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Hopkins, James Charles Alex. "Myocardial glycogen, glucose uptake and insulin sensitivity : interrelations and changes with disease." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363766.
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Luongo, Timothy Scott. "The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/437718.
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Biomedical SciencesPh.D.
The high metabolic demand of the heart makes it essential that an efficient and tightly controlled system be in place to regulate energy production. Contractility is mediated by a variable flux in intracellular calcium (iCa2+), which is proposed to be integrated into mitochondria to regulate cardiac energetics. Moreover, mitochondrial Ca2+ (mCa2+)-overload is known to activate the mitochondrial permeability transition pore (MPTP) and induce cell death. However, the true function of cardiac mCa2+ in physiology remains unknown. Recent studies have reported that the Mcu gene encodes the channel-forming portion of the mitochondrial calcium uniporter (MCU) and is required for mCa2+ uptake (Baughman et al., 2011; De Stefani, Raffaello, Teardo, Szabo, & Rizzuto, 2011). To examine the role of mCa2+ in the heart, we generated a conditional, cardiac-specific knockout model and deleted Mcu in adult mice (Mcu-cKO). Loss of Mcu protected against myocardial ischemia-reperfusion (IR) (40 min occlusion of the left coronary artery (LCA) followed by 24h reperfusion) injury by preventing the activation of the MPTP. We observed a 45% reduction in infarct size per area-at-risk and a 65% reduction in cardiac troponin-I serum levels from 24h post-IR. In addition, while we found no baseline phenotype or change in baseline mCa2+ content, Mcu-cKO mice lacked contractile responsiveness to β-adrenergic receptor stimulation (isoproterenol infusion) as assessed by invasive hemodynamics, and, in parallel, were unable to activate mitochondrial dehydrogenases, thereby decreasing tricarboxylic acid (TCA) cycle flux and cardiac NADH. We found that Mcu-cKO mice had a 3-fold increase in pyruvate dehydrogenase (PDH) phosphorylation and a 50% decrease in PDH activity post-isoproterenol infusion. Further experimental analyses in isolated adult cardiomyocytes confirmed a lack of energetic responsiveness to acute sympathetic stress (isoproterenol failure to mediate an increase in oxidative phosphorylation capacity) supporting the hypothesis that the physiological function of the MCU in the heart is to modulate Ca2+-dependent metabolism during the ‘fight or flight’ response. However, questions still remain on how basal mCa2+ levels are regulated and if it contributes to cardiac disease. The mitochondrial sodium/calcium exchanger (mNCX) is hypothesized as the primary mechanism of mCa2+ efflux, but to date no study has confirmed its identity or function in an in vivo system (Palty et al., 2010). To investigate the role of mNCX in the heart, we generated mutant mice with loxP sites flanking exons 5-7 of the candidate gene, Slc8b1, and crossed them with a tamoxifen-inducible, cardiomyocyte-specific, αMHC-Cre mouse to delete mNCX in the adult heart (mNCX-cKO). Biophysical study of cardiomyocytes isolated from mNCX-cKO mice revealed a significant reduction in mCa2+ efflux rate. Tamoxifen-induced deletion of Slc8b1 in adult hearts caused sudden death with less than 15% of mice surviving after 10 days. Echocardiographic evaluation of mNCX-cKO hearts 3d post-tamoxifen revealed significant left ventricular (LV) remodeling, characterized by significant dilation and a substantial decrease in function. In addition, mNCX-cKO hearts exhibited increased reactive oxygen species generation when assessed by DHE imaging of live myocardial tissue and mitoSOX Red imaging in isolated adult cardiomyocytes. Using an Evan’s blue dye exclusion technique, we found that mNCX-cKO hearts displayed significant sarcolemmal rupture (~8% of all myocytes at a single time point 3d post-tamoxifen), indicative of cellular necrosis. To rescue the sudden death phenotype and acute loss of cells, we crossed our mNCX-cKO mice with the cyclophilin d (a mediator of MPTP-opening) knockout mice. mNCX-cKO x CypD-KO mice had a significant improvement in survival and LV-function. In addition, loss of MPTP activation also rescued mitochondrial pathology on the subcellular level. Since deletion of mNCX was detrimental on cardiac function, we thought that increasing mNCX could protect cardiomyocytes by reducing mCa2+-overload during cardiac disease. To test this, we generated a conditional, cardiac-specific mNCX overexpression mouse model (mNCX-Tg) to assess if increasing mCa2+ efflux would prevent cardiac injury in multiple pathological surgical models. mNCX-Tg and controls were subjected to in vivo IR injury followed by 24h reperfusion and myocardial infarction (MI) (permanent LCA ligation). mNCX-Tg mice displayed reduced cell death (a 43% reduction in infarct size 24h post-IR and a 33% reduction in scar size 4w post-MI), preserved LV function, a reduction in ROS generation, and a decrease in numerous HF indices. For the first time, we showed that mNCX is essential for maintenance of the mCa2+ microdomain in cardiomyocytes and that mNCX represents a novel therapeutic target in HF.
Temple University--Theses
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Steeples, Violetta Rae. "Metabolic modulation through deletion of hypoxia-inducible factor-1α and fumarate hydratase in the heart." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:f546ca24-6226-4846-b492-30de26836e94.
