Wu, Xiaomei. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 163-194). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Thesis (doctoral)--Lund University, 1996. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1996. / Added t.p. with thesis statement inserted.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2002. / Bibliography: leaves 72-92.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2004. / Bibliography: leaves 140-153.

Cardioprotective effects of glucagon-like peptide-1 (GLP-1), the GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4), and GLP-1(9-36), a cleavage product of GLP-1, were examined in ischemia-reperfusion (I/R) models of both isolated mouse hearts and cultured cardiac myocytes (CMs) using both wild-type (WT) and GLP-1R knockout (Glp1r-/-) mice. In WT hearts, GLP-1 and Ex-4 significantly improved left ventricular functional recovery vs. untreated controls following I/R, whether the drugs were administered prior to ischemia (pre-ischemia) or during reperfusion (post-ischemia). Surprisingly, the cardioprotective effects of pre- and post-ischemia treatments with GLP-1, but not Ex-4, remained evident in Glp1r-/- hearts. Although pre-ischemia infusion of GLP-1(9-36) induced lower functional recovery than untreated controls, post-ishemia infusion of GLP-1(9-36) augmented functional recovery and reduced infarct size to a similar extent to that of GLP-1 and Ex-4 in hearts from both WT and Glp1r-/- mice. Mass spectrometry was used to assay conversion of GLP-1 to GLP-1(9-36) in coronary effluents of isolated mouse hearts. Within 15 min of infusing GLP-1, significant amounts of GLP-1(9-36) were generated by the heart. By 30 min, only trace amounts of intact GLP-1 remained in coronary effluents indicating the heart rapidly converts GLP-1 to GLP-1(9-36). In CMs undergoing simulated I/R injury in vitro, both GLP-1(9-36) and Ex-4 significantly improved cell viability, LDH release and caspase-3 activation. These effects were significantly attenuated by co-treatments with LY294002, PD98059 and Ex(9-39), inhibitors of PI3K, ERK1/2, and GLP-1R respectively. The actions of Ex-4, but not GLP-1(9-36), were lost in CMs isolated from Glp1r-/- mice and only GLP-1(9-36), but not Ex-4, improved the survival of human aortic endothelial cells (HAEC) undergoing simulated I/R injury. Of note, both GLP-1 and GLP-1(9-36) treatments also demonstrated potent vasodilatory effects, as manifested by increased coronary flow rates in isolated hearts and increased diameters of pre-constricted mesenteric arteries isolated from both WT and Glp1r-/- mice. The cardioprotective effects on isolated hearts and vasodilatory effects on isolated mesenteric arteries, induced by GLP-1 was blunted by co-treatment with a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor known to block conversion of GLP-1 to GLP-1(9-36). Together, these data suggest that the beneficial effects of GLP-1 in I/R injury are mediated in part by GLP(9-36) and support the existence of a GLP-1(9-36) responsive, but Ex(9-39)-sensitive cardioprotective signaling pathway distinct from that associated with the classical GLP-1R.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2014 / Background: Individuals infected with the human immunodeficiency virus (HIV) are living longer due to effective disease management with highly active antiretroviral therapy (HAART). International literature suggest that mortality in people living with HIV and AIDS (PLWHA) is shifting to non-AIDS defining diseases such as cardiovascular disease. It is suggested that PLWHA are at an increased risk for developing ischemic heart disease (IHD) due to HIV mediated processes, traditional risk factors of IHD and factors related to HAART exposure. In the South African context risk factors for IHD are reported to be on the increase in the general population but published information regarding the risk factors for IHD in PLWHA is limited. Human immunodeficiency virus infection is a significant Sub-Saharan Africa challenge with 5.26 million people living in South Africa (SA) reported to be infected with HIV. Only Swaziland, Lesotho and Botswana report higher prevalence rates of HIV infection. Due to the high prevalence rate of HIV in SA, the reported increase in risk factors for IHD in the general population and the suggested increased risk for IHD in PLWHA, screening these risk factors in PLWHA in the South African context may be necessary. Innovative prevention strategies for IHD are also required to manage the risk for IHD in PLWHA in SA due to the high prevalence rate. A home-based education and pedometer walking programme could be such a strategy. The aims of the research project were therefore firstly to screen selected risk factors for IHD in PLWHA attending a primary care clinic and secondly to evaluate said individuals’ self-perception regarding their risk of IHD. Lastly the project set out to determine