Dissertationen: „Heart Muscles Diseases“

1

Gieseking, Elizabeth Robinson. „Control mechanism for the papillary muscles of the mitral valve : an In Vitro study“. Thesis, Georgia Institute of Technology, 1989. http://hdl.handle.net/1853/10912.

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2

Warner, Anke Sigrid. „The expression, regulation and effects of inducible nitric oxide synthase in hibernating myocardium“. Title page, contents and summary only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phw279.pdf.

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Amendments inserted at back. "May 2002" Includes bibliographical references (leaves 237-290) Experiments described in this thesis address the potential role of inducible nitric oxide synthase (iNOS) in hibernating myocardium. Specifically it was sought to establish a cellular model of hibernating myocardium and investigate the expression, regulation and effects of iNOS in this model. Experiments were performed using primary cultures of neonatal rat ventricular myocytes.

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3

Messaggi-Sartor, Monique 1984. „Respiratory muscle dysfunction in respiratory and non-respiratory diseases : clinical and therapeutic approaches“. Doctoral thesis, Universitat Pompeu Fabra, 2017. http://hdl.handle.net/10803/565809.

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Respiratory muscle dysfunction is a clinical condition that may be present in both respiratory and non-respiratory diseases. This impairment of muscle function can have a negative effect on clinical outcomes, contributing to a further worsening of the patient’s clinical condition. This doctoral thesis has been directed by the ‘Rehabilitation Research Group’ (RERG) in collaboration with the Muscle Wasting and Cachexia in Chronic Respiratory Diseases and Lung Cancer Group (Lung Cancer and Muscle Research Group) of the Institut Hospital del Mar d’Investigacions Mèdiques (IMIM) in Barcelona. Muscle dysfunction has been a priority area of research in these groups from different perspectives: exercise and muscle training in the RERG, Physiopathology and Molecular Biology in the Lung Cancer and Muscle Research Group. The large number of published studies in journals with high impact factor endorses the quality and leadership of these research groups. Up to then, research on RMT had focused on patients with chronic obstructive pulmonary disease, but had been scarcely addressed in other conditions. In the last 5 years, the RERG has aimed to study the effects of RMT in other respiratory diseases (bronchiectasis, lung cancer) and in non-respiratory diseases. The study of respiratory muscle dysfunction in stroke patients has made it possible to start an increasing collaboration with neurorehabilitation researchers, in which RMT plays a role in the management of patients with dysphagia.
La disfunción muscular respiratoria es una condición clínica que puede estar presente tanto en las enfermedades respiratorias como no respiratorias. Este deterioro de la función muscular puede tener un efecto negativo en los resultados clínicos, lo que contribuye a un mayor empeoramiento de la condición clínica del paciente. Esta tesis doctoral ha sido dirigida por el "Grupo de Investigación en Rehabilitación" (RERG) en colaboración con el Grupo de Investigación de Enfermedades Respiratorias Crónicas y Cáncer de Pulmón (Grupo de Investigación de Cáncer de Pulmón y Músculo) del Instituto Hospital del Mar de Investigaciones Mèdiques (IMIM) en Barcelona. La disfunción muscular ha sido un área prioritaria de investigación en estos grupos desde diferentes perspectivas: ejercicio y entrenamiento muscular en el RERG, Fisiopatología y Biología Molecular en el Cáncer de Pulmón y el Grupo de Investigación Muscular. El gran número de estudios publicados en revistas con alto factor de impacto refuerza la calidad y liderazgo de estos grupos de investigación. Hasta entonces, la investigación sobre RMT se había centrado en los pacientes con enfermedad pulmonar obstructiva crónica, pero apenas se había abordado en otras condiciones. En los últimos 5 años, el RERG se ha propuesto estudiar los efectos de la RMT en otras enfermedades respiratorias (bronquiectasias, cáncer de pulmón) y en enfermedades no respiratorias. El estudio de la disfunción de los músculos respiratorios en los pacientes con ictus ha permitido iniciar una creciente colaboración con los investigadores de neurorehabilitación, en los que RMT desempeña un papel en el tratamiento de los pacientes con disfagia.

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4

Spinner, Erin M. „Tricuspid valve mechanics: understanding the effect of annular dilatation and papillary muscle displacement“. Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/45754.

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Tricuspid regurgitation (TR), back flow of blood from the right ventricle to the right atrium, has been reported in approximately 85% of the population, with 16% having mild or severe TR. Patients with untreated moderate to severe TR are likely to experience decreased exercise capacity and have increased morbidity and mortality, thus affecting the patient's quality of life. Current methods of repair offer limited rates of success, and many patients require further operations to correct returning levels of TR. Incomplete repair may be due to incomplete understanding of the functional anatomy and mechanics of the TV and the underlying causes of TR. It was hypothesized that alterations in the geometry of tricuspid valve annular and subvalvular apparatus induced by ventricular dilatation determine the severity of TR. In vivo measurements of papillary muscle (PM) position in patients with single or biventricular dilatation revealed PM displacement away from the center of the annulus as compared to control patients. Additionally, pulmonary arterial pressure, annulus area, ventricular size and apical displacement of the anterior PM were highly correlated with the severity of TR. An in vitro right-heart simulator was developed to investigate isolated mechanics of TR. Through these in vitro studies it was demonstrated that the tricuspid valve begins to leak at only 40% dilation, much lower than the mitral valve. Additionally, it was shown that isolated PM displacement resulted in significant TR. The highest levels of TR were achieved with a combination of annular dilatation and PM displacement. Alterations in leaflet coaptation, as quantified by measuring the amount of leaflet available for coaptation and leaflet mobility were observed with annular dilatation and PM displacement, both isolated and combined. The changes in leaflet coaptation resulted in redistribution of the forces on the chords originating from the anterior PM and inserting into the anterior and posterior leaflets. The findings herein provide the clinical and scientific community with a mechanistic understanding of the tricuspid valve to further improve intervention and repair of TV disease.

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5

Yentrapalli, Venkata Ramesh. „Novel radiation targets in the endothelium and heart muscle“. Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-90429.

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Worldwide, people are being exposed to natural and man-made sources of radiation. Epidemiological studies have shown an increased risk of vascular diseases in populations that have been exposed to ionizing radiation. Vascular endothelium is implicated as one of the targets for radiation leading to the development of cardiovascular diseases. However, the molecular mechanisms behind the development of radiation-induced cardiovascular disease in acute or chronic exposed people are not fully elucidated. The hypothesis that chronic low dose rate ionizing radiation accelerates the onset of senescence of primary human umbilical vein endothelial cells has been tested in papers I and II presented in this thesis. In vitro studies show that, when exposed to continuous low dose rate gamma radiation these cells enter premature senescence much earlier than non-irradiated control cells. Quantitative proteomic analysis using isotope coded protein labeling coupled to LC-ESI-mass spectrometry and followed by protein network analysis identified changes in senescence-related biological pathways including cytoskeletal organisation, cell-cell communication and adhesion, and inflammation influenced by radiation. Moreover, the role of PI3K/Akt/mTOR pathway was implicated during the senescence process. Thus, chronic low dose rated endothelial senescence may contribute to increased risk of radiation-induced cardiovascular disease. Paper III analyse the long-term effects of local high doses of radiation to the heart using a mouse model. The results from proteomic and bioinformatics analysis indicated that an impaired activity of the peroxisome proliferator-activated receptor-alpha (PPARA) is involved in mediating the radiation response. Ionizing radiation markedly changed the phosphorylation and ubiquitination status of PPARA. This was reflected by the decreased expression of PPARA target genes involved in energy metabolism and mitochondrial respiratory chain. This in vivo study suggests that alteration of cardiac metabolism contributes to the impairment of heart structure and function after radiation. Taken together, these in vitro and in vivo studies provide novel information on the pathways in heart and endothelial cells that are affected over longer periods of time by ionizing radiation.

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6

Pandofino, Alexandra. „A molecular analysis of the basis of cardiovirulence of Coxsackievirus B3“. Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267166.

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7

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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8

Vesier, Carol Cockerham. „The role of papillary muscle-mitral valve geometry in systolic anterior motion of the mitral valve“. Diss., Georgia Institute of Technology, 1991. http://hdl.handle.net/1853/10279.

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9

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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10

Johnson, Andrew William. „Metabolic control of energetics in human heart and skeletal muscle“. Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:82c0dce6-a162-4c08-b061-3ea7f2e35134.

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Myocardial and skeletal muscle high energy phosphate metabolism is abnormal in heart failure, but the pathophysiology is not understood. Plasma non-esterified fatty acids (NEFA) increase in heart failure due to increased sympathetic drive, and regulate the transcription of mitochondrial uncoupling protein-3 (UCP3), through peroxisome proliferator-activated receptor-α. The aim of the work in this thesis was to determine whether cardiac PCr/ATP ratios and skeletal muscle PCr kinetics during exercise were related to cardiac and skeletal muscle UCP3 levels respectively, thus providing a mechanism for the apparent mitochondrial dysfunction observed in heart failure. Patients having cardiac surgery underwent pre-operative testing, including cardiac and gastrocnemius 31P magnetic resonance spectroscopy. Intra-operatively, ventricular, atrial and skeletal muscle biopsies were taken for measurement of mitochondrial protein levels by immunoblotting, along with mitochondrial function by tissue respiration rates. Fasting plasma NEFA concentrations increased in patients with ventricular dysfunction and with New York Heart Association (NYHA) class. Ventricular UCP3 levels increased and cardiac PCr/ATP decreased with NYHA class, however, demonstrated no relationship to each other. In skeletal muscle, maximal rates of oxidative ATP synthesis (Qmax) related to functional capacity. Skeletal muscle UCP3 levels increased with NYHA class but were unrelated to skeletal muscle Qmax. Tissue respiration experiments revealed no relationship between ventricular function and indices of mitochondrial coupling, furthermore, indices of mitochondrial coupling were unrelated to tissue UCP3 levels. No evidence was found to support mitochondrial uncoupling, mediated through UCP3, as a cause of the abnormalities in cardiac and skeletal muscle high energy phosphate metabolism.

