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Chronic growth hormone (GH) excess, acromegaly, causes a specific cardiomyopathy, which remains poorly understood. The pattern of hypertrophy is distinct from other forms of cardiac disease and begins to appear before hypertension or diabetes. GH deficiency (GHD) also causes cardiovascular problems, with reduced ability to mount a cardiovascular response to exercise. Acromegaly and GHD patients have increased cardiac mortality. Cardiac magnetic resonance imaging (CMR) is the gold standard for assessment of cardiac mass and provides data on cardiac function, fibrosis, valve function and ischaemia. This study used CMR to assess 23 patients with acromegaly or GHD, before and after treatment of their GH disorder, and 23 healthy controls. Patients with acromegaly demonstrated increased left ventricular mass index (LVMi), end diastolic volume index, stroke volume index and cardiac index, which persisted at one year, despite treatment of underlying disease. Patients with GHD demonstrated LVMi at the bottom (males) or beneath (females) published normal references ranges, which increased with one year of GH replacement. The mechanisms by which GH influences cardiac tissue are poorly understood. Adenosine monophosphate-activated protein kinase (AMPK) is an energy-regulator enzyme, which interacts with several metabolic hormones. Mutations in AMPK cause arrhythmias and cardiac hypertrophy. AMPK activation may be a mechanism by which GH causes some of its cardiac effects. This study used primary cardiomyocytes and mouse and rat models of GH excess and deficiency to study the effects of GH on cardiac AMPK. Acute GH treatment increased AMPK activity in both in vivo and in vitro studies; acute IGF-I treatment had the opposite effect. In 2 and 8 month old bovine GH-overexpressing (bGH) and GH receptor knock out (GHRKO) mice, functional AMPK assay did not demonstrate any difference in cardiac AMPK activity between transgenics and controls. However, Western blotting for Threonine-172 phospho (p)AMPK levels, a marker of AMPK activity, demonstrated increased cardiac pAMPK in 2 month old bGH mice and a reduction in cardiac pAMPK levels in 8 month old animals. A trend towards the same findings was seen in GHRKO mice. This indicates that both GH and IGF-I interact with myocardial AMPK, apparently via different mechanisms.

Oleamide, an endocannabinoid-like mediator, is a fatty acid that shares structural similarities with anandamide. Oleamide induces cannabimimetic responses and is a potent vasodilator of rat small mesenteric arteries. The cardiovascular actions of oleamide have received relatively little attention in comparison to those of anandamide, the prototypical endocannabinoid. The aim of this study was to examine the vascular effects of oleamide in both health and disease, making a comparison with those of anandamide. This study demonstrated that oleamide caused vasorelaxation of the rat isolated aorta. The vasorelaxant actions of oleamide were found to be tissue dependent as oleamide did not evoke vascular responses in the porcine mesenteric and coronary arteries. Anandamide did not produce similar responses to oleamide in any of these vessels, displaying marked differences between the two compounds. Oleamide-induced vasorelaxation of the rat aorta was abolished by capsaicin pre-treatment but this was independent of sensory-nerve activity. This demonstrates a potential additional site of action for oleamide and prompted further investigations into the vascular actions of capsaicin. Oleamide also caused relaxation of the rat perfused whole mesenteric arterial bed. This response was diminished by a depolarising concentration of extracellular K+, implicating the involvement of K+ channels. Capsaicin evoked relaxation of both rat aortae and porcine coronary arteries. The vasorelaxant effect of capsaicin was insensitive to capsaicin pre-treatment and the presence of capsazepine, a TRPV1 antagonist. It was also found that the presence of capsaicin inhibited the uptake of Ca2+ in depolarised porcine coronary arteries and rat aortae on reintroduction of calcium. In porcine coronaries, capsaicin abolished the contractile response to Bay-K 8644, a L-type calcium channel activator. Therefore, it is proposed that capsaicin inhibits L-type calcium channels to drive vasorelaxation, demonstrating a TRPV1-independent mechanism of action for capsaicin. Having described the vasorelaxation of Wistar aortae, the effects of hypertension on the vascular actions of oleamide were determined. Oleamide-induced vasorelaxation was significantly enhanced in aortae from spontaneously hypertensive rats (SHR) compared to those from