With the increased marketing and popularity of a range of dairy products in recent years, research has become widespread concerning the influence of dairy on human health. It is also becoming evident that an individual’s genetic make-up contributes to shaping their health responses to dietary intakes. This research was primarily designed to investigate the impact of genetic variability on responsiveness of cholesterol metabolism, a classic biomarker of cardiovascular health, to the recommended level of dairy consumption in Canada. A secondary objective was to assess the influence of dairy intake on systemic inflammation as an emerging risk factor for cardiovascular disease. In a multicentre, randomized, free-living crossover design, 124 healthy individuals consumed 3 servings/day of conventional low-fat and regular milk, yogurt, and cheese (DAIRY diet) or dairy-free control products (CONTROL diet), each for 28 days as part of a prudent background dietary protocol. At the end of the study, DAIRY was associated with increased plasma concentrations of two established fatty acid biomarkers of dairy fat, pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0), as well as with small increases in serum total cholesterol (TC) and LDL-cholesterol (LDL-C) concentrations. Inter-individual variability in the cholesterol transport gene ABCG5, bile acid synthesis gene CYP7A1, and cholesterol synthesis gene DHCR7 contributed to shaping the degree of TC and LDL-C responsiveness to DAIRY; with higher cholesterol concentrations observed among ABCG5 rs6720173-G/G homozygotes, CYP7A1 rs3808607-G allele carriers, and DHCR7 rs760241-A allele carriers, relative to the C allele, T/T, and G/G carriers of these genes, respectively. Also, after DAIRY, the major allele T homozygosity of CYP7A1 rs3808607 and the minor allele A of DHCR7 rs760241 were associated with reduced plasma [3,4]13C cholesterol enrichment and deuterium incorporation, respectively, suggesting reduced cholesterol absorption and synthesis rates. DAIRY intake did not influence the inflammatory status. Overall, this research has provided evidence of a potential impact of the genomic architecture on responsiveness of cholesterol metabolism to dairy consumption. The novel findings are expected to advance knowledge of the inherited basis by which health biomarkers may be modified in response to whole foods, hence launching an important step towards an era of personalized nutrition. / February 2016

Based on accumulating evidence, adequate intake of whole grains is associated with reduced cardiovascular disease CVD risk. Germinated brown rice (GBR) has been used in East Asian countries as an alternative grain. Preliminary studies suggest GBR has potential health benefits, including reducing CVD risk, but the mechanism remains unclear. The hypothesis of the project is that long-term consumption of GBR would reduce atherogenic risk factors in low-density lipoprotein receptor knockout (LDLr-KO) mice. To test the hypothesis, three groups of male LDLr-KO mice were fed with one of the following diets for 24 weeks: (a) commercial mouse chow, used as the control diet; (b) chow was replaced with 60% (w/w) Chinese white rice (CWR); and (c) chow was replaced with 60% (w/w) GBR. All diets were supplemented with 0.06% (w/w) dietary cholesterol to accelerate atherogenesis. Blood samples, hearts, livers and feces were collected and used for biochemical and histological analyses. The results demonstrated that no significant difference was detected in body weights, plasma or fecal lipid profiles and antioxidant enzyme activities among groups. However, GBR consumption significantly decreased atherosclerotic lesion (P = 0.003) in the aortic roots as compared with that in the CWR group, but there was no significant difference as compared with that in the control group (P = 0.4). In addition, GBR significantly decreased monocyte adhesion to the aorta in LDLr-KO mice as compared to that in the CWR group (P=0.0001), but not with the control group. These data suggested that GBR may be beneficial for the prevention of vascular inflammation and atherogenesis in LDLr-KO mice. Additional studies in animal models and humans may further investigate the mechanisms of the beneficial effects of GBR on vascular inflammation and atherogenesis. / May 2017

The aim of this study is to investigate knowledge, perceptions and attitudes towards cardiovascular diseases and obesity among men and women and current health strategies in Babati, Tanzania. The results of this study can contribute to answers about where focus needs to be added for preventive health interventions. In order to answer the research questions of this study, a qualitative field study was conducted in Babati town, Tanzania during three weeks in February and March 2017. The theoretical framework used in this study is the Theory of planned behavior, a psychological theory that explains human behavior that is used to understand people’s behavior and decision making. The findings of this study shows that people in Babati have a substantial knowledge, which shows that knowledge does not play an important role in the fight against NCDs since it is increasing anyway. People have a negative attitude towards these diseases but claims that there is still people that has a positive attitude. This study conclude that the main problem is people’s behavior and accepting a lifestyle change rather than lack of knowledge as previous research claims.

