There is an association between the human microbiome and disease. Gut microbes metabolize dietary sources to release trimethylamine (TMA). TMA is absorbed and then oxidized by flavin monooxygenase 3 (FMO3) to form trimethylamine N-oxide (TMAO). Elevated TMAO is associated with increased risk of cardiovascular disease and type 2 diabetes; however, the causal nature is unclear. There is also limited evidence supporting the efficacy of strategies to reduce accumulation of TMAO. Therefore, the purpose of these studies is to determine the effects of increases in TMAO on cardiometabolic health. In study 1, healthy sedentary and endurance trained males consumed a high fat diet. Blood samples were obtained in a fasted state and every hour during a 4-hour high fat challenge. We hypothesized sedentary individuals would produce higher TMAO concentrations. In study 2, healthy sedentary individuals consumed an acute 1000 mg dose of choline (CHOL) and placebo (PLC). Fasted blood samples were collected, flow-mediated dilation (FMD) and oral glucose tolerance (OGT) were measured. In study 3, healthy sedentary individuals consumed 4-wks of CHOL and PLC. Fasted blood samples were collected, FMD and OGT were measured. We hypothesized acute and 4-wk choline supplementation would impair FMD and OGT. In study 1, neither fasting (1.49± 1.2 µM vs. 2.25 ± 1.4 µM, p>0.05) or postprandial TMAO changed significantly with the HFD in sedentary or endurance trained individuals even with the endurance group consuming more TMA dietary precursors. Study 2 found increased plasma TMAO concentrations after choline supplementation on day 1(PLC; 4.14 ± 2.6 μM vs. CHOL; 23.6 ± 33.8 μM, p=0.018) and day 2 (PLC; 5.13±4.9 μM vs. CHOL; 32.6±37.5 μM, p=0.082) however, there were no differences in OGT or FMD. Study 3 found no differences in FMD or OGT following 4-wks of choline consumption. In summary, there were no differences between sedentary and endurance trained individuals fasting or post-prandial TMAO. There was also no effect on acute or 4-wk supplementation of choline on FMD and OGT. More research is needed to understand effects of elevated TMAO on cardiometabolic health. / Doctor of Philosophy / For years, research has been performed to identify the health effects of eating large amounts of red meat on cardiovascular disease (CVD). Consuming red meat, fish, poultry and eggs increases a substance created during digestion and metabolism, called trimethylamine N-oxide (TMAO). Elevated TMAO has been associated with increased risk of CVD and type 2 diabetes but the direct causes are unknown. The purpose of these studies is to determine the effects of increases in TMAO on health in humans. Study 1 included healthy, sedentary and endurance trained males who consumed a high fat diet. Blood samples were collected to measure TMAO before and after a high fat meal. Study 2 included healthy, sedentary males and females who consumed 2 days of 1000 mg of choline, which is commonly found in red meat fish and eggs, and a placebo (carbohydrate) after subjects completed a series of tests to evaluate health. Study three included healthy, sedentary males and females who consumed 4-weeks of 1000 mg of choline per day and a placebo (carbohydrate). Following supplementation subjects underwent a series of tests to assess health. Overall, there were no differences found between sedentary and endurance trained individuals. Acute and 4-week supplementation of choline did not affect measures of blood sugar or blood vessel function.