normotensive Wistar Kyoto (WKY) controls. Oleamide caused approximately 40% relaxation of the SHR aorta compared to 15% in the WKY isolated aorta. Similarly, responses to anandamide were also increased in aortae from hypertension causing 30% relaxation compared to 10% in arteries from normotensive controls. Augmented vasorelaxation to oleamide and anandamide was opposed by pre-treatment of vessels with capsaicin, an effect independent of TRPV1 receptors. Inhibition of cyclooxygenase with indomethacin potentiated responses to oleamide in WKY aortae to a level comparable to responses in SHR aortae. Thus, this thesis suggests that changes in the cyclooxygenase pathway are important in regulating responses to oleamide in hypertension and may represent an adaptive change in the early stages of established hypertension in SHR rats. In summary, this study provides further evidence of the vasorelaxant nature of oleamide, which can be enhanced in arteries from hypertension. Augmented responses in hypertension may relate to alterations in the cyclooxygenase pathway during the early stages of established hypertension in the SHR. This investigation also documents the capsaicin-sensitive nature of oleamide responses in aortic rings, which exists independently of sensory-nerve mediated activity. The observation of a non-TRPV1 capsaicin-sensitive mechanism may ultimately lead to the uncovering of an alternative mechanism of action for capsaicin in conduit arteries and a novel site of action for oleamide.

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Both hypertrophic (HCM) and dilated cardiomyopathy (DCM), though differing in their aetiologies, share features of impaired resting energetics. The aim of this thesis was to determine if cardiac high energy phosphate metabolism, measured as the phosphocreatine (PCr)/ATP ratio using 31Phosphorus magnetic resonance spectroscopy (31P MRS), is further impaired during exercise in these pathologies. This would provide a possible explanation for the high incidence of exercise related death in HCM and DCM as well as the blunted inotropic response to exercise in DCM. Furthermore, this thesis investigates the role of stress perfusion and stress tissue oxygenation in HCM (as these are hypothesized to exacerbate the primary defect in energetics) and exercise training in DCM (which is hypothesized to improve function though the mechanisms are uncertain). This work developed a novel protocol for measuring 31P MRS in a clinically acceptable time frame. The traditional acquisition is at least 20 minutes (as much as 40 minutes in subjects with lower pulse rates). This is a particularly long time to allow for exercise in the magnet particularly in the symptomatic DCM cohort. Hence this work meticulously developed a shorter 8 minute protocol. Its validity, reproducibility and application to exercise were confirmed. The post processing of the MRS data was further improved for calculating blood contamination and tested with both simulated and patient data, including normal, hypertrophied and thinned myocardium. Applying this new method, this thesis is the first to report a further decrease in exercise energetics in HCM. The relationship between perfusion, tissue de-oxygenation and energetic compromise during exercise was then explored in HCM. Athletes, with physiological hypertrophy, were used as an additional control group in these experiments. These results demonstrated a strikingly blunted oxygenation response of the HCM heart to stress even in the pre-hypertrophy HCM mutation carriers. However, as a group, the data did not show a correlation between the blunted oxygenation response and the percentage change in PCr/ATP during exercise. None-the-less, these results can potentially be useful for distinguishing between hypertrophy in the athletes and pathological hypertrophy in HCM and for distinguishing HCM mutation carriers’ pre hypertrophy and the normal heart. In the DCM cohort, this thesis explored the impact of exercise training on cardiac metabolism and function. The results showed no change in cardiac energetics and left ventricular ejection fraction during 8 minutes of exercise. In addition, an eight week home exercise programme did not alter resting or exercise cardiac PCr/ATP, but improved cardiac function during rest and exercise, and increased exercise tolerance and quality of life scores. In conclusion, this thesis reports further insights into cardiac exercise energetics in HCM and DCM and its relationship to perfusion and oxygenation in HCM and to exercise training in DCM. Therapies that decrease the energy cost of cardiac work during exercise may prove beneficial targets to explore further in these conditions.

