Heart failure is an illness that requires life-long treatment and often affects everyday aspects of a person’s life. Self-care is a significant part of the treatment. Good self-care resources make it possible for people with heart failure to make the lifestyle changes they often need to maintain or improve their level of health. Self-care means having knowledge of and being able to recognize the symptoms and signs of deterioration that can occur with heart failure, so that the person can take appropriate measures – and it also means knowing when it is time to seek professional help. The significance of self-care for heart failure has increased and will increase even more in the future, when monitoring one’s condition will be left more and more to the people themselves and those who take care of them. The object of the study was to learn what self-care measures people with heart failure say they apply in everyday life. The quantitative method of a questionnaire study (The European Heart Failure Self-Care Behaviour Scale) was used. Of the 94 people registered at a heart failure unit who were asked to complete the questionnaire, 58 of them consented. The results showed that more than 95% of the people with heart failure applied the recommended self-care measure of taking the medicines prescribed by their doctor. Many also applied the self-care measures of taking a rest during the day (83%) and taking it easy when they felt out of breath (78%). On the other hand, the self-care measures of daily weight control were applied only by 41%, daily exercise by only 48% and salt and fluid restrictions by only 59%. The self-care measures of contacting a doctor/nurse when noticing problems or symptoms of deterioration were applied by only 36% of those who felt out of breath and by only 43% of those who felt increased fatigue. The conclusion is that there is a need to improve the knowledge about and confidence in self-care treatment for people with heart failure. One way of achieving this is to show that people with heart failure check for symptoms and apply measures in their homes as part of the treatment and that this leads to an increased quality of life.

Egzistuoja du širdies sensorinių galūnėlių tipai – sudėtingos neinkapsuliuotos ir tinklinės galūnėlės. Šio tyrimo tikslas buvo ištirti sensorinių galūnėlių morfologiją pelės širdies pagrinde ir jų vizualizavimo galimybę skirtingais antikūnais. Tyrimo rezultatai parodė, kad tiek sudėtingos neinkapsuliuotos, tiek tinklinės sensorinės nervinės galūnėlės išryškinamos imunohistochemiškai su antikūnu prieš proteino geno produktą PGP 9.5 (AbD Serotec, JAV). Sudėtingos neinkapsuliuotos galūnėlės paplitusios kaudalinės, kairiosios bei dešiniosios kranialinių venų žiočių srityje. Tinklinės galūnėlės tolygiai pasiskirsto visame širdies pagrinde visuose trijuose širdies sienos sluoksniuose (epikarde, miokarde ir endokarde). Sudėtingos neinkapsuliuotos galūnėlės kaudalinės venos žiočių srityje turi mažiausią plotą palyginus su sensorinėm galūnėlėm šalia kitų dviejų venų žiočių. / There are two types of cardiac sensory endings – complex unencapsulated endings and end-nets. The aim of this study was to examine morphology of sensory terminals in the basis of mouse heart and ability of different antibodies to visualize these terminals. Our results showed that both end-net and complex unencapsulated endings can be visualized with PGP 9.5 (AbD Serotec, USA). Complex unencapsulated endings are localized in heart wall epicardium near the apertures of caudal, right cranial and left cranial veins in the right atrium. End-net terminals are diffusely distributed in all three layers (endocardium, myocardium, epicardium) of heart wall. Complex unencapsulated endings near the caudal vein aperture have the lowest area compared with the sensory endings near the other two veins apertures.

