Background: Patients with heart failure (HF) are characterized by exercise intolerance, breathlessness, fatigue and excessive neurohormonal activation associated with premature mortality. Recently, inflammatory activation has been described as an important factor in the progression of HF. Increased levels of certain pro-inflammatory cytokines (e.g., TNF-ɑ, IL-6) have been related to increased severity of left ventricular dysfunction, the activation of the sympathetic and renin-angiotensin systems and the catabolism of skeletal muscle. Although exercise training is important in the management of HF, acute bouts of exercise may lead to increases in proinflammatory cytokines. It is believed that the skeletal muscle abnormalities associated with HF may increase the risk of damage to skeletal muscle, (i.e., exercise-induced muscle injury (EIMI) with associated inflammatory activation) especially following unaccustomed exercise training. Recently, several training methods have been proposed for patients with HF that challenge the traditional “steady-state” (SS) training model, including interval training (IT). Interval training methods employ greater muscular loading than SS and therefore may increase the risk of inflammatory system activation EIMI, and/or reduced muscle function. There is no study that has examined the effects of IT on EIMI, muscle function and/or inflammatory markers. Material and Methods: Fourteen male participants with HF (mean age: 59 +/- 7.8 yrs; mean VO2 peak: 13.64 +/- 4.5 ml/kg/m-1; EF < 45%) were matched (for body mass and aerobic fitness) and randomized into SS or IT for 20 minutes. The IT involved 2 minute work:recovery phases of 90% and 40% of heart rate reserve, respectively. The SS involved continuous exercise at 65% of heart rate reserve. Biochemical markers of muscle damage and acute inflammation, concentric and eccentric isokinetic muscle torque, and subjective indicators of delayed onset muscle soreness (DOMS) and lower extremity function were evaluated at baseline, and then immediately following the training bout, and at 6, 24, and 48 hours post. Results: There were no significant differences between the IT and the SS training group for markers of skeletal muscle injury or inflammatory activation. Conclusions: The findings from the present study suggest that IT or SS do not result in excessive inflammatory system activation or skeletal muscle injury. These results have important implications for clinicians prescribing exercise regimes for HF patients who may be starting back into activity after a prolonged sedentary period. Additionally, results from this study indicate that there is a need for future research looking at the actual and perceived effect of even a single about of exercise on lower extremity function.

ABSTRACT The Benefits of Yoga Therapy for Heart Failure Patients by Paula R. Pullen STATEMENT OF THE PROBLEM The number of patients living with heart failure (HF) is on the rise. Yoga has been found to improve physical and psychological parameters amongst healthy individuals. The effects of yoga on HF patients are unknown. The purpose of this study was to examine the effects of yoga on cardio-vascular endurance [functional capacity (FC)], flexibility, inflammatory markers, and quality of life (QoL) on medically stable HF patients. METHOD Forty HF patients with compensated systolic or diastolic HF participated in the study. A randomized control design created two groups, yoga (N=21). and control (N=19).The treatment intervention consisted of 16-yoga sessions conducted bi-weekly (YG) vs. standard medical care (control- CG) for two months. All participants were asked to follow a home walk program. Pre- and post-study measurements included a treadmill stress test to peak exertion, flexibility (FLEX), girth, interleukin-6 (IL-6), c- reactive protein (CRP), and extra-cellular dismutase (EC-SOD). Quality of life was assessed by the Minnesota Living with Heart Failure Questionnaire (MLwHFQ). RESULTS Forty patients were randomized to YG (N=21) or CG (N=19). The results were significant for favorable changes in the YG as compared to the CG for flexibility (P=0.012), treadmill time (P=0.002), ~VO2peak (P=0.003), and all biomarkers (IL-6, CRP, and EC-SOD) of inflammation. Within the YG, pre- to post- test scores for the total and physical sub- scale of the MLwHFQ were significant (P=0.02 and P<0.001). CONCLUSIONS Yoga therapy offered additional benefits to the standard medical care of HF patients by improving QoL, exercise capacity, FLEX, and biomarkers of inflammation

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.