L’inflammation joue un rôle crucial dans les processus de réparation du muscle cardiaque consécutifs à un infarctus du myocarde (IM). En particulier, les monocytes (MO) et les macrophages (Mf) assument une fonction majeure dans la régulation de la taille d’infarctus et de la fibrose du coeur infarci. Dans un premier travail, nous avons analysé le rôle coordonné de la myeloidepithelial- reproductive protein tyrosine kinase (Mertk) et du milk fat globule epidermal growth factor (Mfge8) dans la propension des MO et des Mf à éliminer les débris cellulaires. Nous avons notamment émis l'hypothèse que ces médiateurs pourraient jouer un rôle clé dans la synchronisation de l’efférocytose dans le tissu cardiaque infarci. Les souris dépourvues de Mertk et Mfge8 présentaient un phénotype cardiaque défectueux par rapport aux souris contrôles. Fait intéressant, au 3ème jour après l’IM, le niveau de protéine cardiaque d’un facteur pro-angiogénique majeur, le VEGF-A, était plus faible chez les souris chimères Mertk-/ -Mfge8-/-par rapport aux contrôles. À partir de ces données, nous avons postulé qu'une altération du taux de la protéine VEGF-A pourrait être liée à une réduction de la capacité des MO/Mf cardiaques à libérer ces facteurs et donc à participer au remodelage bénéfique du coeur infarci. De fait, après un IM, la suppression du VEGF-A dans les cellules myéloïdes réduit la fonction cardiaque. Ces effets étaient associés à une taille d'infarctus supérieure et à un nombre limité de capillaires dans les coeurs infarcis des souris présentant une invalidation conditionnelle du VEGF-A dans les cellules myéloïdes. Ainsi, le VEGF-A dérivé des cellules myéloïdes joue un rôle essentiel dans la régulation de la fonction cardiaque, probablement grâce à l'activation du processus angiogénique dans la zone ischémique. Dans un deuxième travail, nous nous sommes intéressés au rôle de l’hepcidine dans les fonctions réparatrices des MO et des Mf. L'hepcidine est une hormone qui régule activement le trafic du fer. De façon inattendue, la déficience complète en hepcidine restaure considérablement la fonction cardiaque après un IM. L'hepcidine est exprimée par les Mf cardiaques. En outre, les souris ayant une moelle déficiente en hepcidine (Hamp -/-) ou présentant une invalidation conditionnelle dans les cellules de la lignée myéloide (LysMCre +/Hampf/f) ont une fonction cardiaque fortement améliorée. Cet effet a été associé à une réduction de la taille de l'infarctus, de la fibrose et à une stimulation imprévue du renouvellement des cardiomyocytes. De même, dans un modèle de régénération cardiaque induite par résection apicale chez des souris nouveaux nés, nous avons révélé que les macrophages déficients en hepcidine favorisent la prolifération des cardiomyocytes. L'impact des Mf déficients en hepcidine repose sur l'altération de leur métabolisme du fer et sur la libération d'IL-4 et d'IL-13. D’ailleurs, la suppression génétique de l'IL-4 et de l'IL-13 dans les Mf dépourvus d'hepcidine annihile leur effet bénéfique sur la fonction et la réparation cardiaque. Ainsi, l'hepcidine commande la réparation et la régénération cardiaque induite par les Mf par une voie liée à l'IL-4 / IL-13. Ces travaux ont permis de démontrer l’importance des Mf dans la revascularisation et la régénération post-ischémique et de souligner l’efficacité potentielle d’un traitement basé sur la modulation de l’activité des cellules immunitaires dans les pathologies ischémiques cardiaques. / No abstract