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Hypoxia inducible factor-1α (HIF-1α) plays a critical role in the oxygen homeostasis of all metazoans. HIF-1α is a master transcriptional regulator which coordinates the adaptive response to low oxygen tension. Through activation of a plethora of downstream target genes, HIF-1α facilitates oxygenation by promoting angiogenesis and blood vessel dilation, in addition to modulating metabolic pathways to inhibit oxidative phosphorylation and promote glycolytic energy production. Given the critical roles of hypoxia, insufficient blood supply and perturbed energetics in the pathogenesis of cardiovascular disorders, notably ischaemic heart disease, therapeutic modulation of HIF-1α is of significant clinical interest. Previous studies have demonstrated an acute cardioprotective role for both endogenous and supraphysiological HIF-1α signalling in the context of myocardial ischaemia. In contrast, chronic supraphysiological HIF-1α activation in the unstressed heart has been shown to induce cardiac dysfunction. To address the effect of chronic endogenous HIF-1α activation post-myocardial infarction (MI), the present work employed a murine coronary artery ligation (CAL) model in conjunction with temporally-inducible, cardiac-specific deletion of Hif-1α. While CAL surgery successfully modelled myocardial infarction – eliciting substantial adverse cardiac remodelling and contractile dysfunction – there was no evidence of chronic HIF-1α activation by CAL in HIF knockout or control left ventricular samples. In keeping with this, chronic ablation of Hif-1α (from 2 weeks post-CAL) had no discernible additional effect upon cardiac function. Overall, these findings do not support a potential therapeutic role for inhibition of HIF-1α signalling in the chronic phase post-MI. The fundamental tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) converts fumarate to malate. FH deficiency is associated with smooth muscle and kidney tumours which exhibit normoxic HIF signalling due to fumarate accumulation. To investigate the potential for fumarate accumulation to elicit protective HIF signalling, a cardiac-specific Fh1 null mouse was developed through Cre-loxP recombination. Strikingly, despite interruption of the TCA cycle in a highly metabolically demanding organ, cardiac Fh1 null mice were viable, fertile and survived into adulthood, demonstrating the remarkable metabolic plasticity of the heart. However, by 3-4 months Fh1 null mice develop a lethal cardiomyopathy characterised by cardiac hypertrophy, ventricular dilatation and contractile dysfunction. Despite lack of a pseudohypoxic response, Fh1 null hearts did exhibit another phenomenon observed in FH-deficient cancers and also attributed to fumarate accumulation – activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) antioxidant pathway. Heterozygous, but not homozygous, somatic deletion of Nrf2 extended the life expectancy of cardiac Fh1 null mice. Exploration of redox status revealed a more reductive environment in Fh1 null hearts than controls. As a corollary, inhibition of the rate limiting enzyme of the pentose phosphate pathway – a major source of cellular reducing equivalents – with dehydroepiandrosterone conferred striking amelioration of the Fh1 null cardiomyopathy, suggesting a possible pathogenic role for reductive stress. While loss of mitochondrial Fh1 activity and subsequent TCA cycle dysfunction likely contribute to the Fh1 null phenotype, the importance of cytosolic FH was unclear. To clarify this, FH was expressed specifically in the cytosol in vivo. This was sufficient to substantially rescue the Fh1 null cardiomyopathy, supporting a role for cytosolic FH disruption in its pathogenesis. Taken together, these findings highlight the potential for reductive stress to contribute to cardiac dysfunction and suggest a function for cytosolic FH in cardiac metabolic homeostasis.
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Mahmod, Masliza. "Multiparametric cardiovascular magnetic resonance for the assessment of cardiac function and metabolism in hypertrophy and heart failure." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:ff24c167-e00d-4c6d-9809-82203979ba7a.
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Both hypertrophied and failing hearts are characterised by pathological left ventricular (LV) remodelling, impaired myocardial energy status and alteration in substrate metabolism. Cardiac magnetic resonance imaging (CMR) and magnetic resonance spectroscopy (MRS) are powerful tools in the characterisation of these disease conditions. More recent techniques have allowed assessment of myocardial steatosis using 1H-MRS and tissue oxygenation using blood oxygen level dependent (BOLD) CMR. In hypertrophy and heart failure, studies on steatosis and the relationship with other parameters such as myocardial function and fibrosis, especially in humans are limited. I therefore investigated the presence of steatosis in severe aortic stenosis (AS) and dilated cardiomyopathy (DCM), and further assessed its relation to contractile function. This study found that myocardial triglyceride (TG) content is increased in both symptomatic and asymptomatic AS patients (lipid/water ratio 0.89±0.42% in symptomatic AS; 0.75±0.36% in asymptomatic AS vs. controls 0.45±0.17%, both p<0.05) and DCM patients (lipid/ratio 0.64±0.44% vs. controls 0.40±0.13%, p=0.03). Circumferential strain was lower in both AS (-16.4±2.5% in symptomatic AS; -18.9±2.9% in asymptomatic AS vs. controls 20.7±2.0%, both p<0.05) and DCM patients (-12.3±3.4% vs. controls -20.9±1.7%, p<0.001). In AS, myocardial contractility is related to the degree of steatosis, and were both reversible following aortic valve replacement (AVR), lipid/water ratio 0.92±0.41% vs. pre AVR 0.45±0.17%, p=0.04 and circumferential strain -17.2±2.0% vs. pre AVR -19.5±3.2%, p=0.04. A novel finding of this study was significant correlation of MRS-measured TG content with histological staining of TG of the myocardium, taken from endomyocardial biopsy during AVR. In DCM, myocardial TG was independently associated with LV dilatation and correlated significantly with hepatic TG, which suggests that both cardiac and hepatic steatosis might be a common feature in the failing heart. Additionally, although the hypertrophied heart is characterised by impaired perfusion, it is unknown if this is severe enough to translate into tissue deoxygenation and ischaemia. I assessed this by using adenosine vasodilator stress test and BOLD-CMR in patients with severe AS. It was found that AS patients had reduced perfusion (myocardial perfusion reserve index-MPRI 1.0±0.3 vs. controls 1.7±0.3, p<0.001), and blunted tissue oxygenation (blood-oxygen level dependent-BOLD signal intensity-SI change 4.8±9.6% vs. controls 18.2±11.6%, p=0.001) during stress. Importantly, there was a substantial improvement in perfusion and oxygenation towards normal after AVR, MPRI 1.5±0.4, p=0.005 vs. pre AVR and BOLD SI change 16.4±7.0%, p=0.014 vs. pre AVR. Overall, the work in this thesis supports the powerful role of CMR in assessing LV function and elucidating metabolic mechanisms in the hypertrophied and failing heart.
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Dewan, Aaraf. "A Unique Role for Sarcolemmal Membrane Associated Protein Isoform 1 (SLMAP1) as a Regulator of Cardiac Metabolism and Endosomal Recycling." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35088.
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Altered glucose metabolism is the underlying factor in many metabolic disorders, including diabetes. A novel protein recently linked to diabetes through animal and clinical studies is Sarcolemmal Membrane Associated Protein (SLMAP) but its role in metabolism remains undefined. The data here reveals a novel role for SLMAP isoform1 in glucose metabolism within the myocardium. Neonatal cardiomyocytes (NCMs) harvested from hearts of transgenic mice expressing SLMAP1, presented with increased glucose uptake, glycolytic rate, as well as glucose transporter 4 (GLUT4) expressions with minimal impact on lipid metabolism. SLMAP1 expression markedly increased the machinery required for endosomal trafficking of GLUT4 to the membrane within NCMs, accounting for the observed effects on glucose metabolism. The data here indicates SLMAP1 as a unique regulator of glucose metabolism through endosomal regulation of GLUT4 trafficking and suggests it may uniquely serve as a target to limit cardiovascular disease in metabolic disorders such as diabetes.