La drépanocytose est une maladie génétique caractérisée par la présence d’une hémoglobineanormale. Les travaux de cette thèse visaient à caractériser les fonctions micro-et macrovasculaires chezles enfants atteints de la drépanocytose SS et SC et ses conséquence sur la sévérité clinique. Nosrésultats, réalisées sur une cohorte pédiatrique antillaise, démontrent que les fonctions micro-etmacrovasculaires étaient altérées chez les enfants drépanocytaires homozygotes (SS) et chez les enfantsSC par rapport aux enfants non malades. Ainsi il semble que les patients drépanocytaires présentent, etce dès le plus jeune âge, une défaillance vasculaire marquée. Plusieurs facteurs semblent être impliqués :(1) l’activation endothéliale chronique, (2) la faible biodisponibilité en monoxyde d’azote causée parl’installation d’un état de stress oxydatif et nitrosatif chronique, (3) l’altération du système nerveuxautonome avec un risque vasoconstricteur (4) la défense anti-oxydante sur-sollicitée et (5) le faible niveaud’activité physique. En outre, nos résultats indiquent que la dysfonction vasculaire était plus sévère chezles enfants SS comparé aux enfants SC. Le faible taux d’hémolyse et le moindre stress oxydatif,pourraient expliquer la meilleure fonction vasculaire chez les enfants SC. Cette interaction entre stressoxydatif et hémolyse semble jouer un rôle clefs dans le cercle vicieux de la physiopathologiedrépanocytaire. Dans cette cohorte pédiatrique, le degré de dysfonction vasculaire ne semble pasmoduler la sévérité clinique. Cependant une dysfonction vasculaire plus développée a probablement desconséquences néfastes sur la sévérité clinique dans la drépanocytose. / Sickle cell disease is the most common genetic disease in the West Indies that affectshemoglobin. Because of considerable heterogeneity in clinical outcomes, its complex pathophysiology isstill not totally understood. For many decades it was widely assumed that blood disorders were the solecause of vaso-occlusion. More recently blood vessel dysfunction also seem to be involved. But it isunclear whether vascular function is affected similarly in children with sickle cell anaemia (SS) and childrenwith sickle haemoglobin C (SC) disease. This study with a cohort of Guadeloupean children demonstratedthat microvascular reactivity is impaired already in sickle cell SS and SC children compared to healthychildren. Divers biological and physiological analysis revealed that there are many interacting factors, all ofwhich may contribute to vasculopathy: (1) chronic endothelial stress due to elevated blood flow level, (2)reduced nitric oxide bioavailability due to chronic hemolysis and oxidative stress, (3) altered autonomicnervous system activity with increase risque in vasoconstrictor activity, (4) saturated antioxidant activityand (5) limited physical activity known to improve vascular function. In this children cohort, vascularimpairments were not associated to clinical severity. However vascular dysfunction seems to beexacerbated in SS. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress andcould explain the better preserved microvascular function in this group. Learning more about the progressof vascular dysfunction in sickle cell disease seems to be essential. In advanced state it may possibleseriously worsen clinical severity.

Although blood viscosity is an important component in determining vascular function, it is often assumed constant. Emerging evidence linking individual differences in viscosity to cardiovascular disease casts doubt on this assumption. The purpose of this study was to determine the contribution of whole blood viscosity to key measures of vascular function. To address this aim as comprehensively as possible, first, whole blood viscosity was compared with traditional risk factors for cardiovascular disease. Then flow-mediated dilation (FMD), carotid-femoral pulse wave velocity (cfPWV), and carotid artery compliance were calculated either with or without blood viscosity taken into account. Lastly, we tested whether the removal of blood viscosity could influence well-established associations between age and vascular function. Blood viscosity and vascular function were measured in 97 adults ranging in age from 18-63 years. No significant differences were observed between whole blood viscosity and traditional risk factors for cardiovascular disease. Whole blood viscosity was not significantly correlated with FMD, cfPWV, and carotid compliance. As expected, age was positively correlated with cfPWV (r=0.65, p<0.001) and negatively correlated with FMD (r=-0.21, p<0.05) and carotid compliance (r=-0.45, p<0.01). Even after controlling for viscosity, these relationships remained statistically significant (cfPWV r=0.65, p<0.001; FMD r=-0.24, p<0.05; carotid compliance r=-0.44, p<0.05). These results indicate that whole blood viscosity does not appear to significantly impact measures of vascular function and that the rationale for including whole blood viscosity in the calculation of vascular function remains weak. / text