A spinal cord injury is a serious medical condition, often caused by a physical trauma. An injury to the spinal cord affects the neurotransmission between the brain and spinal cord segments below the level of injury. The SCI causes a loss of motor function, sensory function and autonomic regulation of the body, temporary or permanent. Significantly improved acute care, primary comprehensive rehabilitation and life-long structured follow-up has led to persons with spinal cord injury (SCI) living longer than ever before. However, increased long-time survival has allowed secondary conditions to emerge, like diabetes mellitus and where cardiovascular disease (CVD) now is the most common cause of death among SCI patients. Other possible CVD-related comorbidities in this patient group have been reported to be pain and mood disturbances. There is still lack of, and need for more knowledge in the field of CVD-related screening and prevention after SCI. The overall aim of this thesis was to contribute to a scientific ground regarding the need for CVD-related screening and prevention after SCI. In Paper I and Paper II, patients with wheelchair-dependent post-traumatic SCI (paraplegia) were assessed. The results in paper I showed that 80% of the examined patients had at least one cardiovascular disease risk marker irrespective of body mass index (BMI). Dyslipidemia was common for both men and women at all BMI categories. The study also showed a high prevalence of hypertension, especially in men. Paper II showed a low frequency of self-reported physical activity, where only one out of 5 persons reported undertaking physical activity >30 min/day. The physically active had lower diastolic blood pressure but no significant difference in blood lipids. In paper III and IV, patients with SCI (tetraplegia and paraplegia) participated in the studies. Eighty-one percent of the patients had dyslipidemia, where also a majority of the patients with normal abdominal clinical measures had dyslipidemia. Self-reported physical activity >30min/day was reported by one third of the patients. No differences were found between physically active and not physically active patients when it came to blood glucose, serum lipid values and clinical measures (paper III). Pain was common in the patient group, however, most often on a mild to moderate level. Anxiety and depression was less common than reported in other studies (paper IV).

Although death due to lethal cardiac arrhythmias is the leading cause of mortality in Western Society, many of the fundamental mechanisms underlying their onset, maintenance and termination, still remain poorly understood. In recent years, experimental techniques such as optical mapping have provided useful high-resolution recordings of cardiac electrical dynamics during complex arrhythmias and defibrillation episodes, which have been combined with detailed computer simulations to further our understanding of these phenomena. However, mechanistic enquiry is severely restricted as the optical mapping technique suffers from a number of distortion effects which compromise the fidelity of the experimental measurements, presenting difficulties in the comparison of experimental data with computational simulations. This Thesis presents a thorough investigation into the distortion effects encountered in optical mapping experiments, guided by the development of a coherent series of computational models. The models presented successfully characterise the specific mechanisms of fluorescent signal distortion due to photon scattering. Photon transport in cardiac tissue is modelled using both continuous (reaction-diffusion) and discrete stochastic (Monte Carlo) approaches to simulate the effects of photon scattering within the myocardium upon the recorded fluorescent signal, which include differing levels of detail and associated computational complexity. Specifically, these models are used to investigate the important role played by the complex ventricular structural anatomy, as well as the specifics of the experimental set-up itself. In addition, a tightly coupled electromechanical model of a contracting cardiac fibre is developed which provides an important first-step towards the development of a model to quantitatively assess the distortion observed when recording from a freely contracting cardiac preparation. Simulation of these distortion effects using the models allows discrimination to be made between those parts of the experimental signal which are due to underlying tissue electrophysiology and those due to artifact, facilitating a more accurate interpretation of experimentally-obtained data. The models presented succeed in two main respects. Firstly, they provide a ‘post-processing’ tool which can be added on to computational simulations of electrical activation, allowing for a more accurate and faithful comparison between simulations and experiments, helping to validate predictions made by electrical models. Secondly, they provide a higher degree of mechanistic insight into the fundemental ways in which optical signals are distorted, showing how this distortion can be maximised or controlled. The understanding and quantification of the fundemental mechanisms of optical mapping signal distortion, provided by this Thesis, therefore fulfils an important role in the study of arrhythmia mechanisms.

