3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Fenofibrate prevents isoproterenol-induced left ventricular hypertrophy and pump dysfunction in rats(2011-01-31) Maswanganyi, TlangelaniThe role of metabolic remodelling in heart failure is not fully understood, significant evidence has accumulated to suggest that it may be central to the development of left ventricular (LV) remodelling and LV dysfunction. Heart failure is also characterized by sustained neurohumoral activation. We have previously demonstrated that chronic low dose administration of isoproterenol contributes to cardiac structural and functional changes, however, little is known about metabolic and mitochondrial changes that may accompany the development of isoproterenol-mediated heart failure. In the current study, we hypothesised that metabolic dysregulation and loss of mitochondrial integrity mediates left ventricular hypertrophy (LVH) and left ventricular (LV) systolic dysfunction in the isoproterenol model of heart failure. Furthermore, modulation of expression of key metabolic genes and mitochondrial transcription factors by fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, will preserve left ventricular function. To achieve this, male Sprague-Dawley rats weighing between 250-300g were injected with low dose isoproterenol (0.04 mg.kg-1.day-1) and/or administered with fenofibrate (100 mg.kg-1.day-1) for five weeks. Thereafter, metabolic substrates such as glucose, FFAs and TG concentrations were obtained. Left ventricular hypertrophy (LVH) and cardiac function were assessed using echocardiography. Expressions of metabolic and mitochondrial genes such as PPARα, AMP-activated protein kinase alpha 2 (AMPKα2), PPARγ coactivator-1 (PGC-1α), mitochondrial transcription factor (TFAM) and nuclear respiratory factor-1 (NRF-1) were determined using real-time polymerase chain reaction. Mitochondrial integrity was assessed using transmission electron microscopy. Administration of isoproterenol significantly increased left ventricular mass (LVM) and decreased endocardial fractional shortening (FSend); isoproterenol also induced myofibrillar iv derangement, mitochondrial derangement and cristae disruption. Fenofibrate prevented isoproterenol-induced increase in LVM and improved FSend. Fenofibrate co-administration prevented loss of mitochondrial integrity possibly via TFAM. Furthermore, fenofibrate may have induced metabolic remodelling via upregulation of AMPKα2 and downregulation of cardiac PPARα and PGC-1α. Therefore our data suggests that fenofibrate-mediated cardioprotection against isoproterenol-induced LVH and LV systolic dysfunction was accompanied by metabolic switching and preservation of mitochondrial integrity. While isoproterenol did not induce any changes in metabolic genes, fenofibrate-mediated cardioprotection could have been through changes in metabolic genes.Item Impact of obesity on the susceptibility of the myocardium to hypertensive and adrenergic-induced apoptosis(2010-04-15T09:44:07Z) Vengethasamy, LeandaExcess adiposity may increase the risk of heart failure through interactions with conventional risk factors. As cardiomyocyte apoptosis may be an important mechanism responsible for the development of heart failure the aim of the present study was to determine whether obesity enhances a) the increased cardiomyocyte apoptosis that accompanies pressure-overload hypertrophy and b) sympathetic-induced cardiomyocyte apoptosis. The impact of dietary-induced obesity on cardiomyocyte apoptosis was studied in elderly spontaneously hypertensive rats (SHR) and age-matched (8-9 months of age at the beginning of the study) Wistar Kyoto rats (WKY) after a 5 month feeding period and in young WKY rats (1 month of age at the beginning of the study) receiving either isoproterenol (ISO) or the vehicle (saline) for 5 days at the end of the feeding period. To induce obesity rats were fed a diet that promotes hyperphagia. At the end of the feeding period echocardiography was performed. Cardiac myocyte apoptosis was assessed using a TUNEL staining technique. Rats receiving the obesity-inducing diet had increases in body weight and visceral fat content. No further changes in systolic blood pressure were observed in rats during the feeding period. SHRs on the obesity-inducing diet had an increased left ventricular end-diastolic diameter and a decreased endocardial fractional shortening. As compared to lean rats, dietary-induced obesity resulted in an increase in the percentage of cardiomyocytes that were apoptotic in SHRs (3.4±0.5%, p<0.005 vs all other groups) and in WKYs receiving ISO (0.35±0.05%, p<0.05 vs Control-ISO and p<0.01 vs Control-saline and Diet-saline groups). In conclusion, obesity was associated with cardiomyocyte apoptosis through an interaction with pressure-overload hypertrophy v and excessive sympathetic activation. These findings provide insights into the potential mechanisms through which obesity may promote the development of heart failure.Item Myocardial material properties and cardiac dilatation following chronic sympathetic activation in hypertension(2009-05-06T12:33:46Z) Gibbs, MarkIncreases in internal dimensions of the