Microvascular dysfunction is believed to precede the development and contribute to the progression of obesity related diseases such as insulin resistance, hypertension, and coronary artery disease. Multiple studies have found impaired microvascular endothelium-dependent vasodilation occurs prior to the onset of disease in middle aged adults. In order to test the hypothesis that the cutaneous microvasculature of young obese (BMI>30kg/m²), but otherwise healthy, adults would exhibit impaired microvascular response, we recruited 12 obese and 12 lean (BMI<25 kg/m²) individuals. Each group was age-matched and consisted of 5 females and 7 males. Each participant was instrumented with two microdialysis probes inserted in the dermis of the non-dominant forearm for a wide dose range of infusions of either the endothelium-dependent vasodilator methacholine (MCh) or the endothelium-independent vasodilator sodium nitroprusside (SNP). Each microdialysis site was clamped at 33°C with a local heater and affixed with a laser Doppler flux (LDF) probe for determination of local red blood cell flux, an index of blood flow. LDF was recorded continuously while 7 doses of each drug (MCh: 10⁻³-10³mM; SNP: 5x10⁻⁵-50mM) were infused at a rate of 2 [mu]l/min for 8 minutes per dose. Both sites finished with heating to 43°C and infusion of 50mM SNP to confirm site specific maximal vasodilation. Blood pressure was recorded in the last minute of each stage and the corresponding LDF was used to calculate cutaneous vascular conductance (CVC). Dose response curves for CVC at each dose, as well as maximal CVC were analyzed. MCh dose response showed a trend toward endothelium–dependent impairment in obese (p=0.06) and maximal absolute CVC at the MCh site was attenuated in obese versus lean (2.70 ± 0.73 vs 3.30 ± 0.81 LDF/mmHg, p=0.027). Endothelium-independent vasodilation with SNP was impaired at the 4 highest doses of SNP (all P<0.006) and maximal CVC was attenuated in obese compared to lean (2.44 ± 0.74 vs 3.31 ± 0.65 LDF/mmHg, p=0.004). These results support the hypothesis that microvascular function is impaired in young, healthy obese, individuals; however they suggest the impairment is partially endothelium-independent. / text

African Americans (AA) are at an increased risk for cardio and cerebral vascular disease relative to Caucasians (CA) and the underlying impairments manifest as early as the second generation prior to overt signs of risk. The mechanisms of this increased risk are multifactorial; however, evidence suggests that microvascular dysfunction is a primary contributor. This study tested the hypothesis that microvascular function, indexed by the skin vascular conductance (SkVC) response to local heating, is impaired in young otherwise healthy AAs. Furthermore, we hypothesized that AAs have an attenuated cerebral vasodilator response to hypercapnia. Nineteen healthy young individuals were participated in this study (9 AAs, 10 CAs). SkVC was assessed while the skin was clamped at 34 °C and 40 °C and values were normalized to a maximal value obtained during heating at 43 °C for 30 min. Cerebral vasomotor reactivity (CVMR) was assessed by increases in cerebral vascular conductance (CVC) during a rebreathing protocol. SkVC was lower in the AA group at 34 °C (AA: 10±3 % max vs. CA: 16±7 % max; P < 0.01) In addition, SkVC was reduced in AAs at 40 °C (AA: 56±15 % max vs. CA: 68±12 % max; P=0.03). CVMR was significantly attenuated during hypercapnic rebreathing in AAs relative to CAs (AA: 2.8 ± 1.2 %CVC/Torr vs. CA: 5.7 ±0.9 %CVC/Torr; P < 0.001). Our findings suggest that microvascular function is impaired in young otherwise healthy AAs. / text

Previous reports have demonstrated that children’s physical activity is typically intermittent in nature. Accelerometers are reliable and valid tools for quantifying the pattern of activity in children. However, in order to interpret accelerometer output it is necessary to apply appropriate accelerometer thresholds for classifying physical activity intensity. Currently multiple accelerometer thresholds are available in the literature and it is unclear which are the most appropriate or whether thresholds should be sample specific. Additionally, there is little information regarding how the pattern of activity in children varies across groups and how activity patterns relate to health. The overall aim of the thesis was to describe the pattern of habitual physical activity, using objectively-measured physical activity data, in relation to health outcomes in pre-adolescent boys. The first objective was to characterize the pattern