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Wachowiak, Paul Stephen. "Relationships among Cynical Hostility, Metabolic Syndrome, and Cardiac Structure and Function in Multi-Ethnic Post-Myocardial Infarction Patients: A Structural Modeling Approach." Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_dissertations/291.
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BACKGROUND: Risk factors associated with Metabolic Syndrome (MetS) have been implicated in cardiovascular disease (CVD) development and outcomes. Few studies have investigated relationships between psychological variables, MetS factors, and indices of cardiac structure and function (CSF) among healthy individuals in a single conceptual model. No studies to date have analyzed such relationships in patients with CVD. METHODS: The present study examined associations between cynical hostility (CynHo), MetS factors, and CSF in 186 multi-ethnic post-myocardial infarction (MI) patients. Structural equation modeling was used to test a theory driven model of MetS that had good statistical fit. Primary MetS variables included waist circumference (WC), the homeostatic model of insulin resistance (HOMA-IR), glucose area under the curve (G-AUC), triglycerides (TRIG), high-density lipoprotein cholesterol (HDL-C), and diastolic blood pressures (DBP). Secondary MetS variables included plasminogen activator inhibitor-1 (PAI-1) and a latent inflammation variable comprised of CRP and IL-6. Cardiac function variables were fractional shortening (FS), E/A ratio, and rate-pressure product (RPP). A latent cardiac mass (CM) variable was also created. RESULTS: The final structural model had good model fit (Chi-Square(102)=100.65, p=0.52, CFI=1.00, RMSEA=0.00, and SRMR=0.04). Direct paths were supported between WC and CM and all MetS factors except TRIG and G-AUC. WC was indirectly associated with DBP via CM. The model supported positive direct paths between HOMA-IR and G-AUC, TRIG, and PAI-1, but not inflammation or HDL-C. HOMA-IR demonstrated a direct positive association with RPP and direct inverse associations with FS and E/A ratio. No direct paths were supported between other MetS variables except one between TRIG and HDL-C. CynHo demonstrated a direct positive relationship with HOMA-IR. CONCLUSIONS: Similar to findings in healthy individuals, central adiposity and IR play primary roles in CSF impairment in post-MI patients. Findings suggest that CynHo could promote the progression of metabolic dysfunction and cardiac disease via factors that influence the efficiency of glucose metabolism. Interventions for post-MI patients should take into account both direct and indirect effects of CynHo, central adiposity, and IR on the progression of CVD in this population to reduce adverse outcomes and improve quality of life.
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Cutter, Zachary S. "EFFECTS OF THE NA-CL CO-TRANSPORTER (NCC) IN WESTERN DIET INDUCED METABOLIC AND CARDIAC DYSFUNCTION." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5431.
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Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting blood glucose, and attenuated cardiac diastolic dysfunction after WD compared to wild-type mice. Collectively, the metabolic and cardiac phenotypes of NCCKO mice resembled that of the IL-18KO mice, indicating that NCC may mediate IL-18 signaling in a mouse model of diet-induced obesity and cardiac dysfunction.
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Dumaresq, Danielle Maia Holanda. "AvaliaÃÃo dos efeitos metabÃlico e oxidativo em cirurgia cardÃaca pediÃtrica: influÃncia da tÃcnica anestÃsica." Universidade Federal do CearÃ, 2006. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=409.
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Instituto Dr. Josà FrotaA cirurgia cardÃaca pediÃtrica freqÃentemente necessita de circulaÃÃo extracorpÃrea (CEC) durante a intervenÃÃo cirÃrgica. A combinaÃÃo de estresse cirÃrgico e CEC evoca uma resposta inflamatÃria sistÃmica multifatorial, com ativaÃÃo das cascatas humoral e celular. Somado à isto, a CEC proporciona perÃodos de isquemia-reperfusÃo, levando à condiÃÃes favorÃveis para formaÃÃo de radicais livres e criando uma situaÃÃo de desequilÃbrio que à denominada de estresse oxidativo. As espÃcies reativas do oxigÃnio (ERO) formadas durante o perÃodo de isquemia-reperfusÃo, estÃo intensamente implicadas na patogÃnese da disfunÃÃo miocÃrdica transitÃria (stunning heart), da necrose miocÃrdica devido à peroxidaÃÃo lipÃdica severa, da disfunÃÃo vascular, da morte celular programada (apoptose) e das disritmias pÃs-isquÃmicas. A influÃncia da tÃcnica anestÃsica sobre a resposta metabÃlica e oxidativa foi avaliada em um estudo envolvendo 20 crianÃas portadoras de doenÃas cardÃacas congÃnitas, distribuÃdas aleatoriamente em dois grupos: GP, o grupo em que foi utilizado anestesia venosa total com propofol e GS, grupo em que foi utilizado anestesia balanceada com sevoflurano. Foram determinadas as concentraÃÃes plasmÃticas das SubstÃncias Reativas do Ãcido TiobarbitÃrico (TBARS), glutationa, lactato e piruvato em trÃs tempos: T0 apÃs cateterizaÃÃo da artÃria radial, T1, 30 minutos apÃs o inÃcio da CEC e T2 ao tÃrmino do procedimento. Para a avaliaÃÃo dos marcadores estre os tempos em cada grupo, foi usado o teste de Friedman. A comparaÃÃo das mÃdias entre os dois grupos foi feita atravÃs do teste de Wilcoxon. Realizou-se tambÃm a correlaÃÃo de Pearson, para avaliar os marcadores entre os grupos. Valores de p < 0,05 foram considerados significantes. As concentraÃÃes de TBARS, glutationa, lactato e piruvato nÃo se alteraram significantemente nos tempos observados (p>0,05, teste de Friedman). Ao se comparar os valores mÃdios dos marcadores entre os grupos, nÃo se encontrou diferenÃa significante (p>0,05, teste de Wilcoxon). O quociente obtido da relaÃÃo lactato e piruvato (L/P) foi maior que 10 nos dois grupos, sem significÃncia estatÃstica quando comparado os dois grupos. Encontrou-se uma correlaÃÃo de pearson moderada para o TBARS, durante T1(r=0,50; p=0,13) e T2(r=0,51;p=0,12). Durante a CEC (T1), encontrou-se uma correlaÃÃo alta entre os grupos para o lactato (r=0,68; p=0,02), piruvato (r=o,75; p=0,01) e relaÃÃo L/P (r=0,83; p=0,003). A comparaÃÃo do uso de duas tÃcnicas anestÃsicas com mecanismos de aÃÃo distintos permite confrontar propriedades protetoras jà bem estabelecidas dos anestÃsicos venosos e inalatÃrios. As tÃcnicas anestÃsicas investigadas neste estudo, apresentaram comportamentos semelhantes, nÃo havendo aumento de substratos do estresse metabÃlico e oxidativo, durante a correÃÃo cirÃrgica de cardiopatias congÃnitas em crianÃas acianÃticas.