<p>Functional limitations place youth with cerebral palsy (CP) at an increased risk of physical inactivity and cardiovascular disease. The structure and function of the cardiovascular system of these adolescents has not been previously investigated. In the current cross-sectional study, endothelial function was assessed using flow-mediated dilation (FMD) in eleven adolescents with CP (age 13.2 ± 2.1 y) and compared to eleven healthy, age-and gender-matched control participants (12.4 ± 2.3 y). All participants with CP were ambulatory or ambulatory with assistive devices (lower leg brace) and classified as levels I-II according to the Gross Motor Function Classification System (GMFCS). Baseline arterial stiffness was examined through assessment of central and peripheral pulse wave velocity (cPWV, pPWV,) as well as carotid distensibility, a direct measure of central artery stiffness. A combination of B-mode ultrasound imaging and applanation tonometry was used to calculate carotid distensibility. Carotid intima-media thickness (IMT), a measure of vascular structure, was also quantified using B-mode ultrasound images and a semi-automated edge detection software program. cPWV was calculated using the distance (carotid to femoral via the subtraction method) and time delay between ventricular depolarization and the foot of the femoral waveform. pPWV was calculated from the femoral to dorsalis pedis artery using the distance between each site and time delay between the arrival of the foot of each corresponding waveform. Physical activity (PA) levels were assessed using a 7-day recall questionnaire. Anthropometric measurements as well as measures of resting systolic, diastolic and mean arterial blood pressures were similar in both groups. There were no group differences (p>0.05) in ivabsolute, relative or normalized FMD responses. Both groups also had similar values of carotid IMT as well as all measures of arterial stiffness including carotid distensibility, cPWV and pPWV (p>0.05). No group differences were found in the amount of time spent in light and moderate intensity PA; however, the control group participated in a significantly greater amount of vigorous intensity PA (CON: 196 ± 174 min. vs. CP: 38 ± 80 min). Pearson correlation coefficients with all participants revealed a significant positive relationship between age and cPWV (r=0.485 p=0.026) and negative relationship with carotid compliance (r=-0.436, p=0.048). These findings indicate that the arterial structure and function of youth with CP (GMFCS level I-II), examined in this study are not different from a healthy control group. Future research should include youth with CP of GMFCS levels III-V to gain further insight into the potential consequences of severe mobility impairments and functional limitations on levels of habitual PA and arterial health in this young, clinical population.</p> / Master of Science (MSc)

Le taux du diabète de type 2 (DT2) est en augmentation partout dans le monde, y compris dans les régions du monde où le trait drépanocytaire (TD) est très prévalent. Le TD, la forme hétérozygote de la drépanocytose, est généralement considéré comme bénin. Cependant, une dysfonction vasculaire plus importante a été récemment observée chez les patients DT2 porteurs du TD (DT2-TD) par rapport à des patients DT2 non-porteurs du TD. En outre, certaines études démontrent que le TD pourrait rendre le dépistage du DT2 plus complexe. De ce fait, les deux objectifs principaux de ma thèse étaient d’étudier les difficultés liées au dépistage et le suivi du DT2 chez les porteurs du TD, et d’évaluer les mécanismes et conséquences de la dysfonction vasculaire amplifiée chez les porteurs du TD. La 1ère étude a comparé deux mesures typiques (l’HbA1c et la glycémie à jeun) et une mesure atypique (fructosamine) de la glycémie chez des adultes sénégalais avec et sans le TD. Cette étude a démontré une disparité entre ces mesures qui étaient plus marquées chez des porteurs du TD. La 2ème étude a observé que les prévalences d’hypertension, de rétinopathie, et de néphropathie étaient plus élevées chez les sujets DT2-TD que chez les sujets diabétiques. La dysfonction vasculaire à l’origine de ces complications plus fréquentes semble impliquer les produits de glycation avancés. Les études 3 et 4 étaient réalisées dans un modèle murin du DT2-TD. L’étude 3 a montré une vasodilatation endothélium-dépendante significativement réduite chez des souris DT2-TD. Enfin, l’étude 4 a montré que la vasodilatation in-vivo induite par acétylcholine était augmentée chez la souris DT2-TD