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dc.contributor.advisorScott, Russell
dc.contributor.advisorFlorkowski, Chris
dc.contributor.authorYoung, Joanna Mary
dc.date.available2013-06-05T05:10:15Z
dc.date.copyright2012
dc.identifier.citationYoung, J. M. (2012). Metabolic Regulation of Endothelial Dysfunction and Cardiovascular Risk (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/2441en
dc.identifier.urihttp://hdl.handle.net/10523/2441
dc.description.abstractDespite the use of current therapies for lipid modification, glucose regulation, and blood pressure control, residual cardiovascular risk persists, creating a need for additional treatment modalities. The endothelium is essential for the regulation of vascular tone and the maintenance of vascular homeostasis. Endothelial dysfunction is instrumental in the pathogenesis of vascular disease, and independently predicts cardiovascular risk. The endothelium is thus an important treatment target in addition to traditional cardiovascular risk factors. This thesis describes a series of clinical studies that were designed to address further strategies for cardiovascular risk reduction. Coenzyme Q10 is an obligatory cofactor in the mitochondrial electron transport chain and a lipophilic antioxidant that may have a complementary role in modifying cardiovascular risk. Statins have well proven benefits on endothelial function and cardiovascular risk reduction, but are yet to be established for non-ischemic heart failure. In parallel, strategies are required to improve statin tolerance and thus cardiovascular risk management. In the first study, 12 weeks of coenzyme Q10 supplementation resulted in significantly improved endothelial function in statin-treated patients with the metabolic syndrome. In the second study, 12 weeks of coenzyme Q10 therapy did not lead to clinically significant reductions in systolic or diastolic 24-hr ambulatory blood pressure in patients with the metabolic syndrome and inadequately treated hypertension, despite standard therapies; but there was a significant reduction in daytime diastolic blood pressure loads. In the third study, 12 weeks of supplementation with coenzyme Q10 in combination with upward titration of simvastatin therapy from 10 mg/day to 40 mg/day was not associated with improved simvastatin tolerability, nor reduced muscle symptoms in patients with a history of statin-related myalgia compared to statin monotherapy. In the fourth study, genetic variation of COQ2 and AMPD1 were found to be associated with the risk of statin-induced myopathy in two independent cohorts of cases with a history of statin-induced myopathy and statin tolerant controls. A significant gene interaction was observed between COQ2 SNP-2 and AMPD1 Q12X, highlighting an increased risk of statin myopathy with affected alleles. The fifth study, demonstrated that chronic high-term, long-high statin therapy does not lead to subnormal plasma coenzyme Q10 concentrations in patients with phenotypic or genotypic familial hypercholesterolemia compared to untreated controls, although low coenzyme Q10 levels were associated with increased arterial stiffness in patients with familial hypercholesterolemia. In the final study, short-term treatment with atorvastatin resulted in marked improvements in endothelial function in patients with non-ischemic heart failure that were largely independent of LDL-cholesterol reductions. This was not mediated via reductions in plasma asymmetric dimethylarginine levels. Coenzyme Q10 supplementation may therefore have an important role in reducing residual cardiovascular risk through augmentation of endothelial function in statin-treated patients. Coenzyme Q10 may still have beneficial effects on blood pressure and statin tolerance in specific populations. Further determination of genetic risk factors for statin intolerance could allow individualisation of lipid modifying therapy. The potential benefits of statin therapy on cardiovascular risk reduction in chronic heart failure requires further evaluation.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectEndothelial Function
dc.subjectCardiovascular Disease
dc.subjectStatin therapy
dc.subjectCoenzyme Q10
dc.titleMetabolic Regulation of Endothelial Dysfunction and Cardiovascular Risk
dc.typeThesis
dc.date.updated2012-04-25T22:57:31Z
dc.language.rfc3066en
thesis.degree.disciplineMedicine
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.openaccessOpen
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