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11

Andersen, Kasper. „Physical Activity and Cardiovascular Disease“. Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-217309.

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The aim was to investigate associations of fitness and types and levels of physical activity with subsequent risk of cardiovascular disease. Four large-scale longitudinal cohort studies were used. The exposures were different measures related to physical activity and the outcomes were obtained through linkage to the Swedish In-Patient Register. In a cohort of 466 elderly men without pre-existing cardiovascular disease, we found that skeletal muscle morphology was associated with risk of cardiovascular events. A high amount of type I (slow-twitch, oxidative) skeletal muscle fibres was associated with lower risk of cardiovascular events and high amount of type IIx was associated with higher risk of cardiovascular events. This association was only seen among physically active men. Among 39,805 participants in a fundraising event, higher levels of both total and leisure time physical activity were associated with lower risk of heart failure. The associations were strongest for leisure time physical activity. In a cohort of 53,755 participants in the 90 km skiing event Vasaloppet, a higher number of completed races was associated with higher risk of atrial fibrillation and a higher risk of bradyarrhythmias. Further, better relative performance was associated with a higher risk of bradyarrhythmias. Among 1,26 million Swedish 18-year-old men, exercise capacity and muscle strength were independently associated with lower risk of vascular disease. The associations were seen across a range of major vascular disease events (ischemic heart disease, heart failure, stroke and cardiovascular death). Further, high exercise capacity was associated with higher risk of atrial fibrillation and a U-shaped association with bradyarrhythmias was found. Higher muscle strength was associated with lower risk of bradyarrhythmias and lower risk of ventricular arrhythmias. These findings suggest a higher rate of atrial fibrillation with higher levels of physical activity. The higher risk of atrial fibrillation does not appear to lead to a higher risk of stroke. In contrast, we found a strong inverse association of higher exercise capacity and muscle strength with vascular disease. Further, high exercise capacity and muscle strength are related to lower risk of cardiovascular death, including arrhythmia deaths. From a population perspective, the total impact of physical activity on cardiovascular disease is positive.

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12

Gonçalves, Ana Clara Campagnolo Real [UNESP]. „Exercício resistido em cardiopatas: revisão sistemática da literatura e análise do comportamento autonômico em recuperação pós-exercício resistido aplicado de forma aguda“. Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/87292.

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Made available in DSpace on 2014-06-11T19:22:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-12-10Bitstream added on 2014-06-13T19:47:20Z : No. of bitstreams: 1 goncalves_accr_me_prud.pdf: 684147 bytes, checksum: a81c4f89900e68d55d13d636f49523a1 (MD5)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A perda de massa muscular secundária à idade e à inatividade física é clinicamente relevante na população cardíaca, contudo a prescrição do exercício resistido dinâmico para esses pacientes apresenta-se inconclusiva na literatura. Objetivo: Reunir informações sobre a especificidade dos componentes do treinamento resistido prescrito à população cardiopata. Metodologia: Foi realizada busca sistemática de literatura, a partir das bases de dados LILACS, SciELO e PubMed, utilizando os seguintes descritores na língua portuguesa: força muscular, exercício isométrico, esforço físico, cardiopatia e coronariopatia, e seus correspondentes na língua inglesa (muscle strength, isometric exercise, physical effort, heart disease e artery coronary disease), os quais foram...
Loss of muscle mass secondary to age and physical inactivity is clinically relevant in cardiac population, however dynamic resistance exercise prescription to these patients presents inconclusive in literature. Objective: Adjoin information about specific components of resistance exercise prescribed to cardiac population. Methodology: Systematic search was performed, using the data bases LILACS, SciELO and PubMed. The descriptors used were: muscle strength, isometric exercise, physical effort, heart disease and artery coronary disease, which were surveyed separately and combined, considering for this review articles that ... (Complete abstract click electronic access below)

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13

Morris, Robert Tyler. „Maladaptation of cardiac and skeletal muscle in chronic disease effects of exercise /“. Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://edt.missouri.edu/Summer2007/Dissertation/MorrisR-080307-D8225/.

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Thesis (Ph. D.)--University of Missouri-Columbia, 2007.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "August 2007" Includes bibliographical references.

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14

Bundgaard, Henning. „Potassium regulation in heart and skeletal muscles : relation to level of K intake, disease mechanisms and pharmacotherapy /“. København : Lægeforeningen, 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=013175180&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.

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15

Natarajan, Aruna Ramachandran. „Mechanism of dopamine-mediated activation of BK channels in human coronary artery smooth muscle cells“. Connect to Electronic Thesis (ProQuest) Connect to Electronic Thesis (CONTENTdm), 2008. http://worldcat.org/oclc/457179694/viewonline.

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16

Gonçalves, Ana Clara Campagnolo Real. „Exercício resistido em cardiopatas : revisão sistemática da literatura e análise do comportamento autonômico em recuperação pós-exercício resistido aplicado de forma aguda /“. Presidente Prudente : [s.n.], 2010. http://hdl.handle.net/11449/87292.

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Orientador: Luiz Carlos Marques Vanderlei
Banca: Carlos Marcelo Pastre
Banca: Francis da Silva Lopes
Resumo: A perda de massa muscular secundária à idade e à inatividade física é clinicamente relevante na população cardíaca, contudo a prescrição do exercício resistido dinâmico para esses pacientes apresenta-se inconclusiva na literatura. Objetivo: Reunir informações sobre a especificidade dos componentes do treinamento resistido prescrito à população cardiopata. Metodologia: Foi realizada busca sistemática de literatura, a partir das bases de dados LILACS, SciELO e PubMed, utilizando os seguintes descritores na língua portuguesa: força muscular, exercício isométrico, esforço físico, cardiopatia e coronariopatia, e seus correspondentes na língua inglesa (muscle strength, isometric exercise, physical effort, heart disease e artery coronary disease), os quais foram ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Loss of muscle mass secondary to age and physical inactivity is clinically relevant in cardiac population, however dynamic resistance exercise prescription to these patients presents inconclusive in literature. Objective: Adjoin information about specific components of resistance exercise prescribed to cardiac population. Methodology: Systematic search was performed, using the data bases LILACS, SciELO and PubMed. The descriptors used were: muscle strength, isometric exercise, physical effort, heart disease and artery coronary disease, which were surveyed separately and combined, considering for this review articles that ... (Complete abstract click electronic access below)
Mestre

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17

Jacob, Ashok J. „A study of the prevalence, pathogenesis and natural history of heart muscle disease associated with HIV infection“. Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/20587.

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Heart muscle disease was found in 14.2% of HIV patients and took three principal forms - dilated cardiomyopathy, borderline left ventricular dysfunction and isolated right ventricular dilation. Dilated cardiomyopathy was associated significantly with a very low CD4 count indicative of late stage HIV disease. It was invariably irreversible. In contrast, some patients with borderline left ventricular dysfunction and isolated right ventricular dilation subsequently reverted to normal. The latter was usually related to pressure or volume overload of the right ventricle rather than to a primary myopathic process. Survival curves were calculated and these showed that HIV patients with dilated cardiomyopathy met a significantly earlier death from an AIDS related condition than those from all the other groups, even after accounting for their low CD4 count. This remained true when patients with dilated cardiomyopathy were matched individually with a group of patients identical in every respect except for the presence of cardiac disease. Heart muscle disease in HIV infection is common and takes a number of forms. Dilated cardiomyopathy occurs in late stage disease, is invariably irreversible and is associated with a particularly poor prognosis. This is in contrast to borderline left ventricular dysfunction and isolated right ventricular dilation which occur at an earlier stage of HIV infection, are potentially reversible and do not carry adverse prognostic implications. Neither infection with Toxoplasma gondii and cytomegalovirus nor treatment with zidovudine appear to have a primary role in the development of heart muscle disease. Although HIV is often found within the myocardium, it does not appear to replicate within this tissue. Low serum selenium concentrations are widespread in HIV patients but do not correlate with cardiac dysfunction.

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18

Chappell, Joel. „Vascular smooth muscle cell heterogeneity and plasticity in models of cardiovascular disease“. Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/274543.

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Vascular smooth muscle cell (VSMC) accumulation is a hallmark of atherosclerosis and vascular injury. However, fundamental aspects of proliferation and the phenotypic changes within individual VSMCs, which underlie vascular disease remain unresolved. In particular, it is not known if all VSMCs proliferate and display plasticity, or whether individual cells can switch to multiple phenotypes. To assess whether proliferation and plasticity in disease is a general characteristic of VSMCs or a feature of a subset of cells, multi-colour lineage labelling is used to demonstrate that VSMCs in injury-induced neointimal lesions and in atherosclerotic plaques are oligo-clonal, derived from few expanding cells, within mice. Lineage tracing also revealed that the progeny of individual VSMCs contribute to both alpha Smooth muscle actin (aSma)-positive fibrous cap and Mac-3-expressing macrophage-like plaque core cells. Co-staining for phenotypic markers further identified a double-positive aSma+ Mac3+ cell population, which is specific to VSMC-derived plaque cells. In contrast, VSMC-derived cells generating the neointima after vascular injury generally retained expression of VSMC markers and upregulation of Mac3 was less pronounced. Monochromatic regions in atherosclerotic plaques and injury-induced neointima did not contain VSMC-derived cells expressing a different fluorescent reporter protein, suggesting that proliferation-independent VSMC migration does not make a major contribution to VSMC accumulation in vascular disease. Similarly, VSMC proliferation was examined in an Angiotensin II perfusion model of aortic aneurysm in mice, oligo-clonal proliferation was observed in remodelling regions of the vasculature, however phenotypic changes were observed in a large proportion of VSMCs, suggesting that the majority of VSMCs have some potential to modulate their phenotype. To understand the mechanisms behind the inherent VSMC heterogeneity and observed functionality, the single cell transcriptomic techniques Smart-seq2 and the Chromium 10X system were optimized for use on VSMCs. The work within this thesis suggests that extensive proliferation of a low proportion of highly plastic VSMCs results in the observed VSMC accumulation after injury, and the atherosclerotic and aortic aneurysm models of cardiovascular disease.