of boys’ habitual physical activity, using objectively-measured physical activity data. The second objective was to investigate the relationship between habitual physical activity and specific aspects of the activity pattern and health outcomes in boys. The final objective was to investigate the effects of continuously- versus intermittently- accumulated physical activity on acute health outcomes in boys, using an intermittent activity protocol based on the measured pattern of habitual activity in boys. The first four studies used a sample of 54 boys, aged 8 to 10 years. The final study used a different sample of 10 boys, aged 9 to 11 years. Both samples were from the county of Devon, UK. The first study of this thesis established sample-specific accelerometer-intensity thresholds through calibration research with ActiGraph accelerometers (counts•2s-1) in boys. The second study in the thesis demonstrated that relationships between time accumulated at different activity intensities and health (fatness, peak oxygen consumption and resting blood pressure) in boys were similar irrespective of whether sample-specific or published thresholds were employed as long as the threshold was at least equivalent to a brisk walk (i.e. >4 METs). However, the prevalence of children reported as meeting activity guidelines did differ according to thresholds employed. Study three showed that, despite little difference between overweight and normal weight boys in overall activity, time spent sedentary and minutes of light, moderate and vigorous intensity activity accumulated, aspects of the activity pattern (frequency, intensity and duration of ≥4 s (short) and ≥5-min (long) bouts of ≥light, ≥moderate, ≥vigorous and ≥hard intensity activity) differed by weight status. Overweight boys accumulated fewer and shorter bouts of activity, particularly sustained bouts of activity which were of moderate intensity or greater. Study four examined the relationship between activity pattern and health in boys further, focusing on body fatness, aerobic fitness, blood pressure and microvascular function. Results demonstrated that summary measures of activity were negatively related to body fatness, and positively related with both aerobic fitness (i.e., total, moderate, vigorous and hard activity) and endothelial function (i.e., total and light activity). Time spent sedentary was negatively related to endothelial function. The frequency and duration of activity bouts of ≥moderate intensity and the intensity of all activity bouts (i.e., ≥light intensity) were most important for body fatness and aerobic fitness. The frequency of all bouts (short and long) of at least light intensity was most important for endothelial health. Finally, study five moved away from chronic measures of health and examined the acute physiological effects of the recommended daily amount of physical activity (60 minutes of physical activity of ≥moderate intensity) on postprandial lipaemia and microvascular function in boys the following day. Furthermore, the study aimed to assess whether the effects differed depending on whether the activity was accumulated continuously or in a manner more similar to the children’s typical activity patterns identified in studies 3 and 4. In contrast to findings from adolescents and adults, 60 minutes of >moderate intensity activity did not impact on postprandial lipaemia or microvascular function the following day in healthy, active boys, regardless of how it was accumulated. The results of the present thesis indicate that aspects of the activity pattern are significantly related to health in boys and differ according to type of day and weight status. Furthermore, the benefits of sporadically-accumulated activity are equally as strong as continuously-accumulated activity to body fatness, aerobic fitness and endothelial health in boys. Since children typically accumulate short, intermittent bouts of activity, the promotion of sporadic activity (i.e., in intervention research and current physical activity guidelines for children and youth) might increase enjoyment and adherence. The benefits of acute intermittent exercise (which simulates free-living activity) on postprandial lipaemia and microvascular function in inactive children with risk factors for cardiovascular disease should be investigated. Longitudinal investigations into the activity pattern of a much larger and more age-diverse sample of boys and girls are needed to determine whether any changes in aspects of the activity pattern might alter these and other health outcomes (i.e., cardiovascular risk factors).