chambers of the heart (cardiac dilatation), mediated by right shifts in cardiac chamber diastolic pressure-volume (P-V) relations, predict mortality in patients with established heart failure. However, the mechanisms responsible for the transition from concentric cardiac hypertrophy to cardiac dilatation are unclear. Recent evidence suggests that decreases in the cross-linked properties of myocardial collagen may increase the propensity of collagen to cleavage and hence reduce cardiac myocyte tethering, thus promoting cardiac dilatation. However, decreases in myocardial collagen cross-linking may also reduce myocardial stiffness, thus explaining right shifts in cardiac diastolic P-V relations. In the present dissertation I evaluated whether right shifts in diastolic P-V relations produced by chronic β-adrenoreceptor activation (isoproterenol, a β-adrenoreceptor agonist, 0.02 mg.kg-1.day) in spontaneously hypertensive rats (SHR) with compensated cardiac hypertrophy (12 months of age), can be explained by adverse chamber remodelling or alterations in the myocardial material properties of the heart. After 7 months of daily isoproterenol administration, SHR had marked right shifts in left ventricular (LV) diastolic P-V relations as determined in isolated, perfused hearts, with increases in the volume intercept of these relations, a change that translated into increases in LV cavity diameters (echocardiography). LV dilatation was associated with reductions in LV pump function (decreases in LV endocardial fractional shortening and the slope of the LV systolic P-V relation [LV E]). The reductions in pump function were attributed to the LV dilatation rather than to alterations in intrinsic myocardial contractile properties as LV midwall fractional shortening and myocardial systolic elastance (LV En) were unchanged. Although SHR not receiving isoproterenol had increases in the LV diastolic wall thickness-to-radius ratio, a change commensurate with compensatory concentric LV hypertrophy, LV wall thickness-to-radius ratio in SHR exposed to chronic β-adrenoreceptor activation was reduced to values similar to those noted in normotensive Wistar Kyoto (WKY) control rats, despite further increases in LV weight. SHR not receiving isoproterenol had a marked increase in myocardial stiffness (slope of the linearized LV diastolic stress-strain relationship) as compared to WKY rats, a change that was associated with an increased myocardial collagen of the cross-linked phenotype. Although SHR receiving daily isoproterenol had further increases in myocardial collagen, this did not translate into changes in LV diastolic myocardial stiffness, as the further increase in myocardial collagen was of the non cross-linked phenotype. However, through a susceptibility to digestion, this collagen phenotype could have contributed to LV dilatation. In conclusion, these data suggest that LV dilatation in SHR following chronic β-adrenoreceptor activation is attributed to adverse chamber remodelling rather than to alterations in myocardial material properties as indexed by diastolic stress-strain relations.Item Sympathetic activation and heart failure(2008-03-05T08:29:36Z) Badenhorst, DanelleABSTRACT Chronic activation of the sympathetic nervous system, via β-adrenoreceptor (AR) stimulation, contributes toward progressive heart failure. However, in this regard there are some outstanding issues which require clarity. First, in addition to contributing toward progressive heart failure, it is not clear whether chronic β-AR activation can also initiate cardiac decompensation. If so, the mechanisms of this effect also need to be determined. Second, the role of functional variants of β-AR genes as determinants of either the development or progression of heart failure requires elucidation. Moreover, whether there is any practical value in genotyping of patients for these variants has yet to be determined. These questions were addressed in the present thesis. With respect to the question of whether chronic β-AR activation initiates cardiac decompensation, the mechanisms responsible for the transition from compensated cardiac hypertrophy to heart failure in pressure overload states, such as hypertension, are uncertain. In this thesis I explored whether chronic sympathetic nervous system activation, produced by daily administration of a β-AR agonist, could promote the transition to cardiac pump failure in spontaneously hypertensive rats (SHR) with compensated cardiac hypertrophy. After 5 months of daily administration of a β-AR agonist, SHR developed marked left ventricular pump dysfunction, whereas normotensive control rats maintained pump function. The pump dysfunction noted in SHR was attributed to marked chamber dilatation with wall thinning, whilst myocardial contractile function appeared to be intact. The changes in cardiac structure and function noted after chronic β-AR activation in SHR were similar to those noted in SHR with advanced heart failure. These data provided the first evidence to indicate that chronic β- AR activation can promote the transition to decompensated cardiac hypertrophy in pressure overload states, and that this effect is principally