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19

Maddali, Kamala Kalyani. „A mandatory requirement of PKC-[delta] in testosterone regulated coronary smooth muscle cell differentiation, proliferation and apoptosis /“. Free to MU Campus, others may purchase, 2005. http://proquest.umi.com/pqdweb?did=1232392431&sid=1&Fmt=2&clientId=45247&RQT=309&VName=PQD.

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20

Ohnaka, Motoaki. „Effect of microRNA-145 to prevent vein graft disease in rabbits by regulation of smooth muscle cell phenotype“. Kyoto University, 2014. http://hdl.handle.net/2433/192144.

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The final publication is available at http://dx.doi.org/10.1016/j.jtcvs.2013.11.054. Motoaki Ohnaka, Akira Marui, Kenichi Yamahara, Kenji Minakata, Kazuhiro Yamazaki, Motoyuki Kumagai, Hidetoshi Masumoto, Shiro Tanaka, Tadashi Ikeda, Ryuzo Sakata, Effect of microRNA-145 to prevent vein graft disease in rabbits by regulation of smooth muscle cell phenotype, The Journal of Thoracic and Cardiovascular Surgery, Volume 148, Issue 2, August 2014, Pages 676-682.e2, ISSN 0022-5223.
Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第18544号
医博第3937号
新制||医||1006(附属図書館)
31444
京都大学大学院医学研究科医学専攻
(主査)教授木村剛, 教授野田亮, 教授瀬原淳子
学位規則第4条第1項該当

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Zakariyah, Abeer. „The Characterization of a Human Disease-Associated Mutation Nkx2.5 R142C Using In vitro and In vivo Models“. Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35817.

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Nkx2.5 is a cardiac transcription factor that plays a critical role in heart development. In humans, heterozygous mutations in the NKX2.5 gene result in congenital heart defects (CHDs), but the molecular mechanisms by which these mutations cause the defects are still unknown. NKX2.5 R142C is a mutation that is found to be associated with atrial septal defect and atrioventricular block in 13 patients from one family. The R142C mutation is located within both the DNA-binding domain and the nuclear localization sequence of NKX2.5 protein. The pathogenesis of CHDs in humans with R142C point mutation is not well understood. Also, a previous study in our laboratory has identified Mypt1/PP1 as a novel interacting partner of Nkx2.5 in stem cells during cardiomyogenesis. Nkx2.5 has a PP1-binding consensus sequence RVxF located in the N-terminus of the homeodomain. Notably, the PP1-binding sequence, RVxF, is mutated from arginine to cysteine in patients with the R142C heterozygous mutation. However, the ability of the R142C mutation to bind to the Mypt1/PP1 complex has not been investigated yet. The following thesis addresses the functional deficit associated with R142C by utilizing a combination of in vitro, and in vivo models. It also addresses the interaction of Mypt1/PP1 with the R142C mutation. We have generated a heterozygous mouse embryonic stem cell (mESC) line, harboring the murine homologue (R141C) of the human mutation R142C in Nkx2.5 gene. We show reduced cardiomyogenesis and impaired subcellular localization of Nkx2.5 protein in Nkx2.5R141C/+ mESCs. Gene expression profiling of Nkx2.5R141C/+ mESCs revealed a global misregulation of genes important for heart development and identified putative direct target genes of Nkx2.5 that are affected by the R141C heterozygous mutation. We also generated a mouse model harboring the human mutation R142C. We show that the Nkx2.5R141C/R141C homozygous embryos are developmentally arrested around E10.5 with delayed heart morphogenesis. Moreover, Nkx2.5R141C/+ newborn mice are grossly normal but show variable cardiac defects and downregulation of ion channel genes that later cause AV block in adult mice. Finally, we show that the R141C mutant binds to the Mypt1/PP1 complex but is not inhibited or translocated to the perinuclear region in the presence of Mypt1/PP1 as the WT Nkx2.5 is.

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22

Jenkins, William Stephen Arthur. „Novel applications of positron emission tomography in the non-invasive assessment of cardiovascular disease“. Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31229.

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Introduction. Fused Positron Emission Tomography and Computed Tomography (PET/CT) is an emerging investigative tool in cardiovascular disease that provides an imaging-based quantification of pathophysiological processes of interest. The purpose of this thesis was to study the application of PET to identify fundamental pathophysiological processes driving 3 forms of cardiovascular disease: aortic stenosis, myocardial infarction, and atherosclerosis. Methods. Aortic Stenosis. Patients with a spectrum of calcific aortic valve disease (n=121) who underwent PET-CT imaging for the identification of valvular calcification (18Ffluoride) and inflammation (18F-fluorodeoxyglucose, 18F-FDG) underwent serial imaging and clinical follow-up over 2 years. Baseline imaging findings were compared with echocardiographic and CT markers of disease progression and clinical outcome. Myocardial Infarction. Patients underwent PET-CT imaging with 18F-fluciclatide (a novel αvβ3-selective radiotracer highlighting active angiogenesis, inflammation and fibrosis) after ST-segment elevation MI (n=21), alongside stable patients with chronic total occlusion (CTO) of a major coronary vessel (n=7), and healthy volunteers (n=9). Myocardial radiotracer uptake was compared with clinical and cardiac magnetic resonance imaging (CMR) markers of infarction and remodeling. Atherosclerosis. Patients with a spectrum of atherosclerotic disease categorized as stable or unstable (recent MI) underwent PET/CT imaging with 18F-fluciclatide (n=46). Thoracic aortic 18F-fluciclatide uptake was compared with aortic atherosclerotic burden quantified by CT plaque thickness, plaque volume and calcium scoring. Histological validation. Tissue from the aortic valve, myocardium and carotid arteries of study subjects was acquired and examined ex vivo using histology and autoradiography. Results. Aortic Stenosis. Baseline valvular 18F-fluoride uptake correlated strongly with the rate of progression in AVC (r=0.80, p < 0.001) and with haemodynamic progression (mean aortic valve gradient r=0.32, p=0.001). It emerged as independently associated with clinical outcome after age and sex-adjustment (HR 1.55 [1.33-1.81], p < 0.001). 18F-FDG demonstrated moderate correlations with disease progression as assessed by CT (r=0.43, p=0.001) and echocardiography (18F-FDG r=0.30, p=0.001), and was associated with clinical outcomes independent of age and sex (HR 1.35 [1.16-1.58], p < 0.001). Valvular 18F-fluoride uptake correlated with immunohistochemical markers of calcification activity. There was no correlation between 18F-FDG uptake and inflammation. Myocardial Infarction. 18F-Fluciclatide binding was demonstrated in ex vivo peri-infarct myocardium and uptake was increased in vivo at sites of acute infarction compared to remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17 respectively, p < 0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p < 0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with myocardial activity similar to healthy volunteers (TBRmean 0.71±0.06 vs. 0.70±0.03,p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index ≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p < 0.001), was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. Atherosclerosis. 18F-Fluciclatide vascular binding ex vivo co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide uptake in vivo correlated with measures of aortic atherosclerotic burden: plaque thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and the CT aortic calcium score (r=0.37, p=0.01). Patients with recent MI had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.33 vs 1.21, p=0.01). Conclusions. In a range of cardiovascular diseases, PET-CT can provide insights into key pathophysiological processes, guide patient risk stratification and prognosis, and identify important biomarkers of disease activity that can be used for the development of future therapeutic interventions.

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Braitsch, Caitlin M. „The role of Pod1/Tcf21 in epicardium-derived cells in cardiac development and disease“. University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367925962.

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Tikkanen, Heikki O. „The influence of skeletal muscle properties, physical activity and physical fitness on serum lipids and the risk of coronary heart disease“. Helsinki : University of Helsinki, 2001. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/tikkanen/.

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Raad, Farah [Verfasser], Wolfram-Hubertus [Akademischer Betreuer] [Gutachter] Zimmermann und Lutz [Gutachter] Tietze. „Characterization and Application of Bioengineered Heart Muscle as a New Tool to Study Human Heart Development and Disease / Farah Raad ; Gutachter: Wolfram-Hubertus Zimmermann, Lutz Tietze ; Betreuer: Wolfram-Hubertus Zimmermann“. Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://d-nb.info/1135487642/34.

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Wamhoff, Brian R. „Calcium regulation in coronary smooth muscle : mechanisms of cardioprotection /“. free to MU campus, to others for purchase, 2001. http://wwwlib.umi.com/cr/mo/fullcit?p3013038.

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Hill, Brent J. F. „Myoplasmic calcium regulation and the function of nucleotide and endothelin receptors in models of coronary artery disease“. free to MU campus, to others for purchase, 2000. http://wwwlib.umi.com/cr/mo/fullcit?p9988669.

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Seifert, Elena. „Metabolic Changes in Pulmonary Arterial Smooth Muscle Cells Exposed to Increased Mechanical Forces from an Ovine Model of Congenital Heart Disease with Increased Pulmonary Blood Flow“. Scholarship @ Claremont, 2019. https://scholarship.claremont.edu/cmc_theses/2094.

