions, heart rate, blood pressure, and a rating of perceived exertion (RPE) were obtained after the completion of each exercise. Results: Despite a similar relative mechanical load, the high velocity workout produced significantly lower systolic blood pressure (121.2 vs. 132.8 mmHg), mean arterial pressure (87.8 vs. 93.5), and RPE (3.7 vs.4.8) than the low velocity workout (p<0.05). The high velocity workout was not significantly different from the low velocity workout for heart rate, rate pressure product and diastolic blood pressure. Conclusion: We conclude that the high velocity workout produces more favourable blood pressure responses to resistance training in patients with CHF than the low velocity workout and may be used to enhance functional outcomes in cardiac rehabilitation programs.

Background. Heart failure (HF) is a prevalent chronic cardiovascular disease that is characterized by progressive functional decline. Given the known links between high levels of support and positive health outcomes the objectives of this study were: 1) to determine the levels and patterns of social support, and related gender differences, 2) to determine the influence of support on functional outcomes as defined by a deterioration in physical function over 1-year following exacerbation of HF, and 3) to describe the effects of gender on social support in influencing adverse outcomes. Methods. Data were obtained from a 1-year prospective cohort study that included male and female participants ≥ 65 years of age (n=435; 164 females; 271 males) with HF. Participants completed questionnaires at baseline, 6 and 12-months containing clinical and demographic information and validated measures of 1) physical function, using derived scores from the Medical Outcome Study SF-12, and Kansas City Cardiomyopathy Questionnaire (KCCQ), and 2) social support using the Medical Outcome Study, Social Support Survey. Results. Women were more likely to be single, widowed or divorced, living alone and earned less annual income compared to men (p < .01). Women tended to report lower mean social support scores than men at all time points. When controlling for clinical and demographic variables, being married (OR 12.2; 95%CI: 5.1, 19.2), living with someone (OR 13.6; 95%CI: 6.2, 21.0), and higher income (OR 0.08; 95%CI: .01, .15), were significantly associated with higher levels of social support at baseline. Although women reported significantly lower disease-specific (p= .01) and generic (p= .01) physical function scores, no significant gender differences existed in the proportion of men or women that experienced functional decline or death at 1-year of follow-up. In a multivariate logistic regression modeling, men with lower levels of social support were more likely to experience generic functional decline or adverse outcomes. This was not the same for women. Conclusions. Women, reported less social support and poorer functioning, but the impact of social support on functional decline was more pronounced in men. Gender-sensitive management should be considered to optimize function for men and women living with HF. / Thesis (Master, Nursing) -- Queen's University, 2010-11-29 15:32:00.616

No description available.

A qualitative phenomenological study incorporating Photovoice was conducted to gain insight into the lived experience of patients with end-stage heart failure (ESHF). Seven participants were recruited and in-depth open-ended interviews were conducted with all participants. Three of the seven informants also opted to take part in the Photovoice portion of the project. “Working to preserve a sense of self” emerged as the essence of living with ESHF and was supported by three themes: i) the work of managing a failing and unreliable body, ii) the work of choreographing daily living; and iii) the work of charting the final chapter of one’s life. The findings from this study provide healthcare professionals with empirically grounded information and insights about the needs and everyday challenges individuals living with ESHF experience, and how clinicians can best support them. Such information is essential in order to plan meaningful, holistic, evidence-based care for ESHF patients.