Pediatric cardiac surgery often requires cardiopulmonary bypass (CPB) during the surgical intervention. CPB and surgical stress combination evokes a multifatorial systemic inflammatory response with activation of the humoral and cellular cascade. In addition, CPB provides ischemia-reperfusion periods, leading to favorable conditions to free radical production and creating an imbalance, knew as oxidative stress. Reactive Oxygen Species (ROS) formed during the ischemia-reperfusion period are strongly implicated in the pathogenesis of the transitory myocardial dysfunction (stunning heart), myocardial necrosis, programmed cell death (apoptosis), vascular dysfunction and postischemic dysrhythmias. The anesthetic technique influence on the metabolic and oxidative response was evaluated in 20 children with congenital heart disease, randomized in two groups: GP, group which used venous total anesthesia with propofol, and GS, the group which used balanced anesthesia with sevoflurano. Thiobarbituric acid-reactive substance (TBARS), glutatione, lactate and pyruvate plasmatic concentrations were determined in three times: T0, after radial artery canulation, T1, 30 minutes after CPB start and T2, at the end of procedure. The markers evaluation in the several times and in each group, the Friedman test was used. The Wilcoxon test was used to compare the medians between the groups. Pearson correlation was done to evaluate the markers between the groups. Values of p<0.05 were considered statistically significant. The TBARS, gluthatione, lactate and pyruvate concentrations did not change significantly in the observed times (p>0,05, Friedman test). When the markerâs median values was compared between the groups, it wasnât significant (p>0,05, Wilcoxon test). The quotient of the relationship between lactate and pyruvate (L/P) was greater than 10 in both groups, with no difference statistically significant. There was a moderate Pearson correlation for TBARS, in T1 (r=0,50; p=0,13) e T2(r=0,51;p=0,12). During the CPB (T1), there was a high Pearson correlation between the groups for lactate (r=0,68; p=0,02), piruvato (r=0,75; p=0,01) e L/P rate (r=0,83; p=0,003). The comparison of two anesthetic techniques with distinct action mechanisms, allow confronting inhalator and venous anesthetic protecting proprieties. The anesthetic techniques investigated in this study were similar, without metabolic and oxidative stress substrates augment, in congenital heart disease surgical correction of acianotic children
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Murray, Andrew James. "Control of cardiac metabolism and efficiency." Thesis, University of Oxford, 2003. http://ora.ox.ac.uk/objects/uuid:858cc1f9-7ba0-4999-a1c8-614a950888c2.
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Quigley, Gillian Margaret. "Inflammation of the heart in heart disease." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/inflammation-of-the-heart-in-heart-disease(eae19e58-aeb4-4673-924e-1dbd1c831fec).html.
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Heart failure patients have dysfunction of the cardiac conduction system that contributes to a high burden of arrhythmias including atrial fibrillation and sudden cardiac death. Heart failure has been associated with the inflammatory response, but it is unknown if inflammation is playing a role in the remodelling of the cardiac conduction system in heart failure. Inflammation has been shown to be present in the myocardium from failing hearts and it is known to have detrimental effects on cardiac function, inducing fibrosis, remodelling of ion channels and even arrhythmias. However, the effect of inflammation on the cardiac conduction system has not been investigated. The aims of this study were to determine if there is an increase of pro-inflammatory cytokines and inflammatory cells in the cardiac conduction system in heart failure. In addition, to identify if there is possible inflammation-associated fibrosis and apoptosis in the cardiac conduction system in heart failure. To test these aims, three models of heart failure were used: a rat model of pulmonary arterial hypertension, a rabbit model of congestive heart failure and a rat model of myocardial infarction. In the rat model of pulmonary arterial hypertension there was a bradycardia, a prolongation of the QT interval, and an increase in the atrioventricular and ventricular refractory periods, suggesting electrical remodelling in these animals. The rats with pulmonary arterial hypertension displayed an increase in pro-inflammatory cytokines such as interleukins 1β and TGFβ in the right side of the heart, including the sinoatrial node and right Purkinje fibres of the cardiac conduction system. In addition, in these areas, there was an increase in components of the extracellular matrix, including fibronectin, collagen I and vimentin. Histology revealed regions of non-myocyte nuclei, only in the right ventricle of the rats with pulmonary arterial hypertension. Immunohistochemistry demonstrated patches of CD68 and vimentin expression (markers for macrophages and fibroblasts, respectively) in the right side of the heart in these animals. TUNEL staining also revealed an increase in apoptosis in the right side of the heart. In the rabbit model of congestive heart failure, the region most affected by inflammation was the right atrium, while few changes were measured in the ventricles or cardiac conduction system. Although these results are surprising, it is suggested that the atria could be more sensitive to the physical stretch produced in this model. In the rat model of myocardial infarction, there were regions of non-myocyte nuclei in the border zone. This region also had increases in pro-inflammatory and fibrosis markers. In conclusion, this work has presented the novel finding that there can be inflammation in the cardiac conduction system in heart failure. This could be contributing to the arrhythmias seen in heart failure patients. This could possibly lead the way to anti-inflammatories as a possible novel therapeutic for heart failure patients.
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Berryman, Barbara Michelle Swindell. "Design of a cardiac fitness and lifestyle management tool for phase III cardiac rehabilitation patients." Thesis, Georgia Institute of Technology, 2002. http://hdl.handle.net/1853/23732.
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Turner, J. E. "Collagen metabolism in normal heart and during cardiac hypertrophy." Thesis, Imperial College London, 1988. http://hdl.handle.net/10044/1/47290.
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Steele, Ian Conrad. "Pathophysiology of chronic cardiac failure." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337046.