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An important cause of pulmonary arterial hypertension (PAH) in children with congenital heart disease (CHD) is increased pulmonary blood flow (PBF). To gain a better understanding of the disease process, the changes in biochemical pathways and metabolism of pulmonary arterial smooth muscle cells (PASMCs) were studied using a unique surgical ovine model of increased pulmonary blood flow. PASMCs isolated from 4-week-old lambs with increased PBF (shunt) showed lower oxygen consumption rates and lower extracellular acidification rates linked to glutamine metabolism when compared to controls. Shunt and control PASMCs both exhibited a switch into the reverse tricarboxylic acid (TCA) cycle, while only shunt cells showed a decrease of glucose being transformed into Acetyl CoA to enter the forward TCA cycle. Shunt PASMCs also demonstrated increased levels of yes-associated protein 1 (YAP1) expression in the nucleus. These results indicate changes in glutamine metabolism, glucose metabolism, and protein signaling cascades associated with increased mechanical forces in the setting of increased PBF, as seen in PAH in children with CHD.

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Intaitė, Gintarė. „Relaksacijos taikymas arterinio kraujo spaudimo reguliavimui sergančiųjų išemine širdies liga stacionarinės reabilitacijos etape“. Master's thesis, Lithuanian Academic Libraries Network (LABT), 2008. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2008~D_20080828_135113-12189.

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Darbo problema – vis dar lieka neaiškus PRR efektyvumas ir jos sąsajos su amžiumi, lytimi, išsilavinimu, IŠL forma, subjektyvia savijauta, subjektyviu sveikatos vertinimu bei organizmo raumenų įtampa, sergantiems IŠL. Todėl šio tyrimo tikslas - nustatyti progresuojančios raumenų relaksacijos taikymo efektyvumą AKS reguliavimui, atsižvelgiant į lytį, amžių, ligos formą, subjektyvų sveikatos vertinimą, išsilavinimą, raumenų įtampą ir subjektyvią savijautos įtampą, sergantiems IŠL, stacionarinės reabilitacijos etape. Tyrime buvo pakviesti dalyvauti 204 Abromiškių reabilitacinės ligoninės, kardiologinio skyriaus pacientai, tačiau į 1 užsiėmimą atėjo 53 (48,18 %) vyrai ir 40 (42,55 %) moterų, į 2 – 20 (18,18 %) vyrų ir 14 (14,89 %) moterų, į 3 – 15 (13,63 %) vyrų ir 12 (12,76 %) moterų ir į 4 – 12 (10,9 %) vyrų ir 8 (8,51 %) moterys. Tiriamieji dalyvavo 4 vienos valandos užsiėmimuose, kurie vyko 4 kartus per savaitę. Siekiant įvertinti PRR efektyvumą AKS mažinimui ir efektyvumo sąsajas su prieš tai išvardintais faktoriais, tiriamiesiems buvo pateikiamos anketos, vedami relaksaciniai užsiėmimai. Kiekvieno užsiėmimo pradžioje ir pabaigoje buvo matuojamas AKS ir duodamas užpildyti manekenas (raumenų įtampai įvertinti) bei subjektyvios savijautos skalė. Tyrimo rezultatai parodė, kad po relaksacijos AKS statistiškai reikšmingi sumažėjimai buvo tik vyrų tarpe, taip pat tarp jaunesnių pacientų, žmonėms sergantiems lengvesne IŠL forma, pacientams su aukštuoju išsilavinimu ir blogesniu... [toliau žr. visą tekstą]
It is still unclear if effectiveness of PMR is related with age, gender, education, IHD form, subjective health status, subjective tension and muscle tension for ischemic heart disease patients. So the aim of this survey is to analize how effectiveness of progressive muscle relaxation in blood pressure regulation is related with these factors for ischemic heart disease in-patients at their rehabilitation period. 204 patients from Abromiškės rehabilitation hospital, cardiac department were invited to participate in relaxation groups, but in the first group participated only 53 (48,18%) men and 40 (42,55%) women, in the second - 20 (18,18%) men and 14 (14,89%) women, in the third - 15 (13,63%) men and 12 (12,76%) women and in fourth - 12 (10,9%) men and 8 (8,51%) women. Participants attended in four hourly relaxation groups which were four times per week. With the purpose to evaluate PMR effectiveness for blood pressure regulation and its’ relation with factors, participants were given questionnaires also relaxation groups were provided. At the beginning and at the end of each session blood pressure was measured also muscle tension was evaluated with the given model and 10 score scale was given for subjective feeling evaluation. The results of this study showed that the statistically significant reductions of blood pressure were only for men also for younger patients and patients with higher education, for patients with easier IHD form and for patients with worse... [to full text]

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Hiemann, Nicola. „Histomorphometrische Untersuchungen myokardialer Blutgefäßveränderungen nach Herztransplantation“. Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 1998. http://dx.doi.org/10.18452/14461.

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Anhand von immunhistochemischen Färbemethoden wurde die Expression von CD 31 (immunhistochemischer Marker für Endothelzellen) und -Aktin (immunhistochemischer Marker für glatte Muskelzellen) auf Zellen der intramyokardialen Blutgefäße herztransplantierter Patienten histomorphometrisch ausgewertet. In die Bewertung der myokardialen Strukturen ging auch die Untersuchung der jeweiligen zugehörigen HE-Färbungen mit ein. Ziel dieser Untersuchungen war die Beurteilung von qualitativen und quantitativen Unterschieden dieser Marker während eines Untersuchungszeitraumes von 14 Monaten nach Herztransplantation (HTx) bei Patienten mit einer angiographisch diagnostizierten Transplantatvaskulopathie (TVP) mit Patienten ohne einer prä- bzw. postmortem diagnostizierten TVP. Der Einsatz dieser Immunomarker richtete sich hierbei auf die selektive Darstellung der terminalen Strombahn mit der Fragestellung, ob ein intramyokardiales morphologisches Korrelat zu der TVP der epikardialen Blutgefäße existiert und ob die histomorphometrische Auswertung der bewerteten Strukturen eine mögliche Frühdiagnose der TVP nach HTx zuläßt. Des weiteren sollte eine mögliche Assoziation der TVP mit den demographischen Charakteristika sowie der Anzahl und dem Schweregrad der Rejektionsepisoden der untersuchten Patienten überprüft werden. Als Basis dienten dabei in Paraffin eingebettete rechtsventrikuläre Rejektionskontrollbiopsien, die im Rahmen der routinemäßig durchgeführten Abstoßungsdiagnostik entnommenen wurden. Nach morphologischer Bewertung dieser Schnitte im Hinblick auf die Existenz und den Schweregrad einer Abstoßungsreaktion wurden diese immunhistochemisch aufbereitet und anschließend quantitativausgewertet. Im Rahmen dieser Arbeit weist die quantitativ- histomorphometrische Erfassung intramyokardialer Blutgefäße in rechtsventrikulären Rejektionskontrollbiopsien auf die mögliche Frühdiagnose einer TVP nach HTx hin. Dieses Verfahren könnte die zur Zeit verwendeten diagnostischen Methoden ergänzen. Jedoch sind noch weitere prospektive klinische Studien für die Validierung dieser Ergebnisse notwendig.
In this study, immunohistochemical and histomorphometric investigations were performed in order to investigate the expression of CD 31 (immunohistochemical marker for endothelial cells) and -Aktin (immunohistochemical marker for smooth muscle cells) on cells of intramyocardial blood vessels in heart transplant (HTx) patients. The evaluation of myocardial structures also implicated the investigation of the corresponding histological H & E stainings. The aim of this study was to ascertain whether HTx patients with angiographic evidence of graft vessel disease (GVD) showed different qualitative and quantitative expression of the above mentioned immunomarkers than HTx patients with no angiopraphic or postmortem signs of this phenomenon. The investigation time included the first 14 months after HTx. The use of these immunomarkers made possible the selective representation of the terminal vascular system to answer the question, as to whether there existed an intramyocardial morphological correlate to GVD of epicardial coronary arteries and whether histomorphometric evaluation of small vessels permits early diagnosis of GVD after HTx. In addition, demographic data, as well the number and grade of rejection episodes of the studied patients, were reviewed in order to ascertain whether there might be an association of these characteristics with GVD. The material studied consisted of paraffin-embedded right ventricular rejection control samples from routine postoperative diagnostic management, which were used to reveal acute rejection episodes. After morphological evaluation of histological slices with regard to the appearence and severity of acute rejection, immunohistochemical staining was performed and finally a quantitative investigation was done. According to the results of this study, quantitative histomorphometric investigations of intramyocardial blood vessels in right ventricular rejection control samples permit the early diagnosis of GVD after HTx and completes the present diagnostic tools. But further prospective clinical studies are necessary to confirm these results.

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Fernandes, Adriane Sayuri Nakashima. „Avaliação da efetividade e segurança do treinamento da manobra de empilhamento de ar nas distrofinopatias“. Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-01042015-101822/.