via un mécanisme dépendant de la cyclooxygenase-2. Ce travail de thèse a permis de mieux comprendre les difficultés liées au dépistage du DT2 chez les porteurs du TD, de montrer que le TD est un facteur de risque de complications vasculaire dans le DT2 et d’explorer les mécanismes à l’origine de cette dysfonction vasculaire plus marquée / Rates of type 2 diabetes (T2D) are rapidly increasing worldwide, including in regions, and among populations, of the globe where sickle cell trait (SCT) is prevalent. SCT, the heterozygote form of sickle cell disease, is generally considered a benign condition. However, evidence shows that vascular function is more severely impaired in people with combined T2D and SCT (T2D-SCT) than in those with T2D only. Furthermore, evidence suggests that SCT could complicate screening for T2D, thereby increasing the risk of delayed diagnosis of T2D. In light of this information, the main objectives of this thesis were to study the challenges related to diagnosing and monitoring T2D in individuals with SCT, and to evaluate the mechanisms and consequences of the amplified vascular dysfunction observed in T2D-SCT. Study 1 compared the agreement between two standard measures of glycemia, HbA1c and fasting glucose, and one alternative measure of glycemia, fructosamine, in Senegalese adults with and without SCT. The findings revealed substantial disparities between the markers of glycemia, and these differences were exaggerated in individuals with SCT. Study 2 illustrated that SCT could potentially augment the risk of developing retinopathy, nephropathy, and hypertension in T2D, and demonstrated that AGEs are likely implicated in the vascular dysfunction observed in T2D-SCT. Studies 3 and 4 studied microvascular function in a mouse model of T2D-SCT. Study 3 showed that T2D-SCT mice had significantly impaired endothelium-dependent vasodilation in-vivo. Study 4 revealed that ACH-mediated vasodilation in-vivo was significantly elevated in the microvasculature of mice with combined T2D and SCT due to cyclooxygenase-2 dependent mechanisms. Overall these findings deepen our understanding about the complexities related to diagnosing and managing T2D in individuals with SCT

African Americans have increased risk for cardiovascular and cerebral vascular disease relative to Caucasian Americans. While it is generally accepted that arteries become stiffer at a younger age in African Americans; less is known regarding cerebral vascular function / reactivity (CVMR) to hypercapnia in African Americans. Furthermore, little is known regarding the relationship between arterial stiffness and CVMR, particularly in young healthy adults. We hypothesized that African Americans have stiffer arteries (i.e. arterial stiffness) and reduced CVMR during hypercapnia relative to Caucasian Americans. We also hypothesized that there would be a negative relationship between arterial stiffness and CVMR. Lastly, we hypothesized that these responses would be related to a decrease in Vitamin D status in this population and there would be correlation between Vitamin D status and CVMR. In 11 African American and 19 Caucasian American subjects central arterial stiffness was indexed from carotid-femoral pulse wave velocity (PWV). CVMR was assessed by the cerebral vascular conductance (CVC) response to rebreathing-induced hypercapnia. Vitamin D status was assessed from plasma 25(OH) Vitamin D. PWV was elevated in the African Americans (African American: 581.16 ± 27.7 cm/sec vs. Caucasian American: 502.98 ± 17.6 cm/sec; P < 0.01). CVMR was significantly reduced during hypercapnic rebreathing in the African Americans (African American: 3.05 ± 0.38% of baseline/mmHg vs. Caucasian American: 5.09 ± 0.29% of baseline/mmHg; P < 0.001). When data from all subjects was included there was a trend towards a negative relationship (R = 0.32, P = 0.10) between PWV and CVMR. Vitamin D status was significantly lower in African Americans (African American: 14.96 ± 0.97 ng/ml vs. Caucasian American: 32.73 ± 0.99 ng/ml; P < 0.001); however, there was no significant relationship between Vitamin D status and CVMR (R = 0.23 P = 0.23). In conclusion, these data indicate that African Americans have impaired cerebral vascular responses to hypercapnia, stiffer arteries, and lower Vitamin D status when compared with Caucasian Americans. In addition, there may be a negative relationship between CVMR and PWV; however, no significant correlation between Vitamin D status and vascular function including PWV or CVMR was observed in this study. / text

