Horowitz, John DavidChirkov, YuliyChan, Wai Ping Alicia2014-04-072014-04-072013http://hdl.handle.net/2440/82439Ageing represents an independent and strong risk factor for cardiovascular disease (Lakatta and Levy 2003), and in women, menopause appears to trigger a substantial increase in cardiovascular disease incidence (Castelli 1984). One potential basis for this observation is impairment of vascular endothelial function (Yasue, Matsuyama et al. 1990; Egashira, Inou et al. 1993). However no stratified comparisons of endothelial function or tissue responsiveness to nitric oxide (NO) with increasing age have previously been reported in either gender. The objectives of the experiments contained in this thesis were therefore to:- 1) Characterise the putative variability in platelet and vascular responsiveness to NO in women of ages 18 to 60 years. 2) Compare this variability with that in vascular endothelial function and its biochemical determinants. 3) Compare the above-mentioned putative fluctuations to those present in age-matched patients with PCOS, a condition characterised by presence of impaired NO signalling in early adult life. 4) Determine the possible impact of menopause on NO signalling in vessels and platelets. Methods In order to examine these objectives, we conducted a case-control study of women aged between 18 and 60 years, which allowed us to firstly, examine NO signalling and various parameters in normal ageing women and then secondly, to compare these with women with PCOS. A subset of 40 perimenopausal women was studied prospectively to assess the relationship between menopause and platelet and vascular parameters. PCOS women were selected based on Rotterdam criteria and women who were pregnant or on clopidogrel were excluded from the study. Inhibition of platelet aggregation by nitric oxide was the primary outcome measure. Vascular endothelial function utilizing applanation tonometry, plasma concentrations of NG,NG-dimethyl-L-arginine (ADMA) and endothelial progenitor cell count (EPC) were assessed as markers of endothelial dysfunction. High-sensitivity Creactive protein (hs-CRP) was measured as a marker of inflammation. Results The key findings from this thesis are: (1) With increasing age in normal women, there was progressive attenuation of platelet responses to NO (ANOVA, P<0.0001) with no significant changes in vascular NO responses. (2) There was also evidence of endothelial dysfunction with increasing age (p<0.0001) which was accompanied by elevation of ADMA concentrations with increasing age (p=0.003). (3) Irrespective of age, PCOS women exhibited greater impairment of platelet NO responses and endothelial function (p<0.05, 2 way ANOVA) compared to normal women. Furthermore, these anomalies were evident in PCOS women from an early age but had a tendency to converge with normal women above the age of 40 years. (4) The changes in platelet and endothelial function in normal women were not correlated with oestradiol levels. Conclusions Normal ageing in women is associated with attenuation of NO-based signalling in platelets and blood vessels. In women with PCOS, these changes are present from early adult life, which may form the pathophysiological basis for premature atherogenesis seen in these individuals. The changes in NO signalling are not totally attributable to the onset of menopause.women; ageing; polycystic ovarian syndrome; menopause; nitric oxideThesis20140114101243