the effects of an individualised education and home-based pedometer walking programme on the risk of IHD as a potential prevention management strategy for IHD in PLWHA. Methodology: The research project consisted of four studies divided into phase 1 (study 1, 2, 3) and phase 2 (study 4). The study aims, methods and data analysis approaches were: Study 1: Aimed to screen a sample of PLWHA (on HAART) for physical activity and selected risk factors of IHD using the Yamax SW200 pedometer and other appropriate methods respectively. This study was an observational study and data analysis consisted of descriptive analysis and reviewing associations with univariate logistic regression analysis. A p–value less than 0.05 was considered statistically significant. Study 2: Aimed to evaluate participants’ self-perception and behaviour in relation to the risk of IHD using a semi-structured interview and card sort technique. This study was a qualitative study and data analysis consisted of descriptive and conventional content analysis. Study 3: Aimed to develop the education physical activity diary that was used in phase 2. The methodological processes included a literature review, a review of the education material to be included in the physical activity diary by an academic peer–review panel, review by a clinician working with PLWHA and a sample of PLWHA. Following these activities the diary was constructed and translated into isiZulu. Study 4: Aimed to assess the effects of an education and home-based pedometer walking programme on the risk factors of IHD in a sample of PLWHA (on HAART) with an increased risk for IHD as determined in study 1. The study was a randomised controlled trial consisting of an intervention and control group. Assessments were done at baseline, six and 12 months. Control participants continued with standard clinic care and were phoned once a month for five months during the baseline and six month interval. The intervention participants received a Yamax SW200 pedometer, an education physical activity diary, individualised walking programme and had once a month face-to-face education sessions in the baseline to six month interval. Intervention participants were instructed to continue with their physical activity modification programme during the six to 12 months period. No contact was made with control or intervention participants during this time. Intention-to-treat analysis was the primary approach for study 4. Data analysis consisted of descriptive analysis (mean [±SD] and frequencies [percentages]) and randomisation to group allocation was assessed using a two sample/ independent t-test or Wilcoxon rank–sum (Mann– Whitney) for non-normally distributed continuous data. Categorical data were evaluated with the Pearson Chi Square test. A p–value less than 0.05 was considered statistically significant. To evaluate the effect of time on outcomes assessed, repeated measures ANOVA for within-group changes were performed. To evaluate the effect of the programme on outcomes assessed, repeated measures ANCOVA with baseline values as co-variates were performed to highlight the between-group effect. To assess the associations between dependent variables and the time and intervention/control interaction the pedometer data were log-transformed due to skewness. The generalised estimation equation (GEE) and mixed effects model (MEM) approaches were used to fit the univariate and multivariable models. The correlation structure selected was the exchangeable option with the identity link function suitable for Gaussian data. The relationship between high sensitivity C-reactive protein (hs-CRP) at baseline and evaluated risk factors for IHD was assessed with the Pearson correlation coefficient and univariate logistic regression in MEM respectively on log-transformed hs-CRP. Results: Study 1: Two hundred and five PLWHA (on HAART) were screened for selected risk factors for IHD. The demographic characteristics of participants consisted of the following: mean age (38.2 [±9.5] years), gender (men [n=47; 22.9%] and women [n=158; 77.1%]), most participants had a secondary educational level (n=95; 46.3%), were employed (n=115; 56.1%) and were supporting dependents (n=158; 85.4%). The majority of participants perceived their general health as good (n=120; 58.5%), but felt their body shape had changed in the last six months (n=123; 60%). This was mostly due to a reported increase in weight (n=132; 64.4%). The mean time on HAART was 8.7 (±2.3) months, with the majority of participants being diagnosed as HIV positive between 2009 to 2011 (n=134; 66%). The majority of participants were on Lamivudine, Efavirenz and Tenofovir (n=139; 67.8%) therapy with a mean CD4 count of 285.1 (±157) cells/mm3 and viral load of 12 513.2 (±59 710.6) copies/ml. The physical activity levels of participants were reduced with the mean pedometer step count per day found to be 7 673.2 (±4 