Dissertations / Theses: 'Hypertrophy'

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Bloem, Liezl Margaretha. "Sarcomeric modifiers of hypertrophy in hypertrophic cardiomyopathy (HCM)." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/79795.

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Thesis (PhD)--Stellenbosch University, 2013. ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular morbidity and allcause mortality. Significantly, it is considered a modifiable cardiovascular risk factor as its regression increases overall survival and reduces the frequency of adverse cardiac events. A clear understanding of LVH pathogenesis is thus imperative to facilitate improved risk stratification and therapeutic intervention. Hypertrophic cardiomyopathy (HCM), an inherited cardiac disorder, is a model disease for elucidating the molecular mechanisms underlying LVH development. LVH, in the absence of increased external loading conditions, is its quintessential clinical feature, resulting from mutations in genes encoding sarcomeric proteins. The LVH phenotype in HCM exhibits marked variability even amongst family members who carry the same disease-causing mutation. Phenotypic expression is thus determined by the causal mutation and additional determinants including the environment, epigenetics and modifier genes. Thus far, factors investigated as potential hypertrophy modifiers in HCM have been relatively removed from the primary stimulus for LVH; and the few studies that have been replicated yielded inconsistent results. We hypothesized that the factors that closely interact with the primary stimulus of faulty sarcomeric functioning, have a greater capacity to modulate it, and ultimately the LVH phenotype in HCM. Plausible candidate modifiers would include factors relating to the structure or function of the sarcomere, including known HCM-causal genes; and the enzymes that function in sarcomere-based energetics. Indeed, the literature highlights the relevance of sarcomeric proteins, Ca2+-handling and myocardial energetics in the development of LVH in HCM. This study, therefore, set out to evaluate the hypertrophy-modifying capacity of such factors by means of family-based genetic association testing in 27 South African HCM families in which one of three unique HCM-causing founder mutations segregates. Moreover, the single and combined effects of 76 variants within 26 candidate genes encoding sarcomeric or sarcomere-associated proteins were investigated. The study identified a modifying role in the development of hypertrophy in HCM for each of the candidate genes investigated with the exception of the metabolic protein-encoding gene, PRKAG1. More specifically, single variant association analyses identified a modifying role for variants within the genes MYH7, TPM1 and MYL2, which encode proteins of the sarcomere, as well as the genes CPT1B, CKM, ALDOA and PRKAB2, which encode metabolic proteins. Haplotype-based association analyses identified combined modifying effects for variants within the genes ACTC, TPM1, MYL2, MYL3 and MYBPC3, which encode proteins of the sarcomere, as well as the genes CD36, PDK4, CKM, PFKM, PPARA, PPARG, PGC1A, PRKAA2, PRKAG2 and PRKAG3, which encode metabolic proteins. Moreover, a number of variants and haplotypes showed statistically significant differences in effect amongst the three HCM founder mutation groups. The HCM-modifier genes identified were prioritised for future studies according to the number of significant results obtained for the four tests of association performed. The genes TPM1 and MYBPC3, which encode sarcomeric proteins, as well as the genes PFKM and PRKAG2, which encode metabolic proteins, were identified as stronger candidates for future studies as they delivered multiple significant results for various statistical tests. This study makes a novel contribution to the field of hypertrophy research as it tested the hypothesis that structural or energy-related factors located within the sarcomere may act as modifiers of cardiac hypertrophy in HCM, and succeeded in identifying a modifying role for many of the candidate genes selected. The significant results include substantial single and within-genecontext variant effects; and identified sizeable variation in the risk of developing LVH owing to the compound effect of the modifier and the individual founder mutations. Collectively, these findings enhance the current understanding of genotype/phenotype correlations and may, as consequence, improve patient risk stratification and choice of treatment. Moreover, these findings emphasize the potential for modulation of disease by further elucidation of some of the avenues identified. AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is ‘n onafhanklike voorspeller van kardiovaskulêre morbiditeit en van mortaliteit weens alle oorsake. Van belang is dat dit ‘n wysigbare kardiovaskulêre risiko faktor is, aangesien die afname daarvan algehele oorlewing verhoog en die frekwensie van nadelige kardiale voorvalle verlaag. ‘n Duidelike begrip van LVH patogenese is dus noodsaaklik om verbeterde risiko stratifikasie en terapeutiese intervensie te fasiliteer. Hipertrofiese kardiomiopatie (HKM), ‘n oorerflike hart-siekte, is ‘n model-siekte vir die uitpluis van die molekulêre meganismes onderliggend aan die ontwikkeling van LVH. LVH, in die afwesigheid van verhoogde eksterne lading, is die kern kliniese simptoom van HKM en die gevolg van mutasies in die gene wat kodeer vir sarkomeriese proteïene. Die LVH fenotiepe in HKM toon merkbare veranderlikheid selfs in familie-lede wat dieselfde siekte-veroorsakende mutasie dra. Die fenotiepe word dus bepaal deur die siekte-veroorsakende mutasie asook addisionele determinante insluitend die omgewing, epigenetika en modifiserende gene. Potensiële hipertrofie-modifiseerders wat tot dusver bestudeer is, is betreklik verwyder van die primêre stimulus vir LVH en die paar studies wat gerepliseer is, het teenstrydige resultate gelewer. Ons hipoteseer dat die faktore wat in noue interaksie met die primêre stimulus van foutiewe sarkomeriese funksionering is, ‘n groter kapasitieit het om dit en uiteindelik die LVH fenotiepe in HKM, te moduleer. Aanneemlike kandidaat-modifiseerders sou insluit faktore wat betrekking het tot die struktuur en funksie van die sarkomeer insluitend HKM-oorsaaklike gene en die ensieme wat funksioneer in sarkomeer-gebaseerde energetika. Die literatuur beklemtoon inderdaad die relevansie van sarkomeriese proteïene, Ca2+-hantering en miokardiese energetika in die ontwikkeling van LVM in HKM. Hierdie studie het beoog om die hipertrofie-modifiserende kapasiteit van sulke faktore te evalueer deur middel van familie-gebaseerde genetiese assosiasie toetse in 27 Suid-Afrikaanse HKM families waarin een van drie unieke HKM-stigter mutasies segregeer. Verder was die enkel en gekombineerde effekte van 76 variante binne 26 kandidaat gene wat kodeer vir sarkomeer en sarkomeer-geassosieerde proteïene, ondersoek. Hierdie studie het ‘n modifiserende rol in die ontwikkeling van hipertrofie in HKM geïdentifiseer vir elk van die kandidaat gene wat ondersoek is, met uitsluiting van die PRKAG1, wat kodeer vir ‘n metaboliese proteïen. Meer spesifiek, enkel variant assosiasie analises het ‘n modifiserende rol geïdentifiseer vir variante in die gene MYH7, TPM1 en MYL2, wat kodeer vir sarkomeriese proteïene, asook die gene CPT1B, CKM, ALDOA en PRKAB2, wat kodeer vir metabolise proteïene. Haplotipe-gebaseerde assosiasie-analises het gekombineerde modifiserende effekte geïdentifiseer vir variante in die gene ACTC, TPM1, MYL2, MYL3 en MYBPC3, wat kodeer vir strukturele proteïene van die sarkomeer asook die gene CD36, PDK4, CKM, PFKM, PPARA, PPARG, PGC1A, PRKAA2, PRKAG2 en PRKAG3, wat kodeer vir metabolise proteïene. Verder het ‘n aantal variante en haplotipes statisties betekenisvolle verskille in effek tussen die drie HKM-stigter mutasie groepe getoon. Die HKM-modifiserende gene wat geïdentifiseer is, is verder geprioritiseer vir toekomstige studies volgens die aantal beduidende resultate wat vir die vier assosiasie toetse verkry is. Die gene TPM1 and MYBPC3, wat kodeer vir sarkomeriese proteïene, asook die gene PFKM and PRKAG2, wat kodeer vir metaboliese proteïene, is geïdentifiseer as sterker kandidate vir verdere studies omdat veelvuldige beduidende resultate vir die verskeie statistiese toetse deur hulle gelewer is. Hierdie studie maak ‘n nuwe bydrae tot die veld van hipertrofie navorsing omdat dit die hipotese dat strukturele en energie-verwante faktore, wat binne die sarkomeer geposisioneer is, potensieel as modifiseerders van kardiale hipertropfie in HKM kan optree, ondersoek het. Dit slaag ook daarin om ‘n modifiserende rol vir baie van die geselekteerde kandidaatgene te identifiseer. Die beduidende resultate sluit in aansienlike enkel en binne-geen-konteks variant-effekte en aansienlike variasie in die risiko vir LVH ontwikkeling verskuldig aan die gekombineerde effek van modifiseerder en individuele stigter mutasies. Gesamentlik verbeter hierdie bevindinge die huidige begrip van genotipe/fenotipe korrelasies en dit mag tot gevolg hê verbeterde pasiënt risiko stratifikasie en keuse van behandeling. Verder beklemtoon hierdie bevindinge die potensiaal vir siekte modulering deur verdere uitpluis van sekere van hierdie geïdentifiseerde navorsingsrigtings. National Research Foundation Dr. Paul van Helden Stellenbosch University

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Soana, valentina. "Ornamental Hypertrophy." Thesis, KTH, Arkitektur, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-35924.

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The thesis is exploring the potential of the ornament conceived as inhabitable space, exuberant, blissfull in opulence, flamboyant. The coexistence of opposite elements sensations that are overlapping, intertwining and blurring, generates a space that breathes, perspires and froths, exceeding in its blossom.

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Ferreira, Linda. "A Molecular Analysis of Cardiac Hypertrophy." Thesis, Griffith University, 2007. http://hdl.handle.net/10072/367757.

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Abstract :Cardiac hypertrophy has been identified as the most important independent risk factor for cardiovascular-related morbidity and mortality and is therefore regarded as a pathological condition. Despite this, beneficial physiological forms also appear to exist, such as in response to exercise, leading to maintained or improved cardiac function. The aim of this thesis was to examine two distinct rodent models, an endurance run-trained rat, and the DOCA-salt hypertensive rat, representing physiological and pathological hypertrophy, respectively, in order to develop a better understanding of the molecular changes associated with each condition. The thesis also examined the effect of dietary supplementation of L-arginine to the pathological model, a treatment that has been shown to ameliorate/prevent many of the cardiovascular impairments. Studies examined selected candidate genes (qRT-PCR), including conventional biomarkers of hypertrophy and exploratory analysis of adenosine-related genes (given adenosine’s established regulatory and protective role in the heart, yet minimally studied in cardiac hypertrophy), and explored global transcriptomic shifts via microarrays. The hypothesis of this work was that cardiac hypertrophy lies on a continuum, with similarities existing at the cardiac transcriptional level between early (adaptive) stages of pathological hypertrophy (DOCA-salt rat) and later stages of physiological hypertrophy (endurance run-trained rat). Examination of ten biomarkers of hypertrophy (ANF, BNP, -MHC, -MHC, cardiac -actin, skeletal -actin, SERCA2, PPAR, Coll I and III) revealed that the pathological model displayed alterations in the expression of many of these molecules in line with the literature. These changes were not observed in the physiological model. This therefore reinforces the value of conventional biomarkers in delineating pathological vs. physiological hypertrophies, and reveals fundamental differences in genesis of these two forms of hypertrophy. The adenosine system (receptors and purine handling molecules) was altered in the pathological hypertrophy model as evidenced by the modulation of genes corresponding to A3AR, Ada, and Adk, with a potential shift from purine salvage towards degradation of adenosine to inosine. Furthermore, this study represents the first report of altered regulation of the nucleoside transporter ENT3 in a pathological condition. None of these changes were seen in the physiological model with only modulation of the A2aAR evident. Examination of the transcriptional response to physiological hypertrophy revealed that short (6 week) and long (12 week) training programmes resulted in different profiles, likely reflecting progression of the hypertrophy process. The short programme stimulated genes associated with the mitochondria, oxidoreductase, receptor binding and coenzymemetabolismand repressed the expression of transcripts associated with phosphorylation, catalytic activity, defence/immunity and energy pathways. Thus, initial changes observed are primarily of a metabolic and signalling nature. In contrast, the longer programme resulted in shifts in protein handling and synthesis, and genes involved in structural molecule activity, nucleotide binding and cellular homeostasis. These patterns support a progression with time from initial metabolic adaptations to longer term shifts in protein phenotype and structural adaptations, consistent with longer term changes in heart structure. Similarly, the pathologicalmodel displayed different time-dependent gene expression profiles. Overall, the pattern of changewith early (2week) treatment is suggestive of changes in intracellular signalling and increasing transcriptional capacity with the later changes (at 4 weeks) indicative of structural adaptations (intra- and extracellularly) togetherwith an inflammation response. Genes coding for calciumhandling, ion channels, and gap junctions were altered throughout themodel andmay contribute to electrical conduction defects and cardiac dysfunction. The adrenergic signalling pathway was modulated as associated signalling molecules were down-regulated. The study revealed many expected and novel changes, of which further study should focus on: calcium regulation, metabolic regulation, gap junctions, and (as might be exii pected) signalling via the adrenergic pathway, insulin-like growth factor, PI3K, and Jak/STAT. L-Arginine modulated biomarker expression in pathological hypertrophy, with stimulation of PPAR and SERCA2 with little or no effect on the adenosine-related genes. L-Arginine affected the overall transcriptional response to DOCA-salt treatment, stimulating genes involved in cell growth andmaintenance, nerve transmission, heparin and glycosaminoglycan binding, peptide binding and protein targeting, as well as the repression of genes related to apoptosis (favouring a pro-apoptotic state), intracellular organisation and biogenesis, and enzyme inhibitor activity. The beneficial effects of L-arginine in the setting of pathological hypertrophy may be due to modulation of metabolism, improving calcium handling and overall enhancing cellular functioning. This work demonstrates that cardiac hypertrophy is clearly different at the transcriptional level depending upon the aetiology. This repudiated the hypothesis of the thesis that cardiac hypertrophy lies on a continuum with similarities existing at the cardiac transcriptional level between early (adaptive) stages of pathological hypertrophy and later stages of physiological hypertrophy. Whilst some of the data was in accordance with current knowledge of these states, novel changes were also discovered, contributing to our understanding of the molecular aspects of cardiac hypertrophy. Thesis (PhD Doctorate) Doctor of Philosophy (PhD) Griffith University. School of Medical Science. Griffith Health Full Text

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Paternostro, Giovanni. "Biochemical studies of cardiac hypertrophy." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337538.