The purpose of this study was to determine the association of age, gender, and cardiorespiratory fitness level upon normative heart rate and systolic blood pressure (SBP) responses per MET during the BSU/Bruce Ramp protocol. This research was delimited to 451 subjects, 201 men (mean age 46.5 ± 11.9 yrs) and 250 women (mean age 42.9 ± 11.4 yrs), low to moderate risk subjects. The majority of subjects were tested to enter the Ball State University Adult Physical Fitness Program. These subjects were tested using the BSU/Bruce Ramp protocol between 1992 and 1998.Multiple regression showed gender had a positive association upon submaximal SBP values. Gender's association with heart rate was negative between minute 3-6 and positive between minute 6-9. Age only had an association upon submaximal heart rate, which was negative. Cardiorespiratory fitness had a negative association upon SBP between minute 6-9 and a negative association with heart rate between minute 3-6.SBP increased 6.6 ± 4.4 and 6.0 ± 4.2 mmHg/MET between minute 3-6 for men and women, respectively. Analysis of variance demonstrated gender was not statistically significant between minute 3-6. SBP increased 4.7 ± 3.1 and 3.8 + 2.7 mmHg/MET between minute 6-9 for men and women, respectively. Gender was statisticallysignificant between minute 6-9 (p<.05). Heart rate increased 8.5 + 2.3 and 10.7 + 3.3 bpm/MET between minute 3-6 for men and women, respectively. Analysis of variance demonstrated gender was statistically significant between minute 3-6 (p<.05). The increase was 9.5 + 2.3 and 9.2 + 2.7 bpm/MET between minute 6-9 for men and women, respectively. Gender was not statistically significant between minute 6-9.In conclusion, this study demonstrated that the normative hemodynamic responses during the BSU/Bruce Ramp protocol are similar to submaximal normative data previously reported in the literature for incremental type protocols. / School of Physical Education

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Heart failure is a common and serious chronic condition, which can be as ‘malignant’ as most forms of cancer (Stewart, MacIntyre, Hole, Capewell, & McMurray, 2001). Recent estimates are that around 40,000 men and 45,000 women are living with heart failure in Scotland (Stewart, MacIntyre, Capewell, & McMurray, 2003). Heart failure is significantly influenced by socioeconomic factors, with people on lower incomes being more likely to develop, and die faster from, heart failure (McAlister et al, 2004). There is a growing body of research on the experience of living with heart failure, however, none provides serious consideration of the role of socioeconomic factors in impacting the experience of heart failure, and some qualitative research may actually obscure such factors. There were two main aims in this thesis. One was to explore how qualitative research methods can better consider the relationship between experience and broader context, such as the influence of socio-economic factors on health. The other aim was to examine the experiences of people as they live with and die from heart failure in ways that situate their accounts in the broader context of their lives. An initial research study, on which I was the main researcher, focused on the experiences of 30 people living with advanced heart failure. These people, their carers and key health professionals were interviewed, where possible, three times over a six months period. This thesis re-examines that study, focusing on 20 of those participants, for which a total of 122 interviews were conducted. I used a dialogical approach to see whether the socioeconomic context of heart failure for these respondents, could be captured through exploring experiences, performance, relationships, discourses and institutional practices, the social processes that mediate the relationship between socioeconomic disadvantage and chronic diseases were explored. This offers important learning in relation to the experience of living with heart failure, along with the experience of providing care. The findings highlight the need to broaden our view of chronic illness beyond biomedical approaches, and grow our methodological approaches along with that, in order to develop knowledge and practice that has relevance for people who live with and die from heart failure.

Introduction Management of coronary heart disease (CHD), a major cause of mortality and morbidity in the UK, in primary care, remains sub-optimal. This work aimed to: evaluate impact of a community pharmacy-led intervention on appropriateness of treatment and quality of life of CHD patients; describe opinions and experiences of community pharmacists and GPs and use management of change literature as an explanatory framework for the findings. Methods The thesis comprises: two literature reviews (pharmacy-led interventions for CHD and NHS-based studies using change theories); an RCT evaluating the service; questionnaire surveys and qualitative interviews with community pharmacists and GPs, and comparison of a new model of change with two change theories. Results Review of pharmacy interventions revealed only small-scale studies demonstrating benefit for CHD patients. The change review revealed use of change management theories to implement change and as explanatory frameworks for change initiatives, in the NHS, but not in the pharmacy setting. The RCT recruited 1493 patients (980 intervention, 513 control), 70 pharmacies (102 pharmacists) and 48 practices (208 GPs). No significant differences were found in primary outcomes (appropriateness of treatment or quality of life). Questionnaires revealed positive attitudes to the service but need for pharmacist access to patient records and improved GP/community pharmacist relationships. Qualitative interviews indicated more divergent views. Attitudes were influenced by understanding and previous experience of medicines management, change drivers and implementation processes. Themes conceptualised into a ‘change readiness’ model, had similarities with Lewin’s planned change approach and Pettigrew’s receptivity model. All three models identified areas of sub-optimal intervention implementation and delivery. The new service did not improve appropriateness of treatment or quality of life because it was implemented and delivered sub-optimally. There is a need for greater use of an evidence based systematic approach to introduce new services, but research is required to confirm this approach would confer the hypothesised benefits.