Introduction: Diabetes is characterized by insufficient production of insulin and/or incapacity of this hormone in playing its functions. Such disease impairs the function of the endothelium, the latter capable of regulating the vascular tone and important in the control of inflammatory response as well. Once dysfunctional, the endothelium no longer exhibits such functions, occurring mostly redox imbalance, this one evident in diabetic patients. Nowadays, several studies point to endothelial dysfunction as a contributor in the development of diabetic vascular complications, while the practice of physical activity, although of low intensity, brings benefits in the handling of type 2 diabetes, including reduction of cardiovascular risk factors. Physical intervention as a therapeutic proposal appears to be a promising way in the clinical management of diabetes mellitus, probably avoiding the progression of systemic complications. Aim: To assess the vascular function and the REDOX balance in patients with type 2 diabetes mellitus (T2DM) before and after the cardiovascular rehabilitation for six weeks. Methods: 43 diabetic female patients aged 57.50 ± 2.02 years were selected from the ambulatory of Endocrinology at Prof. Alberto Antunes Teaching Hospital (Federal University of Alagoas). The diagnosis for T2DM was established according to the criteria of the Brazilian Society of Diabetes (2007). Initial assessment was performed by laboratory and clinical evaluation. The cardiovascular rehabilitation program consisted of six weeks of aerobic training (50 to 70% of the maximum heart rate), associated to endurance training. Four patients have completed the six weeks rehabilitation program. Assessment of biochemical profile (fasting and postprandial glucose, glicosilated hemoglobin, total cholesterol, VLDL, LDL, HDL, triglycerides, uric acid, albumin and creatinin), REDOX balance (SOD and catalase activity and lipid peroxidation) and quality of life (through the application of the SF-36) were performed before and after the rehabilitation program period. Indirect assessment of vascular function was performed by the Augmentation Index (AI), wave reflection, systolic and diastolic blood pressure and pulse pressure, which were obtained by the left radial artery tonometry (HEM-9000 AI device). Physical capacity was assessed by the six-minute walk test. Results: After rehabilitation, there was a significant reduction in the serum albumin levels (3.52 ± 0.478 vs 3.85 ± 0.50 mg/dL, P=0.0159) and an increase in the serum acid uric levels (5.00 ± 0.25 vs 4.57 ± 0.21 mg/dL, P=0.0298), without, however, alterations in the creatinin levels (P=0.3760). It was observed a reduction in the systolic and diastolic blood pressure (141.50 ± 3.67 vs 117.00 ± 6.01 mmHg, p<0.01; 77.75 ± 1.48 vs 71.25 ± 3.03 mmHg, P<0.05, respectively) and in the pulse pressure (63.75 ± 2.29 vs 45.750 ± 3.68 mmHg, P<0.01), without improvement in the Augmentation Index, with an improvement in five parameters during the assessment of the quality of life: physical functioning (25.00 ± 17.56 vs 93.75 ± 6.25 %, P<0.05), vitality (31.250 ± 10.48 vs 87.50 ± 5.20 %, P<0.05), social functioning (50.00 ± 17.68 vs 100.00 ± 0.00 %, P<0.05), role physical (47.50 ± 8.53 vs 92.50 ± 3.22 %, P<0.01) and bodily pain (21.62 ± 10.68 vs 65.75± 12.49 %, P<0.01). There were no statistically significant changes neither in the glycemic and lipid profiles nor in the functional capacity. Conclusion: The cardiovascular rehabilitation program during six weeks in diabetic patients was capable of promoting improvement in hemodynamic parametres and in the quality of life, without greater changes in the biochemical profile and functional capacity. These observations permit to consider that in diabetic patients the cardiovascular rehabilitation should be initiated as soon as possible to promote a reduction in the cardiovascular risk in these individuals. / Introdução: O diabetes caracteriza-se pela produção insuficiente de insulina e/ou pela incapacidade desse hormônio em desempenhar suas funções. Tal doença prejudica a função do endotélio, tecido este capaz de regular o tônus vascular e a resposta inflamatória. Quando disfuncional, esta camada celular não mais exibe tais funções, ocorrendo, principalmente, o desbalanço redox, evidente em pacientes diabéticos. Atualmente, diversos estudos apontam para a disfunção endotelial como contribuinte para o desenvolvimento das complicações vasculares diabéticas, ao passo que a prática de atividade física, ainda que de baixa intensidade, traz benefícios no manejo do diabetes mellitus tipo 2, incluindo redução dos fatores de risco cardiovascular. Desta forma, a intervenção física como proposta terapêutica apresenta-se promissora no manejo clinico do diabetes mellitus, podendo evitar a progressão de complicações sistêmicas. Objetivo: Avaliar a função vascular e o balanço redox em pacientes portadores de diabetes mellitus tipo 2 (DMII), antes e após a reabilitação cardiovascular por seis semanas. Método: 43 pacientes do sexo feminino com idade média