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.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 6 uppsatser.

Diss. (sammanfattning) Göteborg : Univ. , 2006. / Härtill 4 uppsatser.

Background: The 12-lead electrocardiogram (ECG) is a pivotal clinical investigation for evaluations of disorders of myocardial electrophysiology and function. Myocardial ischemia is generally diagnosed on the basis of clinical history, combined with ST segment shifts and T wave changes on resting 12-lead ECG. The ECG is also used as a monitoring tool for assessment of resolution of transmural ischemia following emergency treatment. Because this technology is easy, noninvasive, and inexpensive, it represents a convenient central investigative modality. On the other hand, the 12-lead ECG exhibits very low predictive accuracy for the diagnosis of ischemia in the absence of concurrent symptoms. Even if ECG monitoring is combined with treadmill exercise, the sensitivity and positive predictive accuracy for detection of myocardial ischemia are only around 50% - 75%. Therefore, information from the ECG, combined with exercise test, does not usually have a large influence on clinical decision-making. A number of imaging techniques may be combined with pacing-induced tachycardia or pharmacological stress in order to improve the diagnostic accuracy of such provocative tests for ischemia beyond the level provided by continuous ECG monitoring alone. These include echocardiography, nuclear imaging with single photon emission computed tomography (SPECT) or positron emission tomography (PET) and magnetic resonance imaging. All add to the diagnostic accuracy of the provocative tests performed, but involve considerably incremental costs. The question therefore arises: is it possible to refine continuous ECG analysis during provocative testing in such a way that the diagnostic accuracy of the procedure can be improved? The majority of clinical studies has examined the accuracy or otherwise of the diagnosis of myocardial ischemia utilizing fluctuation of the ST segments during either “spontaneous” ischemia or during provocative manoeuvres (e.g. exercise). As previously stated, the diagnostic accuracy of such analyses tends to be mediocre; when subjected to utility evaluation under Bayesian considerations, they often add little to history/physical examination. However, a number of potential refinements of 12-lead ECG analysis have been proposed, in order to improve both detection and as well as localization and quantitation of ischemia. These include evaluation of a variety of the component waveforms of both the QRS complex and the ST segment of the ECG. Current experiments The currently described series of investigations arose from preliminary findings that myocardial ischemia in a canine model was associated with transient fluctuations in QRS entropy. Both evaluations performed related to the hypothesis that reversible myocardial ischemia causes transient increases in entropy within QRS complexes and ST segments of the human 12-lead ECG. A series of preliminary experiments suggested that such changes did indeed occur, mainly within the ST segment. The first series of experiments performed compared conventional continuous ST segment analysis within the 12-lead ECG is vs. continuous evaluation of entropy-derived parameters for the localization of ischemia induced by balloon inflation during non-emergency coronary angioplasty. In a series of 103 patients, localization of ischemia was similarly accurate for the entropy-based method and the ST segment assessment method. Ischemic zones were correctly localized by these approaches in 88% and 80% of cases, respectively (p not significant). There was poor concordance between the extent of ST elevation and changes in ST segment entropy. In a small subset of patients with complete bundle branch block and/or ST depression on resting ECG (n=22), entropy-based localization of ischemia was possible in 55% of cases compared with 41% via ST segment assessment (difference not significant). Post hoc analysis revealed that entropy fluctuations arose throughout the ST segment rather than predominantly at the J-point. The second series of experiments was carried out on patients undergoing pacing-induced provocation of possible myocardial ischemia, with scanning via myocardial perfusion imaging (SPECT) examination. As with the first series, 12-lead ECG recording and ST trend monitoring were performed during the pacing procedure. The ST segment deviation and the entropy-based analyses were used for localization of possible ischemia. Data analyses were correlated with myocardial perfusion imaging results. A total 43 patients were studied. Categorization of ischemia via ST segment assessment had only 30% concordance with myocardial perfusion imaging results, while entropy-based analyses had 58% concordance. Therefore neither “conventional” (i.e. ECG-based ST segment analysis) nor novel entropy-based analyses are currently of clinical utility for detection of tachycardia-induced ischemia. / Thesis (M.Med.Sc.) - University of Adelaide, School of Medicine, 2008

Diss. (sammanfattning) Umeå : Univ., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Virginia Commonwealth University, 2008. / Prepared for: School of Pharmacy. Bibliography: leaves 170-178. Available online via the internet.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 123-130).

Hypothesis: Glucose is known to be protective in moderate low flow ischaemia due to the production of glycolytic ATP. However, it is questioned whether glucose would still be protective in ultra-low flow ischaemia. Firstly, glycolysis is thought to be inhibited, and secondly, deleterious glycolytic metabolites accumulate. Our hypothesis was that in ultra-low flow ischaemia, glucose utilisation is not inhibited at the level of glycolysis, but by delivery. Increased delivery of glucose should result in increased production of protective glycolytic ATP, but the rate of metabolite accumulation would also increase. Using ultra low flow rates, I wished to investigate how to achieve optimal rates of glycolysis, and how such rates would be balanced by any detrimental component of metabolite accumulation. Methods: The isolated Langendorff-perfused rat heart, with a left ventricular balloon to record ischaemic contracture and reperfusion stunning, was used, with severe flow restriction. Glucose concentrations were changed and pre-ischaemic glycogen contents were altered by perfusion with different substrates (acetate - depletion~ glucose + insulin - loading) or by preconditioning, with 5 min ischaemia and 5 min reperfusion prior to sustained ischaemia. Results: Analysis of glucose uptake relative to delivery showed that in severe low flow ischaemia, the extraction of glucose was increased, and glycolysis was thus limited more by substrate supply than by enzyme inhibition. Analysis of metabolites confirmed this concept. The optimal glucose concentration during severe low flow ischaemia was 11 mM, giving maximal recovery on reperfusion. Both lower and higher glucose concentrations increased ischaemic contracture. Changes in pre-ischaemic glycogen levels correlated with the time to onset of contracture, such that a reduction in glycogen accelerated contracture. Prior glycogen depletion or loading did not improve functional recovery. The benefits of preconditioning on reperfusion function following sustained total global ischaemia could not be related to glycogen depletion. If preconditioning were followed by sustained low flow ischaemia, glucose uptake was increased, but no benefit was found, possibly because a low residual flow abolished the effects of preconditioning. Many of the above results are consistent with the hypothesis that too low a rate of glycolysis results. in insufficient ATP production for protection, while excess glycolytic rates lead to excess metabolite accumulation with detrimental effects. Conclusions: Provision of glucose at the correct concentration, when the benefit associated with glycolytic ATP outweighs the detriment associated with moderate metabolite accumulation, is protective to the low-flow ischaemic myocardium, which can upregulate its ability to extract glucose. Improved residual flow enhances this benefit. Prior glycogen depletion is not beneficial, despite a reduced metabolite accumulation. This mechanism cannot be related to the protective effect of preconditioning.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.