Left 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.

Thesis (M.A.)--Boston University

ABSTRACT 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.

No description available.

Left Ventricular Hypertrophy (LVH) is common in Type 2 Diabetes (T2DM) and despite optimal treatment of blood pressure can still persist. We know LVH is a cardiovascular (CV) risk factor in its own right and contributes to high CV event rates in patients with T2DM. Apart from hypertension, other factors contribute to the development of LVH in patients with T2DM, in particular oxidative stress (OS) has been implicated in LVH development. Allopurinol is a potent anti-oxidant, acting by blocking the enzyme Xanthine Oxidase, and has been previously shown to reduce vascular OS. Therefore the main aim of this thesis was to investigate whether allopurinol regresses LVH in patients with T2DM. The trial design was a randomised, double blind, placebo controlled study in 66 patients with T2DM with echocardiographic evidence of LVH. Allopurinol 600mg/day or placebo was given for nine months over the study period. The primary outcome was reduction in left ventricular mass (LVM) as calculated by cardiac magnetic resonance imaging (CMR) at baseline and at nine months follow-up. The secondary end-points were change in flow mediated dilatation (FMD) and augmentation index (AIx). Allopurinol significantly reduced absolute LVM (-2.65 ± 5.91g and placebo group +1.21 ± 5.10g (p=0.012)) and LVM indexed to body surface area (-1.32 ± 2.84g/m2 and placebo group +0.65 ± 3.07g/m2 (p=0.017)). When analysis was made of high and low baseline LVM then the effects of allopurinol were exaggerated in the high LVM mass group. No significant change was seen in either FMD or AIx. This thesis shows that allopurinol regresses LVM in patients with T2DM and LVH and controlled blood pressure. Regressing LVH has been shown previously to improve CV mortality and morbidity. Therefore allopurinol may become a useful therapy to reduce CV events in T2DM patients with LVH.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is a strong independent predictor of cardiovascular morbidity and mortality, while its regression is associated with an improved clinical prognosis. It is, therefore, vital to elucidate and fully comprehend the mechanisms that contribute to LVH development and to identify markers that indicate a strong predisposition to the development of severe cardiac hypertrophy, before its occurrence. Hypertrophic cardiomyopathy (HCM) serves as a model to investigate LVH development. This primary cardiac disease is characterised by LVH in the absence of increased external loading conditions and is caused by defective sarcomeric proteins, as a result of mutations within the genes encoding these proteins. However, the hypertrophic phenotype of HCM is largely complex, as we see strong variability in the extent and distribution of LVH in HCM, even in individuals with the same disease-causing mutation from the same family; this points toward the involvement of additional genetic and environmental modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) influence LVH indirectly, through their key role in blood pressure regulation, but also directly, due to the direct cellular hypertrophic effects of some RAAS components. Previous genetic association studies aimed at investigating the contribution of RAAS variants to LVH were largely centred on a subset of polymorphisms within the genes encoding the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor genes, while the renin section and RAAS components downstream from ACE remained largely neglected. In addition, most previous studies have reported relatively small individual effects for a small subset of RAAS variants on LVH. In the present study we, therefore, employ a family-based genetic association analysis approach to investigate the contribution of the entire RAAS to this complex hypertrophic phenotype by exploring both the individual as well as the compound effects of 84 variants within 22 RAAS genes, in a cohort of 388 individuals from 27 HCM families, in which either of three HCM-founder mutations segregate. During the course of this explorative study, we identified a number of RAAS variants that had significant effects on hypertrophy in HCM, whether alone or within the context of a multi-variant haplotype. Through single variant association analyses, we identified variants within the genes encoding angiotensinogen, renin-binding protein, the mannose-6-phosphate receptor, ACE, ACE2, angiotensin receptors 1 and 2, the mineralocorticoid receptor, as well as the epithelial sodium channel and the Na+/K+-ATPase β-subunits, that contribute to hypertrophy in HCM. Using haplotype-based association analyses, we were able to identify haplotypes within the genes encoding for renin, the mannose-6-phosphate receptor, angiotensin receptor 1, the mineralocorticoid receptor, epithelial sodium channel and Na+/K+-ATPase α- and β subunits, as well as the CYP11B1/B2 locus, that contribute significantly to LVH. In addition, we found that some RAAS variants and haplotypes had statistically significantly different effects in the three HCM founder mutation groups. Finally, we used stepwise selection to identify a set of nine risk-alleles that together predicted a 127.80 g increase in left ventricular mass, as well as a 13.97 mm increase in maximum