de 57,50 ± 2,02 foram selecionadas do ambulatório de Endocrinologia do Hospital Universitário Prof. Alberto Antunes (Universidade Federal de Alagoas). O diagnóstico de DMII foi estabelecido de acordo com os critérios da Sociedade Brasileira de Diabetes (2007). A avaliação inicial foi feita através de exames clínicos e laboratoriais. O programa de reabilitação cardiovascular consistiu de seis semanas de exercício aeróbio (50 a 70% da freqüência cardíaca máxima) associado a exercícios resistidos. Quatro pacientes completaram as seis semanas de reabilitação. Avaliação do perfil bioquímico (glicemia de jejum e pós-prandial, hemoglobina glicosilada, colesterol total, VLDL, LDL, HDL, triglicerídeos, ácido úrico, albumina e creatinina), balanço REDOX (atividades da SOD e catalase e peroxidação lipídica) e qualidade de vida (através da aplicação do SF-36) foram realizadas antes e após o programa de reabilitação. A avaliação indireta da função vascular foi realizada através do Augmentation Index (AI), onda de reflexão, pressões arteriais sistólica e diastólica e pressão de pulso, obtidos por tonometria da artéria radial esquerda (com o equipamento HEM-9000 AI). A capacidade física foi avaliada através do teste de caminhada de seis minutos. Resultados: Após a reabilitação, houve redução significativa dos níveis séricos albumina (3,52 ± 0,478 vs 3,85 ± 0,50 mg/dL, P=0,0159) e aumento dos níveis de ácido úrico (5,00 ± 0,25 vs 4,57 ± 0,21 mg/dL, P=0,0298), sem, entretanto, alterações dos níveis de creatinina (p=0,3760). Também foram reduzidas as pressões arteriais sistêmicas sistólica e diastólica (141,50 ± 3,67 vs 117,00 ± 6,01 mmHg, P<0,01; 77,75 ± 1,48 vs 71,25 ± 3,03 mmHg, P<0,05, respectivamente) e a pressão de pulso (63,75 ± 2,29 vs 45,750 ± 3,68 mmHg, P<0,01), sem redução no Augmentation Index, com melhora em cinco parâmetros da qualidade de vida: aspectos físicos (25,00 ± 17,56 vs 93,75 ± 6,25 %, P<0,05), vitalidade (31,250 ± 10,48 vs 87,50 ± 5,20 %, P<0,05), aspectos sociais (50,00 ± 17,68 vs 100,00 ± 0,00 %, P<0,05), capacidade funcional (47,50 ± 8,53 vs 92,50 ± 3,22 %, P<0,01) e dor (21,62 ± 10,68 vs 65,75 ± 12,49 %, P<0,01). Não foram observadas variações estatisticamente significativas para o perfil glicêmico, lipídico e capacidade funcional. Conclusão: O programa de reabilitação cardiovascular por seis semanas em pacientes diabéticas foi capaz de promover melhora em parâmetros hemodinâmicos e na qualidade de vida, sem maiores mudanças no perfil bioquímico e capacidade funcional. Estas observações permitem considerar que em pacientes diabéticos a reabilitação cardiovascular deve ser iniciada o mais precoce possível a fim de promover redução do risco cardiovascular nestes indivíduos.

Dans le but de vérifier l’impact d’un changement soudain dans l’agrégation érythrocytaire sur certains paramètres cardiovasculaires, une transfusion par échange sanguin du tiers du volume a été effectuée avec du sang hyperagrégeant chez le rat de souche Brown Norway. La pression caudale, le volume cardiaque systolique, la fraction d’éjection, le débit cardiaque, le rythme cardiaque et la résistance périphérique à l’écoulement sanguin ont été observés non-intrusivement sur 19 jours suite à la transfusion. Les rats ont été sacrifiés plus d’un mois suivant la transfusion et une étude ex vivo de la réponse à deux agents dilatateurs (l’acétylcholine et le nitroprussiate de sodium) a été menée sur les artérioles mésentériques. Des variations des paramètres cardiovasculaires, soit le débit, le volume systolique et la résistance périphérique, ont été remarquées dans les trois premiers jours posttransfusion. Une résistance du muscle vasculaire lisse au monoxyde d’azote a été notée chez les rats transfusés au sang hyperagrégeant alors qu’aucune dysfonction endothéliale n’était apparente en réponse à l’acétylcholine. / The aim of this study was to evaluate the effects of an acute change in erythrocyte aggregation on cardiovascular parameters by exchanging one third of the blood volume with hyperaggregating blood in the Brown Norway rat model. Values of caudal pressure, systolic cardiac volume, ejection fraction, cardiac output, heart rate and peripheral resistance to blood flow were observed non-invasively over 19 days after transfusion. The rats were sacrificed after more than a month following the procedure and an ex vivo study in response to pharmacological agents (acetylcholine and sodium nitroprussiate) was performed on mesenteric arterioles. Variations in cardiac output, systolic volume and peripheral resistance were noted for the first three days post-transfusion. The vascular smooth muscles of rats transfused with the hyperaggregating erythrocytes seemed to have developed a resistance to nitric oxide but no endothelial dysfunction was observed in response to acetylcholine.