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Clarke, Samantha Jayne. "Biochemical adaptations in cardiac hypertrophy." Thesis, University of Hull, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395503.

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Tsang, K. K. "Screening for benign prostatic hypertrophy." Thesis, University of Edinburgh, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.663068.

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Benign prostatic hypertrophy (BPH) is a very common disease among men aged 50 and its economic burden on health services continues to grow. The advocation for adopting new screening procedure for BPH begins to emerge. However, a new proposal for screening should be under careful scrutiny and ineffective and inappropriate screening must be avoided. A prospective cohort study has been launched to study the frequency, distribution, and natural history of BPH in two well-defined small communities in Central Scotland. Using the data from the cohort study, the hypothesis that a BPH screening programme justifies the stringent criteria set by Wilson and Jungner (1968) to evaluate any proposed programme, could be tested. The hypothesis has to be rejected after taking all the criteria into account. BPH was a major health problem among apparently well middle-age and elderly men in the community. It imposed significant interference in men's daily routine as well as influenced on their psychological general well-being. Although there was a detectable asymptomatic stage, the natural history of BPH from asymptomatic to a clinical stage was not clear. Because of the obscurity of the natural history, the optimum interval between repeated screens of a continuous screening process was unknown. The facilities for diagnosis and treatment could not be met by the present health services. The economic implications of a screening programme could be enormous, though a systemic analysis to evaluate the worthwhileness of the screening programme in economic terms was not conducted.

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Risto, Morten. "Modelling hypertrophy in dystrophic cardiomyocytes." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3402.

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Duchenne Muscular Dystrophy (DMD) is an X-linked disorder, caused by mutations in the DMD gene. This gene encodes dystrophin, a structural protein that links the sarcomere to the extracellular matrix via a trans-membrane protein complex. In the absence of dystrophin the associated glycoprotein complex fails to assemble, leading to sarcolemmal instability, impaired ion handling, skeletal muscle wasting and fibrosis. Patients become non-ambulant in their teens and seldom live past their third decade. Cardiac failure is one of the leading causes of death. The heart initially compensates for reduced functional capacity by becoming hypertrophic, but eventually becomes fibrotic and develops dilated cardiomyopathy. Several proposed therapies have now reached clinical trial phase, but there is still no cure available for all DMD patients. Some of these therapies target skeletal muscle better than the heart. Sample availability restricts research into cardiac mechanisms of disease and testing treatments. This thesis presents a model that can potentially be used as an in vitro outcome measure for testing DMD therapies. Cardiomyocytes isolated from hearts collected from the DMD mouse model (mdx) embryos became larger than control mouse embryo-derived cardiomyocytes in response to serum starvation in culture. Control and mdx cardiomyocytes were collected at five timepoints of serum starvation and RNA-Seq was performed on the samples to identify pathways responsible for this hypertrophic response observed in dystrophic cells. Several pharmacological compounds as well as a proposed gene therapy method were trialled for their ability to reduce the hypertrophic response. Serum starved cardiomyocytes from mdx mouse embryos were transduced with adeno-associated viruses containing a gene construct expressing a functional internally truncated version of dystrophin. The viral rescue therapy and some pharmacological compounds significantly reduced the dystrophic hypertrophy caused by serum starvation. This model of mdx cardiomyocyte hypertrophy could therefore be used for testing therapies in pre-clinical trials.

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Schans, Veerle Anna Maria van de. "Wnt signaling and cardiac hypertrophy." [Maastricht] : Maastricht : [Maastricht University] ; University Library, Universiteit Maastricht [host], 2009. http://arno.unimaas.nl/show.cgi?fid=14684.

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Stone, Michael H. "Mechanisms of Skeletal Muscle Hypertrophy." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/4532.

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Stone, Michael H. "Mechanisms of Skeletal Muscle Hypertrophy." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etsu-works/4544.

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Stone, Michael H. "Development of Skeletal Muscle Hypertrophy." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/4579.

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RIVERA, NATALIA V. "GENETICS OF LEFT VENTRICULAR HYPERTROPHY." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/169564.

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High blood pressure makes the heart work harder and promotes enlargement of the left ventricle, left ventricular hypertrophy (LVH), which is an important risk factor for cardiovascular disease and death. LVH is characterized for the most part by two different sets of observable characteristics (genetic phenotypes): an enlarged left ventricle (1) due to increasing wall thickness and (2) due to increasing wall dilation. The molecular and pathological mechanisms by which either phenotype occurs is unknown. We do know, however, that both phenotypic variations of LVH are determined by quantitative and qualitive changes in the genetic expression of cardiac cells that result in structural alterations in the muscular tissue that affect the blood flow within the heart. Genetics, the study of heredity and the variation of inherited characteristics, therefore play a prominent role in the development of LVH. A genome-wide association (GWA) study to investigate the genetics of LVH and left ventricular mass index (LVMI) in a cross-sectional-study of 1,212 subjects of white European ancestry and 2.5 million nucleotide polymorphisms (SNPs) yielded a total of 19 genome-wide significant (P < 5x10-7) variants. The GWA revealed no genome-wide significant variants; however, at suggestive P value < 1x10-5 were found two potentially susceptible regions of 97.6 Kb in the SYT14 gene and 3.4 kb in the GAS1 gene for association with LVMI. Nineteen (19) susceptible regions harboring common variants associated with LVH and 2 potential regions associated with LVMI were found. Further functional genetic studies (relating to a variable quantity whose value depends on one or more other variables) are required to characterize the biological relevance of these findings to high blood pressure associated with enlargement of the left ventricle.

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Cloete, Ruben Earl Ashley. "Investigations of Renin-Angiotensin Aldosterone System (RAAS) genes in hypertrophy in hypertrophic cardiomyopathy (HCM) founder families." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/21880.

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Thesis (MScMed)--Stellenbosch University, 2008. ENGLISH ABSTRACT: In hypertrophic cardiomyopathy (HCM), an autosomal dominant disorder, hypertrophy is variable within and between families carrying the same causal mutation, suggesting a role for modifier genes. Associations between left ventricular hypertrophy and left ventricular pressure overload suggested that sequence variants in genes involved in the Renin-Angiotensin Aldosterone System (RAAS) may act as hypertrophy modifiers in HCM, but some of these studies may have been confounded by, amongst other things, lack of adjustment for hypertrophy covariates. To investigate this hypothesis, twenty one polymorphic loci spread across six genes (ACE1, AGT, AGTR1, CYP11B2, CMA and ACE2) of the RAAS were genotyped in 353 subjects from 22 South African HCM-families, in which founder mutations segregate. Genotypes were compared to 17 echocardiographically-derived hypertrophic indices of left ventricular wall thickness at 16 segments covering three longitudinal levels. Family-based association was performed by quantitative transmission disequilibrium testing (QTDT), and mixed effects models to analyse the X-linked gene ACE2, with concurrent adjustment for hypertrophy covariates (age, sex, systolic blood pressure (BP), diastolic BP, body surface area, heart rate and mutation status). Strong evidence of linkage in the absence of association was detected between polymorphisms at ACE1 and posterior and anterior wall thickness (PW and AW, respectively) at the papillary muscle level (pap) and apex level (apx). In single-locus analysis, statistically significant associations were generated between the CYP11B2 rs3097 polymorphism and PW at the mitral valve level (mit) and both PWpap and inferior wall thickness (IW)pap. Statistically significant associations were generated at three AGTR1 polymorphisms, namely, between rs2640539 and AWmit, rs 3772627 and anterior interventricular septum thickness at pap and rs5182 and both IWpap and AWapx. Furthermore, mixed effects model detected statistically significant association between the ACE2 rs879922 polymorphism and both posterior interventricular septum thickness and lateral wall thickness at mit in females only. These data indicate a role for RAAS gene variants, independent of hypertrophy covariates, in modifying the phenotypic expression of hypertrophy in HCM-affected individuals. AFRIKAANSE OPSOMMING: Hipertrofiese kardiomiopatie (HCM), ‘n autosomale dominante afwyking, toon hoogs variërende hipertrofie binne en tussen families wat dieselfde siekte-veroorsakende mutasie het, hierdie dui op die moontlike betrokkenheid van geassosieerde modifiserende gene. Assosiasies tussen linker ventrikulêre hipertrofie en linker ventrikulêre druk-oorlading stel voor dat volgorde variasies in gene betrokke in die Renin-Angiotensin Aldosteroon Sisteem (RAAS) mag optree as hipertrofie modifiseerders in HCM. Sommige van hierdie soort studies is egter beperk omdat hulle nie gekompenseer het vir kovariante van hipertrofie nie. Om hierdie hipotese te ondersoek, is die genotipe bepaal by een-en-twintig polimorfiese lokusse, verspreid regoor ses RAAS gene (ACE1, AGT, AGTR1, CYP11B2, CMA and ACE2), in 353 kandidate vanuit 22 Suid-Afrikaanse HCM-families in wie stigter mutasies segregeer. Genotipes was vergelyk met 17 eggokardiografies afgeleide hipertrofiese indekse van linker ventrikulêre wanddikte by 16 segmente wat oor drie longitudinale vlakke strek. Familie-gebaseerde assosiasies was bestudeer deur kwantitatiewe transmissie disequilibrium toetsing (QTDT) en gemengde effek modelle om die X-gekoppelde geen ACE2 te analiseer, met gelyktydige kompensasie vir hipertrofie kovariate (ouderdom, geslag, sistoliese bloed druk (BP), diastoliese BP, liggaamsoppervlak area, hartritme en mutasie-status). Sterk indikasies van koppeling in die afwesigheid van assosiasie is waargeneem tussen ACE1 lokusse en posterior wanddikte (PW) asook anterior wanddikte (AW) by die papillêre spier vlak (pap) en die apeks vlak (apx). In enkel-lokus analises is statisties-betekenisvolle assosiasies gevind tussen die CYP11B2 rs3097 polimorfisme en PW by die mitraalklep vlak (mit) en beide die PWpap en inferior wanddikte (IW)pap. Statisties-betekenisvolle assosiasies was verder gevind by drie AGTR1 polimorfismes, naamlik, tussen rs2640539 polimorfisme en AWmit, rs3772627 en die anterior interventrikulêre septumdikte (aIVS) by die pap en rs5182 by beide die IWpap en AWapx. Gemengde-effek modelle het verder assosiasies aangetoon tussen die ACE2 rs879922 polimorfisme en die posterior interventrikulêre septumdikte en die laterale wanddikte by die mit, slegs in vrouens. Hierdie data dui op ‘n kovariaat-onafhanklike rol vir RAAS genetiese variante in die modifisering van die fenotipiese uitdrukking van hipertrofie in HCM-geaffekteerde individue.

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Todd, Carol. "Identification of novel sarcomeric modifiers of hypertrophy in hypertrophic cardiomyopathy using the yeast two-hybrid system." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/79819.