Strategies to reduce infarct size in ischaemia-reperfusion (IR) syndromes such as acute myocardial infarction are of high clinical and scientific interest. Remote ischaemic preconditioning (rIPC) is one such strategy but its mechanisms remain incompletely understood. Multiple lines of evidence from animal studies suggest that the endogenous purine nucleoside adenosine is a key mediator of preconditioning pathways but no evidence exists as to adenosine’s role in the more complex physiology of humans. The work in this thesis aims to elucidate the role of endogenous adenosine in the physiological phenomenon of rIPC and to examine the role of exogenous adenosine in triggering preconditioning-like states. In a randomised, placebo controlled study using healthy volunteers and the human forearm model of ischaemia-reperfusion injury, I demonstrate that delivery of the adenosine receptor antagonist caffeine, prior to the initiation of a rIPC stimulus abrogates the protective effect of rIPC on IR. By then selectively infusing caffeine to achieve high local but low systemic concentrations, I also demonstrate that adenosine receptor activation is important in the ‘trigger’ phase of rIPC rather than in the ‘effector’ phase and that blockade of the trigger phase effectively inhibits the release of a circulating humoral protective factor. These studies provide evidence of the crucial role of adenosine receptor activation in human rIPC, demonstrating their sites of action and illuminating their potential mechanism of action. To study whether exogenously delivered adenosine can recapitulate preconditioning-like states, in initial studies in a large mammal model of acute myocardial infarction, I demonstrate that adenosine, given after the onset of ischaemia, but prior to reperfusion, significantly reduces myocardial infarct size. In a subsequent study, translating these findings to humans with coronary disease, I demonstrate that the delivery of adenosine in a range of concentrations is able to illicit the release of a circulating preconditioning factor which is transferrable across species and can reduce infarct size in a murine model of myocardial IR.

Marfan syndrome (MFS) is the commonest inherited disorder of connective tissue and is associated with a high risk of potentially life-threatening complications, including aortic aneurysm, dissection and rupture, and, perhaps, ventricular disease. This work describes the prospective application of advanced cardiovascular magnetic resonance techniques to the aorta and heart of consecutive, unselected subjects with MFS, and to appropriately matched control populations. Comprehensive 3D visualisation of blood flow in the entire thoracic aorta of subjects with MFS was achieved using a time-resolved phase-contrast magnetic resonance technique with 3-directional velocity encoding (4D flow), demonstrating a high prevalence of major flow disturbance (87 ± 12%), compared to controls (28 ±18%), localising to those regions of the aorta known to be most prone to aortic dissection (sinuses of Valsalva and proximal descending aorta). Wall shear stress, recently identified as a potentially important determinant of aneurysm progression and rupture, was interrogated in these datasets at the sinuses of Valsalva (SOV), ascending aorta (AA), arch, and proximal (PDA) and distal descending aorta (DDA), using the 4D flow datasets, and was shown to be significantly reduced at each location (SOV -15%; AA -12%; Arch -17%; PDA -18%; and DDA -14%, p<0.05 for each), in subjects with MFS compared to healthy subjects. 4D flow datasets were used to generate relative pressure maps in healthy subjects and in subjects with several aortic diseases. A novel method for the separate evaluation of the components of relative pressure was applied, revealing marked differences in the relative contribution of the components of pressure (unsteady > convective >> viscous), and characteristic differences between subjects in overall relative pressure, and its components. Left ventricular volumes and function were evaluated in subjects with MFS, and did not differ significantly from healthy subjects in the absence of significant valvular regurgitation and / or shunt. Left ventricular end-diastolic volume varied markedly with degree of regurgitation (r=0.75, p=0.0001). The mechanistic implications of these findings, and the potential role of these techniques in the evaluation of cardiovascular disease, are discussed.

