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Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Introduction: The worldwide escalation in the incidence of obesity and its strong association with insulin resistance, type 2 diabetes and the cardiovascular complications that accompany these disease states have elicited interest in the underlying mechanisms of these pathologies. Preliminary data generated in our laboratory showed that obesity is associated with abnormalities in the insulin signalling pathway. Specifically, we found a down-regulation of protein kinase B (PKB/Akt), which is known to mediate the metabolic effects of insulin. One of the downstream targets of PKB/Akt is glycogen synthase kinase-3 (GSK-3), which is inhibited by this phosphorylation. Detrimental effects of unopposed activity of GSK-3 have recently been described. This may play a pivotal role in some of the adverse consequences of insulin resistance in the heart. Hypothesis: Chronic inhibition of GSK-3 will induce myocardial hypertrophy or exacerbate the development of existing hypertrophy in a pre-diabetic model of diet induced obesity and insulin resistance. Objectives: (1) Assess the extent of the development of myocardial hypertrophy in a rat model of diet induced obesity (DIO) and insulin resistance. (2) Assess the effect of inhibition of GSK-3 protein on the development of myocardial hypertrophy. Methods: Two groups of age-matched male Wistar rats were used. Control animals received standard rat chow, while obese animals received a high caloric diet for 20 weeks. After 12 weeks, half of the animals in both groups received GSK-3 inhibitor treatment (CHIR118637, 30mg/kg/day, Novartis). At the end of 20 weeks, three series of experiments were conducted. (i) The animals were subjected to echocardiography to determine in vivo myocardial function, and biometric, metabolic and biochemical parameters were evaluated. (ii) The ability of the cardiomyocytes to accumulate deoxy-glucose after stimulation with insulin was determined, and (iii) the localization of key proteins was monitored using fluorescence microscopy and cell size was determined using light microscopy and flow activated cell sorter analysis. Results and discussion: The high caloric diet increased body weight (p<0.005) and intraperitoneal fat mass (p<0.01) when compared to controls. Complications associated with obesity, such as impaired glucose tolerance (p<0.05), hyperinsulinemia (p<0.0005) and an increased HOMA-IR index (p<0.01) were observed. Additionally, cardiomyocytes from the DIO animals had a significantly impaired response to insulin, specifically when 10nM (p<0.05) and 100nM (p<0.05) of insulin were used as stimulus. We also found a dysregulation in PKB/Akt, indicated by a down-regulation of phosphorylated PKB/Akt (p<0.01). The diet promoted the development of myocardial hypertrophy, since the ventricular weight (p<0.05) and ventricular weight to tibia length ratio were increased (p<0.01). Echocardiography experiments showed an increase in end diastolic diameter in the DIO animals (p<0.05). Additionally, there was an increase in the cardiomyocyte cell width in the DIO rats (p<0.0001) and a tendency for peri-nuclear localization of NFATc3. GSK-3 inhibition promoted the development of insulin resistance in control animals, as indicated by an increase in the body weight (p<0.05), serum insulin levels (p<0.01) and HOMA-IR index (p<0.01). In the DIO animals, the GSK-3 inhibitor treatment improved insulin resistance, as a decrease in serum insulin concentration (p<0.05) was observed. The cardiomyocytes from the treated DIO animals also showed an increase in glucose uptake (p<0.05) when stimulated with 100nM of insulin. The GSK-3 inhibitor promoted the development of myocardial hypertrophy in the control animals, indicated by an increase in ventricular weight (p<0.05) and cardiomyocyte cell width (p<0.0001), but did not exacerbate hypertrophy in the DIO animals. Conclusion: Both the high caloric diet and the GSK-3 inhibitor promoted the development of insulin resistance and myocardial hypertrophy in the rats. In the DIO animals the GSK-3 inhibitor treatment ameliorated insulin resistance and did not promote the further development of myocardial hypertrophy. / AFRIKAANSE OPSOMMING: Inleiding: Die huidige styging in vetsugtigheid en die sterk assosiasie daarvan met insulien