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Kreshel, Leigh Anne. "Increasing energy expenditure of cardiac rehabilitation patients." Electronic thesis, 2002. http://dspace.zsr.wfu.edu/jspui/handle/10339/175.
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Hsiao, Lien-Cheng. "Cardiac stem cell therapy for heart failure." Thesis, University of Oxford, 2012. https://ora.ox.ac.uk/objects/uuid:c4fcb449-2d05-4dc6-9a8d-f7450c0b200c.
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Cardiovascular disease is a leading cause of death worldwide and becomes increasingly prevalent in the elderly population. Independent of etiopathogenesis, heart failure (HF) is the final common stage of numerous heart diseases. Cardiac stem cell (CSC) therapy has emerged as a promising cell-based strategy for treatment of HF. However, cell replacement is not able to fully restore a structurally damaged myocardium in advanced and end-stage HF. The objective of this project was to test the following hypotheses: that a bioengineered heart extracellular matrix (ECM) with preserved intact geometric structure could be generated using decellularization by coronary perfusion; and that autologous CSCs, to repopulate this ECM, could be isolated and expanded from the adult heart, with the caveat that autologous CSCs are depleted and impaired by both aging and chronic dilated cardiomyopathy. This will help to develop a possible therapeutic approach for advanced HF, using a combination of CSCs and engineering technique. Resident CSCs were isolated from explant-derived cells (EDCs) and expanded into cardiosphere-derived cells (CDCs) via cardiosphere formation. The CDCs expressed CSC markers (c-kit and Sca-1), pluripotent markers (Oct3/4 and Sox2), and the cardiac lineage-committed marker (Nkx2.5), and showed clonal expansion, self-renewal, and cardiomyogenic potential in vitro. In tissue engineering experiments, CDCs survived and proliferated within biomaterial alginate scaffolds for up to 7 weeks. An engineered bioartificial ECM scaffold was successfully produced from a whole rat heart using retrograde coronary perfusion and possessed an intact 3D architecture with functionally perfusable vascular network. Compared with ventricles, cultures derived from atria produced significantly higher number of c-kit+ and Sca-1+ CSCs (c-kit: 13% vs. 3.4%; Sca-1: 82% vs. 53%, respectively) and exhibited greater clonogenic and proliferative capacity. CDCs could be grown from young and aged mice, but the yield of CSCs significantly declined with age, as did cell migration and differentiation potential. In comparison to wild-type mice, atrial-CDCs from dystrophic mice showed no significant differences in CSC subpopulations and characteristics, despite confirmation of cardiac dysfunction using MRI. In conclusion, CDCs could be considered to be a viable cell candidate for cardiac therapy and may be used to treat HF at various stages, in combination with myocardial tissue engineering.
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Suh, Doug Young. "Knowledge-based boundary detection system : on MRI cardiac image sequences." Diss., Georgia Institute of Technology, 1990. http://hdl.handle.net/1853/13291.
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Kay, Edmund. "Cardiac acoustics : understanding and detecting heart murmurs." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/275992.
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Chong, Yuen-yu. "Psychosocial smoking cessation interventions for hospitalized patients with cardiac disease." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43251146.
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Roberts, Timothy Lloyd. "Linoleic acid and sudden cardiac death." Thesis, University College London (University of London), 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281772.
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Rigatto, Claudio. "Cardiac disease in renal transplant recipients /." St. John's, NF : [s.n.], 2001.
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莊婉瑜 and Yuen-yu Chong. "Psychosocial smoking cessation interventions for hospitalized patientswith cardiac disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43251146.
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Morgan, Eric E. "The Cardiac Fatty Acid Metabolic Pathway in Heart Failure." Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1138394643.
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Mahy, Ian Richard John. "Observations on human peripheral microvascular function in cardiac disease." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308969.
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McCance, Alastai J. "Systemic and cardiac noradrenaline kinetics in ischaemic heart disease in man." Thesis, University of Oxford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235891.
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Jamshidi, Yalda. "Role of PPAR#alpha# in coronary heart disease and cardiac hypertrophy." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252393.
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Zhang, Huajun. "Functional characterisation of cardiac progenitors from patients with ischaemic heart disease." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:3b8a7199-c077-436c-bb89-cd354efe4414.
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Ischaemic heart disease (IHD) is the leading cause of death worldwide. Currently, even optimal medical therapies do not attenuate deterioration of the left ventricular (LV) function completely. Stem cell therapies, and recently cardiac stem cell therapies, have emerged as potential novel treatments for IHD. However, clinical evidence from randomised controlled studies has shown mixed results. Thus understanding what patient-related factors may affect the therapeutic performance of the cells may help improving treatment outcomes. The studies described in this thesis aim to understand how cardiac progenitor cells (CPCs) can re-vascularise ischaemic myocardium and promote functional repair of the heart. Resident CPCs were isolated and expanded from the right atrial appendage of 68 patients following the ‘cardiosphere’ method (cardiosphere-derived cells or CDCs). They resemble mesenchymal progenitors as they lack the expression of endothelial and haematopoietic cell surface markers but express mesenchymal progenitor cell markers (e.g. CD105, CD90). Cell function was evaluated by support of angiogenesis, mesenchymal lineage differentiation potential in vitro, and improvement in heart function in vivo. Notably in vitro, CDC from different patients differed in their angiogenic supportive and differentiation potentials. In a rodent model of myocardial infarction (MI), transplantation of CDC reduced infarct size significantly (p<0.05). However, only those CDCs with a robust pro-angiogenic ability in vitro improved vessel density and heart systolic function (p<0.05) in vivo. A multiple regression model, which accounted for 51% of the variability observed, identified New York Heart Association (NYHA) class, smoking, hypertension, type of ischaemic disease and diseased vessel as independent predictors of angiogenesis. In addition, gene expression analyses revealed that differential gene expression of several extracellular matrix components (e.g. CUX1, COL1A2, BMP1 genes and microRNA-29b) could explain the differences observed in CDC’s vascular supportive function. In summary, this is the first description of variability in the pro-angiogenic and differentiation potential of CDCs and its correlation with their therapeutic potential. This study indicates that patient stratification may need to be included in the design of future trials to improve the efficacy of cell-based therapies.
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De’Ath, Henry D. I. "Trauma associated cardiac injury & dysfunction." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8466.