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Thesis (MScMedSc)--Stellenbosch University, 2013. ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) occurs when the cardiomyocytes in the left ventricle become enlarged by increasing in mass in response to haemodynamic pressure overload. This can either be attributed to a normal physiological response to exercise or can be the result of a maladaptive process or disease state, such as chronic hypertension. Hypertrophic cardiomyopathy (HCM) is the most common form of Mendelian-inherited cardiac disease. A defining characteristic thereof is primary LVH that occurs when there are no other hypertrophy-predisposing conditions present. Therefore, HCM provides a unique opportunity to study the molecular determinants of LVH in the context of a Mendelian disorder, instead of in more complex disorders such as hypertension. Over 1000 HCM-causing mutations in 19 genes have been identified thus far, most of them encoding sarcomeric proteins residing in the sarcomeric C-zone. However, for many HCM patients no disease-causing genes have been identified. Moreover, studies have shown phenotypic variation in presentation of disease in, as well as between, families in which the same HCM-causing mutation segregates. This has led many investigators to conclude that genetic modifiers of hypertrophy exist. The aim of the study was to identify novel plausible HCM-causing or modifier genes by searching for interactors of a known HCM-causing protein, namely titin. The hypothesis was that genes encoding proteins, which interact with proteins that are encoded by known HCM-causative genes, may also be considered HCM-causing or may modify the HCM phenotype. To this end, the aim was to identify novel interactors of the 11-domain super-repeat region of titin, which resides within the sarcomeric C-zone, using yeast two-hybrid analysis. Five putative interactors of the 11-domain super-repeat region of titin were identified in this study. These interactions were subsequently verified by colocalisation in H9C2 rat cardiomyocytes, providing further evidence for possible interactions between titin and these proteins. The putative interactor proteins of titin determined from the Y2H library screen were: filamin C (FLNC), phosphatidylethanolamine-binding protein 4 (PEBP4), heart-type fatty acid binding protein 3 (H-FABP3), myomesin 2 (MYOM2) and myomesin 1 (MYOM1). The FLNC gene could be a candidate for cardiac diseases, especially cardiomyopathies that are associated with hypertrophy or developmental defects. The putative interaction of titin and PEBP4 is speculated to be indicative of the formation of the interstitial fibrosis and myocyte disarray seen in HCM. Heart-type fatty acid-binding protein 3 has prognostic value to predict recurrent cardiac events. Its suggested interaction with titin is speculated to play a role in inhibiting its functional abilities. Myomesin 2 is jointly responsible, with MYOM1, for the formation of a head structure on one end of the titin string that connects the Z and M bands of the sarcomere. This is speculated to be linked to a developmental error with the result being a defect in sarcomeric structure formation, which could result in pathologies such as HCM. Therefore, these identified proteins could likely play a functional role in HCM due to their interactions with titin. This research could thus help with new insights into the further understanding of HCM patho-aetiology. AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) ontstaan wanneer die kardiomyosiete in die linkerventrikel vergroot as gevolg van 'n verhoging in massa in reaksie op hemodinamiese drukoorlading. Dit kan toegeskryf word aan 'n normale fisiologiese respons op oefening of kan die gevolg wees van 'n wanaangepaste of siektetoestand, soos chroniese hipertensie. Hipertrofiese kardiomiopatie (HKM) is die mees algemene vorm van Mendeliese oorerflike hartsiekte. 'n Bepalende eienskap daarvan is primêre LVH, wat plaasvind wanneer daar geen ander hipertrofie-predisponerende voorwaardes teenwoordig is nie. Gevolglik bied HKM 'n unieke geleentheid om die molekulêre derterminante van LVH te bestudeer, in die konteks van 'n Mendeliese oorerflike siekte, in plaas van om dit in die meer komplekse siektes soos hoë bloeddruk te bestudeer. Meer as 1000 HKM-veroorsakende mutasies is tot dusver in 19 gene geïdentifiseer. Die meeste van hulle kodeer vir sarkomeriese proteïene wat in die C-sone voorkom. Egter, vir baie HKM-pasiënte is geen siekte-veroorsakende gene al geïdentifiseer nie. Daarbenewens het studies getoon dat variasie in fenotipiese aanbieding van die siekte in, sowel as tussen, families voorkom wat dieselfde HKM-veroorsakende mutasie het. Dit het daartoe gelei dat baie navorsers tot die gevolgtrekking gekom het dat genetiese wysigers van hipertrofie wel bestaan. Die doel van die studie was om nuwe moontlike HKM-veroorsakende of wysiger-gene te identifiseer deur te soek vir interaktors van 'n bekende HKM-veroorsakende proteïen, naamlik titin. Die hipotese was dat gene wat vir proteïene kodeer, wat in wisselwerking is met proteïene wat geïnkripteer word deur bekende HKM-veroorsakende gene, ook oorweeg kan word om HKM te veroorsaak. Dit kan ook die HKM fenotipe verander. Dus was die doel om nuwe interaktors van die 11-domein super-herhaalstreek van titin, soos gevind binne die sarkomeriese C-sone, te identifiseer deur middel van gis-twee-hibried-analise. Vyf vermeende interaktors van die 11-domein super-herhaalstreek van titin is in hierdie studie geïdentifiseer. Hierdie interaksies is later geverifieer met behulp van ko-lokalisering in H9C2-rotkardiomyosiete, wat verdere bewyse vir moontlike interaksies tussen titin en hierdie proteïene verskaf. Die vermeende interaktor-proteïene van titin wat bepaal is vanaf die gis-twee-hibried-biblioteeksifting was as volg: filamin C (FLNC), phosphatidylethanolamine-bindingsproteïen 4 (PEBP4), hart-tipe-vetsuur bindingsproteïen 3 (H-FABP3), myomesin 2 (MYOM2) en myomesin 1 (MYOM1). Die FLNC-geen kan 'n kandidaat vir kardiale siektes, veral kardiomiopatieë, wees wat geassosieer word met hipertrofie of ontwikkelingsafwykings. Die vermeende interaksie van titin en PEBP4 dui daarop om 'n aanduiding te wees vir die vorming van die interstisiële fibrose en miokardiale wanorde, soos gesien in HKM. Hart-tipe-vetsuur bindingsproteïen 3 het prognostiese waarde om herhalende kardiale gebeure te voorspel. Verder dui sy voorgestelde interaksie met titin moontlik daarop dat dit 'n rol kan speel in die inhibering van sy funksionele vermoëns. Myomesin 2 tesame met MYOM1 is verantwoordelik vir die vorming van 'n kopstruktuur aan die een kant van die titinstring wat dan die Z- en M-bande van die sarkomeer verbind. Daar word vermoed dat dit gekoppel is aan 'n ontwikkelingsfout, met die gevolg dat daar 'n defek is in sarkomeriese struktuurvorming, wat weer kan lei tot patologieë soos HKM. Mrs Wendy Ackerman Prof Paul van Helden National Research Foundation (NRF) Stellenbosch University

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Akki, Ashwin. "Lipid overload studies in cardiac hypertrophy." Thesis, University of Hull, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441778.

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Wallis, William Richard James. "The cellular pathophysiology of myocardial hypertrophy." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265997.

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17

Howell, Neil John. "Metabolic support in left ventricular hypertrophy." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1492/.

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Aims: To examine the metabolic changes associated with LVH secondary to AS, to examine the role of GIK as an adjunct to myocardial protection during AVR, and to examine the mechanism of its action. Methods: 220 patients with LVH secondary to AS were randomised 1:1 to receive an infusion of GIK at the time of AVR. The primary endpoint of the trial was incidence of low cardiac output state. At pre-specified time points, biopsies of the LV anterior wall were taken for analysis of metabolic changes associated with LVH, and changes in the phosphorylation state of proteins identified as key regulators of metabolism and cardiac protection. Results: Patients with LVH were found to exhibit a profound down-regulation of the mRNA transcript levels of the master transcriptional regulators of metabolism resulting in a significantly abnormal metabolome. Treatment with GIK was associated with a reduction in LCOS from 33% in the control group to 10% in the treatment group, p=0.0001. Treatment with GIK was associated with a significant increase in the level of protein O-GlcNAcylation. Conclusions: In this trial, treatment with GIK was associated with a significant improvement in post-operative haemodynamics. Patients with LVH may benefit from metabolic therapies at the time of surgery

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Philipot, Didier. "Implication du miR-24 et du miR-199a-5p dans le vieillissement prématuré du chondrocyte au cours de l'arthrose." Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON1T015/document.

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L'arthrose tardive est la plus répandue des maladies ostéo-articulaires dont la prévalence augmente avec l'âge. Dans le cartilage arthrosique, des changements spécifiques des chondrocytes s'opèrent. Ils présentent une diminution de leur propriété de synthèse de la matrice extracellulaire, une diminution de leur réponse aux facteurs de croissance anabolisants et une augmentation de la sénescence cellulaire. Elle est caractérisée par un arrêt irréversible du cycle cellulaire, une érosion des télomères, une activation de la voie de dommages à l'ADN (ATM/p53/p21), une activation de la voie p16INK4a/pRb, l'établissement d'un sécrétome associé à un phénotype sénescent/hypertrophique appelé SAPS. Le sujet de ma thèse porte sur l'identification de microARNs impliqués dans le vieillissement prématuré du chondrocyte. Les microARNs (miRs) sont des petits ARNs non codant endogènes qui contrôlent un certain nombre de fonctions biologiques comme la prolifération, la différenciation ou la sénescence. Deux études ont montré le rôle préventif des miRs dans l'induction de la sénescence et dans l'hypertrophie. Au cours de ma thèse, nous avons utilisé un modèle de chondrocytes arthrosiques en 3D traités à l'IL-1β afin de récapituler le phénotype sénescent observé dans la pathologie. Cela nous a permit d'identifier deux miRs réprimés en réponse à cette cytokine : miR-24 et miR-199a-5p. Nous montrons que la répression de miR-24 conduit à une induction de p16INK4a et MMP1 associé à un phénotype hypertrophique. De plus, nos données préliminaires montrent que le miR-199a-5p est potentiellement un régulateur négatif de l'hormone anti-vieillissement Klotho qui est retrouvée dérégulée dans notre modèle cellulaire Osteoarthritis (OA) is an age-related disease whose prevalence increases with late life. In osteoarthritic cartilage, chondrocytes presents age-specific changes such as a decrease in synthesis properties, a decrease in their response to growth and anabolic factors and an increase of cellular senescence. Senescent chondrocytes are characterized by an irreversible cell cycle arrest, DNA damage response activation (ATM/p53/p21), p16INK4a/pRb signaling pathway activation and the establishment of SAPS triggering to hypertrophy. The aim of my PhD project consisting to identify microRNAs involved in chondrocyte premature aging. microRNAs are small endogenous RNAs controlling several biological processes such as proliferation, differentiation and senescence. Two studies show that microRNAs have a preventive role in senescence and hypertrophy. During my PhD, we perform a cellular model based on OA chondrocytes placed in 3D and treated with IL-1β. We identified two miRs: miR-24 and miR-199a-5p. Repression of miR-24 leads to the induction of p16INK4a and MMP1, associated with chondrocyte hypertrophy. Moreover, preliminary datas suggests that miR-199a-5p is a potential regulator of anti-aging hormone Klotho which is deregulated in our model

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Crampton, Matthew S., and n/a. "Differential Gene Expression in Pathological and Physiological Cardiac Hypertrophy." Griffith University. School of Biomolecular and Biomedical Science, 2006. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20070104.165826.

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Cardiac hypertrophy defines an adaptive process brought about in response to sustained increases in haemodynamic work. Cardiomyocytes undergo an initial compensatory phase in which enlargement and contractility alterations normalise wall stress and maintain adequate perfusion of organs. In pathological hypertrophy, this deteriorates to a decompensated state characterised by ventricular dysfunction and predisposition to heart failure. In contrast, physiological hypertrophy and associated enhanced cardiac functioning arising from chronic exercise training does not progress to heart failure. Determination of the molecular pathways underlying myocardial hypertrophy remains a challenge for cardiovascular research. The objective of the work presented in this thesis was to identify genes differentially expressed during pathological and physiological hypertrophy in order to enhance our knowledge of the mechanistic processes involved. A reverse Northern hybridisation method was applied to profile the expression of specifically selected genes in the hypertrophic models examined. Functional categories represented in the gene panel assembled included cardiac contractile and cytoskeletal markers, matrix metalloproteinases, vasoactive pathway factors, calcium handling genes, ion channels, cardiac regulatory factors, signalling pathway intermediates, apoptotic factors and histone deacetylases. In order to investigate pathological hypertrophy, a deoxycorticosterone acetate-salt (DOCA-salt) rat model was utilised. DOCA-salt treated rats used in this study demonstrated a 1.4-fold increase in heart weight to body weight ratio compared to controls. Impaired cardiac function indicative of a decompensated pathological phenotype in the DOCA-salt treated group was demonstrated by way of decreased chamber size, impaired myocardial compliance and significantly reduced cardiac output. Reverse Northern hybridisation analysis of 95 selected genes identified a number of candidates with differential expression in hearts of DOCA-salt treated rats. Increased gene expression was demonstrated for the collagenase MMP1 and stress-activated signal transduction factor Sin1. In contrast, the sarcoplasmic reticulum calcium ATPase SERCA-2 and anti-apoptotic factor BCL2l-10 genes exhibited decreased expression. To investigate changes in gene expression associated with physiological hypertrophy, use was made of an endurance run-trained rat model. The run-trained rats used in this study demonstrated a 24.1% increase in heart weight to body weight ratio and improvements in performance consistent with physiological cardiac adaptation. These performance indicators included improvements in systolic volume, cardiac output, myocardial compliance and bio-energetic function. Reverse Northern hybridisation expression analysis of 56 genes identified a number of differentially expressed mRNA transcripts in run-trained hypertrophied hearts. Four genes shown to demonstrate reduced expression in the run-trained rat model were interleukin-1 receptor associated kinase (IRAK1) and the developmentally expressed transcription factors Nkx-2.3, dHAND, and IRX-2. Based upon the reverse Northern hybridisation results, four genes were selected for Western blotting analysis of rat cardiac tissue. Of these, MMP1 and a putative isoform of Sin1 exhibited increased levels in DOCA-salt treated hypertrophic left ventricular tissue, results that correlate with the findings of increased mRNA expression for these two genes. Therefore, this study identified MMP1 and Sin1 as candidates involved in pathological but not physiological hypertrophy. This finding is in accord with other recent investigations demonstrating that pathological hypertrophy and physiological hypertrophy are associated with distinct molecular phenotypes. An aside to the major objective of identifying genes differentially regulated in left ventricular hypertrophy involved the application of the P19CL6 cell in vitro model of cardiomyogenesis to compare protein expression during hypertrophy and development. The Sin1 isoform, found to be up-regulated during DOCA-salt induced hypertrophy, was also shown to be more abundant in differentiating, than non-differentiating, P19CL6 cells. This result is consistent with the developing paradigm that implicates 'fetal' genes in the hypertrophic remodelling process.

