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 Factors impacting on left ventricular hypertrophy in haemodialysis patients(2008-10-23T08:35:25Z) Chabu, JamesLeft ventricular hypertrophy (LVH) and increases in large artery stiffness predict cardiovascular outcomes in patients with renal failure. What determines left ventricular mass index (LVMI) and large artery stiffness and the contribution toward LVH and large artery dysfunction is not entirely clear. Consequently, this cross sectional study was aimed at assessing the various factors impacting on LVH in haemodialysis (HD), to contribute toward our understanding of the pathophysiology of LVH and large artery dysfunction in 94 adult HD patients. Pre- and post-dialysis blood pressures (BPs) were determined over 12 sessions of dialysis and averaged. Pulse wave analysis performed at the carotid, femoral and radial arteries was employed to determine pulse wave velocity (PWV) and central augmentation index (AIc). Echocardiography was performed to determine left ventricular mass (LVM) indexed to body surface area (LVMI). Natriuretic peptides, procollagen type I c-peptide (PIP), c-terminal telopeptide of type I collagen (ICTP), matrix metalloproteinases and their inhibitors were studied. The prevalence of LVH was 72.8 % (67/92) .On multivariate analysis pre- (p≤ 0.005), post- (p<0.05) and averaged dialysis (p < 0.015) systolic BP were associated with LVMI and PWV. 24 hour (r = 0.260, p = 0.026), day (r = 0.247, p = 0.036), and night (r= 0.241, p = 0.042) systolic BP were not more closely associated with LVMI than the averaged dialysis systolic BP (r = 0.272, p = 0.010). Similarly 24 hour (r = 0.41, p = 0.0003), day (r=0.400, p = 0.0005), and night (r =0.416, p = 0.0003) systolic BP were not more closely associated with PWV than the post-dialysis systolic BP (r=0.39, p=0.0001) indicating that these BP measurements are as effective as 24-hour ambulatory BP in predicting cardiovascular target organ changes. No relationship between either PWV (r=-0.08), or AIc (r=-0.10) and LVMI, between PWV (r=-0.11), or AIc (r=0.03) and LV MWT was noted. IVCD was independently associated with LVMI (partial r adjusted for average dialysis SBP=0.27, p=0.014; partial r adjusted for 24-hour SBP=0.29, p=0.013), and LV mean wall thickness (p<0.01), but not with LV relative wall thickness (p=0.18), or LV end diastolic diameter (p=0.88). An association between IVCD and AIc (partial r adjusted for average dialysis SBP=0.21, p<0.05), but not PWV was noted. NT-proANP and NT-proBNP were independently associated with LVMI (p<0.0001) but neither were associated with IVCD independent of LVMI suggesting a close association with LVMI in HD. Serum concentrations of matrix metalloproteinases 1, 2 and 9, and their tissue inhibitors (1 and 2) were not associated with LVMI, remodelling or PWV and neither procollagen I nor the C-terminal telopeptide of type I collagen (ICTP) were associated with LVMI. Thus, factors impacting on LVH in this study were systolic BP, NT-proANP, NT-proBNP and IVCD.Item Determinants of left ventricular hypertrophy and its regression in people of African ancestry in South Africa(2008-07-10T09:04:51Z) Libhaber, Elena NeustadtABSTRACT There is substantial evidence to suggest that independent of conventional BP, LV mass (LVM) is higher in African-Americans than in European-Americans a difference that may translate into a higher prevalence of cardiovascular diseases. In the present thesis I assessed whether LVM is similarly elevated in groups of African descent living in Africa, and subsequently whether 24-hour, day or night BP or indices of arterial stiffness could explain the variability in LVM beyond conventional BP in this population group. As there is considerable controversy as to whether 24-hour BP measurements are better predictors of the regression of LVH than conventional BP and whether antihypertensive agents that target the renin-angiotensin system (RAS) regress LV hypertrophy (LVH) independent of BP in groups of African descent, in the present thesis I therefore also assessed these questions. In 141 healthy adult participants obtained from a random sample of nuclear families (n=399) of African ancestry living in