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INTRODUÇÃO: As distrofias musculares (DM) constituem um grupo de doenças genéticas caracterizadas por fraqueza muscular progressiva decorrente da degeneração irreversível do tecido muscular esquelético. O comprometimento da função respiratória é um sinal precoce da progressão da doença. A fraqueza progressiva dos músculos respiratórios torna o paciente com distrofia muscular incapaz de realizar inspirações profundas de forma independente para promover uma tosse eficaz. Portanto, torna-se necessário fornecer insuflações regulares com volumes que o paciente aprende a empilhar com o fechamento da glote, até que atinja a capacidade de insuflação máxima (CIM). A insuflação pulmonar minimiza complicações, tais como atelectasias e pneumonias, e permite níveis apropriados de ventilação e troca gasosa adequada nas eventuais complicações pulmonares, as quais impõem carga sobre os músculos respiratórios. Este mesmo processo pode representar uma alternativa para otimizar a função respiratória (FP) por meio do aumento do pico de fluxo de tosse (PFT) e manter a complacência pulmonar. Nos pacientes com distrofia muscular causada por mutações do gene da distrofina, a abordagem respiratória aumentou a sobrevida, sendo hoje as complicações cardiovasculares a maior causa de mortalidade. Entretanto, a manobra de empilhamento de ar ainda não foi adequadamente avaliada nestes pacientes. OBJETIVOS: Investigar a efetividade e a segurança desta manobra durante um período de um ano de treinamento em pacientes com Distrofia Muscular de Duchenne (DMD). MÉTODOS: Em 60 pacientes com DMD, cardiopatas e não cardiopatas, foram avaliados a FP, o PFT e a resposta cardíaca como frequência cardíaca (FC), pressão arterial (PA) e sintomas associados, antes, durante a sustentação e após a manobra de empilhamento de ar, em uma primeira avaliação, e depois de um ano de orientação e treinamento. Após o treinamento, foi avaliada, também, a variabilidade da frequência cardíaca (VFC). RESULTADOS: Houve um ganho da Capacidade vital forçada (CVF) e do PFT após um ano de treinamento (p < 0,05), Houve uma correlação linear entre o ganho de CIM e o PFT. Houve diferença na FC e na PA sistólica (PAS) durante a sustentação da manobra em comparação aos outros tempos, sendo que, no grupo de pacientes cardiopatas, a resposta cardíaca foi mais evidente, associada, em alguns pacientes, a sintomas relacionados a baixo débito cardíaco, tais como náuseas e tonturas (p < 0,05). Houve diferença significativa nos valores da VFC durante a manobra. (p < 0,05). CONCLUSÃO: O treinamento da manobra de empilhamento, durante um ano, proporcionou ganho e manutenção da função pulmonar, além de alterações cardíacas significativas associadas a sintomas apenas durante a sustentação da manobra, principalmente nos pacientes cardiopatas
INTRODUCTION: Muscular dystrophy (MD) is a genetic disease characterized by progressive muscle weakness resulting from irreversible degeneration of skeletal muscle tissue. An early sign of disease progression is the impairment of respiratory function. The progressive respiratory muscle weakness makes the patient with muscular dystrophy be unable to perform independent deep breaths in order to promote an effective cough. Therefore, it becomes necessary to provide regular inflations with volumes until it reaches the maximum insufflation capacity (MIC). Pulmonary insufflation minimizes complications such as pneumonia and atelectasis, and allows proper ventilation levels and adequate gas exchange in pulmonary complications. This same process can be an alternative to optimize pulmonary function (PF) by increasing peak cough flow (PCF) and maintain pulmonary compliance. In patients with muscular dystrophy respiratory approach increased their survival. Nowadays, cardiovascular complications is main a leading cause of mortality. However the air stacking has not been adequately evaluated in these patients. OBJECTIVES: To investigate the effectiveness of air stacking exercise and its safety profile in DM. METHODS: We evaluated 60 patients with DMD and with and without heart disease, the PF and PCF; cardiac response as heart rate (HR), blood pressure (BP), and associated symptoms before, during sustained time and after air stacking in the first review, and a year after being advised and trained. After twelve months was also measured the heart rate variability (HRV). RESULTS: There was a statistically difference in forced vital capacity (FVC) and PCF after a year of air stacking (p < 0.05). There was a linear correlation between MIC and PCF (R=0.8). Differences in HR and blood arterial systolic pressure (BPS) at sustainet time of air stacking compared to other times, moreover, in the heart disease group cardiovascular response was more evident, associated in some patients with low cardiac output related symptoms such as nausea and dizziness (p < 0.05). There was a significant difference in HRV values during air stacking (p < 0.05). CONCLUSION: The air stacking for twelvemonths provided gain and maintenance of pulmonary function, beyond a significant cardiac response abnormalities only during sustained time specially in heart disease patients associated with symptoms

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Lamotte, Michel. „Contribution à l'étude de la réponse hémodynamique lors d'exercices de renforcement musculaire: sujets sains et patients de réadaptation cardio-vasculaire“. Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209825.

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Picichè, Marco. „L’augmentation de la circulation collatérale non coronarienne : l’hypothèse d’une méthode alternative de revascularisation myocardique“. Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T044/document.

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La circulation collatérale non coronarienne (CCNC) perfuse le cœur en provenant d’artères bronchiques, médiastinales et péricardiques. L’éventualité que la CCNC puisse être artificiellement augmentée pour fournir un traitement alternatif pour les patients ischémiques représente une hypothèse intrigante sans réponse en raison de la nature difficile de ce champ de recherche. En se basant sur plusieurs aspects, tel que (1) l’existence des collatérales naturelles entre les artères coronaires et les artères thoraciques internes (ATIs), (2) les effets potentiels de la ligature des ATIs; (3) la capacité des ATIs de développer d’importantes branches collatérales ; (4) et la disponibilité actuelle des facteurs de croissance vasculaire, l’hypothèse ici décrite est que l’augmentation de la CCNC pourrait représenter une stratégie alternative d’apport sanguin au coeur.Ainsi, l’association d’occlusion des ATIs et de l’administration des facteurs de croissance pourrait représenter un moyen de poursuivre cet objectif. Pour le premier travail de recherche, nous avons établi un modèle canin
Noncoronary collateral circulation (NCCC) comes to the heart from mediastinal, bronchial, and pericardial channels. Whether NCCC can somehow be augmented to provide an alternative therapy for ischemic patients is an intriguing hypothesis with no clear answer yet due to the challenging nature of this research field. Based on several aspects, such as (1) the occurrence of natural collaterals between coronary and the internal thoracic arteries (ITAs), (2) the potentialhemodynamic effects of ITAs ligation, (3) the potential of ITAs for developing important collateral branches, and (4) the current availability of angiogenic growth factors, the hypothesis herein is that enhancement of NCCC may represent an alternative myocardial blood supply strategy, and that combining ITAs occlusion with angiogenic growth factors may represent a way to achieve this objective. We established an ischemic canine model for first experiment

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Ara?jo, Thaise Lucena. „For?a muscular respirat?ria, qualidade de vida e modula??o auton?mica da frequ?ncia card?aca na distrofia miot?nica“. Universidade Federal do Rio Grande do Norte, 2009. http://repositorio.ufrn.br:8080/jspui/handle/123456789/16675.

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Made available in DSpace on 2014-12-17T15:16:06Z (GMT). No. of bitstreams: 1 ThaiseLA.pdf: 779453 bytes, checksum: fe87c118f2c753bc8ffd4a32cb6a1146 (MD5) Previous issue date: 2009-07-22
Background: The myotonic dystrophy (MD) is a multisystem neuromuscular disease that can affect the respiratory muscles and heart function, and cause impairment in quality of life. Objectives: Investigate the changes in respiratory muscle strength, health-related quality of life (HRQoL) and autonomic modulation heart rate (HR) in patients with MD. Methods: Twenty-three patients performed assessment of pulmonary function, sniff nasal inspiratory pressure (SNIP), the maximal inspiratory (MIP) and expiratory (MEP) pressure, and of HRQoL (SF-36 questionnaire). Of these patients, 17 underwent assessment of heart rate variability (HRV) at rest, in the supine and seated positions. Results: The values of respiratory muscle strength were 64, 70 and 80% of predicted for MEP, MIP, and SNIP, respectively. Significant differences were found in the SF-36 domains of physical functioning (58.7 ? 31,4 vs. 84.5 ? 23, p<0.01) and physical problems (43.4 ? 35.2 vs. 81.2 ? 34, p<0.001) when patients were compared with the reference values. Single linear regression analysis demonstrated that MIP explains 29% of the variance in physical functioning, 18% of physical problems and 20% of vitality. The HRV showed that from supine position to seated, HF decreased (0.43 x 0.30), and LF (0.57 x 0.70) and the LF/HF ratio (1.28 x 2.22) increased (p< 0.05). Compared to healthy persons, LF was lower in both male patients (2.68 x 2.99) and women (2.31 x 2.79) (p< 0.05). LF / HF ratio and LF were higher in men (5.52 x 1.5 and 0.8 x 0.6, p <0.05) and AF in women (0.43 x 0.21) (p< 0.05). There was positive correlation between the time of diagnosis and LF / HF ratio (r = 0.7, p <0.01). Conclusions: The expiratory muscle strength was reduced. The HRQoL was more impaired on the physical aspects and partly influenced by changes in inspiratory muscle strength. The HRV showed that may be sympathetic dysfunction in autonomic modulation of HR, although with normal adjustment of autonomic modulation during the change of posture. The parasympathetic modulation is higher in female patients and sympathetic tends to increase in patients with longer diagnosis
Introdu??o: A distrofia miot?nica (DM) ? uma doen?a neuromuscular multissist?mica que pode afetar a musculatura respirat?ria e a fun??o card?aca, e ocasionar preju?zos na qualidade de vida. Objetivos: Investigar as altera??es na for?a muscular respirat?ria, qualidade de vida relacionada ? sa?de (QVRS), e modula??o auton?mica da freq??ncia card?aca (FC) em pacientes com DM. M?todos: Foram avaliados 23 pacientes quanto ? fun??o pulmonar, press?o inspirat?ria nasal sniff (SNIP), press?es respirat?rias m?ximas (PIm?x e PEm?x), e QVRS (question?rio SF-36). Destes, 17 realizaram avalia??o da variabilidade da frequ?ncia card?aca (VFC) em repouso, nas posturas supina e sentada. Resultados: Os valores da for?a muscular respirat?ria foram de 64, 70 e 80%predito para PEm?x, PIm?x, e SNIP, respectivamente. Foi encontrada diminui??o significativa nos dom?nios do SF-36 capacidade funcional (58.7 ? 31,4 vs. 84.5 ? 23, p<0.01) e disfun??o f?sica (43.4 ? 35.2 vs. 81.2 ? 34, p<0.001) comparado a valores de refer?ncia. A an?lise de regress?o linear mostrou que a PIm?x explica 29% da vari?ncia na capacidade funcional, 18% na disfun??o f?sica e 20% na vitalidade. A VFC mostrou que, da postura supina para a sentada, o espectro AF diminuiu (0.43 x 0.30) e o espectro BF (0.57 x 0.70) e a raz?o BF/AF (1.28 x 2.22) aumentaram, com p<0.05. Comparado a valores de refer?ncia, BF foi inferior (p<0.05) tanto nos pacientes homens (2.68 x 2.99), como nas mulheres (2.31 x 2.79). A raz?o BF/AF e o espectro BF foram maiores nos homens (5.52 x 1.5 e 0.8 x 0.6), e o espectro AF, nas mulheres (0.43 x 0.21), com p<0.05. Houve correla??o significativa positiva entre tempo de diagn?stico e raz?o BF/AF (r= 0.7, p< 0.01). Conclus?es: Indiv?duos com DM t?m for?a muscular expirat?ria diminu?da. A QVRS mostrou-se mais prejudicada em rela??o a aspectos f?sicos e parcialmente influenciada por varia??es na for?a muscular inspirat?ria. Pode haver disfun??o simp?tica na modula??o auton?mica da FC, com ajuste normal da postura supina para a sentada. A modula??o parassimp?tica ? superior em pacientes mulheres e a modula??o simp?tica tende a aumentar nos pacientes com maior tempo de diagn?stico