weerstandigheid, tipe 2 diabetes en kardiovaskulêre komplikasies soos hipertrofie, het ‘n belangstelling in die onderliggende meganismes van hierdie siektetoestande ontlok. Voorlopige data uit ons laboratorium het getoon dat vetsug geassosieerd is met abnormaliteite in die insulien seintransduksie-pad soos byvoorbeeld ‘n afregulering van miokardiale proteïen kinase B (PKB/Akt), wat bekend is om die metaboliese effekte van insulien te medieer. Een van die proteïene wat deur PKB/Akt gefosforileer en daardeur geïnhibeer word, is glikogeen sintase kinase-3 (GSK-3). Negatiewe effekte van onge-opponeerde aktiwiteit van GSK-3 is beskryf en dit mag ‘n sleutelrol speel in sommige van die nadelige gevolge van insulien weerstandigheid in die hart. Hipotese: Chroniese onderdrukking van GSK-3 sal miokardiale hipertrofie ontlok of die bestaande hipertrofie in ‘n pre-diabetiese model van dieet-geïnduseerde vetsug en insulien weerstandigheid vererger. Doelstellings: (1) Om die omvang van die ontwikkeling van miokardiale hipertrofie in ‘n rotmodel van dieet-geïnduseerde vetsug te ondersoek en (2) om die effek van inhibisie van GSK-3 op die ontwikkeling van hipertrofie te ondersoek. Metodes: Ouderdomsgepaarde manlike Wistarrotte is in hierdie studie gebruik. Die diere is vir ‘n periode van 20 weke aan verskillende diëte onderwerp, naamlik standaard kommersiële rotkos vir die kontrole diere en ‘n hoë kalorie dieet vir die eksperimenteel vet diere (DIO). Helfte van elke groep diere is vir 8 weke met ‘n GSK-3 inhibitor behandel (CHIR118637, 30mg/kg/day, Novartis). Na die 20 weke is 3 eksperimentele reekse uitgevoer: (i) Die diere is eggokardiografies ondersoek om in vivo miokardiale funksie te bepaal en biometriese, metaboliese en biochemiese parameters is evalueer. (ii) Die vermoë van kardiomiosiete om de-oksiglukose na insulien stimulasie te akkumuleer, is bepaal, en (iii) die lokalisering van sleutelproteïene is met behulp van fluoressensie mikroskopie en die selgrootte met behulp van ligmikroskopie bepaal. Resultate en bespreking: Die hoë kalorie dieet het gepaard gegaan met ‘n beduidende toename in liggaamsgewig (p<0.005) en intraperitoneale vetmassa (p<0.01) in vergelyking met diere op die kontrole dieet. Newe-effekte geassosieerd met vetsug nl. onderdrukte glucose toleransie (p<0.05), hiperinsulinemie (p<0.0005) en ‘n verhoogde HOMA-IR index (p<0.01) is ook waargeneem. Daar was ook ‘n beduidend ingekorte respons van glukose opname deur kardiomiosiete van die vet diere na stimulasie met 10nM (p<0.05) en 100nM (p<0.05) insulien. Disregulering van PKB/Akt is gevind in die vorm van ‘n afregulering van die fosforilering van die proteïen (p<0.01). Die dieet het ook gelei tot die ontwikkeling van miokardiale hipertrofie aangesien die ventrikulêre gewig (p<0.05) asook die verhouding van die ventrikulêre gewig teenoor tibia lengte beduidend toegeneem het (p<0.01). Eggokardiografie het ‘n toename in ventrikulêre end-diastoliese dimensie in die DIO diere aangetoon (p<0.05). Tesame hiermee het die breedte van kardiomiosiete van die DIO diere toegeneem (p<0.0001) en daar was ook ‘n peri-nukluêre lokalisering van NFATc3. Behandeling van kontrole diere met ‘n GSK-3 inhibitor het insulienweerstandigheid ontlok soos afgelei uit ‘n verhoging in liggaamsgewig (p<0.05), serum insulien-vlakke (p<0.01) en die HOMA-IR waarde (p<0.01). In teenstelling het behandeling van die DIO diere met die GSK-3 inhibitor tot ‘n verbetering van insulienweerstandigheid gelei aangesien ‘n verlaging in serum insulien konsentrasies gevind is (p<0.05). Kardiomiosiete vanaf die behandelde DIO diere het ook ‘n verhoogde insulien-gestimuleerde glukose opname met 100nM insulien getoon (p<0.05). Behandeling met die GSK-3 inhibitor het die ontwikkeling van miokardiale hipertrofie in die kontrole diere teweeggebring, soos aangetoon deur ‘n toename in die ventrikulêre gewig (p<0.05) en ‘n groter selwydte in kardiomiosiete terwyl dit geen invloed op die bestaande hipertrofie van die vet diere gehad het nie. Gevolgtrekking: Die huidige studie het getoon dat die betrokke dieet asook behandeling met ‘n GSK-3 inhibitor insulienweerstandigheid sowel as die ontwikkelling van miokardiale hipertrofie in rotte ontlok. In die DIO diere het die behandeling met die GSK-3 inhibitor bloedglukose en insulien-vlakke verlaag en het nie hipertrofie vererger nie.

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.

