Thesis (Ph.D) -- Virginia Commonwealth University, 2005. / Title from title-page of electronic thesis. Prepared for: Dept. of Physiology. Bibliography: p. 160-169.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

Thesis (Ph.D.)--Kent State University, 2006. / Title from PDF t.p. (viewed Sept. 20, 2006). Advisor: Gary Meszaros. Keywords: cardiac fibroblasts; myofibroblasts; extracellular matrix; collagen VI; post-myocardial infarction remodeling. Includes bibliographical references (p. 135-152).

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 143-159).

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 55-63).

Made available in DSpace on 2014-08-13T14:50:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-11-29Bitstream added on 2014-08-13T18:01:10Z : No. of bitstreams: 1 000736321_20141129.pdf: 359412 bytes, checksum: 2b097cc17fda8e667e01f3cd49b99769 (MD5) Bitstreams deleted on 2014-12-01T14:49:47Z: 000736321_20141129.pdf,Bitstream added on 2014-12-01T14:50:25Z : No. of bitstreams: 1 000736321.pdf: 4184687 bytes, checksum: 6844804819f4dc3ee8faded627f4a83d (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Doenças cardiovasculares como infarto do miocárdio e acidente vascular encefálico ainda representam a principal causa de morte no Brasil. A aterosclerose é uma doença progressiva e silenciosa classificada como fator de risco para o desenvolvimento de doenças cardiovasculares. É caracterizada pelo aumento dos níveis de colesterol no plasma os quais são oxidados por radicais livres originando a lipoproteína de baixa densidade oxidada (LDLox). A fagocitose de LDLox por macrófagos permite a transformação destes em células espumosas, que são depositadas na camada íntima dos vasos. Após o rompimento do endotélio há o extravasamento do conteúdo da placa aterosclerótica para a circulação levando à formação de trombo. Este interrompe o fluxo sanguíneo em artérias e vasos, levando ao desenvolvimento de doenças cardiovasculares como infarto do miocárdio e acidente vascular encefálico. A terapia preventiva contra eventos aterotrombóticos é realizada com fármacos antiagregantes plaquetários. O ácido acetilsalicílico (AAS) é um dos fármacos mais utilizados na prevenção de aterotrombose, mas apresenta limitações como indução de ulcerações gástricas e bloqueio de somente uma via de agregação plaquetária. Neste sentido, e em continuidade com a linha de pesquisa visando à busca de novos fármacos antiagregantes plaquetários obtidos por estratégia de modificação molecular implantados no Laboratório de Pesquisa e Desenvolvimento de Fármacos (Lapdesf – UNESP Araraquara), realizou-se a hibridação molecular das subunidades presentes no AAS e furoxanos sendo ambas partes espaçadas pela subunidade N-acilhidrazona. O furoxano é conhecido por suas propriedades doadoras de óxido nítrico (NO) responsável pelo efeito antiagregante plaquetário. Assim, o objetivo deste trabalho é a síntese de novos compostos derivados do AAS, mais potentes e seguros para serem usados como antiagregantes plaquetários. Os ... / Cardiovascular diseases such as myocardial infarction and stroke still represents the leading cause of death in Brazil. Atherosclerosis is a silent progressive disease classified as a risk factor for developing cardiovascular diseases. It is characterized by increased levels of plasma cholesterol which are oxidized by free radicals resulting in oxidized low density lipoprotein (oxLDL). The oxLDL phagocytosis by macrophages allows for transformation into foam cells, which are deposited in the intima of vessels. After the disruption of the endothelium occurs the leak plaque’s contents into the circulation driving to thrombus formation. This blocks the blood flow in arteries and vessels, leading to the development of cardiovascular diseases such as myocardial infarction and stroke. The preventive therapy against atherothrombotic events is performed with antiplatelet drugs. Acetylsalicylic acid (ASA) is a drug commonly used to prevent atherothrombosis, but it has limitations such as induction of gastric ulcer and blocking only one route of platelet aggregation. Continuing goals finding new antiplatelet drugs obtained by molecular modification strategy implemented in the Laboratory of Drug Research and Development (Lapdesf - UNESP Araraquara), held the molecular hybridization of subunits present in AAS and furoxans being spaced by subunit N-acylhydrazone. The furoxano is known for its donor properties of nitric oxide (NO) responsible for the antiplatelet effect. The objective of this work is the synthesis of new compounds derived from AAS, most powerful and safe to use as antiplatelet agents. Compounds were synthesized using divergent route for obtaining derivatives furoxans, N-acilhidrazones spacers and the hybrid compounds. All compounds were purified and characterized by analytical methods such as, Infrared Absorption Spectroscopy, Mass Spectrometry and Nuclear Magnetic Resonance. N-acilhidrazones spacers was possible to perform the ...