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Intra-aortic balloonpump (IABP) counterpulsation therapy is a volume displacement device designed to provide partial assistance to the left ventricle of the heart. Critical care nurses are expected to manage IABP therapy. It is therefore important that the critical care nurse has the knowledge to manage IABP therapy in a safe and therapeutic manner. The question arises: does the critical care nurse have the knowledge to manage IABP therapy? The purpose of this research study is to explore and describe the knowledge of the critical care nurse regarding the management of IABP therapy. The design of this research study is a quantitative, descriptive and contextual study, in which a sample survey was performed, using a questionnaire (based on a literature study) under controlled conditions. The knowledge of the majority of critical care nurses tested was found to be insufficient. Safe management guidelines and in-service training have been proposed to improve the situation. / lntra-aortiese ballonpomp (IABP) teenpulsasie terapie is 'n volume verplasings apparaat, antwerp om gedeeltelike ondersteuning aan die linker ventrikel van die hart te bied. Kritiekesorgverpleegkundiges is verantwoordelik vir die hantering van rASP terapie. Die vraag ontstaan: beskik die kritiekesorgverpleegkundige oor voldoende kennis rakende die hantering van IABP terapie? Die doel van hierdie studie is om die kennis van kritiekesorgverpleegkundiges te ondersoek en te beskryf rakende die hantering van IABP terapie. Die resultate van hierdie navorsingstudie dui daarop dat die meerderheid kritiekesorgverpleegkundiges wat getoets was oor onvoldoende kennis beskik ten opsigte van IABP terapie. Formulering van riglyne en indiensopleiding is aanbeveel om hierdie situasie te verbeter. Die navorsingsontwerp is kwantitatief, beskrywend en kontekstueel van aard, waartydens 'n gerieflikheidsteekproeftrekking gedoen is, met gebruik van 'n vraelys (gebasseer op 'n literatuurstudie) onder gekontrolleerde toestande. / Health Studies / M.A. (Nursing Science)

Strategies to reduce infarct size in ischaemia-reperfusion (IR) syndromes such as acute myocardial infarction are of high clinical and scientific interest. Remote ischaemic preconditioning (rIPC) is one such strategy but its mechanisms remain incompletely understood. Multiple lines of evidence from animal studies suggest that the endogenous purine nucleoside adenosine is a key mediator of preconditioning pathways but no evidence exists as to adenosine’s role in the more complex physiology of humans. The work in this thesis aims to elucidate the role of endogenous adenosine in the physiological phenomenon of rIPC and to examine the role of exogenous adenosine in triggering preconditioning-like states. In a randomised, placebo controlled study using healthy volunteers and the human forearm model of ischaemia-reperfusion injury, I demonstrate that delivery of the adenosine receptor antagonist caffeine, prior to the initiation of a rIPC stimulus abrogates the protective effect of rIPC on IR. By then selectively infusing caffeine to achieve high local but low systemic concentrations, I also demonstrate that adenosine receptor activation is important in the ‘trigger’ phase of rIPC rather than in the ‘effector’ phase and that blockade of the trigger phase effectively inhibits the release of a circulating humoral protective factor. These studies provide evidence of the crucial role of adenosine receptor activation in human rIPC, demonstrating their sites of action and illuminating their potential mechanism of action. To study whether exogenously delivered adenosine can recapitulate preconditioning-like states, in initial studies in a large mammal model of acute myocardial infarction, I demonstrate that adenosine, given after the onset of ischaemia, but prior to reperfusion, significantly reduces myocardial infarct size. In a subsequent study, translating these findings to humans with coronary disease, I demonstrate that the delivery of adenosine in a range of concentrations is able to illicit the release of a circulating preconditioning factor which is transferrable across species and can reduce infarct size in a murine model of myocardial IR.