interventricular septal thickness and a 14.67 mm increase in maximum left ventricular wall thickness in the present cohort. In contrast, we show that a set of previously identified “pro-LVH” polymorphisms rather poorly predicted LVH in the present South African cohort. This is the first RAAS investigation, to our knowledge, to provide clear quantitative effects for a subset of RAAS variants indicative of a risk for LVH development that are representative of the entire pathway. Our findings suggest that the eventual hypertrophic phenotype of HCM is modulated by the compound effect of a number of RAAS modifier loci, where each polymorphism makes a modest contribution towards the eventual phenotype. Research such as that presented here provides a basis on which future studies can build improved risk profiles for LVH development within the context of HCM, and ultimately in all patients with a risk of cardiac hypertrophy. / AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is 'n sterk onafhanklike voorspeller van kardiovaskulêre morbiditeit en mortaliteit, terwyl LVH regressie verband hou met ‘n verbeterde kliniese voorspelling. Dit is dus noodsaaklik om die meganismes wat bydra to LVH ontwikkeling ten volle te verstaan en merkers wat 'n sterk geneigdheid tot die ontwikkeling van ernstige kardiale hipertrofie te identifiseer, voordat dit voorkom. Hipertrofiese kardiomiopatie (HKM) dien as 'n model om LVH ontwikkeling te ondersoek. Hierdie primêre hartsiekte word gekenmerk deur LVH en word meestal veroorsaak deur foutiewe sarkomeer proteïene as gevolg van mutasies binne die gene wat kodeer vir hierdie proteïene. Die hipertrofiese fenotipe van HKM is egter grootliks kompleks; ons sien, by voorbeeld, sterk veranderlikheid in die omvang en die verspreiding van LVH in HKM, selfs in individue met dieselfde siekte-veroorsakende mutasie binne dieselfde gesin, wat dui op die betrokkenheid van addisionele genetiese en omgewing modifiseerders. Komponente van die renien-angiotensien-aldosteroon sisteem (RAAS) beïnvloed LVH indirek, deur middel van hul belangrike rol in bloeddruk regulasie, maar ook direk, as gevolg van die direkte sellulêre hipertrofiese gevolge van sommige RAAS komponente. Vorige genetiese assosiasie studies wat daarop gemik was om die bydrae van RAAS variante LVH te ondersoek, was hoofsaaklik gesentreer op 'n groepie polimorfismes binne die gene wat kodeer vir die “angiotensin converting enzyme” (ACE) en angiotensien II tipe 1-reseptor gene, terwyl die renien gedeelte en RAAS komponente stroomaf van ACE meestal nie ondersoek was nie. Daarbenewens het die meeste vorige studies relatief klein individuele gevolge gerapporteer vir 'n klein groepie RAAS variante op LVH. In die huidige studie het ons dus 'n familie-gebaseerde genetiese assosiasie-analise benadering gebruik om die bydrae van die hele RAAS tot hierdie komplekse hipertrofiese fenotipe te ondersoek deur 'n studie van die individuele-, sowel as die saamgestelde effekte van 84 variante binne 22 RAAS gene, in 'n groep van 388 individue vanaf 27 HKM families, waarin een van drie HCM-stigter mutasies seggregeer. Gedurende die loop van hierdie studie het ons 'n aantal RAAS variante wat ‘n beduidende uitwerking op HKM hipertrofie geïdentifiseer, hetsy alleen of binne die konteks van' n multi-variant haplotipe. Deur middel van enkele variant assosiasie toetsing het ons variante geïdentifiseer binne die gene wat kodeer vir angiotensinogen, renien-bindende proteïen, die mannose-6-fosfaat reseptor, ACE, ACE2, angiotensien reseptore 1 en 2, die mineralokortikoïd reseptor, sowel as die epiteel natrium kanaal en Na+/ K+-ATPase β-subeenhede, wat bydra tot HKM hipertrofie. Deur die gebruik van haplotipe-gebaseerde assosiasie ontleding was ons in staat om haplotipes te identifiseer binne die gene wat kodeer vir renien, die mannose-6-fosfaat reseptor angiotensien reseptor 1, die mineralokortikoïd reseptor, epiteel natrium kanaal en die Na+/ K+-ATPase α-en β subeenhede, sowel as die CYP11B1/B2 lokus, wat aansienlik bydra tot LVH. Verder het ons bevind dat sommige RAAS variante en haplotipes statisties beduidende verskillende effekte gehad het in die drie HKM stigter mutasie groepe. Laastens, het ons stapsgewyse seleksie gebruik om 'n stel van nege risiko-allele wat saam' n toename van 127.80 g in linker ventrikulêre massa, sowel as 'n 13.97 mm toename in maksimum ventrikulêre septale dikte, en' n 14.67 mm verhoging in maksimum linker ventrikulêre wanddikte voorspel, te identifiseer in die huidige kohort. In teenstelling hiermee wys ons dat 'n stel van voorheen geïdentifiseerde "pro-LVH" polimorfismes swakker gevaar het as LVH-voorspellers in die huidige Suid-Afrikaanse kohort. Hierdie is die eerste RAAS ondersoek, tot ons kennis, wat ‘n duidelike kwantitatiewe gevolge vir 'n stel RAAS variante wat ‘n verhoogde risiko tot LVH ontwikkeling aandui, wat verteenwoordigend is van die hele RAAS. Ons bevindinge dui daarop dat die uiteindelike hipertrofiese fenotipe van HKM gemoduleer word deur die saamgestelde effek van 'n aantal RAAS wysiger loki, waar elke polimorfisme ' n beskeie bydrae maak tot die uiteindelike fenotipe. Navorsing soos dié wat hier aangebied word dien as 'n basis waarop toekomstige studies kan bou vir ‘n verbeterde risiko-profiel vir LVH ontwikkeling binne die konteks van die HKM, en uiteindelik in alle pasiënte met' n verhoogde risiko vir kardiale hipertrofie.