Background: Myocardial infarction is one of the most common diseases that cause death in the world. The diagnosis has an immediate impact on the person's life. It's important that nurses are aware of the paramount importance of their role as caregivers and also as their role in monitoring the patient after discharge from hospital. Aim: The aim of the study was to describe patients' experiences after myocardial infarction. Method: In order to understand patients' experiences following myocardial infarction and to contribute to evidence-based nursing, present study was a literature study based on qualitative research. Analysis was conducted according to Friberg's five-step analysis method, which gave four themes and eight subthemes. Results: The result shows that patients had experience of physical and mental changes after myocardial infarction. They felt a loss of energy and strength and experienced fatigue, which limited them in everyday life. Getting support from healthcare professionals was considered important to implement the lifestyle changes that were recommended and to get a pleased recovery. Patients' relatives were also considered important during recovery as they constituted support for the patient and helped them to see a bright future. Conclusion: It´s important that nurses maintain continuous contact with patients after discharge from hospital in order to make a good support system and to encourage the patients for a healthy living.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter that regulates vascular function and blood pressure, and also protects the heart from injury associated with myocardial infarction (MI). The mitochondrial enzyme thiosulfate sulfurtransferase (TST) has a putative role in the breakdown of H2S but its role in the cardiovascular system is unknown. I hypothesised that TST reduces cardiovascular H2S availability and that inhibiting TST activity may therefore ameliorate cardiovascular pathology. In the heart, TST was expressed by cardiomyocytes and vascular smooth muscle cells. Tst-/- mice all survived to adulthood and had normal cardiac structure and function. Cardiac and hepatic H2S breakdown rates were reduced and H2S levels were higher in the blood of Tst-/- mice. However, in heart tissue, protein levels for the H2S-activated Nrf2 downstream targets, thioredoxin (Trx1) and heme oxygenase-1 (HO-1) were comparable. In contrast, protein levels for the cardiac specific H2S-synthetic enzyme, cystathionine gamma lyase (CSE) was reduced, suggesting a homeostatic negative feedback mechanism to maintain H2S at non-toxic levels. Respiration, measured using an oxygen-sensing electrode was normal in isolated mitochondria from whole Tst-/- compared to control C57BL6 hearts. Endothelial nitric oxide synthase (eNOS) protein expression was lower in Tst-/- hearts, highlighting potential cross talk between H2S and nitric oxide (NO) signalling. TST was expressed in whole aorta homogenates and in isolated endothelial cells from aorta and small intramuscular vessels of the hindlimb from C57BL/6N control mice. Myography and western blotting revealed a greater influence of NO in aorta from Tst-/- mice that was associated with increased phosphorylation of the activating serine1177 residue of eNOS (PeNOSSer1177). NO plays a lesser role in resistance arteries, but in comparison to control vessels, small mesenteric vessels from Tst-/- mice was more reliant on small and intermediate calcium activated potassium channels for relaxation. Tst-/- mice were normotensive, despite this alteration in the regulation of vascular tone. However, metabolic cage experiments identified that Tst-/- mice presented with diuresis, polydipsia, and increased urinary electrolyte excretion of sodium, potassium and chloride, possibly to compensate for increased vascular tone in order to maintain stable blood pressure. To investigate the role of TST in regulating the response to pathological challenge, MI was induced by coronary artery ligation (CAL). In control mice, gene expression of CSE was downregulated by 2 days after CAL, but TST expression was 12-fold increased, suggesting regulation of H2S bioavailability during the acute MI-healing phase. Tst-/- male mice had a 40% greater incidence of cardiac rupture during infarct healing and surviving Tst-/- mice had greater left ventricular dilatation and impaired function compared to controls. Ex vivo, isolated perfused hearts from Tst-/- mice were more susceptible to ischaemia/ reperfusion injury, suggesting an additional role of TST in determining cardiomyocyte susceptibility to injury. In conclusion, these data indicate that cardiovascular H2S bioavailability is regulated through degradation by TST. The data presented here provide evidence for significant tissue specific crosstalk between H2S synthetic and degradative mechanisms and between H2S and other local regulatory mechanisms, including ion channels and NOS. We infer TST has a physiological role in the kidney where its loss leads to changes in renal electrolyte and water handling, although other compensatory mechanisms prevent a change in blood pressure. Under conditions of pathological challenge following MI, loss of TST is detrimental, illustrating its key role in removal of H2S. The data refute the original hypothesis that TST inhibition would be protective against cardiovascular pathology. Further studies in mice with tissue specific deletion of TST are now required to more fully reveal the cardiovascular role of TST.