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The existence of a trauma induced secondary cardiac injury (TISCI) remains in doubt. The risk factors and pathological processes that lead to its development are not known, whilst the effects of TISCI on injured patient outcome are uncertain. Concurrently, the incidence of coronary heart disease (CHD) in a trauma population and its influence on mortality are inconclusive. The aim of this research project was to address these specific areas of uncertainty. Critically injured patients (n=135) were retrospectively investigated for the incidence and nature of adverse cardiac events (ACEs), and levels of the cardiac specific biomarkers Troponin I, B-type Natriuretic Peptide and Heart-type Fatty Acid Binding Protein were measured. Biomarkers and cardiac events were evaluated against outcome. Thereafter, the relationship of pro-inflammatory cytokines with TISCI was explored. A prospective cohort study of 199 trauma patients followed, to confirm the existence of TISCI and describe its clinical features, risk factors and outcomes. Finally, coronary artery calcium, as a marker of CHD, was evaluated on 432 CT scans of the chest of trauma patients aged 45 years or over, and its association with survival after injury was established. ACEs and early biomarker rises occurred in trauma patients and both were unrelated to the severity of chest injury. Each was associated with higher mortality, and confirmed the existence of TISCI. Risk factors for the development of the condition included increasing age, worsening tissue injury and shock. A relationship with cytokines was demonstrated, and implicated acute inflammation in the pathogenesis of TISCI. Calcification on CT scans revealed the incidence of CHD in an injured cohort approached 70%, although its presence did not impact survival. There exists a trauma induced secondary cardiac injury which was related to poorer outcome. The condition was associated with inflammation. CHD was widespread in older trauma patients but was not associated with increased in-hospital mortality.
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Shaw, I., BS Shaw, and GA Brown. "Influence of strength training on cardiac risk prevention in individuals without cardiovascular disease." African Journal for Physical, Health Education, Recreation and Dance, 2009. http://encore.tut.ac.za/iii/cpro/DigitalItemViewPage.external?sp=1001650.
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Abstract
It has widely been shown that exercise, particularly aerobic exercise, has extensive cardioprotective
benefits and is an important tool in the prevention of coronary heart disease (CHD). The present
investigation aimed to determine the multivariate impact of strength training, designed to prevent the
development of CHD, on the Framingham Risk Assessment (FRA) score. Twenty-eight healthy
untrained men with low CHD risk (mean age 28 years and 7 months) participated in an eight-week (3-
d/wk) strength training programme. Self-administered smoking records, resting blood pressures, total
cholesterol (TC), high-density lipoprotein cholesterol (HDLC), FRA scores and absolute 10-year risks
for CHD were determined at the pre-test and post-test. After the eight-week period, no significant (p >
0.05) differences were found in number of cigarettes smoked daily, systolic blood pressure, TC, HDLC,
FRA scores and absolute 10-year risks for CHD in both the strength-trained (n = 13) and non-exercising
control (n = 15) groups. The data indicate that strength training did not reduce the risk of developing
CHD and absolute 10-year risk for CHD as assessed by the FRA score.
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Taylor, Carolyn W. "Breast cancer radiotherapy and heart disease." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:c9dda3ca-8cb3-4a38-938d-0b75b4f6471d.
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Introduction: Some past breast cancer radiotherapy regimens led to an increased risk of death from heart disease. Although heart dose from breast cancer radiotherapy has generally reduced over the past few decades, there may still be some cardiac risk. Estimation of future risk for women irradiated today requires both measurement of their cardiac dose and dose-response relationships, which depend on cardiac dosimetry of past regimens, in conjunction with long-term follow-up data. Methods: Virtual simulation and computed tomography 3-dimensional treatment planning on a representative patient were used to estimate mean heart and coronary artery doses for women irradiated since 1950 in 71 randomised trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. Patient-to-patient variability in cardiac dose was assessed. Heart and coronary artery doses were also calculated for breast cancer radiotherapy regimens used since the 1950s in Sweden. Cardiac doses from contemporary (year 2006) radiotherapy were assessed for 55 patients who received tangential breast cancer irradiation at a large UK radiotherapy centre. The maximum heart distance (i.e. the maximum distance between the anterior cardiac contour and the posterior tangential field edges) was measured for the left-sided patients, and its value as a predictor of cardiac doses assessed. Results: Mean heart dose for women irradiated in the EBCTCG trials varied from <1 to 18 Gray, and mean coronary artery dose from <1 to 57 Gray. Patient-to-patient variability was moderate. Mean heart dose for women irradiated in Sweden since the 1950s varied from <1 to 24 Gray, and mean coronary artery dose from <1 to 46 Gray. Heart dose from tangential irradiation has reduced over the past four decades. However, mean heart dose for left-sided patients irradiated in 2006 was 2 Gray and around half of them still received >20 Gray to parts of the heart and left anterior descending coronary artery. For these patients, maximum heart distance was a reliable predictor of cardiac doses. For the other patients, mean heart dose varied little and was usually less than 2 Gray. Conclusions: Cardiac doses from breast cancer radiotherapy can be estimated reliably and are now available for use in deriving dose-response relationships in the EBCTCG data and in a Scandinavian case-control study. Cardiac dose has reduced over the past four decades. Therefore the cardiac risk is also likely to have reduced. Nevertheless, for some patients, parts of the heart still receive >20 Gray in the year 2006.
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Zhang, Wen. "Cardiac function, energetics and substrate metabolism in mouse models of disease." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444950.
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Stewart, Simon. "Optimising therapeutic efficacy in acute and chronic cardiac disease states /." Title page, contents and abstract only, 1999. http://web4.library.adelaide.edu.au/theses/09PH/09phs851.pdf.
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GREGORY, KIMBERLY NICOLE. "SARCOPLASMIC RETICULUM CALCIUM CYCLING AND CARDIAC DISEASE." University of Cincinnati / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1116008332.
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d'Arcy, Joanna Louise. "Valvular heart disease : novel epidemiological and imaging studies." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25476.