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Clark, Amanda. „MEF2-regulated Gtl2-Dio3 noncoding RNAs in cardiac muscle and disease“. Thesis, 2016. https://hdl.handle.net/2144/14521.

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The MEF2 transcription factor is a central regulator of skeletal and cardiac muscle development. Recently, we showed that MEF2A regulates skeletal muscle regeneration through direct regulation of the Gtl2-Dio3 microRNA mega-cluster. In addition to their expression in skeletal muscle, temporal expression analysis of selected Gtl2-Dio3 microRNAs revealed high enrichment in cardiac muscle. Therefore, I investigated the role of selected microRNAs from the Gtl2-Dio3 noncoding RNA locus in the heart. First, I found that Gtl2-Dio3 microRNAs are expressed at higher levels in perinatal hearts compared to adult, suggesting they function in cardiac maturation shortly after birth. I also demonstrated that these microRNAs are dependent on MEF2A in the perinatal heart and in neonatal cardiomyocytes. To determine the specific role in cardiac muscle, I overexpressed selected microRNA mimics in neonatal rat ventricular myocytes (NRVMs). My results showed that miR-410 and miR-495 stimulate cell cycle re-entry and proliferation of terminally differentiated NRVMs. Subsequent target prediction analyses revealed a number of candidate target genes known to function in the cell cycle and/or in cardiac muscle. One of these was Cited2, a cofactor required for proper cardiac development. Subsequently, I showed that Cited2 is a direct target of these miRNAs and that siRNA knockdown of Cited2 in NRVMs resulted in robust cardiomyocyte proliferation. This phenotype was associated with reduced expression of Cdkn1c/p57/Kip2, a cell cycle inhibitor, and increased expression of Vegfa, a growth factor with proliferation-promoting effects. Given the exciting possibility of manipulating the expression of these microRNAs to repair the damaged heart by stimulating cardiomyocyte proliferation, I then investigated whether they were regulated in cardiac disease and function in pathological signaling. Toward this end, I examined expression of miR-410, miR-495, miR-433, as well as the Gtl2 lncRNA in various cardiomyopathies. Interestingly, the microRNAs and lncRNA were dynamically regulated in mouse models of cardiac disease including myocardial infarction and chronic angiotensin II stimulation. Furthermore, I showed for the first time that the Gtl2 lncRNA and miRNAs are differentially regulated in myocardial infarction, indicating that the complex regulation of the Gtl2-Dio3 noncoding RNA locus may be important for response to cardiac injury. Lastly, I showed that inhibiting select Gtl2-Dio3 microRNAs in pathological signaling attenuated cardiomyocyte hypertrophy in vitro. Therefore, differential targeting of the Gtl2-Dio3 noncoding RNAs could provide new therapeutic strategies to control the response of the heart to cardiac diseases with diverse etiologies.

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Raad, Farah. „Characterization and Application of Bioengineered Heart Muscle as a New Tool to Study Human Heart Development and Disease“. Doctoral thesis, 2016. http://hdl.handle.net/11858/00-1735-0000-002B-7C05-A.

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37

Frisk, Emelie. „Lower limb muscle function in children and adolescents with Fontan circulation : A cross-sectional study“. Thesis, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-160552.

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Introduction: Impaired isometric muscle strength and muscle endurance in adults with Fontan circulation has previously been reported. However, the knowledge if corresponding impairment is present in children and adolescents with Fontan circulation is scarce. Aim: The aim was to examine the isometric muscle strength and muscle endurance of the lower limbs in children and adolescents with Fontan circulation in comparison to age and sex matched controls. Method: In this cross-sectional study 43 children and adolescents (6-18 years) with Fontan circulation and 43 controls were included. Isometric knee extension and plantar flexion muscle strength was assessed using dynamometry (Newton:N). Unilateral isotonic heel-lift until exhaustion was used for evaluation of lower limb muscle endurance. Analysis on group level (n=43) and for the subgroups 6-12 years (n=18) and 13-18 years (n=25) was performed. Results: On group level the children and adolescents with Fontan circulation had impaired isometric plantar flexion strength for the left leg compared to controls (393.9±181.1N vs. 492.5±241.6N, p=0.04). In addition, they had impaired isometric knee extension strength bilaterally (right 222.8±101.1N vs. 293.0±164.9N, p=0.02, left 220.7±102.7N vs. 279.5±159.1N, p=0.05). In contrast, lower limb muscle endurance did not differ. In subgroup analysis, the impaired isometric strength was only present in the group of adolescents. Conclusion: Adolescents with Fontan circulation had impaired isometric muscle strength compared to controls. However, no corresponding differences were found in children. Further, lower limb muscle endurance did not differ. This implies that the impaired isometric muscle strength may develop during adolescence whereas the impaired muscle endurance may occur later.
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„Effect of hyperkalemia and ischemia on large conductance calcium-activated potassium channels in porcine coronary arterial smooth muscle: relevance to cardioplegic arrest“. 2008. http://library.cuhk.edu.hk/record=b5893576.