This study determined whether pre-operative exercise and education (PREHAB) improves the frailty status and physical activity behaviour of older adults undergoing elective cardiac surgery, more than standard care (StanC). Using a subset of patients from a multi-centre trial (NCT02219815), twenty-six patients over the age of sixty were randomized to receive StanC (n=12) or PREHAB (n=14). Blinded research assistants collected data at baseline prior to randomization and one week pre-operatively. Changes in frailty were assessed using a 30-item functional frailty index (FFI); whereas, changes in physical activity behaviour were assessed using accelerometers. Baseline data was not different between groups. Frailty status improved by 17%, 5% and 35% amongst StanC, PREHAB “non-completers” and PREHAB “completers”, respectively. No changes in moderate to vigorous physical activity were found pre-operatively. These data suggest that the PREHAB intervention is feasible to implement and may result in improved frailty status amongst frail older adults awaiting elective cardiac surgery. / October 2016

Changes in myocardial energetics have been implicated in the pathophysiology of heart failure (HF). However, the precise contribution of creatine (Cr) / phosphocreatine (PCr) / creatine kinase (CK) energy buffer and transfer remains unclear. The aim of this thesis was to study the effects on murine cardiac function of both impairment and enhancement of creatine metabolism. In order to longitudinally follow the cause and effect relationship of myocardial creatine concentration, a non-invasive method of quantification was required. Cardiac Cr levels measured in vivo by 1H-MRS were therefore compared with gold-standard invasive HPLC and found to correlate over a wide-range (r2=0.91). 1H-MRS was reproducible for measuring Cr levels in the heart, brain, and skeletal muscle. The cardiac phenotype of a novel model of creatine depletion, the AGAT-/- mouse, was characterized using in vivo MRI, 1H-MRS and LV catheterisation, under conditions of gradually reducing Cr concentrations; zero Cr; and attempted phenotype rescue with dietary Cr. For the first time in the heart, the rate of Cr turnover was quantified (~3 % per day) and demonstrated that cardiac function was preserved even when creatine levels reduced by ~70-90%. Total absence of myocardial Cr induced impairment of inotropic and lusitropic cardiac function and reduced inotropic reserve. Cardiac dysfunction was only partially rescued by replenishment of the Cr pool, suggesting this to be a consequence of long-term adaptations to chronic low Cr. Finally, we tested the hypothesis that combined elevation of myocardial creatine and ribose would be beneficial in a mouse model of chronic HF by increasing cardiac energy availability. Despite an increase in myocardial ribose concentration, this did not prevent loss of total adenine nucleotides (TAN), and there was no improvement in post-infarct LV remodeling or function. Future studies are needed to explore alternative approaches for maintaining TAN in combination with total creatine.

The relationship between cardiovascular disease and hearing loss has already been proven. However literature does not provide information on the prevalence of hearing loss in adults with cardiovascular disease. Previous studies provide contradictory information regarding the audiological characteristics in this population. Data relating to the South African context is minimal. The objectives of this descriptive survey research study were to describe the prevalence of hearing loss in adults with this cardiovascular disease and determine the variables which may influence hearing thresholds in this population. Ninety two individuals diagnosed with coronary artery disease or cardiomyopathy were recruited using a non-probability, purposive sampling strategy. This sample, with an average age of 48 years and five months, consisted of more males than females and more participants with coronary artery disease than cardiomyopathy. Participants underwent a comprehensive audiological evaluation including an otoscopic examination, immittance audiometry, pure-tone audiometry, speech audiometry, as well as distortion product otoacoustic emissions. Content analysis, descriptive statistics, t-tests and an analysis of covariance revealed a hearing loss prevalence of 5%. These participants presented with a low frequency sensorineural hearing loss with the right ear being more affected. It was found that duration of cardiovascular disease influenced hearing thresholds. Implications of this study include the importance of prevention and early identification of hearing loss. This highlights the need to establish the role of audiologists within a multi-disciplinary team and the management of individuals with this disease.