Bakgrund: I Sverige är hjärt- kärl sjukdomar den vanligaste dödsorsaken, år 2016 drabbades 25 700 individer av en akut hjärtinfarkt. Efter att ha drabbats av en hjärtinfarkt medför detta förändringar i kroppen och återhämtningsprocessen kan ta tid. För att bemöta dessa patienter med en individanpassad vård behöver sjuksköterskan ha kunskap om vad som påverkar dessa patienter under återhämtningsprocessen och på så sätt hjälpa patienten i deras behov. Syfte: Syftet var att belysa patientens upplevelser och erfarenheter av att ha drabbats av hjärtinfarkt upp till ett år efter insjuknandet. Metod: En litteraturöversikt där tio kvalitativa artiklar från PsychINFO, PubMed och Cinahl complete har granskats och analyserats. Resultat: I denna litteraturöversikt framkommer tre teman: patientens upplevelser som helhet, behovet av stöd samt ett förändrad syn på livet. I dessa teman beskrivs patienternas upplevelser och erfarenheter av att ha drabbats av hjärtinfarkt samt vilka utmaningar de möter i vardagliga livet. Diskussion: Patienterna möter olika utmaningar i det vardagliga livet efter att ha drabbats av hjärtinfarkt. Dessa förändringar kan upplevas som utmaningar och medförde frånvaro av välbefinnande och hälsa. Det är inte bara kroppen som påverkas och behöver behandling, patienter som drabbas av hjärtinfarkt påverkas psykiskt och fysiskt. Teoretikern Katie Eriksson menar att människan består av kropp, själ och ande vilket  utgör kärnan för hälsoprocessen. Många patienter upplever oro och rädsla av att återigen drabbas av ny hjärtinfarkt. Resultatet visade på betydelsen av att bli informera av sjuksköterskan om vilka utmaningar som patienten möjligen kan möta, rehabiliteringens betydelse, symtom, samt vilka livsstilsförändringar som kan ha positiv påverkan på hälsan och välbefinnandet.