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20

Crampton, Matthew S. "Differential Gene Expression in Pathological and Physiological Cardiac Hypertrophy." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/366605.

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Cardiac hypertrophy defines an adaptive process brought about in response to sustained increases in haemodynamic work. Cardiomyocytes undergo an initial compensatory phase in which enlargement and contractility alterations normalise wall stress and maintain adequate perfusion of organs. In pathological hypertrophy, this deteriorates to a decompensated state characterised by ventricular dysfunction and predisposition to heart failure. In contrast, physiological hypertrophy and associated enhanced cardiac functioning arising from chronic exercise training does not progress to heart failure. Determination of the molecular pathways underlying myocardial hypertrophy remains a challenge for cardiovascular research. The objective of the work presented in this thesis was to identify genes differentially expressed during pathological and physiological hypertrophy in order to enhance our knowledge of the mechanistic processes involved. A reverse Northern hybridisation method was applied to profile the expression of specifically selected genes in the hypertrophic models examined. Functional categories represented in the gene panel assembled included cardiac contractile and cytoskeletal markers, matrix metalloproteinases, vasoactive pathway factors, calcium handling genes, ion channels, cardiac regulatory factors, signalling pathway intermediates, apoptotic factors and histone deacetylases. In order to investigate pathological hypertrophy, a deoxycorticosterone acetate-salt (DOCA-salt) rat model was utilised. DOCA-salt treated rats used in this study demonstrated a 1.4-fold increase in heart weight to body weight ratio compared to controls. Impaired cardiac function indicative of a decompensated pathological phenotype in the DOCA-salt treated group was demonstrated by way of decreased chamber size, impaired myocardial compliance and significantly reduced cardiac output. Reverse Northern hybridisation analysis of 95 selected genes identified a number of candidates with differential expression in hearts of DOCA-salt treated rats. Increased gene expression was demonstrated for the collagenase MMP1 and stress-activated signal transduction factor Sin1. In contrast, the sarcoplasmic reticulum calcium ATPase SERCA-2 and anti-apoptotic factor BCL2l-10 genes exhibited decreased expression. To investigate changes in gene expression associated with physiological hypertrophy, use was made of an endurance run-trained rat model. The run-trained rats used in this study demonstrated a 24.1% increase in heart weight to body weight ratio and improvements in performance consistent with physiological cardiac adaptation. These performance indicators included improvements in systolic volume, cardiac output, myocardial compliance and bio-energetic function. Reverse Northern hybridisation expression analysis of 56 genes identified a number of differentially expressed mRNA transcripts in run-trained hypertrophied hearts. Four genes shown to demonstrate reduced expression in the run-trained rat model were interleukin-1 receptor associated kinase (IRAK1) and the developmentally expressed transcription factors Nkx-2.3, dHAND, and IRX-2. Based upon the reverse Northern hybridisation results, four genes were selected for Western blotting analysis of rat cardiac tissue. Of these, MMP1 and a putative isoform of Sin1 exhibited increased levels in DOCA-salt treated hypertrophic left ventricular tissue, results that correlate with the findings of increased mRNA expression for these two genes. Therefore, this study identified MMP1 and Sin1 as candidates involved in pathological but not physiological hypertrophy. This finding is in accord with other recent investigations demonstrating that pathological hypertrophy and physiological hypertrophy are associated with distinct molecular phenotypes. An aside to the major objective of identifying genes differentially regulated in left ventricular hypertrophy involved the application of the P19CL6 cell in vitro model of cardiomyogenesis to compare protein expression during hypertrophy and development. The Sin1 isoform, found to be up-regulated during DOCA-salt induced hypertrophy, was also shown to be more abundant in differentiating, than non-differentiating, P19CL6 cells. This result is consistent with the developing paradigm that implicates 'fetal' genes in the hypertrophic remodelling process. Thesis (PhD Doctorate) Doctor of Philosophy (PhD) School of Biomolecular and Biomedical Sciences Full Text

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Evaristi, Maria Franscesca. "New biomarkers and therapeutic targets in left ventricular hypertrophy." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30047.

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L'hypertrophie ventriculaire gauche (HVG) est un remodelage prédicteur du développement d'une insuffisance cardiaque et de la mortalité cardiovasculaire. L'hypertension artérielle est une cause majeure de l'HVG, puisque 30% des patients hypertendus développent une HVG. Un dépistage biologique précoce de l'HVG post hypertensive permettrait d'optimiser la prise en charge des patients et d'empêcher que l'HVG évolue vers l'insuffisance cardiaque. L'utilisation de biomarqueurs est un outil rapide, efficace et peu couteux pour le diagnostic de nombreuses pathologies. Dans la pratique clinique il n'existe pas de biomarqueurs pour identifier les patients hypertendus avec HVG de ceux sans ce remodelage. Le premier objectif de notre étude a été d'identifier des biomarqueurs plasmatiques de l'HVG post hypertensive. Une analyse métabolomique obtenue par spectroscopie de résonance magnétique nucléaire du proton (H1) a été effectuée sur les échantillons de plasma de 48 patients hypertendus avec HVG, 48 hypertendus sans HVG et 24 témoins. A l'aide d'outils bio-informatiques et d'analyses statistiques adaptées, nous avons mis en évidence la présence d'un ratio des groupements chimiques méthylène/ méthyle (-CH2-/-CH3) des chaines aliphatiques des lipides plasmatiques augmenté chez les patients hypertendus avec HVG (p<0.001). Ce ratio détecte la présence d'une HVG chez les patients hypertendus avec une sensitivité de 52.08% et une spécificité de 85.42%. Nous proposons que le ratio -CH2-/-CH3 des chaines aliphatiques lipidiques présent dans plasma représente un biomarqueur diagnostique de l'HVG dans l'hypertension artérielle. L'incidence de l'HVG est aussi augmentée chez les patients qui souffrent du syndrome métabolique (MetS). Le MetS est défini par la présence d'une obésité abdominale plus deux facteurs parmi la dyslipidémie, l'insulino-résistance et l'hypertension artérielle. Ces facteurs synergisent et sont les responsables de l'instauration d'une HVG et d'une progression vers l'insuffisance cardiaque. Des données publiées montrent que les patients MetS ont un taux réduit de l'insulin-like growth factor binding protein 2 (IGFBP2). L'IGFBP2 a un rôle potentiel dans le diabète et dans le métabolisme, mais il n'existe pas d'étude sur son rôle dans les pathologies cardiaques causées par une dérégulation métabolique. Le premier objectif de notre étude sur l'IGFBP2 a été de mesurer le taux plasmatique d'IGFBP2 et le taux d'expression cardiaque de l'ARN messager d'IGFBP2 dans une cohorte de patients avec et sans MetS. Nous avons montré que le taux plasmatique ainsi que le taux d'ARN messager cardiaque d'IGFBP2 sont diminués chez les patients avec le Mets comparé à des témoins. Puis, nous avons mesuré le tôt cardiaque d'ARN messager de l'IGFBP2 dans un model murin de MetS. Pour générer ce modèle, nous avons nourri des souris C57BL/6J avec du régime gras à 60% pendant 15 semaines. Le taux d'expression cardiaque de l'ARN messager de l'IGFBP2 est réduit chez les souris avec Mets, en accord avec les résultats obtenu chez l'homme. Enfin, nous avons testé si la thérapie génique utilisant un virus adeno-associé qui exprime l'IGFBP2 humaine (AAV9-hIGFBP2) pouvait restaurer un niveau normal d'IGFBP2 et interférer avec l'HVG causé par le MetS chez ces souris. Nos résultats montrent que l'injection de l'AAV9-hIGFBP2 rétabli durablement le niveau cardiaque d'IGFBP2 chez la souris avec MetS et qu'IGFBP2 prévient l'épaississement des parois du ventricule gauche, l'hypertrophie et la dysfonction cardiaque. Nos résultats suggèrent qu'IGFBP2 est une nouvelle cible thérapeutique potentielle de l'HVG Left ventricular hypertrophy (LVH) is a strong predictor of future heart failure and cardiovascular mortality. Arterial hypertension is considered as the main causative agent for LVH as 30% of hypertensive patients develop LVH. These patients have an increased risk for cardiovascular complications and heart failure. Early diagnosis of LVH and prompt treatment are crucial to reduce LVH and stop its progression towards heart failure. Biomarkers could represent a rapid, effective and low-cost tool to discriminate hypertensive patients with LVH from those with normal LV size. Therefore, we aimed to identify plasma metabolomics biomarkers by 1H NMR to provide novel diagnostic tools for rapid detection of LVH in populations of hypertensive individuals. We realized a cross-sectional study including 48 hypertensive patients with LVH matched with 48 hypertensive patients with normal LV size, and 24 healthy controls. Two-dimensional targeted M-mode echocardiography was performed to measure left ventricular mass index. Partial least squares discriminant analysis was used for the multivariate analysis of the 1H NMR spectral data. From the 1H NMR analysis, we found that the methylene/methyl (-CH2-/-CH3) ratio of aliphatic chain from plasma lipids was significantly increased (p<0.001) in hypertensive patients with LVH compared to hypertensive patients without LVH and to control. Receiver operating characteristic curve showed that a cutoff value of 2.34 provided a 52.08% sensitivity and 85.42% specificity for discriminating LVH (AUC=0.703, p-value<0.001). We propose the -CH2/-CH3 ratio from plasma aliphatic lipid chains as a biomarker for the diagnosis of LVH in arterial hypertension. LVH incidence is also increased in patients with metabolic syndrome (MetS). MetS is defined by central obesity plus any two medical conditions such as dyslipidemia, insulin resistance, and hypertension. These factors synergize to cause LV dysfunction and HF. Published data have shown that MetS patients have low plasma insulin-like growth factor binding protein 2 (IGFBP2). IGFBP2 was shown to play a role in diabetes and metabolism, but studies investigating its role in cardiac diseases are lacking. We first aimed to investigate plasma IGFBP2 levels and cardiac IGFBP2 mRNA levels in MetS patients. Both plasma levels and heart expression levels of IGFBP2 were decreased in patients with MetS compared to control patients. Further, in a C57BL/6J mouse model of 60% high fat diet-induced MetS, we measured cardiac mRNA IGFBP2 levels. According to the observed data in human, mice with MetS showed a decreased cardiac IGFBP2 mRNA level. Finally, we investigated whether a gene therapy strategy using adeno-associated virus 9 carrying human IGFBP2 coding sequence (AAV9-hIGFBP2) could prevent from MetS associated left ventricular hypertrophy. Our data showed that AAV9-hIGFBP2 injection restored durably cardiac IGFBP2 levels in mouse heart and prevented from left ventricle wall thickening, hypertrophy and dysfunction. These clinical and animal data suggest that IGFBP2 is a potential new cardiac therapeutic target in MetS

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SASANO, Chieko, Mahmud UZZAMAN, Luni EMDAD, Yoshiko TAKAGISHI, Haruo HONJO, Kaichiro KAMIYA, and Itsuo KODAMA. "Dephosphorylation of Connexin43 Associated with Ventricular Hypertrophy." Research Institute of Environmental Medicine, Nagoya University, 2002. http://hdl.handle.net/2237/2800.

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Aro, J. (Jani). "Novel load-inducible factors in cardiac hypertrophy." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526212173.