Les athlètes utilisent les suppléments nutritionnels avec pour objectif d'améliorer leur performance sportive. La performance sportive dépend de facteurs physiques, mais également de facteurs cognitifs. Les suppléments nutritionnels riches en flavanols issu du cacao (CF) peuvent stimuler la fonction vasculaire, réduire le stress oxydant et améliorer la fonction cognitive. L'objectif de cette thèse est donc d’analyser les effets d'une consommation aigue, ou pendant une semaine, de CF, sur la performance physique et cognitive chez des athlètes, chez des sujets actifs et chez des personnes ayant un diabète de type 1 (DT1). De plus, l’objectif est d’investiguer les effets des CF en altitude simulé, où l’hypoxie limite la performance cognitive et physique.La consommation aigue de 900 mg CF (dont 196 mg d'épicatéchine) suscite une augmentation de l’oxygénation cérébrale, mais pas de la concentration de BDNF sérique et n'a pas d’effet sur la fonction cognitive chez des sportifs sains. L’effet bénéfique des CF sur l’oxygénation cérébrale au repos est dépassé par l’ampleur de l’augmentation de la perfusion et de l’oxygénation cérébrale à l’exercice physique et n'est donc plus visible en post-exercice.En hypoxie (altitude simulée de 4000 m), la consommation aigue de 530 mg CF (dont 100 mg d'épicatéchine) augmente la réponse hémodynamique du cortex préfrontal durant une tâche cognitive, mais n’affecte pas l’activité neuronale. Les CF améliorent la pensée abstraite en normoxie, mais n’améliorent aucun autre domaine des fonctions cognitives. Seule la précision lors du test de Stroop est diminuée par l’hypoxie. De plus, la réponse hémodynamique du cortex préfrontale et l’activité neuronale ne diffèrent pas en hypoxie vs. en normoxie.Le diabète de type 1 (DT1) est associé avec une dysfonction endothéliale, qui constitue un des facteurs de déclin cognitif lié au diabète. Dans une 3ième étude, la fonction cognitive n’est pas altérée chez les patients DT1, en comparaison des sujets sains, alors que l'activation cérébrale diffère entre ces 2 groupes. Cette différence d'activation cérébrale pourrait alors jouer un rôle compensatoire chez les patients DT1. La consommation aigue de CF peut améliorer les fonctions exécutives chez des patients DT1 et des sujets sains, et peut augmenter le signal BOLD dans les régions du cerveau activées par les tâches cognitives.Ainsi, la consommation aigue de CF augmente la vasoréactivité cérébrale. Ces changements sont associés avec une meilleure fonction cognitive chez des patients DT1, alors que ce n’est pas le cas chez des sujets entraînés, ni au niveau de la mer, ni en hypoxie. Malgré ces effets bénéfiques des CF, l’exercice physique semble rester un moyen beaucoup plus efficace pour stimuler la vasoreactivité cérébrale et les fonctions cognitives.Nous nous sommes aussi intéressés aux effets de CF sur la capacité antioxydante, le stress oxydant et la production de NO pendant l’exercice, ainsi que sur les implications pour la performance physique et la récupération, chez des athlètes. La consommation aigue de 903 mg CF augmente la capacité antioxydante au repos et pendant l’exercice, mais sans réduire le stress oxydant et la production de NO. La consommation pendant une semaine de 530 mg CF (dont 100 mg d'épicatéchine) atténue la peroxydation lipidique induite par l’exercice, mais n’influence pas la capacité antioxydante. Les CF ne modifient pas la production et la biodisponibilité du NO pendant un exercice en normoxie et en hypoxie (altitude simulée de 3000 m). La consommation de CF pendant une semaine peut augmenter la fonction endothéliale de repos, et peut réduire les effets nuisibles de l'hypoxie sur l’oxygénation préfrontale au repos et pendant l’exercice modéré. Par contre, cet effet disparait pendant l’exercice intense. La consommation aigue, et pendant une semaine, de CF n’augmente pas la performance physique, ni en normoxie, ni en hypoxie. / Sports performance depends on physical factors, but also on cognitive functioning. Nutritional supplements as potential ergogenic aids can impact muscle, but also the brain. Cocoa flavanols (CF) have antioxidant capacities, can stimulate vascular function, and potentially enhance cognitive function. CF intake might thus improve exercise performance and recovery by reducing oxidative stress, increasing NO availability and/or boosting cognitive function. It is the purpose of this PhD to identify the effects of CF on physical and cognitive performance in healthy athletes at sea level and altitude, as well as in patients with type 1 diabetes. Our systematic review showed that CF can reduce exercise-induced oxidative stress, but without improving exercise performance. Combining CF intake and exercise training improves cardiovascular risk factors and vascular function in healthy and overweight participants, but evidence on the synergistic effects of CF and exercise training on oxidative stress, inflammation and fat and glucose metabolism is lacking.In a randomized, placebo-controlled, double blind cross-over study, we showed that 900 mg CF intake increased