Le remodelage ventriculaire gauche (RVG) est un processus complexe qui intervient après un infarctus du myocarde chez 30% des patients en dépit des meilleurs traitements connus actuellement. Le but de mon travail de thèse consistait à identifier les déterminants moléculaires du RVG dans le but de mieux en comprendre les mécanismes physiopathologiques. Pour cela, nous avons étudié les modifications post-traductionnelles des protéines contractiles du VG et en particulier, la phosphorylation et la O-N-acétylglucosaminylation (O-GlcNAc). Nous nous sommes ensuite particulièrement intéressés à la troponine T (TnT) pour laquelle nous avons ainsi pu mettre en évidence une diminution de la phosphorylation au niveau de la sérine 208 au niveau du VG et du plasma chez le rat, suggérant que cela pourrait être un marqueur du RVG post-infarctus. Pour cette étude, nous avons travaillé en collaboration avec l’unité INSERM U644 de Rouen sur un modèle expérimental d’insuffisance cardiaque. L’infarctus du myocarde est induit chez le rat par ligature de la branche descendante de l’artère coronaire gauche, les rats témoins subissant l’intervention mais sans ligature. Dans un premier temps, nous avons réalisé une étude globale du phosphoprotéome du VG en phase tardive du RVG (2 mois post-ligature). Pour cela, les protéines extraites du VG ont été séparées par électrophorèse bidimensionnelle puis colorées au Pro-Q®Diamond (spécifique des protéines phosphorylées) puis au Sypro®Ruby (spécifique des protéines totales). Par analyse bioinformatique, nous avons mis en évidences 69 spots polypeptidiques présentant des modulations de phosphorylation. Nous avons donc analysé ces spots par spectrométrie de masse et avons identifié 30 protéines correspondant à 53 spots polypeptidiques présentant des modulations de phosphorylation. Parmi ces protéines, nous avons choisi de nous concentrer et d’étudier 6 protéines contractiles : la TnT, l’alpha-tropomyosine 1 (&#945;-Tm 1), la desmine, l’&#945;B-crystalline et les chaînes légères de myosine 1 et 2 (MLC). Pour chacune de ces protéines, nous avons identifié le type d’acide aminé responsable de la phosphorylation et quantifié les modulations de phosphorylation dans le VG des rats insuffisants cardiaques (IC). De manière intéressante, nous avons observé que le VG des animaux IC présentait une diminution significative de la phosphorylation sur les résidus sérine pour l’&#945;-Tm 1, la TnT et la MLC-2 et sur les résidus de tyrosine pour l’&#945;B-crystalline ainsi qu’une augmentation significative de la phosphorylation sur les résidus tyrosine pour la MLC-1 et sur les résidus de sérines pour la desmine, confirmant ainsi les résultats obtenus en électrophorèse bidimensionnelle. Afin de compléter l’analyse des modifications post-traductionnelles, nous avons étudié les modifications de O-GlcNAc pour chacune de ces protéines. Nous avons ainsi observé une diminution significative de la O-GlcNAcylation de l’&#945;-Tm 1, de la desmine et l’&#945;B crystalline ainsi qu’une augmentation de la O-GlcNAcylation de la MLC-3 et de la TnT. Par ailleurs, nous avons pu corréler ces modulations de phosphorylation et de O-GlcNAcylation avec des modulations de l’activité des enzymes impliquées dans ces modulations. En effet, par analyse bioinformatique de la séquence de la TnT et par recherche bibliographique nous avons mis en évidence que la protéine kinase C et la protéine phosphatase 2A pourrait être impliquées dans ces modulations de phosphorylation. Nous avons alors mis en évidence une diminution de l’activité de la protéine kinase C epsilon dans le VG des rats IC mais sans variation de l’activité de la protéine phosphatase 2A. Par ailleurs, nous avons mis en évidence une augmentation de l’activité de la O-GlcNAc transférase et une diminution