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Abstract Cardiac hypertrophy is an adaptive response to increased cardiac workload. It is initially beneficial, since it helps to maintain cardiac output, but ultimately it is considered as an independent predictor for heart failure and sudden cardiac death. The cardiac hypertrophic response is triggered by mechanical and neurohumoral stimuli and is associated with the activation of complex changes in gene programming and intracellular signaling pathways. The purpose of this study was to investigate the expression of some novel load-induced factors i.e. melusin, thrombospondin (TSP)-1 and -4 and LIM and cysteine-rich domains protein 1 (LMCD1)/dyxin during the hypertrophic response. Melusin was expressed in cardiac tissue both in the atria and ventricles, furthermore its expression was very rapidly activated in response to multiple hypertrophic stimuli predominantly in the left atria. Melusin gene expression was activated when cultured cardiac myocytes were subjected to mechanical stretch or hypertrophic agonists such as endothelin-1 or angiotensin (Ang II). TSP-1 and TSP-4 gene expressions were rapidly activated at an early stage of pressure overload. Myocardial infarction (MI) induced the expression of both TSP-4 and TSP-1 mRNA in the heart. TSP-4 may also be an endothelial cell-specific marker of pressure overload since its expression was limited to endothelial cells in the adult heart. The expression of LMCD1/dyxin was found to be induced during the cardiac hypertrophic response and after MI. By itself, mechanical load was a critical regulator of LMCD1/dyxin gene expression. LMCD1/dyxin is a putative novel p38 mitogen-activated protein kinase (MAPK) target since adenovirus-mediated overexpression of p38 MAPK upregulated LMCD1/dyxin expression. In addition, during the Ang II-induced pressure overload p38 MAPK phosphorylation levels correlated with the early induction of LMCD1/dyxin expression. In conclusion, this study provides new information on the expression of melusin, TSP-1 and -4 and LMCD1/dyxin in the cardiac hypertrophic response. Early induction of their gene expression may represent an initial step in the adaptive and protective remodeling processes following increased workload in the heart Tiivistelmä Sydänlihas mukautuu lisääntyneeseen kuormitukseen lihassolujen koon kasvun eli hypertrofian avulla. Pitkittyessään hypertrofinen kasvu on kuitenkin tärkeä sydämen vajaatoimintaa ja äkkikuolemaa ennakoiva riskitekijä. Hypertrofisessa vasteessa mekaaninen venytys sekä neurohumoraaliset tekijät saavat aikaan solunsisäisten signaalinvälitysreittien aktivoitumisen, mikä johtaa lisääntyneeseen geenien luentaan ja proteiinituotantoon. Väitöskirjassa tutkittiin uusien kuormitusaktivoituvien tekijöiden, melusiinin, trombospondiini (TSP) -1:n ja -4:n sekä dyksiinin ilmentymistä hypertrofisen vasteen aikana. Melusiinia ilmentyy sydämessä sekä kammioissa että eteisissä, mutta painekuormituksen myötä se aktivoituu nopeasti pääasiassa vasemmassa eteisessä. Sydänlihassolujen soluviljelymallissa melusiinin luenta lisääntyy suoraan mekaanisen venytyksen ja hypertrofisten agonistien vaikutuksesta. Painekuormitus aktivoi nopeasti myös TSP-1:n ja -4:n luentaa sydämessä. TSP-1:n ja -4:n geeniluenta lisääntyy myös kokeellisessa sydäninfarktimallissa. Lisäksi sydämessä TSP-4:ää havaittiin olevan ensisijaisesti endoteelisoluissa. Dyksiinin ilmentyminen lisääntyi sekä painekuormituksen että sydäninfarktin aiheuttaman sydänlihaksen uudelleenmuovautumisen aikana. Mekaaninen kuormitus riitti jo yksinään aktivoimaan dyksiinin geeniluentaa sydämessä. Lisäksi mitogeeni-aktivoituvan p38-proteiinikinaasin havaittiin säätelevän dyksiinin ilmentämistä. Väitöskirjatyössä saatiin uutta tietoa sydänlihaksen kuormituksen aikaisista muutoksista geenien luennassa sydänlihaksessa. Työssä osoitettiin, että painekuormitus aktivoi sydämessä aiemmin vähän tutkittujen geenien, melusiinin, TSP-1:n ja -4:n sekä dyksiinin, ilmentymistä. Näiden tekijöiden aktivoituminen hypertrofisen vasteen alkuvaiheessa antaa viitettä siitä, että tekijät osallistuvat kuormittuneen sydänlihaskudoksen uudelleenmuovautumiseen. Melusiini voi toimia erityisesti eteiskudosta kuormitukselta suojaavissa mekanismeissa, kun taas TSP-4 osoittautui aktivoituvan painekuormituksessa nimenomaan endoteelisoluissa

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Sin, Yuan Yan. "The roles of HSP20 in cardiac hypertrophy." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3581/.

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Cardiac hypertrophy often develops to compensate for hemodynamic overload and is associated with heart failure. Recent studies have revealed that overexpression and PKA-mediated phosphorylation of heat shock protein 20 (HSP20) at Ser16 can attenuate hypertrophic growth of cardiomyocytes and trigger cardioprotective functions following sustained β-adrenergic stimulation (Fan et al., 2004, 2005, 2006). However, the molecular mechanism of HSP20 induced cardioprotection remains to be fully elucidated. In order to gain insight into the protective mode of action of HSP20, I attempted to (1) investigate the spatiotemporal control of PKA-mediated phosphorylation of HSP20, as well as (2) identifying novel protein binding partners for HSP20 utilising cutting edge ProtoArray technology. Initially, I set up an in vitro hypertrophy model using sustained isoprenaline (ISO)-stimulated neonatal rat cardiomyocytes. Cell size, protein synthesis and fetal gene expression were assessed as parameters of hypertrophic growth. In the first section of my studies, members of the cAMP-specific PDE4 family were shown to form signalling complexes with HSP20, and that the PKA-mediated phosphorylation of HSP20 could be modulated by PDE4. Based on peptide array data, a cell-permeable peptide ‘bs906’ was developed to inhibit the interaction of PDE4 with HSP20. Interestingly, the disruption of the PDE4-HSP20 complex was shown to induce PKA-mediated phosphorylation of HSP20 and trigger cardioprotection against the hypertrophic response measured in neonatal cardiomyocytes upon chronic β-adrenergic stimulation. In the second part of my studies, protein kinase D1 (PKD1) was identified as one interacting partner that robustly associated with HSP20. This interaction was confirmed by biochemical and immunocytochemical means. Using similar approaches to those used for the PDE4-HSP20 interaction, a cell-permeable peptide ‘HJL09’ was generated to promote disruption of the PKD1-HSP20 complex. Experimentation using the peptide concluded that the disruption of the PKD1-HSP20 complex reduced HSP20 phosphorylation and attenuated the hypertrophic response in cultured cardiomyocytes as shown by reduced increases in cell size, protein content and actin reorganisation. In undertaking this work, I also defined a novel PKD phosphorylation site (Ser16) on HSP20 that conforms to the PKD phosphorylation motif of RxxS (also a PKA site). My biochemical data suggested that PKD1 may regulate the cardioprotective function of HSP20 via phosphorylation at Ser16. In situ proximity ligation assay (PLA) further revealed a role of HSP20 as ‘molecular escort’ in targeting the nuclear translocation of PKD1. This function, in part, may be responsible for the induction of fetal gene reexpression as selective disruption of PKD1-HSP20 complex using ‘HJL09’ hindered the nuclear influx of the complex, thereby attenuating hypertrophic signalling. In summary, these studies describe some exciting findings which provide further insight into novel signalling mechanism of cardiac hypertrophy in neonatal rat cardiomyocytes. I have shown that PKA and PKD1 exhibiting opposite functions despite sharing the phosphorylation site on HSP20. In this regard, HSP20 functions as a molecular nexus for the opposing actions of the PKA and PKD1 signalling pathways in hypertrophy, suggesting that crosstalk may occur between anti-hypertrophic and pro-hypertrophic pathways. The identification and characterisation of these complexes should help to build a better understanding of the hypertrophic signalling pathway, and may provide novel therapeutic strategies for the treatment of cardiac hypertrophy.

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Butler, Thomas J. "Impact of dietary manipulation on cardiac hypertrophy." Thesis, University of Hull, 2012. http://hydra.hull.ac.uk/resources/hull:15371.

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Left ventricular hypertrophy (LVH) is a significant risk factor for the development of heart failure (HF), the incidence of which is increased by obesity. Diets high in fat and sugar have been linked with the development of the metabolic syndrome and obesity, and may expose the heart to a unique environment via the differential actions of dietary macronutrients. The main objectives of this study were to determine the effect of differing dietary regimens upon (i) the progression of LVH and whole organism morphology (ii) function and metabolism in the hypertrophied heart, and (iii) cardiac ceramide content. Cardiac hypertrophy was surgically induced in male Sprague-Dawley rats via abdominal aortic constriction (AC). Animals were assigned to either a diet containing 5% sucrose/7% fat (standard diet, SD), 9 % sucrose/45 % fat (high-fat diet, HFD), or 14% sucrose/44% fat (western diet, WD) for 9 weeks. LVH was observed in all AC groups but was greatest in those fed a SD or WD. Both HFD and WD resulted in a significant increase in abdominal fat mass, which was positively associated with serum concentrations of leptin. In vitro cardiac function was unaltered by any dietary regimen alone, but was significantly enhanced in hypertrophied hearts from HFD and WD-fed animals, consistent with a compensated phase of hypertrophic remodelling. This was accompanied by a small reduction in palmitate oxidation and increased reliance upon lactate, an effect which was exacerbated in hearts from WD-fed animals. In WD-fed animals, there was a substantial increase in cardiac triglyceride (TG), which was not affected by AC. PPARα protein was reduced following AC in the hearts of animals fed a SD or WD, whereas the HFD prevented this decline. CD36 protein expression was not different between control and AC animals, but was highest in those fed a WD. In addition to elevated TG, WD hearts also exhibited a significant accumulation of long-chain ceramide species (C16-C24) compared with other dietary groups; consistent with metabolic remodelling. This effect was observed independent of AC. In order to simulate a model of HF, WD animals were treated with adriamycin (ADR), and cardiac ceramide content was further increased with the specific accumulation of C16 and C18 ceramide. These findings suggest that dietary macronutrient composition can have a profound effect upon the progression of LVH. Furthermore, the enhanced ceramide content in WD hearts indicates that the macronutrient composition of this dietary profile is most deleterious to the hypertrophied heart. Prolonged exposure of the hypertrophied heart to the WD may lead to increased apoptosis and accelerate the transition to HF.

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Lozar, Olivia Mae. "Does Proteasome Activity Impact Skeletal Muscle Hypertrophy?" University of Toledo / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1576264202406223.

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Shirazi, Farshad 1963. "Metabolic aspects of neonatal rat cardiomyocyte hypertrophy." Diss., The University of Arizona, 1997. http://hdl.handle.net/10150/282447.

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The consensus view is that cardiac hypertrophy is an adaptive response to increased work caused by a variety of stimuli. While hypertrophy can be defined as an increase in cell mass without an increase in cell number, not all increases are equivalent in type and amount of protein accumulated. Our goal in this study was to identify the common steps in the process of cardiac hypertrophy. Our working hypothesis was that in all forms of cardiac hypertrophy glucose utilization increases and that the percentage of energy derived from fatty-acid oxidation decreases. The first part of this study entailed the development and characterization of a neonatal rat heart cell model. The model had to provide uniform culture conditions for rapid development of hypertrophy by agents acting at different sites in the cardiomyocytes. The second part of this study was composed of an assessment of hypertrophy caused by four pharmacologically distinct agents: norepinephrine, angiotensin-II, endothelin-I and tetradecylglycidic acid. In this part we compared the quantity of protein accumulation and quality of hypertrophy cause by each agent. This task was accomplished by examining the effect of each agent on selected mRNA messages and alteration in DNA content of cardiomyocytes. Here we also examined the effect of protein kinase-C, endothelin-I and angiotensin-II inhibitors on hypertrophy caused by each agent. In the final part of this study, metabolic alteration in hypertrophy caused by each agent was assessed for a potential common pathway to hypertrophy. As part of this analysis, we examined changes in glucose and palmitate oxidation, glucose uptake and role of pentose pathway in hypertrophy resulting from treatment of cardiomyocyte by each agent.

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Carstens, N. "The role of renin-angiotensin-aldosterone system (RAAS) genes in the development of hypertrophy in hypertrophic cardiomyopathy (HCM)." Thesis, Stellenbosch : University of Stellenbosch, 2009. http://hdl.handle.net/10019.1/2667.

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Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009. Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, is considered a model for studying left ventricular hypertrophy (LVH) in the absence of increased external loading conditions. The disease manifests extreme variability in the degree and pattern of LVH, even in HCM patients with the same causal mutation. The clinical phenotype of HCM can therefore be viewed as a product of the effect of sarcomere dysfunction and of additional genetic modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) are plausible candidate modifiers because of their effect on blood pressure and their direct hypertrophic effect on cardiomyocytes. The present study investigated genes encoding components of the RAAS for association with cardiac hypertrophy traits, in 353 individuals comprised of genetically and echocardiographically affected and unaffected family members, belonging to 22 HCM families with HCM founder mutations by employing a multi-SNP approach with TaqMan allelic discrimination technology. Gene-gene interaction analysis was also performed to investigate the effect of epistasis on hypertrophy. Candidate genes for analysis included the angiotensin II type 2 receptor (AT2 receptor), renin, renin-binding protein (RnBP), the (pro)renin receptor, the mineralocorticoid receptor as well as genes encoding subunits of the epithelial sodium channels (ENaC) and Na+/K+-ATPase that showed evidence for cardiac expression. The present study demonstrates for the first time that variations in the renin and RnBP genes play a role in modulating hypertrophy in HCM, independent of blood pressure and confirms the involvement of the AT2 receptor in hypertrophy in HCM. Additionally we report an association between Na+/K+-ATPase α1- and β1-subunits as well as the ENaC α- and β-subunits and hypertrophy. Significant evidence for epistasis was found between renin and downstream RAAS effectors, suggesting a complex interplay between these RAAS variants and the hypertrophic phenotype in HCM. The identification of such modifiers for HCM may offer novel targets for hypertrophy research and ultimately antihypertrophic therapy.

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Voigt, Christian [Verfasser]. "Early Segmental Relaxation Abnormalities in Hypertrophic Cardiomyopathy for Differential Diagnostic of Patients with Left Ventricular Hypertrophy / Christian Voigt." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2021. http://d-nb.info/1238231098/34.

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Gondran, Tellier Victor. "Étude du rôle des protéines GASP dans le développement musculaire par des approches in vivo et de prédiction in silico." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0099/document.