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Han, Jianguo.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2008.
Includes bibliographical references (leaves 66-76).
Abstracts in English and Chinese.
Declaration --- p.i
Acknowledgement --- p.□
Publication --- p.□
Abstract (English) --- p.□xi
Abstract (Chinese) --- p.□
Abbreviations --- p.ix
List of figures / tables --- p.x
Chapter Chapter 1. --- General Introduction
Chapter 1.1 --- Role of vascular smooth muscle cells in the control of coronary circulation --- p.1
Chapter 1.1.1 --- Potassium channels in the coronary smooth muscle cells --- p.2
Chapter 1.1.1.1 --- Voltage -dependent potassium (Kv) channels --- p.3
Chapter 1.1.1.2 --- Inward rectifier K+ (Kir) channels --- p.4
Chapter 1.1.1.3 --- ATP-sensitive potassium (Katp) channels --- p.4
Chapter 1.1.2 --- BKCa channels in the regulation of vascular function --- p.6
Chapter 1.1.2.1 --- The structure of BKCa channels --- p.6
Chapter 1.1.2.2 --- Role of BKCa channels in the regulation of vascular function --- p.6
Chapter 1.2 --- Functional alteration of the coronary SMCs during cardiac surgery --- p.7
Chapter 1.2.1 --- Effect of ischemia on the function of SMCs in the coronary circulation --- p.8
Chapter 1.2.2 --- Effect of cardioplegic/organ preservation solutions on the function of SMCs in the coronary circulation --- p.11
Chapter Chapter 2. --- Materials and Methods --- p.14
Chapter 2.1 --- Isometric force study in small coronary arteries --- p.14
Chapter 2.1.1 --- Preparation of porcine small coronary arteries --- p.14
Chapter 2.1.2 --- Experiment procedure --- p.15
Chapter 2.1.2.1 --- Mounting of small coronary arteries --- p.15
Chapter 2.1.2.2 --- Normalization procedure for small coronary arteries --- p.16
Chapter 2.1.2.3 --- Precontraction and relaxation --- p.17
Chapter 2.1.3 --- Data acquisition and analysis --- p.17
Chapter 2.2 --- Patch-clamp electrophysiology --- p.18
Chapter 2.2.1 --- Preparation of porcine coronary arteries --- p.18
Chapter 2.2.2 --- Enzymatic dissociation of coronary arterial SMCs --- p.18
Chapter 2.2.3 --- Primary cell culture --- p.19
Chapter 2.2.4 --- Recording of BKca channel currents --- p.19
Chapter 2.3 --- Statistical analysis --- p.21
Chapter 2.4 --- Chemicals --- p.21
Chapter Chapter 3. --- The Effect of Ischemia on BKCa channels in the Isolated SMCs of Coronary Arteries --- p.22
Chapter 3.1 --- Abstract --- p.22
Chapter 3.2 --- Introduction --- p.23
Chapter 3.3 --- Experimental design and analysis --- p.25
Chapter 3.3.1 --- Isometric force study in small coronary arteries --- p.25
Chapter 3.3.2 --- Effect of ischemia on NS1619-induced relaxation in small coronary arteries --- p.26
Chapter 3.3.3 --- Effect of ischemia on smooth muscle BKca channel currents --- p.27
Chapter 3.3.3.1 --- Preparation of porcine coronary artery --- p.27
Chapter 3.3.3.2 --- Enzymatic dissociation of coronary arterial SMCs --- p.27
Chapter 3.3.3.3 --- Recording of BKCa channel currents --- p.27
Chapter 3.3.4 --- Data acquisition and analysis --- p.28
Chapter 3.4 --- Results --- p.28
Chapter 3.4.1 --- Electrophysiological studies --- p.28
Chapter 3.4.1.1 --- Effect of IBTX on the whole cell outward currents --- p.29
Chapter 3.4.1.2 --- Effect of ischemia on the IBTX-sensitive BKca currents --- p.30
Chapter 3.4.2 --- Relaxation studies --- p.30
Chapter 3.4.2.1 --- Resting force --- p.30
Chapter 3.4.2.2 --- U46619-induced contraction force --- p.31
Chapter 3.4.2.3 --- Effect of IBTX on the NS1619-induced relaxation --- p.31
Chapter 3.4.2.4 --- Effect of ischemia on the NS1619-induced relaxation --- p.31
Chapter 3.5 --- Discussion --- p.32
Chapter 3.5.1 --- Functional changes of the coronary smooth muscle BKca channels after ischemic exposure --- p.33
Chapter 3.5.2 --- Role of BKca channels in SMCs during ischemia --- p.33
Chapter 3.5.3 --- Clinical implications --- p.35
Chapter Chapter 4. --- The Effect of Hyperkalemia on BKCa channels in the Isolated SMCs of Coronary Arteries --- p.41
Chapter 4.1 --- Abstract --- p.41
Chapter 4.2 --- Introduction --- p.42
Chapter 4.3 --- Experimental design and analysis --- p.44
Chapter 4.3.1 --- Isometric force study in small coronary arteries --- p.44
Chapter 4.3.1.1 --- Effect of hyperkalemia on NS1619-mediated relaxation in small coronary arteries --- p.44
Chapter 4.3.2. --- Effect of hyperkalemia on BKCa currents of SMCs --- p.45
Chapter 4.3.2.1 --- Preparation of porcine coronary arteries --- p.45
Chapter 4.3.2.2 --- Enzymatic dissociation of coronary arterial SMCs --- p.45
Chapter 4.3.2.3 --- Recording of BKca channel currents --- p.46
Chapter 4.3.3. --- Data acquisition and analysis --- p.46
Chapter 4.4 --- Results --- p.47
Chapter 4.4.1 --- Effect of hyperkalemia on the iberiotoxin-sensitive BKCa channel currents --- p.47
Chapter 4.4.2 --- Relaxation studies --- p.48
Chapter 4.4.2.1 --- Resting force --- p.48
Chapter 4.4.2.2 --- U46619- and high K+-induced contraction force --- p.48
Chapter 4.4.2.3 --- Effect of high K+ on the NS1619-induced relaxation --- p.48
Chapter 4.4.2.4 --- Effect of IBTX on the NS1619-induced relaxation --- p.49
Chapter 4.5 --- Discussion --- p.49
Chapter 4.5.1 --- Role of BKCa channels in the isolated SMCs in hyperkalemic solution --- p.50
Chapter 4.5.2 --- Functional changes of BKCa channels in coronary SMCs in hyperkalemia exposure --- p.51
Chapter 4.5.3 --- Clinical implications --- p.52
Chapter Chapter 5. --- General Discussion --- p.58
Chapter 5.1 --- BKCa channels in porcine coronary SMCs --- p.59
Chapter 5.2 --- Alteration of BKCa function related to ischemia in porcine coronary SMCs --- p.60
Chapter 5.3 --- Alteration of BKCa function related to hyperkalemia in porcine coronary SMCs --- p.61
Chapter 5.4 --- Limitation of the study --- p.62
Chapter 5.5 --- Future investigations --- p.63
Chapter 5.6 --- Conclusions --- p.63
References --- p.66

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39

McKenney, Mikaela Lee. „Coronary artery disease progression and calcification in metabolic syndrome“. Thesis, 2014. http://hdl.handle.net/1805/6460.

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Indiana University-Purdue University Indianapolis (IUPUI)
For years, the leading killer of Americans has been coronary artery disease (CAD), which has a strong correlation to the U.S. obesity epidemic. Obesity, along with the presence of other risk factors including hyperglycemia, hypercholesterolemia, dyslipidemia, and high blood pressure, comprise of the diagnosis of metabolic syndrome (MetS). The presentation of multiple MetS risk factors increases a patients risk for adverse cardiovascular events. CAD is a complex progressive disease. We utilized the superb model of CAD and MetS, the Ossabaw miniature swine, to investigate underlying mechanisms of CAD progression. We studied the influence of coronary epicardial adipose tissue (cEAT) and coronary smooth muscle cell (CSM) intracellular Ca2+ regulation on CAD progression. By surgical excision of cEAT from MetS Ossabaw, we observed an attenuation of CAD progression. This finding provides evidence for a link between local cEAT and CAD progression. Intracellular Ca2+ is a tightly regulated messenger in CSM that initiates contraction, translation, proliferation and migration. When regulation is lost, CSM dedifferentiate from their mature, contractile phenotype found in the healthy vascular wall to a synthetic, proliferative phenotype. Synthetic CSM are found in intimal plaque of CAD patients. We investigated the changes in intracellular Ca2+ signaling in enzymatically isolated CSM from Ossabaw swine with varying stages of CAD using the fluorescent Ca2+ indicator, fura-2. This time course study revealed heightened Ca2+ signaling in early CAD followed by a significant drop off in late stage calcified plaque. Coronary artery calcification (CAC) is a result of dedifferentiation into an osteogenic CSM that secretes hydroxyapatite in the extracellular matrix. CAC is clinically detected by computed tomography (CT). Microcalcifications have been linked to plaque instability/rupture and cannot be detected by CT. We used 18F-NaF positron emission tomography (PET) to detect CAC in Ossabaw swine with early stage CAD shown by mild neointimal thickening. This study validated 18F-NaF PET as a diagnostic tool for early, molecular CAC at a stage prior to lesions detectable by CT. This is the first report showing non-invasive PET resolution of CAC and CSMC Ca2+ dysfunction at an early stage previously only characterized by invasive cellular Ca2+ imaging.

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Rodenbeck, Stacey Dineen. „Coronary artery disease in metabolic syndrome: a role for the sarcoplasmic reticulum Ca2+ ATPase“. Diss., 2016. http://hdl.handle.net/1805/10649.

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Indiana University-Purdue University Indianapolis (IUPUI)
Coronary artery disease (CAD) is a leading cause of death among Americans and is fueled by underlying metabolic syndrome (MetS). The prevalence and lethality of CAD necessitates rigorous investigations into its underlying mechanisms and to facilitate the development of effective treatment options. Coronary smooth muscle (CSM) phenotypic modulation from quiescent to synthetic, proliferative, and osteogenic phenotypes is a key area of investigation, with underlying mechanisms that remain poorly understood. Using a well-established pre-clinical model of CAD and MetS, the Ossabaw miniature swine, we established for the first time the time course of Ca2+ dysregulation during MetS-induced CAD progression. In particular, we used the fluorescent Ca2+ dye, fura-2, to examine alterations in CSM intracellular Ca2+ regulation during CAD progression, as perturbations in intracellular Ca2+ regulation are implicated in several cellular processes associated with CAD pathology, including CSM contractile responses and proliferative pathways. These studies revealed that the function of several CSM Ca2+ handling proteins is elevated in early CAD, followed by loss of function in severe atherosclerotic plaques. Decreased intracellular Ca2+ regulation occurred concurrently with reductions in CSM proliferation, measured with Ki-67 staining. In particular, alterations in sarcoplasmic reticulum (SR) Ca2+ store together with altered function of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) were associated with induction of proliferation. Organ culture of coronary arterial segments revealed that culture-induced medial thickening was prevented by SERCA inhibition with cyclopiazonic acid (CPA). Activation of SERCA with the small molecule activator, CDN1163, increased CSM proliferation, which was attenuated by treatment with CPA, thus establishing upregulated SERCA function as a proximal inducer of CSM proliferation. Further, we demonstrated that in vitro treatment of CSM from lean Ossabaw swine with the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, increased SERCA function. However, in vivo treatment of Ossabaw swine with MetS with the GLP-1 receptor agonist, AC3174, had no effect on CAD progression and in vitro examination revealed resistance of SERCA to GLP-1 receptor agonism in MetS. These findings further implicate SERCA in CAD progression. Collectively, these are the first data directly linking SERCA dysfunction to CSM proliferation and CAD progression, providing a key mechanistic step in CAD progression.

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Noblet, Jillian Nicole. „Coronary perivascular adipose tissue and vascular smooth muscle function: influence of obesity“. Diss., 2016. http://hdl.handle.net/1805/9815.

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Indiana University-Purdue University Indianapolis (IUPUI)
Factors released from coronary perivascular adipose tissue (PVAT), which surrounds large coronary arteries, have been implicated in the development of coronary disease. However, the precise contribution of coronary PVAT-derived factors to the initiation and progression of coronary vascular dysfunction remains ill defined. Accordingly, this investigation was designed to delineate the mechanisms by which PVAT-derived factors influence obesity-induced coronary smooth muscle dysfunction. Isometric tension studies of coronary arteries from lean and obese swine demonstrated that both lean and obese coronary PVAT attenuate vasodilation via inhibitory effects on smooth muscle K+ channels. Specifically, lean coronary PVAT attenuated KCa and KV7 channel-mediated dilation, whereas obese coronary PVAT impaired KATP channel-mediated dilation. Importantly, these effects were independent of alterations in underlying smooth muscle function in obese arteries. The PVAT-derived factor calpastatin impaired adenosine dilation in lean but not obese arteries, suggesting that alterations in specific factors may contribute to the development of smooth muscle dysfunction. Further studies tested the hypothesis that leptin, which is expressed in coronary PVAT and is upregulated in obesity, acts as an upstream mediator of coronary smooth muscle dysfunction. Long-term administration (3 day culture) of obese concentrations of leptin markedly altered the coronary artery proteome, favoring pathways associated with calcium signaling and cellular proliferation. Isometric tension studies demonstrated that short-term (30 min) exposure to leptin potentiated depolarization-induced contraction of coronary arteries and that this effect was augmented following longer-term leptin administration (3 days). Inhibition of Rho kinase reduced leptin-mediated increases in coronary artery contractions. Acute treatment was associated with increased Rho kinase activity, whereas longer-term exposure was associated with increases in Rho kinase protein abundance. Alterations in Rho kinase signaling were also associated with leptin-mediated increases in coronary vascular smooth muscle proliferation. These findings provide novel mechanistic evidence linking coronary PVAT with vascular dysfunction and further support a role for coronary PVAT in the pathogenesis of coronary disease.