prefrontal oxygenation in athletes, but without affecting executive function. BDNF was not affected by CF intake. The effects of high-intensity exercise largely overruled the effects of CF intake: large beneficial effects of exercise on prefrontal oxygenation and cognitive function were observed and CF supplementation did not enlarge these effects. In a 2nd study, the effect of acute CF intake (530 mg CF) on performance on a demanding cognitive test was assessed in normoxia and hypoxia (simulated altitude 4000 m). Electroencephalogram and fNIRS were used to analyse neuronal activity and hemodynamic changes. Acute CF intake improved the neurovascular response, but did not affect neuronal activity and cognitive performance in normoxia and hypoxia. Most cognitive functions, the cerebrovascular response and neuronal activity, were not altered in hypoxia in healthy subjects. In a 3rd study, we found that acute intake of 900 mg CF enhanced cognitive performance on the Flanker test in patients with type 1 diabetes, and their healthy matched controls. CF intake increased the BOLD response in brain areas activated during this specific task. While cognitive performance was not deteriorated in patients with type 1 diabetes, a different brain activation pattern during the cognitive task was observed, compared to healthy controls and this brain activation pattern was altered by CF intake. To conclude, acute CF intake improves prefrontal oxygenation and cerebrovascular responsiveness. This can be associated with better cognitive function in patients with type 1 diabetes, but does not result in improved executive function in healthy persons. Compared to exercise, the magnitude of the CF-induced neurovascular changes is small.Two studies were conducted examining the effects of CF on exercise-induced oxidative stress, NO availability and its implications for exercise performance, in well-trained cyclists. We found that acute CF (900 mg) improved the exercise-induced increase in total antioxidant capacity, but did not reduce the exercise-induced increase in lipid peroxidation. One week CF intake (530 mg CF) improved vascular function at rest, and prefrontal oxygenation at rest and during low-intensity exercise, but did not influence muscular oxygenation. One week CF intake partially restored the hypoxia-induced decline in prefrontal oxygenation during rest and low-intensity exercise, but not during high-intensity exercise. One week CF intake reduced exercise-induced lipid peroxidation, but did not alter total antioxidant capacity. Both acute and 1-week CF intake did not improve exercise performance and recovery and do not change NO production during exercise (in normoxia and hypoxia) in well-trained athletes.

Fibroblast growth factor-23 (FGF23) was initially identified as the causative factor of autosomal dominant hypophosphatemic rickets. Further studies confirmed that FGF23 is predominantly expressed in the osteocytes and osteoblasts of bone and that circulating FGF23 acts on the kidney to inhibit renal phosphate reabsorption and 1,25(OH)2D3 hydroxylation. With the progression of chronic kidney disease (CKD), the kidneys become insufficient to maintain a normal systemic mineral homeostasis, resulting in various abnormalities of bone and mineral metabolism, generally referred to as Chronic Kidney Disease – Mineral and Bone Disorders (CKD-MBD). FGF23 increases early in the course of CKD in order to maintain normal serum phosphate levels; long before a significant increase in serum phosphate can be detected. Recent studies suggest that increased FGF23 levels are associated with progression of CKD, mortality, and the development of refractory secondary hyperparathyroidism. Because FGF23 is the very earliest marker of CKD-MBD, it is of particular interest to evaluate the relation between FGF23 and CKD-MBD abnormalities, in the setting of early CKD and also in individuals with normal renal function. In the present work, we show that FGF23 is linked to several dynamic measurements of vascular function, including endothelial dysfunction, arterial stiffness, and atherosclerosis. FGF23 is also positively associated with left ventricular mass index and an increased risk of having left ventricular hypertrophy. All associations were independent of serum phosphate and were strengthened in subjects with diminished renal function. Furthermore, we found significant evidence for an association between higher FGF23 and increased fat mass and dyslipidemia, which could represent a novel pathway linking FGF23 to cardiovascular disease. Finally, we show that FGF23 is a significant predictor of future fracture risk. Although these associations could be reflecting the increased risk associated with hyperphosphatemia and calcitriol deficiency, current evidence points towards FGF23 being more than an innocent bystander. At the very least, FGF23 holds promise of being a bio-marker of cardiovascular status and phosphate-related toxicity both in CKD and in the general population, and might be a therapeutic target that could improve the fatal prognosis in CKD patients.