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La masse musculaire est largement régulée par des voies de signalisation contrôlant l'équilibre entre la synthèse et la dégradation des protéines myofibrillaires. Ainsi, la myostatine, membre de la superfamille des TGFβ, cible un certain nombre de réseaux de signalisation impliqués dans la régulation de la masse musculaire, notamment la voie de signalisation Akt/mTOR. La myostatine est un des inhibiteurs majeurs de la myogenèse en exerçant un contrôle négatif sur la prolifération et différenciation des myoblastes. A l’heure actuelle, la myostatine est au centre de nombreuses stratégies thérapeutiques notamment dans le cadre de thérapies visant à améliorer la fonction musculaire dans les cas d’atrophie ou myopathies. Les protéines GASP-1 et GASP-2, deux protéines sécrétées contenant plusieurs domaines associés à des inhibiteurs de protéases, ont été décrites comme antagonistes de la myostatine. L’Unité de Génétique Moléculaire Animale a mis en place des stratégies in vitro et in vivo afin de déterminer les fonctions des protéines GASP, notamment dans le contexte myogénique. Dans un premier temps, l'équipe a généré une lignée de souris transgéniques TgGasp-1 sur-exprimant le gène Gasp-1. Cette lignée présente une augmentation globale du poids des muscles squelettiques et une hypertrophie, conséquences d'une inhibition de la myostatine. Cependant, contrairement aux souris knock-out pour la myostatine (Mstn-/-), cette lignée ne présente nid’hyperplasie, ni de changement dans la proportion des différents types de fibres musculaires, ni de variation de métabolisme.Afin de mieux comprendre le rôle des protéines GASP dans le développement musculo-squelettique,deux approches complémentaires ont été développées au cours de cette thèse.Une première approche in vivo, avec l'étude d'une lignée murine TgGasp-2 sur-exprimant le gène Gasp-2, a permis de mettre en évidence un phénotype musculaire semblable aux souris sur-exprimant Gasp-1. En effet, l'analyse phénotypique de ce modèle murin montre à 12 semaines, une augmentation globale du poids des souris et de certains muscles squelettiques due à une hypertrophie des fibres musculaires. Comme pour les souris sur-exprimant Gasp-1, à la différence des souris Mstn-/-, le nombre total de fibres des souris TgGasp-2 et leur métabolisme ne présentent pas de variation parrapport aux souris sauvages. Une seconde approche in silico, suite à une étude transcriptomique et protéomique à partir de modèles murins sur-exprimant ou non GASP-1, a permis d'identifier différents processus biologiques et voies de régulation contrôlées par GASP-1 Muscle mass is largely regulated by signaling pathways controlling the balance between synthesis and degradation of myofibrillar proteins. Thus, myostatin, a member of the TGFβ superfamily, targets a number of signaling networks involved in the regulation of muscle mass, in particular the Akt / mTOR signaling pathway. Myostatin is one of the major inhibitors of myogenesis by exerting a negativecontrol on the proliferation and differentiation of myoblasts. Today, myostatin is involved in many therapeutic strategies which aim to improve muscle function in cases of atrophy or myopathies.GASP-1 and GASP-2 are two secreted proteins containing several domains associated with protease inhibitors, and described as myostatin antagonists. The Animal Molecular Genetics laboratory has developed in vitro and in vivo strategies to determine the functions of GASPs proteins in a myogenic context. First, we generated a transgenic mouse line TgGasp-1 over-expressing the Gasp-1 gene. This line shows an overall increase in skeletal muscle weight and hypertrophy, a consequence of myostatin inhibition. However, unlike myostatin knockout mice (Mstn -/-), this line shows neither hyperplasia, nor change in the proportion of different types of muscle fibers. Moreover, the global metabolism is not affected. In order to better understand the role of GASPs proteins in musculoskeletal development, two complementary approaches were developed during this thesis :(i) the study of a murine TgGasp-2 line over-expressing Gasp-2 reveals a muscular phenotype similar to the TgGasp-1 mice. At 12 weeks, we observed an overall increase in body and some skeletal muscles weight due to a hypertrophy of the myofibers. As the TgGasp-1 mice, and unlike the Mstn -/- mice, the number of fibers and the metabolism of TgGasp-2 mice did not vary compared to the wildtype mice (ii) In silico analyses allow us to identify different biological processes and regulated pathways controlled by GASP-1

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31

Pearson, David R. "Comparison of isotonic and isokinetic work induced hypertrophy as evaluated by computed tomography." Virtual Press, 1987. http://liblink.bsu.edu/uhtbin/catkey/487144.

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Six male subjects (26.0+3.1 years), performed an exercise regimen of repeated knee extension exercises in an attempt to induce size and strength changes in the quadriceps muscle (thigh). Their left thigh was trained using an isotonic (IST) lifting protocol and the right thigh was trained using an isokinetic (ISK) device. The total amount of torque produced by each protocol was the same and knee extensions were performed at a common velocity (120 deg/sec). Training was performed 3 days per week for a period of 8 weeks. Data were presented as means (±SD) for pre-and post-training values with a level of significance set at P<0.05.Girth measurements, corrected for subcutaneous fat and expressed as thigh volumes (cc), showed a significant hypertrophy of the IST thigh (3300.67+526.67) after training as compared to that of the IST thigh (3044.13±448.50) before training. No significant difference was found between pre-and post-training ISK thigh volumes. Computed tomography (CT) data were also obtained but could not be statistically analyzed because of technical errors.The mean IST (36.0+0.0) and ISK repetitions (64.54±13.61) necessary to produce equal work bouts (based on total torque produced) were significantly different, resulting in a greater training intensity for the isotonic training.Strength gains as measured isotonically and isokinetically were specific to the training mode. The IST thigh showed a significant strength (Kg) gain when tested on an IST device; the ISK thigh did not. However, the ISK thigh gained significant strength (Kg-m) at all testing velocities (60,180 and 240 deg/sec) while the IST thigh did not.These data would indicate: 1) IST training is superior to ISK training for producing hypertrophy of the thigh; 2) IST training is more intense than ISK training for equal workbouts; and 3) strength gains are specific to training and to the mode of testing.

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Movahed, Mohammad, Deborah Strootman, Sharon Bates, and Sudhakar Sattur. "Prevalence of suspected hypertrophic cardiomyopathy or left ventricular hypertrophy based on race and gender in teenagers using screening echocardiography." BioMed Central, 2010. http://hdl.handle.net/10150/610116.

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BACKGROUND:The goal of this study was to evaluate the prevalence of suspected hypertrophic cardiomyopathy (HCM) in a population of teenagers undergoing screening echocardiography for the detection of HCM.METHOD:The Anthony Bates Foundation performs screening echocardiography for the prevention of sudden death. A total of 2,066 students were studied between the ages of 13 to 19 years. Suspected HCM was defined as any wall thickness greater than or equal to] 15 mm. LVH was defined as wall thickness greater than or equal to] 13 mmRESULTS:Prevalence of suspected HCM was 0.7% (14/2066). After adjusting for hypertension (HTN), the total prevalence was 0.5% (8/1457). In a subgroup analysis, 551 teenagers with documented race and LV wall thickness were identified between the ages of 13 - 19 years. African American teenagers 6% (3/50)] had higher prevalence of suspected HCM 0.8% (4/501), OR 7.93, CI 1.72-36.49, p = 0.002]. After multivariate adjustment for age, gender, BMI and HTN (systolic BP >140 and diastolic BP of > 90), African American race remained independently associated with suspected HCM (OR 4.89, CI 1.24-39.62, p = 0.02).CONCLUSION:The prevalence of suspected HCM in young teenagers is approximately 0.2%. This prevalence appears to be higher in African Americans. However, due to small number of African Americans in our population, our result needs to be confirmed in larger trials.

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Schnell, Frédéric. "Hypertrophie ventriculaire gauche physiologique ou pathologique : Intérêt d’une approche multiparamétrique." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1B021/document.

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Introduction : Le diagnostic de cardiomyopathie hypertrophique (CMH) est difficile chez l’athlète. En effet, le remodelage physiologique induit par l’entraînement physique intense entraîne des modifications électriques et morphologiques qui peuvent mimer une cardiomyopathie. Or il est indispensable de poser le diagnostic de cardiomyopathie avec certitude chez un athlète. Ne pas contre-indiquer un athlète avec une cardiomyopathie l’expose à un risque de mort subite, mais poser un diagnostic par excès l’expose à de lourdes répercussions tant professionnelles que sociales. Méthodes : (1) Nous avons cherché à améliorer les critères ECG actuels de détection de cardiomyopathie chez l’athlète à partir d’une cohorte multicentrique d’athlètes et de CMH. (2) Nous avons cherché à déterminer quel bilan complémentaire réaliser en cas d’anomalie ECG par un suivi longitudinal d’athlètes avec ondes T négatives. (3) Nous avons essayé de mieux caractériser le phénotype des athlètes atteints de CMH par rapport aux CMH sédentaires dans une cohorte multicentrique. (4) Nous avons tenté de déterminer si l’utilisation des nouvelles techniques d’imagerie de déformation myocardique permettait d’améliorer la pertinence diagnostique et pronostique en cas de CMH dans une cohorte de CMH et d’athlètes rennais. Résultats : Nous avons proposé une nouvelle classification ECG permettant de mieux identifier les athlètes avec modifications ECG non pathologiques sans diminuer pour autant la capacité à détecter les CMH. En cas d’ondes T négatives chez l’athlète, nous avons démontré qu’il était indispensable de réaliser une IRM myocardique. En effet l’échocardiographie peut être prise en défaut dans près de 35% des cas. Néanmoins, les critères diagnostiques actuels de CMH peuvent être pris en défaut; en effet les athlètes avec une CMH ont un phénotype différent des CMH sédentaires avec une meilleure fonction systolique, notamment longitudinale, et diastolique. L’évaluation de la fonction longitudinale à l’effort et l’évaluation de la dispersion mécanique sont des paramètres qui semblent prometteurs en terme de diagnostic. En effet l’altération la fonction longitudinale semble être en lien avec la fibrose myocardique. L’échocardiographie d’effort, notamment la présence d’une insuffisance mitrale à l’effort, semble être un facteur pronostic important dans les CMH. Conclusions : les travaux réalisés ont permis de développer des outils pour mieux différencier une hypertrophie ventriculaire gauche (HVG) pathologique d’une HVG physiologique mais également pour mieux caractériser cette HVG et déterminer avec plus de précision le pronostic des CMH Introduction: the diagnosis of hypertrophic cardiomyopathy (HCM) in athlete is difficult. Indeed, intense sports practice induces an electrical and morphological physiological remodeling which can be difficult to differentiate from the changes induced in pathology. However, it is essential to diagnose an athlete with a cardiomyopathy. Indeed, in case of underlying cardiomyopathy the athlete will be at risk of sudden cardiac death, but an excessive over diagnosis has strong professional and social consequences. Methods: (1) we have tried to improve the ECG criteria’s, which enable the differentiation between ECG changes induced by exercise and the ECG changes induced by an underlying cardiomyopathy. (2) We tried to define the best investigation algorithm in case of abnormal ECG changes in athletes. (3) We tried to improve the characterization of the phenotype of athletes with HCM as compared to sedentary HCM. (4) We tried to investigate if the use of new imaging technics, i.e. speckle tracking, might improve the diagnostic accuracy and enable a better prognostic evaluation in HCM. Results: We have proposed a new classification of ECG in athletes enabling to decrease the rate of false positive ECG in athletes without decreasing its diagnostic accuracy in HCM. In case of pathological T wave inversion (PTWI) in athletes, we demonstrated that a CMR is mandatory, as echocardiography missed a diagnosis of pathology in 35% of PTWI athletes. Nevertheless, the diagnosis of HCM with current criteria’s of HCM can be challenging. Indeed, HCM athletes have a different phenotype from HCM sedentary, with a better systolic and diastolic function; they also have a better longitudinal function. The assessment of longitudinal function during exercise and mechanical dispersion are promising tool for the diagnosis of HCM in athletes. Indeed, the alteration of longitudinal strain is related to myocardial fibrosis. Exercise echocardiography, i.e. exercise mitral insufficiency, seems to be a prognostic factor in HCM patients. Conclusions: Ours results enabled to develop tools which might help to better differentiate pathological and physiological left ventricular hypertrophy (LVH); but also to better characterize LVH and the prognosis in HCM patients

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Sundström, Johan. "Left ventricular hypertrophy and the insulin resistance syndrome." Doctoral thesis, Uppsala University, Department of Public Health and Caring Sciences, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-580.

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Left ventricular hypertrophy (LVH) and the insulin resistance syndrome are common conditions associated with a markedly increased cardiovascular risk. In a fairly large prospective longitudinal study of men from the general population, we found that an unfavorable serum fatty acid profile and components of the insulin resistance syndrome such as dyslipidemia, obesity and hypertension at age 50 predicted the prevalence of LVH at age 70. In cross-sectional analyses at age 70, several components of the insulin resistance syndrome were significantly related to left ventricular relative wall thickness and concentric remodeling, but less to LVH. Left ventricular relative wall thickness was inversely related to insulin sensitivity in skeletal muscle and borderline significantly directly related to insulin sensitivity in the myocardium in a healthy, normotensive sample of the cohort investigated with positron emission tomography, whereas left ventricular mass index was not related to myocardial or skeletal muscle insulin sensitivity. At age 70, echocardiographic LVH was related to a variety of common electrocardiographic diagnoses. In a prospective mortality analysis with baseline at age 70 and a median follow-up time of five years, echocardiographic and electrocardiographic LVH predicted mortality independently of each other and of other cardiovascular risk factors, implying that echocardiographic and electrocardiographic LVH in part carry different prognostic information.In summary, components of the insulin resistance syndrome predicted LVH twenty years later, but were cross-sectionally more related to increased left ventricular relative wall thickness and concentric remodeling. Echocardiographic and electrocardiographic LVH predicted mortality independently of each other and of components of the insulin resistance syndrome.

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Gennebäck, Nina. "Cardiac hypertrophy : transcription patterns, hypertrophicprogression and extracellular signalling." Doctoral thesis, Umeå universitet, Medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-59470.