Unlike other regenerative organs such as the liver, the adult mammalian heart does not regenerate tissue lost following injury such as myocardial infarction (MI). Instead a non-contractile fibrous scar develops that in the longer term leads to the development of heart failure (HF). In contrast to the adult, neonatal mammals, including mice and man, retain potent cardiac regenerative capacities and can replace myocardium lost following injury. Understanding the mechanisms underlying scar free repair in the neonate may help in development of new approaches to reduce the impact of myocardial injury in adults. In this thesis MI was induced by coronary artery ligation in mice at post-natal day 1 (P1). Novel electrocardiogram gated high resolution cardiac ultrasound was developed to permit non-invasive confirmation of injury 1 day later and regeneration 21 days later by loss, then restoration, of contractile function. Macrophages (MФ) play important roles in organ growth and homeostasis, and are required for scar-free regeneration of the neonatal mouse heart following MI. WNTs are secreted lipophilic proteins with multiple roles in development. MФ-derived WNTs are essential for scar free tissue regeneration following injury in the kidney, liver, and gut, but their role in the heart is unknown. The primary aim of this thesis was to investigate the role of MФ, and in particular MФ-derived WNTs in determining normal growth of the myocardium from neonate to adult and also in regeneration of the neonatal heart following injury. In wild-type neonatal mouse hearts, Csf1r-expressing cells density (mostly macrophages) was consistent across all time points studied. Three populations of resident cardiac mononuclear phagocytes were identified by flow cytometry: F4/80hi, CD11blo, Ly6C-ve - F4/80lo, CD11bhi, Ly6C-ve - F4/80lo, CD11bhi, Ly6C+ve. F4/80hi, CD11blo, Ly6C-ve cells were hypothesised to correspond to yolk-sac derived mononuclear phagocytes and F4/80lo, CD11bhi, Ly6C-ve - F4/80lo, CD11bhi, Ly6C+ve to foetal liver/bone marrow derived mononuclear phagocytes. Three phases of myocardial growth were identified by ultrasound and histological techniques: hyperplastic (P2-P8, with increased Ki67 and cardiac troponin immunopositive cells), hypertrophic/reorganisation (P8-P21, with increasing cardiomyocyte size and no change in left ventricle wall thickness), and finally hypertrophic solely (P21-P42, with increasing cardiomyocyte size and left ventricle wall thickness). Average coronary vessel size was shown to decrease between P2 and P8 whilst vessel density was increased. The number of α-smooth muscle actin (αSMA) coated vessels greatly increased between P8 and P42, indicating vessel maturation. Throughout all phases cardiac systolic function was maintained at steady state. Diastolic function was however shown to mature from a foetal to an adult pattern between P2 and P8, with reversal of the E:A wave ratio on Doppler ultrasound. In mice globally deficient in MФ due to a germline knock-out of the Csf1r gene (Csf1rnull mice), both body and heart weights were decreased from P7 onwards. The number of proliferating (Ki67+ve) cardiomyocytes at P1 and P7 was unchanged in Csf1r-null mice but there was a trend towards decreased cardiomyocyte size at P7, suggesting an influence on hypertrophic rather than hyperplastic growth of the myocardium. There was also a trend for slowed vascular network maturation, with a delay in the shift from large to smaller vessels in hearts from Csf1r-null mice. In mice with MФ-directed (Csf1r-icre mediated) depletion of Porcupine (Porcn), a gene encoding an enzyme required for WNT acylation and secretion cardiac growth, vascularisation, fibrosis and function were all similar in Cre-ve and Cre+ve animals until P41, when cardiomyocyte size and cardiac systolic function were both significantly increased in Cre+ve animals. However, the underlying mechanism is unknown. In the neonatal mice, Csf1r expressing cells, mostly MФ, were identified in association with regenerating myocardium after induction of MI at P1. Flow cytometry data showed that by P7 the putative resident yolk-sac derived population had mostly disappeared from the heart and was replaced by F4/80lo cells, similar to the pattern reported in the adult. In the regenerating myocardium, Axin2 expression was increased consistent with activation of canonical Wnt signalling. Expression of Wnt5b and Fzd2 receptor, both associated with fibrosis, was significantly increased relative to age matched uninjured hearts. MФ-directed depletion of Porcn did not influence either the functional decrease at day 1 or recovery at day 21 following induction of MI at P1. Coronary re-vascularisation was also unaffected by the genotype. However, retention of intra-myocardial fibrosis (picrosirius red staining) was significantly increased in hearts at day 21 post-MI from mice with MФ-directed depletion of Porcn. MФ-derived WNTs are therefore required for scar-free wound healing in the heart, as they are in the liver and the kidney where they regulate matrix metalloproteinase activity. In summary, novel ECG-gated high-resolution in vivo ultrasound developed in this project has allowed characterisation of cardiac structure and function during early post-natal growth and following injury and regeneration in neonatal mice. The resident MФ population of the heart is established pre-natally, and may play a role in determining maturation of the developing vascular network, although this does not involve MФ-derived Wnt signalling. Following MI, the MФ population may expand from bone marrow cells and MФ accumulate around the regenerating tissue. MФ derived WNTs are not required for regeneration of the neonatal myocardium but do have a role in ensuring scar free wound healing and this merits further investigation.