MSc (Med), University of the Witwatersrand, Faculty of Health Sciences, School of Physiology / The 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.

Haemodialysis (HD) patients have a high mortality risk and most have echocardiographic evidence of abnormal cardiac structure or function. Markers, such as left ventricular hypertrophy (LVH), show association with adverse outcome in the general population and can aid in clinical decision making. The aim of this research was to explore the prognostic utility of established and novel two-dimensional (2DE) and three-dimensional transthoracic echocardiographic (RT3DE) techniques in HD patients. Adult maintenance HD patients from a single tertiary nephrology centre including satellite dialysis units were enrolled. Exclusion criteria were if patients were clinically unstable, unable to consent, or if required ambulance transportation for echocardiography visits. Consented patients underwent 2DE with speckle tracking (STE), RT3DE and VicorderTm measurements of pulse wave velocity (PWV) on a non-dialysis day, after the short inter-dialytic break. Clinical phenotype data, 3-month averaged blood results and dialysis prescriptions were obtained from the hospital electronic patient records. All patients screened were followed-up until death, renal transplantation, moving out of the region, or 16th November 2015. Regression analysis was used to assess the cross-sectional relationship between echocardiographic parameters. Relationship of echocardiographic parameters with outcome was assessed by Cox regression analysis. The first study explored whether patients recruited had similar characteristics and survival compared with patients who declined consent or who were excluded from the study. Patients who declined consent had an adjusted hazard ratio (HR) for all-cause mortality compared with recruited patients of 1.70, 95% confidence interval (CI) 1.10-2.52, and excluded patients had an adjusted HR of 1.30, 95% CI 0.75-2.25. Recruited patients may be a 'fitter' population and this needs to be considered when interpreting results. The second study reports that when global longitudinal strain (GLS) is combined in a multivariable model with PWV; PWV is superior to GLS in its association with mortality (adjusted HR 1.23, 95% CI 1.03-1.47 versus HR 1.00, 95% CI 0.86-1.17). When this analysis was repeated in a sub-group of patients with LVH, neither GLS nor PWV were associated with mortality, whilst both were prognostically significant in a preserved LVEF sub-group (PWV: HR 1.23, 95% CI 1.04-1.4 and GLS: HR 1.16, 95% CI 1.01-1.33). Therefore GLS has different prognostic implications in different patient sub-groups. The third study explored whether tissue motion mitral annular displacement (TMAD) measured by STE may be a more useful alternative to GLS as it measures strain but is quicker and less user-dependent. TMAD was closely correlated to GLS (r=-0.614, p<0.001), but had no prognostic power for mortality (adjusted HR 1.04,95% CI 0.91-1.19). The correlation between 2DE and RT3DE determined LV mass and volume measurements and the prognostic significance of RT3DE measurements were assessed. Although there was good correlation between 2DE and RT3DE LV volume measurements, 2DE overestimated LV mass compared to RT3DE. RT3DE measures gave no added prognostic value, and there were added difficulties in obtaining adequate images for RT3DE (35% of patients who had adequate 2D images). Furthermore, although RT3DE determined LV mechanical dyssynchrony index was prolonged in HD patients compared with published general population controls, it failed to show any prognostic significance (HR 2.16, 95% CI 0.96-4.89) for mortality, but was associated with hospitalisation for heart failure (HR 1.03, 95% CI 1.00-1.06). These results indicate that novel measurements of sub-clinical cardiac dysfunction have the potential to aid prognostication in this high risk population. Follow-up studies exploring the longitudinal change in these parameters is ongoing.

No description available.

No description available.