mediated by adverse structural remodeling of the cardiac chamber. iii The mechanisms responsible for the effect of chronic β-AR activation on cardiac chamber dilatation were subsequently studied. The identified mechanisms included activation of an enzyme that degrades myocardial collagen (matrix metalloproteinase 2) and an increase of myocardial collagen of the type that is susceptible to collagen degradation (non-cross-linked collagen). I also excluded alternative potential mechanisms such as necrosis, apoptosis and an accumulation of type III collagen. However, previous studies have indicated that increases in myocardial collagen concentrations determine myocardial stiffness and not cardiac chamber dilatation. Hence, I performed a study to examine whether the impact of increases in myocardial collagen concentrations on cardiac structure and function depends on the qualitative changes in myocardial collagen. Indeed, using a variety of models of pressure overload hypertrophy associated with increases in myocardial collagen concentrations, I was able to provide evidence to support the theory that increases in myocardial collagen of the cross-linked phenotype will promote myocardial stiffness, whereas increase in myocardial collagen of the non-cross-linked phenotype promotes cardiac dilatation. With respect to the question of whether functional variants of β-AR genes contribute toward either the development or progression of heart failure, I studied the role of both functional β1-AR and β2-AR (together with a α2C-AR) gene variants in black South Africans with idiopathic dilated cardiomyopathy (IDC). In a prospective study I obtained data to indicate that the relationship between functional β2-AR genotypes and the progression to hospitalization, death or transplantation; a reduced exercise capacity, and left ventricular functional responses to b-blocker therapy, as described by other groups, is unlikely to be attributed to an independent effect of genotype on cardiac chamber dimensions and pump function. Moreover, I was able to show that contrary to what had previously been suggested, genotyping black subjects for functional α2C-AR iv and β1-AR gene variants is of little use when predicting the development or severity of IDC in this population group.Item Risk factors for atherosclerosis in black South African patients on Haemodialysis(2006-11-08T08:53:51Z) Amira, Christiana OluwatoyinABSTRACT INTRODUCTION The risk of cardiovascular disease in patients with end stage renal disease (ESRD) is far greater than in the general population. Amongst patients with ESRD, the prevalence of coronary artery disease (CAD) and congestive heart failure is approximately 40% compared with 5-12% in the general population. The excess risk is caused by multiple traditional and non-traditional risk factors for ischaemic heart disease present in these patients. There is little information on CAD and its risk factors in black haemodialysis patients as most of these studies were carried out in the white population. This study is therefore aimed at determining the risk factors for atherosclerosis in Black and non-black (White and Indian) South African patients on haemodialysis. METHODS Fifty-eight black patients and twenty-six non-black patients on haemodialysis were recruited. Sixty-three age and sex matched controls (staff, students and kidney donors) were also recruited. Fasting venous blood samples were drawn for measurement of Creactive protein, homocysteine, Lp (a), serum lipids and adiponectin. Carotid intima-media thickness and plaque occurrence was measured by B-mode ultrasonography. Echocardiography was used to determine LVH. vi RESULTS Haemodialysis (HD) patients had significantly lower total cholesterol, LDL cholesterol and triglycerides compared with controls (p<0.001; p= 0.042). Hs-CRP, adiponectin and homocysteine levels were significantly higher in patients compared with controls (p< 0.001). The prevalence of plaques was significantly higher among HD patients (32%) compared with controls (7%) X2 = 60.72 p< 0.001. LVMI was significantly higher among HD patients (194.25± 7.69gm/m2) compared with controls (93.21 ± 3.27 gm/m2) p < 0.001. No significant difference between patients (Black or Asian/White) and controls with respect to CIMT was found. CVD risk factors in black haemodialysis patients and black controls showed a similar pattern to the whole study population combined. Risk factors associated with CIMT on regression analysis were total cholesterol, LDL-cholesterol, age, Hs-CRP, family history of CKD. Risk factors associated with plaque occurrence on logistic regression analysis were age, systolic blood pressure, male gender, smoking, calcium phosphate product and serum phosphate. CONCLUSION HD patients have a high prevalence of traditional and non-traditional risk factors for atherosclerosis and this is independent of race. Traditional risk factors like lipids were much lower in ESRD patients. HD patients showed a high prevalence of atherosclerosis as measured by increased carotid intima-media thickness and plaque occurrence in carotid arteries. Hs-CRP correlated significantly with a surrogate marker of atherosclerosis (CIMT).