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Since living conditions have improved and antibiotics have entered routine use, valvular heart disease (VHD) in the developed world is mostly degenerative in origin, rather than rheumatic. Our population is increasing with age, and therefore the burden of VHD is likely to increase. Despite this, the epidemiology & prognostication in VHD remain poorly understood. A better understanding of the prevalence of VHD in our population, and improved methods of predicting outcomes, are essential if we are to be better equipped to meet the challenges of this new “epidemic”. This thesis aims to improve our knowledge of the prevalence of VHD in the elderly, and the potential benefits of cardiac magnetic resonance (CMR) assessment of patients with clinically significant mitral regurgitation. The prevalence of undiagnosed valvular heart disease in those aged 65 and over is examined in Chapters 2 and 3. Chapter 2 outlines a population-based screening study for VHD in primary care in Oxfordshire, which the author played a central role in establishing. The results show that VHD is extremely common in this cohort, and is strongly associated with increasing age. In chapter 4, the level of anxiety provoked by screening for VHD is looked at; this demonstrates that only a small number of patients have significant anxiety levels, but it is more likely in those with a new diagnosis of VHD, and in women. From Chapter 5 onwards, the thesis focuses on the use of CMR in patients with significant mitral regurgitation (MR). In Chapter 5, the clinical value of quantitative assessment of MR using CMR is examined, showing that it was able to predict progression to symptoms or surgery in these patients. In conclusion, this thesis offers insights into the prevalence of VHD in the elderly population, and looks at the anxiety associated with looking for VHD in this group. The potential clinical benefits of CMR in patients with MR are examined, and quantification of MR with this modality would appear to be of prognostic utility.
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Soo, Lin Hoe. "Out-of-hospital cardiac arrest in Nottinghamshire." Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.341974.
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Varian, Kenneth Dean. "Cardiac Myofilament Calcium Sensitivity in Health and Disease." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1211898886.
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Thow, Morag Kennedy. "A study of the recruitment patterns of women in cardiac rehabilitation and the evaluation of an exercise based cardiac rehabilitation programme in women post myocardial infarction." Thesis, Glasgow Caledonian University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369996.
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Luk, Ting-hin, and 陸庭軒. "Effect of cardiac rehabilitation on vascular function in patients withcoronary artery disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45153000.
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di, Bernardo Diego. "Computer modelling of cardiac repolarisation for the analysis of the electrocardiogram." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364809.
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Simnett, Sarah Jacqueline. "Relaxation processes in cardiac muscle." Thesis, University of Oxford, 1993. http://ora.ox.ac.uk/objects/uuid:9b670123-f816-42be-8d74-c37917af200b.
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Leong, Yuk-yan Pauline, and 梁玉恩. "The effectiveness of exercise-based cardiac rehabilitation program for secondary prevention of coronary heart disease : a systematic review." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193828.
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Objective: To examine the effect of exercise-based cardiac rehabilitation program for secondary prevention of coronary heart disease on cardiac-related mortality, recurrent cardiovascular event and quality of life.
Methods: All studies published between 1990 and 2013 in PubMed, and from 1980 to 2013 in EMBASE, which evaluated the effectiveness of exercise-based cardiac rehabilitation program for coronary heart disease. Using the specific keywords “Cardiac rehabilitation”, “Coronary heart disease” OR “Ischemic heart disease” [MeSH], “Exercise” OR “Physical activities” AND “Quality of life” OR “Mortality” AND Cardiovascular events” were searched. A total of 7randomized controlled trials out of 5,051articles from PubMed and 117 articles from EMBASE were included in this systematic review. The primary outcome measures used in the included seven studies were HRQOL, restenosis, cardiac event, cardiac related mortality. Similar demographic and clinical characteristics of the subjects between the intervention and the control groups were recorded. The studies were from five countries. The average age of the subjects in the seven studies was 61years, the average half of them have history of myocardial infarction. Though there were discrepancies among the results generated in the included studies, the potential benefits of exercise-based cardiac rehabilitation could be seen.
Results: Compared with the non-exercise-based cardiac rehabilitation, patients allocated to the exercise-based cardiac rehabilitation program had greater improvement in HRQOL and reduction of cardiac events. The result of reducing restenosis was inconsistent. The cardiac related mortality is not significant difference between exercise-based and non-exercise-based cardiac rehabilitation.published_or_final_version
Public Health
Master
Master of Public Health
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Sammut, Eva Clare. "Advanced cardiac magnetic resonance imaging in heart failure and coronary artery disease." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/advanced-cardiac-magnetic-resonance-imaging-in-heart-failure-and-coronary-artery-disease(edf62114-1762-4830-a456-2aa8886ef130).html.
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Recent technical developments have increased the scope for cardiac MRI as a research tool. This work presents novel approaches to the assessment of patients with coronary disease and heart failure. The thesis explores coronary physiology and microarchitecture, ischaemia and perfusion CMR, and in particular the quantification of ischaemia. In addition, in-vivo cardiac diffusion tensor imaging is employed to characterize microarchitecture in heart failure. This work comes to a number of conclusions. We have been able to show, for the first time in patients with heart failure, that even in patients who have thinned and remodelled ventricles, quantitative assessment with high resolution quantitative CMR is feasible and reproducible. Our work is also the first to perform assessment of the prognostic use of quantitative perfusion CMR - in a large group of unselected patients presenting with suspected coronary disease, we have investigated the prognostic value of a quantitative approach. This observational study proposes that this performs at least as well as visual assessment by expert readers. Furthermore, the thesis explores the correlation between CMR and PET using a specialized cardiac phantom which simulates perfusion and a hybrid CMR-PET scanner. In this setting, we have concluded that there is excellent correlation between MR, PET and known true perfusion values. This thesis also presents work on the use of cardiac diffusion tensor imaging in dilated cardiomyopathy, the first study to do so using a dual-phase in-vivo approach. We have been able to demonstrate significant differences in fibre and sheetlet orientation by comparison to controls. Our study used biomechanical modelling and strain data from 3D tagging CMR. Overall this work adds to the body of knowledge of quantitative perfusion CMR analysis and cardiac DTI and merits further larger studies, particularly with regard to translation to the clinical setting.
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Clarkson, Peter Bruce Mark. "Studies of left ventricular diastolic function inhealth and disease." Thesis, University of Dundee, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337397.
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Colegrave, Melanie. "Expression of #beta#-cardiac myosin in a myogenic cell line." Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342254.
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Klipp, Robert Carl. "Catecholamine Interactions with the Cardiac Ryanodine Receptor." PDXScholar, 2013. https://pdxscholar.library.pdx.edu/open_access_etds/1439.