017.7) with men being more active (10 076.3 [±4 885.6] steps per day) than women (6 993.3 [±3 462.6] steps per day). The majority of study participants (n=150; 77%) took less than 10 000 steps per day. Taking less than 10 000 steps per day was related to waist circumference (WC) (odds ratio=1.04; 95% CI: 1.00–1.08; p=0.03) when adjusted for age and gender. Eight participants (3.9%) participated in formal sporting activities that were supervised and 123 participants (60%) tried to incorporate exercise into their daily lives. The preferred activity method for exercise was walking (n=56; 45.5%) and running (n=33; 26.8%). Perceived stress was moderately high with a mean Cohen’s Perceived Stress score at 19.2 (±7.8) with women reporting higher levels of stress (20 [±7.1]) than men (16.9 [±9.1]). A family history of IHD was low in participants (n=29; 14.2%) as well as a known diagnosis of diabetes mellitus (n=1; 0.005%), hypertension (n=19; 9%) and current smoking status (n=33; 16.1%). The majority of participants reported not being able to consume fish weekly (n=114; 55.6%) and reported weekly consumption of fruit and vegetables (n=110; 53.7%). Few participants were able to consume three to five vegetables and fruit combined per day (n=68; 33.2%). The mean resting heart rate (RHR) of the sample was slightly elevated (82.7 [±11.4] bpm) with having a RHR ≥ 80 bpm related to diastolic blood pressure (DBP) (odds ratio=1.07; 95% CI: 1.03–1.11; p<0.00) and physical activity (odds ratio=0.99; 95% CI: 0.99–0.99; p=0.02) as adjusted for age and gender. The sample as a whole was overweight with a mean body mass index (BMI) of 25.6 (±1.4) kg/m2. Having a BMI ≥ 25 kg/m2 was related to systolic blood pressure (SBP) (odds ratio=1.07; 95% CI: 1.04–1.10; p<0.00), WC (odds ratio=1.34; 95% CI: 1.22–1.46; p<0.00), hip circumference (odds ratio=1.53; 95% CI: 1.38–1.75; p<0.00) and CD4 count (odds ratio=1.00; 95% CI: 1.00–1.01; p=0.01) as adjusted for age and gender. Study 2: Thirty PLWHA (on HAART) were purposefully sampled according to the following criteria: individuals had to be on HAART for six to 12 months, between the ages of 20 and 65 years and ambulatory without an assistive device with no pre-existing history of cardiovascular disease, mental illness, current acute infection, current pregnancy or breast-feeding women. The demographic details of participants were as follows: median age 36.5 (31.8–45.0) years; women (n=25; 83.3%) and men (n=5; 16.7%); the majority of participants (n=16; 53.3%) had a secondary school education, were employed (n=17; 56.7%) and were supporting dependents (n=26; 86.7%). Knowledge and understanding related to IHD, insight into own risk for IHD and health character in the HIV context were identified as three prominent themes. An important finding that the study highlighted was that participants did not perceive themselves to be at risk for IHD due to being HIV+ or using HAART in any way. The majority of participants (n=15; 50%) did not perceive themselves to be at risk for IHD due to reporting having adequate coping behaviour and living a healthy lifestyle. Twelve (40%) participants did however perceive a risk for IHD due to physical symptoms experienced and their behaviour consisting of a poor diet, elevated stress levels and lack of exercise. Three (10%) participants were unsure concerning their risk for IHD in the future. Study 3: A selection of pages from the education physical activity diary can be found in Appendix 31. Study 4: Eighty four PLWHA (on HAART) participated in study 4. The education and home-based walking programme implemented in study 4 was successful in improving physical activity levels in both the control and intervention groups, as participants’ pedometer-determined step-count increased from baseline. The within-group change at six months were statistically significant (p=0.03) for both groups but not so for the 12 month period (control group [p=0.33] and intervention group [p=0.21]). It was however of clinical value in the intervention group, due to the group exceeding the step count aim of the programme, that being 3 000 steps above baseline at each assessment point. Translating the step count into time, would amount to approximately 30 minutes of added walking per day. The group therefore reached the Public Health recommendations for physical activity. Social support in the form of encouragement, motivation and participation from friends and family was noted as important enablers that assisted intervention participants to adhere to their programme. No significant differences were observed in the sociodemographic profile, HIV related clinical markers and antiretroviral therapy and IHD risk factors evaluated at baseline. The study highlighted that inflammation (hs-CRP) was a significant risk factor for IHD in the study cohort due to mean baseline values of 8.6 (±8.4) mg/l in the intervention and 5.4 (±6.5) mg/l in the