L'insuffisance cardiaque consécutive à un infarctus du myocarde est une pathologie complexe qui apparaît suite au remodelage du ventricule gauche. Le renouvellement et la dégradation de la matrice extracellulaire cardiaque et l'inflammation sont impliqués dans la mise en place du remodelage post infarctus du myocarde. La métalloprotéinase matricielle 9 (MMP9) et le récepteur de l'immunité innée Toll-like 4 (TLR4) sont des médiateurs clés du remodelage ventriculaire. L'adénosine est un nucléoside cardioprotecteur et anti-inflammatoire dont les effets sur le remodelage sont encore mal caractérisés. Nous avons émis l'hypothèse que l'adénosine pourrait moduler les voies de la MMP9 et du TLR4 dans les macrophages, et ainsi réguler le remodelage ventriculaire. Nos résultats montrent que l'activation du récepteur A3 à l'adénosine augmente la production de MMP9 par les macrophages primaires humains. D'autre part, nous avons observé que l'adénosine réduit l'inflammation par une diminution de l'expression de surface du TLR4. Cet effet se traduit par une inhibition de la synthèse de cytokines pro-inflammatoires et est induit par l'activation du récepteur A2A. Ces résultats ont permis de caractériser certains mécanismes par lesquels l'adénosine agit sur le remodelage ventriculaire. Ils suggèrent de tester, dans un modèle animal, l'administration d'analogues de l'adénosine pour prévenir ou limiter le remodelage. La capacité à prédire la survenue du remodelage ventriculaire après un infarctus du myocarde est importante d'un point de vue clinique et bénéficierait de la découverte de nouveaux biomarqueurs. L'analyse par protéomique du plasma de 30 patients d'une cohorte test ayant développé un infarctus du myocarde a permis d'identifier l'haptoglobine comme biomarqueur pronostique potentiel. L'haptoglobine humaine possède 3 isoformes : [alpha]1-[alpha]1, [alpha]2-[alpha]1 et [alpha]2-[alpha]2. Nos résultats suggèrent que la présence du phénotype [alpha]2 et d'un taux plasmatique d'haptoglobine faible sont associés à l'apparition d'une insuffisance cardiaque. Cette étude preuve-du-concept suggère que l'haptoglobine pourrait être ajoutée à la liste existante des biomarqueurs de l'insuffisance cardiaque / Heart failure following myocardial infarction is a complex pathology that occurs as a result of left ventricular remodeling. Left ventricular remodeling is mediated in part by extracellular cardiac matrix turnover and inflammation. Matrix metalloproteinase 9 (MMP9) and innate immune receptor Toll-like 4 (TLR4) are key mediators of left ventricular remodeling. Cardioprotective and anti-inflammatory nucleoside adenosine acts on left ventricular remodeling through still poorly characterized mechanisms. We hypothesized that adenosine regulates left ventricular remodeling through modulation of MMP9 and TLR4 pathways in macrophages. Using human primary macrophages, we showed that adenosine increases MMP9 production through the A3 receptor. In a second set of experiments, we observed that adenosine dampens inflammation through decreased cell-surface expression of TLR4. This effect, which inhibits pro-inflammatory cytokines production, is induced by adenosine A2A receptor. All together, these results contribute to a better understanding of the mechanisms underlying left ventricular remodeling and suggest a potential therapeutic use of adenosine. Our data suggest testing a therapeutic strategy with different adenosine analogs to prevent or limit left ventricular remodeling. Prediction of left ventricular remodeling after myocardial infarction is clinically relevant and would benefit from the discovery of new biomarkers. Proteomic analysis of plasma samples from a test cohort of 30 myocardial infarction patients identified haptoglobin as a potential prognostic biomarker. Human haptoglobin has 3 distinct isoforms: [alpha]1-[alpha]1, [alpha]2-[alpha]1 and [alpha]2-[alpha]2. Our results suggest that the presence of [alpha]2 isoform, together with low plasma levels of total haptoglobin, is associated with the development of heart failure. This proof-of-concept study suggested that haptoglobin could be added to the panel of existing biomarkers of heart failure