In recent times the potential impact of preeclampsia on the cardiovascular health of offspring has been identified. This thesis explores the relationship between preeclampsia and offspring cardiovascular phenotype during the first three decades of life. A systematic review and meta-analysis provided evidence that there was increased blood pressure and BMI in the offspring of preeclamptic pregnancies (n = 45,249). There was however limited data on metabolic features and inadequate characterisation of the degree of prematurity or growth restriction in existing literature. I therefore studied data on two birth cohorts with up to 28 years of detailed prospective follow up (n = 2868 and n = 926). Those born very preterm to preeclamptic pregnancies had transient perinatal reductions in insulin and cholesterol, although extreme prematurity was the only determinant of variation in cardiovascular risk in later life, with changes in both metabolism and blood pressure. In those born closer to, or at term, gestation was no longer relevant and an independent impact of preeclampsia on blood pressure was evident, so that by age 20, those born at term to preeclamptic pregnancies were four and a half times more likely to demonstrate clinically-apparent hypertension. I then investigated whether there were changes in other features of cardiovascular phenotype, independent of blood pressure, in preterm neonates born following preeclampsia (n = 46). At 3 months of age preterm infants born to hypertensive pregnancies had subclinical alterations in cardiac strain, independent of gestation or birth weight but not differences in blood pressure, or microvascular structure. These findings highlight preeclampsia and prematurity as key, independent perinatal factors, important in determining cardiovascular phenotype and risk during early life. Preeclampsia is associated with a specific lean, hypertensive phenotype, associated with cardiac functional alterations; these findings begin to define a distinct at risk population who may require targeted preventative interventions.

Contexte L’américanisation des habitudes de vie, notamment de l’alimentation, semble être en grande partie responsable de l’augmentation incessante de l’incidence élevée des maladies cardiovasculaires. La période postprandiale, où l’homéostasie vasculaire et métabolique est mise à l’épreuve, est d’une importance considérable dans le développement ou la prévention de l’athérosclérose et représente maintenant la majeure partie du temps d’éveil. La compréhension de l’influence de la composition d’un repas sur son impact postprandial est donc essentielle dans notre lutte dans la prévention de ces maladies. Objectifs L’objectif principal de ce projet de recherche était d’étudier les réponses endothéliale et métabolique à un repas de type méditerranéen mixte (MMM), puisqu’elles sont inconnues. Ce projet avait aussi pour objectifs d’évaluer l’impact microvasculaire d’un tel repas et de caractériser la composition postprandiale des acides gras plasmatiques. À titre comparatif, ces éléments ont aussi été étudiés suite à un repas riche en gras saturés (HSFAM). Méthodes Vingt-huit (28) hommes sains, exempts de facteurs de risque de maladies cardiovasculaires ont reçu de façon randomisée les deux repas à l’étude. Le MMM, composé de saumon frais et de légumes cuits dans l'huile d'olive, contenait 7.87g de SFA et 2.29g d’acides gras polyinsaturés oméga-3, tandis que le HSFAM, composé d'un sandwich déjeuner avec œuf, saucisse et fromage, contenait 14.78g de SFA. Les mesures de la fonction endothéliale mesurée par échographie brachiale (FMD), de la fonction microvasculaire mesurée par spectroscopie proche de l’infrarouge (NIRS) et de la composition des acides gras plasmatique ont été effectuées à jeun et en période postprandiale. Résultats Deux sous-groupes de répondeurs aux repas à l’étude se sont dégagés de ces travaux. Un premier sous-groupe de sujets ayant une triglycéridémie à jeun élevée, mais normale (hnTG) a démontré des altérations endothéliales seulement suivant le repas HSFAM. Un second sous-groupe de sujets ayant une triglycéridémie plus faible et normale (lnTG) n’a quant à lui pas subi d’altérations endothéliales suivant les deux repas à l’étude. Les