Understanding the molecular basis of doxorubicin (Dox)-induced oxidative stress leading to cardiomyopathy is crucial to finding cardioprotective strategies to manage this important clinical problem. Improving the antioxidant defenses of cardiac cells could be one strategy for cardioprotection. The role of oxidative stress in Dox-induced cardiotoxicity as well as testing the efficacy of antioxidant Vitamin C (Vit C) in offering protection to cardiomyocytes was investigated. As stem cells have been suggested to play a role in this cardiotoxicity, Dox-mediated oxidative stress effects, with and without Vit C, on the stem cell antigen-1 (Sca) positive cells from heart as well as bone marrow were also examined. Our time-course studies of the effects of Dox on the isolated cardiomyocytes showed that the phosphorylation of mitogen-activated protein kinases and p53 followed the rise in reactive oxygen species (ROS) production. Dox also downregulated the Sodium-dependent Vit C Transporter-2 (SVCT-2) and this may have enhanced Dox-induced increase in oxidative stress. Pro-apoptotic markers Bax/Bcl-xL ratio and caspase 3 cleavage were higher after the activation of stress-induced pathways and viability of cells was decreased. Dox-induced increase in apoptosis and decrease in cell viability depended in part on the activation of p38/JNK and p53 proteins, but not on the ERK protein. Exposure to Dox, increased membrane leakage, autophagy and lipid peroxidation. On the other hand, Dox decreased overall antioxidant capacity as well as expression of the endogenous antioxidant enzymes glutathione peroxidase, Cu/Zn superoxide dismutase and catalase. Dox affected Sca-1 positive cells in a prominent manner which was marked by a dose-dependent increase in cell loss, cell leakage and ROS levels as well as decrease in cellular ATP levels. Vit C pre-treatment prior to the addition of Dox delayed and reduced Dox-induced injury to cardiomyocytes, preserving viability. Vit C was able to blunt the decrease in SVCT-2 as well as Dox-induced oxidative stress. Vit C also offered protection to Sca-1 positive cells by partially preventing Dox-induced changes to these cells. The data presented in this thesis improves our knowledge of the molecular mechanisms leading to Dox-induced cardiotoxicity as well as suggest cardioprotection by Vit C.

Implantation of a left ventricular assist device (LVAD) is a potential treatment in terminal heart failure. Right ventricular (RV) failure is a severe complication in these patients and sometimes requires additional placement of a right ventricular assist device (RVAD). RVAD implantation, however, is an invasive treatment associated with both increased mortality and morbidity. The aim of this thesis was to study whether partial volume exclusion of the RV through a modified Glenn shunt or cavoaortic shunt could treat severe RV failure. The ultimate goal would be to use it as an alternative to a RVAD in RV failure during LVAD therapy. Swine were used as the model animal in all studies. In Study I, experimental RV failure was induced by ischemia, and verified by hemodynamic measurements and genetic expression. Treatment with a modified Glenn shunt reduced venous stasis and improved hemodynamics in general. In Study II, experimental RV failure was induced by the same method as in Study I. Treatment with a cavoaortic shunt in addition to LVAD therapy proved to reduce venous stasis and improved hemodynamics in general, which was feasible with preserved oxygen delivery despite cyanotic shunting. In Study III, experimental RV failure was induced by pulmonary banding, and verified by hemodynamic measurements and genetic expression. Treatment with a modified Glenn shunt reduced venous stasis but did not improve hemodynamics in general compared with a control group. In Study IV, the effects of LVAD therapy and subsequent treatment with a modified Glenn shunt on the normal RV function were studied. It demonstrated that LVAD therapy can put strain on the RV by increasing stroke work and end-diastolic volume, and that these effects can be reversed by treatment with a modified Glenn shunt during LVAD therapy. In conclusion, partial volume exclusion through a modified Glenn shunt or cavoaortic shunt is a feasible treatment of experimental RV failure. Thus, it could potentially be used as an alternative treatment to a RVAD in severe RV failure during LVAD therapy.

Effective treatment of heart disease and an aging population have led to increases in the incidence of heart failure. Treatment requires complex medication regimes and recognition of symptoms. Best practice guidelines published by the American, European and Canadian cardiac societies promote self-care behaviours and skill building. No concrete examples of education programmes for clients were found in the literature. The purpose of the study was to develop, pilot and evaluate an education series for clients with heart failure within a primary care setting. “LEARN twice”, a three part education series with related resource material, was developed in the context of inter-professional collaboration and drew upon theories of health education, and literacy. The concept of co-management was incorporated as the philosophical basis in the design. The pilot-test used an experimental design, and incorporated pre and post-testing with standardized instrumentation including the Dutch Heart Failure Knowledge Scale and the Minnesota Living with Heart Failure Questionnaire. To pilot the education series, participants attended three education classes highlighting the essential skills for self management of heart failure. A qualitative descriptive component included brief semi-structured interviews with participants and educators to provide feedback about both the process and content of the educational series. Limited participant numbers did not permit statistical testing, however potentially promising results were found in the quantitative data collected. Descriptive participant data indicated that the education series was meaningful, and helped iii understanding of symptoms. Instructors rated the content as good to excellent and anticipate the adoption of the education series as standard practice in the clinic. The pilot test of the education series has provided a foundation for future research endeavours, in particular the replication and completion of this study protocol. As clients with heart failure have the potential to be in regular contact with a primary care provider, subsequent studies could include a longitudinal component to examine whether rates of re-hospitalization are reduced for clients who attend an education series.