Soweto, I determined that LVM adjusted for body surface area to the first power was an appropriate allometric signal to account for growth effects on LVM. The allometric signals established in other populations considerably over-adjusted for LVM in the group that I studied with marked negative relations noted. After adjusting for body surface area I noted upper thresholds of LVM index (LVMI) of 134 g/m2 for men and 112 g/m2 for women. As compared to thresholds described for other population samples these thresholds were noted to be modestly higher. In 187 women from randomly recruited nuclear families of African ancestry, after appropriate adjustments, conventional BP was as closely associated with LVMI as 24- hour BP, and daytime BP was as closely associated with LVMI as night-time BP in women. However, in 110 men from randomly recruited nuclear families of African ancestry, after appropriate adjustments, only night-time BP was associated with LVMI, an effect that was independent of conventional BP (r=0.21, p<0.05). Indices of nocturnal decreases in BP were not associated with LVMI in either gender group. Furthermore, in randomly recruited nuclear families of African ancestry, after appropriate adjustments, including systolic BP or pulse pressure, pulse wave velocity (an index of arterial stiffness assessed using applanation tonometry) was independently associated with LVMI in women (n=204, r=0.25, p<0.0005), but not in men (n=123, r=-0.07). In 173 hypertensive patients of African descent of whom 64 were previously untreated and 109 were previously treated, I assessed whether ambulatory BP is a better predictor of on-treatment decreases in LVMI over a 4 month treatment period. In the previously untreated patients, the regression in LVMI correlated to a similar degree (p<0.09) with decreases in conventional (r=0.34; p<0.005) and 24-hour (r=0.26; p<0.04) systolic BP. In this same study sample followed prospectively for 25 months, accounting for effects on ambulatory BP at each time point, the use of the angiotensin-converting enzyme inhibitor, enalapril, was not associated with LVMI, whereas, on-treatment conventional systolic BP (p=0.01) and night-time systolic BP (p=0.01) were associated with LVMI. In a further study conducted in 87 patients of African ancestry with hypertension and LVH, I showed that changes in systolic ambulatory BP (daytime, r=0.46, p=0.006) were predictive of changes in LVMI after 2 months of treatment with an angiotensin II receptor blocker (candesartan), ACE-I (ramipril) and the diuretic agent, hydrochlorothiazide. Moreover, in a final study I showed that in hypertensive patients of African ancestry, initiating therapy with the diuretic, indapamide SR and then adding the ACE-I, perindopril 4 mg (n=42), was equally as effective as amlodipine (calcium channel blocker) (n=44) therapy at reducing ambulatory BP and LVMI. Thus, in conclusion, groups of African descent living in Africa have only marginally higher thresholds for LVM than other population groups. Moreover, in this population group, nocturnal BP has a conventional BP-independent effect on LVMI in men, but not in women, whereas arterial stiffness has a conventional BP-independent effect on LVMI in women, but not in men. Further, in this population, reductions in LVM produced by antihypertensive therapy appear to be equally as closely related to conventional as ambulatory BP and in contrast to findings in groups of European ancestry, where RAS blockers produce unique benefits on LVM beyond conventional BP reductions, in groups of African ancestry in Africa, RAS blockers produce no BPindependent reductions in LVM. Moreover, in this population, decreases in LVM in patients with LVH produced by RAS blockers are related to ambulatory BP changes and despite the ineffectiveness of RAS blockers on BP when used as monotherapy in this population, RAS blockers together with diuretics are equally as effective in decreasing BP and LVM as compared to a class of antihypertensive agents with established efficacy (calcium channel blockers). Hence when compelling indications for RAS blockade exist, RAS blocker-diuretic combinations are effective therapy in patients of African descent living in Africa.