sujets hnTG ont aussi démontré une charge triglycéridémique postprandiale (iAUC) plus importante et qui était de surcroît enrichie en acide stéarique suivant la HSFAM et en acide gras polyinsaturés oméga-3 suivant le MMM. L’évaluation par NIRS de la fonction microvasculaire nous révèle un ralentissement de la réoxygénation post-ischémique qui suggère une altération postprandiale du recrutement capillaire chez les sujets hnTG seulement. De telles altérations, qui semblent être plus importantes suivant le HSFAM, pourraient être en partie responsables de l’impact endothélial de ce repas. Conclusions Cet essai clinique démontre donc de façon novatrice qu’un repas MMM n’a pas d’effet endothélial délétère et que cette neutralité est indépendante de la triglycéridémie à jeun. De plus, une triglycéridémie à jeun élevée mais normale semble indiquer des dysfonctions endothéliales et métaboliques à des épreuves nutritionnelles tel un repas HSFAM. La consommation de repas méditerranéens par des individus sains à la triglycéridémie marginale serait bénéfique, peut-être même davantage que pour des individus de triglycéridémie plus faible, dans la prévention de l’athérogénèse et des maladies cardiovasculaires. / Background The Westernization of lifestyles, notably dietary habits, seems to be largely responsible for the ongoing increase of incidence of cardiovascular diseases. The postprandial period, where vascular and metabolic homeostatic regulating processes are under pressure, is of considerable importance in the development or prevention of atherosclerosis and now represents the majority of waking hours. The understanding of the postprandial effects of meals of varying composition is therefore essential in our effort to prevent such diseases. Objectives The main objective of this research project was to study the endothelial and metabolic responses to a mixed Mediterranean meal (MMM), since they are unknown. This project also aimed to evaluate the microvascular impact of such a meal and to characterize the composition of postprandial plasma fatty acids. These elements were also evaluated following a saturated fatty meal (HSFAM) for comparison. Methods Twenty-eight (28) healthy men free of cardiovascular diseases and risk factors were randomly assigned one of two test meals. The MMM, consisting of fresh salmon and vegetables cooked in olive oil, contained 7.87g of SFA and 2.29g of omega- 3 fatty acids, while the HSFAM, consisting of a breakfast sandwich with egg, sausage and cheese contained 14.78g of SFA. Evaluations of endothelial function by brachial ultrasound (FMD), of microvascular function by near-infrared spectroscopy (NIRS) and of plasma fatty acids composition were done in the fasted and postprandial states. Results Two subgroups of responders to the test meals emerged from this work. A first subgroup of subjects with high-normal fasting triglyceridemia (hnTG) experienced impairments of endothelial function following the HSFAM while a second subgroup of subjects with low-normal triglyceridemia (lnTG) did not experience any endothelial alterations following this meal. Interestingly, the MMM had no deleterious endothelial impact in any of those subgroups. Moreover, the hnTG subjects demonstrated greater postprandial triglyceridemic load (iAUC) that was in addition enriched with stearic acid after HSFAM and omega-3 PUFA following the MMM. Assessment of microvascular function revealed postprandial prolongation of post-ischemic reoxygenation only in hnTG subjects suggestive of alterations of capillary recruitment. These changes, which seemed to be more important after the HSFAM, could be partly responsible for its negative impact on FMD. Conclusions This clinical trial demonstrates in innovative ways that a MMM has no deleterious effects on endothelial function irrespective of triglyceridemia in normal ranges. In addition, high but normal fasting triglyceride levels suggest metabolic and endothelial dysfunctions following nutritional challenges such as a HSFAM. Consumption of Mediterranean meals by healthy individuals with marginal triglyceride levels would be beneficial, perhaps even more so than for individuals with lower triglyceride levels, in preventing atherogenesis and cardiovascular diseases.