de l’activité de la O-GlcNAcase dans le VG des rats IC. [...] / Despite significant improvements in management of myocardial infarction (MI), left ventricular remodelling (LVR) remains a major complication and a strong predictor of both heart failure (HF) and death after MI. Although several variables, such as MI size, have been identified as risk factors, LVR remains difficult to predict in clinical practice. Better prediction could allow an individualized approach with more intense therapy and follow-up for such high-risk patients. The aim of my work is to identify molecular determinants of LVR to have a better understanding of physiopathological mechanisms of LVR. For that purpose, we studied post-translational modifications of contractile proteins in particular, phosphorylation and O-N-acetylglucosaminylation (O-GlcNAc). Then, we studied particularly troponin T (TnT) for which we could highlight a decrease of phosphorylation of serine 208 in LV and plasma of MI-rats. These results suggest that the level of circulating phosphorylated troponin T could be new biomarker of LVR and may help to predict the development of heart failure after MI. For this study, we worked in collaboration with INSERM unit U644 at Rouen using an experimental model of HF. MI was induced in rat by left coronary ligation and, the control rats undergoing the surgery without ligation. Initially, we performed differential phosphoproteomic study of LV in the late phase of the LVR (2 months post-MI). For this purpose, LV proteins were extracted and separated by two-dimensional electrophoresis. Gels were first stained by Pro-Q®Diamond (specific of phosphorylated proteins) and then by Sypro®Ruby (specific of total proteins). By bioinformatic analysis, we showed that 69 polypeptidic spots were modulated for their phosphorylation levels. We analyzed these spots by mass spectrometry and identified 30 proteins corresponding to 53 spots with modulationof phosphorylation. Among these proteins, we have chosen to study 6 contractile proteins: TnT, alpha-tropomyosin 1 (Tm-&#945;1), desmin, &#945;B-crystallin and myosin light chains 1 and 2 (MLC). For each described proteins, we have validated the modulation of phosphorylation and determined the aminoacid involved in the phosphorylation modulation using immunoprecipitation techniques with specific antibodies against the proteins and phospho-Tyrosine, -Threonine and –Serine antibodies confirming the screening performed by 2D-electrophoresis for the detection of phosphoproteins. We observed a significant decrease of phosphorylation on serine for Tm-&#945;1, TnT and MLC-2 and on tyrosine residues for &#945;B-crystallin as well as a significant increase in phosphorylation on tyrosine for MLC-1 and on serine residues for desmin, thus confirming the results obtained in two-dimensional electrophoresis. In order to complete analysis of the post-translational modifications, we studied the modifications of O-GlcNAc for each one of these proteins. We thus observed a significant decrease in O-GlcNAcylation of Tm-&#945;1, &#945;B-crystallin and desmin as well as an increase in O-GlcNAcylation of the MLC-3 and TnT. In addition, we have correlated these modulations of phosphorylation and O-GlcNAcylation levels with modulations of the activity of enzymes implied in these modulations. Indeed, by bioinformatic analysis of the TnT sequence and literature review, we highlighted that the protein kinase C and the protein phosphatase 2A could be implied in these modulations. We observed a decrease of protein kinase C epsilon isoform expression in the LV of MI- rats without modulation of protein phosphatase 2A activity. In addition, we showed an increase in the activity of O-GlcNAc transferase and a decreaseof O-GlcNAcase activity in LV of MI rats. [...]