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42

Owen, Meredith Kohr. „Effect of coronary perivascular adipose tissue on vascular smooth muscle function in metabolic syndrome“. Thesis, 2013. http://hdl.handle.net/1805/3789.

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Indiana University-Purdue University Indianapolis (IUPUI)
Obesity increases cardiovascular disease risk and is associated with factors of the “metabolic syndrome” (MetS), a disorder including hypertension, hypercholesterolemia and/or impaired glucose tolerance. Expanding adipose and subsequent inflammation is implicated in vascular dysfunction in MetS. Perivascular adipose tissue (PVAT) surrounds virtually every artery and is capable of releasing factors that influence vascular reactivity, but the effects of PVAT in the coronary circulation are unknown. Accordingly, the goal of this investigation was to delineate mechanisms by which lean vs. MetS coronary PVAT influences vasomotor tone and the coronary PVAT proteome. We tested the hypothesis that MetS alters the functional expression and vascular contractile effects of coronary PVAT in an Ossabaw swine model of the MetS. Utilizing isometric tension measurements of coronary arteries in the absence and presence of PVAT, we revealed the vascular effects of PVAT vary according to anatomical location as coronary and mesenteric, but not subcutaneous adipose tissue augmented coronary artery contractions to KCl. Factors released from coronary PVAT increase baseline tension and potentiate constriction of isolated coronary arteries relative to the amount of adipose tissue present. The effects of coronary PVAT are elevated in the setting of MetS and occur independent of endothelial function. MetS is also associated with substantial alterations in the coronary PVAT proteome and underlying increases in vascular smooth muscle Ca2+ handling via CaV1.2 channels, H2O2-sensitive K+ channels and/or upstream mediators of these ion channels. Rho-kinase signaling participates in the increase in coronary artery contractions to PVAT in lean, but not MetS swine. These data provide novel evidence that the vascular effects of PVAT vary according to anatomic location and are influenced by the MetS phenotype.

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Silva, João Gabriel Branco. „The Effects of High Fat Feeding on the Metabolomics of Heart, Kidney and Skeletal Muscle in C57BL6J Mice as Analysed by 1H NMR“. Master's thesis, 2021. http://hdl.handle.net/10316/96156.

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Dissertação de Mestrado em Biologia Celular e Molecular apresentada à Faculdade de Ciências e Tecnologia
A doença do fígado gordo não alcoólico (NAFLD) é uma manifestação hepática associada à síndrome metabólica, com uma prevalência mundial documentada de 25% em 2020 e com tendência para um aumento da sua incidência no futuro. A NAFLD adquiriu um interesse e preocupação global devido ao rápido crescimento da sua prevalência ao longo dos últimos anos, enquanto os métodos de diagnóstico e tratamento atuais continuam incomparáveis à dimensão do problema. Atualmente nenhuma despistagem de rotina está disponível, sendo as técnicas de diagnóstico caras, invasivas e com alto risco associado. Tirando intervenções básicas, como mudanças no estilo de vida e perda de peso, não há nenhum tratamento farmacológico atualmente aprovado para a NAFLD.Dietas ricas em gorduras são conhecidas por induzir a patologia de NAFLD em murganhos C57BL6J, juntamente com aumento de peso e desenvolvimento de resistência à insulina. Estes modelos mimetizam a ingestão calórica das sociedades ocidentais, que é considerados o principal motor na evolução da NAFLD. A maioria dos estudos metabólicos têm-se focado no fígado ou em bio-fluídos, mas tecidos como o coração, rim e músculo esquelético têm sido largamente desconsiderados e podem fornecer informação metabólica crucial no efeito da doença nos restantes órgãos. A metabolómica por Ressonância Magnética Nuclear (RMN) pode oferecer uma visão global de sistemas complexos, com capacidade de identificar e quantificar metabolitos de uma variedade de amostras, potenciando a descoberta de biomarcadores ou interações relevantes. Dois grupo de 16murganhos C57BL6J foram alimentados com uma dieta com alto teor de gordura ou com uma dieta controlo durante 18 semanas e as frações aquosas do músculo cardíaco, rim e músculo esquelético foram analisadas por análise multivariada de 1H RMN. O peso dos murganhos do grupo de dieta de alta gordura variou significativamente desde a quarta semana. Os extratos da fase aquosa revelaram que a cinética do ciclo de Randle estava desregulada nos três tecidos, particularmente no coração, com um aumento no piruvato, alanina e succinato e diminuição no malonato, enquanto os rins e o músculo tinham um perfil menos marcado. Variações nos níveis das acilcarnitinas também foram encontradas, sugerindo alterações no metabolismo lipídico. A microbiota intestinal também apresentou indícios de alteração nas suas dinâmicas, com diminuição em 6 aminoácidos e subprodutos da dieta nos três tecidos, nomeadamente na treonina, glicina, metionina, fumarato, dimetilamina e trimetilamina. Este último, trimetilamina, mostrou uma significativa redução em todos os tecidos e foi destacada por todos os modelos da análise multivariada em sugerindo uma possível importância deste metabolito como um biomarcador.Globalmente, estes resultados sugerem uma alteração metabólica da degradação da glucose para a oxidação dos ácidos gordos, acompanhado de stress oxidativo e isquémico, assim como um impacto na flora microbiana intestinal. Apesar dos modelos da análise multivariada terem pouco poder preditivo, estes resultados oferecem um entendimento aprofundado nos diferentes tecidos dos mecanismos envolvidos em modelos de NAFLD induzida pela alimentação
Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation associated to the metabolic syndrome, with reports showing a worldwide prevalence of 25% in 2020 and suggesting an increased incidence in the future. NAFLD has gained global interest and concern due to a rapid growth in prevalence over recent years, while current diagnostic and treatment protocols are lagging behind. Currently no routine screening is available, with diagnosis tools being costly, invasive and risky. Aside from basic interventions such as lifestyle alterations and weight loss programs, there is currently no pharmacological treatment approved for NAFLD.High-fat diets are known to induce the NAFLD pathology in C57BL6J mice, alongside weight increase and development of insulin resistance. These models mimic the caloric intake of a Western diet, which is considered a major driver of NAFLD. Most metabolic studies have been focused on the liver or bio fluids but tissues such as the heart, kidney or skeletal muscle have been largely disregarded and can provide some crucial metabolic cues on the impact of the disease in extrahepatic organs. Nuclear Magnetic Resonance (NMR) metabolomics can provide a global overview of complex systems, with the ability to identify and quantify metabolites from a variety of samples, possibly uncovering biomarkers or relevant interactions.Two groups of 12 C57BL6J mice were fed with high-fat chow or standard chow for 18 weeks and the aqueous extracts of heart, kidney and skeletal muscle were analysed by 1H NMR multivariate analysis. Mice weight of the high fat-diet group significantly increased since 4th week. Aqueous extracts revealed dysregulated Randle cycle kinetics in all three tissues, particularly in the heart tissue, with increased pyruvate, alanine and succinate, and decreased malonate, while the kidney and skeletal muscle had a less pronounced profile. Variations in the acylcarnitines levels in the cardiac and renal extracts were also found, suggesting alterations in the lipid metabolism. There were cues for gut microbiota altered dynamics, as six amino acids and dietary by-products, such as threonine, glycine, methionine, fumarate, dimethylamine and trimethylamine were shown to be depleted across all three tissues. Trimethylamine had significantly decreased levels in all tissues and was highlighted by all multivariate analysis models, suggesting the possible relevance of this metabolite as a biomarker.Overall, the results suggest a metabolic switch from glucose degradation into fatty acid oxidation, accompanied by oxidative and ischemic stress markers, as well as an impact to the gut microbiota flora. Although the multivariate models lacked predictive power, these results provided an integrated multi-tissue insight in the systemic mechanisms involved in a diet-induced NAFLD model.
FCT
Outro - Financial support from the Portuguese Foundation for Science and Technology (research grant FCT-FEDER-02/SAICT/2017/028147, PTDC/BIA-BQM/28147/2017 and PTDC/BAA-AGR/3550/2020) and from the Portuguese Society for Diabetology Fundamental and Translational Investigation Study Group (SPD-GIFT). Structural funding for the Center for Neurosciences and Cell Biology and the CICECO – Aveiro Institute of Materials is supported in part by FEDER – European Regional Development Fund through the COMPETE Program, Centro 2020 Regional Operational Program, the Portuguese Foundation for Science and Technology through grants UIDB/04539/2020, POCI-01-0145-FEDER-007679, UIDB/50011/2020, UIDP/50011/2020. We also acknowledge Rede Nacional de Ressonância Magnética Nuclear (PTNMR – PhD programme), partially supported by Infrastructure Project Nº 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC) and grants PD/BD/142850/2018, REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012.

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Dissertationen zum Thema „Heart Muscles Diseases“

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