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Les maladies cardiométaboliques sont les principales causes de décès dans le monde, et au Canada elles sont responsables d'environ 700 000 décès par année. Le diabète de type 2 et la maladie coronarienne sont les maladies cardiométaboliques les plus répandues. Malgré des avancées pharmacologiques, la prévalence de ces maladies demeure élevée, ce qui souligne l'importance des thérapies complémentaires qui améliorent le contrôle glycémique ainsi que la fonction vasculaire afin de prévenir les complications liées à ces maladies. Depuis quelques années, l’exposition à la chaleur reçoit une attention accrue pour son potentiel thérapeutique. En outre, des études scientifiques suggèrent que l’exposition à la chaleur pourrait diminuer la glycémie et améliorer la fonction vasculaire. Cependant, le potentiel thérapeutique de l'exposition à la chaleur demeure sous-étudié chez les personnes atteintes du diabète de type 2 ou de la maladie coronarienne. L’objectif général de cette thèse était d’évaluer les effets aigus de l’exposition à la chaleur sur des marqueurs de la fonction cardiométabolique auprès de gens ayant un diabète de type 2 ou une maladie coronarienne. L’article 1 a déterminé l’effet aigu d’une immersion en eau chaude sur la sensibilité à l’insuline, la fonction vasculaire, les concentrations des protéines de choc thermique plasmatique (eHSP70/90) et intracellulaire (iHSP70/90), les marqueurs inflammatoires (IL-6, IL1-RA, NFKB) ainsi que sur les médiateurs de l'action de l'insuline (IRS-1, GLP-1) comparativement à une immersion thermoneutre au sein d’une population ayant le diabète de type 2. Les résultats démontrent qu’une immersion en eau chaude n’améliore pas la sensibilité à l’insuline, ni la fonction vasculaire et elle n’affecte pas les concentrations de HSP70 / 90 et les marqueurs inflammatoires. L’article 2 a déterminé l’effet aigu d’une exposition dans un sauna Finlandais sur la fonction vasculaire, des marqueurs de dysfonction endothéliale (VCAM-1, ICAM-1) et des marqueurs inflammatoires (IL-6, IL-10, TNF-α, IL-1β, CRP) auprès de personnes ayant une maladie coronarienne. Les résultats démontrent qu’une séance de sauna Finlandais améliore la fonction endothéliale et augmente la concentration circulante d’IL-6 sans affecter d’autres marqueurs inflammatoires (IL-10, TNF-α, IL-1β, CRP) ainsi que des marqueurs de dysfonction endothéliale. Combinées, les deux études de cette thèse démontrent que l’exposition passive à la chaleur n’améliore pas de façon aiguë les marqueurs cardiométaboliques chez les personnes diabétiques de type 2. Par contre, la chaleur exerce un effet bénéfique sur la fonction endothéliale chez les personnes ayant une maladie coronarienne. / Cardiometabolic diseases are the leading cause of death globally, and in Canada they are responsible for approximately 700 000 deaths each year. Type 2 diabetes and coronary artery disease are the most prevalent cardiometabolic diseases. Despite advancements in pharmacological treatments, the prevalence of these diseases remains high which underlines the importance of complementary therapies to prevent complications related to these diseases. In recent years, heat exposure has received attention for its therapeutic potential. Studies have demonstrated that heat exposure could be an effective method to decrease glycemia and improve vascular function. However, the therapeutic potential of heat exposure remains understudied in people with type 2 diabetes or coronary artery disease. The general objective of this thesis was to evaluate the acute effects of heat exposure on cardiometabolic markers in people with type 2 diabetes and coronary artery disease. The first article of this thesis determined the acute effect of hot water immersion on insulin sensitivity, vascular function, plasma (eHSP70 / 90) and intracellular (iHSP70 / 90) heat shock protein concentrations, inflammatory markers (IL- 6, IL1-RA, NFKB) as well as mediators of insulin action (IRS-1, GLP-1) compared to thermoneutral water immersion in a population with type 2 diabetes. Findings from this study demonstrate that acute hot water immersion does not improve insulin sensitivity, vascular function or affect HSP70 / 90 concentrations and inflammatory markers. The second article of this thesis determined the acute effects of Finnish sauna bathing on vascular function, markers of endothelial dysfunction (VCAM-1, ICAM-1) and inflammatory markers (IL-6, IL-10, TNF- α, IL-1β, CRP) in older adults with coronary artery disease. Results from this study demonstrate that one bout of Finnish sauna bathing improves endothelial function and increases the circulating concentration of IL-6 without affecting other markers of inflammation (IL-10, TNF-α IL-1β, CRP) or endothelial dysfunction. Combined, these results show that acute heat exposure does not acutely improve cardiometabolic markers in people with type 2 diabetes. On the other hand, heat exposure has a beneficial effect on endothelial function in people with coronary artery disease.