Reguliarios aerobinės treniruotės sąlygoja saikingą ištvermę lavinančių sportininkų kairiojo širdies skilvelio hipertrofiją. Vyrauja nuomonė, kad sportuojančių moterų struktūrinė – miokardo adaptacija yra mažesnė nei vyrų. Nėra tiksliai žinoma, ar ištvermę lavinančiųjų sportininkių miokardo hipertrofija yra kitokia nei sportuojančiųjų vyrų. Mūsų tyrimo tikslas buvo nustatyti ilgųjų nuotolių bėgikų ir bėgikių bei trumpųjų nuotolių bėgikių širdies struktūros ir funkcijos ypatumus. Tyrimo metodai: echokardiografija; anketavimas; antropometrija; matematinė statistika. Tyrimo kontingentą sudarė 10 sprinterių ir 10 ilgųjų nuotolių bėgikės, kurios pagal amžių (amžiaus vidurkis – apie 25 metus), treniravimo stažą ir meistriškumo lygį nesiskyrė, buvo pasiekusios šalies arba tarptautinį pripažinimą. Ilgųjų nuotolių bėgikės (n = 10) specializavosi bėgimuose nuo 3000 m iki maratono; sprinterių grupę sudarė trumpųjų nuotolių (nuo 100 m iki 400 m, n = 8) ir barjerinio bėgimo (100 m b/b, n = 2) bėgikės. Jos mažiausiai penkerius metus reguliariai startavo savo rungtyse, intensyviai treniravosi keturis – septynis kartus per savaitę. Tyrimo kontrolinę grupę sudarė sveikos tokio pat amžiaus nesportuojančios moterys, kurios sportavo ne ilgiau kaip 1 valandą per savaitę. Tyrime taip pat dalyvavo 67 ilgųjų nuotolių bėgikai, kurių amžiaus vidurkis buvo 24,0 ± 6,7 metai. Rezultatai. Reikšmingi echokardiografiniai rodiklių skirtumai tarp sprinterių ir nesportuojančių moterų nenustatėme (p>0,05)... [toliau žr. visą tekstą] / Regular participation in certain competitive endurance sports such as cycling, rowing, paddling, and running causes moderate left ventricular (LV) hypertrophy in males. Female athletes, however, are considered to possess less pronounced structural cardiac adaptation, and the type of cardiac hypertrophy in female (endurance) athletes remains vaguely understood. The aim of this study was to shed more light on the topic of gender influence on the extent and type of cardiac hypertrophic response to two different types athletic conditioning.   Raktiniai žodžiai   Methods. Standard transthoracic two-dimensional M-mode and Doppler echocardiography was performed at rest in Caucasian female sprinters (n = 10) and long?distance runners (n = 10) of similar age (average 25 years, range 16 to 34 years), training experience (5 to 18 years), and competitive level, as well as in age-matched healthy female sedentary controls (n = 10), and also compared with Caucasian male endurance runners (n = 67) of similar age, training experience, and competitive level. Runners were considered endurance athletes if their favorite event was 3000 m or longer, and sprinters, if they preferred to compete in distances of 400 m or shorter (two of our sprinters were 100 m hurdlers). Results. No significant echocardiographic differences between female sprinters and sedentary controls were detected (p>0,05). Interventricular septum and LV wall (p<0,05) were thicker, and LV mass was greater (p<0,01) in female... [to full text]

Orientador: Silméia Garcia Zanati Bazan / Resumo: Fundamento: A história de pré-eclâmpsia (PE) tem sido associada a doença cardiovascular em mulheres. Existem evidências de que alterações cardiovasculares decorrentes da PE podem permanecer mesmo após o término da gestação.Objetivos: 1-avaliar a frequência de fatores de risco cardiovascular em mulheres com história de PE há 12 meses e sua associação com hipertrofia miocárdica e espessura médio-intimal de carótidas (EMIC); 2-avaliar o efeito da hipertrofia miocárdica na função do ventrículo esquerdo e na capacidade funcional.Métodos: Estudo prospectivo transversal incluindo 118 pacientes consecutivas com história de PE há 12 meses. Foram efetuadas avaliações clínicas e laboratoriais, ecocardiograma, teste ergométrico e ultrassom de carótidas. A hipertrofia miocárdica (HVE) foi definida para massa miocárdica indexada ≥ 45 g/m2,7. Foram consideradas como EMIC aumentadas quando as medidas estivessem acima do percentil 75 para a faixa etária. Foram considerados os fatores de risco clássicos para doença cardiovascular e calculado o escore de risco cardiovascular global em 30 anos (RCVG_30). Os dados foram analisados por meio de regressão logística ou linear e coeficiente de correlação de Spearman. Nível de significância p<0,05.Resultados: A hipertensão arterial sistêmica (HAS) foi identificada em 52 pacientes (44%), sobrepeso/obesidade (Sob/obes) em 82 (69%), dislipidemia em 68 (57%) e síndrome metabólica em 47 pacientes (40%). Um total de 48 mulheres (41%) apresentaram RCVG_... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: A history of preeclampsia (PE) has been associated with cardiovascular disease in women. There is substantial evidence that cardiovascular alterations resulting from PE can persist even after termination of pregnancy.Objectives: 1-evaluate the frequency of cardiovascular risk factors in women with 12-month history of PE and their association with myocardial hypertrophy and carotid intima-media thickness (CIMT); 2-evaluate the effect of myocardial hypertrophy on left ventricular function and functional capacity.Methods: Transversal prospective study including 118 consecutive patients with 12-month PE history. Clinical and laboratory evaluations, echocardiogram, ergometric and carotid ultrasound were performed. Myocardial hypertrophy (LVH) was defined as indexed myocardial mass ≥ 45 g/m2,7. CMIT was considered elevated when the measures were above the 75th percentile for the age range. The classical risk factors for cardiovascular disease were considered, and the 30-year global cardiovascular risk score was calculated (GCVR_30). The data were analyzed by linear or logistic regression and Spearman’s correlation coefficient. Significance level p<0.05.Results: Systemic arterial hypertension (SAH) was identified in 52 patients (44%), overweight/obesity (OOB) in 82 (69%), dyslipidemia in 68 (57%) and metabolic syndrome in 47 patients (40%). A total of 48 women (41%) presented GCVR _30 greater than or equal to 10%, with these patients aged 34±5.4 years. LVH was pres... (Complete abstract click electronic access below) / Doutor

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Die Entwicklung und der Verlauf einer Myokardhypertrophie (MH) und Herzinsuffizienz (HF) unterscheiden sich deutlich zwischen Frauen und Männern. Diese Geschlechterunterschiede können zumindest partiell auf Sexualhormone, insbesondere Östrogen, zurückgeführt werden. Östrogene wirken biologisch über zwei verschiedene Östrogenrezeptoren (ER): ERalpha und ERbeta. Viele Befunde weisen auf eine positiv modulierende Wirkung der Östrogene und speziell auf eine besondere Rolle des ERbeta bei der Entwicklung der druckinduzierten MH und HF hin. Diese Studie befasst sich mit der Untersuchung der Geschlechterunterschiede in der Ausprägung einer pathologischen MH und den myokardialen Veränderungen unter dem Einfluss des ERbeta. Grundlage der Arbeit bildete ein Mausmodell mit ERbeta-/-- und Wildtyp- Mäusen, denen durch eine transversale Aortenkonstruktion (TAC) eine artifizielle MH induziert wurde. Zur Dokumentation der Progression und den damit verbundenen Veränderungen wurden zwei Zeitpunkte gewählt, welche die adaptive und maladaptive kardiale Antwort darstellen. Die Entwicklung der Myokardhypertrophie wurde sowohl durch Echokardiographie als auch hämodynamischen Messungen charakterisiert und durch biochemische und molekulare Techniken sowie den Einsatz von Mikroarrays untersucht. Es konnte der Einfluss des Geschlechts auf die Entwicklung der MH bei andauernder Druckbelastung nachgewiesen werden. ERbeta modulierte dabei die kardiale Funktion sowie die molekulare Antwort in hypertrophie- assoziierten Prozessen, wie dem kardialen Metabolismus, der kardialen Fibrose und der Apoptose in weiblichen und männlichen Tieren. ERbeta trug in den weiblichen Tieren zum Erhalt des kardialen Energiehaushaltes bei und limitierte dadurch die Entwicklung einer kardialen Fibrose und Apoptose. Ein positiver Einfluss des ERbeta konnte in auch in den männlichen Tieren beobachtet werden: Ein starker Funktionsverlust des Herzens und apoptotische Prozesse wurden durch ERbeta verlangsamt oder inhibiert. / Development and progress of myocardial hypertrophy (MH) and the transition to heart failure (HF) differ between the sexes in humans. There is evidence that sex- related differences are mediated through sex hormones, especially the sex hormone estrogen. Effects of estrogen are mediated by two different estrogen receptors (ER): ERalpha und ERbeta. Many studies indicate a beneficial role of estrogen and particularly for ERbeta in the development of pressure overload induced MH and HF. This study investigates sex differences in the development of pathological MH and accompanying myocardial changes under the influence of ERbeta. For this purpose wildtype and estrogen receptor beta lacking (ERbeta-/-) mice were investigated. Myocardial hypertrophy was induced by using the method of transversal aortic constriction (TAC). To determine the progression of MH to HF two time points were studied, which describe the adaptive and the maladaptive response to cardiac pressure overload. The development of MH was characterized by echocardiography and hemodynamic measurements in vivo. Additionally microarrays, molecular and biochemical analyses were performed in left ventricles. We identified sex differences in the development of MH induced by chronic pressure overload. ERbeta modulated the cardiac function and the molecular response in hypertrophy associated processes like cardiac metabolism, fibrosis and apoptosis in female and male animals. ERbeta contribute to the maintenance of energy homeostasis in female mice and limits the development of maladaptive cardiac hypertrophy, fibrosis and apoptosis in female and in male mice and slows the progression to heart failure consequently down.