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Background: The aim of this thesis was to study transcription patterns and extracellular signalling of the hypertrophic heart to better understand the mechanisms initiating, controlling and maintaining cardiac hypertrophy. Cardiac hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophy of the myocardium is a state, independent of underlying disease, where the myocardium strives to compensate for an increased workload. This remodelling of the heart includes physiological changes induced by a changed gene expression, alteration of the extracellular matrix and diverse cell-to-cell signalling. Shedding microvesicles and exosomes are membrane released vesicles derived from the plasma membrane, which can mediate messages between cells and induce various cell-related processes in target cells. Methods and materials: Two different microarray studies on different materials were performed. In the first study, cardiac myectomies from 8 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 5 controls without cardiac disease were used. In the second study, myocardial tissue from 6 aorta ligated and 6 sham operated (controls) rats at three different time points (1, 6 and 42 days post-surgically) were analysed. To reveal differences in gene expression the materials were analyzed with Illumina whole genome microarray and multivariate data analysis (PCA and OPLS-DA). Cultured cardiomyocytes (HL-1) were incubated with and without growth factors (TGF-β2 or PDGF BB). Microvesicles and exosomes were collected and isolated after differential centrifugations and ultracentrifugations of the cell culture medium. The microvesicles and exosomes were characterized with dynamic light scattering (DLS), flow cytometry, western blot, electron microscopy and Illumina whole genome microarray. Results: The two different microarray studies revealed differentially expressed gene transcripts and groups of transcripts. When comparing HOCM patients to controls significant down-regulation of the MYH6 gene transcript and two immediate early genes (IEGs, EGR1 and FOS), as well as significant up-regulation of the ACE2, JAK2 and HDAC5 gene transcripts were found. In the rat model, 5 gene groups showed interesting clustering after multivariate data analysis (OPLS-DA) associated with the hypertrophic development: “Atherosclerosis”, “ECM and adhesion molecules”, “Fatty acid metabolism”, “Glucose metabolism” and “Mitochondria”. The shedding microvesicles were rounded vesicles, 40-300 nm in size and surrounded by a bilayered membrane. Chromosomal DNA sequences were identified in the microvesicles. The microvesicles could be taken up by fibroblasts resulting in an altered gene expression in the fibroblasts. The exosomes from cultured cardiomyocytes (incubated with TGF-β2 or PDGF BB) had an average diameter of 50-80 nm, similar to the unstimulated control exosomes. A large, for all cardiomyocyte derived exosomes, common pool of mRNA seems stable and a smaller pool varied in mRNA content according to treatment of the cardiomyocyte. Of the common mRNA about 14% were ribosomal, 14% were of unknown locus and 5% connected to the function of the mitochondria. Conclusions: The microarray studies showed that transcriptional regulation at a stable stage of the hypertrophic development is a balance of pro and anti hypertrophic mechanisms and that diverse gene groups are differently regulated at different time points in the hypertrophic progression. OPLS-DA is a very useful and powerful tool when analyzing gene expression data, especially in finding clusters of gene groups not seen with traditional statistics. The extracellular vesicle studies suggests that microvesicles and exosomes released from cardiomyocytes contain DNA and can be involved in events in target cells by facilitating an array of processes including gene expression changes. Different treatment of the cardiomyocyte influence the content of the exosome produced, indicating that the signal function of the exosome might vary according to the state of the cardiomyocyte. Bakgrund: Syftet med den här avhandlingen var att studera transkriptions-mönster och extracellulär signalering vid hjärthypertrofi för att bättre förstå de mekanismer som startar, styr och underhåller tillväxten. Hjärthypertrofi, onormal tillväxt av hjärtmuskeln, är en riskfaktor för andra hjärt-kärlsjukdomar och dödlighet. Hypertrofi av hjärtmuskeln är ett tillstånd, oberoende av bakomliggande sjukdom, där hjärtmuskeln strävar efter att kompensera för ökad arbetsbelastning. Denna omställning av hjärtat innefattar fysiologiska förändringar orsakade av ett förändrat genuttryck, modifiering av miljön utanför cellen och ändrad cell-till-cell signalering. Mikrovesiklar och exosomer är små membranomslutna bubblor som frisätts från cellmembranet, ut i cellens omgivning. De kan förmedla budskap mellan celler och påverka olika processer i målceller. Metoder och material: Avhandlingen innefattar två olika microarraystudier på olika material. I den första studien användes hjärtbiopsier från 8 patienter med hypertrofisk obstruktiv kardiomyopati (HOCM) och 5 kontroller utan hjärtsjukdom. I det andra projektet användes hjärtvävnad från 6 aortaligerade och 6 skenopererade (kontroller) råttor vid tre olika tidpunkter (1, 6 och 42 dagar efter kirurgiskt ingrepp). För att påvisa skillnader i genuttryck analyserades proverna med Illumina helgenom microarray och multivariat dataanalys. Avhandlingens andra del innehåller två studier om mikrovesiklar och exosomer. Odlade hjärtmuskelceller (HL-1) stimulerades med tillväxt-faktorer (TGF-β2 eller PDGF BB) och ostimulerade celler användes som kontroll. Mikrovesiklar och exosomer renades fram med centrifugeringar och ultracentrifugering av cellodlingsmediet för att sedan karakteriseras med olika metoder för att studera storlek, ytmarkörer och innehåll. Illumina helgenom microarray användes för att studera microvesiklarnas och exosomernas mRNA innehåll. Resultat: I de två olika microarraystudierna hittades gentranskript och grupper av gentranskript som skiljde sig mellan kontroller och den hypertrofa hjärtvävnaden. När HOCM patientproverna jämfördes med kontroller hittades nedreglering av MYH6, EGR1 och FOS samt uppreglering av ACE2, JAK2 och HDAC5. Efter multivariat dataanalys av materialet från råtta, hittades 5 grupper av gentranskript med intressanta mönster som kunde kopplas till den hypertrofiska utvecklingen av hjärtmuskeln: "Ateroskleros", "ECM och adhesionsmolekyler", "Fettsyrametabolism", "Glukosmetabolis-men" och "Mitokondrien". Mikrovesiklarna hade en diameter på 40-300 nm och innehöll kromosomala DNA-sekvenser. När mikrovesiklarna överfördes till en annan celltyp (fibroblaster) resulterade det i ett förändrat genuttryck i fibroblasterna. Exosomer från hjärtmuskelcellerna som odlats med eller utan tillväxtfaktor hade en diameter på 50-80 nm. En stor pool av olika gentranskript var gemensam för alla exosomer oavsett stimulering eller ej. En mindre pool av gentranskript varierade i innehåll mellan de stimulerade och ostimulerade hjärtmuskelcellerna. I den gemensamma gentranskript poolen var ca 14 % ribosomala, ca 14 % var okända och ca 5 % var associerade till mitokondrien och dess funktion. Slutsats: Microarraystudierna visade att transkriptionsreglering i ett stabilt skede av hypertrofiutvecklingen är en balans mellan pro- och anti-hypertrofiska mekanismer och att olika gengrupper var olika reglerade vid olika tidpunkter i hjärtmuskeltillväxten. OPLS-DA är ett mycket användbart och kraftfullt verktyg när man analyserar genexpressionsdata, särskilt för att hitta grupper av gen-transkript som är svåra att upptäcka med traditionell statistik. Microvesikel- och exosomstudierna visade att mikrovesiklar och exosomer som frisätts från hjärtmuskelceller innehåller både DNA och RNA och kan vara inblandade i händelserna i målceller genom att underlätta en rad processer, inklusive ändringar av genuttryck. Olika stimulering av hjärtmuskelcellen kan påverka innehållet i exosomernas som produceras, vilket indikerar att exosomernas signalfunktion kan variera beroende på hjärtmuskelcellens tillstånd.

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Sundström, Johan. "Left ventricular hypertrophy and the insulin resistance syndrome /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-4919-0/.

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37

Silberberg, Jonathan S. "Left ventricular hypertrophy in end-stage renal disease." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61836.

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38

Braga, Luca. "Identification and characterization of MicroRNAs modulating cardiac hypertrophy." Thesis, Open University, 2017. http://oro.open.ac.uk/51095/.

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The adult heart is capable of remodelling in response to different pathological stimuli; in most cases, a phase of compensated hypertrophy evolves into frank dysfunction and heart failure. To identify microRNAs able to prevent cardiac hypertrophy and preserve cardiac function, we performed a high-content microscopy, high-throughput functional screening for human microRNAs able to reduce neonatal cardiomyocyte (CM) cell size using a whole-genome microRNA library. The most effective anti-hypertrophic microRNA was hsa-miR-665. In a model of transverse abdominal aortic constriction (TAC) in 8 weeks old CD1 mice (n=14 per group), AAV9-mediated delivery of miR-665 showed remarkable capacity to protect against pathological cardiac hypertrophy and preserve function over time. This effect was observed when the vectors were delivered either before (LVEF at 60 day after TAC: 51.3% ±5.8% in treated vs 34.82% ±0.77% in controls; P < 0.005) or after hypertrophy onset (LVEF at 60 days after TAC: 57.5%±5.60% in treated vs 28.4%±15% in controls; P < 0.001). Global mRNA changes in hearts treated with miR-665 were evaluated by mRNA deep sequencing. All the 43 genes, for which siRNA were available, out of the 67 genes that were found to be significantly expressed ≤2 fold over control were individually down-regulated by specific siRNAs and tested for being direct miR-665 targets. This approach identified three sarcomeric proteins as direct mediators of miR-665 activity, namely Enah, Fhl1 and Xirp2, which are known to be involved in sarcomeric mechanotransduction and myofibrillar remodelling. In conclusion, miR-665 represents an important tool to decipher the molecular mechanisms of hypertrophy and offers a potential lead for the development of new biotherapeutics.

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Sayeed, Rana Ahmed. "Patterns of ion channel expression in cardiac hypertrophy." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616262.

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Richardson, Simon. "Studies of ischaemia and reperfusion in cardiac hypertrophy." Thesis, University of Hull, 2002. http://hydra.hull.ac.uk/resources/hull:13202.

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Cardiac hypertrophy may be associated with an enhanced susceptibility to ischaemic/reperfusion injury but the mechanisms remain unresolved. There is evidence for an increased dependence on glucose metabolism in cardiac hypertrophy, which may be beneficial in normoxia but detrimental in ischaemia. The role of glycogen, the major endogenous substrate during ischaemia, to the enhanced susceptibility of the hypertrophied heart to ischaemic/reperfusion injury is unclear. Work in this thesis investigates the role of glycogenolysis to the severity of ischaemia, and assesses oxidative substrate utilisation following reperfusion, in the hypertrophied heart. Pressure overload cardiac hypertrophy was induced surgically in male Sprague-Dawley rats by intra-renal constriction. A moderate hypertrophy was observed nine weeks post surgery as evidenced by between a 4 and 25 % increase in heart weight: tibia length ratio. Hearts were perfused in an isovolumic mode, and function was recorded. ¹³C-NMR spectroscopy was performed on extracts from hypertrophied and control hearts reperfused with ¹³C labelled substrates to determine the profile of substrate use. Glycogen content was unchanged in hypertrophied hearts compared to control hearts and there was no evidence for glycogen loading in the presence of physiological substrates and insulin. In addition, no further glycogen loading occurred when insulin concentrations were increased to pharmacological levels. Provision of other carbohydrate substrates, such as lactate, did result in a further increase in myocardial glycogen content. Hypertrophied hearts experienced the same extent of ischaemia as controls with no evidence of increased ischaemic injury, implying that a compensated model of hypertrophy was generated in this study. Myocardial function decreased during low flow ischaemia and stopped during global ischaemia, but contracture was not observed. The severity of ischaemia was the determining factor in the degree of glycogen degradation. Increased glycogen degradation during ischaemia did not correlate with increased ischaemic injury, suggesting that the availability of glycogen for energy provision limited ischaemic injury. Recovery on reperfusion was markedly improved in the presence of insulin. This improvement appeared to be mediated by the inotropic actions of insulin rather than by alterations in substrate provision. The profile of substrate use in hypertrophied hearts during reperfusion was found to be the same as that in controls. No metabolic alterations were observed in the hypertrophied heart that enhanced susceptibility to ischaemic/reperfusion injury, implying that compensated hypertrophy is a beneficial response of the heart.

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Woltz, John W. "Cardiovascular Risk and Left Ventricular Hypertrophy in Firefighters." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367940479.

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XU, JIAN. "TRANSCRIPTIONAL REGULATION OF CARDIAC HYPERTROPHY AND HEART FAILURE." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148396901.

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Patel, Parth Mahendra, and Parth Mahendra Patel. "Deciphering the Role of FXR1 in Cardiac Hypertrophy." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625115.

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Rationale: Cardiac hypertrophy is the enlargement of the heart and can be induced by pathological and non-pathological events. The Fragile X family of RNA-binding proteins have been shown to be involved in cardiac structure and development (Mientjes et al, 2004) (Padje et al, 2009). Potential links between FXR1 and hypertrophy have not been significantly studied. Objective: To study the effect that varying expression of FXR1 has upon hypertrophy, and the molecular role FXR1 plays in hypertrophy. Method and Results: Following a voluntary running protocol, FXR1 wild-type mice had significant cardiac hypertrophy while FXR1 heterozygous mice (reduced FXR1 expression) had a blunted response with no significant hypertrophy. Cardiomyocyte size analysis showed that FXR1 overexpression (~9-fold increase) caused significant size reduction and FXR1 knockdown caused significant size increase. RNA immunoprecipitation showed multiple components of the PI3K/AKT/mTOR pathway associating with FXR1 in a protein/RNA complex. Western blotting showed that exercised FXR1 heterozygous mice had an increased expression of phosphorylated AKT versus non-exercised wild-type mice. Varying FXR1 expression in cells did not affect p-AKT expression. Conclusions: The amount of FXR1 in mice and cells appears to alter the severity of cardiac hypertrophy. FXR1 may regulate cardiac hypertrophy, but how this occurs is still unclear.