Cardiovascular disease is the leading cause of death worldwide. Due to the extremely low natural regeneration rate of heart muscle, development of new therapeutics directed towards heart repair is challenging. A potential approach to regenerate damaged heart is offered by cardiac tissue engineering. Specifically, it aims at engineering cardiac muscle in vitro and implanting it into the site of injury so that it can be integrated into the host tissue and restore the heart’s function. To ensure the effectiveness of this technique, the engineered tissue needs to recapitulate structural and functional properties of the native myocardium. Myocardium consists of laminar sheets of uniaxially aligned cardiac muscle cells (cardiomyocytes) wrapped around the heart. Therefore, achieving high cardiomyocyte alignment in engineered muscle is crucial. In this study we aimed at stimulating cardiomyocyte alignment by mimicking their niche in the embryonic heart. We hypothesized that recapitulating the extracellular cues that guide myocardial development in the embryo can guide cardiac tissue organization in vitro. To test this hypothesis, we imaged the structure of fibronectin – the most abundant protein in embryonic heart’s extracellular matrix (ECM) – and derived a 2D pattern from it that was then microcontact printed onto a substrate to guide cell alignment. We compared chick cardiomyocyte alignment on the biomimetic pattern and line patterns that have been extensively studied in the past. Results revealed a unique cell density-dependent response of cardiomyocytes to the biomimetic pattern that allowed us to elucidate the role of cell-cell and cell-ECM interactions in cardiomyocyte alignment on fibronectin patterns by looking at the effect of local pattern features on alignment and inhibiting N-cadherin-based cell-cell junctions. Further, to engineer more clinically relevant tissues, we differentiated human induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) into cardiomyocytes and seeded them onto the fibronectin patterns. Cardiac tissues produced with these cells showed significant differences compared to the chick tissues due to their immature phenotype. We showed that co-culture with cardiac fibroblasts (CFBs) as well as maturation of iPSC-derived cardiomyocytes (iPSC-CMs) increased tissue alignment, indicating the important role of both of these factors in developing novel methods to engineer functional cardiac tissues.

Heart failure (HF) is a complex, debilitating disease that affects approximately 6.5 million Americans (Ades et al., 2013). HF is a large reason for hospital readmissions, and subsequently, a major contributor to rising health care costs. Unfortunately, there is no cure for HF, but various interventions such as cardiac rehabilitation (CR) have been employed to help patients manage the symptoms. However, the lack of patients ever being referred to cardiac rehabilitation is disturbing. Healthcare providers play an essential role in providing education about heart failure and CR, and thus should be knowledgeable about these principles themselves. Therefore, the aim of this project is to evaluate data from a survey sent to nurse practitioners (NPs) regarding whether HF patients are being referred to CR appropriately, and if barriers are limiting use of CR programs. This was a descriptive, nonexperimental study with a survey design seeking to understand if NP providers are following evidence-based guidelines when treating HF patients and if providers consider CR programs to be an appropriate treatment tool. A survey questionnaire was distributed to NPs who are members of Coalition of Arizona Nurses in Advanced Practice (CAZNAP). Data from 27 surveys were used for analysis. Results showed that nurse practitioner respondents felt they had a good understanding of heart failure education and diagnosis. A majority also considered CR to be a useful tool for HF patients, and all agreed that health care providers affect CR enrollment and participation rates. A mere nine respondents (33%) reported being introduced to the outcomes and benefits of CR in their graduate education. Findings also confirmed previous work suggesting that providers are not adequately referring HF patients to CR, as 33% of NPs reported they have never referred a patient to CR. With respect to these findings, it is important to identify methods to assist providers with proper education about CR and its referral methods. As supported by the literature review, improved referral rates to CR can lead to better management and health outcomes for HF patients. Therefore, further research is needed to identify interventions that promote increased CR referral rates.

Rho Kinase (Rho-K) has been implicated in the pathophysiology of many deleterious conditions and its inhibition was shown to ameliorate these compromising effects. It is unclear; however, whether inhibition of Rho-K would decrease infarct size in hearts after ischemia/reperfusion. Adult ICR mice were randomized to 1 of 4 treatments: saline, fasudil (Rho-K inhibitor (10 mg/kg i.p.), Fasudil+L-NAME (Nitric Oxide synthase inhibitor, 15 mg/kg), and L-NAME. Hearts were isolated, perfused in Langendorff mode and subjected to 30 min stabilization before 30 min ischemia and 60 min reperfusion. Left ventricular (LV) function was monitored. Hearts were stained and infarct size measured. Fasudil reduced infarct size as compared with control hearts; however, this protective effect was abolished by L-NAME. LV function mirrored these trends. The loss of cardioprotection after L-NAME administration indicates that cardioprotection by Rho-K inhibition is mediated through nitric oxide-dependent pathway. Furthermore, Fasudil administration at and throughout reperfusion showed similar cardioprotection.