control group. Inflammation (hs-CRP) was related to perceived stress (Pearson correlation [r=0.23; p=0.03] and MEM univariate logistic regression [log B=0.04; 95% CI: 0.0004– 0.08; p=0.03]), weight (Pearson correlation [r=2.8; p=0.01] and MEM univariate logistic regression [log B=0.02; 95% CI: 0.01–0.04; p=0.01]), BMI (Pearson correlation [r=0.35; p<0.00] and MEM univariate logistic regression [log B=0.07; 95% CI: 0.03–0.12; p<0.00]), WC (Pearson correlation [r=0.28; p=0.01] and MEM univariate logistic regression [log B=0.03; 95% CI: 0.06–0.36; p=0.01]) and hip circumference (Pearson correlation [r=0.28; p=0.01] and MEM univariate logistic regression [log B=0.02; 95% CI: 0.01–0.04; p=0.01]). The risk for IHD according to Framingham Risk Score (FRS) calculation was low as baseline FRS points were 3.3 (±6.5) points in the control group and 2.5 (±6.5) points in the intervention group. The education and home-based walking programme was effective in increasing physical function capacity (six-minute walk test mean difference: 15.70 [±9.33] meters), reducing waist: hip ratio (mean difference of -0.003 [±0.01] cm), reducing glucose level (mean difference of -0.12 [±0.09] mmol/l) and increasing HDL (mean difference of 0.07 [±0.05] mmol/l) as evaluated during betweengroup analysis. The within-group analysis indicated that a significant reduction in SBP occurred in both groups at the six months time period (control group: p=0.03 and intervention group: p<0.00). A slight increase in BMI occurred in both groups at the six and 12 month period that were statistically significant (p<0.00). A significant reduction in total cholesterol (p=0.04) and LDL (p<0.00) at the 12 month period were also noted in the control group. The log-transformed univariate logistic regression model highlighted many associations between the interaction (time and treatment: control or intervention group effect) and secondary outcomes assessed. The inverse associations between perceived stress levels (p<0.00) and BMI (p=0.02) with the six month time interval of the control and intervention groups compared to baseline control findings were confirmed during multivariable analysis in the log-transformed GEE model. Additionally an inverse association between perceived stress levels (p<0.00), BMI (p<0.00), LDL (p=0.01) and triglycerides (TG) (p=0.01) at the six month time interval of the intervention group compared to baseline control findings were confirmed in the multivariable analysis in the logtransformed MEM model. Conclusion: This project showed that physical inactivity, elevated perceived stress levels, inadequate diet of fruit, vegetable and fish intake, elevated RHR, increased BMI and raised hs-CRP were risk factors for IHD in the study cohort. These risk factors screened indicated an elevated risk for IHD in the future even though the FRS demonstrated a low risk for IHD. An IHD predictive model that incorporate hs-CRP when evaluating risk for IHD and which has been validated for use in PLWHA is therefore necessary to adequately evaluate the risk for IHD in this population. This is especially of relevance in the South African context considering the prevalence of HIV infection in women and the association of female gender with hs-CRP as indicated in the literature. The project highlighted that an elevated stress level was a significant risk factor for IHD in the study cohort and was also given as one reason why participants perceived themselves to be at risk for IHD. The positive association between perceived stress and hs-CRP was also of value. The stress lowering effect of the education and home-based pedometer walking programme was therefore of significant importance as it could manage this risk factor. Additionally if stress declines it could potentially also influence hs-CRP in the long term. The study therefore contributes to the body of knowledge related to the effects of exercise on psychological parameters in PLWHA. Additionally the project confirmed that an optimistic bias in individuals living with HIV is present regarding their future possibility for developing IHD. Their perception for the risk for IHD did not always align with the risk factors present as screened. This might be due to the fair application of knowledge related to IHD when evaluating their risk for IHD. It also confirmed that education strategies are needed to explain the risk factors for IHD and how HIV infection and HAART influence these risk factors of IHD. Lastly the project found that an education and individualised home-based pedometer walking programme was able to influence physical activity levels positively and was successful in reducing the risk of some factors for IHD in PLWHA at primary care level. Such a programme can be implemented as an innovative method to manage risk factors for IHD in PLWHA by physiotherapists especially in regions where physiotherapy numbers are low and HIV prevalence high.