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Davies, Justin Edgar Rees. "Coronary haemodynamics in hypertension and left ventricular hypertrophy." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/7793.

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The coronary blood flow waveform is unique, being determined by simultaneous changes in pressure originating at either end of the coronary artery. However, by measuring the coronary pressure waveform alone, it is not possible to separate the pressure contributions originating from the coronary microcirculation from those originating in the aorta. In this thesis wave intensity analysis was applied to unobstructed human coronary arteries to separate the contributions originating in the coronary microcirculation from those originating in the aorta, in subjects with and without left ventricular hypertrophy. I found that coronary blood flow is predominantly regulated by changes in microcirculatory-originating pressure, and not be aortic-originating pressure as is the case in other vascular beds. I identified six waves which were responsible for directing these changes in pressure. Coronary blood flow peaks during diastole due to a dominant backward-travelling 'suction' wave, generated when microcirculatory compression is relieved and pressure in the distal artery falls rapidly. This backward-travelling 'suction' wave was found to be significantly reduced in subjects with left ventricular hypertrophy. Finally, wave intensity was applied in the proximal aorta to assess the contribution of distal reflections to coronary blood flow. Wave reflections could be seen travelling back from the proximal aorta into the coronary arteries. These reflections augment coronary blood flow during systole and are more marked in older subjects.

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Chang, Ching-Jey George. "Prostate, benign hypertrophy and prostatic carcinoma - a study of cell biology of prostate and chemotherapy for prostatic hypertrophy and prostatic cancer /." The Ohio State University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487856906256116.

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46

Gerhardt, Florian. "Einfluss einer 24-stündigen Behandlung von ventrikulären neonatalen Kardiomyozyten mit einem Adipozyten-konditionierten Medium auf Hypertrophie-assoziierte Signalwege und Zellproteine." Doctoral thesis, Universitätsbibliothek Leipzig, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-224990.

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Die weltweite Zunahme der Prävalenz von Übergewicht und Adipositas und den damit verbundenen medizinischen und sozioökonomischen Herausforderungen stellt eine der wesentlichen Herausforderungen der modernen medizinischen Versorgung dar. Im Mittelpunkt stehen dabei insbesondere die Auswirkungen von Übergewicht und Adipositas auf das kardiovaskuläre System und den damit verbundenen funktionellen und strukturellen Veränderungen der kardiovaskulären Funktion. Als Mediatoren dieser funktionellen und strukturellen Veränderungen stehen dabei zunehmend Adipozytokine im Interesse wissenschaftlicher Arbeiten. Unter Adipozytokinen versteht man in diesem Zusammenhang einen Sammelbegriff für von Adipozyten und anderen Fettgewebszellen sezernierten autokrin-, endokrin- und parakrin wirkenden bioaktiven Molekülen. Insbesondere bei Übergewicht und Adipositas kommt es zu einer charakteristischen Veränderung im Sekretionsmuster dieser Adipozytokine. Die Wirkung einzelner Adipozytokine auf die kardiovaskuläre Funktion wurde in den letzten Jahren intensiv untersucht, über die Wirkung ganzer Adipozytokinprofile ist bisher jedoch nur wenig bekannt. Ziel der vorliegenden Arbeit war es zu klären, welchen Einfluss eine 24-stündige Behandlung von neonatalen ventrikulären Kardiomyozyten mit einem physiologischen Adipozytokin-Profil auf Hypertrophie-assoziierte Signalwege und Zellproteine hat.

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Al, Jaam Bilal. "Aspects biochimiques et cellulaires de la dérégulation du processus myogénique chez des souris hypomorphes pour le gène Pofut I." Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0086/document.

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La croissance musculaire postnatale chez la souris s’effectue principalement par une hypertrophie et un allongement des fibresmusculaires. L’augmentation de l’aire des fibres est contrôlée par plusieurs voies de signalisation telle que la voie Notch, qui est impliquée dans l’activation des cellules satellites (CS) en début de croissance musculaire postnatale chez la souris. La O-fucosylation, médiée par la protéine O-fucosyltransférase 1 (POFUT1), des répétitions EGF-like de la partie extracellulaire des récepteurs NOTCH joue un rôle déterminant dans la modulation des interactions récepteur-ligand (R-L), nécessaires à l’activation de la voie Notch.Les souris Pofut1cax/cax sont hypomorphes pour le gène Pofut1 et nosrésultats montrent, en plus de malformations squelettiques, unehypertrophie musculaire post-natale, pas d’hyperplasie et une réduction du pool de CS. Pour comprendre l’origine de cette hypertrophie, des cultures primaires de myoblastes dérivés de CS (MDCS) de muscles squelettiques ont été réalisées dans des conditions de prolifération ou de différenciation. Les MDCS Pofut1cax/cax présentent une activité réduite de la signalisation Notch, due à une moins bonne interaction R-L provoquée par une O-fucosylation amoindrie des répétitions EGF-like. Il en résulte une diminution de l’expression de Pax7, marqueur de l’état indifférencié, et une dérégulation de l’expression des facteurs régulateurs de lamyogenèse (Myod, Myf5 et Myogénine). La conséquence ultime est laréduction de la proportion en progéniteurs Pax7+/MyoD- au profit decellules Pax7-/MyoD+ engagées dans la différenciation. Ces observations sont en accord avec la différentiation précoce des MDCS Pofut1cax/cax. Nos résultats indiquent que cette hypertrophie musculaire post-natale chez les souris Pofut1cax/cax est due à une propension plus importante des CS activées à se différencier et à fusionner avec des fibres pré-existantes plutôt que retourner à l’état de quiescence Postnatal muscle growth in mice mainly occurs by hypertrophy and by anincrease of myofibres length. This increase in myofibres area is controlled by multiple signaling pathways such as Notch signaling, which is involved in activation of satellite cells (SC) at the beginning of postnatal muscle growth in mice. The O-fucosylation of EGF-like repeats within the extracellular domain of NOTCH receptors, mediated by protein O-fucosyltransferase 1 (POFUT1), plays a key role in the modulation of receptor-ligand interactions (R-L), necessary for activation of Notch signaling. Pofut1cax/cax mice are hypomorphic for the Pofut1 gene. In addition to skeletal defects, our results show postnatal muscular hypertrophy, no hyperplasia and a reduced pool of SC. To understand the origin of this hypertrophy, primary cultures of myoblasts derived from SC (SCDM) from skeletal muscles were studied in proliferating and differentiating conditions. Pofut1cax/cax SCDM showed a reduced Notch signaling due to aless efficient R-L interactions provoked by a low O-fucosylation of EGF-like repeats. This results in decreased expression of Pax7, a marker of undifferentiated state, and a change in the expression of myogenic regulatory factors (Myod, Myf5 and Myogenin). Subsequently, the proportion of Pax7+/MyoD- progenitors decreased while the proportion of Pax7-/MyoD+ cells committed in differentiation increased. These findings corroborate early differentiation of Pofut1cax/cax SCDM.Our results indicate that this postnatal muscle hypertrophy in Pofut1cax/caxmice is due to the fact that activated satellite cells are more prone todifferentiate and fuse with pre-existing myofibres that returning toquiescence

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Orlando, Silvia. "DIFFERENTIATION BETWEEN HYPERTROPHIC CARDIOMYOPATHY AND HYPERTENSIVE LEFT VENTRICULAR HYPERTROPHY: THE ROLE OF STRAIN RATE IMAGING STUDY AND INTEGRATED BACKSCATTER ANALYSIS." Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3426557.

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Background: To date, any non-invasive technique is satisfactory to differentiate Hypertrophic Cardiomyopathy (HCM) from hypertensive left ventricular hypertrophy (H-LVH). We hypothesized that in HCM the presence of local peculiar tissue abnormalities results in the significant impairment of the regional systolic deformation and myocardial reflectivity, even if global function appears normal. Methods: Twenty non-obstructive HCM patients, 20 age- and gender-matched hypertensive patients (HTN) and 15 healthy volunteers (NTN) underwent grey-scale and tissue Doppler ultrasound imaging from three apical views (16 left ventricular segments model). Afterwards, high resolution deformation traces and integrated backscatter curves were analysed for each segment. Results: HCM patients showed lower average values of systolic strain (Ssys), systolic strain rate (SR) and cyclic variation of integrated backscatter (CVIB) when compared to HTN or NTN, even if there was a substantial overlap between HCM segments and HTN segments. However, when identifying segments with quasi absent deformation (ND segments with Ssys>-5.68%), we found at least 2 ND segments in each HCM patient, heterogeneously distributed within the ventricle, while none of the HTN or NTN patient had one. Furthermore, in HCM, Ssys, SR and CVIB of the mid- and basal segments of the septum and lateral wall from 3 and 4 chamber views did not correlate with M-mode end-diastolic interventricular septum (IVS) and posterior wall (PW) thicknesses (linear regression analysis), demonstrating no differences in performance between asymmetric and concentric HCM LV pattern. Overall, HTN patients showed slightly but significantly reduced global Ssys, SR and CVIB when compared to NTN, with the most significant reduction in the basal septum. Moreover, post-systolic strain appeared a relevant phenomenon which may contribute to systolic and diastolic impairment in pathological left ventricular hypertrophy. Additionally, a linear regression analysis revealed a significant correlation between Ssys and CVIB (R=0.54, P<0.0001). Conclusions: Deformation and reflectivity analysis can easily discriminate HCM from H-LVH. In particular, HCM is uniquely characterized by the presence of non-deforming segments, distributed non-uniformly within the ventricle and independent on the degree or pattern of ventricular hypertrophy. Premessa: Sino ad ora, nessuna tecnica diagnostica non invasiva appare soddisfacente nel differenziare la Miocardiopatia Ipertrofica (HCM) dalla Cardiopatia ipertensiva (H-LVH). Abbiamo ipotizzato che nella HCM la presenza di peculiari e localizzate alterazioni tessutali causi una significativa riduzione della deformazione sistolica regionale e della riflettività tessutale, nonostante la funzione sistolica globale possa apparire normale. Metodi: Venti pazienti con HCM non ostruttiva, 20 pazienti ipertesi (HTN) e 15 controlli sani (NTN), tutti simili per età e sesso, sono stati sottoposti ad acquisizione ecocardiografica standard e mirata all’acquisizione dei segnali in radiofrequenza e dei segnali doppler tessutali dalle tre camere apicali, seguendo un modello ventricolare sinistro a 16 segmenti. In seguito, per ciascun segmento sono state ottenute curve di deformazione ad elevata risoluzione e curve di Integrated Backscatter. Risultati: I pazienti HCM hanno presentato valori medi di strain sistolico (Ssys), strain rate sistolico (SR) e di variazioni cicliche dell’Integrated Backscatter (CVIB) significativamente ridotti rispetto ai soggetti ipertesi o normotesi, anche se si è evidenziata una rilevante sovrapposizione tra i valori dei segmenti HCM e dei segmenti HTN. Tuttavia, quando si sono identificati segmenti con deformazione quasi assente (segmenti ND con Ssys>-5.68%), si sono riscontrati almeno 2 segmenti ND in ciascun soggetto HCM, eterogeneamente distribuiti nel ventricolo sinistro, mentre nessun HTN o NTN ne possedeva alcuno. Inoltre, nei pazienti HCM, Ssys, SR e CVIB dei segmenti medio-basali del setto interventricolare e della parete posteriore non correlavano con i relativi spessori tele-diastolici rilevati in M-mode dalla parasternale asse-lungo (analisi di regressione lineare), dimostrando che non vi sono differenze nella performance cardiaca tra i pattern asimmetrico e concentrico di HCM. Nel complesso, i pazienti HTN hanno presentato valori di Ssys, SR e CVIB lievemente ma significativamente ridotti rispetto ai controlli, con le riduzioni più importanti a livello del setto basale. Inoltre, la presenza di strain post-sistolico è risultato essere un fenomeno rilevante che può contribuire alla disfunzione sistolica e diastolica nell’ipertrofia ventricolare sinistra patologica. Oltretutto, un’analisi di regressione lineare ha evidenziato la correlazione tra Ssys e CVIB (R=0.54, P<0.0001). Conclusioni: L’analisi della deformazione e delle riflettività tessutale può facilmente discriminare HCM da H-LVH. In particolare, HCM è caratterizzata in modo esclusivo dalla presenza di segmenti con deformazione quasi assente, distribuiti in modo non uniforme nel ventricolo sinistro ed indipendenti dal grado o dal pattern di ipertrofia ventricolare.

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Drawnel, Faye Marie. "Control of myocardial hypertrophic remodelling by integration of calcium signals, kinase cascades and microRNAs." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609969.

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Archer, Caroline Rose. "Interactions between GPCR- and growth factor-activated signalling pathways in the induction of cardiac hypertrophy." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648427.

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Dissertations / Theses on the topic 'Hypertrophy'

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