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The cardiac ryanodine receptor (RyR2) is a Ca2+ ion channel found in the sarcoplasmic reticulum (SR), an intracellular membranous Ca2+ storage system. It is well known that a destabilization of RyR2 can lead to a Ca2+ flux out of the SR, which results in an overload of intracellular Ca2+; this can also lead to arrhythmias and heart failure. The catecholamines play a large role in the regulation of RyR2; stimulation of the Beta-adrenergic receptor on the cell membrane can lead to a hyperphosphorylation of RyR2, making it more leaky to Ca2+. We have previously shown that strong electron donors will inhibit RyR2. It is hypothesized that the catecholamines, sharing a similar structure with other proven inhibitors of RyR2, will also inhibit RyR2. Here we confirm this hypothesis and show for the first time that the catecholamines, isoproterenol and epinephrine, act as strong electron donors and inhibit RyR2 activity at the single channel level. This data suggests that the catecholamines can influence RyR2 activity at two levels. This offers promising insight into the potential development of a new class of drugs to treat heart failure and arrhythmia; ones that can both prevent the hyperphosphorylation of RyR2 by blocking the Beta;-adrenergic receptor, but can also directly inhibit the release of Ca2+ from RyR2.
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Tien, Pamela. "Reductive metabolism of aliphatic tertiary amine n-oxides." Thesis, De Montfort University, 1999. http://hdl.handle.net/2086/10714.
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This study is based on a proposal concerning the feasibility of using aliphatic tertiary amine N-oxides as antiarrhythmic agent prodrugs. Lignocaine was selected as a candidate for prodrug development, because the N-oxide is a non-active, polar derivative of lignocaine and the drug of choice for ventricular arrhythmia, a symptom associated with ischaemic episodes leading to regions of transiently hypoxic heart tissue. An HPLC analytical method was developed to study the metabolism of lignocaine N-oxide. The rapid and sensitive analysis of lignocaine and its metabolites was demonstrated with good reproducibility, stability and high recovery. In this study, it was identified that lignocaine N-oxide can be reduced to its active parent compound, lignocaine with no other metabolites detected in the absence of oxygen. Under anaerobic conditions, no further metabolism of lignocaine was demonstrated in rat liver microsomes and heart S9 fractions suggesting no secondary metabolites were formed. The reduction of lignocaine N-oxide has been shown to be both enzymic and non-enzymic, NADPH dependent, oxygen sensitive and can be suppressed by CO, CN- and protein denaturation. Under anaerobic conditions, in vitro lignocaine N-oxide reduction was found to occur in NADPH supplemented rat liver homogenates, microsomal suspensions; rat heart homogenates, cytosolic solutions; human phenotyped cytochrome P450 isoforms; purified enzymes- cytochrome P450 reductase, xanthine oxidase, deoxymyoglobin and NADPHI ascorbate reduced protohaem (haemin). This reaction can be suppressed through the chemically mediated decrease ofP450 and bs levels in rat liver microsomes. Previous studies demonstrated that lignocaine N-oxide was non-active in aerobic rat heart in vivo and was potent under ischaemic conditions. In this study, high recovery of lignocaine N-oxide was found in the urine of normal rats suggesting low metabolism of the prodrug in oxic tissues. However, in hypoxic isolated rat hearts, lignocaine N-oxide was found to be reduced to lignocaine. The data presented suggested that the bioactivation of lignocaine N-oxide could be regulated by the prevailing oxygen tension in the ischaemic arrhythmic heart. Essentially the pro drug activation of lignocaine N-oxide may be triggered by the ischaemic state of the heart and terminated as the oxygen content in the heart returns to a more normal level. A controlled release and site-specific active drug delivery of lignocaine N-oxide, a hypoxia-mediated antiarrhythmic agent, may thus be achieved.
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Rahimi-Larijani, B. "Dynamic Fourier phase and amplitude analysis and computational techniques in gated cardiac scintigraphy." Thesis, University of Brighton, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382224.
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Mansor, Latt Shahril. "Effect of hypoxia on cardiac metabolism and function in the type 2 diabetic heart." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:e84a3068-0c7d-46d7-a37f-3433cc06b3d4.
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Type 2 diabetic patients have impaired cardiac ischaemia-reperfusion recovery and higher rates of mortality following a myocardial infarction. Hypoxia is a key component of ischaemia and therefore, this thesis is aimed to investigate the effect of hypoxia on metabolism and contractile function of the type 2 diabetic heart. In combination with high fat feeding, different doses of streptozotocin (STZ) (15, 20, 25 and 30 mg/kg) were used to determine the optimal dose needed for induction of diabetes in male Wistar rats. A novel type 2 diabetic model was developed and characterised by hyperinsulinaemia, hyperglycaemia and dyslipidaemia. The effects of chronic hypoxia were investigated by housing diabetic rats in a hypoxic chamber (11% O2) for 3 weeks. Results showed that the HIF signalling pathway was not impaired in diabetic hearts. PPARa targets (MCAD, UCP3 and PDK4) were downregulated by chronic hypoxia in control hearts but not in diabetic hearts, suggesting PPARa overactivation in diabetic hearts. Acute hypoxic perfusions (16 minutes normoxia, 36 minutes hypoxia and 20 minutes reoxygenation) were performed to investigate the effect of acute hypoxia on metabolism and cardiac function. Diabetic hearts had impaired metabolic response to acute hypoxia, associated with decreased cardiac function during acute hypoxia and reoxygenation. In the final study, sulfo-N-succinimidyl oleate (SSO), a FAT/CD36 inhibitor was administered prior to acute hypoxia to modulate metabolism in diabetic hearts. The previously seen maladaptation of diabetic hearts to acute hypoxia was improved by SSO. In diabetic hearts, SSO increased glycolysis during acute hypoxia, and normalised fatty acid oxidation and decreased triglyceride deposition upon reoxygenation, associated with improved cardiac function at the end of experiment compared to untreated diabetic hearts. In conclusion, the elevated lipid metabolism contributed to metabolic inflexibility in diabetic hearts, which is associated with the impaired response to hypoxia, and the inhibition of lipid metabolism was associated with improved cardiac function in diabetic hearts following hypoxia.
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Watkins, Hugh Christian. "Demonstrations that cardiac troponin T mutations cause hypertrophic cardiomyopathy." Thesis, St George's, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269224.
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de, Gannes Matthew K. "Dioxin Impact on Cardiac Development, Structure, Function, and Health, and Implications for Disease." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613748020897261.
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Chung, Jae-Hoon. "Regulation of Human Cardiac Muscle Contraction and Relaxation in Health and Disease." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1522851185767187.
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