Hypertension is a risk factor for myocardial ischemia via the promotion of endothelial dysfunction and atherosclerosis (Ogita et al., 2004). Hypertension not only a predisposes the heart to ischemic events, but as shown by clinical and experimental studies, exacerbates the heart’s susceptibility to ischemia-reperfusion injury (Golden et al., 1994; Besík et al., 2007; Snoeckx et al., 1986) due to impairments in regulation of calcium handling, ion homeostasis, and energy metabolism (Galiñanes et al., 2004). Nutraceuticals have demonstrated beneficial and protective effects on both hypertension and ischemia reperfusion injury. Resveratrol, a naturally occurring polyphenol which is present in grapes and wine, acts as a cardioprotective agent and can be used to protect the heart against ischemia reperfusion injury. Here we investigate the effectiveness of chronic dietary resveratrol intake in normotensive and hypertensive rats on protection against ischemia-reperfusion injury, assessed in an isolated perfused Langendorff heart model. Rats ingested either a High dose of 2.7mg/day-which mimicked the resveratrol content in daily supplemental intake levels, a Low dose of 0.027mg/day- which mimicked the resveratrol content in moderate red wine intake, or no resveratrol in the drinking water for 28 days, at which point hearts were excised and mounted on a Langendorff apparatus. Once stable conditions were established all hearts were subjected to 30 minutes of no flow ischemia followed by 2 hours of reperfusion. Interestingly, SHR animals did not exhibit reduced recovery, or increased infarct size as compared to WKY. Infarct size as measured by triphenyltetrazolium chloride staining after 2 hours of reperfusion was significantly reduced in High and Low groups (combined WKY and SHR) as compared to Controls (19.9±0.9 and 19.4±0.8 vs 27.7±0.7 % of baseline, p<0.0001). Left ventricular developed pressure was significantly improved 2 hours post ischemia in both High and Low groups (combined SHR and WKY) compared to Controls (83.1±4.1 and 78.6±3.4 vs.67.9±3.2% of baseline, p<0.01). A higher rate of maximal pressure development was maintained in High and Low groups (combined SHR and WKY) compared to Controls (90.5±4.7 and 95.6±5.0 vs.73.5±4.8% of baseline, p<.05). Resveratrol treatment at a High and Low dose reduced contracture of the myocardium as compared to Control (7.2±3.0 and 6.9±2.9 vs. 20.1±2.9 mmHg- LVEDP, p<0.01). In conclusion resveratrol treatment at both a High and Low dose protects against a decline in cardiac function, and reduces infarct size post ischemia reperfusion. Additionally, tolerance to ischemia reperfusion injury in SHR is not reduced as compared to WKY.

Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2002. / Includes bibliographical references (leaves 180-202). Also available in electronic version. Access restricted to campus users.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: impedance spectroscopy; non-invasive instrumentation; ischemia. Includes bibliographical references (p. 146-149).